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J Thromb Haemost. 2019 Sep 24. doi: 10.1111/jth.14642. [Epub ahead of print]

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

Author information

1
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
2
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
3
Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
4
Department of Pediatrics, Neonatal and Perinatal Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
5
Department of Biomedical Engineering, School of Medicine, Oregon Health & Sciences University, Portland, Oregon.
6
Division of Hematology and Medical Oncology, School of Medicine, Oregon Health & Sciences University, Portland, Oregon.
7
Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
8
Departments of Cell Biology, Pathology and Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.

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.

KEYWORDS:

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

PMID:
31549765
DOI:
10.1111/jth.14642

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