1. VON WILLEBRAND DISEASE Nairobi, Kenya June 25, 2013

2. OBJECTIVES Examine the history of VWD Discuss the genetics Define the function of VWF Compare and contrast the types/subtypes of VWD Describe typical bleeding encountered Discuss treatment options Explain the diagnostic approach for VWD

3. VON WILLEBRAND DISEASE (VWD) First investigated 1924 Originally termed “hereditary pseudohemophilia” Most common of the genetically transmitted bleeding disorders Prevalence rate thought to be 1-2% Since symptoms are often mild, a significant majority of patients remain undiagnosed Miller CH, et al. Blood. 1987; 70(suppl): 377a

4. VWD: HISTORY Erick von Willebrand described a large family with a severe bleeding disorder from the Aland Islands in 1926. Differences in bleeding from classic hemophilia: −Lack of joint bleeding −Presence of mucosal bleeding Proband died of bleeding during 4th menstrual period

5. GENETICS OF VWD Usually inherited, though spontaneous mutations do occur Inheritance is usually autosomal dominant, although subtypes may have varying inheritance patterns Equally passed to males and females Inheritance may occur from either parent Gene defect on chromosome 12 Ginsburg D and Sadler JE. Thromb Haemost. Feb 1 1993; 69(2): 177-184.

6. INHERITANCE OF VWD

7. VON WILLEBRAND FACTOR (VWF) A large multimeric protein that: −circulates in the blood −stabilizes FVIII −provides the initial link between the platelet and the ruptured blood vessel Therefore, in VWD, bleeding tends to be platelet-like, but, depending on the factor VIII level, there may also be defects in fibrin blood clot formation Zimmerman TS, et al. J Clin Invest.1971; 50: 244-254.

8. MECHANISM OF ACTION OF VWF

9. TYPES OF VWD Type 1 (~80%) Lower than normal levels of VWF Symptoms usually mild Type 2 (~20%) Defect in structure of VWF, so doesn’t work properly Different subtypes: 2A, 2B, 2N, 2M Symptoms usually moderate Type 3 (rare) Very little or no VWF Symptoms are more severe, including bleeding into muscles and joints, sometimes without injury.

10. SUBTYPES OF TYPE 2 VWD Type 2A reduced platelet-dependent function abnormal multimers Type 2B increased affinity for platelet binding Type 2M reduced platelet-dependent function normal multimers Type 2N reduced FVIII binding

11. TESTING FOR VWD Diagnostic criteria 1.Personal history of excessive mucocutaneous bleeding 2.Laboratory tests of hemostasis consistent with VWD 3.Family history of excessive bleeding

12. COMMON BLEEDING SYMPTOMS Easy bruising Prolonged bleeding from lacerations Epistaxis Bleeding from gums Menorrhagia Post-dental procedural bleeding Post-surgical bleeding Excessive post-partum bleeding Muscle hematomas (type 3 VWD) Hemarthroses (type 3 VWD)

13. COMMON BLEEDING SYMPTOMS (CONT’D) Normals (%) Type 1 VWD (%) Types 2 VWD (%) Type 3 VWD (%) Epistaxis4.6 – 22.738.1 – 62.56366 - 77 Menorrhagia23 – 68.447 - 603256 - 69 Bleeding after dental extractions 4.8 – 41.928.6 – 51.53953 - 70 Ecchymoses11.8 – 41.949.2 – 50.4N.R. Bleeding from minor cuts 0.2 – 33.3364050 Post-op bleeding 1.4 – 28.219.5 - 282341 GI Bleeding0.6 – 27.714820 See NHLBI guidelines for references

14. TESTING FOR VWD VWD cannot be diagnosed with routine blood tests – testing is complex Involves measuring a person’s level and activity of VWF and FVIII. Testing is often repeated because a person’s VWF and FVIII levels can vary

15. LABORATORY TESTS (CONT’D) TestPurpose Factor VIII coagulant activity (FVIII:C) Measures the functional activity of factor VIII von Willebrand factor antigen (VWF:Ag) Measures the amount of VWF Ristocetin co-factor and/or collagen binding activity (VWF:RCo and/or VWF:CB) Measures the functional activity of VWF von Willebrand factor multimers Provides a visualization of how well the VWF monomer is multimerized (joined into chains) Ristocetin induced platelet aggregation (RIPA) Measures how sensitive VWF is to ristocetin (useful in diagnosing Type 2B VWD)

16. Non-Medical *Rest *Ice *Compression *Elevation DDAVP Oral antifibrinolytics Fibrin glue Oral contraceptive products / Intrauterine device (IUD) Factor replacement with VWF/FVIII concentrates Kingman CE, et al. BJOG. Dec 2004; 111(12): 1425-1428 TREATMENT OF BLEEDING EPISODES

17. ISSUES FOR WOMEN AND GIRLS WITH VWD Women tend to have more symptoms than men because of menstruation and childbirth Heavier and/or longer menstrual flow Girls may have especially heavy bleeding when they begin to menstruate Check for anemia regularly Women entering menopause are at increased risk of unpredictable and heavy bleeding

18. ISSUES FOR WOMEN AND GIRLS WITH VWD Pregnancy and delivery A woman with VWD should see an obstetrician as soon as she suspects she is pregnant. The obstetrician should work with a bleeding disorders treatment centre to provide the best care during the pregnancy and childbirth. During pregnancy, VWF and FVIII levels increase → protection from bleeding during delivery After delivery, levels decrease and bleeding may occur.

19. SUMMARY VWD is the most common bleeding disorder VWD is not a sex-linked bleeding disorder Bleeding is often mucocutaneous in nature but can be severe in some forms of the disease Testing and diagnosis can be difficult and repeat testing is often required Women may have heavy menses and post-partum bleeding and should be followed in a HTC Various treatments are available to control and prevent bleeding in VWD

20. WFH RESOURCES What is von Willebrand disease? Von Willebrand Disease: An Introduction for the Primary Care Physician Reproductive Health in Women with Bleeding Disorders