A COMPARATIVE-STUDY OF THE ANTICOAGULANT AND ANTITHROMBOTIC EFFECTS OF UNFRACTIONATED HEPARIN AND A LOW-MOLECULAR-WEIGHT HEPARIN (FRAXIPARINE(R)) IN AN EXPERIMENTAL-MODEL OF HUMAN VENOUS THROMBOSIS

We have compared the anticoagulant and the antithrombotic effects of u nfractionated heparin (Calciparine(R)) and low molecular weight hepari n (Fraxiparine(R)) in an experimental human venous thrombosis model. O ne single subcutaneous injection of Calciparine(R) or Fraxiparine(R) w as administered to healthy male volunteers at one month interval in a randomised and cross-over design. Ten subjects received doses used in man for preventing venous thrombosis (5,000 IU and 3,075 IU, respectiv ely), and seven other subjects received curative doses (12,500 IU and 6,150 IU, respectively). Thrombus formation was measured 3 h and 8 h a fter drug administration. Non-anticoagulated human blood was drawn for 5 min directly from an antecubital vein over confluent cultured endot helial cells positioned in a parallel-plate perfusion chamber. The cel ls were previously stimulated for 4 h with lipopolysaccharides (10 mu g/ml) and interleukin 1 beta (50 U/ml), resulting in optimal expressio n of biological active tissue factor. The wall shear rate at the cell surface was 50 s(-1) and mimicked venous blood flow conditions. Immuno logically quantified fibrin deposition on the stimulated cells was red uced only by curative doses of Calciparine(R) and Fraxiparine(R) at 3 h (3.4 +/- 0.8 versus 1.0 +/- 0.2 mu g/cm(2) and 2.6 +/- 0.8 versus 1. 0 +/- 0.1 mu g/cm(2), respectively, p less than or equal to 0.05). The influence of Calciparine(R) and Fraxiparine(R) on the formation of th rombin and fibrin was determined by measuring the plasma levels of thr ombin-antithrombin III complexes and fibrinopeptide A (FPA) in blood s amples collected distally to the perfusion chamber. The generation of these markers was significantly inhibited (50-83%) by both prophylacti c and curative doses of Calciparine(R) and Fraxiparine(R) (p less than or equal to 0.05). However, Fraxiparine(R) still significantly inhibi ted the thrombin and fibrin generation at 8 h (p less than or equal to 0.05), whereas Calciparine(R) did nor. The antithrombotic effects of both heparins were correlated with their plasma activities as measured by the antifactor Xa or the antithrombin assays. Thus, it appears in this model that Calciparine(R) and Fraxiparine(R) produce comparable a ntithrombotic effects at clinically comparable doses. However Fraxipar ine(R) has a longer-lasting anticoagulant activity than Calciparine(R) These results are in good agreement with clinical observations in man , and thus in favour of our model of human venous thrombogenesis for f urther studies of antithrombotic molecules.