Von Willebrand Disease. Alison Street Malaysia April 2010

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1 Von Willebrand Disease Alison Street Malaysia April 2010

2

3 Physiology of VWF OUTLINE Clinical presentation of VWD Classification of VWD with emphases on Type 1, 2B and 2N disease Testing for VWD Treatment

4 Pedigree of the original family described by Erik von Willebrand in 1926

5 VWF Gene Located at chromosome 12p exons spanning 178 kb 9kb mrna Partial pseudogene at chromosome 22 VWF and pseudogene diverge by 3.1% in sequence Probable relatively recent origin of pseudogene by partial gene duplication

6 VWF mrna VWF biosynthesis and processing 5 3 Pro-VWF N C RER Pro-VWF dimer C --S-- C N N Pro-VWF multimers C --S-- C --S-- C --S-- C Golgi Propeptide dimer VWF multimers C --S-- C --S-- C --S-- C

7 VWF synthesis and processing VWF synthesised in endothelial cells and megakaryocytes Primary translation product processed in ER to form pro-vwf dimers In Golgi apparatus VWF propolypeptide mediates assembly of dimers into multimers of molecular wt. up to 20 x 10 6 Mature VWF secreted directly into plasma or subendothelium, or stored in endothelial cell Weibel-Palade bodies and platelet alpha granules

8 VWF FUNCTION Platelet-dependent function in primary haemostasis High shear stress High molecular weight multimers Carrier for FVIII VWF plasma half-life ~12 h

9 VWF gene and protein structure / function relationships VWF gene (chromosome 12) Region duplicated in partial VWF pseudogene (chromosome 22) VWF primary translation product Mature secreted VWF protomer - functional sites

10 VWF binds via A3 domain to collagen inducing a conformational change Which allows GP1b to bind to VWF A1 domain This slows the platelet travel and allows activation of FVIII Activation of platelets leads to the binding of GPIIb/IIIa to VWF C2 domain which is slower but has higher affinity

11 VWF functionality - high molecular weight multimers Essential to promote platelet-vessel wall and platelet-platelet interactions at high shear Circulating VWF multimer size is controlled by proteolytic cleavage by ADAMTS13

12 ADAMTS 13 A specific plasma protease which proteolyses the bond between Tyr 1605 and Met 1606 (Tyr 842 and Met 843 of mature sub-unit) Generates a spectrum of circulating vwf species (single twenty dimer multimers) of which larger ones have most affinity for platelet Gp1b and Gp11b/111a receptors

13 VWF multimer analysis High MW Crucial for normal function Normal Low MW

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15 Von Willebrand Disease Inherited deficiency or dysfunction of VWF Bleeding results due to impaired platelet adhesion and lower levels of FVIII VWD prevalence haemostasis centres : % Abnormal VWF prevalence (screening): %

16 Clinical presentations Bleeding: mucous membrane and skin sites Personal history of bleeding Family history of bleeding Bleeding: severity, site, duration, type of injury or insult, ease of stopping, concurrent medications e.g. aspirin, clopidogrel, warfarin, heparin Liver,kidney, bone marrow disorder Examination: bruising/bleeding & exclude other diagnoses

17 Bleeding symptoms are common in people with normal levels of VWF! 23%of healthy controls, replying to a bleeding questionnaire, report at least one symptom of bleeding compared with 88% of patients with a diagnosis of VWD Type 1. Standardised bleeding scores do not predict VWF gene or plasma levels within families but do predict for post-operative bleeding

18 1994 Classification of VWD Type 1 VWD (~ 70% of cases??) Partial quantitative deficiency of VWF Type 2 VWD Qualitative deficiency of VWF Sub-types 2A, 2B, 2M, 2N Type 3 VWD Virtual complete deficiency of VWF Sadler, Thromb Haemost 1994, 71, 520-5

19 Clinical assessment Bleeding: mucous membrane and skin sites Personal history of bleeding Family history of bleeding Bleeding: severity, site, duration, type of injury or insult, ease of stopping, concurrent medications e.g. aspirin, clopidogrel, warfarin, heparin Exclusion of liver, kidney or bone marrow disorders Examination: bruising/bleeding & exclusion of other diagnoses

20 Classification type description inheritance prevalence bleeding 1* partial quantitative deficiency AD up to 1% Mild-mod 2A 2B 2M VWF-dep platelet adhesion Loss high & int MW multimers affinity for platelet GPIb Loss high MW multimers VWF-dep platelet adhesion without selective loss high MW multimers AD or AR AD 2N binding affinity for FVIII AR AD or AR uncommon variableusually moderate 3* almost complete deficiency AR rare high * Quantitative deficiency vs qualitative deficiency

21 Laboratory testing Skin Bleeding Time Platelet Function Analyser/ Aggregation Plasma testing for VWF antigenic and activity levels Activity measured by Ristocetin Co Factor and Collagen Binding assays Full Blood Examination F VIII levels/ F VIII binding

