ANTICOAGULANT EFFECTS AND TISSUE FACTOR PATHWAY INHIBITOR AFTER INTRAPULMONARY LOW-MOLECULAR-WEIGHT HEPARIN

The present study was designed to investigate the anticoagulant action of inhaled low-molecular-weight (LMW) heparin on the release of tissu e factor pathway inhibitor (TFPI) and on antifactor Xa activity, Hepte st, activated partial thromboplastin time (AMT) and thrombin clotting time (TCT) in healthy volunteers. 3000 IU (group 1), 9000 IU (group 2) , 27000 IU (group 3) or 54000 IU (group 4) LMW-heparin were given to 2 0 healthy volunteers each at 4 weeks intervals by inhalation. For safe ty reasons a dose escalating design was chosen. APTT and TCT did not c hange after inhalation of any dose of LMW-heparin as well as all param eters in group 1. In group 2, Heptest coagulation times were prolonged from 18.7 +/- 2.0 s before to 26.1 +/- 5.2 s 6 h and 20.5 +/- 1.9 s 2 4 h after inhalation and the other parameters remained uneffected In g roup 3, S2222 method and the protamine assay increased from 0.01 to ab out 0.1 IU/ml 6 h after inhalation and returned to normal values after 24 h. TFPI antigen increased from 74.1 +/- 13.9 to 80.5 +/- 14.2 ng/m l 3 h after inhalation. TFPI activity remained unchanged Heptest coagu lation values were prolonged to 42 +/- 7.6 s after 6 h and returned to normal within 72 h after inhalation. In group 4, the following change s were observed: antifactor Xa activity increased to 0.343 +/- 0.1% U/ ml after 6 h and normalized after 72 h. The protamine assay detected 0 .2 +/- 0.18 ULMWH/ml after 6 h, TFPI antigen increased to 103 +/- 17.9 ng/ml and TFPI activity to 1.14 +/- 0.23 U 3 h after inhalation. Ail tests were normal after 24 h. Heptest coagulation values increased to 77.5 +/- 11.8 s 6 h after inhalation and normalized after 144 h. The a rea under the activity time curve of the S2222 method and of the Hepte st assay increased with increasing doses (r=0.677 and r=0.571), respec tively. The calculated elimination half-life of the aXa-effect was 7.5 h using S2222-, Heptest- and protamine assays. The data demonstrate a resorption of LMW-heparin by intrapulmonary route in man. The dose to produce antifactor Xa levels, prolongations of Heptest coagulation va lues and in releasing TFM is about ten-fold higher than after subcutan eous administration.