Disseminated intravascular coagulation
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| Disseminated intravascular coagulation or Disseminated intravascular coagulopathy Classification and external resources |
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| ICD-10 | D65. |
|---|---|
| ICD-9 | 286.6 |
| DiseasesDB | 3765 |
| eMedicine | med/577 emerg/150 |
| MeSH | D004211 |
Disseminated intravascular coagulation (DIC), also called consumptive coagulopathy, is a pathological process in the body where the blood starts to coagulate throughout the whole body. This depletes the body of its platelets and coagulation factors, resulting in the paradoxic situation in which there is a high risk for simultaneous catastrophic thrombosis as well as massive hemorrhage. It occurs in critically ill patients in fulminant sepsis as well those with malignancy. It is more commonly seen in Gram-negative sepsis (particularly meningococcal sepsis) than in Gram-positive sepsis. In the past, it was a common consequence of treatment of acute promyelocytic leukemia, and may occur in other hematogenic malignancies, but can occur in solid tumors as well as a paraneoplastic syndrome.
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[edit] Etiology
There are a variety of causes of DIC[1], all usually causing the release of chemicals into the blood that instigates the coagulation.
- Infections:
- Sepsis, particularly with Gram-negative bacteria but also occurring with Gram-positive bacteria, viruses, and fungi
- Malaria
- Rickettsial
- Obstetric complications (most common cause), with chemicals from the uterus being released into the blood. These include:
- amniotic fluid embolism
- eclampsia
- abruptio placentae
- placenta praevia
- intrauterine death
- Tissue trauma such as burns, accidents, surgery, heat stroke or shock.
- Liver disease:
- Incompatible blood transfusion reactions or massive blood transfusion (when more than the total circulatory volume is tranfused)
- graft-versus-host disease
- Cancers, particularly of the following types, and especially when metastatic:
- stomach cancer
- colorectal cancer
- pancreatic cancer (first described as Trousseau phenomenon)
- mucin-secreting adenocarcinoma
- acute promyelocytic leukemia
- Viral hemorrhagic fevers bring about their frank effects by causing DIC.
- Envenomation by some species of venomous snakes, such as those belonging to the genus Echis (saw-scaled vipers).
[edit] Diagnosis
Although numerous blood tests are often performed on patients prone to DIC, the important measures are: full blood count (especially the platelet count), fibrin degradation products or D-dimer tests (markers of fibrinolysis), bleeding time and fibrinogen levels. The protamine paracoagulation phenomenon can also be observed. Decreased platelets, elevated FDPs or D-dimers, prolonged bleeding time and decreased fibrinogen are markers of DIC. On peripheral blood smear, evidence of microangiopathic hemolytic anemia (specifically schistocytes) may be present (as in thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS))
[edit] 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.
The release of endotoxin is the mechanism by which Gram-negative sepsis provokes DIC. In acute promyelocytic leukemia, treatment causes the destruction of leukemic granulocyte precusors, resulting in the release of large amounts of proteolytic enzymes from their storage granules, causing microvascular damage. Other malignancies may enhance the expression of various oncogenes that result in the release of TF and plasminogen activator inhibitor-1 (PAF-1), which prevents fibrinolysis.[2]
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 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 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.
[edit] Treatment
The only effective treatment is the reversal of the underlying cause. Anticoagulants are given exceedingly rarely when thrombus formation is likely to lead to imminent death (such as in coronary artery thrombosis or cerebrovascular thrombosis). Platelets may be transfused if counts are less than 5,000-10,000/mm3 and massive hemorrhage is occurring, and fresh frozen plasma may be administered in an attempt to replenish coagulation factors and anti-thrombotic factors, although these are only temporizing measures and may result in the increased development of thrombosis.
DIC results in lower fibrinogen levels (as it has all been converted to fibrin), and this can be tested for in the hospital lab. A more specific test is for "fibrin split products" (FSPs) or "fibrin degradation products" (FDPs) which are produced when fibrin undergoes degradation when blood clots are dissolved by fibrinolysis.
In some situations, infusion with antithrombin may be necessary. A new development is drotrecogin alfa (Xigris), a recombinant activated protein C product. Activated Protein C (APC) deactivates clotting factors V and VIII, and the presumed mechanism of action of drotrecogin is the cessation of the intravascular coagulation. Due to its high cost and its severe adverse effects, it is only used strictly on indication in intensive care patients with severe sepsis.[3] The large, multicenter ENHANCE trial provided more evidence that there may be a favorable benefit/risk ratio to administering activated protein C in adults[4], but was unable to make definitive conclusions about efficacy due to the lack of a placebo control, and particularly in children, there is a high risk of hemorrhage (27.4% in patients aged 0-18 years)[5]
The prognosis for those with DIC, regardless of cause, is often grim, leading the initials to be known colloquially as "death is coming".[6]
[edit] References
- ^ Ledingham, J; D Warrell (2000). Concise Oxford Textbook of Medicine. Oxford University Press. ISBN 0-19-262870-4,.
- ^ Rak J, Yu JL, Luyendyk J, Mackman N (2006). "Oncogenes, trousseau syndrome, and cancer-related changes in the coagulome of mice and humans". Cancer Res. 66 (22): 10643–6. doi:. PMID 17108099.
- ^ Dhainaut J, Yan S, Joyce D, Pettilä V, Basson B, Brandt J, Sundin D, Levi M (2004). "Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation.". J Thromb Haemost 2 (11): 1924-33. doi:. PMID 15550023.
- ^ Vincent JL, Bernard GR, Beale R, et al (2005). "Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: further evidence for survival and safety and implications for early treatment". Crit. Care Med. 33 (10): 2266–77. doi:. PMID 16215381.
- ^ Goldstein B, Nadel S, Peters M, et al (2006). "ENHANCE: results of a global open-label trial of drotrecogin alfa (activated) in children with severe sepsis". Pediatr Crit Care Med 7 (3): 200–11. doi:. PMID 16575354.
- ^ Norman K (2004). "Alternative treatments for disseminated intravascular coagulation.". Drug News Perspect 17 (4): 243-50. doi:. PMID 15334173.
