Hypercoagulable State in

Hemoglobinopathies

Thromboembolic Events in a Large

Cohort of Beta Thalassemia Patients

bull Patients (N = 8860)

ndash 6670 with TM

ndash 2190 with TI

bull 146 (165) thrombotic events

ndash 61 (09) with TM

ndash 85 (39) with TI

Taher A et al Thromb Haemost 200696488-91

DVT = deep vein thrombosis

PVT = portal vein thrombosis

STP = superficial thrombophlebitis Thromboembolic events ()

Typ

e o

f eve

nt

12

8

19

12

39

9

66

30

0

11

8

23

28

48

0 20 40 60 80

Others

STP

PVT

PE

DVT

Stroke

Venous

TM (n = 61)

TI (n = 85)

Cerebral lesions

Focal bright lesions in the cerebral white matter

Most of the lesions in frontal lobes and bilateral

Maximal diameter up to 7 mm

All lesions negative in diffusion with no susceptibility

artifacts

Study Number of patients Age (years) Prevalence of SCI

(95 CI)

Manfre et al 1999 16 Mean29 375 (184-617)

Taher et al 2010 30 Range 9-48

Mean321

600 (422-755)

Karimi et al 2010 30 Mean 243 267 (142-446)

Teli et al 2012 24 Range 18-34

Mean12

0

Karimi e t al 2012 95 Range 23plusmn8

Mean 23

158

59 Splenectomized 46 Regularly transfused

Incidence of silent cerebral infarction (SCI) in

195 patients with β-TI obtained by MRI

Coronal FLAIR thin section through parietal

amp occipital lobes and cerebellum

demonstrates high intensity lesions as

marked by arrows

Axial FLAIR superior thin section

demonstrates high intensity lesions in

the frontal amp parietal lobes as marked by

arrows

3T MR Imaging of the Brain of a Multi-

Transfused β-TM Patient

1

2

3

Mechanism of denaturation of α or β

hemoglobin changes and of sickle hemoglobin

Role of iron in oxidation

Fe2+ + H2O2 --gt Fe3+ + OHl + OHlndash

(Fenton reaction)

bull Iron atom creates reactive oxygen species

Oxidative Stress in Hemolytic Anemias

The Causes of Oxidative Stress

bull Hemoglobin instability (hemoglobinopathies)

bull Iron-overload (due to increased absorption andor therapeutic

blood transfusion

bull Hemolysis

Although oxidative stress is not the primary etiology of these

diseases it participates in causing damage to RBC (as well as

neutrophils and platelets)

Oxidative status in RBC

Red Blood Flow Properties

RBC

self-aggregability

RBC deformability

RBC adherence

to endothelium

17

Schematic diagram of the computerized image analyzer of RBC flow properties aggregation deformation adherence

Cell-Flow Properties Analyzer

Pressure transducer

P

S Yedgar

RBC aggregability under flow

Chen Eldor et al Am J Physiol 1996

control TM

19

Thalassemic RBC adhesion to EC

is PS dependent

An

nexin

V p

osit

ive c

ells

0

1

2

3

4Control

TM

TI

Ad

here

nt

RB

Cm

m2

0

500

1000

1500

2000

2500

3000Control

Thalassemia

Th + Annexin V

Th + Trypsine

Ramot BJH

2008

Micrographs of retinal veins (angiograms) (1) and of RBC aggregates (2)

corresponding diagrams of aggregate size distribution (3) from thalassemic patient

taken prior to (A) and after (B) transfusion of blood stored for 7 days

AGGREGATE SIZE (No of RBC Aggregate)

RB

C

3

2

1

A B

Blood Transfusion improves blood flow in vivo

Borshtein Transf Med Rev 2010

The incidence of SCI in 28

transfusion dependent patients

15 males 13 females - mean age 30 years

Exclusion criteria

Diabetes mellitus

History of thromboembolic event

Aspirin or anticoagulation treatment

Pazgal I et al Thrombosis Research 2016

Results

Patients without SCI Patients with SCI

N=11 (393) N=17 (60)

FERRITIN (ngml)

(Plt0031)

3910 6200

(2600 ndash 12400) (5000-9600)

P valuePatients without SCIN = 25

Patients with SCIN = 15

Group Parameters

000925 plusmn66311 plusmn65Age (years)Mean plusmnSD

027352069Sex (malefemaleratio)

0905931 plusmn088935 plusmn 123Hemoglobin (gdL)mean plusmn SD

0559388750 plusmn 152073423571 plusmn 210429Plateletmicrolitermeans plusmn SD

08682400 23302550 2875Ferritin (ngmL)median IQR

0150111 plusmn44135 plusmn 59Blood transfusion(cckgmonth) meanplusmn SD

0019 (36)12 (80)Splenectomized(number )

Statistically significant IQR interquartile range

Karimi M et al Ann Hematol 2016

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

Thromboembolic Events in a Large

Cohort of Beta Thalassemia Patients

bull Patients (N = 8860)

ndash 6670 with TM

ndash 2190 with TI

bull 146 (165) thrombotic events

ndash 61 (09) with TM

ndash 85 (39) with TI

Taher A et al Thromb Haemost 200696488-91

DVT = deep vein thrombosis

PVT = portal vein thrombosis

STP = superficial thrombophlebitis Thromboembolic events ()

Typ

e o

f eve

nt

12

8

19

12

39

9

66

30

0

11

8

23

28

48

0 20 40 60 80

Others

STP

PVT

PE

DVT

Stroke

Venous

TM (n = 61)

TI (n = 85)

Cerebral lesions

Focal bright lesions in the cerebral white matter

Most of the lesions in frontal lobes and bilateral

Maximal diameter up to 7 mm

All lesions negative in diffusion with no susceptibility

artifacts

Study Number of patients Age (years) Prevalence of SCI

(95 CI)

Manfre et al 1999 16 Mean29 375 (184-617)

Taher et al 2010 30 Range 9-48

Mean321

600 (422-755)

Karimi et al 2010 30 Mean 243 267 (142-446)

Teli et al 2012 24 Range 18-34

Mean12

0

Karimi e t al 2012 95 Range 23plusmn8

Mean 23

158

59 Splenectomized 46 Regularly transfused

Incidence of silent cerebral infarction (SCI) in

195 patients with β-TI obtained by MRI

Coronal FLAIR thin section through parietal

amp occipital lobes and cerebellum

demonstrates high intensity lesions as

marked by arrows

Axial FLAIR superior thin section

demonstrates high intensity lesions in

the frontal amp parietal lobes as marked by

arrows

3T MR Imaging of the Brain of a Multi-

Transfused β-TM Patient

1

2

3

Mechanism of denaturation of α or β

hemoglobin changes and of sickle hemoglobin

Role of iron in oxidation

Fe2+ + H2O2 --gt Fe3+ + OHl + OHlndash

(Fenton reaction)

bull Iron atom creates reactive oxygen species

Oxidative Stress in Hemolytic Anemias

The Causes of Oxidative Stress

bull Hemoglobin instability (hemoglobinopathies)

bull Iron-overload (due to increased absorption andor therapeutic

blood transfusion

bull Hemolysis

Although oxidative stress is not the primary etiology of these

diseases it participates in causing damage to RBC (as well as

neutrophils and platelets)

Oxidative status in RBC

Red Blood Flow Properties

RBC

self-aggregability

RBC deformability

RBC adherence

to endothelium

17

Schematic diagram of the computerized image analyzer of RBC flow properties aggregation deformation adherence

Cell-Flow Properties Analyzer

Pressure transducer

P

S Yedgar

RBC aggregability under flow

Chen Eldor et al Am J Physiol 1996

control TM

19

Thalassemic RBC adhesion to EC

is PS dependent

An

nexin

V p

osit

ive c

ells

0

1

2

3

4Control

TM

TI

Ad

here

nt

RB

Cm

m2

0

500

1000

1500

2000

2500

3000Control

Thalassemia

Th + Annexin V

Th + Trypsine

Ramot BJH

2008

Micrographs of retinal veins (angiograms) (1) and of RBC aggregates (2)

corresponding diagrams of aggregate size distribution (3) from thalassemic patient

taken prior to (A) and after (B) transfusion of blood stored for 7 days

AGGREGATE SIZE (No of RBC Aggregate)

RB

C

3

2

1

A B

Blood Transfusion improves blood flow in vivo

Borshtein Transf Med Rev 2010

The incidence of SCI in 28

transfusion dependent patients

15 males 13 females - mean age 30 years

Exclusion criteria

Diabetes mellitus

History of thromboembolic event

Aspirin or anticoagulation treatment

Pazgal I et al Thrombosis Research 2016

Results

Patients without SCI Patients with SCI

N=11 (393) N=17 (60)

FERRITIN (ngml)

(Plt0031)

3910 6200

(2600 ndash 12400) (5000-9600)

P valuePatients without SCIN = 25

Patients with SCIN = 15

Group Parameters

000925 plusmn66311 plusmn65Age (years)Mean plusmnSD

027352069Sex (malefemaleratio)

0905931 plusmn088935 plusmn 123Hemoglobin (gdL)mean plusmn SD

0559388750 plusmn 152073423571 plusmn 210429Plateletmicrolitermeans plusmn SD

08682400 23302550 2875Ferritin (ngmL)median IQR

0150111 plusmn44135 plusmn 59Blood transfusion(cckgmonth) meanplusmn SD

0019 (36)12 (80)Splenectomized(number )

Statistically significant IQR interquartile range

Karimi M et al Ann Hematol 2016

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

Cerebral lesions

Focal bright lesions in the cerebral white matter

Most of the lesions in frontal lobes and bilateral

Maximal diameter up to 7 mm

All lesions negative in diffusion with no susceptibility

artifacts

Study Number of patients Age (years) Prevalence of SCI

(95 CI)

Manfre et al 1999 16 Mean29 375 (184-617)

Taher et al 2010 30 Range 9-48

Mean321

600 (422-755)

Karimi et al 2010 30 Mean 243 267 (142-446)

Teli et al 2012 24 Range 18-34

Mean12

0

Karimi e t al 2012 95 Range 23plusmn8

Mean 23

158

59 Splenectomized 46 Regularly transfused

Incidence of silent cerebral infarction (SCI) in

195 patients with β-TI obtained by MRI

Coronal FLAIR thin section through parietal

amp occipital lobes and cerebellum

demonstrates high intensity lesions as

marked by arrows

Axial FLAIR superior thin section

demonstrates high intensity lesions in

the frontal amp parietal lobes as marked by

arrows

3T MR Imaging of the Brain of a Multi-

Transfused β-TM Patient

1

2

3

Mechanism of denaturation of α or β

hemoglobin changes and of sickle hemoglobin

Role of iron in oxidation

Fe2+ + H2O2 --gt Fe3+ + OHl + OHlndash

(Fenton reaction)

bull Iron atom creates reactive oxygen species

Oxidative Stress in Hemolytic Anemias

The Causes of Oxidative Stress

bull Hemoglobin instability (hemoglobinopathies)

bull Iron-overload (due to increased absorption andor therapeutic

blood transfusion

bull Hemolysis

Although oxidative stress is not the primary etiology of these

diseases it participates in causing damage to RBC (as well as

neutrophils and platelets)

Oxidative status in RBC

Red Blood Flow Properties

RBC

self-aggregability

RBC deformability

RBC adherence

to endothelium

17

Schematic diagram of the computerized image analyzer of RBC flow properties aggregation deformation adherence

