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© 2008 Schattauer GmbH, Stuttgart Blood Coagulation, Fibrinolysis and Cellular Haemostasis Venous and arterial thromboembolism in severe sepsis Robert L. Levine1, Jacques R. LeClerc2, Joan E. Bailey3, Matthew J. Monberg4, Samiha Sarwat5 1 Department of Neurosurgery, University of Texas School of Medicine at Houston, Houston, Texas, USA; 2Retired employee and current shareholder/beneficiary of Eli Lilly & Co., 2404 Sunny Slope, Bridgewater, New Jersey, USA; 3Eli Lilly and Company, Lilly Corporate Center, Drop Code 6072, Indianapolis, Indiana, USA; 4Eli Lilly and Company, Drop Code 6831, Indianapolis, Indiana, USA; 5Eli Lilly and Company, Lilly Corporate Center, Drop Code 6025, Indianapolis, Indiana, USA Summary The burden of thromboembolism (TE) in severe sepsis is largely unknown.We assessed the prevalence of venous and arterial TE in patients with severe sepsis over a four-week period. We performed a retrospective analysis of a pooled database of three randomized, placebo-controlled trials of two novel pharmacological agents for the treatment of severe sepsis, drotrecogin alfa (activated) (DrotAA)and secretory phospholipase A2 inhibitor (sPLA2I).The study was conducted at intensive care units of the participating institutions.A total of 2,649 patients with known or suspected infection and sepsis-associated acute organ dysfunction were enrolled in the three trials and were assigned to treatment groups (DrotAA=850; sPLA2I =578; placebo=1221). The database was queried for venous and arterial TE, using investigator reports of serious adverse events. Eighty-four of 2,649 patients (3.2%; 95% confidence interval, 2.5% to 3.9%) developed Keywords Sepsis, thromboembolism, stroke, venous thrombosis, pulmonary embolism, drotrecogin alfa (activated) Introduction Venous thromboembolic disease and arterial thromboses are well-recognized causes of in-hospital death, particularly among postoperative and immobilized medical patients (1–4). However, there are far fewer data on the burden of venous and arterial thromboembolism (TE) in critical illness, particularly in the context of severe sepsis. Severe sepsis patients may be at risk for venous TE, as they harbor many of the traditional risk factors including mechanical ventilation, endovascular catheters, along with disease-specific factors such as the host inflammatory response, activation of haemostasis (e.g. platelet, endothelial cell, coagulation), and reduced fibrinolysis (5–14). Sepsis-related at least one thromboembolic event over 28 days. Nearly threequarters of episodes were atheroembolic (n=62); 25% involved the deep venous system (n=25). Ischemic stroke (n=30) and venous thromboembolism (n=25) each occurred in about 1% of patients. Ischemic stroke and acute coronary syndrome had a higher peak incidence during the first five days compared to venous TE onset, which was more constant over the 28-day period. Subgroup analysis by pooled treatment groups yielded TE rates of 2.0% (DrotAA), 3.5% (placebo), and 4.0% (sPLA2I), respectively. Clinically manifest TE occurred in about 3% of severe sepsis patients treated in the intensive care unit over a 28-day period.Arterial TE may be more common than previously recognized. More accurate estimates of TE prevalence and relationship to sepsis await future studies. Thromb Haemost 2008; 99: 892–898 systemic hypotension, septic shock, tissue hypoxemia, and need for vasopressor support may also predispose to acute venous and arterial TE (15–20). Several studies have documented the prevalence of venous TE in the general intensive care unit (ICU) population, with estimates of venous TE prevalence in critical illness ranging from 10% to 30%, in the absence of thromboprophylaxis (21–22). Unfortunately, none of these studies specifically examined venous TE in severe sepsis. Similarly, while previous studies documented rates of cardiomyonecrosis of 5–25% and ischemic stroke of