Congenital Haemophilia A and B: An Overview of Pathophysiology, Clinical Expression and Contemporary Management
Yasmin Mohammed Alnajiar
Mashreq University, Khartoum, Sudan.
Khalid Hussein Bakheit *
Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
*Author to whom correspondence should be addressed.
Abstract
Haemophilia A and B are X-linked bleeding disorders caused by deficiency of coagulation factor VIII and factor IX, respectively. Therapeutic options have changed more in the past decade than in the preceding half-century, with subcutaneous substitution and rebalancing agents, ultra-extended factor concentrates and liver-directed gene transfer all entering routine or near-routine use. This critical narrative review examines how far that therapeutic transformation is matched by the underlying evidence, and where the clinical and conceptual foundations of haemophilia care remain unsettled. Literature was identified through structured searching of bibliographic and open scholarly sources, supplemented by citation tracking and authoritative institutional reporting, and was appraised for design, measurement validity, representativeness and consistency rather than catalogued descriptively. Several conclusions are robust: factor activity determines broad bleeding risk but predicts individual phenotype only loosely; early prophylaxis prevents structural joint damage whereas prophylaxis begun after arthropathy is established improves function without reversing structure; and all currently licensed bleed-prevention strategies reduce bleeding rates substantially when compared with episodic treatment. Other widely held positions are weaker than their citation frequency suggests. The relative immunogenicity of plasma-derived and recombinant factor VIII remains contested between a randomised trial and large observational cohorts whose discrepancy is not fully explained by design alone. Annualised bleeding rate, the endpoint on which almost all regulatory evidence rests, is insensitive to subclinical joint bleeding and to the outcomes patients prioritise. Gene therapy produces durable but declining and highly variable factor expression, and its comparative position against modern non-factor prophylaxis has not been tested directly. Across every domain, the evidence base is geographically narrow, drawn predominantly from high-income settings in which fewer than one in five people with haemophilia worldwide receive care. Priorities for the next decade include head-to-head comparisons of bleed-prevention strategies, joint-structure endpoints with demonstrated measurement properties, prospective evaluation of thrombotic risk with rebalancing agents, and evidence generated in the settings where most undiagnosed disease resides.
Keywords: Haemophilia A, haemophilia B, haemophilic arthropathy, factor VIII, factor IX, emicizumab, gene therapy, health equity