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A5313 - Acquired Antithrombin Deficiency and Heparin Resistance in Septic Shock: The Clot Thickens
Author Block: S. Gu, A. L. Miller, E. P. Schmidt; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, United States.
Introduction:
Antithrombin (AT) is a serine protease inhibitor which binds to activated forms of Factors II (thrombin), VII, X, IX, XI, and XII. The rate of protease activity inhibition is greatly potentiated by binding to heparin, which is the mechanism by which heparin results in anticoagulation. Antithrombin activity level of at least 70% is necessary for effective inhibition of blood coagulation proteases. While there are congenital forms of AT deficiency, more commonly, acquired AT deficiency develops by three mechanisms: increased excretion, decreased production, and accelerated consumption in states including sepsis, disseminated intravascular coagulation (DIC), thromboembolic disease, trauma, major surgery, extracorporeal membrane oxygenation (ECMO), or cardiopulmonary bypass.
Case:
A 35-year-old man with active intravenous drug use presented with fevers and leg pain after falling unconscious with his legs crossed. On examination, he was febrile, tachycardic, and hypotensive, with warmth, erythema and tenderness of his left lower extremity. Ultrasound showed an occlusive thrombus in his left common femoral vein. Blood cultures were positive for Group A Streptococcus. He was diagnosed with septic shock due to thrombophlebitis complicated by rhabdomyolysis, renal failure, and liver failure. Heparin therapy was initiated, but despite escalating doses up to 3900 units/hour, he remained sub-therapeutic. His AT level was found to be 33% (normal 80-100%). He then received transfusions of FFP, resulting in therapeutic levels of anti-Xa and demonstrating reversal of heparin resistance.
Discussion:
Antithrombin levels are frequently low in sepsis and are inversely correlated with higher severity of sepsis and septic shock. The rate of heparin resistance (HR) due to acquired AT deficiency from sepsis is unknown. A 2016 Cochrane Review did not find sufficient evidence to support routinely giving AT in critically ill patients, including subsets with sepsis and DIC, and found an association with increased risk of bleeding. However, some studies have shown that administering AT benefits patients who develop HR on ECMO or cardiopulmonary bypass by reducing the cumulative heparin dose and time needed to achieve therapeutic anticoagulation. Two units of FFP contain approximately 500 international units of AT. Using FFP to replace AT has been studied retrospectively, but no prospective trials have evaluated the efficacy of giving FFP for AT deficiency or compared head to head replacement with FFP vs. AT concentrate. This case demonstrates a clinical scenario in which there may be a role for AT replacement and suggests that FFP may be effectively used for replacement in acquired AT deficiency.