Cell-Flow Properties Analyzer

Pressure transducer

P

S Yedgar

RBC aggregability under flow

Chen Eldor et al Am J Physiol 1996

control TM

19

Thalassemic RBC adhesion to EC

is PS dependent

An

nexin

V p

osit

ive c

ells

0

1

2

3

4Control

TM

TI

Ad

here

nt

RB

Cm

m2

0

500

1000

1500

2000

2500

3000Control

Thalassemia

Th + Annexin V

Th + Trypsine

Ramot BJH

2008

Micrographs of retinal veins (angiograms) (1) and of RBC aggregates (2)

corresponding diagrams of aggregate size distribution (3) from thalassemic patient

taken prior to (A) and after (B) transfusion of blood stored for 7 days

AGGREGATE SIZE (No of RBC Aggregate)

RB

C

3

2

1

A B

Blood Transfusion improves blood flow in vivo

Borshtein Transf Med Rev 2010

The incidence of SCI in 28

transfusion dependent patients

15 males 13 females - mean age 30 years

Exclusion criteria

Diabetes mellitus

History of thromboembolic event

Aspirin or anticoagulation treatment

Pazgal I et al Thrombosis Research 2016

Results

Patients without SCI Patients with SCI

N=11 (393) N=17 (60)

FERRITIN (ngml)

(Plt0031)

3910 6200

(2600 ndash 12400) (5000-9600)

P valuePatients without SCIN = 25

Patients with SCIN = 15

Group Parameters

000925 plusmn66311 plusmn65Age (years)Mean plusmnSD

027352069Sex (malefemaleratio)

0905931 plusmn088935 plusmn 123Hemoglobin (gdL)mean plusmn SD

0559388750 plusmn 152073423571 plusmn 210429Plateletmicrolitermeans plusmn SD

08682400 23302550 2875Ferritin (ngmL)median IQR

0150111 plusmn44135 plusmn 59Blood transfusion(cckgmonth) meanplusmn SD

0019 (36)12 (80)Splenectomized(number )

Statistically significant IQR interquartile range

Karimi M et al Ann Hematol 2016

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

Study Number of patients Age (years) Prevalence of SCI

(95 CI)

Manfre et al 1999 16 Mean29 375 (184-617)

Taher et al 2010 30 Range 9-48

Mean321

600 (422-755)

Karimi et al 2010 30 Mean 243 267 (142-446)

Teli et al 2012 24 Range 18-34

Mean12

0

Karimi e t al 2012 95 Range 23plusmn8

Mean 23

158

59 Splenectomized 46 Regularly transfused

Incidence of silent cerebral infarction (SCI) in

195 patients with β-TI obtained by MRI

Coronal FLAIR thin section through parietal

amp occipital lobes and cerebellum

demonstrates high intensity lesions as

marked by arrows

Axial FLAIR superior thin section

demonstrates high intensity lesions in

the frontal amp parietal lobes as marked by

arrows

3T MR Imaging of the Brain of a Multi-

Transfused β-TM Patient

1

2

3

Mechanism of denaturation of α or β

hemoglobin changes and of sickle hemoglobin

Role of iron in oxidation

Fe2+ + H2O2 --gt Fe3+ + OHl + OHlndash

(Fenton reaction)

bull Iron atom creates reactive oxygen species

Oxidative Stress in Hemolytic Anemias

The Causes of Oxidative Stress

bull Hemoglobin instability (hemoglobinopathies)

bull Iron-overload (due to increased absorption andor therapeutic

blood transfusion

bull Hemolysis

Although oxidative stress is not the primary etiology of these

diseases it participates in causing damage to RBC (as well as

neutrophils and platelets)

Oxidative status in RBC

Red Blood Flow Properties

RBC

self-aggregability

RBC deformability

RBC adherence

to endothelium

17

Schematic diagram of the computerized image analyzer of RBC flow properties aggregation deformation adherence

Cell-Flow Properties Analyzer

Pressure transducer

P

S Yedgar

RBC aggregability under flow

Chen Eldor et al Am J Physiol 1996

control TM

19

Thalassemic RBC adhesion to EC

is PS dependent

An

nexin

V p

osit

ive c

ells

0

1

2

3

4Control

TM

TI

Ad

here

nt

RB

Cm

m2

0

500

1000

1500

2000

2500

3000Control

Thalassemia

Th + Annexin V

Th + Trypsine

Ramot BJH

2008

Micrographs of retinal veins (angiograms) (1) and of RBC aggregates (2)

corresponding diagrams of aggregate size distribution (3) from thalassemic patient

taken prior to (A) and after (B) transfusion of blood stored for 7 days

AGGREGATE SIZE (No of RBC Aggregate)

RB

C

3

2

1

A B

Blood Transfusion improves blood flow in vivo

Borshtein Transf Med Rev 2010

The incidence of SCI in 28

transfusion dependent patients

15 males 13 females - mean age 30 years

Exclusion criteria

Diabetes mellitus

History of thromboembolic event

Aspirin or anticoagulation treatment

Pazgal I et al Thrombosis Research 2016

Results

Patients without SCI Patients with SCI

N=11 (393) N=17 (60)

FERRITIN (ngml)

(Plt0031)

3910 6200

(2600 ndash 12400) (5000-9600)

P valuePatients without SCIN = 25

Patients with SCIN = 15

Group Parameters

000925 plusmn66311 plusmn65Age (years)Mean plusmnSD

027352069Sex (malefemaleratio)

0905931 plusmn088935 plusmn 123Hemoglobin (gdL)mean plusmn SD

0559388750 plusmn 152073423571 plusmn 210429Plateletmicrolitermeans plusmn SD

08682400 23302550 2875Ferritin (ngmL)median IQR

0150111 plusmn44135 plusmn 59Blood transfusion(cckgmonth) meanplusmn SD

0019 (36)12 (80)Splenectomized(number )

Statistically significant IQR interquartile range

Karimi M et al Ann Hematol 2016

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

Coronal FLAIR thin section through parietal

amp occipital lobes and cerebellum

demonstrates high intensity lesions as

marked by arrows

Axial FLAIR superior thin section

demonstrates high intensity lesions in

the frontal amp parietal lobes as marked by

arrows

3T MR Imaging of the Brain of a Multi-

Transfused β-TM Patient

1

2

3

Mechanism of denaturation of α or β

hemoglobin changes and of sickle hemoglobin

Role of iron in oxidation

Fe2+ + H2O2 --gt Fe3+ + OHl + OHlndash

(Fenton reaction)

bull Iron atom creates reactive oxygen species

Oxidative Stress in Hemolytic Anemias

The Causes of Oxidative Stress

bull Hemoglobin instability (hemoglobinopathies)

bull Iron-overload (due to increased absorption andor therapeutic

blood transfusion

bull Hemolysis

Although oxidative stress is not the primary etiology of these

diseases it participates in causing damage to RBC (as well as

neutrophils and platelets)

Oxidative status in RBC

Red Blood Flow Properties

RBC

self-aggregability

RBC deformability

RBC adherence

to endothelium

17

Schematic diagram of the computerized image analyzer of RBC flow properties aggregation deformation adherence

Cell-Flow Properties Analyzer

Pressure transducer

P

S Yedgar

RBC aggregability under flow

Chen Eldor et al Am J Physiol 1996

control TM

19

Thalassemic RBC adhesion to EC

is PS dependent

An

nexin

V p

osit

ive c

ells

0

1

2

3

4Control

TM

TI

Ad

here

nt

RB

Cm

m2

0

500

1000

1500

2000

2500

3000Control

Thalassemia

Th + Annexin V

Th + Trypsine

Ramot BJH

2008

Micrographs of retinal veins (angiograms) (1) and of RBC aggregates (2)

corresponding diagrams of aggregate size distribution (3) from thalassemic patient

taken prior to (A) and after (B) transfusion of blood stored for 7 days

AGGREGATE SIZE (No of RBC Aggregate)

RB

C

3

2

1

A B

Blood Transfusion improves blood flow in vivo

Borshtein Transf Med Rev 2010

The incidence of SCI in 28

transfusion dependent patients

15 males 13 females - mean age 30 years

Exclusion criteria

Diabetes mellitus

History of thromboembolic event

Aspirin or anticoagulation treatment

Pazgal I et al Thrombosis Research 2016

Results

Patients without SCI Patients with SCI

N=11 (393) N=17 (60)

FERRITIN (ngml)

(Plt0031)

3910 6200

(2600 ndash 12400) (5000-9600)

P valuePatients without SCIN = 25

Patients with SCIN = 15

Group Parameters

000925 plusmn66311 plusmn65Age (years)Mean plusmnSD

027352069Sex (malefemaleratio)

0905931 plusmn088935 plusmn 123Hemoglobin (gdL)mean plusmn SD

0559388750 plusmn 152073423571 plusmn 210429Plateletmicrolitermeans plusmn SD

08682400 23302550 2875Ferritin (ngmL)median IQR

0150111 plusmn44135 plusmn 59Blood transfusion(cckgmonth) meanplusmn SD

0019 (36)12 (80)Splenectomized(number )

Statistically significant IQR interquartile range

Karimi M et al Ann Hematol 2016

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

1

2

3

Mechanism of denaturation of α or β

hemoglobin changes and of sickle hemoglobin

Role of iron in oxidation

Fe2+ + H2O2 --gt Fe3+ + OHl + OHlndash

(Fenton reaction)

bull Iron atom creates reactive oxygen species

Oxidative Stress in Hemolytic Anemias

The Causes of Oxidative Stress

bull Hemoglobin instability (hemoglobinopathies)

bull Iron-overload (due to increased absorption andor therapeutic

blood transfusion

bull Hemolysis

Although oxidative stress is not the primary etiology of these

diseases it participates in causing damage to RBC (as well as

neutrophils and platelets)

Oxidative status in RBC

Red Blood Flow Properties

RBC

self-aggregability

RBC deformability

RBC adherence

to endothelium

17

Schematic diagram of the computerized image analyzer of RBC flow properties aggregation deformation adherence

Cell-Flow Properties Analyzer

Pressure transducer

P

S Yedgar

RBC aggregability under flow

Chen Eldor et al Am J Physiol 1996

control TM

19

Thalassemic RBC adhesion to EC

is PS dependent

An

nexin

V p

osit

ive c

ells

0

1

2

3

4Control

TM

TI

Ad

here

nt

RB

Cm

m2

0

500

1000

1500

2000

2500

3000Control

Thalassemia

Th + Annexin V

Th + Trypsine

Ramot BJH

2008

Micrographs of retinal veins (angiograms) (1) and of RBC aggregates (2)

corresponding diagrams of aggregate size distribution (3) from thalassemic patient

taken prior to (A) and after (B) transfusion of blood stored for 7 days

AGGREGATE SIZE (No of RBC Aggregate)

RB

C

3

2

1

A B

Blood Transfusion improves blood flow in vivo

Borshtein Transf Med Rev 2010

The incidence of SCI in 28

transfusion dependent patients

15 males 13 females - mean age 30 years

Exclusion criteria

Diabetes mellitus

History of thromboembolic event

Aspirin or anticoagulation treatment

Pazgal I et al Thrombosis Research 2016

Results

Patients without SCI Patients with SCI

N=11 (393) N=17 (60)

FERRITIN (ngml)

(Plt0031)

3910 6200

(2600 ndash 12400) (5000-9600)

P valuePatients without SCIN = 25

Patients with SCIN = 15

Group Parameters

000925 plusmn66311 plusmn65Age (years)Mean plusmnSD

027352069Sex (malefemaleratio)

