What is Von Willebrand disease?

Von Willebrand Disease: A Comprehensive Overview

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting approximately 1% of the general population, characterized by deficiency or dysfunction of von Willebrand factor (VWF), a multimeric plasma glycoprotein critical for normal hemostasis. 1

What is Von Willebrand Factor?

• Von Willebrand factor (VWF) is a multimeric plasma glycoprotein that serves two critical hemostatic functions: mediating platelet adhesion and aggregation at sites of blood vessel injury, and carrying and stabilizing coagulation factor VIII (FVIII) in the circulation 2, 1
• VWF is essential for normal hemostasis, playing a crucial role in the formation of the initial platelet plug at sites of vascular injury 2, 1

Pathophysiology of Von Willebrand Disease

• VWD results from either quantitative or qualitative deficiencies in VWF, leading to compromised hemostatic functions 2
• When VWF is deficient or defective, both platelet adhesion/aggregation and factor VIII stabilization are impaired, resulting in bleeding manifestations 2
• The impaired platelet-adhesive function prevents formation of the initial platelet plug at sites of vascular injury, resulting in mucocutaneous bleeding and easy bruising 2
• Reduced VWF leads to secondary deficiency of factor VIII, contributing to impaired secondary hemostasis 2

Classification of Von Willebrand Disease

• VWD is classified into three main types 1, 3:
  • Type 1: Partial quantitative deficiency of VWF (most common)
  • Type 2: Qualitative deficiency of VWF (further subdivided into types 2A, 2B, 2M, and 2N)
  • Type 3: Complete or virtually complete absence of VWF (most severe form)

Clinical Manifestations

• VWD is characterized by excessive mucocutaneous bleeding 3
• Common bleeding manifestations include 3:
  • Nosebleeds and bruising
  • Bleeding from minor wounds
  • Menorrhagia or postpartum bleeding in women
  • Bleeding after surgery
• Less frequent symptoms include gastrointestinal bleeding, hematomas, or hemarthroses 3
• The severity of bleeding ranges from mild in Type 1 to severe, life-threatening bleeding in Type 3 2
• In women, menorrhagia is the most common symptom, with 5-20% of women with menorrhagia found to have previously undiagnosed VWD 4

Diagnosis

• Diagnosis of VWD begins with clinical assessment of the bleeding phenotype, typically characterized by mucocutaneous and provoked bleeding 5
• Laboratory diagnosis requires multiple specialized assays to evaluate the various functions of VWF 1, 5:
  • Factor VIII coagulant activity
  • Factor VIII ristocetin cofactor activity
  • Factor VIII von Willebrand factor antigen
  • Skin bleeding time may be helpful in some cases
• VWF levels can fluctuate as an acute phase reactant, potentially resulting in falsely elevated results during stress or inflammation 1
• Testing may need to be repeated up to 3 times to ensure reliable results 1
• Molecular genetic testing of the VWF gene may be required for definitive diagnosis in complex cases 3

Treatment Options

General Approaches

• Treatment of VWD is tailored by VWD type and symptoms 5
• Main treatment options include 5, 6:
  • Antifibrinolytic agents (tranexamic acid)
  • Desmopressin (DDAVP)
  • VWF replacement therapy (plasma-derived or recombinant)

Specific Treatments

• Desmopressin (DDAVP) is indicated for 7:
  • Patients with mild to moderate classic von Willebrand's disease (Type I) with factor VIII levels greater than 5%
  • Maintaining hemostasis during surgical procedures when administered 30 minutes prior
  • Stopping bleeding in mild to moderate VWD patients with spontaneous or trauma-induced injuries
• Desmopressin is not indicated for 7:
  • Severe classic von Willebrand's disease (Type I)
  • Cases with evidence of an abnormal molecular form of factor VIII antigen
  • Patients with factor VIII levels equal to or less than 5%
• VWF replacement therapy is necessary for patients who do not respond to desmopressin, particularly those with Type 3 VWD 6

Special Considerations for Women

• For management of menorrhagia, hormonal contraceptives are the first choice of therapy for women who do not desire childbearing 4
• Women who fail hormonal contraceptives or desire pregnancy are candidates for hemostatic therapy, generally reserved for patients with VWF levels less than 50 IU/dL 4
• During pregnancy, VWF levels typically rise, often reducing the need for hemostatic therapy at delivery 4
• Interdisciplinary management of childbirth and prophylaxis in the postpartum period are needed to reduce the risk of postpartum hemorrhage 5

Important Precautions

• Desmopressin should be used with caution in patients with 7:
  • Coronary artery insufficiency and/or hypertensive cardiovascular disease
  • Conditions associated with fluid and electrolyte imbalance (cystic fibrosis, heart failure, renal disorders)
  • Predisposition to thrombus formation
• Severe allergic reactions, including anaphylaxis, have been reported rarely with desmopressin 7
• Careful fluid intake restriction is necessary when using desmopressin, especially in pediatric patients, to prevent hyponatremia and water intoxication 7

Future Directions

• As understanding of VWD pathogenesis advances, novel treatment options are likely to emerge 6
• Genomic approaches to VWD can inform diagnosis, treatment selection, assay selection, reproductive planning, and family counseling 5
• Most VWD patients have an identifiable VWF gene DNA variant, and next-generation sequencing is being increasingly adopted for more comprehensive VWF sequence information 5