Disseminated intravascular coagulation pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

• DIC is a hemorrhagic syndrome originating in the small blood vessels
• DIC is caused by uncontrolled activation of clotting factors and fibrinolytic enzymes
• Tissue necrosis and bleeding are results of DIC

Pathophysiology

Under homeostatic conditions, the body is maintained in a finely tuned balance of coagulation and fibrinolysis. The activation of the coagulation cascade yields thrombin that converts fibrinogen to fibrin; the stable fibrin clot being the final product of hemostasis. The fibrinolytic system then functions to break down fibrinogen and fibrin. Activation of the fibrinolytic system generates plasmin (in the presence of thrombin), which is responsible for the lysis of fibrin clots. The breakdown of fibrinogen and fibrin results in polypeptides called fibrin degradation products (FDPs) or fibrin split products (FSPs). In a state of homeostasis, the presence of thrombin is critical, as it is the central proteolytic enzyme of coagulation and is also necessary for the breakdown of clots, or fibrinolysis.

In DIC, the processes of coagulation and fibrinolysis lose control, and the result is widespread clotting with resultant bleeding. Regardless of the triggering event of DIC, once initiated, the pathophysiology of DIC is similar in all conditions. One critical mediator of DIC is the release of a transmembrane glycoprotein called tissue factor(TF). TF is present on the surface of many cell types (including endothelial cells, macrophages, and monocytes) and is not normally in contact with the general circulation, but is exposed to the circulation after vascular damage. For example, TF is released in response to exposure to cytokines (particularly interleukin), tumor necrosis factor, and endotoxin. This plays a major role in the development of DIC in septic conditions. TF is also abundant in tissues of the lungs, brain, and placenta. This helps to explain why DIC readily develops in patients with extensive trauma. Upon activation, TF binds with coagulation factors that then trigger both the intrinsic and the extrinsic pathways of coagulation.

Excess circulating thrombin results from the excess activation of the coagulation cascade. The excess thrombin cleaves fibrinogen, which ultimately leaves behind multiple fibrin clots in the circulation. These excess clots trap platelets to become larger clots, which leads to microvascular and macrovascular thrombosis. This lodging of clots in the microcirculation, in the large vessels, and in the organs is what leads to the ischemia, impaired organ perfusion, and end-organ damage that occurs with DIC.

Coagulation inhibitors are also consumed in this process. Decreased inhibitor levels will permit more clotting so that a feedback system develops in which increased clotting leads to more clotting. At the same time, thrombocytopenia occurs because of the entrapment of platelets. Clotting factors are consumed in the development of multiple clots, which contributes to the bleeding seen with DIC.

Simultaneously, excess circulating thrombin assists in the conversion of plasminogen to plasmin, resulting in fibrinolysis. The breakdown of clots results in excess amounts of FDPs, which have powerful anticoagulant properties, contributing to hemorrhage. The excess plasmin also activates the complement and kinin systems. Activation of these systems leads to many of the clinical symptoms that patients experiencing DIC exhibit, such as shock, hypotension, and increased vascular permeability. The acute form of DIC is considered an extreme expression of the intravascular coagulation process with a complete breakdown of the normal homeostatic boundaries. DIC is associated with a poor prognosis and a high mortality rate. As a summary:

• It seems that the formation of both thrombin and plasmin are required for the development of DIC.
• A variety of triggering events can result in thrombin and plasmin formation, including damage to RBCs, platelets, or the endothelium.
• After the coagulation system has been activated, the pathophysiology of DIC is similar in all disorders.
• Circulating thrombin cleaves fibrinopeptides A and B from fibrinogen resulting in the formation of fibrin monomers.

  • These monomers polymerize into a fibrin clot, which traps platelets and results in thrombosis, organ ischemia and thrombocytopenia.
  • Thrombin also induces endothelial cells to release:

    • endothelin, a potent vasoconstrictor, and,
    • E selectin, which binds granulocytes and lymphocytes, resulting in further cytokine release as well as release of platelet activating factor.

• At the same time, plasmin cleaves the carboxy-terminal end of fibrinogen into fibrinogen degradation products, and cleaves fibrin into fibrin degradation products.

  • The circulating FDPs (fibrin and fibrinogen) interfere with the polymerization of fibrin monomers, resulting in further hemorrhage.
  • Additionally, the fibrinogen degradation products D and E impair platelet function, worsening the bleeding.
  • The fibrin degradation products and D-dimer induce synthesis of IL-1 and IL-6, which cause further endothelial damage, as well as plasminogen activator inhibitor type 1 (PAI-1) which inhibits fibrinolysis resulting in accelerated thrombus formation.
  • FDPs also stimulate the release of tissue factor, which accelerates thrombosis via the extrinsic coagulation pathway.

    • The release of large amounts of tissue factor (i.e. in obstetrical cases) can also initiate DIC.

  • Other effects of plasmin include:

    • biodegredation of factors V, VII, IX and XI --> hemorrhage.
    • complement activation, which results in RBC lysis --> release of ADP and membrane phospholipids (procoagulant material).

• As can be seen, the above soup results in a mess of thrombosis and hemorrhage.
• DIC is seen in a wide variety of clinical conditions and is most commonly associated with infection (esp. GN org --> endotoxin), malignancy and obstetrical complications.

References