L09: Haemostasis 4 – Von Willebrand Disease and Vascular Disorders

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting approximately 1% of the population. It is caused by quantitative or qualitative defects in von Willebrand factor (vWF), the large multimeric glycoprotein critical for platelet adhesion at high shear and as a carrier for factor VIII in the circulation.

vWF is synthesised by endothelial cells and megakaryocytes. In plasma it circulates as multimers ranging from small dimers to enormous ultra-large forms comprising up to 40 subunits, held together by disulfide bonds. ADAMTS13, a plasma metalloprotease, cleaves these multimers into smaller, less adhesive forms, preventing pathological platelet aggregation. The largest multimers are the most haemostatically active: they uncoil under arterial shear stress to present binding sites for GPIb on platelets and for collagen on the subendothelium.

vWF also binds and protects factor VIII from premature proteolytic degradation; consequently, vWF deficiency leads to secondary FVIII deficiency and may mildly prolong the APTT.

VWD is classified into three main types. Type 1 is the most common (70–80% of cases) and involves a partial quantitative reduction in vWF; inheritance is autosomal dominant. Affected individuals bleed from mucosal surfaces: epistaxis, menorrhagia, and excessive post-operative bleeding. Type 2 comprises qualitative subtypes (2A, 2B, 2M, 2N) involving dysfunctional vWF. Type 3 is rare, severe, and involves near-complete absence of vWF with both mucocutaneous and deep-tissue bleeding.

Laboratory diagnosis: PFA-100 closure time is prolonged (platelet-dependent primary haemostasis is impaired). Specific tests include vWF antigen level, vWF ristocetin cofactor activity (measures functional vWF), and vWF multimer analysis by gel electrophoresis. APTT may be mildly prolonged due to secondary FVIII deficiency.

Treatment of Type 1 VWD: desmopressin (DDAVP) is a synthetic vasopressin analogue that triggers release of vWF from Weibel-Palade bodies in endothelial cells, raising plasma vWF levels two- to fourfold within 30–60 minutes. It is given IV or intranasally for minor procedures and bleeding episodes. Tachyphylaxis (reduced response with repeated doses) occurs because endothelial stores are depleted. Tranexamic acid (an antifibrinolytic agent that competitively inhibits lysine binding sites on plasminogen, blocking fibrin degradation) is used as adjunctive treatment, particularly for mucosal bleeding and menorrhagia.

Vascular disorders cause bleeding by weakening or disrupting blood vessel walls. Senile purpura results from age-related loss of perivenular connective tissue support, causing easy bruising in sun-exposed skin. Scurvy (vitamin C deficiency) causes perifollicular haemorrhage because ascorbic acid is required for hydroxylation of proline and lysine in collagen synthesis; without proper collagen, vessels are structurally fragile. IgA vasculitis (Henoch-Schönlein purpura) is an immune-complex–mediated small-vessel vasculitis causing palpable purpura predominantly on the buttocks and lower extremities, arthritis, abdominal pain, and renal involvement. In all vascular disorders, platelet count, PT, and APTT are normal.