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Fibrinogen binding to human blood platelets: effect of gamma chain
carboxyterminal structure and length
EI Peerschke, CW Francis and VJ Marder
Recent evidence suggests that fibrinogen binding to platelets is mediated
by the 12 carboxyterminal amino acid residues of the gamma chain. Because
human plasma fibrinogen gamma chains differ in mol wt and carboxyterminal
amino acid sequence, we examined the effect of such gamma chain
heterogeneity on platelet-fibrinogen interactions, using two fibrinogens of
distinct composition, separated by ion exchange chromatography. One
fibrinogen possessed only gamma chains of mol wt 50,000 (F gamma 50), the
predominant gamma chain species found in plasma. The other fibrinogen
possessed equal amounts of gamma chains with mol wt 50,000 and 57,500 (F
gamma 50,57.5), with the longer gamma chain (gamma 57.5) possessing an
amino acid extension at the carboxyterminal end. The latter fibrinogen was
50% less effective than F gamma 50 in supporting ADP-induced platelet
aggregation at concentrations of .01 to 2 mg/mL. Scatchard analysis
revealed no difference in the binding affinities of the two fibrinogens to
ADP- treated platelets, but the amount of F gamma 50,57.5 that was bound to
platelets at saturation was only 50% that of F gamma 50. Fibrinogen
receptors that remained unoccupied in the presence of saturating
concentrations of F gamma 50,57.5, however, could be occupied by fresh F
gamma 50. Excess unlabeled F gamma 50 displaced both radiolabeled
fibrinogens from activated platelets, and both fibrinogens bound to the
same platelet receptor, as judged by the inhibition of binding to
stimulated platelets by a monoclonal antibody directed against the
glycoprotein (GP) IIb/IIIa complex. Furthermore, an intact GPIIb/IIIa
complex was required for these reactions, since platelets incubated with
EDTA at 37 degrees C at alkaline pH failed to aggregate and bound neither
fibrinogen in response to ADP following recalcification. Approximately 50%
of each fibrinogen bound irreversibly to platelets after one hour and
failed to dissociate in the presence of 10 mmol/L of EDTA or excess
unlabeled F gamma 50. The data demonstrate that heterodimeric F gamma
50,57.5 binds less well to platelets and supports platelet aggregation only
half as well as homodimeric F gamma 50. These results support prior
conclusions that the carboxyterminal portion of the gamma chain is
important in platelet-fibrinogen interactions, and suggest that the 20
amino acid, hydrophobic gamma chain carboxyterminal extension of F gamma
50,57.5 may sterically hinder the interaction of this fibrinogen with
platelet receptors.
Volume 67,
Issue 2,
pp. 385-390,
02/01/1986
Copyright © 1986 by The American Society of Hematology
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