2Cardiovascular Disease 30% of all deaths in Canada54% ischemic heart disease20% stroke23% heart attack
3Venous Thromboembolism Incidence5 cases per 100,000 person/year(<15 years old)5 cases per 1,000 person/year(80 years old)
4Incidence in General Population The hemophilias are less frequent than VWD, and have X-linked inheritanceDeficientCoagulationFactorIncidence in General PopulationChromosomeMode of Inheritancevon Willebrand Factor1:1000or even more12Autosomal dominantFactor VIII(Hemophilia A)1:10 000XX-linked recessiveFactor IX(Hemophilia B)1:50 000The hemophilias are less frequent than VWD where VWD occurs ~1 in 1000 live births or even more frequently than this.In comparision, FVIII deficiency (which causes HA) occurs approximately 1 in live births, or 1 in 5000 male births.FIX deficiency (which causes HB) is more rare than FVIII deficiency, and occurs about 1 in births, or 1 in males.HA and HB are also inherited differently than VWD. VWD is autosomal dominant inheritance, whereas the hemophilias follow sex-linked inheritance, since the FVIII and FIX genes are encoded by the X chromosome.
5Hemophilia in Canada: 2015 Hemophilia A 2,913 Hemophilia B 691 Severe 28%Moderate 10%Mild 62%Hemophilia B 691Severe 25%Moderate 33%Mild 42%
14Untreated hemarthrosis of the knee in severe hemophilia This is an example of the type of bleeding that you can see , so here we have an untreated bleed into the knee of a patient with severe hemophilia.
21Plasma Coagulation Factor Level The circulating plasma level of FVIII or FIX is related to disease severityNORMAL plasma range: 50 – 150%SeverityPlasma Coagulation Factor LevelMILDhemophilia5 - 40%MODERATE hemophilia1 to 5%SEVERE hemophilia<1%The circulating plasma level of FVIII or FIX is releated to the severity of the disease.So the normal range for FVIII and FIX levels in between %. Once we`re under 50%, there becomes a risk for bleeding.So patients with MILD hemophilia have plasma factor levels between 6 to 40% of normal.MODERATE hemophila between 2 to 5% factor levels.SEVERE hemophilia 1% or less.And these levels will vary slightly depending on the reference youre looking at.
22Protein Prevalence of Severe Factor Deficiency Size of Gene (kb) Numberof ExonsFVIII1 in 10,000186 kb26FIX1 in 30,00033 kb8VWF1 in 100,000175 kb52FXI1 in 1,000,00023 kb15FVII1 in 1,000,00012 kb9FX1 in 500,00022 kb8FGA 8kbFGB 8 kbFGG 9 kbFGA 7FGB 8FGG 11Fibrinogen1 in 1,000,000FV1 in 1,000,00080 kb25Subunit A 160 kbSubunit B kbSubunit A Subunit B 12FXIII1 in 2,000,000Prothrombin1 in 1,000,00020 kb14
33The Mature VWF Subunit with Associated Ligands FVIIIP-selectinVWFppβ2 integrinsαIIbβ3αvβ3ADAMTS13A1A2A3CKD’D3D4C1C2C3C4C5C6GPIbαCollagen VIOPGPSGL-1β2GPIAng2Collagen ICollagen IIITSP1The Mature VWF Subunit with Associated Ligands
34adhesion/aggregation AtherothrombosisPlateletadhesion/aggregationVenous thrombosisVWF FunctionsInflammationCell proliferation/apoptosisAngiogenesisLenting et al. JTH 2012
35Diagnosis of von Willebrand Disease 1. Personal history of excessive mucocutaneous bleeding.Laboratory results consistent with deficiency ofnormally functional VWF or presence of a dysfunctionalVWF protein.3. Family history of von Willebrand disease.
36Standardized measurement of VWF:Ag VWF:RCo The Diagnosis of von Willebrand DiseaseStandardized measurement ofVWF:AgVWF:RCo
37Von Willebrand Disease Classification (ISTH 2006)Qualitative Variants20%Type 1 Type 2 Type380%1 per millionQuantitative Variants
38ISTH 2006 VWD Classification Type qualitative traits2A2B2M2N~20%