TTP, aHUS and TMA: Spectrum of One Disease or Different ... · Spectrum of One Disease or Different...

TTP, aHUS and TMA:

Spectrum of One Disease or Different Diseases?

Han-Mou Tsai, M.D.

Hematology, E-Da Hospital

Schistocytes in Microangiopathic Hemolytic Anemia (MAHA)

Thrombotic Thrombocytopenic Purpura: A Brief History of Therapeutic Advances

• Moschcowitz, 1924

– MAHA, thrombocytopenia, neurological deficits and other symptoms

– Widespread arteriolar and capillary thrombi at autopsy

• Byrne et al and Bukowski, 1976

– Plasma transfusion and plasma exchange resulted in high rates of remission and survival

• Rock GA et al, 1991

– Plasma exchange: 80% survival rate at 6 months

– Plasma infusion: 60% survival rate at 6 months

Challenges in TTP

• What causes the disease?

• Why is plasma exchange effective?

• How to improve the outcome?

• How to simply the treatment?

Deficiency of ADAMTS13 in TTP

TTP Treat Rem

Patient plasma

VW

F c

lea

vin

g a

cti

vit

y (

% o

f c

on

tro

l)

Tsai HM & Lien E C-Y, N Engl J Med 1998;339:1585

Random Misc HIT

Control plasma

VW

F c

lea

vin

g a

cti

vit

y (

% o

f c

on

tro

l)

Misc TTP Rem

Patient + normal plasma

VW

F c

lea

vin

g a

cti

vit

y (

% o

f c

on

tro

l)

= 5 cases

= 1 case

Families with Hereditary Deficiency of VWF Cleaving Protease

1 2 0.67 0.57

1 2 3 4 5 6 7

0.06 0.02 0.63 0.60 0.97 0.45 0.64

II

I 1 2

1 2

I

II

B

1 2

1 2 3 4 0.07 0.55 0.55 0.62

0.58 0.59

I

II

C D

1.02 0.61 0.80 1.04 0.63 0.90 0.92 1.09 0.97 1.04 0.53 0.65

0.64 0.05 0.05 0.57 1.01 0.63 0.65 0.06 0.98

0.68

1 1.16

2 1 3 4 6 7 8 9 10 11 13

1 2 3 4 5 6

III

II 5 12

A

0.53 0.51

0.06 0.48

7

I

8 9

Levy G et al, Nature 2001;413:488

Patients of Hereditary TTP and Their Family Members

0.0 0.5 1.0 1.5

Protease level (U/mL)

Normal individuals

Patients and family members

Patient

Obligate carrier

At risk

Not at risk

0.0 0.5 1.0 1.5

Protease level (U/mL)

Levy G et al, Nature 2001;413:488

Signal

PrP MP Disintegrin

TSR

Cys

TSR CUB

Spacer

HEIGHSFGLEHD

1 1427

RGDS

Non-sense

Mis-sense

Deletion/

insertion

Splice

ADAMTS13: Structure And Mutations

Q44X

H96D

R102C

V108M

R193W

T196I L232Q

D235H

718-724del

A250V

S263C

R268P

C311Y P353L

W390X

R398H

Q449X

P457L

C508Y

R528G

1873-4del

I673F

R692C

A732V

2279del

2376-2401del

2549-2550del

C908Y

R910X

C951G

C1024G

R1034X

R1123C R1123H

C1213Y

W1245X

3769-3770insT

R1336W

4143-4144insA

331+1 414+1

686+1

687-2 1244+2

1584+5

R910X

W390C

I79M

S203P

R507Q

A596V C758R

C908S

R1096X

R1060W

2930-5del 3252-3del

29bp-del

Intron12

Levy G et al, Nature 2001 + others

Shear Stress Increases the Adhesive Activity of VWF In TTP Plasma

50

150

200

vW

F R

Cof (%

)

