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DIFFERENTIAL MECHANISMS OF ANTICOAGULANT ACTIONS OF ANGIOMAX AND HEPARIN: POTENTIAL PHARMACOLOGIC IMPLICATIONS
Author(s) -
Wahi Rakesh,
Iqbal O,
Hoppensteadt D,
Cunanan J,
Neville B,
Baltasar F,
Walenga J,
Fareed J
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a654-c
Subject(s) - argatroban , anticoagulant , medicine , heparin , pharmacology , hirudin , tissue factor pathway inhibitor , thrombin , discovery and development of direct thrombin inhibitors , tissue factor , coagulation , platelet
The mechanisms by which direct thrombotic inhibitors such as Angiomax, hirudin and argatroban produce their anticoagulant actions are markedly different than those produced by unfractionated (UFH) and low molecular weight (LMWH) heparins. The REPLACE trial (Linkoff et al JAMA 2004; 292 , –696) reported on the long term efficacy of Angiomax/provisional IIb/IIIa blockade vs. UFH/planned IIb/IIIa blockade during PCI. To compare the mechanisms of the anticoagulant regimens in the REPLACE trial, a primate model (macaca mulatta) was used. Two groups of individual primates (n=8) were compared. Group A received 0.75 mg/kg bolus followed by 1.75 mg/kg/hr of Angiomax, whereas group B received UFH at 65 u/kg IV. Blood samples were drawn prior to and up to three hours following the administration of the drugs, mimicking the REPLACE trial. While the ACT responses were comparable in the two groups, marked differences in other hemostatic parameters were noted and are tabulated below.The group treated with Angiomax did not show any increase in the TFPI levels. However the group treated with UFH exhibited an increase in the TFPI levels. In addition circulating tissue factor levels were higher in the Angiomax group. Markers of thrombin generation such as TAT, F1.2 were also higher in the Angiomax group. These results clearly demonstrate that the anticoagulant effects of Angiomax are mostly mediated by a single mechanism (thrombin inhibition) whereas the UFH produces anticoagulant effects via multiple mechanisms. The clinical implications of these differences are yet to be elucidated.