Haemophilia and Von Willebrand Disease

Introduction

Haemostasis depends on two linked processes: primary haemostasis, in which platelets adhere and aggregate to form an initial plug, and secondary haemostasis, in which the coagulation cascade generates fibrin to stabilise it. The inherited bleeding disorders in this article span both - haemophilia disrupts the cascade, while von Willebrand disease primarily disrupts platelet adhesion, and in severe forms disrupts the cascade too.¹

Haemophilia

Genetics

Both haemophilia A and B are X-linked recessive. Males are affected (having only one X chromosome), while females are usually carriers, though carriers can have mildly reduced factor levels and a genuine bleeding tendency, particularly menorrhagia - a point often overlooked. Around one third of cases arise from a spontaneous new mutation, so a negative family history does not exclude the diagnosis.

Severity

Clinical features

• Haemarthrosis - the hallmark. Bleeding into joints (knees, ankles, elbows) causing pain, swelling, warmth and reduced movement. Recurrent bleeds cause chronic haemophilic arthropathy with joint destruction, deformity and disability
• Muscle haematomas - particularly iliopsoas bleeds, which can present with hip/groin pain, a flexed hip and femoral nerve compression, and can conceal litres of blood with few external signs
• Delayed bleeding after surgery, dental extraction or circumcision - often the presenting event in mild disease
• Intracranial haemorrhage - the leading cause of bleeding-related death; may follow apparently minor head trauma
• Prolonged bleeding from the umbilical stump, or excessive bruising as an infant begins to crawl and walk, in severe disease
• Petechiae are characteristically absent - this is deep-tissue, not mucocutaneous, bleeding

Von Willebrand disease

VWD is the commonest inherited bleeding disorder, affecting up to 1% of the population, though many cases are mild and never diagnosed. Unlike haemophilia, it is usually autosomal dominant and therefore affects males and females equally - and because menorrhagia is such a prominent feature, it is disproportionately diagnosed in women.

The two functions of von Willebrand factor

• Platelet adhesion: VWF binds exposed subendothelial collagen at sites of injury and to platelet GPIb, tethering platelets to the vessel wall - the first step of primary haemostasis
• Factor VIII carriage: VWF binds and stabilises factor VIII in the circulation, protecting it from degradation. Loss of VWF therefore causes a secondary fall in factor VIII, which is why severe VWD can prolong the APTT and mimic mild haemophilia A

Types

Clinical features

• Mucocutaneous bleeding - the characteristic pattern: epistaxis, easy bruising, gum bleeding, prolonged bleeding from minor cuts
• Menorrhagia - often the presenting complaint, and an important cause of iron deficiency anaemia in young women; VWD should be considered in any woman with heavy menstrual bleeding since menarche
• Post-operative and post-dental bleeding
• Gastrointestinal bleeding, sometimes from associated angiodysplasia
• Haemarthroses are uncommon except in severe type 3 disease

Acquired von Willebrand syndrome can also occur - notably in aortic stenosis (shear stress destroys large VWF multimers, causing GI bleeding from angiodysplasia, known as Heyde syndrome), and in myeloproliferative neoplasms with very high platelet counts.

Investigations

Initial clotting screen

Specific tests

• Factor VIII and factor IX assays - diagnose and grade haemophilia A and B respectively
• VWF antigen (quantity) and VWF activity/ristocetin cofactor assay (function) - the ratio between them distinguishes quantitative (type 1/3) from qualitative (type 2) defects
• VWF multimer analysis to subtype type 2 disease
• Mixing studies - if a prolonged APTT corrects on mixing with normal plasma, it indicates factor deficiency; if it fails to correct, it indicates an inhibitor (such as an acquired factor VIII antibody or a lupus anticoagulant)
• Genetic testing - to confirm the mutation, guide carrier detection and enable antenatal counselling
• Blood group - a practical caveat, since VWF levels are physiologically lower in blood group O, which can cause borderline results to be over-interpreted
• FBC and ferritin - to detect iron deficiency anaemia from chronic bleeding, particularly menorrhagia

Management

Haemophilia

• Factor replacement - recombinant factor VIII (haemophilia A) or factor IX (haemophilia B). Given either on demand for bleeding episodes, or as regular prophylaxis, which is now standard of care in severe haemophilia and dramatically reduces the joint damage that historically caused lifelong disability²
• Emicizumab - a bispecific monoclonal antibody that bridges factors IXa and X, mimicking the function of factor VIII. Given subcutaneously rather than intravenously and effective even in patients with inhibitors, it has substantially changed the management of haemophilia A
• Desmopressin (DDAVP) - releases stored factor VIII and VWF from endothelial cells, useful in mild haemophilia A only. It is ineffective in haemophilia B (factor IX is not stored in this way) and in severe disease
• Tranexamic acid - a helpful adjunct, particularly for mucosal and dental bleeding, though generally avoided in haematuria
• Gene therapy is now available for selected patients and offers the prospect of sustained endogenous factor production
• Avoid intramuscular injections, aspirin and NSAIDs; give vaccinations subcutaneously where possible
• Specialist haemophilia centre care, including physiotherapy to preserve joint function, dental care planning, and genetic counselling

Von Willebrand disease

• Desmopressin (DDAVP) - first line for most type 1 disease; generally avoided in type 2B (where it can worsen thrombocytopenia) and ineffective in type 3
• VWF-containing concentrate (or VWF/factor VIII concentrate) for type 3, severe type 2, or major bleeding and surgery
• Tranexamic acid - especially effective for menorrhagia, epistaxis and dental procedures
• Combined oral contraceptive pill or levonorgestrel intrauterine system for menorrhagia, which is often the dominant symptom in women
• Iron replacement for the iron deficiency anaemia that frequently accompanies chronic mucosal blood loss

Complications

• Inhibitor development - alloantibodies against infused factor, occurring in up to a third of patients with severe haemophilia A. Standard replacement becomes ineffective, requiring bypassing agents (e.g. recombinant factor VIIa, activated prothrombin complex concentrate), emicizumab, or immune tolerance induction
• Chronic haemophilic arthropathy - recurrent haemarthroses cause synovial hypertrophy, cartilage destruction and permanent joint damage, the leading cause of long-term morbidity
• Intracranial haemorrhage - the leading cause of bleeding-related death
• Compartment syndrome and nerve palsy from muscle haematomas (classically femoral nerve palsy from an iliopsoas bleed)
• Iron deficiency anaemia from chronic bleeding, particularly menorrhagia in VWD
• Transfusion-transmitted infection - historically catastrophic, with large numbers of people with haemophilia infected with HIV and hepatitis C through contaminated plasma-derived products in the 1970s and 1980s. Modern recombinant products have eliminated this risk, but affected patients still require ongoing care³

Red flags

Prognosis

With access to modern prophylactic factor replacement and specialist centre care, people with haemophilia in the UK now have a life expectancy approaching that of the general population, and children starting prophylaxis early can expect to avoid the severe arthropathy that defined the condition in previous generations.² The advent of emicizumab and, more recently, gene therapy has further reduced treatment burden.

Von Willebrand disease generally carries an excellent prognosis and a normal life expectancy, with most patients having mild type 1 disease requiring treatment only around surgery, dental work or for menorrhagia. Severe type 3 disease requires ongoing specialist management comparable to severe haemophilia. The principal remaining challenges across both conditions are inhibitor development and ensuring that milder cases - particularly women with menorrhagia - are recognised rather than going undiagnosed for years.