title: Humanized mouse model of thrombosis is predictive of the clinical efficacy of antiplatelet agents.
abstract: BACKGROUND
  In vivo testing of novel antiplatelet agents requires informative biomarkers. By genetically modifying mouse von Willebrand factor (VWF(R1326H)), we have developed a small animal model that supports human but not mouse platelet-mediated thrombosis. Here, we evaluate the use of this biological platform as a pharmacodynamic biomarker for antithrombotic therapies.
  
  
  RESULTS
  The antithrombotic effects of several αIIbβ3 inhibitors were determined in VWF(R1326H) mutant mice infused with human platelets. Administration of abciximab, eptifibatide, or tirofiban at doses recommended for percutaneous coronary intervention (per 1 kg of body weight) significantly reduced human platelet-mediated thrombus formation in laser-injured arterioles by > 75% (P < 0.001). In contrast, clot size in wild-type control animals remained essentially unchanged (P > 0.05), results consistent with observed species differences in IC₅₀ values obtained by aggregometry. To further demonstrate that our biological platform is unique among standard mouse models, we evaluated the thrombogenic potential of platelets from healthy volunteers before and after clopidogrel therapy. Consistent with the antithrombotic effect of this agent, platelets postdrug administration formed smaller thrombi than cells before therapy and were less responsive to ADP-induced aggregation (P < 0.001).
  
  
  CONCLUSIONS
  The ability of αIIbβ3 and P2Y₁₂ inhibitors to limit human platelet clot formation at doses recommended by the American College of Cardiology/American Heart Association suggests that VWF(R1326H) mutant mice can serve as both a pharmacodynamic and a functional response biomarker, attributes essential for not only expediting drug development but also designing clinical studies.
authors.affiliation: Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Magallon
authors.forename: Jianchun
authors.initials: J
authors.lastname: Chen
authors.forename: Leroy
authors.initials: L
authors.lastname: Rabbani
authors.forename: George
authors.initials: G
authors.lastname: Dangas
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: James
authors.initials: J
authors.lastname: Bussel
authors.forename: Thomas
authors.initials: T
authors.lastname: Diacovo
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D002448:Cell Adhesion / Q000187:drug effects; D000077144:Clopidogrel; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics*; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008817:Mice, Mutant Strains; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D017713:Platelet Transfusion; D011237:Predictive Value of Tests; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism; D013045:Species Specificity; D013927:Thrombosis / Q000188:drug therapy* / Q000235:genetics; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014841:von Willebrand Factor / Q000235:genetics
chemical_list: D015415:Biomarkers; D005343:Fibrinolytic Agents; C548577:P2ry12 protein, mouse; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D058925:Receptors, Purinergic P2Y12; D014841:von Willebrand Factor; D000077144:Clopidogrel; D013988:Ticlopidine