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Safety of Recombinant Human Factor XIII in a Cynomolgus Monkey Model of Extracorporeal Blood Circulation
1 ZymoGenetics, Inc., Seattle, Washington, USA Correspondence: Address correspondence to Dr. Rafael Ponce, ZymoGenetics, Inc., 201 Eastlake Ave. E., Seattle, Washington 98102, USA; e-mail:reap{at}zgi.com
Factor XIII (FXIII) is a thrombin-activated plasma coagulation factor critical for blood clot stabilization and longevity. Administration of exogenous FXIII to replenish depleted stores after major surgery, including cardiopulmonary bypass, may reduce bleeding complications and transfusion requirements. Thus, a model of extracorporeal circulation (ECC) was developed in adult male cynomolgus monkeys (Macaca fascicularis) to evaluate the nonclinical safety of recombinant human FXIII (rFXIII). The hematological and coagulation profile in study animals during and after 2 h of ECC was similar to that reported for humans during and after cardiopulmonary bypass, including observations of anemia, thrombocytopenia, and activation of coagulation and platelets. Intravenous slow bolus injection of 300 U/kg (2.1 mg/kg) or 1000 U/kg (7 mg/kg) rFXIII after 2 h of ECC was well tolerated in study animals, and was associated with a dose-dependent increase in FXIII activity. No clinically significant effects in respiration, ECG, heart rate, blood pressure, body temperature, clinical chemistry, hematology (including platelet counts), or indicators of thrombosis (thrombin:antithrombin complex and D-Dimer) or platelet activation (platelet factor 4 and beta-thromboglobulin) were related to rFXIII administration. Specific examination of brain, heart, lung, liver, and kidney from rFXIII-treated animals provided no evidence of histopathological alterations suggestive of subclinical hemorrhage or thrombosis. Taken as a whole, the results demonstrate the ECC model suitably replicated the clinical presentation reported for humans during and after cardiopulmonary bypass surgery, and do not suggest significant concerns regarding use of rFXIII in replacement therapy after extracorporeal circulation.
Key Words: Factor XIII • cardiopulmonary bypass • extracorporeal circulation • preclinical safety • cynomolgus monkey • coagulation factor Abbreviations: rFXIII: rA2, Recombinant human FXIII [A2] dimer • FXIII pFXIII, A2B2, Plasma FXIII [A2B2] heterotetramer • cFXIII, Cellular, placental, or platelet FXIII [A2] dimer • A2, Factor XIII A-dimer • A2*, Activated Factor XIII A-dimer • CPB, Cardiopulmonary bypass • ECC, Extracorporeal circulation • ECG, Electrocardiography • TAT, Thrombin:antithrombin complex • PF4, Platelet factor 4 • β-TG, β-Thromboglobulin • ACT, Activated whole blood clotting time • aPTT, Activated partial thromboplastin time • PT, Prothrombin time • PPACK, Phe-Pro-Arg-chloromethylketone
Toxicologic Pathology, Vol. 33, No. 6,
702-710 (2005) |
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