22 Summary of criteria for diagnosis and classification of VWD Type 1 Type 3 Type 2A Type 2B Type 2M Type 2N VWF:Ag Decreased < 5% Decreased (Normal) VWF activity RIPA Decreased Absent Markedly decreased Reduced (Normal) Multimers Essentially normal VWF: FVIIIB Absent Markedly reduced Absent HMW absent Decreased (Normal) Decreased (Normal) Variable Decreased relative to VWF:Ag Increased Reduced (Normal) HMW usually absent Normal Normal Normal Normal Normal Normal NA Normal Normal Normal Reduced

23 Approach to classification of VWD Quantitative defect Type 1 or Type 3 VWD Qualitative defect Type 2 VWD Normal platelet-dependent Defective platelet- VWF function & dependent VWF function defective FVIII binding Type 2N VWD Gain in function Type 2B VWD Loss of HMW multimers Type 2A VWD Reduced function HMW multimers present Type 2M VWD

24 Laboratory features of Type I VWD Partial quantitative deficiency of VWF Concordant VWF:Ag & CBA/RistoCoF Normal multimer pattern When VWF <20 IU/dL may identify mutations which interfere with intracellular transport of dimeric provwf or promote rapid clearance of VWF from circulation Lower VWF levels, more likely to have VWF gene mutations, significant bleeding history + strong Family History* *Goodeve et al. Blood 2007;109: , James et al. Blood 2007;109:

25 Many diagnoses of Type 1 VWD are false positives Past bleeding history is a better guide to risk assessment for future bleeding particularly when the VWF is between 30 and 50 IU/dl (RR %) Neither symptoms nor VWF level are predicted by VWF genetic testing at this level of deficiency

26 Incomplete Penetrance VWF Mutations missense splicing transcriptional + ABO Blood Group + Other Genetic Modifiers ~35% of cases Highly Penetrant eg. Dominant Negative VWF Mutations 50% VWF Level 0%

27 Is it just a low VWF level or VWD? Genetic factors account for minority of heritable variation in VWF levels No linkage to VWF locus when VWF >30 Other inheritable and environmental factors influence plasma VWF *Mannucci et. al. Blood 1989;74:

28 ISTH VWF mutation database ( Pre-Canadian, EU, and UK studies - 14 different VWF gene mutations reported in association with type 1 VWD By 31 July different mutations or candidate mutations reported

29 NH2 Propeptide Sequence Mutations G19R L129M D141G G160W N166I c t>c (splice) c c>a (splice) M576I A641V W642X D3, A1-A3 Mutations 1546_1548del3 V1229G N1231T P1266L V1279I c.3839_3845dup7 R1315C L1361S R1379C K1405del P1413L N1421K Q1475X R1583W Y1584C c.4944delt R1668S D1 D2 D D3 A1 A2 A3 D4 B1-B3,C1,C2 Mutations C2304Y T2647M R2313H C2693Y C2340R P2722A G2343V c.8412instccc R2379C R2464C c g>a (splice) S2497P G2518S Q2544X B1-3 C1 C2 COOH CK preprovwf VWF Monomer 22aa 741aa 2050aa 5 Regulatory Sequence Mutations -2731C>T -2714G>A -2639G>A -2615A>G -2533G>A -2522C>T -2487G>A -2328T>G -1896C>T -1886A>C -1873A>G -1665G>C -1522del13 K762E M771I c.2435delc R816W R854Q c t>c (splice) c g>a (splice) c g>c (splice) R924Q R924W C996E D -D3 Mutations c.3072delc c g>a (splice) I1094T C1111Y c g>a (splice) Y1146C C1190R R1205H A3-D4 Mutations c.5180instt E2233G V1760I c g>t (splice) L1774S R2287W K1794E N1818S V1850M P2063S R2185Q c a>t (splice) T2104I Candidate VWF mutations in type 1 VWD Canadian, EU and UK studies

30 Genetics of type 1 VWD (2010) Molecular mechanisms more clearly understood But functional studies assessed in only about 10% of reported candidate mutations A proportion of type 1 VWD likely to be due to defects away from VWF locus Definition of type 1 VWD not restricted to VWF mutations

31

32 Type 2 VWD Qualitative variants of VWF The proportion of large VWF multimers is reduced in Types 2A and B with consequent loss of function in 2A and gain in 2B Mutations lead to interference with assembly or secretion of large multimers or increased susceptibility to proteolytic degradation Type 2N results in impaired binding of FVIII and may be confused with mild haemophilia

33 Proposed model of VWF synthesis and catabolism Normal VWD variants Sadler et al, JTH 2006, 4,

34 Summary of criteria for diagnosis and classification of VWD Type 1 Type 3 Type 2A Type 2B Type 2M Type 2N VWF:Ag Decreased < 5% Decreased (Normal) VWF activity RIPA Decreased Absent Markedly decreased Reduced (Normal) Multimers Essentially normal VWF: FVIIIB Absent Markedly reduced Absent HMW absent Decreased (Normal) Decreased (Normal) Variable Decreased relative to VWF:Ag Increased Reduced (Normal) HMW usually absent Normal Normal Normal Normal Normal Normal NA Normal Normal Normal Reduced

