PLASMINOGEN-ACTIVATOR INHIBITOR-1 GENE DEFICIENT MICE .2. EFFECTS ON HEMOSTASIS, THROMBOSIS, AND THROMBOLYSIS
PLASMINOGEN-ACTIVATOR INHIBITOR-1 GENE DEFICIENT MICE .2. EFFECTS ON HEMOSTASIS, THROMBOSIS, AND THROMBOLYSIS
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DOI：
10.1172/jci116893
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发表时间：
1993-12-01
影响因子：
15.9
通讯作者：
COLLEN, D
中科院分区：
文献类型：
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作者：
CARMELIET, P;STASSEN, JM;COLLEN, D
以D3胚胎干细胞同源重组产生的纯合PAI-1缺陷(PAI-1-/-)小鼠为模型，研究纤溶酶原激活物抑制物-1(PAI-1)基因失活对止血、血栓形成和溶栓的影响。PAI-1-/-和PAI-1野生型(PAI-1+/+)小鼠稀释10倍的全血凝块在3h内的自发溶解能力有限但有显著差异(P<；0.001)(分别为6+/-1比3+/-1%)。在PAI-1+/+、杂合型PAI-1+/-和PAI-I-/-小鼠中，注射入颈静脉内的正常小鼠血浆凝块在8h内分别裂解47+/-5、66+/-3和87+/-7%(PAI-1+/-和PAI-1-/-小鼠P=0.002)。PAI-I+I+和PAI-1-/-小鼠给予内毒素0.5 mg/kg后，4h内的对应值分别为35+/-5和91+/-3%(P<；0.001)。足垫注射10或50µg内毒素后6d内，26只PAI-1+/+小鼠中有11只发生静脉血栓形成(P=0.004)，而25只PAI-1-/-小鼠中仅有1只发生静脉血栓形成。PAI-1-/-小鼠在尾巴或盲肠部分截断后不能记录到自发性出血或迟发性再出血。因此，PAI-I基因的破坏似乎会导致小鼠轻微的纤溶亢进状态，并对静脉血栓有更大的抵抗力，但不会损害止血。
The effects of plasminogen activator inhibitor-1 (PAI-1) gene inactivation on hemostasis, thrombosis and thrombolysis were studied in homozygous PAI-1-deficient (PAI-1-/-) mice, generated by homologous recombination in D3 embryonic stem cells. Diluted (10-fold) whole blood clots from PAI-1-/- and from PAI-1 wild type (PAI-1+/+) mice underwent limited but significantly different (P < 0.001) spontaneous lysis within 3 h (6+/-1 vs 3+/-1%, respectively). A 25-mul I-125-fibrin-labeled normal murine plasma clot, injected into a jugular vein, was lysed for 47+/-5, 66+/-3, and 87+/-7% within 8 h in PAI-1+/+, heterozygous PAI-1-deficient (PAI-1+/-), and PAI-I-/- mice, respectively (P = 0.002 for PAI-1+/+ vs PAI-1-/- mice). Corresponding values after pretreatment with 0.5 mg/kg endotoxin in PAI-I+I+ and PAI-1-/- mice, were 35+/-5 and 91+/-3% within 4 h, respectively (P < 0.001 ). 11 out of 26 PAI-1+/+ but only 1 out of 25 PAI-1-/- mice developed venous thrombosis (P = 0.004) within 6 d after injection of 10 or 50 mug endotoxin in the footpad. Spontaneous bleeding or delayed rebleeding could not be documented in PAI-1-/- mice after partial amputation of the tail or of the caecum.Thus, disruption of the PAI-I gene in mice appears to induce a mild hyperfibrinolytic state and a greater resistance to venous thrombosis but not to impair hemostasis.