von Willebrand’s Disease
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von Willebrand’s DiseaseThe Diagnosis of von Willebrand’s
Disease Among Iranian Women with Gynaecological Bleeding
Baghaipour Mohammad Reza, MD,Pediatrician, Hemophilia Fellow
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history
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Dr Erik von Willebrand
1870-1949
history
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history
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history
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history
Bleeding from mucosal tissuesSignificant bleeding in womenProlonged BTNo X linked inheritance
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1926
1928
1951
1964
1971
1973
1977
First description by Erik von Willebrand
5 patients described in Boston by Minot
Cross transfusion by HA plasma in vWD
Pool’s cryoprecipitate in vWD
Immunologic difference of HA and vWD
Synthesis of vWF by cultured EC
First report on the use of DDAVP in vWD
history
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1981
1982
1984
1985
1992
1994
2002
2007
Introduction of Haemate P in the market
Epidemiology of vWD in general population
1st classification based on multimer
Discovery of vWF gene by four laboratories
First PK trials with FVIII/vWF concentrates
2nd Classification based on pathogenesis
National guidelines for vWD management
Molecular & clinical markers of vWD type 1
history
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Genetics
vWF gene is located near the tip of the short arm of chromosome 12, at 12p13.3 approximately 178 kb of DNA and contains 52 exons.
Mutations causing vWD have been identified throughout the vWF gene ( >500 mutations)
good correlation between the location of mutations in the vWF gene and the subtype of vWD
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The von Willebrand factor (vWF) protein sequence (amino acid 1–2813) is aligned with the cDNA sequence (nucleic acid 1–8439). The vWF signal peptide is the first 22 aa, the propeptide (vWFpp) aa 23–763, and mature vWF aa 764–2800. Type 2 mutations are primarily located in specific domains (regions) along the vWF protein. Types 2A, 2B, and 2M vWF mutations are primarily located within exon 28 that encodes for the A1 and A2 domains of vWF. The two different types of 2A are those that have increased proteolysis (2A2) and those with abnormal multimer synthesis (2A1). Type 2N mutations are located within the D’ and D3 domains. Ligands that bind to certain vWF domains are identified, including FVIII, heparin, GPIb (platelet glycoprotein Ib complex), collagen, and GPIIb/IIIa (platelet glycoprotein IIb/IIIa complex that binds to the RGD [arginine-glycine-aspartate] amino acid sequence in vWF).
Genetics
Adams13↑
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Genetics
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Type Inheritance
1 Autosomal Dominant 2A Autosomal Dominant (recessive) 2B Autosomal Dominant 2M Autosomal Dominant (recessive) 2N Autosomal Recessive 3 Autosomal Recessive
Genetics
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vWF Molecule
Vascular endothelium Stored in secretory granules
(Weibel-Palade bodies)Released by stress or DDAVP
Bone marrow megakaryocyteStored in alpha-granulesReleased by platelet
activation.DDAVP does not release
platelet vWF
Endoplasmic ReticulumDimerization
Golgi ApparatusMultimerization
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vWF Molecule
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Plasma vWF has a half-life of approximately 12 hours (range 9–15 hours).
vWF is present as very large multimers that are subjected to physiologic degradation by ADAMTS13
ADAMTS13 TTP
ADAMTS13 Type 2A
vWF Molecule
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vWF blood level
Blood type O (25%)HypothyroidismValproate
Old ageAfrican-American blackExercises, Surgery, TraumaPregnancyHyperthyroidismRenal failureDiabetesLiver diseaseAtherosclerosisInflammatory state and cancer
vWF Molecule
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Function
Hemostasis (1) Vascular factors(2) Platelet factors(3) Plasma factors
vWF Molecule
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Function
Hemostasis (1) Vasoconstriction (2) Platelet plug formation (3) Coagulation
vWF Molecule
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vWF Molecule
Function
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A3 Collagen
A1 Gp I b
C1 Gp II b III a
A2 ADAMS 13
Fibrinogen Gp II b
vWF Molecule
Function
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Function
• Platelet to exposed sub-endothelium
(collagen & GPIb )• Platelet to platelet
( GP IIb/IIIa )• Carry FVIII ( protect
from proteolysis)
vWF Molecule
Exposed sub- endothelium
CollagenvWF
GPIb
GPIIb/IIIa
Platelet
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1984 ( Multimer Based )
Term Definition
Type I All sizes multimer, decreased Quan.
