von willebrand disease nairobi, kenya june 25, 2013
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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 multimers
Type 2B
• increased affinity for platelet binding
Type 2M
• reduced platelet-dependent function
• normal multimers
Type 2N
• reduced FVIII binding
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
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 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)
• 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
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