Cosmi B, Fredenburgh J C, Rischke J, Hirsh J, Young E, Weitz J I
McMaster University, Hamilton, Ontario, Canada.
Circulation. 1997 Jan 7;95(1):118-24. doi: 10.1161/01.cir.95.1.118.
Nonspecific binding to plasma proteins decreases the anti-factor Xa (anti-Xa) activity of unfractionated heparin (UFH) but not that of low-molecular-weight heparin (LMWH). However, plasma proteins could influence the anti-thrombin (anti-IIa) activity of LMWH. To explore this possibility, we compared the effects of plasma proteins on the anti-IIa activities of UFH and LMWH. We also examined their effects on the anti-IIa activity of dermatan sulfate (DS) because, like UFH, DS binds to plasma proteins.
There was almost complete recovery of anti-IIa activity when UFH, LMWH, or DS was added to plasma from each of 20 healthy volunteers. The addition of a chemically modified heparin with low affinity for antithrombin III to plasma containing UFH increased the anti-IIa activity in a concentration-dependent fashion by displacing UFH from plasma proteins. In contrast, addition of low-affinity heparin had no effect on the anti-IIa activity of LMWH. LMWH does not bind to plasma proteins because the bulk of the LMWH chains are < 6000 D, and only heparin fractions > 6000 D bind nonspecifically to plasma proteins. As further evidence that plasma proteins do not influence the anti-IIa activity of LMWH, the rate of thrombin inhibition in plasma in the presence of LMWH is virtually identical to that in buffer containing physiological amounts of the major antithrombins. In contrast, with UFH or DS, the rate of thrombin inhibition is twofold slower in plasma than in buffer.
Nonspecific binding of UFH to plasma proteins most likely contributes to the variable anti-IIa response to UFH in patients with thromboembolic disease. Although DS also binds to plasma proteins, the clinical significance of this finding is unclear. In contrast, because LMWH does not bind to plasma proteins, the anti-IIa activity of LMWH should be just as predictable as its anti-Xa activity.
普通肝素（UFH）与血浆蛋白的非特异性结合会降低其抗Xa因子（抗Xa）活性，但低分子量肝素（LMWH）则不会。然而，血浆蛋白可能会影响LMWH的抗凝血酶（抗IIa）活性。为探究这种可能性，我们比较了血浆蛋白对UFH和LMWH抗IIa活性的影响。我们还研究了它们对硫酸皮肤素（DS）抗IIa活性的影响，因为DS与UFH一样，也会与血浆蛋白结合。
当将UFH、LMWH或DS添加到20名健康志愿者的血浆中时，抗IIa活性几乎完全恢复。将对抗凝血酶III亲和力低的化学修饰肝素添加到含有UFH的血浆中，通过将UFH从血浆蛋白中置换出来，以浓度依赖的方式增加了抗IIa活性。相比之下，添加低亲和力肝素对LMWH的抗IIa活性没有影响。LMWH不会与血浆蛋白结合，因为大部分LMWH链的分子量小于6000 D，只有分子量大于6000 D的肝素部分会非特异性地与血浆蛋白结合。作为血浆蛋白不会影响LMWH抗IIa活性的进一步证据，在LMWH存在的情况下，血浆中凝血酶抑制率与含有生理量主要抗凝血酶的缓冲液中的抑制率几乎相同。相比之下，对于UFH或DS，血浆中凝血酶抑制率比缓冲液中慢两倍。
UFH与血浆蛋白的非特异性结合很可能是导致血栓栓塞性疾病患者对UFH的抗IIa反应存在差异的原因。尽管DS也会与血浆蛋白结合，但这一发现的临床意义尚不清楚。相比之下，由于LMWH不会与血浆蛋白结合，其抗IIa活性应该与其抗Xa活性一样具有可预测性。
