Increased reactivity of platelets induced by fibrinogen independent of its binding to the IIb-IIIa surface glycoprotein: A potential contributor to cardiovascular risk

Objectives. To determine whether augmented activation (degranulation) of platelets might contribute to the association between higher concentrations of fibrinogen and risk of myocardial infarction, we characterized adenosine diphosphate (ADP)induced expression of P-selectin by platelets in whole blood as a function of this exposure to selected concentrations of fibrinogen. Background. An increased risk of myocardial infarction has been associated with increased concentrations of fibrinogen. Methods. Fibrinogen was added to blood anticoagulated with corn trypsin inhibitor (a specific inhibitor of Factor XIIa without effect on other coagulation factors). Degranulation of platelets was identified by dow cytometry. Results. Addition of fibrinogen to blood did not activate platelets under basal conditions (without ADP). By contrast, a concentration-dependent increase in ADP and thrombin receptor agonist peptide (TRAP)-induced activation occurred with increasing concentrations of fibrinogen. Increased ADP-induced degranulation was apparent with the addition of 100 mg/dl of fibrinogen (p less than or equal to 0.001 for 1.5 mu mol/liter ADP, n = 10 subjects). Inhibition by abciximab of binding of fibrinogen to the surface glycoprotein IIb-IIIa did not attenuate the observed augmentation of reactivity induced by fibrinogen. Augmented degranulation was associated with uptake of fibrinogen into alpha-granules without surface binding despite pretreatment with abciximab as shown by laser scanning confocal microscopy. Conclusions. Fibrinogen in blood augments degranulation of platelets in response to ADP and is accompanied by uptake of fibrinogen into alpha-granules. Thus, elevated concentrations of fibrinogen secondary to inflammation implicated in cardiovascular risk may operate, in part, by increasing reactivity of platelets. (C) 1998 by the American College of Cardiology.