100

0 2500 5000 7500

Shear rate (sec-1)

vWF/TTP

vWF/NP

Tsai HM & Lien EC-Y, N Engl J Med 1998;339:1585

ADAMTS13

Normal circulation

Shear ADAMTS13

vWF ADAMTS13

Platelet Shear Shear

EC

Subendothelial matrix


EC

Platelet

Unfolded vWF

ADAMTS13 deficiency

vWF

Shear stress

Platelet



EC

EC


Unfolded vWF

At sites of microvascular injury

Shear rate Flow velocity 0

Vessel injury

EC



EC

Platelet

VWF

ADAMTS13

Mechanism of Microvascular Thrombosis in ADAMTS13 Deficiency

Tsai HM, Am J Med 2013;126:200-209

vWF

ADAMTS13

Platelet

TTP: Arteriolar and Capillary Thrombosis

Heart Kidney

Tsai HM, Am J Med 2013;126:200-209

Brain Brain

P&F

Impact of ADAMTS13 Discovery

• A molecular basis for the diagnosis of TTP – Distinction from other disorders of MAHA

– Subclinical and incomplete forms of TTP

• An immunological basis for

– Tracking the development of relapse

• A biological basis for plasma therapy – Replenishment of ADAMTS13

– Removal of ADAMTS13 inhibitors (by plasma exchange)

• New directions of therapeutic development

– Immunosuppressive therapy

• Rituximab

• Cyclosporin A

• Proteosome inhibitors (e.g. bortezomab)

• Anti-BAFF (e.g. belimumab)

– Recombinant ADAMTS13

• Non-suppressible variants of ADAMTS13

– Blockers of VWF-platelet binding

• Anti-VWF aptamer (e.g. ARC1799)

• Anti-VWF antibodies (e.g. nanobody ALX-8100

Variable Course of ADAMTS13 Autoimmunity in TTP

1

2

3

ADAMTS13

ADAMTS13 <10%

Symptomatic

Time

AD

AM

TS

13

in

hib

ito

r le

ve

l

Persistent disease

Time

AD

AM

TS

13

in

hib

ito

r le

ve

l

Brief duration

Time

AD

AM

TS

13

in

hib

ito

r le

ve

l

Relapse

Time

AD

AM

TS

13

in

hib

ito

r le

ve

l

A Case of Recurrent and Protracted TTP

Yomtovian R et al, Brit J Haematol 2004;124:787

Rituximab Suppresses ADAMTS13 Inhibitors

Rituximab


Sustained Remission of TTP Following Rituximab

Rituximab


Early Death of TTP

PEx

EF = 30% Death

Personal unpublished data

Early Relapse and Death

PEx PEx

Personal unpublished data

Inhibitor titer

Death due to Surging ADAMTS13 Inhibitors

Tsai HM, Sem Thromb Hemost 38:469, 2012

Death

Rituximab

Preemptive Rituximab for TTP

Rituximab ≤3 days

from admission, n = 52

Rituximab >3 days

from admission, n = 30 P

Death 2 2 P >0.05

Median No. of PEX to remission

(range) 16 (4–36) 24 (6–40) P = 0.03

Median time to remission from first

infusion, days (range) 10 (2–50) 9 (0–30) P = 0.67

Westwood J-P et al, J Thromb Haemost 2013;11:481

Rituximab ≤3 days


Rituximab >3 days


Death 2 2 P >0.05

Median No. of PEX to remission

(range) 16 (4–36) 24 (6–40) P = 0.03

Rituximab ≤3 days


Rituximab >3 days


Death 2 2 P >0.05

Consecutive Non-Referral TTP Cases at Montefiore, 1997-2006

HIV- group HIV+ group

Number of cases 26 13

No. of plasma exchange, median (range) 13 (3 – 42) 16 (7 – 39)

Follow-up duration, months, mean (SD) 53 (37) 39 (37)

Number of death (%)

During initial episode (TTP + not TTP)

After remission (TTP + not TTP)

2 (7.7%) (2+0)

2 (8.3%) (1+1)

2 (15.4%) (0+2)

1 (9.1%) (0+2)

Rituximab Decreases the Risk of TTP Relapse

Westwood J-P et al, J Thromb Haemost 2013;11: 481

Relapse-free survival (months)

