"Normal" thrombin generation
"Normal" thrombin generation
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DOI：
10.1182/blood.v94.7.2169.419k22_2169_2178
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发表时间：
1999-10-01
期刊：
影响因子：
20.3
通讯作者：
Mann, KG
中科院分区：
文献类型：
--
作者：
Butenas, S;van't Veer, C;Mann, KG
我们研究了血浆凝血因子水平在其平均值的50%和150%之间变化对凝血酶原、因子X、因子XI、因子IX、因子VII、因子VIII、因子V、蛋白C、蛋白S、抗凝血酶III（AT-III）和组织因子途径抑制物（TFPI）以及极端组合的影响，例如，50%抗凝剂和150%促凝血剂或50%促凝血剂和150%抗凝剂在合成“血浆”系统中。使用纯化的、天然的和重组的蛋白质和合成的磷脂囊泡或血小板在体外构建反应体系，反应由重组组织因子（TF）-因子VIIa复合物（5 pmol/L）引发。为了研究蛋白C系统的影响，还将可溶性血栓调节蛋白（Tm）加入到反应混合物中。对于最极端的情况，其中基本血浆凝血酶原（凝血酶原和因子X、IX、V和VIII）和化学计量抗凝剂（AT-III和TFPI）共同反向改变50%，观察到产生的总可用凝血酶差异为28倍。大多数这些蛋白质的变化50%以上和以下的“正常”范围，其余的在100%，只有适度的影响凝血酶的峰值和总水平产生。影响凝血酶生成的主要因素是凝血酶原和AT-Ⅲ。当这2种组分保持在100%，所有其他血浆促凝剂减少至50%时，产生的可用凝血酶减少60%。当评价除凝血酶原以外的所有血浆凝血酶原的150%水平时，未观察到产生的凝血酶增加。当只有凝血酶原升高到150%，而所有其他因素都保持在100%时，产生的凝血酶增加了71%至121%。当AT-III为50%，所有其他成分为100%时，凝血酶产量增加了104%至196%。在Tm为0.1 nmol/L的情况下，在50%至150%范围内添加蛋白C和蛋白S对凝血酶生成的影响有限。因子VII、XI和X浓度的个体差异对起始阶段的持续时间、达到的凝血酶峰值水平或产生的可用凝血酶几乎没有影响。巧合的是，因子IX浓度增加至150%导致凝血酶生成降低，而降低至50%导致凝血酶生成增强，这很可能是因子IX作为因子VIIa-TF与因子X的竞争性底物的结果。因子V或因子VIII浓度的降低导致起始阶段的缩短，而TFPI降低至50%导致该阶段的缩短。然而，这些改变都没有导致产生的可用凝血酶的显著变化。基于这些数据，可以推测在正常范围内凝血酶原的增加和AT-III的减少将是血栓形成的潜在风险因素，并且可能需要结合联合收割机正常因子水平的算法来开发血栓形成的预测测试。(C)1999年，美国血液学会。
We have investigated the influence of alterations in plasma coagulation factor levels between 50% and 150% of their mean values for prothrombin, factor X, factor XI, factor IX, factor VII, factor VIII, factor V, protein C, protein S, antithrombin III (AT-III), and tissue factor pathway inhibitor (TFPI) as well as combinations of extremes, eg, 50% anticoagulants and 150% procoagulants or 50% procoagulants and 150% anticoagulants in a synthetic "plasma" system. The reaction systems were constructed in vitro using purified, natural, and recombinant proteins and synthetic phospholipid vesicles or platelets with the reactions initiated by recombinant tissue factor (TF)-factor VIIa complex (5 pmol/L). To investigate the influence of the protein C system, soluble thrombomodulin (Tm) was also added to the reaction mixture. For the most extreme situations in which the essential plasma procoagulants (prothrombin, and factors X, IX, V, and VIII) and the stoichiometric anticoagulants (AT-III and TFPI) were collectively and inversely altered by 50%, a 28-fold difference in the total available thrombin generated was observed. Variations of most of these proteins 50% above and below the "normal" range, with the remainder at 100%, had only modest influences on the peak and total levels of thrombin generated. The dominant factors influencing thrombin generation were prothrombin and AT-III. When these 2 components were held at 100% and all other plasma procoagulants were reduced to 50%, there was a 60% reduction in the available thrombin generated. No increase in the thrombin generated was observed when the 150% level of all plasma procoagulants other than prothrombin was evaluated. When only prothrombin was raised to 150%, and all other factors were maintained at 100%, the thrombin generated increased by 71% to 121%. When AT-III was at 50% and all other constituents were at 100%, thrombin production was increased by 104% to 196%. The additions of protein C and protein S over the 50% to 150% ranges with Tm at 0.1 nmol/L concentration had limited influence on thrombin generation. Individual variations in factors VII, XI, and X concentrations had little effect on the duration of the initiation phase, the peak thrombin level achieved, or the available thrombin generated. Paradoxically, increases in factor IX concentration to 150% led to lowered thrombin generation, while decreases to 50% led to enhanced thrombin generation, most likely a consequence of factor IX as a competitive substrate with factor X for factor VIIa-TF. Reductions in factor V or factor VIII concentration led to prolongations of the initiation phase, while the reduction of TFPI to 50% led to shortening of this phase. However, none of these alterations led to significant changes in the available thrombin generated. Based on these data, one might surmise that increases in prothrombin and reductions in AT-III, within the normal range, would be potential risk factors for thrombosis and that algorithms that combine normal factor levels may be required to develop predictive tests for thrombosis. (C) 1999 by The American Society of Hematology.