The Anti-Inflammatory Effects of Argatroban Can Be Differentiated from Other Direct Thrombin Inhibitors: Experimental and Clinical Observations

Abstract

The direct thrombin inhibitors (DTIs) argatroban, lepirudin, and bivalirudin are used for the management of thrombosis in patients with heparin-induced thrombocytopenia (HIT). Based on the structure of argatroban, there may be additional pharmacological effects beyond thrombin inhibition, such as vasomodulation, anti-inflammatory, and cellular modulatory effects. Plasma samples collected from HIT patients treated with argatroban (n = 20), lepirudin (n = 15), or bivalirudin (n = 15) were profiled for markers of inflammation. Circulating levels of myeloperoxidase (MPO), CD-40 ligand (CD40L), and functional microparticles (thrombin generating) were higher in HIT patients versus controls. MPO, CD40L, and microparticles significantly decreased with argatroban (p < 0.05) but were unaffected with lepirudin and bivalirudin treatment. Circulating nitric oxide (NO) levels were upregulated in HIT patients, but no significant changes were observed with any DTI treatment. However, NO levels measured in platelets were increased with argatroban treatment, suggesting that NO may be involved in the suppression of platelet activation in HIT. These observations demonstrate a robust inflammatory state associated with HIT, and biological effects of argatroban beyond thrombin inhibition that are not characteristic of lepirudin or bivalirudin.