von Willebrand Factor disease

Background

• Deficiency in quantity or quality of von Willebrand Factor (vWF) increasing risk of bleeding

Classification

• Type 1 (80%): mild quantitative deficiency
• Type 2 (20%): qualitative deficiency (i.e. doesn't work properly)
  • Type 2A: normal quantity, abnormal quality
  • Type 2B: enhanced GP1b-binding, leading to platelet adhesion and clearance
  • Type 2M, Type 2N
• Type 3 (<1%): autosomal-recessive absolute quantitative deficiency (i.e. none made)
• Acquired: vWF cleared by autoantibodies, sheared by aortic stenosis, or sequestered by thrombocytosis

Pathophysiology

• vWF is long multimer that helps platelet aggregation in response to endothelial damage
• vWF is released by endothelium in response to damage
• vWF binds Factor VIII as well as platelets
• It unravels, thereby exposing platelet binding sites

Epidemiology

• Most common bleeding disorder with a prevalence of 1 in 100
• Prevalence of significant bleeding is 1 in 10,000
• Most are inherited in autosomal dominant pattern (including types 1 and 2B and most 2A and 2M), though type 2N and 3, and some type 2A and 2M, are autosomal recessive

Clinical Manifestations

• Abnormal bleeding

Investigations

• CBC, PT/INR, PTT
• vWD screen: Factor VIII, vWF antigen, vWF activity (either ristocetin cofactor or collagen)
• Consider PFA-100 (in-vitro bleeding time) and blood type
• If suspecting Type 2:
  • RIPA (ristocetin-induced platelet agglutination)
  • Multimer studies for high molecular weight multimers (MHWM)
  • vWF genetic testing

	vWF-Ag	vWF-RCo	FVIII	RIPA	Multimers
Type 1	↓	↓	↓	↓	N
Type 2A	↓/N	↓↓	↓/N	↓↓	Lack of HMWM
Type 2B	↓/N	↓	↓/N	↑	Lack of HMWM
Type 2M	N	↓↓	N	↓↓	N
Type 2N	N	N	↓	N	N
Type 3	Absent	Absent	0.05 u/mL	Absent	Absent

Management

• For Type 1 and 2A
  • Desmopressin (ddAVP) 0.3mg/kg (max 20mg) IV/SC can promote release of vWF from endothelium
  • Lasts 8-12h, so can repeat q12-24h as long as needed
  • Monitor for tachyphylaxis after 4 doses