Von Willebrand Disease

The commonest inherited bleeding disorder, caused by quantitative or qualitative deficiency of von Willebrand factor (VWF), a large multimeric glycoprotein with two essential haemostatic functions: mediating platelet adhesion to exposed subendothelial collagen at sites of vascular injury, and acting as a carrier protein that stabilises factor VIII in the circulation, protecting it from premature clearance.

Classification

• Type 1 (roughly 75% of cases): partial quantitative deficiency, generally mild, autosomal dominant.
• Type 2: qualitative functional defects, subdivided:
• Type 2A: reduced high-molecular-weight multimers with decreased platelet-dependent function.
• Type 2B: gain-of-function mutation causing increased affinity for platelet GPIb, leading to spontaneous binding and clearance of high-molecular-weight multimers, often with mild thrombocytopenia (important --- DDAVP is contraindicated in this subtype, as it can worsen thrombocytopenia).
• Type 2M: decreased platelet-dependent function without loss of high-molecular-weight multimers.
• Type 2N: mutation in the factor VIII binding site, causing markedly reduced factor VIII binding and clearance, mimicking mild haemophilia A but with autosomal (not X-linked) inheritance --- an important distinction, particularly relevant when a female presents with a haemophilia-like phenotype.
• Type 3 (rare): virtually complete VWF deficiency, autosomal recessive, causing severe bleeding resembling haemophilia with markedly reduced factor VIII.
• Acquired von Willebrand syndrome: not inherited, occurs with lymphoproliferative disorders, myeloproliferative neoplasms (particularly with marked thrombocytosis, adsorbing high-molecular-weight multimers), aortic stenosis and other high-shear cardiac conditions (Heyde syndrome --- aortic stenosis with gastrointestinal angiodysplasia bleeding), hypothyroidism, and certain drugs.

• Mucocutaneous bleeding pattern, the hallmark distinguishing von Willebrand disease and platelet disorders from coagulation factor deficiencies (which cause deep tissue/joint bleeding): easy bruising, epistaxis, gum bleeding, menorrhagia (often the presenting and most burdensome symptom in women, sometimes leading to iron deficiency anaemia).
• Prolonged bleeding after surgery, dental extraction or trauma.
• Postpartum haemorrhage risk, particularly relevant given physiological VWF/factor VIII rise in pregnancy can mask type 1 disease antenatally with bleeding risk emerging postpartum as levels fall.
• Gastrointestinal bleeding, particularly in type 2/3 disease and in acquired von Willebrand syndrome (angiodysplasia bleeding, notably in aortic stenosis).
• Joint and deep muscle bleeding is uncommon and generally confined to severe type 3 disease with markedly reduced factor VIII.
• Family history of a similar bleeding pattern (though absent in de novo mutations and in the recessive/severe forms with unaffected carrier parents).

• A structured bleeding history/bleeding assessment tool (quantifying bleeding symptoms across multiple domains) is the most useful initial screening step, given the variable and sometimes subtle presentation.
• Von Willebrand factor antigen (VWF:Ag) --- quantifies the amount of protein present.
• Von Willebrand factor activity --- historically ristocetin cofactor activity (VWF:RCo), increasingly replaced by VWF activity assays with better precision (VWF:GPIbM).
• Factor VIII activity --- reduced in proportion to VWF deficiency given its carrier-protein dependence.
• The ratio of activity to antigen helps distinguish quantitative (type 1, ratio near 1) from qualitative (type 2, reduced ratio, generally below 0.7) defects.
• Multimer analysis distinguishes type 2 subtypes by pattern of multimer loss.
• Ristocetin-induced platelet aggregation at low-dose ristocetin is characteristically enhanced in type 2B, a useful discriminating test given the differing treatment implications.
• Platelet count (mild thrombocytopenia in type 2B).
• Genetic testing available for type 2N (distinguishing from haemophilia A) and for definitive subtype characterisation.
• Testing should ideally be performed outside of acute illness, pregnancy, oestrogen use or inflammation, all of which raise VWF as an acute phase reactant and can mask mild disease; repeat testing is often needed given natural variability.

• Desmopressin (DDAVP), which stimulates release of endogenous VWF and factor VIII from endothelial storage (Weibel-Palade bodies), is first-line for type 1 disease and many type 2A/2M cases, given intranasally or intravenously before minor procedures or to treat mild bleeding. A trial dose with pre/post factor level measurement ("DDAVP trial") should be performed before relying on it clinically, since response is variable.
• DDAVP is contraindicated in type 2B (risks worsening thrombocytopenia by releasing more abnormal high-affinity VWF) and ineffective in type 3 (no endogenous VWF stores to release).
• Monitor for hyponatraemia and fluid restriction with repeated DDAVP dosing, particularly in young children and the elderly.
• VWF-containing factor concentrate (plasma-derived, containing both VWF and factor VIII, or recombinant VWF concentrate) for type 2B, type 3, severe bleeding, major surgery, or when DDAVP is contraindicated or ineffective.
• Tranexamic acid as an adjunct for mucosal bleeding (menorrhagia, dental procedures, epistaxis), often combined with DDAVP or used alone for milder symptoms.
• Hormonal therapy (combined oral contraceptive, levonorgestrel intrauterine system) for menorrhagia, both controlling bleeding and, via oestrogen, raising VWF levels.
• Iron supplementation for associated iron deficiency anaemia from chronic mucosal blood loss.
• Peripartum management requires specialist planning: VWF and factor VIII typically rise substantially by term (masking mild disease), but fall rapidly postpartum, so postpartum haemorrhage risk requires proactive monitoring and prophylactic treatment planning around delivery.
• Avoid antiplatelet agents and NSAIDs where possible given additive bleeding risk.
• A full haemophilia/bleeding disorder centre with a written management plan for surgery, dental procedures and pregnancy is recommended for all but the mildest cases.
• Acquired von Willebrand syndrome: treat the underlying cause (aortic valve replacement in Heyde syndrome, treatment of the lymphoproliferative/myeloproliferative disorder), which often resolves the coagulopathy.