Pro

po

rtio

n in

re

mis

sio

n

Early rituximab

Late rituximab

Long-Term Outcome of TTP

0 20 40 60 80 100 1200

20

40

60

80

100

HIV-

HIV+

Months

Overa

ll s

urv

ival

%

Overall survival

0 20 40 60 80 100 1200

20

40

60

80

100

HIV-

HIV+

MonthsR

ela

pse-f

ree s

urv

ival

%

Relapse free survival

Tsai HM, Hem Onc Clin NA 2013;27:565

ADAMTS13-Guided Rituximab for Prevention of TTP Relapse


No

rma

l ran

ge

Years from rituximab #1

Factors Affecting the Morbidity and Mortality of TTP

Process Consequence Measures

• Vital functions are affected • Death

• Blockers of VWF-platelet binding − Anti-VWF aptamers (e.g. ARC1799)

− Nano anti-VWF A1 (e.g. ALX8100)

• Non-suppressible rADAMTS13 variants

• High and/or persistent ADAMTS13

inhibitor levels

• Protracted course

• Death

• Preemptive rituximab?

• Blockers of VWF-platelet binding


• Iatrogenic complications (e.g. line

sepsis)

• Increased morbidity

• Death • Specialized catheter team

• Fluctuation of autoimmune B-cell

clones • Relapse • ADAMTS13-guided rituximab

• Unrelated causes

− e.g. HCV liver cirrhosis, HIV

disease, recurrent breast cancer

• Determined by the

concurrent disease • Management of concurrent diseases







inhibitor levels


• Death





sepsis)



• Fluctuation of autoimmune B-cell

clones • Relapse • ADAMTS13-guided rituximab







inhibitor levels


• Death





sepsis)








• Persistent ADAMTS13 inhibitor

levels • Protracted course

• Rituximab








Atypical Presentation of TTP

Time

Mic

rova

scu

lar

thro

mb

osi

s Typical course

Thrombocytopenia

MAHA, Neuro. deficits

Coma

Seizures

Death

ADAMTS13 deficiency

Subclinical thrombosis

TIA/stroke

Normal blood counts

Forme fruste

From Tsai HM, in Enclopedia of Human Biology (in press)

How Should TTP Be Defined?

• Clinical definition:

• Pentad: MAHA, platelet, hematuria, neurological deficits, and fever

• Triad: MAHA, platelet, and neurological deficits

• Diad: MAHA and platelet

– Not specific: These complications may result from other disorders

with different etiology or pathogenesis

– Not inclusive: Some patients of TTP do not present with MAHA

and/or thrombocytopenia

• Pathological definition: microvascular thrombosis

– Microvascular thrombosis may result from different causes

– Thrombosis may be few and not detectable, especially in milder

cases

• Molecular definition

A Molecular Definition of TTP

• ADAMTS13 deficiency, with a propensity to develop microvascular thrombosis

• Autoimmune inhibitors

• Genetic mutations

• Clinical presentation

‒ Active thrombosis: ADAMTS13 <10%

• Conventional TTP

− Thrombocytopenia, MAHA, neurologic complications, and other organ dysfunction

• Chronic thrombosis

− MAHA with mild thrombocytopenia or even thrombocytosis

• Incomplete phenotype

− Thrombocytopenia only (often mistaken to be ITP)

− Neuro. defects without thrombocytopenia or MAHA (often mistaken to be CVA)

− Neuro. defects with thrombocytopenia but no MAHA (often mistaken to be CVA)

‒ No active thrombosis (remission): ADAMTS13 is normal, decreased or <10%

• Patients still have the disease during clinical remission and are prone to develop

thrombosis

TTP without ADAMTS13 Deficiency: Difference in Definition

Authors, year No. Severe def. Excl. renal failure Excl. co-morbidity

Tsai et al, 1998 39 100% Yes (Crmax > 2.5) Yes (overall)

Furlan et al, 1998 24 83% Yes (HUS by referral) No

Veyradier et al, 2001 111 89% Yes (HUS by referral) Yes (by referral)

