EFFECT OF NONSPECIFIC-BINDING TO PLASMA-PROTEINS ON THE ANTITHROMBIN ACTIVITIES OF UNFRACTIONATED HEPARIN, LOW-MOLECULAR-WEIGHT HEPARIN, AND DERMATAN SULFATE

Background Nonspecific binding to plasma proteins decreases the anti-f actor Xa (anti-Xa) activity of unfractionated heparin (UFH) but not th at of low-molecular-weight heparin (LMWH). However, plasma proteins co uld influence the antithrombin (anti-IIa) activity of LMWH. To explore this possibility, we compared the effects of plasma proteins on the a nti-IIa activities of UFH and LMWH. We also examined their effects on the anti-IIa activity of dermatan sulfate (DS) because, like UFH, DS b inds to plasma proteins. Methods and Results There was almost complete recovery of anti-IIa activity when UFH, LMWH, or DS was added to plas ma from each of 20 healthy volunteers. The addition of a chemically mo dified heparin with low affinity for antithrombin III to plasma contai ning 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 c hains are <6000 D, and only heparin fractions >6000 D bind nonspecific ally to plasma proteins. As further evidence that plasma proteins do n ot influence the anti-IIa activity of LMWH, the rate of thrombin inhib ition 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 twof old slower in plasma than in buffer. Conclusions Nonspecific binding o f 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 fi nding is unclear. In contrast, because LMWH does not bind to plasma pr oteins, the anti-IIa activity of LMWH should be just as predictable as its anti-Xa activity.