0905931 plusmn088935 plusmn 123Hemoglobin (gdL)mean plusmn SD

0559388750 plusmn 152073423571 plusmn 210429Plateletmicrolitermeans plusmn SD

08682400 23302550 2875Ferritin (ngmL)median IQR

0150111 plusmn44135 plusmn 59Blood transfusion(cckgmonth) meanplusmn SD

0019 (36)12 (80)Splenectomized(number )

Statistically significant IQR interquartile range

Karimi M et al Ann Hematol 2016

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

Mechanism of denaturation of α or β

hemoglobin changes and of sickle hemoglobin

Role of iron in oxidation

Fe2+ + H2O2 --gt Fe3+ + OHl + OHlndash

(Fenton reaction)

bull Iron atom creates reactive oxygen species

Oxidative Stress in Hemolytic Anemias

The Causes of Oxidative Stress

bull Hemoglobin instability (hemoglobinopathies)

bull Iron-overload (due to increased absorption andor therapeutic

blood transfusion

bull Hemolysis

Although oxidative stress is not the primary etiology of these

diseases it participates in causing damage to RBC (as well as

neutrophils and platelets)

Oxidative status in RBC

Red Blood Flow Properties

RBC

self-aggregability

RBC deformability

RBC adherence

to endothelium

17

Schematic diagram of the computerized image analyzer of RBC flow properties aggregation deformation adherence

Cell-Flow Properties Analyzer

Pressure transducer

P

S Yedgar

RBC aggregability under flow

Chen Eldor et al Am J Physiol 1996

control TM

19

Thalassemic RBC adhesion to EC

is PS dependent

An

nexin

V p

osit

ive c

ells

0

1

2

3

4Control

TM

TI

Ad

here

nt

RB

Cm

m2

0

500

1000

1500

2000

2500

3000Control

Thalassemia

Th + Annexin V

Th + Trypsine

Ramot BJH

2008

Micrographs of retinal veins (angiograms) (1) and of RBC aggregates (2)

corresponding diagrams of aggregate size distribution (3) from thalassemic patient

taken prior to (A) and after (B) transfusion of blood stored for 7 days

AGGREGATE SIZE (No of RBC Aggregate)

RB

C

3

2

1

A B

Blood Transfusion improves blood flow in vivo

Borshtein Transf Med Rev 2010

The incidence of SCI in 28

transfusion dependent patients

15 males 13 females - mean age 30 years

Exclusion criteria

Diabetes mellitus

History of thromboembolic event

Aspirin or anticoagulation treatment

Pazgal I et al Thrombosis Research 2016

Results

Patients without SCI Patients with SCI

N=11 (393) N=17 (60)

FERRITIN (ngml)

(Plt0031)

3910 6200

(2600 ndash 12400) (5000-9600)

P valuePatients without SCIN = 25

Patients with SCIN = 15

Group Parameters

000925 plusmn66311 plusmn65Age (years)Mean plusmnSD

027352069Sex (malefemaleratio)

0905931 plusmn088935 plusmn 123Hemoglobin (gdL)mean plusmn SD

0559388750 plusmn 152073423571 plusmn 210429Plateletmicrolitermeans plusmn SD

08682400 23302550 2875Ferritin (ngmL)median IQR

0150111 plusmn44135 plusmn 59Blood transfusion(cckgmonth) meanplusmn SD

0019 (36)12 (80)Splenectomized(number )

Statistically significant IQR interquartile range

Karimi M et al Ann Hematol 2016

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

Role of iron in oxidation

Fe2+ + H2O2 --gt Fe3+ + OHl + OHlndash

(Fenton reaction)

bull Iron atom creates reactive oxygen species

Oxidative Stress in Hemolytic Anemias

The Causes of Oxidative Stress

bull Hemoglobin instability (hemoglobinopathies)

bull Iron-overload (due to increased absorption andor therapeutic

blood transfusion

bull Hemolysis

Although oxidative stress is not the primary etiology of these

diseases it participates in causing damage to RBC (as well as

neutrophils and platelets)

Oxidative status in RBC

Red Blood Flow Properties

RBC

self-aggregability

RBC deformability

RBC adherence

to endothelium

17

Schematic diagram of the computerized image analyzer of RBC flow properties aggregation deformation adherence

Cell-Flow Properties Analyzer

Pressure transducer

P

S Yedgar

RBC aggregability under flow

Chen Eldor et al Am J Physiol 1996

control TM

19

Thalassemic RBC adhesion to EC

is PS dependent

An

nexin

V p

osit

ive c

ells

0

1

2

3

4Control

TM

TI

Ad

here

nt

RB

Cm

m2

0

500

1000

1500

2000

2500

3000Control

Thalassemia

Th + Annexin V

Th + Trypsine

Ramot BJH

2008

Micrographs of retinal veins (angiograms) (1) and of RBC aggregates (2)

corresponding diagrams of aggregate size distribution (3) from thalassemic patient

taken prior to (A) and after (B) transfusion of blood stored for 7 days

AGGREGATE SIZE (No of RBC Aggregate)

RB

C

3

2

1

A B

Blood Transfusion improves blood flow in vivo

Borshtein Transf Med Rev 2010

The incidence of SCI in 28

transfusion dependent patients

15 males 13 females - mean age 30 years

Exclusion criteria

Diabetes mellitus

History of thromboembolic event

Aspirin or anticoagulation treatment

Pazgal I et al Thrombosis Research 2016

Results

Patients without SCI Patients with SCI

N=11 (393) N=17 (60)

FERRITIN (ngml)

(Plt0031)

3910 6200

(2600 ndash 12400) (5000-9600)

P valuePatients without SCIN = 25

Patients with SCIN = 15

Group Parameters

000925 plusmn66311 plusmn65Age (years)Mean plusmnSD

027352069Sex (malefemaleratio)

0905931 plusmn088935 plusmn 123Hemoglobin (gdL)mean plusmn SD

0559388750 plusmn 152073423571 plusmn 210429Plateletmicrolitermeans plusmn SD

08682400 23302550 2875Ferritin (ngmL)median IQR

0150111 plusmn44135 plusmn 59Blood transfusion(cckgmonth) meanplusmn SD

0019 (36)12 (80)Splenectomized(number )

Statistically significant IQR interquartile range

Karimi M et al Ann Hematol 2016

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

Oxidative Stress in Hemolytic Anemias

The Causes of Oxidative Stress

bull Hemoglobin instability (hemoglobinopathies)

bull Iron-overload (due to increased absorption andor therapeutic

blood transfusion

bull Hemolysis

Although oxidative stress is not the primary etiology of these

diseases it participates in causing damage to RBC (as well as

neutrophils and platelets)

Oxidative status in RBC

Red Blood Flow Properties

RBC

self-aggregability

RBC deformability

RBC adherence

to endothelium

17

Schematic diagram of the computerized image analyzer of RBC flow properties aggregation deformation adherence

Cell-Flow Properties Analyzer

Pressure transducer

P

S Yedgar

RBC aggregability under flow

Chen Eldor et al Am J Physiol 1996

control TM

19

Thalassemic RBC adhesion to EC

is PS dependent

An

nexin

V p

osit

ive c

ells

0

1

2

3

4Control

TM

TI

Ad

here

nt

RB

Cm

m2

0

500

1000

1500

2000

2500

3000Control

Thalassemia

Th + Annexin V

Th + Trypsine

Ramot BJH

2008

Micrographs of retinal veins (angiograms) (1) and of RBC aggregates (2)

corresponding diagrams of aggregate size distribution (3) from thalassemic patient

taken prior to (A) and after (B) transfusion of blood stored for 7 days

AGGREGATE SIZE (No of RBC Aggregate)

RB

C

3

2

1

A B

Blood Transfusion improves blood flow in vivo

Borshtein Transf Med Rev 2010

The incidence of SCI in 28

transfusion dependent patients

15 males 13 females - mean age 30 years

Exclusion criteria

Diabetes mellitus

History of thromboembolic event

Aspirin or anticoagulation treatment

Pazgal I et al Thrombosis Research 2016

Results

Patients without SCI Patients with SCI

N=11 (393) N=17 (60)

FERRITIN (ngml)

(Plt0031)

3910 6200

(2600 ndash 12400) (5000-9600)

P valuePatients without SCIN = 25

Patients with SCIN = 15

Group Parameters

000925 plusmn66311 plusmn65Age (years)Mean plusmnSD

027352069Sex (malefemaleratio)

0905931 plusmn088935 plusmn 123Hemoglobin (gdL)mean plusmn SD

0559388750 plusmn 152073423571 plusmn 210429Plateletmicrolitermeans plusmn SD

08682400 23302550 2875Ferritin (ngmL)median IQR

0150111 plusmn44135 plusmn 59Blood transfusion(cckgmonth) meanplusmn SD

0019 (36)12 (80)Splenectomized(number )

Statistically significant IQR interquartile range

Karimi M et al Ann Hematol 2016

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

Oxidative status in RBC

Red Blood Flow Properties

RBC

self-aggregability

RBC deformability

RBC adherence

to endothelium

17

Schematic diagram of the computerized image analyzer of RBC flow properties aggregation deformation adherence

Cell-Flow Properties Analyzer

Pressure transducer

P

S Yedgar

RBC aggregability under flow

Chen Eldor et al Am J Physiol 1996

control TM

19

Thalassemic RBC adhesion to EC

is PS dependent

An

nexin

V p

osit

ive c

ells

0

1

2

3

4Control

TM

TI

Ad

here

nt

RB

Cm

m2

0

500

1000

1500

2000

2500

3000Control

Thalassemia

Th + Annexin V

Th + Trypsine

Ramot BJH

2008

Micrographs of retinal veins (angiograms) (1) and of RBC aggregates (2)

corresponding diagrams of aggregate size distribution (3) from thalassemic patient

taken prior to (A) and after (B) transfusion of blood stored for 7 days

AGGREGATE SIZE (No of RBC Aggregate)

RB

C

3

2

1

A B

Blood Transfusion improves blood flow in vivo

Borshtein Transf Med Rev 2010

The incidence of SCI in 28

transfusion dependent patients

15 males 13 females - mean age 30 years

Exclusion criteria

Diabetes mellitus

History of thromboembolic event

Aspirin or anticoagulation treatment

Pazgal I et al Thrombosis Research 2016

Results

Patients without SCI Patients with SCI

N=11 (393) N=17 (60)

FERRITIN (ngml)

(Plt0031)

3910 6200

(2600 ndash 12400) (5000-9600)

P valuePatients without SCIN = 25

Patients with SCIN = 15

Group Parameters

000925 plusmn66311 plusmn65Age (years)Mean plusmnSD

027352069Sex (malefemaleratio)

0905931 plusmn088935 plusmn 123Hemoglobin (gdL)mean plusmn SD

0559388750 plusmn 152073423571 plusmn 210429Plateletmicrolitermeans plusmn SD

08682400 23302550 2875Ferritin (ngmL)median IQR

0150111 plusmn44135 plusmn 59Blood transfusion(cckgmonth) meanplusmn SD

0019 (36)12 (80)Splenectomized(number )

Statistically significant IQR interquartile range

Karimi M et al Ann Hematol 2016

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

Red Blood Flow Properties

RBC

self-aggregability

RBC deformability

RBC adherence

to endothelium

17

Schematic diagram of the computerized image analyzer of RBC flow properties aggregation deformation adherence