Bohm et al, 2002 22 91% Not indicated No

Rick et al, 2002 50 78% Not indicated No

Zhou et al, 2004 34 100% Yes (Crmax > 2.5) Yes (overall)

Hovinga et al, 2004 396 57% Yes (HUS by referral) Yes (by referral)

Matsumoto et al, 2004 108 52% Yes (HUS by referral) Yes (by referral)

Coppo et al, 2004 46 67% No Yes (by referral)

Peyvandi et al, 2004 100 48% No No

Terrel et al, 2005 70 31% No Yes (by referral)

Kokame et al, 2005 41 80% Not indicated Not indicated

Authors, year No. Severe def. Excl. renal failure

Tsai et al, 1998 39 100% Yes (Crmax >2.5)

Furlan et al, 1998 24 83% Yes (HUS by referral)

Veyradier et al, 2001 111 89% Yes (HUS by referral)

Bohm et al, 2002 22 91% Not indicated

Rick et al, 2002 50 78% Not indicated

Zhou et al, 2004 34 100% Yes (Crmax >2.5)

Hovinga et al, 2004 396 57% Yes (HUS by referral)

Matsumoto et al, 2004 108 52% Yes (HUS by referral)

Coppo et al, 2004 46 67% No

Peyvandi et al, 2004 100 48% No

Terrel et al, 2005 70 31% No

Kokame et al, 2005 41 80% Not indicated

Authors, year No. Severe def.

Tsai et al, 1998 39 100%

Furlan et al, 1998 24 83%

Veyradier et al, 2001 111 89%

Bohm et al, 2002 22 91%

Rick et al, 2002 50 78%

Zhou et al, 2004 34 100%

Hovinga et al, 2004 396 57%

Matsumoto et al, 2004 108 52%

Coppo et al, 2004 46 67%

Peyvandi et al, 2004 100 48%

Terrel et al, 2005 70 31%

Kokame et al, 2005 41 80%

MAHA: Mechanical Injury of Red Blood Cells

RBC fragmentation

Arteriolar

Stenosis

Abnormal

shear stress

Organ

Ischemia/

dysfunction

Vascular devices

−LVAD

−ECMO

−Prosthetic valves

Thrombocytopenia

Thrombotic

Based on Tsai HM, Am J Med 2013;126:200-209

Pathological Basis of MAHA and Thrombocytopenia

Microvascular

Stenosis/thrombosis

DIC, HELLP CAPS, HIT, PNH

Neoplastic metastasis

Autoimmune dis. Infection

Stx-HUS Pneumo-HUS

aHUS, etc.

Adapted from Tsai HM, in Wintrobe’s Clinical Hematology 13/e (in press)

Tumor cells Fibrin clots

TTP

VWF-platelet

thrombosis

Vasculitis

Thrombocytopenia

Red cell fragmentation

shear stress

Thrombotic

Organ dysfunction

Ischemia

Thrombotic

microangiopathy

ADAMTS13 Activity Segregates TTP from aHUS

Crmax >2.5 mg/dL (Excluding 26 cases of hTTP)

Number and % with TTP

Tsai HM, Hem Onc Clin NA 2013;27:565-584

Atypical HUS (vs. typical, E.coli-HUS)

• Sporadic

• No prodrome of hemorrhagic diarrhea

Regulation of Complement Activation

C4, C2 C4b2a (C3 convertase)

C3

Immune complex + C1qC1r2C1s2 or Microbial mannose + MBL/MASP-1, 2, & 3

C5b C5

C5b-9 (MAC)

C6, C7, C8, C9 C5a

C3a C4b2a3b

(C5 convertase)

Alternative pathway CFP

CFB C3bBb, Ba

(C3 convertase) C3b C3bB CFD

C3bBbC3b (C5 convertase)

