VON WILLEBRAND DISEASE

Nairobi, Kenya

June 25, 2013

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

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

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

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.

INHERITANCE OF VWD

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.

MECHANISM OF ACTION OF VWF

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.

SUBTYPES OF TYPE 2 VWD

Type 2A• reduced platelet-dependent function • abnormal multimersType 2B• increased affinity for platelet bindingType 2M• reduced platelet-dependent function • normal multimersType 2N• reduced FVIII binding

TESTING FOR VWD

Diagnostic criteria1. Personal history of excessive mucocutaneous

bleeding2. Laboratory tests of hemostasis consistent with VWD3. Family history of excessive bleeding

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)

COMMON BLEEDING SYMPTOMS (CONT’D)

Normals (%) Type 1 VWD (%)

Types 2 VWD (%)

Type 3 VWD (%)

Epistaxis 4.6 – 22.7 38.1 – 62.5 63 66 - 77

Menorrhagia 23 – 68.4 47 - 60 32 56 - 69

Bleeding after dental extractions

4.8 – 41.9 28.6 – 51.5 39 53 - 70

Ecchymoses 11.8 – 41.9 49.2 – 50.4 N.R. N.R.

Bleeding from minor cuts 0.2 – 33.3 36 40 50

Post-op bleeding 1.4 – 28.2 19.5 - 28 23 41

GI Bleeding 0.6 – 27.7 14 8 20

See NHLBI guidelines for references

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

LABORATORY TESTS (CONT’D)

Test PurposeFactor 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 factormultimers

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)

• 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

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

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.

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

WFH RESOURCES

• What is von Willebrand disease?• Von Willebrand Disease: An Introduction for the

Primary Care Physician• Reproductive Health in Women with Bleeding

Disorders