title: Thrombotic safety of prothrombin complex concentrate (Beriplex P/N) for dabigatran reversal in a rabbit model.
abstract: BACKGROUND
  In vivo animal data have shown prothrombin complex concentrate (PCC) to be effective in preventing bleeding induced by excessive plasma levels of the direct thrombin inhibitor dabigatran. This animal model study was designed to determine the risk of thrombosis associated with administration of a PCC (Beriplex P/N) to reverse dabigatran-induced bleeding.
  
  
  METHODS
  Anesthetized rabbits were treated with initial 0, 75, 200 or 450 μg kg(-1) dabigatran boluses followed by continuous infusions to maintain elevated plasma dabigatran levels. At 15 min after the start of dabigatran administration, PCC doses of 0, 50 or 300 IU kg(-1) were administered. Thereafter, coagulation in an arteriovenous (AV) shunt was evaluated and histopathologic examination for thrombotic changes performed. Venous thrombosis was also assessed in a modified Wessler model.
  
  
  RESULTS
  At the suprapharmacologic dose of 300 IU kg(-1), PCC increased thrombus weight during AV shunting, but this effect could be prevented by dabigatran at all tested doses. AV shunt occlusion after PCC administration was delayed by 75 μg kg(-1) dabigatran and abolished by progressively higher dabigatran doses. High-dose treatment with 300 IU kg(-1) PCC resulted in histologically evident low-grade pulmonary thrombi; however, that effect could be blocked by dabigatran in a dose-dependent manner (p=0.034). In rabbits treated with high-dose PCC, dabigatran inhibited thrombus formation during venous stasis. PCC effectively reversed dabigatran-induced bleeding.
  
  
  CONCLUSIONS
  In this animal study, thrombosis after PCC administration could be prevented in the presence of dabigatran. PCC reversed dabigatran-induced excessive bleeding while retaining protective anticoagulatory activity of dabigatran.
authors.affiliation: CSL Behring GmbH, Marburg, Germany. Electronic address: Eva.Herzog@cslbehring.com.
authors.forename: Eva
authors.initials: E
authors.lastname: Herzog
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Franz J
authors.initials: FJ
authors.lastname: Kaspereit
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Krege
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Baerbel
authors.initials: B
authors.lastname: Doerr
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
authors.forename: Joanne
authors.initials: J
authors.lastname: van Ryn
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dickneite
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Pragst
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D000069604:Dabigatran; D004195:Disease Models, Animal; D004338:Drug Combinations; D005164:Factor IX / Q000008:administration & dosage / Q000633:toxicity*; D005167:Factor VII / Q000008:administration & dosage / Q000633:toxicity*; D005170:Factor X / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D006470:Hemorrhage / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D006490:Hemostatics / Q000008:administration & dosage / Q000633:toxicity*; D011516:Prothrombin / Q000008:administration & dosage / Q000633:toxicity*; D011817:Rabbits; D018570:Risk Assessment; D012307:Risk Factors; D013917:Thrombin / Q000378:metabolism; D013997:Time Factors; D020246:Venous Thrombosis / Q000097:blood / Q000139:chemically induced* / Q000517:prevention & control
chemical_list: D004338:Drug Combinations; D006490:Hemostatics; C525441:factor IX, factor VII, factor X, prothrombin drug combination; D005167:Factor VII; D011516:Prothrombin; D005164:Factor IX; D005170:Factor X; D013917:Thrombin; D000069604:Dabigatran
keywords: Anticoagulants; Antithrombins; Hemorrhage; Prothrombin complex concentrates; Thrombosis