C3b

C4a, C2a

MCP

THBD

iC3b

CFI CFH

iC5a

iC3a

CPB2a CPB2 Thrombin/

THBD

Cla

ssic

/le

ctin

pat

hw

ay


CD55

CD59

Genetics of aHUS

Based on

Noris et al, CJASN 2010; 5:1844

Fremeaux-Bacchi et al, CJASN 2013;8:554

Vertical bar = 95% CI

American, N=144

French, N=200

Maga CH et al, Hum Mutat 2010;31:E1445

Italian, N=260

Defective regulation of the alternative complement pathway

Uncontrolled complement activation

Organ dysfunction Ischemia Thrombosis

Thrombocytopenia RBC fragmentation

Shear Stress Stenosis

Stenosis Ischemia

Endothelial injury

C5b-9 (MAC)

C3a, C5a

Vascular permeability

Histamine

release

Tissue edema

Effusions

Pathophysiology of aHUS

Endothelial swelling

Subendothelial expansion


TTP and aHUS: Different Pathology

aHUS

TTP

Based on Tsai HM, Am J Med 2013;126:200-209

Kidney Kidney Kidney Kidney

Silver stain

Heart Kidney Brain Brain

aHUS: Common Findings at Autopsy

Interstitial edema

Brain

Lung

Heart

Pancreas

Gastrointestinal tract

Mesentery

Skin

Thrombotic

microangiopathy

Kidney

Uncommon in other organs

Cavitary fluids

Pleural effusion

Pericardial effusion

Ascites

Posterior Reversible Encephalopathy Syndrome (PRES)

T2-weighted FLAIR

Purtscher's-like Retinopathy

Clinical Features of aHUS

• Age: Children Adults

• Gender: Female Male

• A systemic disease affecting multiple organs

– Kidney: acute and chronic renal failure

– Hypertension

– CNS: headache, mental change, seizure, retinopathy, focal deficit

– Digestive: abdominal pain, N/V, diarrhea, pancreatitis, DM

– Lung: chest pain, dyspnea, airway wall thickening, pleural effusions,

pulmonary infiltrates, ARDS

– C-V: chest pain, myocardial injury, arrhythmia, CHF, pericardial effusion

– Liver: abnormal liver functions

• Laboratory correlation

– Organ dysfunction does not always correlate with thrombocytopenia

and/or MAHA

Laboratory Diagnosis of aHUS

• Conventional complement tests: C3, C4, CH50, AH50

– Abnormal in 30%

– Not specific for aHUS

• Plasma CFH and CFI protein concentrations

− Decreased in 30% of patients with CFH or CFI mutations

• Mutation analysis (CFH, MCP, CFI, CFB, C3, THBD)

– Abnormal in 40% (sporadic) - 70% (familial)

• CFH antibody

– 5% - 10%

• Skin biopsy?

− Immunodetection of complement activation products

• Measurement of sMAC?

− Technically unreliable

aHUS: Molecular Defects is A Major Determinant of Prognosis

Event: relapse, death or ESRD

Eve

nt

free

su

rviv

al,

%

Time, months

CFH antibodies

MCP

C3

THBD

CFH

No mutations

CFI

Noris M et al, CJASN 2010;5:1844

0 10 20 30 40 50 60 70 80 900

100

200

300

400

PEx

Abd. pain vision

Days after admission

Pla

tele

ts/L

(10

-9)

aHUS: Unpredictable Responses to Plasma Exchange

Death

0 10 20 30 40 50 60 70 80 900

2

4

6

8

10 HD


Cre

ati

nin

e,

mg

/dL

0 10 20 30 40 50 60 70 80 900

2

4

6

8


LD

H (

x10

3),

U/m

LUnconscious

Lessons

• The response to plasma therapy is unpredictable in aHUS

− Response, followed by lack of response

− Response and resolution

− Response, requiring maintenance

− No or partial response

• Improvement in CBC is not always indicative of disease

resolution in aHUS

Eculizumab Replaces Plasma Exchange for Active aHUS

Legendre CM et al, NEJM 2013;368:2169

Active disease, N = 17

Eculizumab Replaces Maintenance Plasma Therapy for aHUS

Legendre CM et al, NEJM 2013;368:2169

Plasma maintenance , N = 20

MAHA with Comorbidity

Crmax >2.5 mg/dL (Excluding 26 cases of hTTP)


• HIV infection

• HSCT

• Neoplastic dis.

