The dual FXa/thrombin inhibitor SATI prevents fibrin and platelet deposition in hypercoagulant rats. Issue 193 (September 2020)

• Record Type: Journal Article
• Authors: López, Mercedes; Heitmeier, Stefan; Laux, Volker; Nowak, Goetz
• Is Part Of: Thrombosis research. Issue 193(2020)
• Page Start: 15
• Page End: 21
• Publication Date: 2020-09
• Subjects: SATI -- Thrombin -- FXa -- Hypercoagulation -- Dual inhibitor -- 125I-fibrin -- 111In-platelet; Thrombosis -- Periodicals; 616.135
• DOI: 10.1016/j.thromres.2020.05.016
• Languages: English
• ISSNs: 0049-3848

Abstract

Abstract: Introduction: Systemic hypercoagulation is often a severe complication of infective and inflammatory diseases, which overcome the hemostatic balance and lead to multiple thrombotic occlusions in the microvasculature and organ damage and is related to high mortality rates. SATI is a potent dual inhibitor of FXa and thrombin with antithrombotic efficacy in venous and arterial thrombosis models. In this study, the antithrombotic efficacy of SATI was investigated in a microthrombosis model in rats with an induced hypercoagulant state. Materials and methods: The hypercoagulant state was generated by infusion of TF in sixty rats (12 groups, consisting of 5 rats each). SATI was administered in two different doses by constant infusion and its antithrombotic efficacy was investigated using two different approaches: 1) measuring 125 I-fibrin deposition in various organs and 2) continuous whole-body imaging of 111 In-platelet biodistribution in anesthetized animals. Results: After start of the TF infusion in rats with radioactively-labeled fibrinogen, the radioactivity was accumulated in liver, spleen, kidney, and mostly in the lung as a consequence of fibrin generation. SATI efficiently reduced the pulmonary deposition of fibrin in a dose- and time-dependent manner. In the SATI groups the splenic and renal radioactivity was enhanced at later time points probably as consequence of the clearance of 125 I-fibrin(ogen). Imaging of rats that received 111 In-platelets prior to systemic TF administration showed retention of the radioactivity mainly in the lungs in the control group. SATI efficiently blocked the platelet accumulation in the lungs and increased platelet recruitment by the spleen. Conclusions: SATI is a promising candidate for prevention of microcirculatory disturbances by inhibiting fibrin deposition and platelet accumulation in the lungs and thereby conferring organ protection. Both methods used in this study are suitable for investigating the antithrombotic efficacy of new drugs in microthrombosis. Continuous imaging of 111 In-platelets allowed for follow-up of thrombus formation in living animals without the need for tissue harvesting. Highlights: Fibrin accumulates in liver, spleen, kidney, but mainly in the lung in hypercoagulant rats. Platelets are sequestered in the lung during systemic tissue factor administration. The short-acting thrombosis inhibitor (SATI) inhibits both thrombin and activated FX. SATI diminished intravascular fibrin deposition and platelet accumulation in the lung.