Pathophysiology of bleeding diathesis in haemophilia-A: A sequential and critical appraisal of non-FVIII related haemostatic dysfunctions and their therapeutic implications

Abstract

Haemophilia-A is characterized by deficiency of FVIII, but the bleeding diathesis is not a mere reflection low FVIII activity. The pathophysiology of haemophilic bleeding diathesis is a complex interplay between defective procoagulant function and up-regulated fibrinolysis. Moreover, haemophilic bleeding diathesis is frequently compounded by treatment-related and infective complications such as FVIII inhibitors, hepatitis, HIV infection, non-steroidal anti-inflammatory drugs (NSAID) induced gastritis, and infective mucosal injuries such as H pylori gastritis and intestinal and urinary helminthiasis. Hence, pathophysiology of haemophilic bleeding is multi-factorial, encompassing both FVIII and non-FVIII haemostatic defects. Currently available literature on pathophysiologic roles of non-FVIII haemostatic defects in haemophilia is fragmented. This articles is aimed at providing a composite and comprehensive review of the roles of non-FVIII haemostatic defects and their therapeutic implications in haemophilic bleeding diathesis, which will enable a holistic approach towards clinical management of the bleeding diathesis. This is necessary because FVIII therapy alone maybe insufficient in managing complicated haemophilic bleeding unless compounding non-FVIII-related haemostatic dysfunctions and comorbidities are identified, targeted and treated. This will necessitate appropriate use of non-FVIII therapeutic modalities, which may include anti-fibrinolytic agents, FVIII by-passing agents, immune modulation, and anti-microbial agents. Lots of work has been done in the areas of non-FVIII agents and FVIII by-pass therapy in the management of haemophilia, but more research is needed to validate many of these targeted therapeutic techniques. Meanwhile, healthcare personnel must consider the roles of both FVIII and non-FVIII haemostatic defects when evaluating haemophilic bleeding diathesis for the purpose of choosing appropriate and optimal treatment options.

Keywords: Haemophilia, Bleeding diathesis, Pathophysiology, Targeted therapy, Non-FVIII therapy, FVIII by-pass