Type II Absent of large multimer in plasma
Type II A Absent of large multimers from Plt and plasma, no DDAVP response
Type II B Largest multimers present in Plt, Appear in plasma after DDAVP
Type III No multimers
Platelet Type - vWD Largest multimers absent from plasma
Classification
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1994 , 2006 ( Pathogenesis Based )
Term Definition
Type 1 ( platelet nor/ low, IA,I-1,I-3) Partial quantitative deficiency of vWF
Type 2 Qualitative vWF defect
Type 2A ( IIA, IB, I platelet discor, IIC,IID, IIE, IIF, IIG, IIH, II-1, IIA-1, IIA-2, IIA-3 )
Decreased vWF-dependent platelet adhesion with selective deficiency of high-molecular-weight Multimers
Type 2B ( IIB, I New york, Malmo ) Increased affinity for platelet GPIb
Type 2M ( IC, ID, B, Vicenza ) Decreased vWF-dependent platelet adhesion without selective deficiency of high-molecular-weight multimers
Type 2N ( Normandy ) Markedly decreased binding affinity for FVIII
Type 3 Virtually complete deficiency of vWF
Pseudo- vWD ( not vWF defect ) Increased affinity of platelet GPIb for vWF
Classification
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Type 1Level of vWF in plasma is low.
vWF mediates platelet adhesion and binding FVIII normally.
FVIII is normal or mildly decreased.
vWF multimer gels are normal.
Classification
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Type 2 APlatelet adhesion is decreased because the proportion of
large vWF multimers is decreased.
Levels of vWF:Ag and FVIII may be normal or modestly decreased.
vWF:Rco is markedly decreased.
Classification
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Type 2 B
Mutations increase platelet–vWF binding and leads to the proteolytic degradation and depletion of large vWF multimers.
Patients have thrombocytopenia that is exacerbated by surgery, pregnancy, or other stress.
RIPA is increased at low concentrations of ristocetin.
Classification
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Type 2 M
Reduced interaction of vWF with platelet GPIb or with connective tissue.
Screening laboratory results are similar with type 2A vWD and the distinction between them depends on multimer gel electrophoresis.
Classification
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Type 2 NImpaired binding to FVIII, lowering FVIII levels.
Type 2 N masquerade as an autosomal recessive H.A.
The FVIII level is low but vWF:Ag and vWF:Rco are normal.
Discrimination from hemophilia A needs FVIII–vWF binding assay.
Classification
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Type 3
Type 3 vWD is characterized by undetectable vWF protein and activity, and FVIII levels usually are very low.
Classification
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vWD , the most frequent inherited bleeding disorder.
1% of General population
Clinically significant patients = 100-200 / milion
Mild form thought to be healthy
Epidemiology
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Epidemiology
vWD sub/type prevalence:
Type 1 , 55- 75 %
Type 2 , 10- 30 %
Type 3 , 5 – 20 % ( 0.5 – 6 / million )
2A 2B
2M
2N
France 30 28
8 34
Italy 17 14 66 3
Germany
74 10
13
3
Average 30 30
30
10
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Epidemiology
Non X-linked Disorder ( F ═ M )
Type 1, 60% F
Type 2, 55% F
Type 3, 50% F
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Diagnosis
Family History
Patient medical history
Physical exam
Laboratory findings
Genetics
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Diagnosis
Family History
Although a positive family history of documented vWF is useful for diagnosis of vWD, such a history is frequently not present.
But a family history of bleeding symptoms is not helpful.
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Diagnosis
Physical examEcchymoses,Haematomas,Petechiae Evidence of liver disease (e.g. jaundice),SplenomegalyArthropathyJoint and skin laxity (e.g. Ehlers-Danlos syndrome),Telangiectasia (e.g. hereditary haemorrhagic telangiectasia),Signs of anemia Gynaecological examination.
