Anti-Inflammatory Effects of Argatroban Can Be Differentiated from Other Direct Thrombin Receptors. Experimental and Clinical Observations.

Abstract

Direct thrombin inhibitors (DTI's) such as the argatroban, bivalirudin and hirudin are currently used in the anticoagulant management of heparin induced thrombocytopenia (HIT). All of these agents are administered via parenteral (IV) continuous infusion, to maintain a APTT of 1.5–2.5 times the baseline. The relative potency of these agents is usually expressed in terms of the inhibition of thrombin in the amidolytic and clot based assays. Moreover, some of these agents are also capable of inhibiting thrombin generation in plasmatic and whole blood assays which may of may not be proportional to their antithrombin effects. Because of the structural and molecular differences these DTI's are capable of additional pharmacologic effects such as the vasomodulation, anti-inflammatory and cellular modulatory effects. Previous reports have described the effects of argatroban on the endogenous upregulation of nitric oxide. However, such information on bivalirudin and hirudin is not available. Since endogenously generated nitric oxide (NO) may modulate platelet and cellular activation processes, plasma samples collected from HIT patients treated with standard IV infusion regimen of argatroban (n=10), bivalirudin (n=7) and hirudin (n=14) were profiled for NO levels measured by using a chemilluminescence method (Sievers, Boulder, CO). Such markers of inflammation as the myeloperoxidase (MPO) and CD 40 ligand (CD 40L) were also measured using ELISA methods. Blood plasma samples were collected at baseline (pretreatment) and 3 days after treatment. The control group was comprised of 50 adult normal male and female volunteers. The circulating levels of MPO and CD 40L, at baseline, did not significantly differ among the different treatment groups. However, these markers were relatively higher in comparison to the control group. The MPO and CD 40L levels were not significantly decreased after treatment with bivalirudin and hirudin. In the argatroban treated group, these markers were significantly decreased (p< 0.05) The NO levels were upregulated in the baseline samples for each of the individual groups. No significantly changes were observed between the groups studied. However, when the NO levels were measured in platelets an increase in the NO levels were noted in the argatroban group only. These studies suggest that argatroban is capable of upregulating intraplatelet NO levels which may be involved in the suppression of the activation of platelets in HIT. Together with this observation and a down regulation of various inflammatory markers, these observations are highly suggestive of the differential effects of argatroban in contrast to other DTI's.GroupMPO (ng/ml)CD 40L (pg/ml)NO (μM)PrePostPrePostPrePostArgatroban98±1241±9170±8090±3639±1243±15Bivalirudin81±1666±20210±60190±6846±1545±16Hirudin90±1675±16198±12230±6037±1131±12Normals27±1227±1278±1278±1219±1619±16