von Willebrand Disease Level Basic Version No I

von Willebrand Disease Level: Basic Version No: I Version Date: 02/2012 Author(s): William Gwin, MD Affiliation(s): Duke University, Division of Hematology/Oncology L. I. T. Reviews

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Financial Disclosures (past 3 years) Please include all financial disclosures the for the past 3 years. • No Disclosures L. I. T. Reviews

Outline and Learning Objectives • • • Case Physiology of von Willebrand Factor (VWF) von Willebrand Disease (VWD) Types of von Willebrand Disease Diagnostic workup Treatment L. I. T. Reviews

Case • 70 year old male presents • Previous Surgical History: with increasing nocturia – Tonsillectomy 1943. – Sinus polypectomy • PSA of 8 ng/m. L 2002, associated with • Referred to Urology heavy bleeding – Scheduled for prostate – Sinus polypectomy biopsy 2005, complicated by • Previous Medical History: bleeding – VWD: diagnosed 2005 • Diagnosis: von – Sinus polyps Willebrand disease L. I. T. Reviews

Biology of von Willebrand Factor • Produced by: – Endothelial cells – Megakaryocytes • Produced as a monomer • Functional state: Multimers • High-molecular-weight, (HMW) VWF multimers – Most hemostatically active L. I. T. Reviews www. drugdevelopment-technology. com

VWF Role in Adhesion and Aggregation Gp. IIb/IIIa v. WF Gp. IIb/IIIa Platelet Adhesion Endothelium Gp. Ib v. WF Gp. Ib binding Induces Gp. IIb/IIIa expression Subendothelial Collagen Fibers L. I. T. Reviews Kroonen, et at.

Association with Factor VIII • D 3 binding domain binds to Factor VIII • Stabilizes Factor VIII • Patients with VWD have decreased plasma levels of Factor VIII – Can result in an increased PTT L. I. T. Reviews http: //www. haemtech. com/Cofactors/v. WF. htm

VON WILLEBRAND DISEASE L. I. T. Reviews

von Willebrand Disease • Original description - 1926 – Erik Adolf von Willebrand, Finnish pediatrician • Most common inherited bleeding disorder • Autosomal dominant trait - majority • Mutations affecting synthesis or action of von Willebrand factor (VWF) • Symptoms: – Easy bruising, – Prolonged bleeding from mucosal surfaces L. I. T. Reviews

VWD Classification • Type I: most common, quantitative deficiency • Type II: qualitative abnormalities of VWF • Type III: marked decrease or absence of detectable VWF L. I. T. Reviews

Acquired von Willebrand Syndrome (AVWS) • Acquired defects in VWF concentration, structure or function • No personal or family history of bleeding disorder • Associated with various underlying disease states • Thorough bleeding history – Easy bruising – Prolonged bleeding from mucosal surfaces – Procedural history L. I. T. Reviews

Lab Evaluation • CBC • PT, PTT – Isolated prolonged PTT • Due to concomitant decrease in Factor VIII – PTT corrects with 1: 1 mixing study L. I. T. Reviews • Further Evaluation: – Plasma VWF antigen – Plasma VWF activity (ristocetin cofactor activity and VWF collagen binding) – Factor VIII

Case Review • No personal history of prolonged bleeding prior to age 65 • No family history of bleeding disorders • Prolonged bleeding workup found: – – – PTT: 45. 0 sec VWF: Antigen 24 IU/d. L (40 -150 IU/d. L) VWF: Ristocetin Cofactor <12. 5 IU/d. L (45 -130 IU/d. L) Factor VIII of 22 (74 -212) Abnormal multimer pattern L. I. T. Reviews

Subtype Diagnosis • Type I: quantitative deficiency – Reduced VW factor antigen – Reduced VW activity (Ristocetin/collagen) – Reduced Factor VIII activity • Type II: qualitative abnormalities of VWF, 4 subtypes – Ristocetin cofactor activity is lower than the VWF antigen (ratio <0. 5 to 0. 7) – Multimer analysis • Type III: marked decrease or absence of detectable VWF – VWF antigen is unmeasurable or extremely low – Ristocetin cofactor activity is very low or undetectable – Factor VIII is 1 -10% of normal L. I. T. Reviews

Treatment • Desmopressin (DDAVP) • VWF concentrates (Humate-P) – High molecular weight (HMW) von Willebrand factor multimers (HMW-VWF) L. I. T. Reviews

Summary • Role in platelet adhesion and aggregation at sites of vascular injury. • VWF stabilizes Factor VIII • VWD is the most common inherited bleeding disorder • There are 3 types of VWD leading to quantitative and qualitative defects in VWF • Initial treatment for patients with VWD who are bleeding are Desmopressin and VWF concentrates L. I. T. Reviews

Key References • • • Wagner DD. Cell biology of von Willebrand factor. Annu Rev Cell Biol. 1990; 6: 217. Sadler JE, Mannucci PM et al. Impact, diagnosis and treatment of von Willebrand disease. Thromb Haemost. 2000; 84(2): 160. Haberichter SL, Fahs SA, Montgomery RR. von Willebrand factor storage and multimerization: 2 independent intracellular processes. Blood. 2000; 96(5): 1808. Levy G, Ginsburg D. Getting at the variable expressivity of von Willebrand disease. Thromb Haemost. 2001; 86(1): 144. Fernandez MF et al. Multimeric structure of platelet factor VIII/von Willebrand factor: the presence of larger multimers and their reassociation with thrombin-stimulated platelets. Blood. 1982; 60(5): 1132. www. intreavws. com Shaji, et al. Acquired von Willebrand Disease. Mayo Clin Proc. 2002; 77: 181 -187 van Genderen et al. Acquired von Willebrand disease caused by an autoantibody selectively inhibiting the binding of von Willebrand factor to collagen. Blood. 1994; 84: 3378 -3384. Tiede A, et al. Diagnostic workup of patients with acquired von willebrand syndrome: a retrospective singlecentre cohort study. J Thromb Haemost 2008: 6: 569 -76. Goudemand J, et al. Acquired type II von Willebrand’s disease: demonstration of a complexed inhibitor of the von Willebrand factor-platelet interaction and response to treatment. Br J Haematol. 1988; 68: 227 -233 Leo T. Kroonen et al, Orthopedic Manifestations and Management of Patients With von Willebrand Disease. ORTHOPEDICS March 2008; 31(3): 263. L. I. T. Reviews

Acknowledgements • Dr. Ara Metjian • Dr. Phil Blatt L. I. T. Reviews