The coagulation system in melioidosis: from pathogenesis to new treatment strategies

Abstract

Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a dreadful disease common in South-East Asia and Northern Australia and is characterized by chronic suppurative lesions and pneumonia. Melioidosis may evolve into severe sepsis with multi-organ failure with high mortalities, despite proper antibiotic therapy. Besides activation of a strong pro-inflammatory host response, the coagulation system plays an important role during melioidosis, which is thought to be host-protective. In particular, a procoagulant state together with downregulation of anticoagulant pathways and activation of fibrinolysis are present, all closely interrelated with parameters of inflammation. This review presents an overview of recent studies in which the role of coagulation, anti-coagulation and fibrinolysis during melioidosis was investigated both in patients and in experimental settings.

Keywords::

• Burkholderia pseudomallei
• coagulation
• fibrinolysis
• inflammation
• melioidosis
• pneumonia
• protein C system
• sepsis

Acknowledgements

We thank Kees van ‘t Veer for fruitful discussions leading towards this article.

Financial & competing interests disclosure

WJ Wiersinga is supported by the Netherlands Organization for Health Research and Development (ZonMW) and The Netherlands Organization for Scientific Research (NWO). LM Kager is sponsored by research grants of ZonMW (projectnumber: 92003504), the Stichting BeGeTu and the Mr. Willem Bakhuys Roozeboom Stichting. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Melioidosis, caused by the aerobic intracellular Gram-negative bacterium Burkholderia pseudomallei, is a dreadful disease common in Southeast Asia and Northern Australia, often leading to severe sepsis and associated with high mortality.

• Besides activation of proinflammatory parameters, the coagulation system becomes activated in clinical melioidosis as well as the fibrinolytic system, while anticoagulant mechanisms are downregulated.

• During experimental melioidosis, activated protein C (APC) plays a bidirectional role: on one hand, a minimal amount of APC is necessary to mount an adequate antibacterial response; on the other hand, APC overexpression is associated with an unfavorable disease outcome.

• The lectin-like domain of thrombomodulin plays a detrimental role during murine melioidosis, and this is associated with increased activation of proinflammatory parameters.

• Fibrin formation in the lung is protective during experimental melioidosis: assumably, fibrin may serve to ‘wall off’ bacteria, thereby containing the primary infection and preventing bacterial dissemination. In line, too much anticoagulation may slow down clot formation and decrease fibrin deposition, facilitating bacterial dissemination throughout the body, which in turn may aggravate the inflammatory response.

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