Hemophilia — Symptoms, Causes & Treatment | MyMedicPlus

Hemophilia is an inherited bleeding disorder caused by deficiency of clotting factors, resulting in prolonged or spontaneous bleeding. Hemophilia A (factor VIII deficiency) is the most common, affecting 1 in 5,000 male births. Hemophilia B (factor IX deficiency, Christmas disease) affects 1 in 25,000 male births. Both are X-linked recessive disorders predominantly affecting males; females are typically carriers who may have mildly reduced factor levels. Severity is classified by factor activity: severe (below 1%), moderate (1–5%), and mild (5–40%). The condition is classified by factor activity levels: severe hemophilia (factor VIII or IX below 1% of normal) causes spontaneous bleeding into joints and muscles without any injury; moderate hemophilia (1–5%) bleeds with minor trauma; and mild hemophilia (5–40%) bleeds only with significant trauma or surgery. Female carriers with lyonization can have factor levels in the mild-to-moderate range and experience significant bleeding. Extended half-life (EHL) clotting factor concentrates now allow less frequent prophylactic infusions — once or twice weekly instead of three times weekly.

Hemophilia A is caused by mutations in the F8 gene (encoding factor VIII) on the X chromosome; hemophilia B by mutations in the F9 gene (encoding factor IX). The most common F8 mutation in severe hemophilia A is intron 22 inversion (accounting for 40–45% of severe cases). Approximately 30% of hemophilia cases arise de novo (new mutations) with no family history. Female carriers with one normal and one mutant X chromosome typically have approximately 50% factor levels but may experience bleeding in low-factor-level carriers (lyonization). Acquired hemophilia — autoantibodies against clotting factors — occurs rarely as an autoimmune condition. X-linked inheritance means affected males have no normal F8 or F9 gene on their single X chromosome, causing complete or near-complete factor deficiency. Female carriers who have one normal X and one mutant X chromosome typically have around 50% of normal factor activity but can have significantly lower levels due to skewed X-inactivation (lyonization). Sporadic mutations account for approximately one-third of all new cases.

Severe hemophilia presents with spontaneous hemarthroses (bleeding into joints) — causing painful swelling, warmth, and limited movement, most commonly in knees, elbows, and ankles. Repeated hemarthroses cause progressive hemophilic arthropathy with joint destruction. Muscle hematomas (especially iliopsoas) cause severe pain and neurovascular compromise. Intracranial hemorrhage is the most dangerous complication. Moderate hemophilia bleeds with minor trauma. Mild hemophilia bleeds with significant trauma or surgery. Neonatal circumcision bleeding or intracranial hemorrhage during delivery may be the first presentation. Iliopsoas hematoma — bleeding into the iliopsoas muscle — is a particularly dangerous complication causing severe hip flexion contracture, femoral nerve compression (weakness, numbness in the anterior thigh and knee), and may be life-threatening if large. Hemarthroses in severe hemophilia can occur spontaneously, without any identifiable injury, several times per month in unprotected patients, leading to progressive synovitis, cartilage destruction, and joint destruction (hemophilic arthropathy).

The key screening test is activated partial thromboplastin time (APTT) — prolonged in hemophilia A and B, while prothrombin time (PT) and platelet count are normal. Specific clotting factor assays confirm diagnosis: factor VIII activity for hemophilia A, factor IX activity for hemophilia B. Genetic testing identifies the specific mutation for carrier detection in female relatives and prenatal diagnosis. Inhibitor testing (Bethesda assay) is essential, as approximately 25–30% of severe hemophilia A patients develop neutralizing antibodies (inhibitors) against infused factor VIII, dramatically complicating treatment. Clotting factor assays using one-stage (clotting) and chromogenic methods may give discordant results — chromogenic assays detect splice-site and missense mutations that produce functionally deficient but immunologically detectable factor VIII better than one-stage assays. This is clinically important for monitoring emicizumab therapy, which interferes with one-stage APTT-based factor VIII assays. Bethesda inhibitor titre: 1 Bethesda Unit (BU) = the antibody amount that neutralises 50% of factor activity in normal plasma.

Prophylactic factor replacement therapy — regular infusions of recombinant factor VIII (Hemophilia A) or factor IX (Hemophilia B) 2–3 times per week to maintain trough levels above 1% — is the standard of care for severe disease, preventing spontaneous bleeds and joint damage. On-demand treatment infuses factor at the time of bleeding episodes. Emicizumab (Hemlibra) is a bispecific antibody mimicking factor VIII function, given subcutaneously weekly to monthly — a major advance particularly for patients with inhibitors. Gene therapy for hemophilia A and B has achieved sustained near-normal factor levels in clinical trials, representing a potential cure. Desmopressin (DDAVP) releases endogenous factor VIII stores and is effective in mild hemophilia A. Emicizumab (Hemlibra) is a revolution for hemophilia A with inhibitors — a bispecific antibody that bridges factor IXa and factor X, mimicking the cofactor function of factor VIII, administered subcutaneously once weekly, biweekly, or monthly. It reduces annualized bleed rates by over 80% compared to prior bypassing agents. Gene therapy using adeno-associated virus (AAV) vectors has achieved sustained factor level increases — etranacogene dezaparvovec (Hemgenix) for hemophilia B and valoctocogene roxaparvovec (Roctavian) for hemophilia A received regulatory approval in 2022–2023, potentially offering functional cures.

Hemophilic arthropathy — progressive, destructive joint disease from recurrent hemarthroses — causes permanent disability in inadequately treated patients. Development of inhibitors (neutralizing antibodies to replacement factor) occurs in 25–30% of severe hemophilia A patients and is the most serious treatment complication, requiring immune tolerance induction therapy. Intracranial hemorrhage carries significant mortality and morbidity. Prior to virally inactivated recombinant products (post-1985), many hemophilia patients contracted HIV and hepatitis C from contaminated pooled plasma products — a historical tragedy that transformed global blood safety regulation.

There is no prevention for hereditary hemophilia but genetic counseling enables carrier testing and informed reproductive decisions. Preimplantation genetic diagnosis (PGD) allows selection of unaffected embryos during IVF. Prophylactic factor replacement started in early childhood (before first hemarthrosis) prevents joint damage and preserves musculoskeletal function. Avoid aspirin, NSAIDs, and anticoagulants that worsen bleeding tendency. Register with a Hemophilia Treatment Center (HTC) for comprehensive multidisciplinary care. Wear medical alert identification. Contact sports should be avoided in severe hemophilia — recommended activities include swimming and cycling.

Call emergency services (999/112) immediately for: any head injury in a person with hemophilia — even minor bumps require urgent medical assessment and brain CT scan as intracranial hemorrhage can be life-threatening; severe, rapidly expanding muscle hematoma (particularly iliopsoas — which can compress femoral nerve causing leg weakness and severe groin/hip pain); significant joint bleeding causing severe pain and inability to move the joint; any suspected internal bleeding (sudden severe abdominal pain, blood in urine without injury, neurological symptoms such as weakness or speech difficulty). Administer factor replacement immediately (at home if available) while seeking emergency care — do not wait for hospital admission before treating a serious bleed. See your haematologist urgently for: any new or unusual bleeding pattern; loss of response to factor replacement (possible inhibitor development); and planned procedures or surgery requiring haemostatic cover. All patients with hemophilia should carry a medical alert card or bracelet and have the Hemophilia Treatment Center emergency contact number accessible at all times.