Ponce R, Armstrong K, Andrews K, Hensler J, Waggie K, Heffernan J, Reynolds T, Rogge M
ZymoGenetics, Inc, Seattle, Washington 98102, USA.
Toxicol Pathol. 2005;33(6):702-10. doi: 10.1080/15459620500330625.
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:anti-thrombin 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.
因子 XIII（FXIII）是一种凝血酶激活的血浆凝血因子，对血凝块的稳定和持久存在至关重要。在包括体外循环在内的大手术后，给予外源性 FXIII 以补充耗尽的储备，可能会减少出血并发症和输血需求。因此，在成年雄性食蟹猴（猕猴属）中建立了体外循环（ECC）模型，以评估重组人 FXIII（rFXIII）的非临床安全性。ECC 2 小时期间及之后研究动物的血液学和凝血指标与人类体外循环期间及之后报告的情况相似，包括贫血、血小板减少以及凝血和血小板激活的观察结果。在 ECC 2 小时后，对研究动物静脉缓慢推注 300 U/kg（2.1 mg/kg）或 1000 U/kg（7 mg/kg）的 rFXIII 耐受性良好，并且与 FXIII 活性的剂量依赖性增加相关。rFXIII 给药与呼吸、心电图、心率、血压、体温、临床化学、血液学（包括血小板计数）或血栓形成指标（凝血酶：抗凝血酶复合物和 D - 二聚体）或血小板激活指标（血小板因子 4 和β - 血小板球蛋白）方面无临床显著影响。对接受 rFXIII 治疗动物的脑、心、肺、肝和肾进行的特异性检查未发现提示亚临床出血或血栓形成的组织病理学改变证据。总体而言，结果表明 ECC 模型适当地复制了人类体外循环手术期间及之后报告的临床表现，并且未提示在体外循环后替代治疗中使用 rFXIII 存在重大问题。
