title: A 2-step mechanism of arterial thrombus formation induced by human atherosclerotic plaques.
abstract: OBJECTIVE
  The aim of this study was to understand the initial mechanism of arterial thrombus formation induced by vulnerable human atherosclerotic plaques to re-assess and improve current antithrombotic strategies.
  
  
  BACKGROUND
  Rupture of atherosclerotic plaques causes arterial thrombus formation that might lead to myocardial infarction and ischemic stroke. Atherothrombosis is considered as an inseparable tangle of platelet activation and coagulation processes, involving plaque components such as tissue factor (TF) and collagen as well as blood-borne TF and coagulation factor XIIa (FXIIa). A combination of anticoagulants and antiplatelet agents is the present treatment.
  
  
  METHODS
  Human atheromatous plaque material was exposed to blood or blood components at physiological calcium/magnesium concentration. Platelet aggregation and coagulation were measured under static and arterial flow conditions by state-of-the-art microscopic and physiological techniques. Plaque TF, plaque collagen, FXIIa, and platelet glycoprotein VI (GPVI) were specifically inhibited.
  
  
  RESULTS
  Plaques induced thrombus formation by 2 discrete steps. The rapid first phase of GPVI-mediated platelet adhesion and aggregation onto plaque collagen occurred within 1 min. The second phase of coagulation started after a delay of >3 min with the formation of thrombin and fibrin, and was driven entirely by plaque TF. Coagulation occurred only in flow niches provided by platelet aggregates, with no evidence for a role of blood-borne TF and FXIIa. Inhibition of GPVI but not plaque TF inhibited plaque-induced thrombus formation.
  
  
  CONCLUSIONS
  The major thrombogenic plaque components--collagen and TF--induce platelet activation and coagulation, respectively, in 2 consecutive steps. Targeting specifically the first step is crucial and might be sufficient to inhibit atherothrombus formation.
authors.affiliation: Department of Transfusion Medicine and Hemostaseology, Clinic of Anaesthesiology, University Clinic Munich, Munich, Germany.
authors.forename: Armin J
authors.initials: AJ
authors.lastname: Reininger
authors.forename: Isabell
authors.initials: I
authors.lastname: Bernlochner
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Penz
authors.forename: Catherine
authors.initials: C
authors.lastname: Ravanat
authors.forename: Peter
authors.initials: P
authors.lastname: Smethurst
authors.forename: Richard W
authors.initials: RW
authors.lastname: Farndale
authors.forename: Christian
authors.initials: C
authors.lastname: Gachet
authors.forename: Richard
authors.initials: R
authors.lastname: Brandl
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Siess
mesh_terms: D050197:Atherosclerosis / Q000150:complications* / Q000473:pathology; D003094:Collagen; D005260:Female; D005337:Fibrin; D006801:Humans; D008297:Male; D015539:Platelet Activation / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins; D013917:Thrombin; D013925:Thromboplastin; D013927:Thrombosis / Q000209:etiology* / Q000503:physiopathology*
chemical_list: D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D005337:Fibrin; D003094:Collagen; D013925:Thromboplastin; D013917:Thrombin