Cell-Flow Properties Analyzer

Pressure transducer

P

S Yedgar

RBC aggregability under flow

Chen Eldor et al Am J Physiol 1996

control TM

19

Thalassemic RBC adhesion to EC

is PS dependent

An

nexin

V p

osit

ive c

ells

0

1

2

3

4Control

TM

TI

Ad

here

nt

RB

Cm

m2

0

500

1000

1500

2000

2500

3000Control

Thalassemia

Th + Annexin V

Th + Trypsine

Ramot BJH

2008

Micrographs of retinal veins (angiograms) (1) and of RBC aggregates (2)

corresponding diagrams of aggregate size distribution (3) from thalassemic patient

taken prior to (A) and after (B) transfusion of blood stored for 7 days

AGGREGATE SIZE (No of RBC Aggregate)

RB

C

3

2

1

A B

Blood Transfusion improves blood flow in vivo

Borshtein Transf Med Rev 2010

The incidence of SCI in 28

transfusion dependent patients

15 males 13 females - mean age 30 years

Exclusion criteria

Diabetes mellitus

History of thromboembolic event

Aspirin or anticoagulation treatment

Pazgal I et al Thrombosis Research 2016

Results

Patients without SCI Patients with SCI

N=11 (393) N=17 (60)

FERRITIN (ngml)

(Plt0031)

3910 6200

(2600 ndash 12400) (5000-9600)

P valuePatients without SCIN = 25

Patients with SCIN = 15

Group Parameters

000925 plusmn66311 plusmn65Age (years)Mean plusmnSD

027352069Sex (malefemaleratio)

0905931 plusmn088935 plusmn 123Hemoglobin (gdL)mean plusmn SD

0559388750 plusmn 152073423571 plusmn 210429Plateletmicrolitermeans plusmn SD

08682400 23302550 2875Ferritin (ngmL)median IQR

0150111 plusmn44135 plusmn 59Blood transfusion(cckgmonth) meanplusmn SD

0019 (36)12 (80)Splenectomized(number )

Statistically significant IQR interquartile range

Karimi M et al Ann Hematol 2016

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

Schematic diagram of the computerized image analyzer of RBC flow properties aggregation deformation adherence

Cell-Flow Properties Analyzer

Pressure transducer

P

S Yedgar

RBC aggregability under flow

Chen Eldor et al Am J Physiol 1996

control TM

19

Thalassemic RBC adhesion to EC

is PS dependent

An

nexin

V p

osit

ive c

ells

0

1

2

3

4Control

TM

TI

Ad

here

nt

RB

Cm

m2

0

500

1000

1500

2000

2500

3000Control

Thalassemia

Th + Annexin V

Th + Trypsine

Ramot BJH

2008

Micrographs of retinal veins (angiograms) (1) and of RBC aggregates (2)

corresponding diagrams of aggregate size distribution (3) from thalassemic patient

taken prior to (A) and after (B) transfusion of blood stored for 7 days

AGGREGATE SIZE (No of RBC Aggregate)

RB

C

3

2

1

A B

Blood Transfusion improves blood flow in vivo

Borshtein Transf Med Rev 2010

The incidence of SCI in 28

transfusion dependent patients

15 males 13 females - mean age 30 years

Exclusion criteria

Diabetes mellitus

History of thromboembolic event

Aspirin or anticoagulation treatment

Pazgal I et al Thrombosis Research 2016

Results

Patients without SCI Patients with SCI

N=11 (393) N=17 (60)

FERRITIN (ngml)

(Plt0031)

3910 6200

(2600 ndash 12400) (5000-9600)

P valuePatients without SCIN = 25

Patients with SCIN = 15

Group Parameters

000925 plusmn66311 plusmn65Age (years)Mean plusmnSD

027352069Sex (malefemaleratio)

0905931 plusmn088935 plusmn 123Hemoglobin (gdL)mean plusmn SD

0559388750 plusmn 152073423571 plusmn 210429Plateletmicrolitermeans plusmn SD

08682400 23302550 2875Ferritin (ngmL)median IQR

0150111 plusmn44135 plusmn 59Blood transfusion(cckgmonth) meanplusmn SD

0019 (36)12 (80)Splenectomized(number )

Statistically significant IQR interquartile range

Karimi M et al Ann Hematol 2016

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

RBC aggregability under flow

Chen Eldor et al Am J Physiol 1996

control TM

19

Thalassemic RBC adhesion to EC

is PS dependent

An

nexin

V p

osit

ive c

ells

0

1

2

3

4Control

TM

TI

Ad

here

nt

RB

Cm

m2

0

500

1000

1500

2000

2500

3000Control

Thalassemia

Th + Annexin V

Th + Trypsine

Ramot BJH

2008

Micrographs of retinal veins (angiograms) (1) and of RBC aggregates (2)

corresponding diagrams of aggregate size distribution (3) from thalassemic patient

taken prior to (A) and after (B) transfusion of blood stored for 7 days

AGGREGATE SIZE (No of RBC Aggregate)

RB

C

3

2

1

A B

Blood Transfusion improves blood flow in vivo

Borshtein Transf Med Rev 2010

The incidence of SCI in 28

transfusion dependent patients

15 males 13 females - mean age 30 years

Exclusion criteria

Diabetes mellitus

History of thromboembolic event

Aspirin or anticoagulation treatment

Pazgal I et al Thrombosis Research 2016

Results

Patients without SCI Patients with SCI

N=11 (393) N=17 (60)

FERRITIN (ngml)

(Plt0031)

3910 6200

(2600 ndash 12400) (5000-9600)

P valuePatients without SCIN = 25

Patients with SCIN = 15

Group Parameters

000925 plusmn66311 plusmn65Age (years)Mean plusmnSD

027352069Sex (malefemaleratio)

0905931 plusmn088935 plusmn 123Hemoglobin (gdL)mean plusmn SD

0559388750 plusmn 152073423571 plusmn 210429Plateletmicrolitermeans plusmn SD

08682400 23302550 2875Ferritin (ngmL)median IQR

0150111 plusmn44135 plusmn 59Blood transfusion(cckgmonth) meanplusmn SD

0019 (36)12 (80)Splenectomized(number )

Statistically significant IQR interquartile range

Karimi M et al Ann Hematol 2016

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

Thalassemic RBC adhesion to EC

is PS dependent

An

nexin

V p

osit

ive c

ells

0

1

2

3

4Control

TM

TI

Ad

here

nt

RB

Cm

m2

0

500

1000

1500

2000

2500

3000Control

Thalassemia

Th + Annexin V

Th + Trypsine

Ramot BJH

2008

Micrographs of retinal veins (angiograms) (1) and of RBC aggregates (2)

corresponding diagrams of aggregate size distribution (3) from thalassemic patient

taken prior to (A) and after (B) transfusion of blood stored for 7 days

AGGREGATE SIZE (No of RBC Aggregate)

RB

C

3

2

1

A B

Blood Transfusion improves blood flow in vivo

Borshtein Transf Med Rev 2010

The incidence of SCI in 28

transfusion dependent patients

15 males 13 females - mean age 30 years

Exclusion criteria

Diabetes mellitus

History of thromboembolic event

Aspirin or anticoagulation treatment

Pazgal I et al Thrombosis Research 2016

Results

Patients without SCI Patients with SCI

N=11 (393) N=17 (60)

FERRITIN (ngml)

(Plt0031)

3910 6200

(2600 ndash 12400) (5000-9600)

P valuePatients without SCIN = 25

Patients with SCIN = 15

Group Parameters

000925 plusmn66311 plusmn65Age (years)Mean plusmnSD

027352069Sex (malefemaleratio)

0905931 plusmn088935 plusmn 123Hemoglobin (gdL)mean plusmn SD

0559388750 plusmn 152073423571 plusmn 210429Plateletmicrolitermeans plusmn SD

08682400 23302550 2875Ferritin (ngmL)median IQR

0150111 plusmn44135 plusmn 59Blood transfusion(cckgmonth) meanplusmn SD

0019 (36)12 (80)Splenectomized(number )

Statistically significant IQR interquartile range

Karimi M et al Ann Hematol 2016

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

Micrographs of retinal veins (angiograms) (1) and of RBC aggregates (2)

corresponding diagrams of aggregate size distribution (3) from thalassemic patient

taken prior to (A) and after (B) transfusion of blood stored for 7 days

AGGREGATE SIZE (No of RBC Aggregate)

RB

C

3

2

1

A B

Blood Transfusion improves blood flow in vivo

Borshtein Transf Med Rev 2010

The incidence of SCI in 28

transfusion dependent patients

15 males 13 females - mean age 30 years

Exclusion criteria

Diabetes mellitus

History of thromboembolic event

Aspirin or anticoagulation treatment

Pazgal I et al Thrombosis Research 2016

Results

Patients without SCI Patients with SCI

N=11 (393) N=17 (60)

FERRITIN (ngml)

(Plt0031)

3910 6200

(2600 ndash 12400) (5000-9600)

P valuePatients without SCIN = 25

Patients with SCIN = 15

Group Parameters

000925 plusmn66311 plusmn65Age (years)Mean plusmnSD

027352069Sex (malefemaleratio)

0905931 plusmn088935 plusmn 123Hemoglobin (gdL)mean plusmn SD

0559388750 plusmn 152073423571 plusmn 210429Plateletmicrolitermeans plusmn SD

08682400 23302550 2875Ferritin (ngmL)median IQR

0150111 plusmn44135 plusmn 59Blood transfusion(cckgmonth) meanplusmn SD

0019 (36)12 (80)Splenectomized(number )

Statistically significant IQR interquartile range

Karimi M et al Ann Hematol 2016

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

The incidence of SCI in 28

transfusion dependent patients

15 males 13 females - mean age 30 years

Exclusion criteria

Diabetes mellitus

History of thromboembolic event

Aspirin or anticoagulation treatment

Pazgal I et al Thrombosis Research 2016

Results

Patients without SCI Patients with SCI

N=11 (393) N=17 (60)

FERRITIN (ngml)

(Plt0031)

3910 6200

(2600 ndash 12400) (5000-9600)

P valuePatients without SCIN = 25

Patients with SCIN = 15

Group Parameters

000925 plusmn66311 plusmn65Age (years)Mean plusmnSD

027352069Sex (malefemaleratio)

0905931 plusmn088935 plusmn 123Hemoglobin (gdL)mean plusmn SD

0559388750 plusmn 152073423571 plusmn 210429Plateletmicrolitermeans plusmn SD

08682400 23302550 2875Ferritin (ngmL)median IQR

0150111 plusmn44135 plusmn 59Blood transfusion(cckgmonth) meanplusmn SD

0019 (36)12 (80)Splenectomized(number )

Statistically significant IQR interquartile range

Karimi M et al Ann Hematol 2016

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

Results

Patients without SCI Patients with SCI

N=11 (393) N=17 (60)

FERRITIN (ngml)

(Plt0031)

3910 6200

(2600 ndash 12400) (5000-9600)

P valuePatients without SCIN = 25

Patients with SCIN = 15

Group Parameters

000925 plusmn66311 plusmn65Age (years)Mean plusmnSD

027352069Sex (malefemaleratio)

0905931 plusmn088935 plusmn 123Hemoglobin (gdL)mean plusmn SD

0559388750 plusmn 152073423571 plusmn 210429Plateletmicrolitermeans plusmn SD

08682400 23302550 2875Ferritin (ngmL)median IQR

0150111 plusmn44135 plusmn 59Blood transfusion(cckgmonth) meanplusmn SD

0019 (36)12 (80)Splenectomized(number )

Statistically significant IQR interquartile range

Karimi M et al Ann Hematol 2016

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

P valuePatients without SCIN = 25

Patients with SCIN = 15

Group Parameters

000925 plusmn66311 plusmn65Age (years)Mean plusmnSD

027352069Sex (malefemaleratio)

