COMPARATIVE PHARMACODYNAMICS OF SUBCUTANEOUSLY ADMINISTERED HEPARIN (HEP) AND A LOW MOLECULAR WEIGHT HEPARIN (LMWH) AS STUDIED BY AN EX VIVO FIBRINOPEPTIDE A (FPA) GENERATION TEST

Subcutaneously administered heparins do not produce any sizeable effects on the global tests and their activities are currently measured using amidolytic anti Xa and anti Ila assays. These methods are sensitive only to the individual enzyme and do not reflect other biologic actions. We have used a thromboplastin C activated FPA generation test to measure the pharmacodynamic effects of subcutaneously administered HEP and a LMWH in primates. 400μl of citrated plasma was equilibrated at 37°C for 2 minutes and was activated with 100 μl thromboplastin diluted in .020M CaCl₂. FPA was generated for 2 min, inhibited with 50 μl of an inhibitor cocktail and measured using an RIA kit (Mallinckrodt, St, Louis, M0). Marked dose dependent suppression of the FPA generation was noted for varying periods of time by both HEP and LMWH. Stronger effects were observed with LMWH, suggesting better subcutaneous bioavailability and functional effects. Significant FPA generation inhibition was observed even when there was no circulating antiprotease activity present in the plasma. These results suggest that FPA generation test is a sensitive test to measure the pharmacologic effect of heparins. Furthermore the FPA generation tests can be modified to activate the coagulation system at certain sites to study the effect of heparins.