Controversies in the Diagnosis of Type 1 VWD Paula James MD, FRCPC ISLH Honolulu, Hawaii Friday, May 5, 2017
Disclosures for Paula James Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board CSL Behring, Bayer, Shire No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare CSL Behring, Shire CSL Behring, Shire
Dr. Eric von Willebrand 1926 - first patient described died with her 4 th menstrual period pseudohemophilia
House of Hjördis - Föglö
Von Willebrand Factor synthesized by endothelial cells and megakaryocytes stored in Weibel-Palade bodies (endothelial cells) and alpha granules (platelets) platelet adhesion and aggregation chaperones FVIII
Von Willebrand Disease quantitative or qualitative abnormalities of VWF published prevalence ~1 in 100 Rodeghiero, Blood 1987; Werner J Pediatr 1993 symptomatic prevalence ~1 in 1000 Bowman JTH 2010; Bowman Ped Blood and Cancer 2010 autosomal inheritance M=F females diagnosed 2-3:1
ISTH Classification Type 1 - mild/moderate quantitative trait ~80% Type 2 - qualitative traits dominant recessive 2A 2B 2M 2N ~20% Type 3 - severe quantitative trait ~ 1 per million Sadler et al JTH 2006
Why is Accurate VWD Diagnosis Important? Undiagnosed Affected symptomatic prevalence 1 in 1000 ~ 34,000 Canadians affected far fewer diagnosed symptoms are treatable Diagnosed Unaffected labeled genetic disease exposed to unnecessary/inappropriate treatment unnecessary limitations risk to insurability
Controversies in Type 1 VWD Diagnosis 1. Are Bleeding Assessment Tools useful? 2. Should genetic testing be done routinely? 3. What cut-off of VWF should be used?
Are BATs useful in the diagnosis of Type 1 VWD?
Evolution of Vicenza-Based BATs Vicenza 2005 0 to +3 40 minutes MCMDM- 1VWD 2006-1 to +4 40 minutes Condensed MCMDM- 1VWD 2008-1 to +4 5-10 minutes PBQ 2009-1 to +4 20 minutes ISTH BAT 2010 0 to +4 20 minutes Self-BAT 2013-1 or 0 to +4 5 10 minutes
Condensed MCMDM-1 VWD Bleeding Questionnaire -1 0 1 2 3 4 Epistaxis -- No or trivial ( 5 per year) > 5 per year or more than 10 Consultation only Packing or cauterization or antifibrinolytic Blood transfusion or replacement therapy or desmopressin Cutaneous -- No or trivial ( 1 cm) > 1 cm and no trauma Consultation only -- -- Bleeding from minor wounds -- No or trivial ( 5 per year) > 5 per year or more than 5 Consultation only Surgical hemostasis Blood transfusion or replacement therapy or desmopressin Oral cavity -- No Referred, no consultation Consultation only Surgical hemostasis or antifibrinolytic Blood transfusion or replacement therapy or desmopressin Gastrointestinal bleeding -- No Associated with ulcer, portal hypertension, hemorrhoids, angiodysplasia Spontaneous Surgical hemostasis, blood transfusion, replacement therapy, desmopressin, antifibrinolytic -- Tooth extraction No bleeding in at least 2 extractions None done or no bleeding in 1 extraction Reported, no consultation Consultation only Resuturing or packing Blood transfusion or replacement therapy or desmopressin Surgery No bleeding in at least 2 surgeries None done or no bleeding in 1 surgery Reported, no consultation Consultation only Surgical hemostasis or antifibrinolytic Blood transfusion or replacement therapy or desmopressin Menorrhagia -- No Consultation only Antifibrinolytics, oral contraceptive pill use Dilation & curettage, iron therapy, ablation Blood transfusion or replacement therapy or desmopressin or hysterectomy Postpartum hemorrhage No bleeding in at least 2 deliveries None done or no bleeding in 1 delivery Consultation only Dilation & curettage, iron therapy, antifibrinolytics Blood transfusion or replacement therapy or desmopressin Hysterectomy Muscle hematomas -- Never Post trauma, no therapy Spontaneous, no therapy Spontaneous or traumatic, requiring desmopressin or replacement therapy Hemarthrosis -- Never Post trauma, no therapy Spontaneous, no therapy Spontaneous or traumatic, requiring desmopressin or replacement therapy Spontaneous or traumatic, requiring surgical intervention or blood transfusion Spontaneous or traumatic, requiring surgical intervention or blood transfusion Central nervous system bleeding -- Never -- -- Subdural, any intervention Intracerebral, any intervention
Condensed MCMDM-1 VWD Bleeding Questionnaire Prospectively validated Primary Care Setting, n=217 adults For Type 1 VWD, BS 4 Sensitivity = 100% Specificity = 87% PPV = 0.20 NPV 1.0 LR+ = 7.5 (95% CI 5.3 10.5) Bowman et al, JTH 2008
Condensed MCMDM-1 VWD Bleeding Questionnaire ROC n=217 AUC 0.963 p<0.001 Bowman et al, JTH 2008
BAT Limitations current BATs cannot distinguish one mild bleeding disorder from another are not helpful if the patient has not bled pediatrics males cannot capture changes in bleeding over time cumulative
Should genetic testing be routinely performed for the diagnosis of Type 1 VWD?
VWF 5 10 28 45 52 178 kb genomic sequence 12p13.3 VWF mrna 8.7 kb Ginsburg, Science, 1985; Lynch, Cell, 1985; Sadler, PNAS, 1985; Verweij, EMBO, 1985
Type 1 VWD James et al, Blood 2007
Sequence variation more common VWF < 0.30 IU/mL Flood et al, Blood 2016
Mutation Detection Rydz, Am J Hematol, 2013; Goodeve, JTH, 2015; Yadegari, Thromb Haemost, 2012; James, Blood, 2007; Goodeve, Blood, 2007; Cumming, Thromb Haemost, 2006; Bowman, JTH, 2013; Bogdanova, Hum Mutat, 2007; Johnsen JTH, 2015
Influence of other Genetic Loci James et al, Blood 2007
Type 1 VWD if genetic variation identified challenge to determine pathogenicity new variants are common multiple variants no worse phenotype contribution of other/novel loci ABO CLEC4M VWF clearance evaluating inheritance within a family challenging variable expressivity incomplete penetrance
Highly Heritable Dominant Negative VWF Mutations Low Heritability VWF Mutations missense splicing transcriptional + ABO Blood Group + Other Genetic Modifiers ~35% of cases 0% VWF Level 50%
What cut-off of VWF should be used to diagnose Type 1 VWD?
Type 1 VWD vs. Low VWF Type 1 VWD Low VWF VWF < 0.30 IU/mL VWF 0.30 0.50 IU/mL Bleeding phenotype? Optimal management? Nichols et al, Haemophilia 2008; Laffan et al, Brit J Haem 2014
Bleeding Scores by VWF Level Flood et al, Blood 2016
Should we use Low VWF PROS not labelled as disease treat VWF as a risk factor for bleeding CONS lack of recognition of the importance barrier to care
Conclusions Are bleeding scores helpful in the diagnosis of Type 1 VWD? YES Should genetic testing be routinely performed for Type 1 VWD diagnosis? NO Should we reserve the diagnosis of Type 1 VWD for those with VWF:Ag < 0.30 IU/mL PROBABLY
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