Fibrinogen fragments and platelet dysfunction in uremia

Background. The uremic state is characterized by subnormal platelet aggrega tion. Fibrinogen fragments, usually absent in normal human blood, but prese nt in uremic plasma, may play a role in uremic platelet dysfunction, Methods. To examine this hypothesis, we investigated the availability and f unction of fibrinogen receptors [glycoprotein (GP) IIb-IIIa] on uremic and normal platelets, as well as the effect of fragments obtained from chymotry psin digestion of human fibrinogen on normal platelets. The availability of fibrinogen receptors was examined using anti-GP IIb-IIIa antibodies and fl ow cytometry, whereas receptor function was assessed by the receptor's abil ity to mediate fibrinogen binding and platelet aggregation. Results. Platelet aggregation and the availability of GP IIb-IIIa were lowe r in uremic patients when compared with normal controls. Flow cytometric an alysis showed that Abrinogen fragments decreased the binding of anti-CD61, an activation-independent anti-GP IIIa monoclonal antibody, to resting norm al platelets. These fragments also reduced the binding of PAC-1, an activat ion-dependent anti-GP IIb-IIIa monoclonal antibody, to adenosine diphosphat e (ADP)-activated normal platelets. In addition, the binding of radiolabele d fibrinogen to activated normal platelets and platelet aggregation in resp onse to ADP were both decreased by fibrinogen fragments. Conclusions. These: findings suggest that fibrinogen fragments impair plate let function by occupying fibrinogen receptors prior to cell activation, th us preventing the binding of intact fibrinogen to platelets after subsequen t stimulation. These observations also suggest a plausible mechanism by whi ch endogenous fibrinogen fragments present in uremic plasma may contribute to platelet dysfunction.