Heparin promotes platelet responsiveness by potentiating αIIbβ3-mediated outside-in signaling. Blood 2011 May 05;117(18):4946-52
Date
03/04/2011Pubmed ID
21368290Pubmed Central ID
PMC3100701DOI
10.1182/blood-2010-09-307751Scopus ID
2-s2.0-79955964309 (requires institutional sign-in at Scopus site) 111 CitationsAbstract
Unfractionated heparin (UFH) is a widely used anticoagulant that has long been known to potentiate platelet responses to subthreshold doses of platelet agonists. UFH has been reported to bind and induce modest conformational changes in the major platelet integrin, αIIbβ3, and induce minor changes in platelet morphology. The mechanism by which UFH elicits these platelet-activating effects, however, is not well understood. We found that both human and murine platelets exposed to UFH, either in solution or immobilized onto artificial surfaces, underwent biochemical and morphologic changes indicative of a potentiated state, including phosphorylation of key cytosolic signaling molecules and cytoskeletal changes leading to cell spreading. Low molecular weight heparin and the synthetic pentasaccharide, fondaparinux, had similar platelet-potentiating effects. Human or mouse platelets lacking functional integrin αIIbβ3 complexes and human platelets pretreated with the fibrinogen receptor antagonists eptifibatide or abciximab failed to become potentiated by heparin, demonstrating that heparin promotes platelet responsiveness via its ability to initiate αIIbβ3-mediated outside-in signaling. Taken together, these data provide novel insights into the mechanism by which platelets become activated after exposure to heparin and heparin-coated surfaces, and suggest that currently used glycoprotein IIb-IIIa inhibitors may be effective inhibitors of nonimmune forms of heparin-induced platelet activation.
Author List
Gao C, Boylan B, Fang J, Wilcox DA, Newman DK, Newman PJAuthors
Debra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of WisconsinDebra K. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Peter J. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
David A. Wilcox PhD Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdultAnimals
Antibodies, Monoclonal
Anticoagulants
Drug Synergism
Heparin
Humans
Immunoglobulin Fab Fragments
In Vitro Techniques
Mice
Models, Biological
Peptides
Platelet Activation
Platelet Aggregation Inhibitors
Platelet Glycoprotein GPIIb-IIIa Complex
Polysaccharides
Signal Transduction
