Physical and pharmacologic manipulation of the vascular system as measured by the release of TFPI and other mediators of antithrombotic actions.

Utilizing highly sensitive monoclonal based assays, we have measured various mediators of antithrombotic action including t-PA, prostacyclin and tissue factor pathway inhibitor (TFPI). To evaluate the pharmacologic stimulation of these mediators, blood from patients treated with heparin and low molecular weight heparin in (LMWH) at various dosages, group of patients treated with oral polydeoxyribonucleotide (defibrotide), a synthetic analogue of heparin, namely aprosulate (Luitpold Pharma, Munich, Germany) were analyzed for various vascular mediators. Similarly, to evaluate patients treated with physical modalities such as the sequential compression devices alone and sequential compression devices in combination with LMWHs were tested for these same parameters. Heparin produced a marked release of TFPI and t-PA after i.v. administration. After subcutaneous administration, a relatively smaller elevation of these parameters were seen. Several of the LMWHs produced varying effects on the release of TFPI and t-PA and the area under the curve after the s.c. injection was found to be much higher than i.v. administration. Defibrotide administration after i.v. and oral administration also resulted in a significant increase in the TFPI and t-PA antigen levels. However, the prostacyclin metabolite 6-keto-PGF1 alpha was much higher than the values obtained the heparins. Repeated administration of a hypersulfated heparin analogue produced marked increase in TFPI in both i.v. and s.c. studies. These results indicate that besides directly 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. Thus, both physical and pharmacologic means can be used to produce an antithrombotic state to mediate their prophylactic and therapeutic effects.