Antithrombin Gamma (Genetical Recombination)

Tissue microcirculation is essential for the maintenance of organ homeostasis. Following acute infections, activation of coagulation and inflammation, which are critical interconnected responses, lead to thromboinflammation and microthrombosis, thereby contributing to multiorgan dysfunction. Sepsis is the most common underlying disease and has been extensively studied. However, the COVID-19 pandemic further illustrated the pathomechanisms of diseases in which thromboinflammation plays a critical role. During thromboinflammation, injury to monocytes, neutrophils, platelets, and endothelial cells, along with coagulation and complement activation, was further characterized. Thrombin is pivotal in orchestrating thrombosis and inflammation and has long been considered a potential therapeutic target in sepsis. Although thromboprophylaxis for venous thromboembolism with heparins is part of standard management for COVID-19, it also potentially attenuates organ dysfunction due to thrombotic sequela. In contrast, the effectiveness of anticoagulation with heparin, antithrombin, or thrombomodulin to reduce mortality has not conclusively been proven in sepsis. Nonetheless, thromboinflammation has also been reported as an important pathophysiologic mechanism in other critical illnesses, including heatstroke, trauma, and ischemia/reperfusion injury, and may provide a potential therapeutic target for future clinical studies.

Heparin resistance is often encountered during cardiopulmonary bypass. Heparin dose and activated clotting time target values for the initiation of cardiopulmonary bypass are not yet universally standardized; further no consensus exists on the management of heparin resistance. This study aimed to investigate the current real-world practice on heparin management and anticoagulant treatment for heparin resistance in Japan.

A questionnaire survey was conducted at medical institutions nationwide with which The Japanese Society of Extra-Corporeal Technology in Medicine members are affiliated, targeting surgical cases with cardiopulmonary bypass performed from January 2019 through December 2019.

Among 69% (230/332) of the participating institutions, the criterion for heparin resistance was defined as “the target activated clotting time value not reached even with an additional dose of heparin administration”. Cases of heparin resistance were reported in 89.8% (202/225) of the responded institutions. Of note, 75% (106/141) of the responded institutions reported heparin resistance associated with antithrombin activity ≥ 80%. Antithrombin concentrate was used in 38.4% (238/619 responses) or third dose of heparin in 37.8% (234/619 responses) for advanced heparin resistance treatment. Antithrombin concentrate was found to be effective in resolving heparin resistance in patients having normal, as well as lower antithrombin activity.

Heparin resistance has occurred in many cardiovascular centers, even among patients with normal antithrombin activities. Interestingly, the administration of antithrombin concentrate resolved heparin resistance, regardless of the baseline antithrombin activity value.