Sepsis-Induced Coagulopathy: A Comprehensive Narrative Review of Pathophysiology, Clinical Presentation, Diagnosis, and Management Strategies

Abstract

Physiological hemostasis is a balance between pro- and anticoagulant pathways, and in sepsis, this equilibrium is disturbed, resulting in systemic thrombin generation, impaired anticoagulant activity, and suppression of fibrinolysis, a condition termed sepsis-induced coagulopathy (SIC). SIC is a common complication, being present in 24% of patients with sepsis and 66% of patients with septic shock, and is often associated with poor clinical outcomes and high mortality. 1 , 2 Recent preclinical and clinical studies have generated new insights into the molecular pathogenesis of SIC. In this article, we analyze the complex pathophysiology of SIC with a focus on the role of procoagulant innate immune signaling in hemostatic activation--tissue factor production, thrombin generation, endotheliopathy, and impaired antithrombotic functions. We also review clinical presentations of SIC, the diagnostic scoring system and laboratory tests, the current standard of care, and clinical trials evaluating the efficacies of anticoagulant therapies.

Figure 1.

Thrombin generation and propagation during sepsis. Thrombin is a powerful positive feedback signaler for its own propagation. Sepsis results in the release of PAMPs from microbial sources, or DAMPs from injured host cells, both of which lead to immune cell activation and TF expression from monocytes, endothelial cells, and neutrophils with subsequent thrombin generation. Moreover, activated NETs serve as polyanionic surface for further thrombin generation. Platelet degranulation, leukocyte TF expression, NET formation, and PLA formation propagate (dotted lines) thrombin generation leading to fibrin production and platelet consumption resulting in microvascular thrombosis. DAMPs indicates danger-associated molecular patterns; NETs, neutrophil extracellular traps; PAMPs, pathogen-associated molecular patterns; PLA, platelet-leukocyte aggregate; PSGL-1, p-selection (CD62p) glycoprotein ligand-1; TF, tissue factor; vWF, von Willebrand factor; WPB, Weibel Palade body. Created with BioRender.com.

Figure 2.

Toll-like receptors and procoagulant DAMPs. Sepsis results in widespread cell injury with the release of host-associated danger molecules or DAMPs. DAMPs signal via specific TLRs to induce proinflammatory or procoagulatory responses in sepsis independent of initial infection. Histones and HMGB-1 signal via TLR2/4 on the cell surface, while cfDNA, ssRNA, and dsRNA signal via TLR9, TLR7/8, and TLR3, respectively, in the endosomes. Activation of these receptors results in nuclear translocation of transcription factors NF-kB and AP-1 via MyD88 except for TLR3 signaling, which induces Trif signaling and translocation of IRF. These signaling pathways result in induction of proinflammatory cytokines and TF expression in immune cells furthering procoagulant signaling. AP-1 indicates activator protein 1; DAMPs, danger-associated molecular patterns; dsRNA, double-stranded RNA; HMGB-1, high mobility group box-1; IRF, interferon regulatory factor; MyD88, myeloid differentiation primary response 88; NF-kB, nuclear factor kappa B; ssRNA, single-stranded RNA; TF, tissue factor; TLR, toll-like receptor; TRIF, TIR-domain-containing adapter inducing IFN-β. Created with BioRender.com.

Figure 3.

Clinical laboratory features and trends in SIC. Sepsis-induced coagulopathy is a form of nonovert DIC in septic patients in which intravascular coagulation driven by inflammatory-mediated TF expression results in TAT and mild-to-moderate consumption of platelets and endogenous anticoagulants (ATIII). Further, PAI-1 is significantly elevated, resulting in early suppression of fibrinolysis. The coagulopathy in SIC can progress to overt DIC of a thrombotic phenotype with overactive clotting and worsening consumption of clotting factors and platelets. Finally, elevated tPA antigen and markers of fibrinolysis (d-dimer) characterize overt DIC of a predominant fibrinolytic phenotype. ↔ = no change, ↑ = mild changes, ↑↑ = moderate changes, and ↑↑↑ = severe changes. ATIII indicates antithrombin III; DIC, disseminated intravascular coagulation; FDP fibrin degradation products; PAI-1, plasminogen activator inhibitor-1; SIC, sepsis-induced coagulopathy; TAT, Thrombin-antithrombin complex; TF, tissue factor; TFPI, tissue factor pathway inhibitor; tPA, tissue plasminogen activator. Created with BioRender.com.