Von Willebrand Disease in Children

Topic Name Introduction Pathophysiology Classification Clinical Presentation Diagnosis Treatment Management

Introduction to Von Willebrand Disease in Children

Von Willebrand Disease (VWD) is the most common inherited bleeding disorder, affecting up to 1% of the general population. It is particularly important in pediatrics due to its potential impact on a child's growth, development, and quality of life. VWD is caused by a deficiency or dysfunction of von Willebrand factor (VWF), a crucial protein involved in primary hemostasis and coagulation.

In children, VWD can present unique challenges due to the increased risk of bleeding during normal childhood activities, the potential for delayed diagnosis, and the need for long-term management strategies that adapt as the child grows. Understanding VWD in the pediatric population is essential for early recognition, appropriate management, and optimal outcomes.

Pathophysiology of Von Willebrand Disease

The pathophysiology of VWD centers around abnormalities in the VWF protein:

• Function of VWF:
  1. Mediates platelet adhesion to damaged endothelium
  2. Facilitates platelet-platelet interactions during clot formation
  3. Serves as a carrier protein for Factor VIII, protecting it from premature degradation
• Genetic basis: VWD is primarily inherited in an autosomal dominant pattern, with some subtypes showing autosomal recessive inheritance.
• Molecular defects: Can involve quantitative deficiencies or qualitative abnormalities of VWF, leading to impaired platelet adhesion and/or reduced Factor VIII levels.
• Impact on hemostasis: The deficiency or dysfunction of VWF results in impaired primary hemostasis and, in some cases, affects secondary hemostasis due to reduced Factor VIII levels.

Understanding these pathophysiological mechanisms is crucial for interpreting diagnostic tests and tailoring treatment approaches in children with VWD.

Classification of Von Willebrand Disease

VWD is classified into three main types, with several subtypes:

1. Type 1 VWD (60-80% of cases):
   • Partial quantitative deficiency of VWF
   • Mild to moderate bleeding symptoms
   • Autosomal dominant inheritance
2. Type 2 VWD (15-30% of cases):
   • Qualitative defects in VWF
   • Subtypes: 2A, 2B, 2M, 2N
   • Variable bleeding severity
   • Mostly autosomal dominant, except 2N (recessive)
3. Type 3 VWD (1-5% of cases):
   • Complete or near-complete absence of VWF
   • Severe bleeding symptoms
   • Autosomal recessive inheritance

This classification is important for determining appropriate management strategies and predicting clinical outcomes in children with VWD.

Clinical Presentation of Von Willebrand Disease in Children

The clinical presentation of VWD in children can vary widely, depending on the type and severity of the disease. Common manifestations include:

• Mucocutaneous bleeding:
  • Epistaxis (nosebleeds)
  • Easy bruising
  • Prolonged bleeding from minor cuts or abrasions
  • Gingival bleeding, especially during tooth brushing or loss of baby teeth
• Menorrhagia: Heavy or prolonged menstrual bleeding in adolescent girls
• Gastrointestinal bleeding: May occur in more severe cases
• Hemarthrosis and muscle bleeds: Rare, but can occur in Type 3 VWD
• Postoperative bleeding: Excessive bleeding following surgical procedures or tooth extractions
• Intracranial hemorrhage: Rare, but can occur in severe cases or after trauma

It's important to note that symptoms may not be apparent in infancy and can become more evident as the child becomes more active or undergoes surgical procedures. A thorough family history is crucial, as many children with VWD have affected family members.

