Von Willebrand Disease

Overview

Von Willebrand Disease is named after Finnish physician Erik Adolf von Willebrand, who first described the condition in 1926. The disease is caused by defects in the von Willebrand factor (vWF), a large glycoprotein that plays a crucial role in hemostasis - the process by which bleeding is stopped. vWF helps platelets stick to damaged blood vessel walls and also carries factor VIII, another important clotting protein, in the bloodstream.

The condition is inherited in an autosomal pattern, meaning it affects both males and females equally. There are three main types of VWD: Type 1 (mild deficiency), Type 2 (qualitative defects with several subtypes), and Type 3 (severe deficiency). Type 1 is the most common, accounting for about 75% of cases, while Type 3 is the rarest but most severe form. Many people with mild VWD may go undiagnosed for years because their symptoms are subtle or attributed to other causes.

The prevalence of VWD varies depending on the diagnostic criteria used, but symptomatic disease requiring treatment affects approximately 0.1% of the population. The condition can significantly impact quality of life, particularly for women who may experience heavy menstrual bleeding. Early diagnosis and appropriate management can help prevent complications and improve outcomes for affected individuals.

Symptoms

Von Willebrand Disease symptoms primarily involve bleeding and bruising that is more frequent, prolonged, or severe than normal. The severity of symptoms varies significantly between individuals and types of VWD.

Common Bleeding Symptoms

• Frequent nosebleeds - often prolonged and difficult to stop
• Easy bruising from minor trauma
• Excessive bleeding from cuts or dental procedures
• Prolonged bleeding after surgery
• Heavy menstrual bleeding (menorrhagia) in women

Gastrointestinal Symptoms

• Blood in stool - may appear as dark, tarry stools or bright red blood
• Gastrointestinal bleeding from ulcers or other sources
• Bleeding from hemorrhoids that is excessive
• Rectal bleeding that is prolonged or recurrent

Musculoskeletal Symptoms

• Muscle swelling from internal bleeding (hematomas)
• Joint bleeding and swelling (hemarthrosis) - more common in severe Type 3
• Muscle pain from bleeding into muscle tissue
• Limited range of motion due to joint bleeding

Oral and Dental Symptoms

• Bleeding gums, especially during dental hygiene
• Excessive bleeding following tooth extraction
• Prolonged bleeding from mouth injuries
• Blood blisters in the mouth

Gynecological Symptoms

• Heavy menstrual periods lasting longer than 7 days
• Menstrual bleeding with clots larger than a quarter
• Bleeding between periods
• Postpartum hemorrhage
• Excessive bleeding during childbirth

Symptoms by VWD Type

• Type 1 (Mild):
  • Easy bruising
  • Occasional nosebleeds
  • Heavy menstrual bleeding
  • Mild bleeding after surgery
• Type 2 (Moderate):
  • More frequent and severe bleeding
  • Gastrointestinal bleeding
  • Significant surgical bleeding
  • May have mild joint bleeding
• Type 3 (Severe):
  • Spontaneous bleeding episodes
  • Joint and muscle bleeding
  • Life-threatening bleeding
  • Hemophilia-like symptoms

Warning Signs

• Bleeding that doesn't stop after 15 minutes of direct pressure
• Signs of anemia (fatigue, pale skin, shortness of breath)
• Sudden severe abdominal pain (possible internal bleeding)
• Neurological symptoms (possible brain bleeding)

Causes

Von Willebrand Disease is caused by genetic mutations that affect the production, structure, or function of von Willebrand factor, a crucial protein in the blood clotting process.

Genetic Basis

Von Willebrand Factor Gene

• Located on chromosome 12
• Contains 52 exons spanning 178 kilobases
• Mutations can affect quantity or quality of vWF
• Over 250 different mutations identified

Inheritance Patterns

• Type 1 and 2: Autosomal dominant inheritance
  • Only one affected parent needed
  • 50% chance of passing to each child
  • Variable expression between family members
• Type 3: Autosomal recessive inheritance
  • Both parents must carry mutations
  • 25% chance with two carrier parents
  • Most severe form

Pathophysiology by Type

Type 1 VWD

• Quantitative deficiency of normal vWF
• vWF levels 20-50% of normal
• Mild bleeding symptoms
• Most common type (75% of cases)

Type 2 VWD

• Type 2A: Loss of high molecular weight multimers
• Type 2B: Increased affinity for platelet glycoprotein Ib
• Type 2M: Decreased platelet-dependent function
• Type 2N: Decreased binding to factor VIII

Type 3 VWD

• Complete or near-complete absence of vWF
• Severe bleeding symptoms
• Often associated with factor VIII deficiency
• Rarest form (<1% of cases)

