Von Willebrand disease

Background

• 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

Diagnosis

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

Treatment

• Avoid ASA, NSAIDs, heparin

Intermediate purity factor VIII

• Goal to increase VWF activity by 50-100%
• Initial infusion of 20-40 IU/Kg
• High replacement doses may be indicated in more severe disease

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%), Humate-P
Type 2B	Abnormal protein with increased binding to gpIIb leading to lower levels of high weight multimers	Humate-P
Type 2N	Lack of Factor VIII binding site leading to low Factor VIII levels	Desmopressin
Type 2M	Abnormal protein but normal multimer size	Humate-P
Type 3	No von Willebrand or Factor VIII present	Humate-P
Pseudo Von Willebrand (platelet-type)	Abnormal gpIIb leading to lower levels of high molecular weight multimers	Platelets + Humate-P, rVIIa

References

• Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 7e (2010), Chapter 230. Hemophilias and Von Willebrand Disease