PHYSICAL AND PHARMACOLOGICAL MANIPULATION OF THE VASCULAR SYSTEM AS MEASURED BY THE RELEASE OF TFPI AND OTHER MEDIATORS OF ANTITHROMBOTIC ACTIONS

Utilizing hihgly sensitive monoclonal based assays, we have measured v arious mediators of antithrombotic action including t-PA, prostacyclin and tissue factor pathway inhibitor (TFPI). To evaluate the pharmacol ogic stimulation of these mediators, blood from patients treated with heparin and low molecular weight heparin (LMWH) at various dosages, gr oups of patients treated with oral polydeoxyribonucleotide (defibrotid e), a synthetic analogue of heparin, namely aprosulate (Luit-pold Phar ma, Munich, Germany) were analyzed for various vascular mediators. Sim ilarly, to evaluate patients treated with physical modalities such as the sequential compression devices alone and sequential compression de vices in combination with LMWHs were tested for these same parameters. Heparin produced a marked release of TFPI and t-PA after i.v. adminis tration. After subcutaneous administration, a relatively smaller eleva tion of these parameters were seen. Several of the LMWHs produced vary ing effects on the release of TFPI and t-PA and the area under the cur ve after the SC injection was found to be much higher than i.v. admini stration. Defibrotide administration after i.v. and oral administratio n also resulted in a significant increase in the TFPI and t-PA antigen levels. However, the prostacyclin metabolite 6-keto-PGF1 alpha. was m uch higher than the values obtained with heparins. Repeated administra tion of a hypersulfated heparin analogue produced marked increase in T FPI in both IV and SC studies. These results indicate that besides dir ectly acting on plasmatic mediators, antithrombotic drugs are capable of releasing endogenous mediators of antithrombotic actions. Physical manipulation of the vascular system can also produce these effects. Th us, both physical and pharmacologic means can be used to produce an an tithrombotic state to mediate their prophylactic and therapeutic effec ts.