von-Willebrand's disease (vWD)

Classification

• Type 1
  • most common form (90% of cases)
  • heterozygotes with variable symptomatology
• Type 2
  • decreased functional activity of von Willebrand factor (vWF)
  • Type 2A
    • absence of HMW vWF multimers
  • Type 2B (rare)
    • absence of HMW vWF multimers
    • increased affinity for glycoprotein 1b resulting in platelet agglutination (in vivo) & thrombocytopenia
    • enhanced ristocetin-induced platelet aggregation
  • Type 2M
    • abnormal vWF without absence of HMW vWF multimers
  • Type 2N
    • qualitative variants with defective binding of factor VIII resulting in low factor VIII due to increased catabolism
• Type 3 (rare)
  • joint & deep muscle bleeding
  • vWF assays reflect severe deficiency

Etiology

Acquired form:

• antibody to von Willebrand factor (vWF), may be associated with:
  • B-cell lymphoproliferative disorders
  • systemic autoimmune disorders
  • hypothyroidism
  • myeloproliferative disorders
• disruption of HMW vWF multimers due to turbulent blood flow
  • aortic valvular stenosis -> Heyde's syndrome
  • LV assist device

Epidemiology

• most common bleeding disorder
• most common platelet disorder (others are rare)
• 20% of individuals with type O blood have mild vWD
• acquired form is uncommon

Pathology

• vWF deficiency
• vWF adheres platelets to injured blood vessels
• vWF acts as carrier for factor VIII & protects factor VIII from degradation

Genetics

• autosomal dominant (types 1 & 2)
• compound heterozygote disorder (type 3)
• associated with defects in vWF
• associated with defects in GP1BA

Clinical manifestations

• mucocutaneous bleeding that mimics thrombocytopenia
• bleeding is generally mild
  • epistaxis
  • skin ecchymoses
  • easy bruising, cutaneous hematomas
  • prolonged bleeding from trivial wounds
  • oral cavity bleeding, bleeding gums
  • bleeding from tooth extractions
• heavy bleeding at menarche is often the presenting symptom
  • menorrhagia
  • endometriosis
  • postpartum hemorrhage
• bleeding associated with surgery or trauma
  • severe post-operative hemorrhage is uncommon
• hemarthrosis is rare
• bleeding may be exacerbated by aspirin

Laboratory

• von Willebrand factor antigen
  • low normal levels may be difficult to interpret if factors that increase levels are present
  • levels increase in response to estrogens, stress, bleeding, exercise, inflammation
• vWF activity in plasma is < 30% of normal
  • ristocetin cofactor activity is low
• bleeding time is prolonged*
  • may be normal in mild cases
• aPTT may be increased* - factor VIII effect
  • may cause slight prolongation of the aPTT
  • aPTT corrects in mixing studies even with acquired von Willebrand disease
• PT is normal
• coagulation factor VIII in plasma may be low
• platelet function analysis (PFA)
  • ristocetin-induced platelet aggregation response is impaired (except type 2B)
  • response to ADP, collagen, epinephrine & thrombin is normal
  • in acquired form, ristocetin-induced platelet aggregation response may NOT be impaired
    • antibody may be a cell surface immunoglobulin
    • antibody may not bind to active site of vWF, but rather increases clearance of vWF from circulation
  • type 2B shows enhanced ristocetin-induced platelet aggregation
• vWF multimers in plasma is used to identify subtypes (see Classification)
• VWF gene mutation
• complete blood count
  • platelet count is normal
• see ARUP consult
• Test results for vWD are affected by pregnancy, use of estrogen/progestin contraceptives, menstrual cycle timing, & laboratory quality

* only hereditary disorder characterized by prolonged bleeding time & prolonged aPTT (initial diagnostic studies)

Complications

• coagulation factor VIII may be low in von Willebrand's disease

Differential diagnosis

• hereditary hemorrhagic telangiectasia
  • associated with arteriovenous malformations, headache
• factor XII deficiency
  • not associated with clinical bleeding
• factor XIII deficiency
  • aPTT normal, severe bleeding
• acquired factor VIII inhibitor
  • severely prolonged aPTT (90 sec) not corrected by mixing with normal plasma
  • 3 weeks after caesarean section
  • massive subcutaneous or intramuscular bleeding if not associated with pregnancy
• platelet storage disorder
  • Glanzmann thrombasthenia
    • no decrease in factor VIII
    • primarily manifests as mucosal bleeding & petechiae

Management

• intranasal desmopressin (DDAVP, Stimate) PRN for mild cases
  • causes release of vWF & factor VIII from endothelial cells
  • useful for type 1
  • contraindicated for type 2B & with active cardiovascular disease
    • induces platelet aggregation
  • prophylactic administration prior to dental procedures & other minimally invasive procedures
  • associated with hyponatremia
• estrogen-containing oral contraceptives for menorrhagia
• cryoprecipitate for active bleeding
  • do not use due to risk of transfusion-associated infection
• viral-inactivated vWF-rich factor VIII concentrate is effective for all patients
  • useful for treatment of type 1 (most common type)
  • used to treat types 2B & 3
  • indicated for patients undergoing major surgery
  • useful for bleeding complications after minor surgery
• recombinant von Willebrand factor (Vonvendi)
  • FDA-approved Dec 2015
  • used for major bleeding & rare subtypes 2B & 3
• vWD not necessarily an absolute contraindication to antiplatelet therapy or anticoagulant therapy in patients with cardiovascular disease
• after major surgery, goal for factor VIII & VWF is >= 0.50 IU/mL for >= 3 days
• hormonal therapy (combined hormonal contraception or an intrauterine device) or tranexamic acid preferred vs desmopressin in women with menorrhagia
• with neuraxial anesthesia during labor, target vWF 0.5-1.5 IU/mL during anesthesia & for >= 5 hours after

More general terms

• platelet disorder; thromboasthenia
• chronic hematologic disease (chronic blood disorder)

Additional terms

• bleeding time
• von Willebrand factor; vWF; ristocetin cofactor; factor VIII related antigen; contains: von Willebrand antigen 2 (VWF, F8VWF)
• von Willebrand's disease in pregnancy

Patient information

von-Willebrand's disease (vWD) patient information

Database

• OMIM: https://mirror.omim.org/entry/177820
• OMIM: https://mirror.omim.org/entry/277480