What is the pathophysiology of how sepsis can cause Disseminated Intravascular Coagulation (DIC)?

Pathophysiology of Sepsis-Induced Disseminated Intravascular Coagulation (DIC)

Sepsis causes DIC through a complex interaction between inflammation and coagulation, where pathogen-induced inflammatory responses trigger endothelial dysfunction, leading to systemic activation of coagulation pathways, microvascular thrombosis, and consumption coagulopathy. 1

Key Pathophysiological Mechanisms

Inflammatory Response and Endothelial Activation

• Sepsis initiates a systemic inflammatory response with release of inflammatory cytokines and mediators that convert the normally anticoagulant endothelium to a procoagulant state 1
• Microorganisms and damage-associated molecular patterns (DAMPs) trigger the inflammatory cascade, activating complement and releasing inflammatory mediators 1
• Endothelial injury is a central component of sepsis pathophysiology, with disruption of tight junctions and conversion from anticoagulant to procoagulant properties 1
• Inflammatory cytokines damage the endothelium, exposing collagen fibers and activating von Willebrand factor (VWF), which further increases tissue factor expression 1

Procoagulant Pathway Activation

• The primary mechanism involves upregulation of tissue factor (TF) expression, mainly by activated monocytes/macrophages and specific cells in target tissues 2
• Tissue factor pathway activation leads to thrombin generation, which converts fibrinogen to fibrin, resulting in widespread microvascular thrombosis 1
• The contact factor pathway is also activated through factor XII activation by negatively charged aggregates and activated platelets 1
• Platelets are directly activated by many bacterial and viral pathogens, contributing to systemic thrombosis and multi-organ failure 3

Impairment of Natural Anticoagulant Systems

• Sepsis causes dysfunction of three major anticoagulant pathways: 2, 4
  1. Antithrombin system
  2. Protein C pathway
  3. Tissue factor pathway inhibitor (TFPI)
• Endothelial dysfunction leads to decreased production and increased consumption of these natural anticoagulants 1
• Thrombomodulin (TM) expression is reduced on endothelial cells, impairing protein C activation 1

Suppression of Fibrinolysis

• Inflammatory cytokines increase plasminogen activator inhibitor-1 (PAI-1) activity, inhibiting tissue plasminogen activator (t-PA) and suppressing fibrinolysis 1, 2
• Thrombin also activates thrombin-activatable fibrinolysis inhibitor (TAFI), further inhibiting fibrinolysis 2
• This impaired fibrinolysis prevents the normal breakdown of clots, contributing to microvascular thrombosis 4

Self-Perpetuating Cycle

• A vicious cycle develops where inflammation promotes coagulation, and coagulation amplifies inflammation 1
• Thrombin and other clotting enzymes can activate cellular responses that further amplify inflammatory reactions 2
• Products released from dead cells, particularly extracellular histones and nucleosomes, propagate further inflammation, coagulation, and cell death 2, 5
• This cycle leads to consumption of platelets and coagulation factors, eventually resulting in bleeding complications in severe cases 4

Clinical Manifestations and Progression

• Early stages (sepsis-induced coagulopathy or SIC) show mild coagulation abnormalities with organ dysfunction 1
• Advanced stages (overt DIC) demonstrate widespread microvascular thrombosis, consumption of platelets and coagulation factors, and potential bleeding 1
• Laboratory findings typically include thrombocytopenia, prolonged prothrombin time, elevated D-dimer, and decreased fibrinogen in advanced cases 1
• Biomarkers of inflammation (procalcitonin, IL-6, IL-8, IL-10, TNFα) correlate with DIC severity 5

Specific Molecular Mediators

• Angiopoietin-2 is released from Weibel-Palade bodies in endothelial cells during sepsis, inducing prothrombotic responses by expressing endothelial tissue factor and phosphatidylserine exposure 1
• Angiopoietin-2 acts as an antagonist to the anti-inflammatory angiopoietin-1, increasing endothelial permeability and contributing to multiple organ dysfunction 1
• Recent research highlights the role of extracellular DNA and DNA-binding proteins (histones) in DIC pathogenesis 4
• Neutrophil extracellular traps (NETs) contribute to thrombosis in sepsis-induced DIC 6

The pathophysiology of sepsis-induced DIC represents a complex interplay between infection, inflammation, and coagulation, where the normal protective responses become dysregulated and harmful, leading to microvascular thrombosis, organ dysfunction, and potentially life-threatening bleeding complications 1, 4.