Kelly A B, Hanson S R, Henderson L W, Harker L A
Department of Basic and Clinical Research, Research Institute of Scripps Clinic, La Jolla, California.
J Lab Clin Med. 1989 Oct;114(4):411-8.
Because heparin anticoagulation during hemodialysis with hollow-fiber devices is associated with progressive loss of volume of fiber bundles subsequent to thrombotic occlusion, we examined the antithrombotic and antihemostatic effects of the irreversible synthetic thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginyl-chloromethylketone (FPRCH2Cl) during repeated exposure of cupramonium cellulose hollow-fiber hemodialyzers in an extracorporeal blood circuit in baboons. By contrast with full anticoagulating doses of heparin, FPRCH2Cl (100 nmol/kg/min) decreased both the loss of fiber bundle volume (19.1% +/- 7.0% vs 6.4% +/- 3.6% p less than 0.01) and deposition of 111In-labeled platelets within the dialyzer (15.7 +/- 5.9 x 10(9) vs 3.2 +/- 1.2 x 10(9) platelets; p less than 0.01). Additionally, blood markers of thrombus formation in vivo (i.e., plasma beta-thromboglobulin, platelet factor 4, and fibrinopeptide A) remained at low levels throughout infusion of FPRCH2Cl, whereas levels were elevated during heparin therapy (p less than 0.01 in each case). FPRCH2Cl, but not heparin, prolonged bleeding times (p less than 0.001) without affecting the capacity of platelets to aggregate in response to the presence of either collagen or adenosine diphosphate ex vivo. Complement activation by the dialyzer was not affected by FPRCH2Cl. We conclude that the progressive loss of dialyzer hollow fibers is a platelet-dependent, thrombin-mediated process that, although resistant to heparin, is interrupted by the synthetic antithrombin FPRCH2Cl.
由于使用中空纤维装置进行血液透析时肝素抗凝与血栓形成性闭塞后纤维束体积的逐渐减少有关，我们在狒狒的体外血液回路中，对铜氨纤维素中空纤维血液透析器进行反复暴露的过程中，研究了不可逆合成凝血酶抑制剂D-苯丙氨酰-L-脯氨酰-L-精氨酰-氯甲基酮（FPRCH2Cl）的抗血栓和抗止血作用。与全量抗凝剂量的肝素相比，FPRCH2Cl（100 nmol/kg/分钟）既减少了纤维束体积的减少（19.1%±7.0%对6.4%±3.6%，p<0.01），也减少了透析器内111In标记血小板的沉积（15.7±5.9×10^9对3.2±1.2×10^9个血小板；p<0.01）。此外，在整个FPRCH2Cl输注过程中，体内血栓形成的血液标志物（即血浆β-血小板球蛋白、血小板因子4和纤维蛋白肽A）保持在低水平，而在肝素治疗期间这些水平升高（每种情况p<0.01）。FPRCH2Cl而非肝素延长了出血时间（p<0.001），且不影响血小板在体外对胶原或二磷酸腺苷存在时的聚集能力。透析器引起的补体激活不受FPRCH2Cl影响。我们得出结论，透析器中空纤维的逐渐丧失是一个血小板依赖性、凝血酶介导的过程，尽管对肝素耐药，但被合成抗凝血酶FPRCH2Cl所阻断。
