Thrombosis with associated inflammation, also known as thromboinflammation, has been observed in a wide range of health conditions and is especially well recognized in the context of superficial thrombophlebitis. However, when it develops in the microvasculature of injured tissues and organs, it can be quite deleterious. Microvascular thrombosis can occur in several settings. It is most commonly observed in sepsis and ischemia-reperfusion injury but it can also occur in patients who have experienced organ transplant rejection, an episode of major trauma, severe burns, antiphospholipid syndrome, preeclampsia, sickle cell disease, or biomaterial-induced thromboinflammation.

In a review article published in Blood, Shaun P Jackson, MBBS, BMedSci, PhD, of the Heart Research Institute and Charles Perkins Centre at the University of Sydney in Australia, and colleagues discussed some of the basic mechanisms underlying thromboinflammatory responses and, importantly, the challenges of treatment, primarily in the setting of sepsis and ischemia-reperfusion injury.

Underlying Mechanisms

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Sepsis is often associated with hemostatic changes that can vary widely from subclinical activation of blood coagulation, which may contribute to localized venous thromboembolism, to acute disseminated intravascular coagulation (DIC), which is characterized by systemic activation of blood coagulation. This leads to the generation and deposition of fibrin and, subsequently, to microvascular thrombi in various organs that contribute to multiple organ dysfunction syndrome and death. Therefore, defining the molecular mechanisms that regulate thromboinflammation in specific disease states is of major clinical importance, noted the authors.

The endothelium, which lines the lumen of the entire circulatory system, is a critical regulator of thromboinflammation. In the setting of pathological conditions including sepsis, ischemia-reperfusion injury, and DIC, humoral mediators disrupt the homeostatic function of endothelial cells. In sepsis, for example, bacterial cell wall components activate pattern recognition receptors on the endothelial surface, inducing the production of cytokines, and bacterial endotoxins accelerate tissue factor expression and elevate levels of plasminogen activation inhibitor 1. This blocks fibrinolysis and eventually results in a procoagulant endothelial surface.

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Tissue factor’s high affinity binding and activation of factor VII makes tissue factor expression within blood vessels instrumental in initiating and sustaining coagulation in a variety of thromboinflammatory conditions. Tissue factor is primarily produced by cells surrounding the vessel wall but can also be produced intravascularly by endothelial cells, monocytes, and circulating microparticles.

In the setting of sepsis, pathogen-associated molecular patterns expressed by bacteria are recognized by pattern recognition receptors located on the surface of endothelial cells, platelets, and leukocytes. Signals from the pattern recognition receptors lead to the release of inflammatory cytokines and chemokines as well as elevated expression of leukocyte adhesion molecules, thereby undermining the natural anticoagulant and fibrinolytic system on endothelial cells and increasing tissue factor expression.


“Reducing the deleterious influence of microvascular thrombosis and inflammation in the context of sepsis and ischemia-reperfusion injury continues to represent a major therapeutic challenge,” the authors said. They noted that part of the difficulty arises from “the complex and variable nature of the innate immune and hemostatic responses that drive the various stages of the thromboinflammatory process.”