Von Willebrand Disease. Dre Françoise Boehlen Haemostasis Unit University Hospitals of Geneva

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1 Von Willebrand Disease Dre Françoise Boehlen Haemostasis Unit University Hospitals of Geneva Lausanne SSH May 12 th, 2011

2 Von Willebrand Disease (VWD) Well known bleeding disorder caused by Inherited defect in the concentration, structure, or function of the von Willebrand factor (VWF) Acquired defect Most common inherited bleeding disorder 1/100 of screened population (epidemiological studies) Symptoms in 1/1 000 (clinically significant in 1/10 000?)

3 Simple classification of VWD Type 1 Type 2 Type 3 Partial quantitative deficiency of VWF Qualitative deficiency of VWF Virtually complete deficiency of VWF Why diagnosis and management are sometimes so difficult to perform?

4 Schedule Why diagnosis is often difficult? From symptoms to genetic analysis... Which tests? How to treat VWD? Some particular problems

5 VWD a simple definition Criteria for diagnosis 1. Personal history of bleeding symptoms 2. Laboratory finding (VWF deficiency) 3. Family history of VWD Diagnosis considered as certain only if all 3 criteria present

6 1. Bleeding symptoms Mucosal bleeding (epistaxis, menorrhagia, etc.) Skin bleeding (bruises) Bleeding after minor wounds / trauma Bleeding after surgery (tooth extraction, tonsillectomy, etc.) or postpartum haemorrhage Muscular haematoma and haemarthrosis (only in severe VWD) Question: how to precise & quantify bleeding symptoms?

7 Type of bleeding assessment 3 haemorrhagic symptoms reported by 23% of Swedish girls with a self-reported questionnaire < 1% of normal subjects with a physician-guided questionnaire Friberg B et al. Acta Obstet Gynecol Scand 2006;85:200 Rodeghiero F et al. J Thromb Haemost 2005;3:2619 Standardised questionnaire-based bleeding score to precise bleeding symptoms Tosetto A et al. J Thromb Haemost 2006;4:766

8 Limitations of bleeding scores Physician-driven questionnaire Designed for adults and VWD Paediatric bleeding score in validation Insufficient haemostatic challenges Problems with children and males Bias of the results by use of prophylaxis Family history, drugs Which is the best score? Bowman M et al. JTH 2009;7:1418

9 2. Laboratory investigations Phenotypic assays Factor VIII (FVIII:C) VWF antigen (VWF:Ag) VWF activity Ristocetin cofactor (VWF:RCo) Collagen binding (VWF:CB) Other tests PFA-100 TM VWF multimer analysis Ristocetin-induced platelet agglutination (RIPA) VWF:FVIII binding Genetic analysis

10 Limitations of VWF:RCo Variable expressivity due to Genetic factors (ABO blood group) Environmental factors Exercise, stress, infection, pregnancy, age, etc. Cycle (lowest levels during menstrual phase)? High degree of assay variability Reference range? Below the ABO blood group adjusted 2.5 th percentile VWF < 30 IU/dL (or 40 IU/dL) Lower limit of assay sensitivity (10-20%?)

11 VWF:Ag and VWF gene mutation Rate of mutations (%) < > 50 VWF:Ag (U/dl) Mutation present Mutation absent Adapted from Peake I & Goodeve A. JTH 2007;5(suppl. 1):7

12 3. Personal history (VWD inheritance) Type 1 Type 2 Type 3 2A 2B 2M 2N Autosomal dominant Incomplete penetrance and variable expressivity (type 1) Strong penetrance (type 2) Usually autosomal recessive

13 Question At least for mildest forms of VWD, it remains unclear whether the benefits of a diagnosis outweigh its disadvantages (burdens associated with an unjustified genetic stigma, anxiety that may be caused by overestimates of a patient s bleeding risk and inappropriate resource expenditures...) Rodeghiero F et al. Blood 2009;114:1158

