Haemophilia is an inherited bleeding disorder caused by deficiency or dysfunction of a coagulation factor required for effective formation of stable fibrin clots. The two principal inherited forms are Haemophilia A, caused by factor VIII deficiency or dysfunction, and Haemophilia B, caused by factor IX deficiency or dysfunction. Both impair the intrinsic pathway of coagulation and reduce the generation of thrombin needed to convert fibrinogen into fibrin.
The resulting clot is insufficiently stable, so bleeding may persist or recur after apparently minor trauma. Haemophilia is classically X-linked, meaning pathogenic variants in the relevant genes are located on the X chromosome. Because males usually have one X chromosome, a pathogenic variant can produce disease in an affected male, whereas females with one affected X chromosome are commonly carriers, although some can have clinically significant low factor levels because of lyonisation, chromosomal abnormalities or other biological factors. Severity is generally classified according to baseline factor activity, with severe disease associated with very low factor levels and spontaneous bleeding, moderate disease associated with bleeding after relatively minor trauma, and mild disease often becoming apparent during surgery, dental procedures or significant injury.
The coagulation defect in Haemophilia is a failure of adequate thrombin generation rather than an inability of blood vessels to constrict or platelets to form an initial plug. After vascular injury, platelets provide a primary haemostatic response, while the coagulation system reinforces this response with fibrin. Factor VIII normally functions as a cofactor for activated factor IX within the intrinsic tenase complex on phospholipid surfaces, substantially accelerating factor X activation.
Factor IX is a serine protease that participates in this complex after activation. When either factor is deficient, the amplification phase of coagulation is impaired and insufficient thrombin is generated to produce robust fibrin formation. This explains why routine platelet counts are generally normal and why the bleeding pattern differs from disorders primarily affecting platelets. Laboratory testing commonly shows a prolonged activated partial thromboplastin time in significant factor VIII or IX deficiency, while the prothrombin time is usually normal. Definitive diagnosis requires measurement of factor activity and, where appropriate, genetic investigation.
The clinical pattern of Haemophilia is dominated by bleeding into deep tissues and joints rather than the superficial mucosal bleeding more typical of many platelet disorders. Recurrent haemarthroses commonly affect large joints such as the knees, ankles and elbows in severe disease. Blood within a joint produces swelling and pain and, when repeated, stimulates synovial inflammation and progressive cartilage and bone damage, resulting in haemophilic arthropathy.
Muscle haematomas can compress nerves or blood vessels and can become clinically serious depending on location and volume. Intracranial haemorrhage is a medical emergency because bleeding within the skull can rapidly cause neurological injury. Gastrointestinal, urinary and postoperative bleeding can also occur. The severity of spontaneous bleeding generally correlates with baseline factor activity, but individual patients can have different bleeding phenotypes despite similar measured factor levels. Treatment history, inhibitor status, previous joint damage and other biological factors influence risk. A major objective of modern care is therefore prevention of bleeding and preservation of joint health rather than repeatedly treating established haemorrhage after it occurs.
Diagnosis begins with clinical history, family history and coagulation testing. A prolonged activated partial thromboplastin time suggests a defect affecting factors within the intrinsic or common coagulation pathways, but the test does not itself establish Haemophilia because several other conditions can produce similar results. Mixing studies can help distinguish a factor deficiency from an inhibitor by assessing whether the abnormal clotting time corrects when patient plasma is mixed with normal plasma.
Specific factor assays measure factor VIII or IX activity and establish the diagnosis and severity category. Genetic testing can identify pathogenic variants, assist carrier assessment and support family counselling. Acquired haemophilia is a distinct disorder in which autoantibodies inhibit coagulation factors, most often factor VIII, and it is not inherited in the classical X-linked manner. Differentiating inherited from acquired disease is essential because treatment strategies differ. Another important diagnostic complication is the presence of factor inhibitors, which are antibodies that neutralise replacement factor and can make standard therapy less effective.
