Topical recombinant thrombin at a concentration of 1000 IU/mL reliably shortens in vivo TTH and delivers durable hemostasis in the presence of heparin anticoagulation and clopidogrel platelet inhibition in a rabbit model of vascular bleeding.

Steven D Hughes, Paul D Bishop, Richard Garcia, Tracy Zhang, W Allan Alexander
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引用次数: 14

Abstract

Background: This study was designed to evaluate the effect of recombinant human thrombin (rThrombin) concentration on time to hemostasis (TTH), clot durability, and clot strength in settings that replicate the heparinization and platelet inhibition often found in surgical populations.

Methods: A modified, anticoagulated rabbit arteriovenous shunt preparation was selected to model vascular anastomotic bleeding. Rabbits were treated with heparin or heparin + clopidogrel and TTH was measured after applying a range of topical rThrombin concentrations or placebo, in combination with absorbable gelatin sponge, USP. Treatments (placebo, rThrombin) were randomly assigned and the investigator was blinded to treatment. TTH was evaluated with the Kaplan-Meier method. After hemostasis was achieved, clot burst assessment was performed for heparin + clopidogrel treated animals. Clot viscoelastic strength and kinetics were measured in ex-vivo samples using thromboelastography (TEG) methods.

Results: TTH decreased with increasing concentrations of rThrombin in heparin-treated animals and was shorter after treatment with 1000 IU/mL rThrombin (73 seconds) than with 125 IU/mL rThrombin (78 seconds; p = 0.007). TTH also decreased with increasing concentrations of rThrombin in heparin + clopidogrel treated animals; again it was significantly shorter after treatment with 1000 IU/mL rThrombin (71 seconds) than with 125 IU/mL rThrombin (177 seconds; p < 0.001). Variability in TTH was significantly smaller after treatment with 1000 IU/mL rThrombin than after 125 IU/mL rThrombin, indicating greater reliability of clot formation (p < 0.001 for heparin or heparin + clopidogrel treatments). Clot durability was examined in heparin + clopidogrel treated animals. Clots formed in the presence of 1000 IU/mL rThrombin were significantly less likely to rupture during clot burst assessment than those formed in the presence of 125 IU/mL rThrombin (0% versus 79%, p < 0.001). In vitro clot strength and clot kinetics, as determined by TEG in heparin + clopidogrel samples, were positively associated with the amount of rThrombin activity added for clot initiation.

Conclusion: In an animal model designed to replicate the anti-coagulation regimens encountered in clinical settings, topical rThrombin at 1000 IU/mL more reliably controlled the pharmacological effects of heparin or heparin + clopidogrel on hemostasis than rThrombin at 125 IU/mL. Results from in vitro assessments confirmed a positive relationship between the amount of rThrombin activity and both the rate of clot formation and clot strength.

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在兔血管出血模型中,外用浓度为1000 IU/mL的重组凝血酶可靠地缩短体内TTH,并在肝素抗凝和氯吡格雷血小板抑制存在下提供持久止血。
背景:本研究旨在评估重组人凝血酶(r凝血酶)浓度对手术人群中常见的肝素化和血小板抑制情况下的止血时间(TTH)、凝块耐久性和凝块强度的影响。方法:采用改良抗凝兔动静脉分流器制备血管吻合口出血模型。用肝素或肝素+氯吡格雷治疗家兔,在应用一定范围的局部凝血酶浓度或安慰剂,联合可吸收明胶海绵(USP)后测量TTH。治疗(安慰剂、凝血酶)随机分配,研究者对治疗采取盲法。用Kaplan-Meier法对TTH进行评价。止血完成后,对肝素+氯吡格雷治疗的动物进行凝块破裂评估。使用血栓弹性成像(TEG)方法测量离体样品的凝块粘弹性强度和动力学。结果:肝素治疗动物TTH随凝血酶浓度的增加而降低,1000iu /mL r凝血酶治疗后(73秒)较125iu /mL r凝血酶治疗后(78秒)缩短;P = 0.007)。在肝素+氯吡格雷治疗的动物中,TTH也随着凝血酶浓度的增加而降低;同样,1000iu /mL r凝血酶治疗后(71秒)明显短于125iu /mL r凝血酶治疗后(177秒;P < 0.001)。1000iu /mL凝血酶治疗后TTH变异性明显小于125iu /mL凝血酶治疗后,表明凝块形成的可靠性更高(肝素或肝素+氯吡格雷治疗的p < 0.001)。在肝素+氯吡格雷治疗的动物中检测凝块耐久性。在血块破裂评估中,1000iu /mL凝血酶形成的血块破裂的可能性明显低于125iu /mL凝血酶形成的血块(0% vs 79%, p < 0.001)。肝素+氯吡格雷样品中TEG测定的体外凝块强度和凝块动力学与用于凝块起始的凝血酶活性添加量呈正相关。结论:在一个旨在复制临床抗凝方案的动物模型中,局部使用1000iu /mL的凝血酶比125 IU/mL的凝血酶更可靠地控制肝素或肝素+氯吡格雷的止血药理作用。体外评估的结果证实了凝血酶活性与凝块形成率和凝块强度之间的正相关关系。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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