Sepsis: network pathophysiology and implications for early diagnosis

Abstract

Sepsis, a medical emergency, is the overwhelming host response to infection leading to organ failure. The pathophysiology of this heterogeneous disease includes an inflammatory response that stimulates a complex interaction between endothelial and complements with associated coagulation abnormalities. Despite a more comprehensive understanding of sepsis pathophysiology, there exists a translational gap to improve sepsis diagnosis clinically. Many of the proposed biomarkers to diagnose sepsis lack sufficient specificity and sensitivity to be used in routine clinical practice. There has also been a lack of progress in diagnostic tools due to the focus on the inflammatory pathway. Inflammation and coagulation are known to be linked to the innate immune response. Early immunothrombotic changes could result in the early switch from infection to sepsis and aid in sepsis diagnosis. This review integrates both preclinical and clinical studies that highlight sepsis pathophysiology providing a framework for how the development of immunothrombosis could be used as a starting point to investigate biomarkers for early sepsis diagnosis.

Keywords: biomarkers; immunothrombosis; innate immunity; neutrophil extracellular traps; platelets.

Figure 1.

Pathophysiology of sepsis. A schematic outline of the critical switch from infection to sepsis is termed “Time Zero.” The host-defense mediators elicit exaggerated immune cell response stimulating the complement system and collaterally damaging the endothelium and microvasculature. This figure was created with BioRender.com. ARDS, acute respiratory distress syndrome; EWS, early warning score; iNOS, inducible nitric oxide synthase; SOFA, sequential organ failure assessment.

Figure 2.

Immune system activation in sepsis. During sepsis, the systemic activation of the immune system results in an inflammatory response characterized by cytokine storm with associated fever, shock, and multiple organ dysfunction. The adaptive immune response produces pathogen-specific antibodies with immunological memory for subsequent exposures to the same antigen. Sepsis-induced immunosuppression causes apoptotic depletion of immune cells, immune exhaustion, and decreased CD4 and CD8 cells. This figure was created with BioRender.com. PAMPS, pathogen-associated molecular patterns; PRP, pattern recognition protein; TCR, T-cell receptor.

Figure 3.

Endothelial activation and coagulation dysfunction in sepsis. Weibel Palade bodies release P-selectin and VWF. ADAMTS13, a metalloprotease, cleaves highly procoagulant VWF multimers into lesser procoagulant forms. Platelets interact with activated neutrophils to induce NETs formation. NETs shift the balance toward excessive coagulation together with downregulation of anticoagulation and antifibrinolysis. The cascade of endothelial injury induces increased vascular permeability with associated coagulation abnormalities, altered microvascular flow, and micro thrombosis. This figure was created with BioRender.com. ADAMTS13, a disintegrin and metalloproteinase with thrombospondin motifs; ICAM-1, intercellular adhesion molecule 1; iNOS, inducible nitric oxide synthase; NETs, neutrophil extracellular traps; PAI-1, plasminogen activator inhibitor-1; VCAM-1, vascular cell adhesion molecule; VWF, von Willebrand factor.