Von Willebrand Factor Function

• Primary hemostasis:
  • Mediates platelet adhesion to damaged vessels
  • Forms bridges between platelets
  • Essential for platelet plug formation
• Secondary hemostasis:
  • Carries and protects factor VIII
  • Prevents factor VIII degradation
  • Delivers factor VIII to sites of injury

Acquired von Willebrand Syndrome

• Cardiovascular conditions:
  • Aortic stenosis
  • Left ventricular assist devices
  • Hypertrophic cardiomyopathy
• Hematologic disorders:
  • Myeloproliferative neoplasms
  • Lymphoproliferative disorders
  • Monoclonal gammopathy
• Other causes:
  • Certain medications
  • Autoimmune conditions
  • Hypothyroidism
  • Uremia

Modifying Factors

• ABO blood group: Type O individuals have lower vWF levels
• Age: vWF levels increase with age
• Pregnancy: vWF levels typically increase during pregnancy
• Stress: Can temporarily increase vWF levels
• Exercise: Acute exercise can release vWF from storage

Risk Factors

Several factors influence the likelihood of having von Willebrand Disease or experiencing more severe bleeding symptoms.

Genetic Risk Factors

• Family history:
  • Strong predictor of VWD
  • May be underdiagnosed in family members
  • Variable expression within families
• Consanguinity:
  • Increased risk in related parents
  • Higher chance of recessive Type 3 VWD
• Ethnicity:
  • Type 3 more common in certain populations
  • Specific mutations associated with ethnic groups

Blood Type Influences

• Type O blood:
  • Naturally lower vWF levels (25% lower)
  • More likely to be diagnosed with Type 1 VWD
  • May have more bleeding symptoms
• Non-O blood types:
  • Higher baseline vWF levels
  • May mask mild VWD
  • Better compensated bleeding symptoms

Hormonal Factors

• Gender:
  • Equal prevalence in males and females
  • Women more likely to be diagnosed due to menorrhagia
  • Pregnancy and childbirth reveal bleeding tendencies
• Estrogen levels:
  • Can increase vWF levels
  • May improve symptoms temporarily
  • Oral contraceptives may help some patients
• Thyroid function:
  • Hypothyroidism can worsen VWD
  • Thyroid hormone affects vWF metabolism

Environmental and Lifestyle Factors

• Medications:
  • Aspirin and NSAIDs worsen bleeding
  • Anticoagulants increase bleeding risk
  • Some antibiotics affect platelet function
• Medical procedures:
  • Surgery reveals bleeding tendency
  • Dental procedures often first sign
  • Childbirth may cause severe bleeding
• Trauma and sports:
  • Contact sports increase bleeding risk
  • Even minor trauma can cause significant bleeding

Age-Related Factors

• Childhood:
  • Frequent nosebleeds and bruising
  • Bleeding after circumcision or tonsillectomy
  • May be misdiagnosed as child abuse
• Adolescence:
  • Menorrhagia in teenage girls
  • Sports-related bleeding
  • Dental procedure bleeding
• Adulthood:
  • Surgical bleeding complications
  • Pregnancy and delivery bleeding
  • Gastrointestinal bleeding

Comorbid Conditions

• Acquired conditions that worsen bleeding:
  • Liver disease
  • Kidney disease
  • Cardiovascular disease
  • Autoimmune disorders
• Conditions that may mask VWD:
  • Chronic inflammation (increases vWF)
  • Pregnancy (temporarily increases vWF)
  • Stress and illness

Diagnosis

Diagnosing von Willebrand Disease requires a combination of clinical assessment, family history, and specialized laboratory testing. The diagnosis can be challenging due to variable symptoms and test results.

Clinical Assessment

Bleeding History

• Detailed personal bleeding history
• Family history of bleeding disorders
• Response to previous surgeries or dental procedures
• Menstrual history in women
• Use of bleeding assessment tools (BAT score)

Physical Examination

• Signs of anemia (pallor, fatigue)
• Bruising patterns and severity
• Joint examination for hemarthrosis
• Lymphadenopathy or splenomegaly

Laboratory Testing

Initial Screening Tests

• Platelet count: Usually normal in VWD
• PT (Prothrombin Time): Typically normal
• aPTT (Activated Partial Thromboplastin Time):
  • May be prolonged if factor VIII is low
  • Normal in many VWD patients

Specific VWD Tests

• von Willebrand Factor Antigen (vWF:Ag):
  • Measures total amount of vWF protein
  • Reduced in Types 1 and 3
  • May be normal in Type 2
• von Willebrand Factor Activity (vWF:RCo or vWF:GPIbM):
  • Measures functional activity
  • Reduced in all types of VWD
  • Key diagnostic test
• Factor VIII Activity:
  • Often reduced in VWD
  • Severely reduced in Type 3
  • May be normal in Type 1

