What is the pathophysiology of disseminated intravascular coagulation (DIC)?

Pathophysiology of Disseminated Intravascular Coagulation

DIC is an acquired syndrome characterized by widespread intravascular activation of coagulation with loss of localization, leading to simultaneous microvascular thrombosis and consumption of platelets and coagulation factors, ultimately causing organ dysfunction through tissue ischemia. 1

Core Pathophysiologic Mechanisms

Systemic Coagulation Activation

• Tissue factor-mediated activation of the coagulation cascade is the primary initiating event, with massive tissue factor stimulus generating excess intravascular thrombin that overwhelms natural anticoagulant systems. 2, 3
• The coagulation activation is systemic and uncontrolled, resulting in widespread intravascular fibrin deposition throughout the microvasculature rather than localized clot formation. 1, 4

Endothelial Injury and Dysfunction

• Endothelial dysfunction is an essential component and critical early event in DIC development, preceding the overt coagulation disorder. 5, 6
• The degree of endothelial involvement varies by underlying disease: highly significant in sepsis-induced coagulopathy, moderate in trauma-induced coagulopathy, and variable in hematologic malignancy-associated coagulopathy. 6

Consumption Coagulopathy

• Ongoing clot formation depletes platelets and coagulation factors (including fibrinogen), creating a paradoxical state where patients are simultaneously at risk for both thrombosis and hemorrhage. 6, 2
• Thrombocytopenia develops from platelet consumption in microvascular thrombi, representing one of the characteristic laboratory hallmarks. 6

Impaired Anticoagulant Mechanisms

• Natural anticoagulant pathways become defective, including decreased levels of antithrombin, protein C, and protein S, which normally regulate coagulation. 5, 2
• The antithrombin system and protein C system fail to control the excessive thrombin generation, allowing uncontrolled propagation of coagulation. 2

Fibrinolytic Dysregulation

• Fibrinolysis is impaired due to elevated levels of plasminogen activator inhibitor type 1 (PAI-1), preventing adequate breakdown of fibrin clots. 2
• Secondary fibrinolysis eventually occurs as a compensatory mechanism, leading to elevated fibrin degradation products (D-dimer, FDP) that serve as diagnostic markers. 6, 7

Disease-Specific Mechanisms

Sepsis-Induced DIC

• Endotoxin absorption leads to sustained inflammation that triggers platelet and coagulation activation, with endothelial dysfunction playing a particularly prominent role. 1, 5
• Sepsis is the most common cause of DIC, with mortality of 24.8% in septic patients who develop DIC according to Japanese nationwide data. 6

Cancer-Associated DIC

• Malignancies trigger DIC through three distinct patterns: procoagulant DIC, hyperfibrinolytic DIC, and subclinical (chronic) DIC with ongoing thrombin generation. 5
• Pancreatic adenocarcinomas and other adenocarcinomas carry particularly high risk for precipitating DIC. 5

Liver Disease-Associated Mechanisms

• Multiple pathways contribute in liver disease: activation of coagulation factors in the low-flow portal system with incomplete removal by the diseased liver, endotoxin absorption from intestines into systemic circulation, and hepatocyte necrosis with consequent tissue factor release. 1
• Activated endothelial surface in dilated collateral circulation and congestive splenomegaly facilitates coagulation activation in the context of blood stasis and local inflammation. 1

Clinical Consequences

Microvascular Thrombosis

• Intravascular fibrin deposition in the microvasculature is the central pathologic feature, demonstrated by pathological, experimental, and clinical findings linking DIC to organ dysfunction. 2
• Organ dysfunction develops when microvascular thrombosis becomes sufficiently severe, representing the most serious complication beyond bleeding. 6

Hemorrhagic Complications

• The consumption of coagulation factors and platelets creates a hemorrhagic phase, with diffuse bleeding occurring despite the underlying prothrombotic state. 7, 3
• Prolonged prothrombin time and decreased fibrinogen levels in advanced cases reflect the consumption of clotting factors, though fibrinogen may initially be normal or elevated as an acute phase reactant. 6

Critical Diagnostic Requirement

• A mandatory prerequisite for diagnosing DIC is identification of an underlying disorder known to be associated with DIC—DIC is not a disease itself but rather a mechanistic process involved in disease progression. 1, 6