AGING AND VENOUS THROMBOEMBOLISM INFLUENCE THE PHARMACODYNAMICS OF THE ANTI-FACTOR XA AND ANTI-THROMBIN ACTIVITIES OF A LOW-MOLECULAR-WEIGHT HEPARIN (NADROPARIN)

Venous thromboembolism may be efficiently treated by one single daily administration of a high dose of low molecular weight heparin (LMWH). The present study investigates if the physiological deterioration of r enal function associated with normal aging or the presence of an acute venous thromboembolism influences the pharmacodynamic pattern of the anti-factor Xa and anti-thrombin activities. Three groups of 12 subjec ts were investigated. The first 2 groups were composed of healthy volu nteers differing by age (25 +/- 4 and 65 +/- 3 yrs) and creatinine cle arance (114 +/-: 15 and 62 +/- 6 ml.min(-1)). The third group was comp osed of patients hospitalized for deep vein thrombosis, having a mean age of 65 +/- 11 yrs and creatinine clearance of 76 +/- 8 ml.min(-1). Nadroparin was administered subcutaneously once daily at the dose of 1 80 anti-factor Xa IU.kg(-1) for 6 to 10 days. Serial sampling on day 1 and on the last day of administration (day n) allowed the pharmacodyn amic parameters of the anti-factor Xa and anti-thrombin activities to be compared at the begining and at the end of the treatment. The main findings were the following: (1) After repeated administration, a sign ificant accumulation of the anti-factor Xa activity was observed in th e healthy elderly and in the patients but not in the healthy young sub jects (accumulation factor: 1.3). There was no evidence of accumulatio n of anti-thrombin activity; (2) There were significant correlations b etween the clearance of creatinine and the clearance of the anti-facto r Xa activity but not with that of the anti-thrombin activity; (3) In the patients, the clearance of the anti-factor Xa and of the anti-thro mbin activities were 1.4 and 2 times higher respectively than those ca lculated in the healthy elderly; (4) The mean ratio of the of anti-fac tor Xa and antithrombin clearances was close to 2 in the healthy subje cts but equal to 5.4 in the patients. These results suggest that the m echanisms involved in the clearance of polysaccharide chains which sup port the antithrombin activity are different from those of the anti-fa ctor Xa activity and that the enhanced binding properties of plasma pr oteins to unfractionated heparin reported in patients presenting an ac ute venous thromboembolism also exists for LMWH, predominantly for the anti-thrombin activity.