0905931 plusmn088935 plusmn 123Hemoglobin (gdL)mean plusmn SD

0559388750 plusmn 152073423571 plusmn 210429Plateletmicrolitermeans plusmn SD

08682400 23302550 2875Ferritin (ngmL)median IQR

0150111 plusmn44135 plusmn 59Blood transfusion(cckgmonth) meanplusmn SD

0019 (36)12 (80)Splenectomized(number )

Statistically significant IQR interquartile range

Karimi M et al Ann Hematol 2016

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

CONCLUSIONS1 The results of the 2 studies in 68 transfused patients with β-Thalassemia

Major demonstrate an incidence of 67 (28 patients) and 375

(40patients)

2 Significant correlations between the number of SCI were found with

serum ferritin (28 patients) and with age iron overload and splenectomy

(40 patients)

3 These findings may suggest that the increased number of pathological

circulating RBCs in β-TI may not be the only pathophysiological factor

in the etiology of SCI

4 Consequently there are other factors that contribute to etiology of

hypercoagulability in thalassemia

5 It should be noted that in sickle cell anemia regular transfusions for 3

years decreased the number of SCI (MRDeBaun NEJM371699

2014)

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

0

100

200

300

400

500

600

MFC

ROS GSH

NOR THAL NOR THAL

n =46

plt 00001 by studentrsquos t-test

Mean 139Mean 230 Mean 305

Mean 102

ROS and GSH in platelets

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

Effect of thalassemic plasma on ROS generation

by normal platelets

0

100

200

300

400

Untreated Treated

RO

SNormal platelets+

Normal plasma

Normal pletelets +

Thalassemic plasma

Normal platelets were incubated with autologous plasma or

ABO compatible thalassemic plasma

ROS generation of the platelets was measured using the DCF assay

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

Support amp

TrainingH

elpLogged

in as

wolf199L

ogoff

e

Pathological findings on EEG

related to protein C and platelets in NTDT patients

Teli A Blood Coagulation amp Fibrinolysis 2012

Platelet Deposition Under Flow Conditions in Thalassemia

Goldschmidt Throb Haemost 2008

0

5

10

15

20

25

30

0

20

40

60

80

100

Surface coverage

Average size

Controls ControlsPatients Patients

Su

rface

cov

erag

e

Avera

ge size m

m2

Plt005Pgt05

A

Platelet adhesion (SC) and average size (AS) in 22 patients and controls

Increased platelet deposition under flow conditions is induced by both thalassemic platelets

and red blood cells Thrombosis and Haemostasis 2008

0

5

10

15

20

25

0

10

20

30

40

50

No thrombosis

Thrombosis

No thrombosis

Thrombosis

A

Plt0005 Plt001

Microparticles generation from RBC and platelets

in HbEβ-thalassemia

Rhoda Elison Hirsch et al Antioxidants and Redox Signaling2016

Increased TEE

by circulating MPin β-Thal Major (87 patients)

Significant factors

1 SPLENECTOMY

2 MP - RBC

3 MP - ENDOTHELIAL derived

4 HYPERBILIRUBINEMIA

Youssry I et al Ann Hematol 2017 (96)

Van Beers Haematologica 2009

Stein AJM 2006

WTThalassemic

1

4

3

2

Kalish Y et al Thrombosis Research 2014

PS

Kalish Y et al Thrombosis Research 2014

Carotid Artery Occlusion Model

Carotid Artery ndash Time to OcclusionHypergoagulable state

Role of platelets

wt wt+ASA Thal Thal+ASA0

20

40

60

80

10000309

01204

00011

01286

00119

Mean

Std Deviation

wt

6460

8017

wt+ASA

7250

1306

Thal

4910

9758

Thal+ASA

5870

8538

Tim

e t

o o

cclu

sio

n (

min

)

The hypercoagulable state in thalassemia Blood 2002

Β-Thalassemia and sickle cell anemia as paradigms of Hypercoagulability Br J Hematol 2007

Platelets

bullIncreased platelet aggregation

bullIncreased expression of activation

markers

bullPresence of platelet morphologic

abnormalities

Hypercoagulability

Other factors

bullCardiac dysfunction

bullHepatic dysfunction

bullEndocrine dysfunction

Peripheral

blood elements

bullExpression of endothelial

adhesion molecules and tissue

factor on endothelial cells

bullFormation of microparticles

Nitric oxide

bullHallmark of haemolysis

bulldarr Levels leading to vasoconstrictionRBCs

bull Formation of reactive oxygen

species

bullExpression of negatively

charged phospholipids

bullEnhanced cohesiveness and

aggregability

Thrombophilia

bullNo role for prothrombotic

mutations

bullDecreased levels of antithrombin III

protein C and protein S

bullAnti-phospholipid antibodies

Splenectomy

bullHigh platelet counts and

hyperactivity

bullHigh levels of negatively

charged RBCs

Summary

bull Hemoglobinopathies are associated with hypercoagulable state

bull Iron over load and oxidative stress are major factors leading to

- Increased RBCs and plateletrsquos activation and adhesion

- Increased procoagulant effect of RBCs platelets and MPs

bull Splenectomy is a major factor due to

- Thrombocytosis

- Elimination of a scavenger of pathological RBCs and MP

bull Clinical manifestations include VTE AT CVA PAH and potentially others

bull Increased number of SCI in SPX multitransfused TM and in NTDT patients

Low dose Aspirin is indicated to prevent

thromboembolic phenomena in SPX- regularly

transfused TM an in NTDT patients

The direct correlation between the degree of iron

overload and the number of SCI suggests that

effective iron chelation therapy is mandatory

Therapeutic Implications

Effect of LD aspirin on TXB2 excreation

Eldor Blood 1991

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

0

5

10

15

20

25

30

0

20

40

60

80

100

Surface coverage

Average size

Controls ControlsPatients Patients

Su

rface

cov

erag

e

Avera

ge size m

m2

Plt005Pgt05

A

Platelet adhesion (SC) and average size (AS) in 22 patients and controls

Increased platelet deposition under flow conditions is induced by both thalassemic platelets

and red blood cells Thrombosis and Haemostasis 2008

0

5

10

15

20

25

0

10

20

30

40

50

No thrombosis

Thrombosis

No thrombosis

Thrombosis

A

Plt0005 Plt001

Microparticles generation from RBC and platelets

in HbEβ-thalassemia

Rhoda Elison Hirsch et al Antioxidants and Redox Signaling2016

Increased TEE

by circulating MPin β-Thal Major (87 patients)

Significant factors

1 SPLENECTOMY

2 MP - RBC

3 MP - ENDOTHELIAL derived

4 HYPERBILIRUBINEMIA

Youssry I et al Ann Hematol 2017 (96)

Van Beers Haematologica 2009

Stein AJM 2006

WTThalassemic

1

4

3

2

Kalish Y et al Thrombosis Research 2014

PS

Kalish Y et al Thrombosis Research 2014

Carotid Artery Occlusion Model

Carotid Artery ndash Time to OcclusionHypergoagulable state

Role of platelets

wt wt+ASA Thal Thal+ASA0

20

40

60

80

10000309

01204

00011

01286

00119

Mean

Std Deviation

wt

6460

8017

wt+ASA

7250

1306

Thal

4910

9758

Thal+ASA

5870

8538

Tim

e t

o o

cclu

sio

n (

min

)

The hypercoagulable state in thalassemia Blood 2002

Β-Thalassemia and sickle cell anemia as paradigms of Hypercoagulability Br J Hematol 2007

Platelets

bullIncreased platelet aggregation

bullIncreased expression of activation

markers

bullPresence of platelet morphologic

abnormalities

Hypercoagulability

Other factors

bullCardiac dysfunction

bullHepatic dysfunction

bullEndocrine dysfunction

Peripheral

blood elements

bullExpression of endothelial

adhesion molecules and tissue

factor on endothelial cells

bullFormation of microparticles

Nitric oxide

bullHallmark of haemolysis

bulldarr Levels leading to vasoconstrictionRBCs

bull Formation of reactive oxygen

species

bullExpression of negatively

charged phospholipids

bullEnhanced cohesiveness and

aggregability

Thrombophilia

bullNo role for prothrombotic

mutations

bullDecreased levels of antithrombin III

protein C and protein S

bullAnti-phospholipid antibodies

Splenectomy

bullHigh platelet counts and

hyperactivity

bullHigh levels of negatively

charged RBCs

Summary

bull Hemoglobinopathies are associated with hypercoagulable state

bull Iron over load and oxidative stress are major factors leading to

- Increased RBCs and plateletrsquos activation and adhesion

- Increased procoagulant effect of RBCs platelets and MPs

bull Splenectomy is a major factor due to

- Thrombocytosis

- Elimination of a scavenger of pathological RBCs and MP

bull Clinical manifestations include VTE AT CVA PAH and potentially others

bull Increased number of SCI in SPX multitransfused TM and in NTDT patients

Low dose Aspirin is indicated to prevent

thromboembolic phenomena in SPX- regularly

transfused TM an in NTDT patients

The direct correlation between the degree of iron

overload and the number of SCI suggests that

effective iron chelation therapy is mandatory

Therapeutic Implications

Effect of LD aspirin on TXB2 excreation

Eldor Blood 1991

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

0

5

10

15

20

25

0

10

20

30

40

50

No thrombosis

Thrombosis

No thrombosis

Thrombosis

A

Plt0005 Plt001

Microparticles generation from RBC and platelets

in HbEβ-thalassemia

Rhoda Elison Hirsch et al Antioxidants and Redox Signaling2016

Increased TEE

by circulating MPin β-Thal Major (87 patients)

Significant factors

1 SPLENECTOMY

2 MP - RBC

3 MP - ENDOTHELIAL derived

4 HYPERBILIRUBINEMIA

Youssry I et al Ann Hematol 2017 (96)

Van Beers Haematologica 2009

Stein AJM 2006

WTThalassemic

1

4

3

2

Kalish Y et al Thrombosis Research 2014

PS

Kalish Y et al Thrombosis Research 2014

Carotid Artery Occlusion Model

Carotid Artery ndash Time to OcclusionHypergoagulable state

Role of platelets

wt wt+ASA Thal Thal+ASA0

20

40

60

80

10000309

01204

00011

01286

00119

Mean

Std Deviation

wt

6460

8017

wt+ASA

7250

1306

Thal

4910

9758

Thal+ASA

5870

8538

Tim

e t

o o

cclu

sio

n (

min

)

The hypercoagulable state in thalassemia Blood 2002

Β-Thalassemia and sickle cell anemia as paradigms of Hypercoagulability Br J Hematol 2007