Additional Specialized Tests

• vWF Multimer Analysis:
  • Determines vWF structure
  • Distinguishes Type 2 subtypes
  • Loss of large multimers in Type 2A
• Platelet Function Tests:
  • Platelet aggregometry
  • Platelet function analyzer (PFA-100)
  • Bleeding time (rarely used now)
• Factor VIII Binding (vWF:FVIIIB):
  • Reduced in Type 2N VWD
  • Helps distinguish from hemophilia A

Diagnostic Criteria

Type 1 VWD

• vWF:RCo and/or vWF:Ag <30 IU/dL
• Bleeding symptoms
• Family history helpful
• Normal vWF multimers

Type 2 VWD

• vWF:RCo/vWF:Ag ratio <0.6
• Abnormal vWF multimers (most subtypes)
• Type-specific additional tests
• Bleeding symptoms

Type 3 VWD

• vWF:RCo and vWF:Ag <3 IU/dL
• Factor VIII <10 IU/dL
• Absent vWF multimers
• Severe bleeding symptoms

Diagnostic Challenges

• Variable test results:
  • vWF levels affected by stress, illness
  • May need repeat testing
  • Blood type O complicates diagnosis
• Mild symptoms:
  • May be overlooked
  • Normal initial screening tests
  • Requires high clinical suspicion
• Genetic testing:
  • May be needed in unclear cases
  • Can identify specific mutations
  • Helpful for family counseling

Treatment Options

Treatment of von Willebrand Disease aims to prevent and control bleeding episodes through various medications and supportive measures. The approach depends on the type and severity of VWD.

Pharmacological Treatments

Desmopressin (DDAVP)

• Mechanism: Releases vWF and factor VIII from storage sites
• Indications:
  • Type 1 VWD (most effective)
  • Some Type 2A patients
  • Mild bleeding episodes
  • Prophylaxis before procedures
• Administration:
  • Intravenous: 0.3 μg/kg
  • Subcutaneous: 0.3 μg/kg
  • Intranasal: 150-300 μg
  • Response typically lasts 6-8 hours
• Contraindications:
  • Type 2B VWD (can worsen thrombocytopenia)
  • Infants under 2 years
  • Severe cardiovascular disease
  • Hyponatremia risk

Factor Replacement Therapy

• vWF-containing concentrates:
  • Humate-P, Wilate, Vonvendi
  • Contains both vWF and factor VIII
  • Plasma-derived products
• Indications:
  • Type 3 VWD
  • Severe Type 2 VWD
  • DDAVP non-responders
  • Major surgery
  • Severe bleeding episodes
• Dosing:
  • Based on vWF:RCo activity
  • Loading dose: 40-80 IU/kg
  • Maintenance: 20-40 IU/kg every 8-24 hours

Antifibrinolytic Agents

• Aminocaproic acid:
  • Prevents clot breakdown
  • Useful for mucosal bleeding
  • Dose: 75-100 mg/kg every 6 hours
• Tranexamic acid:
  • More potent than aminocaproic acid
  • Oral or IV administration
  • Effective for dental procedures
  • Dose: 10-15 mg/kg three times daily

Hormonal Treatments

• Combined oral contraceptives:
  • Increase vWF levels
  • Reduce menstrual bleeding
  • First-line for menorrhagia
• Levonorgestrel IUD:
  • Dramatically reduces menstrual flow
  • Local progestin effect
  • Excellent option for women with VWD

Supportive Treatments

• Iron supplementation:
  • For iron deficiency anemia
  • Common in women with menorrhagia
  • Monitor response to therapy
• Topical agents:
  • Thrombin-containing products
  • Fibrin sealants
  • Useful for local bleeding control

Treatment by Clinical Scenario

Minor Bleeding

• Local pressure and ice
• Antifibrinolytic agents
• DDAVP if responsive
• Avoid aspirin and NSAIDs

Major Surgery

• Preoperative hematology consultation
• Factor replacement therapy
• Monitor vWF and factor VIII levels
• Postoperative bleeding precautions

Dental Procedures

• Pre-procedure DDAVP or factor concentrate
• Antifibrinolytic agents
• Local hemostatic measures
• Coordinate with dentist

Pregnancy and Delivery

• Monitor vWF levels during pregnancy
• Multidisciplinary team approach
• Delivery planning with obstetrics
• Postpartum hemorrhage prevention

Emergency Treatment

• Severe bleeding:
  • Immediate factor replacement
  • Blood transfusion if needed
  • Platelet transfusion in severe cases
  • Surgical intervention if necessary

Novel Therapies

• Emicizumab: Being studied for VWD
• Recombinant vWF: In development
• Gene therapy: Experimental approaches
• Aptamers: Potential future treatments

Prevention

While von Willebrand Disease cannot be prevented as it is inherited, bleeding complications can be minimized through proper management and lifestyle modifications.

