Aetiology

Disease states that trigger systemic activation of coagulation may lead to disseminated intravascular coagulation (DIC). Causes include:​[1][2]​[6][7]

  • Sepsis/severe infection, including severe coronavirus disease 2019 (COVID-19) infection[3]

  • Major trauma or burns

  • Some malignancies (acute myelocytic leukemia or metastatic mucin-secreting adenocarcinoma)

  • Obstetric disorders (amniotic fluid embolism, eclampsia, abruptio placentae, retained dead fetus syndrome)

  • Severe organ destruction or failure (severe pancreatitis, acute hepatic failure)

  • Vascular disorders (Kasabach-Merritt syndrome or giant haemangiomas, large aortic aneurysms)

  • Severe toxic or immunological reactions (blood transfusion reaction or haemolytic reactions, organ transplant rejection, snake bite).

DIC induced by these causes may be acute or chronic.

Acute DIC is more common with rapid-onset underlying conditions such as major trauma, sepsis/severe infection, and massive blood transfusion.

Chronic DIC is more common with less acute disorders such as malignancies, paroxysmal nocturnal haemoglobinuria, and Raynaud's disease. Localised DIC (characterised by bleeding or thrombosis limited to a specific anatomical location) is associated with an underlying disorder such as aortic aneurysm, giant haemangioma, and hyperacute renal allograft rejection.​[1][2]

Pathophysiology

Two important hallmarks of DIC are continuous generation of intravascular fibrin and consumption/depletion of procoagulants and platelets.[8] Increased clotting is accompanied by decreased fibrinolysis. Thrombin production is increased by activation of the extrinsic tissue factor (VIIa) pathways.[9] Thrombin, a proteolytic enzyme, cleaves fibrinogen to form fibrin. Without the functional counteraction from the anticoagulant pathways, increased thrombin continuously amplifies the coagulation cascade through its positive feedback and consumptive depletion of procoagulants and platelets, finally leading to widespread fibrin deposition, resulting in multi-organ failure.

A coexisting mechanism in the development of DIC relates to the impaired fibrinolytic system, which includes tissue factor pathway inhibitor, antithrombin III, and the protein C system. Plasmin, which degrades fibrin into measurable fibrin degradation products, is a key component of the fibrinolytic system. The impaired fibrinolytic system probably results from decreased production of plasmin due to a sustained increase in plasma level of plasminogen activator inhibitor type I (PAI-I).

Another mechanism involves the mutual potentiation between the inflammatory and coagulation pathways. A systemic inflammatory response can activate the coagulation pathways by activating the cytokine network. Interleukin-6 and tumour necrosis factor are cytokines that activate the coagulation pathway. Because activated protein C has an anti-inflammatory effect through its inhibition of cytokine production, depression of protein C promotes inflammation, which favours coagulation. In addition, the products produced by coagulation, such as factor Xa, thrombin, and fibrin, activate endothelial cells to release pro-inflammatory cytokines. Thus, both coagulation and inflammatory pathways positively reinforce each other, forming a vicious circle and causing uncontrolled activation of systemic coagulation.​[1][2]

Classification

DIC subtypes[1]

  • Acute DIC is characterised by rapid-onset generalised bleeding and microcirculatory/macrocirculatory thrombosis, resulting in hypoperfusion, infarction, and end-organ damage.

  • Chronic DIC is characterised by subacute bleeding and diffuse thrombosis.

In addition to clinical classification as acute/chronic subtypes, the International Society on Thrombosis and Haemostasis recommends classifying DIC as overt or non-overt. Overt DIC refers to a decompensated haemostatic system, whereas non-overt DIC refers to a stressed but compensated haemostatic system.[4]

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