Platelets

bullIncreased platelet aggregation

bullIncreased expression of activation

markers

bullPresence of platelet morphologic

abnormalities

Hypercoagulability

Other factors

bullCardiac dysfunction

bullHepatic dysfunction

bullEndocrine dysfunction

Peripheral

blood elements

bullExpression of endothelial

adhesion molecules and tissue

factor on endothelial cells

bullFormation of microparticles

Nitric oxide

bullHallmark of haemolysis

bulldarr Levels leading to vasoconstrictionRBCs

bull Formation of reactive oxygen

species

bullExpression of negatively

charged phospholipids

bullEnhanced cohesiveness and

aggregability

Thrombophilia

bullNo role for prothrombotic

mutations

bullDecreased levels of antithrombin III

protein C and protein S

bullAnti-phospholipid antibodies

Splenectomy

bullHigh platelet counts and

hyperactivity

bullHigh levels of negatively

charged RBCs

Summary

bull Hemoglobinopathies are associated with hypercoagulable state

bull Iron over load and oxidative stress are major factors leading to

- Increased RBCs and plateletrsquos activation and adhesion

- Increased procoagulant effect of RBCs platelets and MPs

bull Splenectomy is a major factor due to

- Thrombocytosis

- Elimination of a scavenger of pathological RBCs and MP

bull Clinical manifestations include VTE AT CVA PAH and potentially others

bull Increased number of SCI in SPX multitransfused TM and in NTDT patients

Low dose Aspirin is indicated to prevent

thromboembolic phenomena in SPX- regularly

transfused TM an in NTDT patients

The direct correlation between the degree of iron

overload and the number of SCI suggests that

effective iron chelation therapy is mandatory

Therapeutic Implications

Effect of LD aspirin on TXB2 excreation

Eldor Blood 1991

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

Microparticles generation from RBC and platelets

in HbEβ-thalassemia

Rhoda Elison Hirsch et al Antioxidants and Redox Signaling2016

Increased TEE

by circulating MPin β-Thal Major (87 patients)

Significant factors

1 SPLENECTOMY

2 MP - RBC

3 MP - ENDOTHELIAL derived

4 HYPERBILIRUBINEMIA

Youssry I et al Ann Hematol 2017 (96)

Van Beers Haematologica 2009

Stein AJM 2006

WTThalassemic

1

4

3

2

Kalish Y et al Thrombosis Research 2014

PS

Kalish Y et al Thrombosis Research 2014

Carotid Artery Occlusion Model

Carotid Artery ndash Time to OcclusionHypergoagulable state

Role of platelets

wt wt+ASA Thal Thal+ASA0

20

40

60

80

10000309

01204

00011

01286

00119

Mean

Std Deviation

wt

6460

8017

wt+ASA

7250

1306

Thal

4910

9758

Thal+ASA

5870

8538

Tim

e t

o o

cclu

sio

n (

min

)

The hypercoagulable state in thalassemia Blood 2002

Β-Thalassemia and sickle cell anemia as paradigms of Hypercoagulability Br J Hematol 2007

Platelets

bullIncreased platelet aggregation

bullIncreased expression of activation

markers

bullPresence of platelet morphologic

abnormalities

Hypercoagulability

Other factors

bullCardiac dysfunction

bullHepatic dysfunction

bullEndocrine dysfunction

Peripheral

blood elements

bullExpression of endothelial

adhesion molecules and tissue

factor on endothelial cells

bullFormation of microparticles

Nitric oxide

bullHallmark of haemolysis

bulldarr Levels leading to vasoconstrictionRBCs

bull Formation of reactive oxygen

species

bullExpression of negatively

charged phospholipids

bullEnhanced cohesiveness and

aggregability

Thrombophilia

bullNo role for prothrombotic

mutations

bullDecreased levels of antithrombin III

protein C and protein S

bullAnti-phospholipid antibodies

Splenectomy

bullHigh platelet counts and

hyperactivity

bullHigh levels of negatively

charged RBCs

Summary

bull Hemoglobinopathies are associated with hypercoagulable state

bull Iron over load and oxidative stress are major factors leading to

- Increased RBCs and plateletrsquos activation and adhesion

- Increased procoagulant effect of RBCs platelets and MPs

bull Splenectomy is a major factor due to

- Thrombocytosis

- Elimination of a scavenger of pathological RBCs and MP

bull Clinical manifestations include VTE AT CVA PAH and potentially others

bull Increased number of SCI in SPX multitransfused TM and in NTDT patients

Low dose Aspirin is indicated to prevent

thromboembolic phenomena in SPX- regularly

transfused TM an in NTDT patients

The direct correlation between the degree of iron

overload and the number of SCI suggests that

effective iron chelation therapy is mandatory

Therapeutic Implications

Effect of LD aspirin on TXB2 excreation

Eldor Blood 1991

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

Increased TEE

by circulating MPin β-Thal Major (87 patients)

Significant factors

1 SPLENECTOMY

2 MP - RBC

3 MP - ENDOTHELIAL derived

4 HYPERBILIRUBINEMIA

Youssry I et al Ann Hematol 2017 (96)

Van Beers Haematologica 2009

Stein AJM 2006

WTThalassemic

1

4

3

2

Kalish Y et al Thrombosis Research 2014

PS

Kalish Y et al Thrombosis Research 2014

Carotid Artery Occlusion Model

Carotid Artery ndash Time to OcclusionHypergoagulable state

Role of platelets

wt wt+ASA Thal Thal+ASA0

20

40

60

80

10000309

01204

00011

01286

00119

Mean

Std Deviation

wt

6460

8017

wt+ASA

7250

1306

Thal

4910

9758

Thal+ASA

5870

8538

Tim

e t

o o

cclu

sio

n (

min

)

The hypercoagulable state in thalassemia Blood 2002

Β-Thalassemia and sickle cell anemia as paradigms of Hypercoagulability Br J Hematol 2007

Platelets

bullIncreased platelet aggregation

bullIncreased expression of activation

markers

bullPresence of platelet morphologic

abnormalities

Hypercoagulability

Other factors

bullCardiac dysfunction

bullHepatic dysfunction

bullEndocrine dysfunction

Peripheral

blood elements

bullExpression of endothelial

adhesion molecules and tissue

factor on endothelial cells

bullFormation of microparticles

Nitric oxide

bullHallmark of haemolysis

bulldarr Levels leading to vasoconstrictionRBCs

bull Formation of reactive oxygen

species

bullExpression of negatively

charged phospholipids

bullEnhanced cohesiveness and

aggregability

Thrombophilia

bullNo role for prothrombotic

mutations

bullDecreased levels of antithrombin III

protein C and protein S

bullAnti-phospholipid antibodies

Splenectomy

bullHigh platelet counts and

hyperactivity

bullHigh levels of negatively

charged RBCs

Summary

bull Hemoglobinopathies are associated with hypercoagulable state

bull Iron over load and oxidative stress are major factors leading to

- Increased RBCs and plateletrsquos activation and adhesion

- Increased procoagulant effect of RBCs platelets and MPs

bull Splenectomy is a major factor due to

- Thrombocytosis

- Elimination of a scavenger of pathological RBCs and MP

bull Clinical manifestations include VTE AT CVA PAH and potentially others

bull Increased number of SCI in SPX multitransfused TM and in NTDT patients

Low dose Aspirin is indicated to prevent

thromboembolic phenomena in SPX- regularly

transfused TM an in NTDT patients

The direct correlation between the degree of iron

overload and the number of SCI suggests that

effective iron chelation therapy is mandatory

Therapeutic Implications

Effect of LD aspirin on TXB2 excreation

Eldor Blood 1991

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

Van Beers Haematologica 2009

Stein AJM 2006

WTThalassemic

1

4

3

2

Kalish Y et al Thrombosis Research 2014

PS

Kalish Y et al Thrombosis Research 2014

Carotid Artery Occlusion Model

Carotid Artery ndash Time to OcclusionHypergoagulable state

Role of platelets

wt wt+ASA Thal Thal+ASA0

20

40

60

80

10000309

01204

00011

01286

00119

Mean

Std Deviation

wt

6460

8017

wt+ASA

7250

1306

Thal

4910

9758

Thal+ASA

5870

8538

Tim

e t

o o

cclu

sio

n (

min

)

The hypercoagulable state in thalassemia Blood 2002

Β-Thalassemia and sickle cell anemia as paradigms of Hypercoagulability Br J Hematol 2007

Platelets

bullIncreased platelet aggregation

bullIncreased expression of activation

markers

bullPresence of platelet morphologic

abnormalities

Hypercoagulability

Other factors

bullCardiac dysfunction

bullHepatic dysfunction

bullEndocrine dysfunction

Peripheral

blood elements

bullExpression of endothelial

adhesion molecules and tissue

factor on endothelial cells

bullFormation of microparticles

Nitric oxide

bullHallmark of haemolysis

bulldarr Levels leading to vasoconstrictionRBCs

bull Formation of reactive oxygen

species

bullExpression of negatively

charged phospholipids

bullEnhanced cohesiveness and

aggregability

Thrombophilia

bullNo role for prothrombotic

mutations

bullDecreased levels of antithrombin III

protein C and protein S

bullAnti-phospholipid antibodies

Splenectomy

bullHigh platelet counts and

hyperactivity

bullHigh levels of negatively

charged RBCs

Summary

bull Hemoglobinopathies are associated with hypercoagulable state

bull Iron over load and oxidative stress are major factors leading to

- Increased RBCs and plateletrsquos activation and adhesion

- Increased procoagulant effect of RBCs platelets and MPs

bull Splenectomy is a major factor due to

- Thrombocytosis

- Elimination of a scavenger of pathological RBCs and MP

bull Clinical manifestations include VTE AT CVA PAH and potentially others

bull Increased number of SCI in SPX multitransfused TM and in NTDT patients

Low dose Aspirin is indicated to prevent

thromboembolic phenomena in SPX- regularly

transfused TM an in NTDT patients

The direct correlation between the degree of iron

overload and the number of SCI suggests that

effective iron chelation therapy is mandatory

Therapeutic Implications

Effect of LD aspirin on TXB2 excreation

Eldor Blood 1991

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

Stein AJM 2006

WTThalassemic

1

4

3

2

Kalish Y et al Thrombosis Research 2014

PS

Kalish Y et al Thrombosis Research 2014

Carotid Artery Occlusion Model

Carotid Artery ndash Time to OcclusionHypergoagulable state

Role of platelets

wt wt+ASA Thal Thal+ASA0

20

40

60

80

10000309

01204

00011

01286

00119

Mean

Std Deviation

wt

6460

8017

wt+ASA

7250

1306

Thal

4910

9758

Thal+ASA

5870

8538

Tim

e t

o o

cclu

sio

n (

min

)

The hypercoagulable state in thalassemia Blood 2002

Β-Thalassemia and sickle cell anemia as paradigms of Hypercoagulability Br J Hematol 2007

Platelets

bullIncreased platelet aggregation

bullIncreased expression of activation

markers

bullPresence of platelet morphologic

abnormalities

Hypercoagulability

Other factors

bullCardiac dysfunction

bullHepatic dysfunction

bullEndocrine dysfunction

Peripheral

blood elements

bullExpression of endothelial

adhesion molecules and tissue

factor on endothelial cells

bullFormation of microparticles

Nitric oxide

bullHallmark of haemolysis

bulldarr Levels leading to vasoconstrictionRBCs

bull Formation of reactive oxygen

species

bullExpression of negatively

charged phospholipids

bullEnhanced cohesiveness and

aggregability

Thrombophilia

bullNo role for prothrombotic

mutations

bullDecreased levels of antithrombin III

protein C and protein S

bullAnti-phospholipid antibodies

Splenectomy

bullHigh platelet counts and

hyperactivity

bullHigh levels of negatively

charged RBCs

Summary

bull Hemoglobinopathies are associated with hypercoagulable state

bull Iron over load and oxidative stress are major factors leading to

- Increased RBCs and plateletrsquos activation and adhesion

- Increased procoagulant effect of RBCs platelets and MPs

bull Splenectomy is a major factor due to

- Thrombocytosis

- Elimination of a scavenger of pathological RBCs and MP

bull Clinical manifestations include VTE AT CVA PAH and potentially others

bull Increased number of SCI in SPX multitransfused TM and in NTDT patients

Low dose Aspirin is indicated to prevent

thromboembolic phenomena in SPX- regularly

transfused TM an in NTDT patients

The direct correlation between the degree of iron

overload and the number of SCI suggests that

effective iron chelation therapy is mandatory

Therapeutic Implications

Effect of LD aspirin on TXB2 excreation

Eldor Blood 1991

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

WTThalassemic

1

4

3

2

Kalish Y et al Thrombosis Research 2014

PS

Kalish Y et al Thrombosis Research 2014

Carotid Artery Occlusion Model

Carotid Artery ndash Time to OcclusionHypergoagulable state

Role of platelets

wt wt+ASA Thal Thal+ASA0

20

40

60

80

10000309

01204

00011

01286

00119

Mean

Std Deviation

wt

6460

8017

wt+ASA

7250

1306

Thal

4910

9758

Thal+ASA

5870

8538

Tim

e t

o o

cclu

sio

n (

min

)

