Endothelial Microparticles as a Biomarker for Diagnosis and Prognosis in Early Sepsis

In the presence of infection, normal immune and physiologic responses act in concert to eradicate pathogens. When these responses are inappropriately regulated, sepsis develops. Sepsis is characterized by systemic manifestations of infection. The diagnosis is made by identifying at least 2 of the components of the systemic inflammatory response syndrome (SIRS), based on four clinical and laboratory criteria: respiratory rate, tachycardia, temperature, and leukocyte level in the presence of a documented infection. The presence of acute organ dysfunction in this setting defines severe sepsis, and hypotension that is not reversed with fluid administration defines the entity of septic shock. Severe sepsis as well as its most severe form, septic shock, are significant global health concerns, afflicting millions of patients worldwide, increasing in incidence, and having an associated mortality rate of >25%. In the United States alone, an estimated 750,000 people develop sepsis or severe sepsis each year, and sepsis/septic shock is the 11th leading illness leading to mortality in the US. The annual cost burden of sepsis is estimated to be more than $17 billion. For these reasons, clinical investigators interested in sepsis have directed efforts toward identifying a biomarker that would be useful in making an early diagnosis of sepsis. In addition to early diagnosis, biomarkers for prognosis have been sought to guide severity assessment and to guide more personalized treatment of individual patients.

Endothelial Activation in Sepsis Endothelial activation occurs early in systemic infections and is an adaptive response, allowing leukocyte migration to sites of microbial invasion. In sepsis, however, endothelial activation is excessive and poses the following risks: harm via tissue damage due to excessive leukocyte recruitment, disseminated intravascular coagulation (DIC) relating to loss of endothelial anticoagulant properties, apoptotic death of endothelial cells, and loss of microvascular barrier function. The dysfunctional endothelial barrier leads to vascular leak and tissue edema, hallmarks of sepsis. This loss of endothelial barrier function is linked to increased morbidity and mortality in animal models of sepsis.

Endothelial Microparticles Microparticles are intact vesicles of a size 0.2-2.0 μm which are released from plasma membranes of multiple cell types in the setting of cell injury, activation, and/or apoptosis. In healthy individuals, microparticles found in the plasma are derived from platelets, erythrocytes, leukocytes, and endothelial cells. EMPS generally circulate at a relatively low level and reflect normal endothelial cell turnover. Elevated circulating levels of EMPs can be identified in a number of illnesses including sickle cell disease, immune-mediated thrombotic syndromes such as antiphospholipid syndrome and heparin-induced thrombocytopenia, diabetes, chronic renal failure, acute coronary syndrome, stroke, venous thromboembolic disease, metabolic syndrome, severe hypertension, paroxysmal nocturnal hemoglobinuria, and multiple sclerosis. The functional roles that may be played by endothelial microparticles are diverse and include neutrophil activation, chemotactic attraction of leukocytes, platelet aggregation, generation of thrombin (in vitro) and superoxide anions, stimulation of endothelial proliferation, induction of angiogenesis, MMP-2 and MMP-9 expression enabling vascular invasion of the basement membrane, and carrying of endothelial proteins and protein C.

Given the importance of the endothelium in the pathogenesis of sepsis, we propose to examine the role of endothelial-derived microparticles (EMPs) as a biomarker in sepsis.