Review: Determinants and modifiers of bleeding phenotypes in haemophilia-A: General and tropical perspectives

Abstract

Haemophilia-A is an X-linked recessive bleeding disorder characterized by deficiency of FVIII. Although severity of haemophilia is largely determined by the extent to which different mutations abolish FVIII production, the overall phenotypic variations among haemophiliacs is determined by a combination of several other factors, which range from general to tropical factors on the one hand, and from genetic to immunologic and infective factors on the other hand. Determinants and modifiers of haemophilic bleeding phenotypes are important predictors of prognosis. However,  tropical determinants of haemophilic bleeding phenotypes are virtually ignored because majority of haemophilia research originated from developed non-tropical countries. The aim of this paper is to present a balanced review of the haemophilic bleeding phenotypes from general and tropical perspectives. Hence, we present a concisely updated comprehensive review of the  pathophysiologic and clinical significance of general vis-à-vis tropical determinants and modifiers of haemophilic bleeding phenotypes from genetic, immunologic and infective perspectives. Understanding of general phenotypic determinants such as FVIII gene mutations, immunological (inhibitors) and infective (e.g. hepatitis and HIV)  complications, classical thrombophilias (e.g. FV-Leiden) and non-classical thrombophilias (e.g. non-O blood groups) will throw more light into the mechanisms by which some tropical prothrombotic gene mutations (such as sickle b-globin gene) and certain chronic tropical pro-haemorrhagic parasitic infections (such as urinary and gastrointestinal helminthiasis) may modify frequency, intensity and pattern of bleeding among haemophiliacs in the tropics. The clinical significance of iron deficiency within the context of helminthiasis and haemophilia is also reviewed. More research is needed to determine the precise effect of non-classical thrombophilias such as sickling disorders and ABO blood groups on haemophilic bleeding phenotypes. Meanwhile, tropical healthcare workers should incorporate regular screening and treatment for common prohaemorrhagic parasitic diseases and iron deficiency into standard of care for management of haemophilia.

Keywords: Haemophilia Bleeding Phenotype Thrombophilia ABO blood  group Sickle cell Helminthiasis Iron deficiency