皮下注射重组水蛭素治疗Ⅱ型肝素诱导的血小板减少症患者的新治疗选择：一项试点研究。

Huhle G, Hoffmann U, Hoffmann I, Liebe V, Harenberg J F, Heene D L

Department of Medicine I., Faculty of Clinical Medicine, University Clinic of the University of Heidelberg, Heidelberg, Germany.

Thromb Res. 2000 Aug 15;99(4):325-34. doi: 10.1016/s0049-3848(00)00253-x.

We prospectively studied 15 patients suffering from acute heparin-induced thrombocytopenia (HIT) type II with and without thromboembolic events and 4 patients with anamnestically known HIT type II recurrently requiring thromboprophylaxis in order to develop new therapeutic strategies by subcutaneous recombinant hirudin administration. Patients with acute venous or arterial thromboembolism were treated with aPTT-controlled intravenous (mean: 19.3 days) followed by subcutaneous r-hirudin (mean: 22.5 days). Patients without thromboembolism were treated with subcutaneous r-hirudin (mean: 25.9 days). Four patients were readmitted to subcutaneous r-hirudin (mean: 32 days). When r-hirudin was administered subcutaneously following intravenous treatment, mean baseline (prior to the injection) and mean peak (1.5-2.5 hours after the injection) aPTT ratios were 1.1 (+/-0.2) to 1.7 (+/-0.48) and 2. 48 (+/-0.43) to 2.52 (+/-0.4) times normal value, respectively. Mean baseline and mean peak ECT ratios were 1.2 (+/-0.12) to 1.9 (+/-0. 22) and 2.2 (+/-0.25) to 2.6 (+/-0.11) times the upper normal value, respectively. When r-hirudin was initially administered subcutaneously, mean baseline and mean peak aPTT ratios were 1.41 (+/-0.25) to 1.61 (+/-00.28) and 1.88 (+/-0.26) to 2.06 (+/-0.09) times the normal value, respectively. Mean baseline and mean peak ECT ratios were 1.25 (+/-0.2) to 1.5 (+/-0.38) and 2.01 (+/-0.21) to 2.23 (+/-0.25) times the upper limit of normal, respectively. Patients who received recurrent subcutaneous r-hirudin had mean baseline and peak aPTT values of 1.5 (+/-0.35) to 1.75 (+/-0.156) and 2.0 (+/-0.33) to 2.1 (+/-0.18) times the normal value, respectively. Mean baseline and peak ECT ratios were 1.3 (+/-0.26) to 1.65 (+/-0.09) and 1.94 (+/-0.256) to 2.7 (+/-0.23) times the upper limit of normal, respectively. The overall cumulative incidence of r-hirudin antibodies was 12/19 (63%) with a significant accumulation of r-hirudin in antibody-positive patients compared to antibody-negative patients (p<0.05). No patient suffered a new thromboembolic or major bleeding event. Subcutaneous administration of recombinant hirudin provides a long-term thromboprophylaxis regimen in HIT type II patients after passivation of acute thromboembolism.

我们前瞻性地研究了15例患有急性II型肝素诱导的血小板减少症（HIT）且伴有或不伴有血栓栓塞事件的患者，以及4例有II型HIT病史且反复需要进行血栓预防的患者，目的是通过皮下注射重组水蛭素制定新的治疗策略。患有急性静脉或动脉血栓栓塞的患者先接受活化部分凝血活酶时间（aPTT）控制的静脉治疗（平均：19.3天），随后接受皮下重组水蛭素治疗（平均：22.5天）。无血栓栓塞的患者接受皮下重组水蛭素治疗（平均：25.9天）。4例患者再次接受皮下重组水蛭素治疗（平均：32天）。静脉治疗后皮下注射重组水蛭素时，平均基线（注射前）和平均峰值（注射后1.5 - 2.5小时）aPTT比值分别为正常值得1.1（±0.2）至1.7（±0.48）倍和2.48（±0.43）至2.52（±0.4）倍。平均基线和平均峰值欧洲水蛭素检测（ECT）比值分别为正常上限值的1.2（±0.12）至1.9（±0.22）倍和2.2（±0.25）至2.6（±0.11）倍。最初皮下注射重组水蛭素时，平均基线和平均峰值aPTT比值分别为正常值得1.41（±0.25）至1.61（±0.28）倍和1.88（±0.26）至2.06（±0.09）倍。平均基线和平均峰值ECT比值分别为正常上限值的1.25（±0.2）至1.5（±0.38）倍和2.01（±0.21）至2.23（±0.25）倍。接受反复皮下重组水蛭素治疗的患者平均基线和峰值aPTT值分别为正常值得1.5（±0.35）至1.75（±0.156）倍和2.0（±0.33）至2.1（±0.18）倍。平均基线和峰值ECT比值分别为正常上限值的1.3（±0.26）至1.65（±0.09）倍和1.94（±0.256）至2.7（±0.23）倍。重组水蛭素抗体的总体累积发生率为(12/19)（63%），与抗体阴性患者相比，抗体阳性患者体内重组水蛭素明显蓄积（(p<0.05)）。无患者发生新的血栓栓塞或严重出血事件。皮下注射重组水蛭素为急性血栓栓塞消除后的II型HIT患者提供了一种长期血栓预防方案。