Oldgren Jonas, Johnston Nina, Siegbahn Agneta
Uppsala Clinical Research Center, Uppsala University Hospital, Uppsala, Sweden.
Am Heart J. 2008 Mar;155(3):493.e1-8. doi: 10.1016/j.ahj.2007.12.006.
We evaluated coagulation activity in relation to gender in patients with acute coronary syndromes and in healthy individuals of similar age, and related coagulation activity to levels of Xa inhibition during dalteparin treatment.
Serial blood samples were obtained from 555 (172 women) of 2267 patients in the Scandinavian FRISC II study, and a single sample in 457 (151 women) apparently healthy age- and sex-matched individuals. After randomization, all patients received dalteparin 120 IU/kg s.c. (maximum 10,000 IU) twice daily for 5 to 7 days inhospital and thereafter placebo (n = 285) or sex- and weight-adjusted doses of dalteparin (5000 or 7500 IU) twice daily (n = 270) for 3 months.
Before randomization, 96% of the patients had open-label anticoagulation with unfractionated heparin or dalteparin. Therapeutic anti-Xa levels (> 0.5 IU/mL) were found in 74%, 55%, 58%, and 33% of the dalteparin-treated patients at randomization, 2 days, 4 to 7 weeks, and 3 months, respectively, and were significantly related to lower levels of coagulation activity, ie, factor VIIa, prothrombin fragment 1+2, and D-dimer, during prolonged treatment. Female patients had higher anti-Xa levels than men at randomization (median 0.69 vs 0.60 IU/mL, P = .01) and at 2 days (0.65 vs 0.59 IU/mL, P < .001). Female patients had also significantly higher levels of all 3 coagulation markers at randomization, 2 days, 4 to 7 weeks, and 3 and 6 months. Similarly, healthy women had higher prothrombin fragment 1+2 levels (median 1.19 vs 0.94 nmol/L) and D-dimer levels than men (26 vs 21 microg/L) (both P < .001).
Despite weight-adjusted dosing, female patients reached higher anti-Xa levels, suggesting increased sensitivity to dalteparin treatment. Healthy women and female patients also had higher coagulation activity, which might increase the risk of thrombus formation. The large proportion of patients with subtherapeutic anti-Xa during prolonged dalteparin treatment may reflect poor compliance and could thus contribute to the gradual loss of clinical efficacy.
我们评估了急性冠状动脉综合征患者及年龄相仿的健康个体的凝血活性与性别的关系，并将凝血活性与达肝素治疗期间的Xa抑制水平相关联。
从斯堪的纳维亚FRISC II研究的2267例患者中的555例（172例女性）获取系列血样，并从457例（151例女性）年龄和性别匹配的明显健康个体中获取单个血样。随机分组后，所有患者住院期间接受达肝素120 IU/kg皮下注射（最大10,000 IU），每日两次，共5至7天，此后接受安慰剂（n = 285）或根据性别和体重调整剂量的达肝素（5000或7500 IU），每日两次（n = 270），共3个月。
随机分组前，96%的患者接受了普通肝素或达肝素的开放标签抗凝治疗。在随机分组、2天、4至7周和3个月时，接受达肝素治疗的患者中，治疗性抗Xa水平（> 0.5 IU/mL）分别为74%、55%、58%和33%，且在延长治疗期间与较低的凝血活性水平显著相关，即因子VIIa、凝血酶原片段1+2和D-二聚体。随机分组时（中位数0.69 vs 0.60 IU/mL，P = 0.01）和2天时（0.65 vs 0.59 IU/mL，P < 0.001），女性患者的抗Xa水平高于男性。在随机分组、2天、4至7周、3个月和6个月时，女性患者的所有3种凝血标志物水平也显著更高。同样，健康女性的凝血酶原片段1+2水平（中位数1.19 vs 0.94 nmol/L）和D-二聚体水平高于男性（26 vs 21 μg/L）（均P < 0.001）。
尽管进行了体重调整剂量，但女性患者达到了更高的抗Xa水平，表明对达肝素治疗的敏感性增加。健康女性和女性患者也具有更高的凝血活性，这可能会增加血栓形成的风险。在延长的达肝素治疗期间，很大一部分患者的抗Xa水平低于治疗剂量，这可能反映了依从性差，因此可能导致临床疗效逐渐丧失。
