title: In vitro effects of recombinant activated factor VII on thrombin generation and coagulation following inhibition of platelet procoagulant activity by prasugrel.
abstract: BACKGROUND
  Prasugrel is a thienopyridyl P2Y12 antagonist with potent antiplatelet effects. At present, little is known about its effects on thrombin generation or what strategies may emergently reverse its anticoagulant effects. In the current study we evaluated whether recombinant activated factor VII may reverse prasugrel induced effects and increase thrombin generation in an in vitro model.
  
  
  METHODS
  The effect of prasugrel active metabolite, PAM (R-138727), was evaluated on platelet aggregation, thrombin generation, and rotational thromboelastometry parameters using blood from 20 healthy volunteers. Additionally, we evaluated the effects of adenosine diphosphate (ADP) and recombinant activated factor VII on restoring these parameters towards baseline values.
  
  
  RESULTS
  PAM reduced maximum platelet aggregation and led to platelet disaggregation. It also decreased peak thrombin, increased lag time, and increased time to peak thrombin. Treatment with recombinant activated factor VII restored all three parameters of thrombin generation towards baseline. ADP decreased lag time and time to peak thrombin, but had no effect on peak thrombin. When recombinant activated factor VII and ADP were combined they had a greater effect on thrombin parameters than either drug alone. PAM also increased thromboelastometric clotting time and clot formation time, but had no effect on maximum clot firmness. Treatment with either recombinant activated factor VII or ADP restored these values towards baseline.
  
  
  CONCLUSIONS
  Recombinant activated factor VII restores thrombin generation in the presence of PAM. In patients taking prasugrel with life-threatening refractory bleeding it has the potential to be a useful therapeutic approach. Additional clinical studies are needed to validate our findings.
authors.affiliation: Emory University School of Medicine, Cardiothoracic Anesthesiology and Critical Care, Emory Healthcare, Atlanta, Georgia, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Mazzeffi
authors.forename: Fania
authors.initials: F
authors.lastname: Szlam
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.forename: Kenichi A
authors.initials: KA
authors.lastname: Tanaka
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Sugidachi
authors.forename: Jerrold H
authors.initials: JH
authors.lastname: Levy
mesh_terms: D000328:Adult; D000368:Aged; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects; D015942:Factor VIIa / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D000068799:Prasugrel Hydrochloride; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*; D013916:Thrombelastography; D013917:Thrombin / Q000378:metabolism*; D055815:Young Adult
chemical_list: D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D011994:Recombinant Proteins; D013876:Thiophenes; C103587:recombinant FVIIa; D015942:Factor VIIa; D013917:Thrombin; D000068799:Prasugrel Hydrochloride
keywords: Anti-platelet drugs; Bleeding; Prasugrel; rFVIIa