14 VWD prevalence of types 20% < 5% 45% < 5%? 75% 55%

15 Types of VWD Type 1 Type 2 Type 3 1C 2A 2B 2M 2N 2A 2C 2D 2E 1B v

16 Types 2 VWD Type 2A Type 2M Type 2B VWF-dependant platelet adhesion with a selective deficiency of HMWM VWF-dependant platelet adhesion without a selective deficiency of HMWM affinity for platelet GPIb (reduction or absence of HMWM) Type 2N affinity for FVIII

17 Usefulness of other tests? RIPA Type 2B VWD VWF:FVIII binding Type 2N VWD VWF:RCo/Ag No formal consensus of the ratio that best identify patients with type 2 (< ?) VWF:CB No consensus of its usefulness Distinction between 2A and 2M (reflects HMW VWF)? Better than VWF:RCo versus little clinical utility Variation depending on the type of collagen used

18 When to perform multimers? Theoretically, VWF multimer analysis = Assistance for the diagnosis of VWD Prevention of some misdiagnosis Reality = misdiagnosis in up to 20-40% of laboratories Identification of loss of HMW in normal or type 1 Failure to distinguish type 1 and 2M VWD

19 Type 2 VWD multimers Sadler JE et al. JTH 2006;4:2103

20 VWF gene and protein Chromosome 12 (52 exons) De Meyer SF et al. Blood 2009;113:5049

21 When to perform genetic analysis? Very useful (therapeutic implications) Type 2N (discrimination from haemophilia A/carrier) Type 2B (discrimination from platelet-type VWD) Type 3 (prenatal assessment/family studies and alloantibody risk assessment) Perhaps useful Type 2A/2M? Type 1 with VWF levels < IU/ml? Not useful in most cases Expensive and exhaustive evaluation of the entire VWF gene (polymorphism?) without clinical utility

22 VWD treatments Release of endogenous (endothelial-cell stored) VWF Desmopressin/DDAVP Replacement therapy FVIII/VWF concentrates Antifibrinolytics Tranexamic acid Adjunctive treatments Local haemostasis and biological glues Oral contraceptives / IUD Mirena No drug that inhibit platelet function

23 Response to DDAVP in VWD Type Response to DDAVP 1 Usually good response 2A et 2M 2B 2N May be ineffective or transient effect Usually contra-indicated Good response but often short 3 Not effective Cave: tachyphylaxis, tachycardia, headache, flushing, fluid retention & hyponatremia, cardiovascular risk factors Federici AB et al. Blood 2004;103:2038

24 What is a good response to DDAVP? «DDAVP responders» Peak level for VWF:RCo and FVIII:C > 50 IU/dL (concentration that may be considered sufficient for effective haemostasis during minor invasive procedures) Assessment at 4 hours from infusion (increased clearance) Tachyphylaxis after 3-4 infusions Need of prolonged haemostatic cover in mild form of VWD DDAVP safe during pregnancy/delivery? Safe level for spinal or epidural anaesthesia? Safe postpartum level for PPH?

25 Treatement with VWF concentrates Goal = correction of FVIII and/or VWF? FVIII level = best predictor of soft tissue or surgical bleeding? VWF:RCo normalisation required for appropriate treatment of mucosal bleeding? Normal haemostasis in patients treated with all kinds of FVIII/VFW concentrates? VWF:RCo per unit of FVIII:C Contents of larger VFW multimers Rodeghiero F et al. Blood 2009;114:1158

26 Thromboprophylaxis? Antithrombotic prophylaxis in patients with VWD undergoing surgery? VTE complications extremely rare in patients prophylactically treated with VWF/FVIII concentrates Orthopaedic surgery Known thrombotic risk factors (advanced age, obesity, HRT, high post-infusion FVIII levels) Individual evaluation of VTE risk factors + daily monitoring of FVIII plasma level Franchini M et al. J Thromb Thrombolysis 2009;28:215

27 Summary VWD Frequent constitutional haemorrhagic disorder Clinical and genotype heterogeneity VWF level to be interpreted carefully and integrated with bleeding symptoms Despite the recent multicenter studies, the diagnosis of mild type 1 VWD remains a challenge