• Lupus, etc.

Number and % with TTP

Roles of Co-Morbidity in MAHA and Thrombocytopenia

Mechanism Examples

I: Idiopathic

• VWF-platelet aggregation

• Endothelial injury by complement activation

• Endothelial injury by DAGKE mutations

• TTP: ADAMTS13 deficiency: Inhibitors or genetic mutations

• aHUS: Defective complement regulation, genetic or auto-Ab

• DAGKE deficiency (aHUS?)

II: Triggers in patients with pre-existing TTP or aHUS

• TTP:

− ↑VWF secretion, shear stress, ADAMTS13 inhibitors

− ↓ADAMTS13 activity

• Complement activation in aHUS

• Infection, surgery, trauma, pregnancy, IV contrast, hemodialysis

III: Inducers of TTP or aHUS

• ADAMTS13 inhibitors

• Auto-Ab (e.g. CFH antibodies)

• Ticlopidine-TTP; HSCT-TTP, HIV? CTD?

• HSCT-HUS, HIV-HUS? CTD-HUS?

IV: TMA (endothelial injury) via other mechanisms

• Direct toxin cytotoxicity

• Natural Ab binding to T-Ag

• Deprivation of angiogenesis signals

• Malignant hypertension

• Others

• Shiga toxins of E. coli O157:H7 in typical HUS

• Microbial neuraminidase of S. pneumoniae sepsis

• Excessive sVEGFR2/sFlt1 of preeclampsia, anti-VEGF (bevacizumab)

• (A consequence of aHUS)

• (Various drugs?)

V: Other types of pathology

• Fibrin thrombosis

• Vasculitis

• Intravascular tumor cells

• Vascular devices

• DIC, CAPS, HIT, HELLP syndrome of pregnacy, PNH

• Lupus vasculitis, scleroderma crisis, Rocky Mountain spotted fever, anthrax

• Metastatic diseases

• VAD, ECMO, prosthetic heart valves

Mechanism Examples

I: Idiopathic








• TTP:








• Ticlopidine-TTP; HSCT-TTP, HIV? CTD?

• HSCT-HUS, HIV-HUS? CTD-HUS?

IV: TMA (endothelial injury) via other mechanisms

• Direct toxin cytotoxicity

• Natural Ab binding to T-Ag

• Deprivation of angiogenesis signals

• Endothelial injury?

• Others

• Shiga toxins of E. coli O157:H7 in typical HUS

• Microbial neuraminidase of S. pneumoniae sepsis

• Excessive sVEGFR2/sFlt1 of preeclampsia, anti-VEGF (bevacizumab)

• CNI inhibitors, malignant hypertension (may be a consequence of aHUS)

• Gemcitabine, cocaine, etc.

Mechanism Examples

I: Idiopathic








• TTP:








• Ticlopidine-TTP; HSCT-TTP; HIV? CTD?

• HSCT-HUS; HIV-HUS? CTD-HUS?

Mechanism Examples

I: Idiopathic








• TTP:





Mechanism Examples

I: Idiopathic


• Endothelial injury by unregulated complement activation

• EC injury by excessive AA-diacyglycerol



• TMA due to DAGKE mutations (aHUS?)

Atypical HUS after Autologous HSCT

54 year-old female

• Three months after auto-HSCT for myeloma

• Day -9:

– Abdominal pain, vomiting, diarrhea – Mild thromobocytopenia, anemia & azotemia

– Stool: C. difficile + – Tx: metronidazole

• Day -7:

– Seizures, anuric

– Platelet 25x109/L, MAHA

– Thalidomide, acyclovir were discontinued

– PEx for ‘TTP’; HD for ARF

• Day -1: DMS, vomiting, intubated

• Labs at transfer: – Hb 85 g/L, platelet 99x109/L, , LDH 1,271 U/L

– Cr 4.0 mg/dL

– Smear: schistocytes

– ANA, shiga toxin assay, viral cultures: negative

– (ADAMTS13: 60%)