Bleeding Prevention Strategies

• Medication awareness:
  • Avoid aspirin and NSAIDs
  • Use acetaminophen for pain relief
  • Inform healthcare providers about VWD
  • Carry medical alert information
• Activity modifications:
  • Avoid high-contact sports
  • Use protective equipment when appropriate
  • Choose safer recreational activities
  • Be cautious with sharp objects

Dental and Oral Care

• Preventive care:
  • Regular dental checkups
  • Good oral hygiene
  • Soft-bristled toothbrush
  • Fluoride treatments to prevent decay
• Procedure planning:
  • Coordinate with hematologist
  • Pre-procedure medication
  • Use of antifibrinolytic agents
  • Avoid elective procedures during illness

Menstrual Management

• Hormonal options:
  • Birth control pills
  • Progestin-containing IUD
  • Hormonal injections or patches
• Non-hormonal approaches:
  • Iron supplementation
  • Antifibrinolytic agents
  • DDAVP for heavy periods

Surgical Preparation

• Pre-operative planning:
  • Hematology consultation
  • Optimize treatment regimen
  • Coordinate with surgical team
  • Arrange blood products if needed
• Timing considerations:
  • Avoid surgery during illness
  • Plan around menstrual cycles
  • Consider seasonal factors

Family Planning

• Genetic counseling:
  • Understanding inheritance patterns
  • Risk assessment for children
  • Family screening recommendations
• Pregnancy planning:
  • Pre-conception counseling
  • Multidisciplinary care team
  • Delivery planning
  • Postpartum monitoring

Lifestyle Recommendations

• Nutrition:
  • Iron-rich diet
  • Vitamin C to enhance iron absorption
  • Adequate protein intake
  • Avoid excessive alcohol
• General health:
  • Regular medical check-ups
  • Manage comorbid conditions
  • Stress management
  • Adequate sleep

Emergency Preparedness

• Emergency kit:
  • Medical alert bracelet
  • Current medication list
  • Emergency contact information
  • Treatment summary
• Education:
  • Recognize serious bleeding
  • When to seek emergency care
  • First aid measures
  • Family member education

When to See a Doctor

Seek immediate emergency care for:

• Severe bleeding that won't stop after 15 minutes of pressure
• Blood in stool with signs of significant blood loss
• Signs of severe blood loss (dizziness, fainting, rapid heart rate)
• Head injury with bleeding or neurological symptoms
• Internal bleeding symptoms (severe abdominal pain)
• Difficulty breathing due to blood loss

Schedule urgent medical care for:

• Unusual muscle swelling or joint swelling
• Frequent, severe nosebleeds
• Heavy menstrual bleeding lasting more than 7 days
• Bleeding that interferes with daily activities
• Easy bruising from minor trauma
• Bleeding gums or oral bleeding

Consider evaluation for possible VWD if you have:

• Family history of bleeding disorders
• Excessive bleeding with surgery or dental procedures
• Heavy menstrual periods requiring frequent pad/tampon changes
• Bruising larger than a quarter from minor bumps
• Nosebleeds lasting more than 10 minutes
• Iron deficiency anemia without obvious cause

Routine follow-up needed for:

• Diagnosed VWD patients for ongoing management
• Medication monitoring and adjustment
• Pre-procedural planning
• Family members who may need screening
• Women planning pregnancy
• Children with suspected bleeding disorders

Before any surgery or procedure, inform your healthcare team if you have:

• Known von Willebrand Disease
• History of excessive bleeding
• Family history of bleeding disorders
• Current use of blood-thinning medications

Related Conditions

• Hemophilia
• Platelet Function Disorders
• Factor XI Deficiency
• Iron Deficiency Anemia
• Menorrhagia
• Thrombocytopenia

References

1. James AH, Kouides PA, Abdul-Kadir R, et al. Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel. Am J Obstet Gynecol. 2009;201(1):12.e1-8.
2. Nichols WL, Hultin MB, James AH, et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia. 2008;14(2):171-232.
3. Sadler JE, Budde U, Eikenboom JC, et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost. 2006;4(10):2103-2114.
4. Castaman G, Goodeve A, Eikenboom J. Principles of care for the diagnosis and treatment of von Willebrand disease. Haematologica. 2013;98(5):667-674.
5. Leebeek FW, Eikenboom JC. Von Willebrand's Disease. N Engl J Med. 2016;375(21):2067-2080.
6. Flood VH, Gill JC, Morateck PA, et al. Common VWF exon 28 polymorphisms in African Americans affecting the VWF activity assay by ristocetin cofactor. Blood. 2010;116(2):280-286.