Fondaparinux pentasaccharide reduces sepsis coagulopathy and promotes survival in the baboon model of Escherichia coli sepsis

Ravi S. Keshari, Robert Silasi, Narcis I. Popescu, Constantin Georgescu, Hala Chaaban, Cristina Lupu, Owen J.T. McCarty, Charles T. Esmon, Florea Lupu

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Background: Sepsis triggers dysfunction of coagulation and fibrinolytic systems leading to disseminated intravascular coagulation (DIC) that contributes to organ failure and death. Fondaparinux (FPX) is a synthetic pentasaccharide that binds to antithrombin (AT) and selectively inhibits factor (F) Xa and other upstream coagulation proteases but not thrombin (T). Objectives: We used a baboon model of lethal Escherichia coli sepsis to investigate the effects of FPX treatment on DIC, organ function, and outcome. Methods: Two experimental groups were studied: (a) E. coli challenge (n = 4); and (b) E coli plus FPX (n = 4). Bacteremia was modeled by intravenous infusion of pathogen (1-2 × 1010 CFU/kg). Fondaparinux (0.08 mg/kg) was administered subcutaneously, 3 h prior to and 8 h after bacteria infusion. Results: Bacteremia rapidly increased plasma levels of inhibitory complexes of AT with coagulation proteases. Activation markers of both intrinsic (FXIa-AT), and extrinsic (FVIIa-AT) pathways were significantly reduced in FPX-treated animals. Factor Xa-AT and TAT complexes were maximal at 4 to 8 h post challenge and reduced >50% in FPX-treated animals. Fibrinogen consumption, fibrin generation and degradation, neutrophil and complement activation, and cytokine production were strongly induced by sepsis. All parameters were significantly reduced, while platelet count was unchanged by the treatment. Fondaparinux infusion attenuated organ dysfunction, prolonged survival, and saved two of four challenged animals (log-rank Mantel-Cox test, P =.0067). Conclusion: Our data indicate that FPX-mediated inhibition of coagulation prevents sepsis coagulopathy; protects against excessive complement activation, inflammation, and organ dysfunction; and provides survival benefit in E. coli sepsis.

Original languageEnglish (US)
Pages (from-to)180-190
Number of pages11
JournalJournal of Thrombosis and Haemostasis
Volume18
Issue number1
DOIs
StatePublished - Jan 1 2020

Keywords

  • Escherichia coli
  • disseminated intravascular coagulation
  • nonhuman primates
  • pentasaccharide
  • sepsis

ASJC Scopus subject areas

  • Hematology

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