von Willebrand’s Disease

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 DefinitionType 1 ( platelet nor/ low, IA,I-1,I-3) Partial quantitative deficiency of vWFType 2 Qualitative vWF defectType 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 GPIbType 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 vWFPseudo- 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 BMutations 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 MReduced 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 ScoreDiagnosisRodeghiero 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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DiagnosisTosetto A,et al,2006

Bleeding Score

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Diagnosis Bleeding ScoreTosetto 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 TherapyTreatment

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Replacement TherapyTreatment

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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

Menorrhagia in women with bleeding disorders

Pictorial Blood Assessment Chartscore 100 = 80ml blood

Women with inherited bleeding disorders

116 women studied at Royal Free Hospital

66 vWd30 carriers of hemophilia20 with factor XI deficiency

Prevalence rates of von Willebrand disease in988 women presenting with menorrhagia

13% (5-24%)

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

The frequency of bleeding symptoms in the normal population comparedwith 264 Scandinavian patients with VWD

Predictive value of bleeding symptoms indiagnosis of type 1 VWD

< 10%

10-30%

30-50%Type 1

Type 2

Type 3

RCof:

VWD – 0.82%(480.000 patients?)

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!