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Role of collagen-adherent platelets in mediating fibrin formation in
flowing whole blood
D Kirchhofer, TB Tschopp, B Steiner and HR Baumgartner
F. Hoffmann-La Roche Ltd, Pharma Division, Preclinical Research, Basel,
Switzerland.
Activated platelets provide assembly sites for coagulation enzyme complexes
and in this way can mediate coagulation during hemostasis and thrombosis.
In this study, we examined the procoagulant activity of platelets adhering
directly to fibrillar collagen, a main thrombogenic constituent of
subendothelium. For this purpose, we used a human ex- vivo thrombosis model
in which collagen-coated coverslips were exposed to flowing
nonanticoagulated blood (shear rate, 65/s) for 5.5 minutes, which led to
the deposition of adherent platelets, platelet thrombi, and fibrin. To
examine the procoagulant activity of adherent platelets only, a selective
antagonist of the platelet GPIIb-IIIa complex, Ro 44- 9883, was infused via
a mixing device, resulting in a complete abrogation of platelet thrombus
formation but leaving the collagen- adherent platelet layer intact. This
platelet layer generated increased postchamber fibrinopeptide A (FPA)
levels (203 +/- 33 ng/mL) as compared with control experiments without
infusion of inhibitor (95 +/- 13 ng/mL). Concomitantly, fibrin deposition
measured by morphometric analysis of cross-sections was also increased, as
was the platelet adhesion to collagen. An immunochemical staining of fibrin
fibers further showed that the adherent platelets formed the nuclei for
fibrin fiber formation. This increase in fibrin deposition was mediated by
the intrinsic factor X (F.X) activation complex on adherent single
platelets, because almost complete inhibition of FPA generation (9 ng/mL)
and fibrin deposition (0.4% +/- 0.2% coverage) was achieved upon coinfusion
of the GP IIb-IIIa antagonist and active site-inhibited F.IXa. The large
platelet thrombi that were deposited in control experiments contained no
significant amounts of immunodetectable fibrin except at the thrombus base,
where adherent platelets anchored the thrombi to the collagen surface.
These results suggest that the collagen-adherent platelets are important
promoters of coagulation during the initial phase of thrombogenesis by
providing assembly sites for the F.X activation complex.
Volume 86,
Issue 10,
pp. 3815-3822,
11/15/1995
Copyright © 1995 by The American Society of Hematology
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