The hypercoagulable state in thalassemia Blood 2002

Β-Thalassemia and sickle cell anemia as paradigms of Hypercoagulability Br J Hematol 2007

Platelets

bullIncreased platelet aggregation

bullIncreased expression of activation

markers

bullPresence of platelet morphologic

abnormalities

Hypercoagulability

Other factors

bullCardiac dysfunction

bullHepatic dysfunction

bullEndocrine dysfunction

Peripheral

blood elements

bullExpression of endothelial

adhesion molecules and tissue

factor on endothelial cells

bullFormation of microparticles

Nitric oxide

bullHallmark of haemolysis

bulldarr Levels leading to vasoconstrictionRBCs

bull Formation of reactive oxygen

species

bullExpression of negatively

charged phospholipids

bullEnhanced cohesiveness and

aggregability

Thrombophilia

bullNo role for prothrombotic

mutations

bullDecreased levels of antithrombin III

protein C and protein S

bullAnti-phospholipid antibodies

Splenectomy

bullHigh platelet counts and

hyperactivity

bullHigh levels of negatively

charged RBCs

Summary

bull Hemoglobinopathies are associated with hypercoagulable state

bull Iron over load and oxidative stress are major factors leading to

- Increased RBCs and plateletrsquos activation and adhesion

- Increased procoagulant effect of RBCs platelets and MPs

bull Splenectomy is a major factor due to

- Thrombocytosis

- Elimination of a scavenger of pathological RBCs and MP

bull Clinical manifestations include VTE AT CVA PAH and potentially others

bull Increased number of SCI in SPX multitransfused TM and in NTDT patients

Low dose Aspirin is indicated to prevent

thromboembolic phenomena in SPX- regularly

transfused TM an in NTDT patients

The direct correlation between the degree of iron

overload and the number of SCI suggests that

effective iron chelation therapy is mandatory

Therapeutic Implications

Effect of LD aspirin on TXB2 excreation

Eldor Blood 1991

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

Kalish Y et al Thrombosis Research 2014

PS

Kalish Y et al Thrombosis Research 2014

Carotid Artery Occlusion Model

Carotid Artery ndash Time to OcclusionHypergoagulable state

Role of platelets

wt wt+ASA Thal Thal+ASA0

20

40

60

80

10000309

01204

00011

01286

00119

Mean

Std Deviation

wt

6460

8017

wt+ASA

7250

1306

Thal

4910

9758

Thal+ASA

5870

8538

Tim

e t

o o

cclu

sio

n (

min

)

The hypercoagulable state in thalassemia Blood 2002

Β-Thalassemia and sickle cell anemia as paradigms of Hypercoagulability Br J Hematol 2007

Platelets

bullIncreased platelet aggregation

bullIncreased expression of activation

markers

bullPresence of platelet morphologic

abnormalities

Hypercoagulability

Other factors

bullCardiac dysfunction

bullHepatic dysfunction

bullEndocrine dysfunction

Peripheral

blood elements

bullExpression of endothelial

adhesion molecules and tissue

factor on endothelial cells

bullFormation of microparticles

Nitric oxide

bullHallmark of haemolysis

bulldarr Levels leading to vasoconstrictionRBCs

bull Formation of reactive oxygen

species

bullExpression of negatively

charged phospholipids

bullEnhanced cohesiveness and

aggregability

Thrombophilia

bullNo role for prothrombotic

mutations

bullDecreased levels of antithrombin III

protein C and protein S

bullAnti-phospholipid antibodies

Splenectomy

bullHigh platelet counts and

hyperactivity

bullHigh levels of negatively

charged RBCs

Summary

bull Hemoglobinopathies are associated with hypercoagulable state

bull Iron over load and oxidative stress are major factors leading to

- Increased RBCs and plateletrsquos activation and adhesion

- Increased procoagulant effect of RBCs platelets and MPs

bull Splenectomy is a major factor due to

- Thrombocytosis

- Elimination of a scavenger of pathological RBCs and MP

bull Clinical manifestations include VTE AT CVA PAH and potentially others

bull Increased number of SCI in SPX multitransfused TM and in NTDT patients

Low dose Aspirin is indicated to prevent

thromboembolic phenomena in SPX- regularly

transfused TM an in NTDT patients

The direct correlation between the degree of iron

overload and the number of SCI suggests that

effective iron chelation therapy is mandatory

Therapeutic Implications

Effect of LD aspirin on TXB2 excreation

Eldor Blood 1991

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

PS

Kalish Y et al Thrombosis Research 2014

Carotid Artery Occlusion Model

Carotid Artery ndash Time to OcclusionHypergoagulable state

Role of platelets

wt wt+ASA Thal Thal+ASA0

20

40

60

80

10000309

01204

00011

01286

00119

Mean

Std Deviation

wt

6460

8017

wt+ASA

7250

1306

Thal

4910

9758

Thal+ASA

5870

8538

Tim

e t

o o

cclu

sio

n (

min

)

The hypercoagulable state in thalassemia Blood 2002

Β-Thalassemia and sickle cell anemia as paradigms of Hypercoagulability Br J Hematol 2007

Platelets

bullIncreased platelet aggregation

bullIncreased expression of activation

markers

bullPresence of platelet morphologic

abnormalities

Hypercoagulability

Other factors

bullCardiac dysfunction

bullHepatic dysfunction

bullEndocrine dysfunction

Peripheral

blood elements

bullExpression of endothelial

adhesion molecules and tissue

factor on endothelial cells

bullFormation of microparticles

Nitric oxide

bullHallmark of haemolysis

bulldarr Levels leading to vasoconstrictionRBCs

bull Formation of reactive oxygen

species

bullExpression of negatively

charged phospholipids

bullEnhanced cohesiveness and

aggregability

Thrombophilia

bullNo role for prothrombotic

mutations

bullDecreased levels of antithrombin III

protein C and protein S

bullAnti-phospholipid antibodies

Splenectomy

bullHigh platelet counts and

hyperactivity

bullHigh levels of negatively

charged RBCs

Summary

bull Hemoglobinopathies are associated with hypercoagulable state

bull Iron over load and oxidative stress are major factors leading to

- Increased RBCs and plateletrsquos activation and adhesion

- Increased procoagulant effect of RBCs platelets and MPs

bull Splenectomy is a major factor due to

- Thrombocytosis

- Elimination of a scavenger of pathological RBCs and MP

bull Clinical manifestations include VTE AT CVA PAH and potentially others

bull Increased number of SCI in SPX multitransfused TM and in NTDT patients

Low dose Aspirin is indicated to prevent

thromboembolic phenomena in SPX- regularly

transfused TM an in NTDT patients

The direct correlation between the degree of iron

overload and the number of SCI suggests that

effective iron chelation therapy is mandatory

Therapeutic Implications

Effect of LD aspirin on TXB2 excreation

Eldor Blood 1991

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

Carotid Artery Occlusion Model

Carotid Artery ndash Time to OcclusionHypergoagulable state

Role of platelets

wt wt+ASA Thal Thal+ASA0

20

40

60

80

10000309

01204

00011

01286

00119

Mean

Std Deviation

wt

6460

8017

wt+ASA

7250

1306

Thal

4910

9758

Thal+ASA

5870

8538

Tim

e t

o o

cclu

sio

n (

min

)

The hypercoagulable state in thalassemia Blood 2002

Β-Thalassemia and sickle cell anemia as paradigms of Hypercoagulability Br J Hematol 2007

Platelets

bullIncreased platelet aggregation

bullIncreased expression of activation

markers

bullPresence of platelet morphologic

abnormalities

Hypercoagulability

Other factors

bullCardiac dysfunction

bullHepatic dysfunction

bullEndocrine dysfunction

Peripheral

blood elements

bullExpression of endothelial

adhesion molecules and tissue

factor on endothelial cells

bullFormation of microparticles

Nitric oxide

bullHallmark of haemolysis

bulldarr Levels leading to vasoconstrictionRBCs

bull Formation of reactive oxygen

species

bullExpression of negatively

charged phospholipids

bullEnhanced cohesiveness and

aggregability

Thrombophilia

bullNo role for prothrombotic

mutations

bullDecreased levels of antithrombin III

protein C and protein S

bullAnti-phospholipid antibodies

Splenectomy

bullHigh platelet counts and

hyperactivity

bullHigh levels of negatively

charged RBCs

Summary

bull Hemoglobinopathies are associated with hypercoagulable state

bull Iron over load and oxidative stress are major factors leading to

- Increased RBCs and plateletrsquos activation and adhesion

- Increased procoagulant effect of RBCs platelets and MPs

bull Splenectomy is a major factor due to

- Thrombocytosis

- Elimination of a scavenger of pathological RBCs and MP

bull Clinical manifestations include VTE AT CVA PAH and potentially others

bull Increased number of SCI in SPX multitransfused TM and in NTDT patients

Low dose Aspirin is indicated to prevent

thromboembolic phenomena in SPX- regularly

transfused TM an in NTDT patients

The direct correlation between the degree of iron

overload and the number of SCI suggests that

effective iron chelation therapy is mandatory

Therapeutic Implications

Effect of LD aspirin on TXB2 excreation

Eldor Blood 1991

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

Carotid Artery ndash Time to OcclusionHypergoagulable state

Role of platelets

wt wt+ASA Thal Thal+ASA0

20

40

60

80

10000309

01204

00011

01286

00119

Mean

Std Deviation

wt

6460

8017

wt+ASA

7250

1306

Thal

4910

9758

Thal+ASA

5870

8538

Tim

e t

o o

cclu

sio

n (

min

)

The hypercoagulable state in thalassemia Blood 2002

Β-Thalassemia and sickle cell anemia as paradigms of Hypercoagulability Br J Hematol 2007

Platelets

bullIncreased platelet aggregation

bullIncreased expression of activation

markers

bullPresence of platelet morphologic

abnormalities

Hypercoagulability

Other factors

bullCardiac dysfunction

bullHepatic dysfunction

bullEndocrine dysfunction

Peripheral

blood elements

bullExpression of endothelial

adhesion molecules and tissue

factor on endothelial cells

bullFormation of microparticles

Nitric oxide

bullHallmark of haemolysis

bulldarr Levels leading to vasoconstrictionRBCs

bull Formation of reactive oxygen

species

bullExpression of negatively

charged phospholipids

bullEnhanced cohesiveness and

aggregability

Thrombophilia

bullNo role for prothrombotic

mutations

bullDecreased levels of antithrombin III

protein C and protein S

bullAnti-phospholipid antibodies

Splenectomy

bullHigh platelet counts and

hyperactivity

bullHigh levels of negatively

charged RBCs

Summary

bull Hemoglobinopathies are associated with hypercoagulable state

bull Iron over load and oxidative stress are major factors leading to

- Increased RBCs and plateletrsquos activation and adhesion

- Increased procoagulant effect of RBCs platelets and MPs

bull Splenectomy is a major factor due to

- Thrombocytosis

- Elimination of a scavenger of pathological RBCs and MP

bull Clinical manifestations include VTE AT CVA PAH and potentially others

bull Increased number of SCI in SPX multitransfused TM and in NTDT patients

Low dose Aspirin is indicated to prevent

thromboembolic phenomena in SPX- regularly

transfused TM an in NTDT patients

The direct correlation between the degree of iron

overload and the number of SCI suggests that

effective iron chelation therapy is mandatory

Therapeutic Implications

Effect of LD aspirin on TXB2 excreation

Eldor Blood 1991

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

The hypercoagulable state in thalassemia Blood 2002

Β-Thalassemia and sickle cell anemia as paradigms of Hypercoagulability Br J Hematol 2007

