Harenberg J, Malsch R, Angelescu M, Lange C, Michaelis H C, Wolf H, Heene D L
1st Department of Medicine, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Klinikum Mannheim, Germany.
Blood Coagul Fibrinolysis. 1996 Jun;7(4):477-83. doi: 10.1097/00001721-199606000-00008.
The present study was designed to investigate the anticoagulant action of inhaled low-molecular-weight (LMW) heparin on the release of tissue factor pathway inhibitor (TFPI) and on antifactor Xa activity, Heptest, activated partial thromboplastin time (APTT) and thrombin clotting time (TCT) in healthy volunteers. 3000 IU (group 1), 9000 IU (group 2), 27,000 IU (group 3) or 54,000 IU (group 4) LMW-heparin were given to 20 healthy volunteers each at 4 weeks intervals by inhalation. For safety reasons a dose escalating design was chosen. APTT and TCT did not change after inhalation of any dose of LMW-heparin as well as all parameters in group 1. In group 2, Heptest coagulation times were prolonged from 18.7 +/- 2.0 s before to 26.1 +/- 5.2 s 6 h and 20.5 +/- 1.9 s 24 h after inhalation and the other parameters remained uneffected. In group 3, S2222 method and the protamine assay increased from 0.01 to about 0.1 IU/ml 6 h after inhalation and returned to normal values after 24 h. TFPI antigen increased from 74.1 +/- 13.9 to 80.5 +/- 14.2 ng/ml 3 h after inhalation. TFPI activity remained unchanged. Heptest coagulation values were prolonged to 42 +/- 7.6 s after 6 h and returned to normal within 72 h after inhalation. In group 4, the following changes were observed: antifactor Xa activity increased to 0.343 +/- 0.196 U/ml after 6 h and normalized after 72 h. The protamine assay detected 0.2 +/- 0.18 U LMWH/ml after 6 h, TFPI antigen increased to 103 +/- 17.9 ng/ml and TFPI activity to 1.14 +/- 0.23 U 3 h after inhalation. All tests were normal after 24 h. Heptest coagulation values increased to 77.5 +/- 11.8 s 6 h after inhalation and normalized after 144 h. The area under the activity time curve of the S2222 method and of the Heptest assay increased with increasing doses (r = 0.677 and r = 0.571), respectively. The calculated elimination half-life of the aXa-effect was 7.5 h using S2222-, Heptest- and protamine assays. The data demonstrate a resorption of LMW-heparin by intrapulmonary route in man. The dose to produce antifactor Xa levels, prolongations of Heptest coagulation values and in releasing TFPI is about ten-fold higher than after subcutaneous administration.
本研究旨在调查吸入低分子量（LMW）肝素对健康志愿者组织因子途径抑制物（TFPI）释放、抗Xa因子活性、希普测试（Heptest）、活化部分凝血活酶时间（APTT）和凝血酶凝血时间（TCT）的抗凝作用。将3000 IU（第1组）、9000 IU（第2组）、27000 IU（第3组）或54000 IU（第4组）的LMW肝素每隔4周通过吸入方式给予20名健康志愿者。出于安全考虑，采用了剂量递增设计。吸入任何剂量的LMW肝素后，APTT和TCT以及第1组的所有参数均未改变。在第2组中，希普测试凝血时间从吸入前的18.7±2.0秒延长至吸入后6小时的26.1±5.2秒和24小时的20.5±1.9秒，其他参数未受影响。在第3组中，吸入后6小时S2222法和鱼精蛋白测定值从0.01增加至约0.1 IU/ml，24小时后恢复至正常值。吸入后3小时TFPI抗原从74.1±13.9增加至80.5±14.2 ng/ml。TFPI活性保持不变。希普测试凝血值在吸入后6小时延长至42±7.6秒，并在吸入后72小时内恢复正常。在第4组中，观察到以下变化：抗Xa因子活性在6小时后增加至0.343±0.196 U/ml，并在72小时后恢复正常。鱼精蛋白测定在6小时后检测到0.2±0.18 U LMWH/ml，吸入后3小时TFPI抗原增加至103±17.9 ng/ml，TFPI活性增加至1.14±0.23 U。24小时后所有测试均正常。吸入后6小时希普测试凝血值增加至77.5±11.8秒，并在144小时后恢复正常。S2222法和希普测试的活性时间曲线下面积分别随剂量增加而增加（r = 0.677和r = 0.571）。使用S2222法、希普测试和鱼精蛋白测定计算的aXa效应消除半衰期为7.5小时。数据表明人可通过肺内途径吸收LMW肝素。产生抗Xa因子水平、延长希普测试凝血值和释放TFPI的剂量比皮下给药高约10倍。
