Introduction: If thrombosis contributes to sepsis, heparin titrated using activated partial thromboplastin times may be efficacious. We investigated heparin in preclinical models.
Methods and Main Results: In unchallenged mice (n = 107), heparin at 100, 500, or 2500 units/kg produced activated partial thromboplastin time levels less than, within, or greater than a prespecified therapeutic range (1.5–2.5 times control), respectively. In animals (n = 142) administered intratracheal Escherichia coli challenge, compared to placebo treatment, heparin at 100, 500, or 2500 units/kg were associated with dose dependent increases in the hazard ratios of death (hazard ratio [95% confidence interval]: 1.08 [0.66, 1.76]; 1.34 [0.80, 2.24]; 3.02 [1.49, 6.10], respectively) (p = .001 for the dose effect). Compared to normal saline challenge, E. coli without heparin (i.e., with placebo) increased the activated partial thromboplastin time (p = .002) close to the therapeutic range. While heparin at 100 and 500 units/kg with E. coli further increased activated partial thromboplastin time (p < .0001 vs. placebo) within or above the therapeutic range, respectively, these did not decrease inflammatory cytokines or lung injury. In metaregression analysis of published preclinical studies, heparin improved survival with lipopolysaccharide (n = 23, p < .0001) or surgically induced infection (n = 14, p < .0001) but not monobacterial (n = 7, p = .29) challenges.
Conclusion: Coagulopathy with sepsis or other variables, such as type of infectious source, may influence the efficacy of heparin therapy for sepsis.
From the Critical Care Medicine Department (YL, J-FS, XC, RLD, XL, J-WS, YF, PQE), Clinical Center, National Institutes of Health, Bethesda, MD; Department of Pathology (HM), Penn State Hershey Medical Center, Hershey, PA; Department of Nephrology (XL), Peking Union Medical College, Beijing, China; and Surgical Department of Pediatric Cardiology (J-WS), Anzhen Hospital, Capital Medical University, Beijing, China.
Supported, in part, by the Intramural Program of the National Institutes of Health, Clinical Center.
Presented, in part, at the 2005 and 2009 American Thoracic Society meetings, San Diego, CA, May 20–25, 2005, and May 15–20, 2009.
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All of the authors have received funding from the National Institutes of Health.
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