PROLONGED ANTITHROMBIN ACTIVITY OF LOW-MOLECULAR-WEIGHT HEPARINS - CLINICAL IMPLICATIONS FOR THE TREATMENT OF THROMBOEMBOLIC DISEASES

Background The mechanism for the efficacy of once- or twice-daily subc utaneous injections of low-molecular-weight heparins (LMWHs) for the t reatment of venous thromboembolism has been difficult to explain. The confusion exists because the observation from experimental studies tha t the antithrombin activity of LMWHs is necessary for their antithromb otic effect is inconsistent with the reported short half-life of the a ntithrombin activity of LMWHs. Previous pharmacokinetic studies were p erformed with lower doses of LMWHs than have been used in contemporary trials, and antithrombin activity was assessed with the barely sensit ive chromogenic assay. Methods and Results We performed a pharmacokine tic study to compare the relative half-lives of prophylactic and thera peutic doses of LMWHs assessing antithrombin activity with both the ch romogenic and a more sensitive assay (plasma thrombin neutralization a ssay). An eight-way cross-over randomized study in healthy volunteers was performed. Enoxaparin (20 and 40 mg and 1 and 2 mg/kg) and nadropa rin (7500 and 10 000 ICU and 225 and 450 ICU/kg) were administered sub cutaneously. The maximal peak activity for aPTT ratio was 1.7. A dose- dependent peak activity was found for both antifactor Xa and antithrom bin activities. Disappearance time of these activities after the highe st dose of both LMWHs was longer than 16 hours. Overall mean antifacto r Xa activity half-life was 4.6 hours. Overall mean antithrombin activ ity half-life was longer than 4 hours. Conclusions Our results provide an explanation for the effectiveness of LMWHs administered either onc e or twice daily. High and sustained plasma antithrombin activity is a chieved when LMWHs are administered in therapeutic doses used in conte mporary trials with only a moderate prolongation of the aPTT.