Mochizuki T, Olson P J, Szlam F, Ramsay J G, Levy J H
Department of Anesthesiology, Emory University School of Medicine, The Emory Clinic, Atlanta, Georgia, USA.
Anesth Analg. 1998 Oct;87(4):781-5. doi: 10.1097/00000539-199810000-00008.
Bleeding after cardiopulmonary bypass (CPB) is related to multiple factors. Excess protamine weakens clot structure and decreases platelet function; therefore, an increased activated clotting time (ACT) after protamine reversal of heparin may be misinterpreted as residual heparin anticoagulation. We evaluated the effects of protamine, recombinant platelet factor 4 (rPF4), and hexadimethrine on ACT in blood obtained after CPB. In addition, we examined the effect of protamine on in vitro platelet aggregation. Incremental doses of protamine, rPF4, and hexadimethrine were added to heparinized blood from CPB, and ACTs were performed. Incremental concentrations of protamine were added to heparinized platelet-rich plasma, and aggregometry was induced by adenosine diphosphate (ADP) and collagen. The mean heparin concentration at the end of CPB was 3.3 U/mL. Protamine to heparin ratios >1.3:1 produced a significant prolongation of the ACT that was not seen with rPF4 and was observed only with 5:1 hexadimethrine to heparin ratios. ADP-induced platelet aggregation was reduced with protamine administration > or =1.3:1. Excessive protamine reversal of heparin prolongs ACT and alters ADP-induced platelet aggregation in a dose-dependent manner in vitro. Additional protamine administered to treat a prolonged ACT may further increase clotting time, reduce platelet aggregation, and potentially contribute to excess bleeding after CPB.
We found that excess protamine prolonged the activated clotting time and altered platelet function after cardiopulmonary bypass, whereas heparin antagonists, such as recombinant platelet factor 4 and hexadimethrine, exhibited a wider therapeutic range without adversely affecting the activated clotting time. Approaches to avoid excess protamine or use of alternative heparin antagonists after cardiopulmonary bypass may be beneficial.
体外循环（CPB）后的出血与多种因素有关。过量的鱼精蛋白会削弱凝块结构并降低血小板功能；因此，在鱼精蛋白逆转肝素后活化凝血时间（ACT）增加可能会被误解为残留肝素抗凝作用。我们评估了鱼精蛋白、重组血小板因子4（rPF4）和己二甲铵对CPB后采集血液中ACT的影响。此外，我们研究了鱼精蛋白对体外血小板聚集的影响。将递增剂量的鱼精蛋白、rPF4和己二甲铵添加到CPB后的肝素化血液中，并进行ACT检测。将递增浓度的鱼精蛋白添加到肝素化的富含血小板血浆中，并用二磷酸腺苷（ADP）和胶原诱导血小板聚集检测。CPB结束时的平均肝素浓度为3.3 U/mL。鱼精蛋白与肝素的比例>1.3:1会导致ACT显著延长，rPF4则不会出现这种情况，只有在己二甲铵与肝素的比例为5:1时才会观察到。给予≥1.3:1的鱼精蛋白会降低ADP诱导的血小板聚集。在体外，过量的鱼精蛋白逆转肝素会以剂量依赖的方式延长ACT并改变ADP诱导的血小板聚集。为治疗延长的ACT而额外给予鱼精蛋白可能会进一步延长凝血时间、降低血小板聚集，并可能导致CPB后出血过多。
我们发现，过量的鱼精蛋白会延长体外循环后的活化凝血时间并改变血小板功能，而肝素拮抗剂，如重组血小板因子4和己二甲铵，具有更宽的治疗范围，且不会对活化凝血时间产生不利影响。避免体外循环后使用过量鱼精蛋白或使用替代肝素拮抗剂的方法可能是有益的。
