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VON WILLEBRAND DISEASE
Nairobi, Kenya
June 25, 2013
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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
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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
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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
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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.
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INHERITANCE OF VWD
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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.
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MECHANISM OF ACTION OF VWF
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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.
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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
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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
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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)
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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
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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
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LABORATORY TESTS (CONT’D)
Test Purpose
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 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)
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• 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
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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
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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.
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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
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WFH RESOURCES
• What is von Willebrand disease?
• Von Willebrand Disease: An Introduction for the Primary Care Physician
• Reproductive Health in Women with Bleeding Disorders