von Willebrand Disease

Transcription

1 von Willebrand Disease Jeremy Robertson Paediatric Haematologist Royal Children s s Hospital & Pathology Queensland

2 Foglo,, April 1924: the journey begins

3 Oskar and Augusta sail to Helsinki...

4 ...to o see Dr Erik von Willebrand 5 year old daughter, Hjordis, recurrent bleeding from 1 yo Nose, lips, gums, minor cuts Almost bled to death age 3 (lip laceration) Ankle bleed after injury Strong family history of mild and major bleeding

5 Family S S Dagny: : nose bleeds from 1 yo; died age 2 from GI bleeding Anna: : nose bleeds from 1yo; died from tongue injury age 4 Thomas (15): frequent mild nose bleeds Stillborn boy Dagny: : severe bleeding from thrush at 4 weeks of age; died age 2, GI bleeding Harald (12): frequent mild nose bleeds Sylvia (10) and Runar (8), both well Hjordis (5) as described Greta (3): easy bruising from 1 yo; frequent nose bleeds; feeble, weak and fidgety Gerda (18 mo): healthy

6 Family S

7 Hereditary pseudohaemophilia (1926) Both sexes Women > Men Pattern of bleeding distinct from haemophilia Similarities to Glanzmann thrombasthenia Unable to reconcile inheritance pattern Epistaxis, bruising, menorrhagia, gums, cuts (not joints) Bleeding Time very prolonged (> 2 hours) Normal Coagulation Time Normal platelet count -?functional defect

8 VWD and Haemophilia Anti-haemophilic globulin (AHG) Patek & Taylor 1937 precipitate from plasma Measurement in 1950 s s revealed deficiency in both haemophilia A and patients with VWD Development of Cohn Fractionation in 1940 s Refinement by Blomback & Blomback Nilsson used Fraction I-0 I to treat a woman with VWD; soon after demonstrated different I-0 I 0 from haemophilia and VWD patients Decreased platelet adhesiveness (but normal aggregation) demonstrated in 1963 Deficiency of AHF-related antigen in VWD demonstrated in 1971 (Zimmerman) AHG separated into 2 fractions - one large, one small in 1972 (Owen & Wagner)

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10 Ristocetin Cofactor Ristocetin - antibiotic, known to cause aggregation of human platelets, even in thrombaesthenia Normal platelet aggregation to most agonists in VWD but abnormal adhesiveness 1973: Barry Firkin identified that ristocetin induced platelet aggregation was reduced or absent in patients with VWD Confirmed that reduced ristocetin effect correlated with reduced platelet adhesiveness Also demonstrated that a factor in plasma was required to produce this effect (the ristocetin cofactor )

11 The modern stage is set Quantitative assays developed: FVIII assay already established = FVIII:C Factor VIII-related antigen = VWF:Ag Ristocetin cofactor effect = VWF:RCo Identification of the VWF:Ag within megakaryocytes and vascular endothelium New electrophoretic techniques in late 70 s s allowed study of VWF multimers

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13 von Willebrand Disease Inherited bleeding disorder - deficiency or dysfunction of von Willebrand factor VWF is a large adhesive glycoprotein Synthesised and stored in endothelium & MK Assembled into multimers of variable size prior to release - form stacks which stretch under shear Adheres to exposed connective tissue at sites of vessel injury - a foothold for platelets Also carries / protects FVIII in circulation

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15 Clinical Features Easy bruising Recurrent epistaxis Menorrhagia Oral bleeding lips, gums, tongue Prolonged bleeding from cuts Prolonged post-surgical surgical bleeding Post-partum haemorrhage Gastrointestinal bleeding Deep soft-tissue tissue / joint bleeding severe forms only

16 Screening tests: VWD: Assays APTT, FBC, PFA-100, Bleeding Time Quantitative (VWF:Ag) Variety of immunoassays Factor VIII (FVIII:C) - APTT based Qualitative - assessment of function VWF:RCo - classical method, automated methods Ristocetin induced platelet aggregation (RIPA) Collagen binding assay (VWF:CBA) Factor VIII binding assay Multimer analysis Separation of VWF multimers by molecular weight

17 Normal Type 2B Type 3 Type 1 Vicenza Type 2A Type 1 Type 1 Type 1 Type 1

18 VWD: Classification Quantitative deficiency - reduction of VWF:RCo parallels reduction of VWF:Ag Partial (type 1) or complete (type 3) Mild (>30%), moderate (>15%) or severe (<15%) Qualitative (functional) defect - type 2 Further subdivided according to absence (2A) or presence (2M) of high molecular weight multimers 2B - increased sensitivity to ristocetin 2N - loss of FVIII binding activity alone Platelet-type VWD - defect in platelet gp1b Inheritance is AD in all except type 3 and 2N

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20 Genetics & pathophysiology VWF gene cloned in exons,, 9 kb mrna 2813 aa pre-pro pro-vwf Multimer assembly requires propeptide Released from stores following stimulus Cleared from plasma by unknown receptor Defects of synthesis and clearance - type 1 Mutations in critical functional domains - type 2 Recessive inheritance of null mutations - type 3

21 VWD: type 2 geneticsg

22 VWD: type 1 genetics

23 Heterogeneity of type 1 VWD

24 VWD: Treatment No treatment available until 1956 Plasma fraction I-O I O rich in VWF and FVIII Cryoprecipitate 1964 (Judith Pool, Stanford) Desmopressin (DDAVP) introduced 1977 Release of endogenous VWF stores Virally inactivated VWF/FVIII concentrates from mid 1980 s s (Haemate( Haemate-P) Recombinant VWF-FVIII FVIII product in development

25 Hjordis: : journey s s end