Diagnosis of Von Willebrand Disease in Children

Diagnosing VWD in children can be challenging due to the variability in clinical presentation and the influence of age-related factors on laboratory tests. The diagnostic approach includes:

1. Clinical assessment:
   • Detailed personal and family bleeding history
   • Physical examination focusing on signs of recent bleeding
   • Use of standardized bleeding assessment tools (e.g., ISTH-BAT for pediatrics)
2. Laboratory testing:
   • Initial screening tests:
     • Complete blood count
     • Prothrombin time (PT)
     • Activated partial thromboplastin time (aPTT)
   • VWD-specific tests:
     • VWF antigen (VWF:Ag)
     • VWF activity (VWF:RCo or VWF:GPIbM)
     • Factor VIII activity (FVIII:C)
     • VWF multimer analysis (for typing)
     • VWF propeptide (VWFpp) to VWF:Ag ratio (in some cases)
3. Genetic testing: May be helpful for confirming diagnosis, determining inheritance pattern, and identifying specific mutations

Interpretation of test results should consider age-specific reference ranges and the potential influence of stress, exercise, and hormonal factors on VWF levels. Repeat testing may be necessary for accurate diagnosis.

Treatment of Von Willebrand Disease in Children

Treatment of VWD in children aims to control bleeding episodes and prevent complications. The approach is tailored based on the type and severity of VWD, as well as the specific clinical situation:

1. Desmopressin (DDAVP):
   • First-line treatment for most Type 1 and some Type 2 VWD patients
   • Increases endogenous VWF and FVIII levels
   • Available in intranasal and intravenous formulations
   • Caution needed in children <2 years due to risk of hyponatremia
2. VWF concentrate replacement therapy:
   • Used for Type 3 VWD, some Type 2 VWD, and when DDAVP is ineffective or contraindicated
   • Various plasma-derived and recombinant products available
   • Dosing based on VWF:RCo units
3. Antifibrinolytic agents:
   • Tranexamic acid or epsilon-aminocaproic acid
   • Useful for mucosal bleeding and as adjunct therapy
4. Hormonal therapy:
   • Combined oral contraceptives or levonorgestrel-releasing intrauterine devices for menorrhagia in adolescent girls
5. Topical agents:
   • Fibrin sealants or bovine thrombin for local hemostasis

Treatment should be individualized, considering the child's age, type of VWD, severity of bleeding, and the specific procedure or situation requiring hemostatic support.

Management of Von Willebrand Disease in Children

Effective management of VWD in children extends beyond acute treatment and involves a comprehensive, multidisciplinary approach:

1. Regular follow-up:
   • Periodic assessments by a pediatric hematologist
   • Monitoring growth, development, and quality of life
   • Reassessment of bleeding symptoms and treatment efficacy
2. Education:
   • Age-appropriate education for the child about VWD
   • Family education on recognizing and managing bleeding episodes
   • School staff education on the child's condition and necessary precautions
3. Preventive measures:
   • Avoidance of medications that interfere with platelet function (e.g., aspirin, NSAIDs)
   • Use of protective gear during physical activities
   • Dental hygiene to prevent gingival bleeding
4. Preparation for procedures:
   • Developing individualized treatment plans for surgeries or invasive procedures
   • Coordination with surgeons, anesthesiologists, and dentists
5. Psychosocial support:
   • Addressing emotional and social impacts of VWD
   • Encouraging normal activities with appropriate precautions
6. Transition planning:
   • Preparing adolescents for transition to adult care
   • Discussing implications for future career choices and family planning

Effective management requires a collaborative effort between the child, family, hematology team, primary care provider, and other specialists to ensure optimal outcomes and quality of life for children with VWD.