35 Genetic diagnosis in type 2 VWD Generally well-characterised genetic disorders Screening for type 2N VWD in non X-linked mild or moderate FVIII deficiency Differentiation of type 2B VWD and platelet-type pseudo VWD Differential diagnosis of type 1 and type 2M VWD

36 Type 2B VWD Increased affinity of mutant VWF for platelet glycoprotein 1b Circulating platelets coated with mutant VWF - may prevent platelet adhesion at sites of injury Variable thrombocytopenia - reversible sequestration of VWF-platelet aggregates in microcirculation

37 Type 2B VWD VWF bound to platelets susceptible to proteolysis by ADAMTS13 high molecular weight multimers usually absent in plasma VWF activity usually reduced VWF:Ag reduced or normal Increased Ristocetin Induced Platelet Aggregation. May be confused with platelet type or pseudo VWD

38 Genetics of Type 2B VWD Autosomal dominant inheritance Gain of function missense mutations confined to VWF A1 domain (containing platelet GP1b binding site) 4 VWF gene mutations account for ~ 90% of type 2B VWD

39 Type 2N VWD (VWD Normandy) Reduced affinity of VWF for factor VIII Phenotype similar to mild or moderate haemophilia A or haemophilia A carriers. Should be considered and tested in all cases of spontaneous mild haemophilia

40 VWF-FVIII binding assay (VWF:FVIIIB) Normal Patient Heterozygous control Homozygous control

41 Functional domains and mutations reported in VWF up to 2006

42 Type 2N VWD Recognition and differentiation of type 2N VWD from haemophilia A important for: Precise genetic counselling Accurate carrier or prenatal diagnosis Appropriate treatment of bleeding episodes Consider type 2N VWD as a possible diagnosis in patients with FVIII deficiency which is not clearly X-chromosome linked

43 Treatment of VWD Selected according to Past bleeding experiences Level of VWF activity Type of procedure Product availabilty (need to use VWF containing concentrates, not recombinant Factor VIII)

44 DDAVP Stimulates endothelial production and secretion of VWF from endothelial cells. Can give for 4-5 days Of particular value in Type 1 disease where baseline level >10% Should give a trial dose to assess effect and tolerability (need to monitor Na+)

45 Special considerations Beware all cases of mild Haemophilia, it might be VWD Type 2N It is important to develop and communicate care plans for delivery and post partum management in women with VWD, secondary bleeding is common. Acquired VWD may complicate lymphoproliferative disorders (Type 2A like)

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47 THANK YOU

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50 Plasma VWF levels rise with Increased age Non-O blood group (mean VWF O=75U/dL, 95% VWF levels for O blood donors = U/dL* due to reduced vwfsurvival) Lewis blood group (secretor) Adrenaline, Thrombin (DDAVP) Inflammatory mediators Endocrine hormones (periods/pregnancy/ocp) *Gill et. al. Blood 1987;69:

51 Von Willebrand Factor cleavage Chromosome 12, 178kb, 52 exons ADAMTS13 cleavage site Platelet GPIb binding site THBS-1 binding site Probable ADAMTS13 binding site Sadler et. al. J Thromb & Haemost 2006, 4:

52 Normal physiology of ADAMTS13 ADAMTS13 Binding site Unusually large von Willebrand multimers Endothelial cell Weibel Palade body Secretion of multimers Adapted from Moake JL. NEJM 2002;347:

53 ADAMTS13 processing & VWF: a delicate balance between thrombosis and bleeding Type IIA vwd TTP ULvWF ULvWF: Congenital or acquired deficiency of ADAMTS13 ADAMTS13 Monomers vwf Monomers vwf: Mutations in vwf cleavage by ADAMTS13

54 NHLBI Guideline VWD 2007 Normal conditions FVIII VWF multimers Resting platelets FVIII-VWF circulates but doesn t strongly interact with platelets or endothelial cells

55 Vascular injury VWF adheres to vessel subendothelial matrix With shear, VWF multimers uncoil, platelets adhere and become activated VWF multimers activated platelets NHLBI Guideline VWD 2007

56 NHLBI Guideline VWD 2007 Platelet-fibrin plug Activated platelets expose phosphatidyl serine and bind and activate FVIII clotting Platelet-fibrin plug thrombolysis tissue repair

57 Platelet type pseudo-vwd (pvwd) Rare autosomal dominant disorder Mutations in platelet GpIb/IX receptor cause increased platelet-vwf binding Clinical presentation variable Laboratory presentation very similar to type 2B VWD (mild thrombocytopenia, increased RIPA, decreased HMW multimers) Potential for misdiagnosis

58 Differentiation of type 2B VWD and platelet-type pseudo-vwd (pvwd) Genotyping Targeted screening of VWF gene exon 28 and platelet GpIb/IX receptor gene Plasma / platelet mixing studies Patient platelets (PRP) + normal VWF (cryoprecipitate) Spontaneous aggregation in pvwd Absence of platelet aggregation in type 2B VWD (reliability?) Patient VWF (PPP) + normal platelets (PRP) Enhanced RIPA in type 2B VWD RIPA not enhanced in pvwd

59 A Disintegrin and Metalloprotease with ThromboSpondin motifs 13 Levy,G.G. et al. Blood 2005;106:11-17

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