Hemophilia Inhibitors Prevalence, Causes and Diagnosis

Hemophilia is a bleeding disorder that results from genetic alteration in production of coagulation factors that are important to maintain hemostasis. The commonest type is hemophilia A due to deficiency of factor VIII (FVIII), which is important zymogen co factor for clot formation. Hemophilia A is an X-linked disease that affects males at prevalence of 1:5000-10000. Hemophilia B is due to deficiency in factor (FIX) but less common with prevalence of 1:34,500 males. It is inherited also as Xlinked. Although both disorders are rarely observed; they can be very serious (life threatening) and costly for families and countries. Treatment of hemophilia is based on replacement of the deficient factor. Two types of factor concentrates are available, plasma derived (pdFVIII/IX) and recombinant (rFVIII/IX) which are associated with variable incidence of inhibitor formation rates.The development of inhibitor is the most serious and challenging complication of hemophilia treatment with the enormous economic burden (1). FVIII inhibitors are immunoglobulin IgG (IgG1 and IgG4) antibodies that neutralize FVIII procoagulant activity in plasma. Inhibitors are usually classified according to their levels in plasma as a “high-titer” inhibitors, those with the highest activity >5 Bethesda Units (BU)/ml or a low-titer inhibitor type. In hemophilia A aproximately 60-70% of inhibitors are high titer inhibitors, and the remainder are low titer. Some patients develop transient inhibitors (usually low titer inhibitors that never exceed a titer of 5 BU/ml and disappear spontaneously with time (2). The development of inhibitors is associated with changes in the clinical picture with major effect on bleeding control, arthropathy status and overall quality of life. Patients with mild or moderate hemophilia may change to severe clinical behavior because of increase in factor clearance. Patients with inhibitors are resistant to the replacement therapy and thereby their bleeding symptoms become difficult to control and require either large doses of FVIII/IX or alternative hemostatic therapy with bypassing agents. During almost 50 years many studies have addressed different aspects of inhibitors issue from risk factors to diagnosis and management of patients who developed these antibodies.