Dominant role of αIIbβ3 in platelet interactions with cross-linked fibrin fragment D-dimer

Author:

Buitrago Lorena1ORCID,Zafar Hina1,Zhang Yixiao2,Li Jihong1,Walz Thomas2,Coller Barry S.1

Affiliation:

1. Laboratory of Blood and Vascular Biology and

2. Laboratory of Molecular Electron Microscopy, Rockefeller University, New York, NY

Abstract

AbstractAlthough much is known about the interaction of fibrinogen with αIIbβ3, much less is known about the interaction of platelets with cross-linked fibrin. Fibrinogen residue Lys406 plays a vital role in the interaction of fibrinogen with αIIbβ3, but because it participates in fibrin cross-linking, it is not available for interacting with αIIbβ3. We studied the adhesion of platelets and HEK cells expressing normal and constitutively active αIIbβ3 to both immobilized fibrinogen and D-dimer, a proteolytic fragment of cross-linked fibrin, as well as platelet-mediated clot retraction. Nonactivated platelets and HEK cells expressing normal αIIbβ3 adhered to fibrinogen but not D-dimer, whereas activated platelets as well as HEK cells expressing activated αIIbβ3 both bound to D-dimer. Small-molecule antagonists of the αIIbβ3 RGD (Arg-Gly-Asp) binding pocket inhibited adhesion to D-dimer, and an Asp119Ala mutation that disrupts the β3 metal ion–dependent adhesion site inhibited αIIbβ3-mediated adhesion to D-dimer. D-dimer and a polyclonal antibody against D-dimer inhibited clot retraction. The monoclonal antibody (mAb) 10E5, directed at αIIb and a potent inhibitor of platelet interactions with fibrinogen, did not inhibit the interaction of activated platelets with D-dimer or clot retraction, whereas the mAb 7E3, directed at β3, inhibited both phenomena. We conclude that activated, but not nonactivated, αIIbβ3 mediates interactions between platelets and D-dimer, and by extrapolation, to cross-linked fibrin. Although the interaction of αIIbβ3 with D-dimer differs from that with fibrinogen, it probably involves contributions from regions on β3 that are close to, or that are affected by, changes in the RGD binding pocket.

Publisher

American Society of Hematology

Subject

Hematology

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