Video Notes

Von Willebrand Disease: Objective QnA

1. QUESTION: What is the primary defect in von Willebrand disease (VWD)?
   ANSWER: Quantitative or qualitative deficiency of von Willebrand factor (VWF)
2. QUESTION: Which type of VWD is the most common?
   ANSWER: Type 1 VWD
3. QUESTION: What is the inheritance pattern of Type 1 and Type 2 VWD?
   ANSWER: Autosomal dominant
4. QUESTION: Which type of VWD is characterized by a complete absence of VWF?
   ANSWER: Type 3 VWD
5. QUESTION: What are the two primary functions of VWF?
   ANSWER: Platelet adhesion to subendothelium and carrier protein for Factor VIII
6. QUESTION: Which of the following is NOT a typical symptom of VWD in children?
   ANSWER: Hemarthrosis (joint bleeding)
7. QUESTION: What is the most common bleeding symptom in children with VWD?
   ANSWER: Mucocutaneous bleeding (e.g., epistaxis, easy bruising)
8. QUESTION: Which of the following laboratory tests is most specific for VWD?
   ANSWER: VWF antigen (VWF:Ag) and VWF activity (VWF:RCo) levels
9. QUESTION: What is the typical pattern of inheritance for Type 3 VWD?
   ANSWER: Autosomal recessive
10. QUESTION: Which of the following factors can affect VWF levels in the body?
    ANSWER: ABO blood type
11. QUESTION: What is the primary treatment for mild bleeding episodes in Type 1 VWD?
    ANSWER: Desmopressin (DDAVP)
12. QUESTION: Which of the following is NOT a typical indication for VWF concentrate in VWD patients?
    ANSWER: Mild epistaxis responsive to local measures
13. QUESTION: What is the mechanism of action of desmopressin in treating VWD?
    ANSWER: Stimulation of endothelial release of stored VWF
14. QUESTION: Which subtype of Type 2 VWD is characterized by increased affinity of VWF for platelet GPIb?
    ANSWER: Type 2B VWD
15. QUESTION: What is the role of factor VIII levels in diagnosing VWD?
    ANSWER: Factor VIII levels are often decreased in VWD due to reduced VWF carrier function
16. QUESTION: Which of the following is a potential complication of severe VWD in female adolescents?
    ANSWER: Menorrhagia
17. QUESTION: What is the recommended approach for dental procedures in children with VWD?
    ANSWER: Use of antifibrinolytic agents (e.g., tranexamic acid) in addition to local hemostatic measures
18. QUESTION: Which of the following is NOT a typical feature of acquired von Willebrand syndrome?
    ANSWER: Positive family history of bleeding disorders
19. QUESTION: What is the role of VWF multimer analysis in diagnosing VWD?
    ANSWER: To distinguish between different subtypes of Type 2 VWD
20. QUESTION: Which of the following conditions can mimic VWD in children?
    ANSWER: Platelet function disorders
21. QUESTION: What is the typical bleeding time in patients with VWD?
    ANSWER: Prolonged
22. QUESTION: Which of the following is a potential complication of repeated DDAVP use in VWD patients?
    ANSWER: Hyponatremia
23. QUESTION: What is the role of genetic testing in diagnosing VWD?
    ANSWER: To confirm diagnosis in complex cases and identify specific mutations
24. QUESTION: Which of the following is NOT a typical feature of Type 2N VWD?
    ANSWER: Decreased platelet-dependent VWF activity
25. QUESTION: What is the recommended prophylactic treatment for children with severe VWD undergoing major surgery?
    ANSWER: VWF concentrate
26. QUESTION: Which of the following is a potential long-term complication of severe VWD in children?
    ANSWER: Iron deficiency anemia due to chronic blood loss
27. QUESTION: What is the role of platelet transfusion in managing bleeding in VWD patients?
    ANSWER: Generally not effective unless there is concomitant thrombocytopenia
28. QUESTION: Which of the following is NOT a typical feature of platelet-type (pseudo) VWD?
    ANSWER: Decreased VWF antigen levels
29. QUESTION: What is the recommended approach for managing VWD in pregnancy?
    ANSWER: Close monitoring of VWF levels and factor VIII levels throughout pregnancy and postpartum period
30. QUESTION: Which of the following is a potential trigger for increased VWF levels in VWD patients?
    ANSWER: Exercise or stress

Further Reading

• ASH ISTH NHF WFH 2021 Guidelines on the Diagnosis of von Willebrand Disease - Comprehensive guidelines from major hematology organizations
• International clinical practice guidelines for the management of von Willebrand disease - Journal of Thrombosis and Haemostasis guidelines
• Von Willebrand Disease in Pediatrics: A Review of the Literature - Comprehensive review article from the Journal of Pediatric Hematology/Oncology
• MASAC Document 244 - Management of Von Willebrand Disease - National Hemophilia Foundation guidelines