Platelets

bullIncreased platelet aggregation

bullIncreased expression of activation

markers

bullPresence of platelet morphologic

abnormalities

Hypercoagulability

Other factors

bullCardiac dysfunction

bullHepatic dysfunction

bullEndocrine dysfunction

Peripheral

blood elements

bullExpression of endothelial

adhesion molecules and tissue

factor on endothelial cells

bullFormation of microparticles

Nitric oxide

bullHallmark of haemolysis

bulldarr Levels leading to vasoconstrictionRBCs

bull Formation of reactive oxygen

species

bullExpression of negatively

charged phospholipids

bullEnhanced cohesiveness and

aggregability

Thrombophilia

bullNo role for prothrombotic

mutations

bullDecreased levels of antithrombin III

protein C and protein S

bullAnti-phospholipid antibodies

Splenectomy

bullHigh platelet counts and

hyperactivity

bullHigh levels of negatively

charged RBCs

Summary

bull Hemoglobinopathies are associated with hypercoagulable state

bull Iron over load and oxidative stress are major factors leading to

- Increased RBCs and plateletrsquos activation and adhesion

- Increased procoagulant effect of RBCs platelets and MPs

bull Splenectomy is a major factor due to

- Thrombocytosis

- Elimination of a scavenger of pathological RBCs and MP

bull Clinical manifestations include VTE AT CVA PAH and potentially others

bull Increased number of SCI in SPX multitransfused TM and in NTDT patients

Low dose Aspirin is indicated to prevent

thromboembolic phenomena in SPX- regularly

transfused TM an in NTDT patients

The direct correlation between the degree of iron

overload and the number of SCI suggests that

effective iron chelation therapy is mandatory

Therapeutic Implications

Effect of LD aspirin on TXB2 excreation

Eldor Blood 1991

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

Β-Thalassemia and sickle cell anemia as paradigms of Hypercoagulability Br J Hematol 2007

Platelets

bullIncreased platelet aggregation

bullIncreased expression of activation

markers

bullPresence of platelet morphologic

abnormalities

Hypercoagulability

Other factors

bullCardiac dysfunction

bullHepatic dysfunction

bullEndocrine dysfunction

Peripheral

blood elements

bullExpression of endothelial

adhesion molecules and tissue

factor on endothelial cells

bullFormation of microparticles

Nitric oxide

bullHallmark of haemolysis

bulldarr Levels leading to vasoconstrictionRBCs

bull Formation of reactive oxygen

species

bullExpression of negatively

charged phospholipids

bullEnhanced cohesiveness and

aggregability

Thrombophilia

bullNo role for prothrombotic

mutations

bullDecreased levels of antithrombin III

protein C and protein S

bullAnti-phospholipid antibodies

Splenectomy

bullHigh platelet counts and

hyperactivity

bullHigh levels of negatively

charged RBCs

Summary

bull Hemoglobinopathies are associated with hypercoagulable state

bull Iron over load and oxidative stress are major factors leading to

- Increased RBCs and plateletrsquos activation and adhesion

- Increased procoagulant effect of RBCs platelets and MPs

bull Splenectomy is a major factor due to

- Thrombocytosis

- Elimination of a scavenger of pathological RBCs and MP

bull Clinical manifestations include VTE AT CVA PAH and potentially others

bull Increased number of SCI in SPX multitransfused TM and in NTDT patients

Low dose Aspirin is indicated to prevent

thromboembolic phenomena in SPX- regularly

transfused TM an in NTDT patients

The direct correlation between the degree of iron

overload and the number of SCI suggests that

effective iron chelation therapy is mandatory

Therapeutic Implications

Effect of LD aspirin on TXB2 excreation

Eldor Blood 1991

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

Platelets

bullIncreased platelet aggregation

bullIncreased expression of activation

markers

bullPresence of platelet morphologic

abnormalities

Hypercoagulability

Other factors

bullCardiac dysfunction

bullHepatic dysfunction

bullEndocrine dysfunction

Peripheral

blood elements

bullExpression of endothelial

adhesion molecules and tissue

factor on endothelial cells

bullFormation of microparticles

Nitric oxide

bullHallmark of haemolysis

bulldarr Levels leading to vasoconstrictionRBCs

bull Formation of reactive oxygen

species

bullExpression of negatively

charged phospholipids

bullEnhanced cohesiveness and

aggregability

Thrombophilia

bullNo role for prothrombotic

mutations

bullDecreased levels of antithrombin III

protein C and protein S

bullAnti-phospholipid antibodies

Splenectomy

bullHigh platelet counts and

hyperactivity

bullHigh levels of negatively

charged RBCs

Summary

bull Hemoglobinopathies are associated with hypercoagulable state

bull Iron over load and oxidative stress are major factors leading to

- Increased RBCs and plateletrsquos activation and adhesion

- Increased procoagulant effect of RBCs platelets and MPs

bull Splenectomy is a major factor due to

- Thrombocytosis

- Elimination of a scavenger of pathological RBCs and MP

bull Clinical manifestations include VTE AT CVA PAH and potentially others

bull Increased number of SCI in SPX multitransfused TM and in NTDT patients

Low dose Aspirin is indicated to prevent

thromboembolic phenomena in SPX- regularly

transfused TM an in NTDT patients

The direct correlation between the degree of iron

overload and the number of SCI suggests that

effective iron chelation therapy is mandatory

Therapeutic Implications

Effect of LD aspirin on TXB2 excreation

Eldor Blood 1991

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

Summary

bull Hemoglobinopathies are associated with hypercoagulable state

bull Iron over load and oxidative stress are major factors leading to

- Increased RBCs and plateletrsquos activation and adhesion

- Increased procoagulant effect of RBCs platelets and MPs

bull Splenectomy is a major factor due to

- Thrombocytosis

- Elimination of a scavenger of pathological RBCs and MP

bull Clinical manifestations include VTE AT CVA PAH and potentially others

bull Increased number of SCI in SPX multitransfused TM and in NTDT patients

Low dose Aspirin is indicated to prevent

thromboembolic phenomena in SPX- regularly

transfused TM an in NTDT patients

The direct correlation between the degree of iron

overload and the number of SCI suggests that

effective iron chelation therapy is mandatory

Therapeutic Implications

Effect of LD aspirin on TXB2 excreation

Eldor Blood 1991

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

Low dose Aspirin is indicated to prevent

thromboembolic phenomena in SPX- regularly

transfused TM an in NTDT patients

The direct correlation between the degree of iron

overload and the number of SCI suggests that

effective iron chelation therapy is mandatory

Therapeutic Implications

Effect of LD aspirin on TXB2 excreation

Eldor Blood 1991

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

Effect of LD aspirin on TXB2 excreation

Eldor Blood 1991

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

This talk is dedicated to my colleague and dear friend

Amiram Eldor who left us tragically a few years ago and who was

one of the original contributors to this area

Acknowledgements

bull Eitan Fibach1 Ada Goldfarb1 Johnny Amer 1

David Varon1 Neta Goldschmidt 1

bull Ali Taher2 ndash Khaled Mussalem2

bull M Domenica Cappellini3

bull Rachid Merchant4

bull Mehran Karimi5

1 Dept of Hematology Hadassah University Hospital Ein-Kerem Jerusalem Israel2 Internal Medicine American University of Beirut Beirut Lebanon

3 Centro Anemie Congenite Policlinico Hospital IRCCS Milano Italy

4 Nanavati Hospital Mumbai India

5 Shiraz University of Medical Sciences Shiraz Iran

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

Amiramrsquos contribution to the field1

The hypercoagulable state in thalassemia

Eldor A Rachmilewitz EA

Blood 2002 Jan 199(1)36-43 ReviewPMID 11756150 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

2

A chronic hypercoagulable state in patients with beta-thalassaemia major is already present in childhood

Eldor A Durst R Hy-Am E Goldfarb A Gillis S Rachmilewitz EA Abramov A MacLouf J Godefray YC De Raucourt E Guillin MC

Br J Haematol 1999 Dec107(4)739-46PMID 10606878 [PubMed - indexed for MEDLINE]Related citations

3

In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major

Ruf A Pick M Deutsch V Patscheke H Goldfarb A Rachmilewitz EA Guillin MC Eldor A

Br J Haematol 1997 Jul98(1)51-6PMID 9233563 [PubMed - indexed for MEDLINE]Related citations

4

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia

Helley D Eldor A Girot R Ducrocq R Guillin MC Bezeaud A

Thromb Haemost 1996 Sep76(3)322-7PMID 8883264 [PubMed - indexed for MEDLINE]Related citations

5

Enhanced aggregability of red blood cells of beta-thalassemia major patients

Chen S Eldor A Barshtein G Zhang S Goldfarb A Rachmilewitz E Yedgar S

Am J Physiol 1996 Jun270(6 Pt 2)H1951-6PMID 8764243 [PubMed - indexed for MEDLINE]Related citations

6

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes

Borenstain-Ben Yashar V Barenholz Y Hy-Am E Rachmilewitz EA Eldor A

Am J Hematol 1993 Sep44(1)63-5PMID 8342566 [PubMed - indexed for MEDLINE]Related citations

7

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major

Eldor A Maclouf J Lellouche F Ben-Yashar V Barenholz Y Durst R Hy-Am E Goldfarb A Rachmilewitz E

Southeast Asian J Trop Med Public Health 199324 Suppl 192-5 ReviewPMID 7886616 [PubMed - indexed for MEDLINE]Related citations

8

In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites

Eldor A Lellouche F Goldfarb A Rachmilewitz EA Maclouf J

Blood 1991 Apr 1577(8)1749-53PMID 2015401 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

9

Platelet survival in patients with beta-thalassemia

Eldor A Krausz Y Atlan H Snyder D Goldfarb A Hy-Am E Rachmilewitz EA Kotze HF Heyns AD

Am J Hematol 1989 Oct32(2)94-9PMID 2757016 [PubMed - indexed for MEDLINE]Related citations

10

Aberrant congenital dyserythropoietic anemia with negative acidified serum tests and features of thalassemia in a Kurdish family

Eldor A Matzner Y Kahane I Levene C Polliack A

Isr J Med Sci 1978 Nov14(11)1138-43PMID 750540 [PubMed - indexed for MEDLINE]Related citations

11

Hemorrhagic tendency in beta-thalassemia major

Eldor A

Isr J Med Sci 1978 Nov14(11)1132-4PMID 750538 [PubMed - indexed for MEDLINE]Related citations

12

Abnormal platelet functions in beta thalassaemia

Eldor A

Scand J Haematol 1978 May20(5)447-52PMID 663557 [PubMed - indexed for MEDLINE]Related citations

Prof Amiram Eldor

1942-2001

D Noubouossie et al Blood Reviews 2016