0 20 40 60 80 100

50

100

150

200PEx

Eculizumab

Discharge

Days from admission

Pla

tele

ts/L

(x10

-9)

Slow Recovery of Renal Function during Eculizumab Therapy

0 200 400 600 8000

2

4

6

8

0

20

40

60

80Hemodialysis

Cr

CCr

Eculizumab

Days from admission

Cr,

mg

/dL

CC

r , mL

/min

/1.7

3 m

2

0 200 400 600 8000

50

100

150

200

250

0

100

200

300

400EculizumabPEx

RituximabPlatelet count

CFH Ab

Days from admission

Pla

tele

ts/L

(10

-9) C

FH

Ab

(U/m

L)


Lessons

• Atypical HUS with anti-CFH may occur after HSCT

‒ Deranged regulation of autoimmunity during post-myeloablation

recovery of the immune system

• Anti-complement therapy may be effective for aHUS after

HSCT

• The recovery of renal function may occur over many months.

• Do not give up hope prematurely and rush the patient to renal

transplantation.

Difference between TTP and aHUS

Disease TTP aHUS

Molecular pathogenesis

• ADAMTS13-inhibitory autoantibodies • Genetic mutations, <5%

• Defective complement regulation Genetic defects Auto-Ab of CFH, 5%-10%

Pathology • Arteriolar and capillary thrombosis comprising VWF and platelets

•Thrombotic microangiopathy Endothelial injury, sub-endothelial widening Thrombosis Abnormal vascular permeability

Mechanisms of organ dysfunction

• Thrombotic ischemia •Thrombotic ischemia • Non-thrombotic ischemia • Interstitial edema

Clinical • Thrombocytopenia precedes MAHA and organ dysfunction • CNS: focal deficits, mental changes, seizures, coma • Cardiac: arrhythmia, heart failure

• Organ dysfunction does not always correlate with thrombocytopenia or MAHA • Renal failure • Hypertension • Tissue edema, fluid accumulation

Diagnosis • ADAMTS13 activity assays • Exclusion of TTP • Exclusion of other TMA or pathology • Clinical features • Laboratory dx: problematic

Treatment • Plasma exchange or infusion • Rituximab immunosuppression • Future: rADAMTS13 proteins Blockers of VWF-platelet binding

• Anti-complement therapy with eculizumab (anti-C5) •Plasma exchange or infusion only when eculizumab is not available • Soluble r-thrombomodulin?

Disease TTP aHUS










Diagnosis • ADAMTS13 activity assays • Exclusion of TTP by ADAMTS13 assays • Exclusion of other TMA or pathology • Clinical features • Laboratory dx: helpful but problematic

Disease TTP aHUS










Disease TTP aHUS








Disease TTP aHUS





•Thrombotic microangiopathy (TMA) Endothelial injury, sub-endothelial widening Thrombosis Abnormal vascular permeability

Disease TTP aHUS




Summary

• Microangiopathic hemolysis is a consequence of red cell injury by

mechanical force.

• In patients without vascular devices, MAHA signifies one of the

following pathological conditions

– Arteriolar VWF-platelet thrombosis of TTP

– Fibrin thrombosis of DIC, HELLP syndrome, or less commonly heparin

induced thrombocytopenia, catastrophic antiphospholipid syndrome, or

paroxysmal nocturnal hemoglobinuria

– Intravascular cancer cells

– Vasculitis, or

– Thrombotic microangiopathy of shiga toxin-HUS, HUS in association with

pneumococcal sepsis, defective complement regulation of the alternative

complement system, (aHUS) or mutations of diacylglycerol kinase epsilon

(DAGKE)

Common Misuse of Diagnostic Terms

• MAHA and thrombocytopenia TTP

• MAHA and thrombocytopenia TMA

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TTP, aHUS and TMA: Spectrum of One Disease or Different ... · Spectrum of One Disease or Different...

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Transcript of TTP, aHUS and TMA: Spectrum of One Disease or Different ... · Spectrum of One Disease or Different...