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Sunday, May 30, 2010

Disseminated Intravascular Coagulation

Disseminated Intravascular Coagulation (DIC) is a disorder of coagulation that always occurs in the presence of one or more underlying conditions in patients. It is not a disease process that occurs on its own; rather it is the product of an underlying illness that can overwhelm the body. In this disorder the coagulation cascade is thrown so out of balance that thrombosis and hemorrhage can occur at the same time. DIC is defined as the systemic activation of the coagulation system within the blood vessels that leads to depletion of clotting factors, multiple organ damage, and eventually death.

Although the actual mechanism is extremely complex, in general there are four processes that are responsible for the coagulation imbalance that is DIC. To begin to understand these processes it is necessary to remember the coagulation cascade. The instrinisc pathway is activated by procoagulants such as lipids and high molecular weight kininogen within the blood vessels causing clotting factors to activate all the way down the cascade until factor X activates the cleavage of prothrombin to thrombin. In the extrinsic pathway tissue factor activates the pathway and clotting factors are activated until factor X activates thrombin as well. The big picture here is that thrombin is made and thrombin converts fibrinogen into a fibrin clot. In DIC the first process that goes wrong is that thrombin is generated out of control in vast amounts. This constant generation of thrombin depletes the body of clotting factors and platelets. This excess of thrombin in the body also promotes the generation of fibrin clots throughout the vasculature. The second process that goes wrong is that the regulatory proteins that keep thrombin in check are themselves overwhelmed. Antithrombin III, Protein C, and Protein S all normally would work together to limit the action of thrombin. However in DIC these proteins are incapacitated for various reasons. Most notably antithrombin III is constantly consumed during the process of coagulation. It is degraded by the enzyme elastase which is produced by neutrophils that are activated by inflammatory response. Protein C and Protein S are also degraded by cytokines given off in the inflammatory response. Finally production of all three of these proteins is affected once microvascular damage occurs to the liver. The third process that becomes impaired is fibrinolysis. Fibrinolysis is the breakdown of clot formation. This occurs when plasminogen is converted to plasmin which acts upon fibrinogen, fibrin, and fibrin clots. The endothelial cells of blood vessels release chemicals that activate and inhibit plasminogen. In DIC the destruction of vessel walls and the constant consumption of coagulants overwhelm this system causing levels of plasmin to increase out of control (just like thrombin). The result is that plasmin inhibitors are overwhelmed and fibrin/fibrinogen degradation products are produced in great amounts. The fourth process that occurs is inflammatory activation. This is really a circular process as both DIC and the inflammatory state feed off of each other. It is believed that the underlying medical condition sets in motion an inflammatory state which introduces procoagulants (tissue factor, bacteria, lipids, etc.) into the system causing the coagulation cascade to set itself in motion. Many clotting factors, once activated, actually stimulate the release of cytokines from the vascular endothelium to promote inflammation which causes normal events like platelet and neutrophil aggregation. In DIC this adds fuel to the fire. Clots begin to settle into vascular walls and into organs causing more tissue damage and the release of more procoagulants thus propagating the cycle further. At this point the body has no way to bring the system back into balance and without treatment of the underlying condition death will occur.

There are many illnesses that can cause DIC and depending on what type of illness a patient has can determine whether or not DIC is acute or chronic. In acute DIC large amounts of procoagulants are released into the bloodstream within a very short period of time. In this short time the consumption of clotting factors and platelets occurs far more rapidly than the body can replenish them causing mass bleeding. Acute DIC is usually caused by systemic infections due to bacteria but can be caused by viruses, parasites, and even fungi. The idea with acute DIC is that the underlying medical condition is something that damages the body quickly. Other events that can trigger acute DIC include any type of severe trauma, burns, transfusions, obstetric complications, and even snake bites. Some disease states can also provide the right conditions to allow for the development of acute DIC. Acute hepatic failure can trigger a state of acute DIC as can acute myelocytic leukemia. It is important to monitor and treat the underlying condition in order to prevent the possibility of the development of DIC. Chronic DIC is different in that the body is able to compensate for the consumption of coagulation factors and platelets. The body is able to compensate because smaller amounts of procoagulant are being released into the body over a longer period of time. Partners of chronic DIC include diseases such as rheumatoid arthritis, sarcoidosis, ulcerative colitis, and crohn disease. Cancers such as solid tumors, leukemias, and myeloproliferative disorders can also lead to DIC. Even retained products of conception from either miscarriage or an abortion can cause chronic DIC. The key to chronic DIC is that the procoagulant in question leaks into the system slowly over a period of time. In chronic DIC there is little chance for the massive bleeding that is seen with acute DIC, however the chance for tissue and organ damage is just as great.

In order to determine if DIC is present the doctor must use both clinical and laboratory findings. Laboratory testing includes both hematology and coagulation testing. The most important finding early on in patients suspected of having DIC is thrombocytopenia. This can be found by simply running a CBC with differential. When seen under a microscope a peripheral smear will usually include schistocytes, the presence of a left shift in leukocytes, and possibly large young platelets. This would all reflect the presence of clotting in vessels, inflammation, and the high turnover of platelets. The normal values for platelets is age dependent, however the critical value cutoff is around <50,000 platelets/uL and any value under this would certainly be considered thrombocytopenic. The remaining testing is all coagulation. The prothrombin time and activated thromboplastin time will be prolonged since clotting factors are being constantly consumed. Although normal value will differ from lab to lab generally normal ranges for PT are around 9.0-11.0 seconds and for APTT are around 24.0-33.0 seconds. Fibrinogen levels are expected to be decreased since thrombin is busy using it up to make fibrin. However fibrinogen is an acute phase reactant, which will increase in levels in cases of inflammation, so sometimes the levels will remain within normal ranges. A general normal range is 200-475 mg/dL for fibrinogen. The final test that can be run is d-dimer. D-dimer is a degradation product of the cross-linked fibrin polymers that are broken apart during fibrinolysis. D-dimer levels are usually elevated in cases of DIC due to constant formation of fibrin and fibrinolysis. However d-dimer levels are also high after surgery, in cases of trauma, in infections and in cases of inflammation so theses results have to be used in conjunction with other findings. A general normal range for d-dimer is 0.0-3.0 mg/L.

Currently there is no definitive treatment for DIC. The best course of treatment for the patient is to treat the underlying illness in order to rid the body of the procoagulants causing DIC. Through the course of treatment replacement of platelets and clotting factors can be given if needed, however this is only done to stop active bleeding. Although it seems to be common practice there has been no definitive data that giving heparin to reverse the coagulation process is of any benefit to the patient. Heparin will inactivate thrombin but it can only be given to DIC patients in small controlled amounts in order to prevent bleeding. Currently research is being done on giving patients antithrombin III and activated protein C. This research looks promising but the trials are still in their early stages. In the end the best that can be done for the patient is diligent laboratory work and treatment by the clinicans.


* Kusuma, B., Schulz, T. (2009). Acute Disseminated Intravascular Coagulation. Hospital Physician, 35-40. Retrieved December 5, 2009 from http://www.turner-white.com/memberfile.php?PubCode=hp_mar09_coagulation.pdf
* Riley, R. (2005). Disseminated Intravascular Coagulation. Retrieved December 5, 2009 from http://www.pathology.vcu.edu/clinical/coag/DIC.pdf
* Becker, J., Wira, C. (2009). Disseminated Intravascular Coagulation. Emedicine from WebMD. Retrieved December 5, 2009 from http://emedicine.medscape.com/article/779097-overview

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