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Common BleedingsNose 60% ( common in kids )Gyn/Obs 60% ( 15% have vWD ) Teeth 50%Ecchymosis 50%Post surgical 25%GI Tract 15%Musculoskeletal 10% ( type 3 )
Diagnosis
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Mild bleeding symptoms are very common in healthy populations.
Menorrhagia has good sensitivity but low specificity.
Three findings that predict abnormal menstrual blood loss of >80 mL include:Clots greater than approximately 1 inch in diameterLow serum ferritinChanging a pad or tampon more than hourly.
Diagnosis
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Bleeding Score
The bleeding symptoms are very Important.
The bleeding score (BS) is a quantitative index summarizing both the number of episodes and their severity.
The BS has shown good sensitivity and specificity for the diagnosis of type 1 VWD.
Diagnosis
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Bleeding ScoreDiagnosis
Rodeghiero et al,2005
A score of >3 in a male or >5 in a female is 99% specific and 64% sensitive in identifying obligate carriers of VWD.
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Diagnosis
Tosetto A,et al,2006Bleeding Score
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DiagnosisBleeding Score
Tosetto A,et al,2006
Positive BS (4 or more) has a sensitivity of 100% and a specificity of 87%.
The positive predictive value is 0.20 and the negative predictive value is 1.
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Diagnosis
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DDAVP : release endogenous VWF stores through stimulation of endothelial cells
Plasma-derived, viral-inactivated concentrates.
Agents that promote hemostasis and wound healing but do not substantially alter the plasma concentration of VWF.
Treatment
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DDAVP:
0.3 µg/kg , IV, (30–50 mL of N/S) over 30 min, peak increments of FVIII and VWF 30 to 90 min post infusion.
Sub cutaneous way is usually identical to IV.
Nasal DDAVP ( Simate, 150 micro/g / dose )>50 kg: 2 puffs
Treatment
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DDAVP:
Use with caution:Under 3 yearsvWD type1 with low PLTvWD type 3vWD type 2B ( some physicians recommend DDAVP)Pseudo platelet vWDOlder age with atherosclerosisUremiaMajor surgery ( long term prophylaxis is needed )Several dosesBrain, ocular, and coronary artery surgeries
Treatment
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DDAVP:
Complications:HeadacheFlushingTachycardiaWater intoxication ( only maintenance fluid for 24h) DVT MIRelease of tPA ( anti fibrinolytic agents ?)
Treatment
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Cryoprecipitate
Each bag contains about 100 IU vWF
Virally non safe
Volume overload
Not available always
Immunological reaction
Not reliable response
Treatment
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Replacement Therapy
Treatment
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Replacement Therapy
Treatment
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Other Therapies
Antifiibrinolytic agentsAminocaproic acid (25-50 mg/kg/dose QID )and Tranexamic acid
(5-10 mg/kg/dose TDS), PO or IV or topically in oral cavity.DIC and U.T bleeding are contraindications.
Topical agentsTopical bovine thrombin Fibrin sealantTopical collagen sponges
Women BleedingsOCP, IUD, hysterectomy
Treatment
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Other therapies
Platelet transfusion
:may control bleeding that is non- or poorly responsive to
replacement therapy with VWF concentrate.
Treatment
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Menorrhagia in women with bleeding disorders
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Pictorial Blood Assessment Chartscore 100 = 80ml blood
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Women with inherited bleeding disorders
116 women studied at Royal Free Hospital
66 vWd30 carriers of hemophilia20 with factor XI deficiency
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Prevalence rates of von Willebrand disease in988 women presenting with menorrhagia
13% (5-24%)
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Frequency of inherited bleeding disorders inwomen with menorrhagia12% general gynecology referrals are for
menorrhagia150 women with PBAC score > 100Frequency of VWD 13% compared with 0.1 to 1%
in the normal population
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The frequency of bleeding symptoms in the normal population comparedwith 264 Scandinavian patients with VWD
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Predictive value of bleeding symptoms indiagnosis of type 1 VWD
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< 10%
10-30%
30-50%
Type 1
Type 2
Type 3
RCof:
VWD – 0.82%
(480.000 patients?)
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Please Reffer :
• Women with menorrhagia whom surgical and Endocrinal abnormalities have been ruled out.
• جامع – مرکز ، فلسطین زرتشت تقاطع هموفیلی
• Thank you for your attention!