EFFECTS OF ANTITHROMBIN ON MICROCIRCULATION IN SEPSIS

• Applicant: Dr. Lars Heubner
• Subject Area: Clinical Infectiology and Tropical Medicine
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 574083336

Sepsis remains a leading cause of death in intensive care units worldwide, with persistently high mortality rates and long-term morbidity despite standardized treatment protocols. A hallmark of severe sepsis is the development of sepsis-induced coagulopathy (SIC), characterized by dysregulated thrombin generation, impaired fibrinolysis, and endothelial injury, leading to widespread microvascular dysfunction. These microcirculatory disturbances critically contribute to organ failure and poor outcomes. Antithrombin (AT) is a key endogenous anticoagulant with potent anti-inflammatory and endothelial-protective effects. During sepsis, AT levels are rapidly depleted, correlating with increased mortality. Despite promising mechanistic properties, AT has not yet been successfully translated into clinical therapy due to limitations in patient selection, dosing strategies, and concurrent heparin administration. This project aims to re-evaluate the therapeutic potential of AT under conditions that reflect clinically relevant pathophysiology, focusing on endothelial protection and microvascular function. In a structured experimental approach, the study investigates whether AT—alone or in combination with clinically established anticoagulants—can restore thrombin regulation, stabilize the endothelial barrier, and preserve capillary perfusion under septic conditions. Special attention is given to argatroban as a potentially synergistic partner, as it does not interfere with AT’s anti-inflammatory mechanisms. Functional validation will be performed using an endothelialised capillary model to assess thrombus formation, flow resistance, and glycocalyx integrity under physiologic shear. Clinically, the project addresses an urgent need for targeted therapies that go beyond general anticoagulation and instead modulate the complex interaction between inflammation, coagulation, and endothelial dysfunction. By identifying effective AT-based strategies, the study aims to improve both short- and long-term outcomes in sepsis patients and provide a rationale for patient stratification in future interventional trials.

• DFG Programme: Research Grants
• International Connection: Austria
• Cooperation Partners: Privatdozentin Mirjam Bachler, Ph.D.; Professor Dr. Dietmar Fries