Changes in plasma haptoglobin and alpha-2-macroglobulin in hemophiliacs receiving factor replacement therapy

Plasma proteins were studied in 84 patients with hemophilia A, who were receiving factor replacement therapy. Compared with age-matched controls, 63 patients (75%) had subnormal haptoglobin and 58 (69%) had elevated alpha-2-macroglobulin. Causes for depressed haptoglobin were sought by correlating ABO blood types, liver function tests, factor VIII procoagulant levels, and intensity of yearly exposure to clotting factor products. Subnormal haptoglobin levels in chronically transfused patients may relate in part to hemolysis from AB incompatability. However, depressed haptoglobin levels were also found in group O hemophiliacs without other evidence of hemolysis. Most patients lacked evidence of active liver disease, making synthetic deficiency unlikely. There was close correlation between depressed haptoglobin and severity of clotting factor deficiency. The degree of alpha-2-macroglobulin elevation correlated with severity of procoagulant deficiency but not with intensity of clotting factor replacement therapy. Since alpha-2-macroglobulin plays a major role in the catabolism of fibrinogen, elevated levels may represent a compensatory increase in response to exogenous fibrinogen contained in the clotting factor concentrates. Alternatively, since alpha-2-macroglobulin has potent immunosuppressive properties, the elevation may represent a response to transfused alloantigens. Whatever the underlying cause, it is likely the elevations are due to endogenous production rather than to transfusions since clotting factor concentrates contain minimal amounts of alpha-2-macroglobulin.