Disseminated intravascular coagulation

Disseminated intravascular coagulation is a pathologically acquired state in which the vascular system is affected by upregulated coagulative activity that begins by the creation of tremendous amount of micro-thrombi in the capillary system, which leads to depletion of plasmatic coagulation factors, resulting in haemorrhage. DIC can be acute or chronic.

DIC is a secondary process as a result of tissue impairment.

Risk factors of disseminated intravascular coagulation:

 * Sepsis
 * Trauma (neural damage mostly)
 * Tumor
 * Severe post-transfusion reaction
 * Rheumatism
 * Gynecology and Obstetrics: amniotic fluid embolism, abruption of placenta, HELLP syndrome, eclampsia, dead fetus syndrome
 * Severe liver failure
 * Microcirculatory disorders (shock)
 * Exposure of circulating blood to foreign materials (extracorporeal circulation) [1]

Organs that do mostly contribute to DIC (due to high thromobokinase count)
4 P
 * Pulmonary system (lungs)
 * Prostate
 * Pancreas
 * Placenta [2]

In these pathological states molecules or cells with potential to cause DIC can enter the blood flow like: Foreign tissue cells (aspiration of amnionic fluid in birth, severe trauma, operation, metastatic cells), pathological myeloid or lymphoid proliferative cells, endothelial cells and monocytes that are activated by cytokines (IL-1 and TNF) or endotoxin (in septic shock caused by G- bacteria), or cytoplasmic tissue factor from ruptured erythrocytes.

Pathophysiology
Coagulation of blood is physiologically a local process, whereas in DIC the coagulation is spread uncontrollably (as the name suggests) around the vascular system.

Main factors of DIC:


 * Increase in thrombin production
 * Anticoagulant mechanisms supression
 * Fibrinolysis disorder
 * Activation of inflammatory response

The whole process is started by activating the "external (extravascular) pathway" of coagulation - by activating plasma coagulation factor VII by binding to tissue factor III. Tissue factor is a molecule contained in the phospholipid membrane of cells and does not normally occur in the circulation. However, it is present on the surface of non-vascular cells and in the cytoplasm of some blood cells (blood cells do not express it on their surface). In addition to activating factor IX (activation of the "internal pathway" by components of the the external) and X, factor VII is also able to activate itself, promoting the whole reaction. Activation of factor IX further leads to increased production of activated factor X.

Activated factor X then leads to the conversion of prothrombin to thrombin and the subsequent cleavage of fibrinogen to fibrin monomer, which forms fibers (fibrin polymer) and leads to the formation of an intravascular "fibrin network". Thrombin also activates platelets. Activation of platelets includes changes in platelet shape, increased movement, release of granule contents, and aggregation [3]. This disseminated coagulation activity causes micro-embolization to the periphery, thereby significantly impairing organ perfusion and aiding in the development of ischemia in the affected areas.

The coagulation and anticoagulation system is in balance under normal circumstances. Coagulation is regulated by negative feedback between the individual stages of the coagulation cascade and by circulating coagulation inhibitors. The most effective inhibitor is antithrombin III, which inhibits their activity by binding to thrombin and other factors of the coagulation cascade (IXa, Xa, XIa, XIIa). The effect of antithrombin III represents about 3/4 of the antithrombotic activity. The remaining 25% are factors such as α2-macroglobulin, heparin cofactor II and α1-antitrypsin [3]. The activity of antithrombin III is increased by the presence of acidic proteoglycans such as heparin. Antithrombin-bound heparin alters its conformation and allows binding to more substrates. Thrombin further binds to thrombomodulin and converts protein C to active protein C, which in combination with its cofactor protein S, degrades activated coagulation factors V and VIII [3].

The formed fibrin chains are cleaved by the activated plasminogen - plasmin, which is activated by the action of the tissue plasminogen activator tPA. Cleaved fibrin chains can be detected in blood as fibrin degradation products (FDPs), also known as fibrin split products, which are blood components produced by clot degeneration.[1] The most notable subtype of fibrin degradation products is D-dimer. Fibrin and fibrinogen degradation product (FDP) testing is commonly used to diagnose disseminated intravascular coagulation.[2] In DIC, the processes of coagulation and fibrinolysis are dysregulated, and the result is widespread clotting with resultant bleeding.

Coagulation inhibitors are consumed in the process of DIC. Decreased inhibitor levels will permit more clotting so that a positive feedback loop develops in which increased clotting leads to more clotting. At the same time, thrombocytopenia occurs and this has been attributed to the entrapment and consumption 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 an excess 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.

Coagulation and anticoagulation processes are closely related to the inflammatory response, and many proteins involved in the coagulation chain are also proteins of the acute phase of the inflammatory response. In the development of DIC, both coagulation and anticoagulant activity takes place, but also an inflammatory reaction that further deepens DIC.

Antithrombin is consumed during DIC to inhibit coagulation and it is also cleaved by enzymes produced by neutrophils activated by the inflammatory response. In addition, antithrombin production in the liver may be impaired as a result of liver damage due to insufficient perfusion and ischemia caused by microembolizations in the hepatic vessels [4]. Anticoagulant activity is also impaired by the consumption of other coagulation and anticoagulation factors. Inflammatory cytokines reduce thrombomodulin expression on cell membranes. Therefore, fibrinolysis and anticoagulation cannot keep pace with increasing coagulation activity, leading to further micro-embolization into tissues, development of ischemia, organ damage, development of inflammation and SIRS and MODS and finally depletion of coagulation and anticoagulant factors which leads to subsequent bleeding with shock. Inflammatory activity supports this by increasing permeability of blood vessel walls and following leakage of fluids from the intravascular space.

Diagnosis
Diagnosis of DIC involves a combination of laboratory tests and clinical evaluation. Laboratory findings suggestive of DIC include a low platelet count, elevated D-dimer concentration, decreased fibrinogen concentration, and prolongation of clotting times such as prothrombin time (PT). 3

Video
https://www.youtube.com/watch?v=Gmh01S0msfY