Hemophilia

Hemophilia is a hereditary bleeding disorder characterized by a deficiency or dysfunction of specific coagulation factors, leading to impaired hemostasis and a propensity for spontaneous or excessive bleeding. The pathogenesis involves mutations in genes responsible for producing clotting factors, most commonly factor VIII or IX, resulting in reduced or absent activity of these proteins within the coagulation cascade. This deficiency disrupts the formation of a stable fibrin clot, causing prolonged bleeding following injury, surgical procedures, or even spontaneously, particularly into joints and muscles. Chronic joint bleeding leads to hemarthrosis, which can progress to debilitating arthropathy, chronic pain, and decreased mobility. Intracranial and internal hemorrhages, though less common, pose significant morbidity and mortality risks. The disease primarily affects males due to its X-linked recessive inheritance, though rare cases in females may occur due to skewed X-chromosome inactivation or homozygosity. Hemophilia significantly impacts quality of life, necessitating lifelong medical management and multidisciplinary care to prevent and treat bleeding episodes and their sequelae.

Hemophilia A

Hemophilia A, also known as classic hemophilia, results from a deficiency or dysfunction of coagulation factor VIII. It is the most common form of hemophilia, accounting for approximately 80–85% of all cases. The severity of Hemophilia A is classified based on residual factor VIII activity: severe (<1% activity), moderate (1–5%), and mild (6–40%). Clinical manifestations range from spontaneous joint and muscle bleeds in severe cases to excessive bleeding after trauma or surgery in milder forms. The underlying genetic defect most often involves inversions, deletions, or point mutations in the F8 gene located on the X chromosome.

Hemophilia B

Hemophilia B, also known as Christmas disease, is caused by a deficiency or abnormality of coagulation factor IX. It represents about 15–20% of hemophilia cases and shares clinical features with Hemophilia A, including spontaneous hemorrhages, hemarthroses, and excessive bleeding after trauma. The severity depends on the level of factor IX activity. Mutations in the F9 gene, also located on the X chromosome, are responsible for this disorder, and a rare variant known as Hemophilia B Leyden is characterized by increased factor IX levels after puberty.

Hemophilia C

Hemophilia C is a rare autosomal recessive bleeding disorder resulting from deficiency of coagulation factor XI. Unlike Hemophilia A and B, it affects both sexes equally and is more prevalent in certain populations, such as Ashkenazi Jews. Bleeding manifestations are generally milder and less predictable, often occurring after surgical procedures or trauma rather than spontaneously. The responsible gene, F11, is located on chromosome 4.

Epidemiology

Hemophilia is a rare disorder with an estimated global prevalence of approximately 1 in 5,000 male births for Hemophilia A and 1 in 25,000 to 30,000 male births for Hemophilia B. The incidence of Hemophilia C is much lower and varies by population, with higher rates observed among Ashkenazi Jews (approximately 8% heterozygote frequency). The majority of affected individuals are male due to the X-linked inheritance pattern of Hemophilia A and B, though symptomatic female carriers and rare homozygous females have been reported. The World Federation of Hemophilia estimates that over 400,000 individuals worldwide are affected by hemophilia, but underdiagnosis and limited access to diagnostic facilities in low-resource settings suggest the true prevalence may be higher. Life expectancy and quality of life have improved substantially in high-income countries due to advances in factor replacement therapy and comprehensive care, but morbidity and mortality remain elevated in areas with limited access to treatment.

Diagnosis

The diagnosis of hemophilia is based on a combination of clinical evaluation, family history, and specialized laboratory testing. Initial assessment includes a detailed personal and family bleeding history, focusing on the frequency, severity, and circumstances of bleeding episodes. Physical examination may reveal signs of chronic joint damage or soft tissue hematomas. Laboratory evaluation begins with screening tests such as prolonged activated partial thromboplastin time (aPTT) with normal prothrombin time (PT) and platelet count, suggestive of intrinsic pathway defects. Definitive diagnosis is established by specific coagulation factor assays, which quantify the activity levels of factors VIII, IX, and XI to distinguish between Hemophilia A, B, and C, respectively. Genetic testing can identify causative mutations and is particularly useful for carrier detection, prenatal diagnosis, and family counseling. In cases of acquired hemophilia or inhibitor development, additional tests such as mixing studies and inhibitor titers (Bethesda assay) are performed. Diagnostic procedures may also include imaging studies, such as ultrasound or MRI, to assess joint or soft tissue involvement in patients with recurrent bleeding.

Launched Drugs

Marstacimab is a therapeutic agent developed for the management of hemophilia, functioning as a monoclonal antibody targeting the tissue factor pathway inhibitor to enhance coagulation. Fitusiran is an RNA interference therapy designed to lower antithrombin levels and thereby rebalance hemostasis in patients with hemophilia A or B, with or without inhibitors. Concizumab is another monoclonal antibody acting against tissue factor pathway inhibitor, aiming to restore thrombin generation in individuals with hemophilia. Etranacogene dezaparvovec is an adeno-associated virus vector-based gene therapy delivering a functional copy of the factor IX gene, offering a long-term therapeutic approach for hemophilia B. Efanesoctocog alfa is a recombinant factor VIII product engineered for extended half-life, providing prophylactic and on-demand treatment for bleeding episodes in hemophilia A. Valoctocogene roxaparvovec is a gene therapy that utilizes an adeno-associated viral vector to introduce the factor VIII gene, facilitating sustained endogenous production of factor VIII in patients with hemophilia A. Coagulation factor VIIa (recombinant)-jncw, also known as eptacog beta, is a recombinant form of activated factor VII indicated for the treatment of bleeding episodes in patients with hemophilia who have developed inhibitors to factor VIII or IX. Turoctocog alfa pegol is a glycoPEGylated recombinant factor VIII concentrate with an extended half-life, used for prophylaxis and treatment of bleeding in hemophilia A. Damoctocog alfa pegol is an extended half-life recombinant factor VIII product intended for routine prophylaxis and control of bleeding in individuals with hemophilia A. Nonacog beta pegol is an extended half-life recombinant factor IX product indicated for prophylaxis and treatment of bleeding episodes in patients with hemophilia B.