Multiple pathways of thrombin-induced platelet activation differentiated by desensitization and a thrombin exosite inhibitor

Biochem Biophys Res Commun. 1991 Dec 16;181(2):636-43. doi: 10.1016/0006-291x(91)91238-8.


Recently a thrombin receptor with a unique mechanism of activation was cloned from a megakaryocyte-like cell line (Vu et al., Cell 64:1057-1068, 1991). Thrombin cleaves a portion of this receptor creating a new N-terminus that acts as a "tethered-ligand" to activate the receptor. A thrombin receptor activating peptide (SFLLRNPNDKYEPF) homologous to the new N-terminus was shown to activate platelets. We synthesized this peptide and demonstrated that it desensitized platelets to activation by low concentrations of alpha-thrombin but not gamma-thrombin. We also synthesized a thrombin exosite inhibitor (BMS 180742) that inhibited platelet aggregation induced by low, but not high, concentrations of alpha-thrombin. In contrast, a thrombin active site inhibitor, N alpha-(2-naphthylsulfonyl-glycyl)-D,L-amidinophenylalanylpiperi dide, competitively inhibited thrombin-induced platelet aggregation. We conclude that thrombin-induced platelet activation is mediated by at least two pathways: one activated by low concentrations of alpha-thrombin and blocked by a thrombin exosite inhibitor that appears to be coupled to the "tethered-ligand" thrombin receptor, and another that is stimulated by higher concentrations of alpha-thrombin and by gamma-thrombin and does not require the thrombin exosite for activation. Both pathways are blocked by a thrombin active site inhibitor.

MeSH terms

  • Amino Acid Sequence
  • Drug Tolerance
  • Humans
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology*
  • Peptides / pharmacology*
  • Platelet Activation / drug effects*
  • Signal Transduction
  • Thrombin / antagonists & inhibitors
  • Thrombin / pharmacology*


  • Peptide Fragments
  • Peptides
  • thrombin receptor peptide (42-55)
  • BMS 180742
  • Thrombin