Von Willebrand disease

Background

• Abbreviation: vWD
• Most common inherited bleeding disorder
• vWF has two roles:
  • 1. Acts as cofactor for platelet adhesion
  • 2. Acts as carrier protein for factor VIII extending its half life
• vWD results from quantitative or qualitative dysfunction of Von Willebrand factor

Clinical Features

• Skin and mucosal bleeding
  • Epistaxis, gingival bleeding, menorrhagia
• Hemarthrosis is unusual

Differential Diagnosis

Coagulopathy

Platelet Related

• Too few
  • Thrombocytopenia
• Nonfunctional
  • Aspirin
  • Von Willebrand disease

Factor Related

• Acquired (Drug Related)
  • Warfarin (Coumadin)
  • Unfractionated heparin
  • Low molecular weight heparin (i.e. enoxaparin (Lovenox), dalteparin)
  • Factor Xa Inhibitors (e.g. rivaroxaban, apixaban, fondaparinux, edoxaban)
  • Direct thrombin inhibitors (e.g. dabigatran, argatroban, bivalirudin)
• Illness induced
  • Vitamin K deficiency
  • Disseminated Intravascular Coagulation (DIC)
  • Liver disease induced coagulopathy
  • Uremic bleeding syndrome
• Genetic
  • Hemophilia
  • Factor VIII inhibitor
  • Lupus anticoagulant

Evaluation

• Platelet count: normal
• Bleeding time: prolonged
• PT: normal
• PTT: normal-mildly prolonged
• vWF activity level: low

Management

• Avoid ASA, NSAIDs, heparin and coordinate with hematology prior to any invasive or surgical procedures.
• Multiple therapeutic options exist for prophylaxis or treatment of bleeding. The majority of therapy utilizes Humate-P and/or desmopressin

Intermediate-Purity Factor VIII

Humate-p

VWF and factor VIII concentration is the first line therapy for vWD bleeding patients. It is contraindicated for any patient with prior history of anaphylaxis to Humate-p

• Loading dose 40 to 60 IU/kg, then 40 to 50 IU/kg every 8 to 12 hours for 3 days to keep the trough level of VWF:RCo >50%; then 40 to 50 IU/kg daily for a total of up to 7 days of treatment.
• For severe bleeding the loading dose is increased to 50 to 75 IU/kg

Wilate

Type of Hemorrhages/Surgery	Loading Dosage (IU VWF:RCo/ kg BW)	Maintenance Dosage (IU VWF:RCo/ kg BW)	Therapeutic Goal
Minor Hemorrhages	20-40 IU/kg	20-30 IU/kg every 12-24 hours	VWF:RCo and FVIII activity trough levels of >30%
Major Hemorrhages	40-60 IU/kg	20-40 IU/kg every 12-24 hours	VWF:RCo and FVIII activity trough levels of >50%
Minor Surgeries	30-60 IU/kg	15-30 IU/kg or half the loading	VWF:RCo peak level of 50% after loading dose

Platelet transfusion

• Consider if replacement therapy instituted and persistent bleeding

Desmopressin

• Induces release of vWF from endothelial storage sites
• 0.3mcg/kg IV (max 20mcg) over 30min

Aminocaproic acid (Amicar)

• Analogue of the amino acid lysine making it an inhibitor for proteolytic enzymes like plasmin, the enzyme responsible for fibrinolysis.

Recombinant Factor VIIa

• Consider in type 3 VWD patients who have developed antibodies to VWF replacement
• Increased risk of thrombosis, especially in patients with coronary artery disease

Types of Von Willebrand Disease	Pathophysiology	Therapy	Procedures
Type 1	Low levels of all proteins	Desmopressin	Desmopressin Responsive: Infuse 0.3 ug/kg to end 45 minutes before procedure. May repeat every 24 hours. For major procedures follow factor VIII levels with plan to keep troughs over 80% Not desmopressin responsive: Humate-P to achieve peak over 120% and troughs of 80%. Levels below 30%: 40-50 IU/kg followed by 20 IU/kg every 12 hours Levels above 30%: 20-40 IU/kg every day
Type 2	Abnormal protein
Type 2A	Abnormal protein leading to lower levels of high weight multimers	Desmopressin (only effective in 10%), Intermediate-Purity Factor VIII
Type 2B	Abnormal protein with increased binding to gpIIb leading to lower levels of high weight multimers	Intermediate-Purity Factor VIII
Type 2N	Lack of Factor VIII binding site leading to low Factor VIII levels	Desmopressin
Type 2M	Abnormal protein but normal multimer size	Intermediate-Purity Factor VIII
Type 3	No von Willebrand or Factor VIII present	Intermediate-Purity Factor VIII
Pseudo Von Willebrand (platelet-type)	Abnormal gpIIb leading to lower levels of high molecular weight multimers	Platelets + Intermediate-Purity Factor VIII, rVIIa

See Also

• Coagulopathy (Main)