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CLINICAL STUDIES

Increased reactivity of platelets induced by fibrinogen independent of its binding to the IIb-IIIa surface glycoprotein:

a potential contributor to cardiovascular risk

^a Department of Medicine, The University of Vermont College of Medicine, Burlington, Vermont, USA
^b Department of Pathology, The University of Vermont College of Medicine, Burlington, Vermont, USA

Manuscript received November 18, 1997; revised manuscript received August 10, 1998, accepted September 10, 1998.

Address for correspondence: Dr. David J. Schneider, Cardiovascular Division, Colchester Research Facility, University of Vermont, 55A South Park Drive, Colchester, Vermont 05446
djschnei{at}zoo.uvm.edu

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 flow 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 0.001 for 1.5 µmol/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 -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 -granules. Thus, elevated concentrations of fibrinogen secondary to inflammation implicated in cardiovascular risk may operate, in part, by increasing reactivity of platelets.

Abbreviations and Acronyms   ADP = adenosine diphosphate   FITC = fluorescein isothiocyanate   PBS = phosphate buffered saline   PE = phycoerythrin   TRAP = thrombin receptor agonist peptide

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