Replacement of the deficient coagulation factor is a central treatment strategy. Factor VIII concentrates are used for Haemophilia A, while factor IX concentrates are used for Haemophilia B. Products may be plasma-derived or recombinant, with modern manufacturing and screening substantially improving safety compared with historical blood-product practices. Treatment can be episodic, meaning factor is given when bleeding occurs, or prophylactic, meaning regular administration is used to maintain haemostatic protection and reduce spontaneous bleeding.
Desmopressin can increase endogenous factor VIII and von Willebrand factor in many people with mild Haemophilia A, although its effectiveness depends on the individual's response and it is not a treatment for Haemophilia B. Antifibrinolytic medicines can provide additional support for mucosal or dental bleeding in appropriate circumstances. Modern non-factor therapies have changed management, particularly emicizumab for Haemophilia A, which mimics an important function of activated factor VIII and can be administered subcutaneously. Gene therapy has also become an important therapeutic development for selected adults, aiming to introduce genetic material capable of producing functional coagulation factor, although eligibility, durability, risks and availability require specialist assessment.
Inhibitors are among the most important complications of replacement therapy because the immune system can develop antibodies against infused factor VIII or IX. Inhibitors are particularly significant in severe Haemophilia A and can make standard factor replacement ineffective. Laboratory inhibitor measurement helps determine the magnitude of the immune response and guides treatment. Patients with inhibitors may require bypassing agents or non-factor therapies, depending on the haemophilia type and clinical situation.
Haemophilia care also involves comprehensive joint protection, physiotherapy, dental care, vaccination planning and management of surgery or invasive procedures. Exercise is generally encouraged when appropriate because stronger muscles can protect joints, but activities are selected according to individual bleeding risk and treatment coverage. Historically, repeated exposure to contaminated blood products caused devastating transmission of viruses in some haemophilia populations, particularly before modern screening and pathogen-reduction practices; this history strongly influenced contemporary emphasis on product safety. Current treatment also requires attention to venous access, adherence, treatment burden and the economic and practical implications of lifelong prophylaxis.
The inheritance pattern of Haemophilia explains why family history and genetic counselling are particularly important. An affected male passes his Y chromosome to sons and his affected X chromosome to all daughters, while a carrier female has a probability of transmitting the pathogenic X chromosome in each pregnancy. However, the absence of a known family history does not exclude Haemophilia because new pathogenic variants can occur and some family members may have been undiagnosed. Women who carry an HBB?
No, Haemophilia A involves F8 and Haemophilia B involves F9, and accurate gene identification is important for molecular counselling. Carrier women may have factor levels ranging from normal to substantially reduced and therefore should not automatically be considered protected from bleeding. Genetic testing can identify the familial variant and support reproductive choices where desired. Prenatal diagnosis and preimplantation genetic testing may be available in appropriate circumstances. Haemophilia therefore illustrates how a disorder traditionally viewed as affecting males can require lifelong recognition and care across an entire family network.
Haemophilia is distinct from von Willebrand disease and from platelet disorders even though all can cause abnormal bleeding. Haemophilia primarily impairs secondary haemostasis through deficient coagulation-factor activity, whereas platelet disorders primarily impair primary haemostasis and commonly cause mucosal bleeding, petechiae or easy bruising. Von Willebrand disease affects platelet adhesion and can secondarily reduce factor VIII stability, producing a different laboratory and clinical profile.
Another misconception is that people with Haemophilia simply bleed continuously; bleeding is instead most likely when haemostatic demand exceeds the person's ability to generate an adequate clot. Mild disease may remain undetected for many years. The modern concept of Haemophilia care has shifted from treating individual bleeding events towards sustained prophylaxis, early treatment, prevention of joint damage and individualised therapy. Advances in recombinant factors, extended-half-life products, non-factor therapies and gene therapy have substantially expanded available approaches. Nevertheless, no single treatment is appropriate for every patient, and inhibitor status, genotype, severity, age, bleeding history, comorbidities and treatment availability all affect management decisions.
