What causes disseminated intravascular coagulation (DIC)?

Updated: Oct 06, 2020
  • Author: Irene S Pakos, DO; Chief Editor: Perumal Thiagarajan, MD  more...
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The etiology and progression of DIC are multifactorial and are characterized by defects in the protein C system and in the antithrombin and tissue-factor inhibitor pathways. Tissue factor–dependent activation of coagulation, defective physiological anticoagulant pathways, and impaired fibrinolysis caused by elevated levels of plasminogen activator inhibitor type 1 (PAI-1) can all lead to DIC. Release of tissue factor from endothelial cells or other circulating cells is the most common initiating event. Bacterial factors also release tissue factor as well as proinflammatory and anti-inflammatory cytokines.

Tumor necrosis factor (TNF) and interleukin 8 (IL-8) increase the inflammatory response, while IL-10 inhibits it. IL-1 beta, IL-12, IL-2, G-CSF, and IFN-gamma have all been reported to induce coagulation. IL-4, IL-13, and TGF-beta have anticoagulant activity.

These imbalances all promote the development of DIC. Persistence of the triggering agent (eg, a septic locus) leads to a consumption coagulopathy with loss of fibrinogen and platelets and the potential for diffuse bleeding. Failure of the fibrinolytic system elicits deposition of microvascular fibrin and multisystem organ failure (MSOF). [79]

Vervloet and colleagues are proponents of the theory that DIC is an imbalance between coagulation and fibrinolysis mediated by various cytokines and caused by increased levels of PAI-1. [80] Increased levels of PAI-1 produce a procoagulant state characterized by thrombin generation in excess of plasmin and impaired fibrin degradation, leading to widespread fibrin deposition. Thrombin generation proceeds via the extrinsic tissue factor/factor VIIa route simultaneous with consumption of the natural coagulation inhibitors antithrombin III, protein C, and protein S increases. Although levels of plasminogen activator antigen are increased, its activity is almost completely inhibited by PAI-1. High plasma levels of thrombin-antithrombin (TAT) complex can be found.

Vervloet and colleagues found that increased PAI-1 levels are associated with poorer outcome and increased severity of MSOF in patients with DIC from sepsis as well as other causes. Hardaway and Vasquez believe that DIC may be initiated by release of a thrombogenic aminophospholipid from dying tissue or bacterial cells. [82] Coagulation abnormalities secondary to DIC are coupled to the inflammatory response, which aggravates vascular permeability, inflammation, and cell damage in tissues. This combination of events leads to multisystem organ failure and death. DIC may produce acute respiratory distress syndrome through the mechanism of intravascular fibrin formation, vessel occlusion, and localized hypoxia. [83]

In Japan, Watanabe and colleagues measured plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI) activity and antigen in patients with DIC in a study designed to examine the role of hypofibrinolysis in this disorder. [84] Both TAFI activity and antigen levels were significantly below reference ranges in patients with DIC. Decreases in TAFI activity were inversely correlated with increases in plasma TAT III complex and D-dimer, suggesting that TAFI activity is reduced by thrombin generation and consumption of coagulation factors. TAFI activity levels were not correlated with fibrinogen, plasma alpha2-plasmin inhibitor complex, and tissue plasminogen activator (TPA)/PAI-1 complex levels, thus supporting a role for TAFI as a secondary modulator of fibrinolysis.

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