Disseminated intravascular coagulation

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Disseminated intravascular coagulation or Disseminated intravascular coagulopathy
ICD-10 D65
ICD-9 286.6
DiseasesDB 3765
MeSH D004211

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Related Key Words and Synonyms:: Disseminated intravascular coagulation, Disseminated intravascular coagulopathy, Consumptive coagulopathy, DIC

Overview

Disseminated intravascular coagulation, 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, and there is a paradoxically increased risk of hemorrhage. It occurs in critically ill patients, especially those with Gram-negative sepsis (particularly meningococcal sepsis) and acute promyelocytic leukemia.[1] [2] [3] [4]

General characteristics:

  • 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

Definition

DIC is a complex and highly variable disorder, whose manifestations depend upon the inciting event, the host response and underlying comorbid disease. Additionally, the morbidity and mortality in patients with DIC often depends more on the underlying disease and he specific pathophysiology. As such, well-designed studies are obviously difficult to design, and there is therefore little consensus regarding management. The term DIC has evolved from the terms ‘consumptive coagulopathy’ and later, ‘defibrination syndrome’. Although most physicians are aware of the hemorrhage that is seen in patients with DIC, the ‘coagulation’ in DIC actually refers to both hemorrhage and thrombosis. In actuality, the thrombosis, both micro and macro-vascular, with resulting ischemia, contributes more to morbidity and mortality than the hemorrhage.

Bick defines DIC as ‘a systemic thrombohemorrhagic disorder seen in association with well-defined clinical situations AND laboratory evidence for procoagulant activation, fibrinolytic activation, inhibitor consumption, and evidence of end-organ damage’.

Etiology

There are a variety of causes of DIC[5], all usually causing the release of chemicals into the blood that instigates the coagulation.

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.

History and Symptoms

  • The signs and symptoms of DIC are highly variable, and for a large part depend upon the precipitating cause.
    • Common features include:
    • More specific signs include petechiae, purpura, hemorrhagic bullae, acral cyanosis and occasionally frank gangrene.
    • Bleeding from wounds or puncture sites is also commonly seen.
    • Microvascular thrombi are most often seen in the cardiac, pulmonary, renal, hepatic and CNS (central nervous system) circulation.
    • Patients with low-grade DIC tend to have subacute bleeding and thrombosis, and although most tests of global coagulation are normal, FDPs (flexor digitorum profundus) are uniformly elevated.
  • The peripheral smear will reveal schistocytes and RBC (red blood cell) fragments in ~ 50%, and the absence of schistocytes does not rule out DIC.
    • Most patients will have a mild reticulocytosis and leukocytosis, as well as thrombocytopenia with an increased population of young platelets (due to increased destruction and turnover).
  • Pathologically, early signs include platelet-rich microthrombi, which are then replaced by fibrin-rich microthrombi.

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. Decreased platelets, elevated FDPs or D-dimers, prolonged bleeding time and decreased fibrinogen are markers of DIC. In general;

  • The diagnosis of DIC is suggested when the appropriate clinical picture (hemorrhage and thrombosis with end-organ dysfunction) is accompanied by lab evidence of procoagulant activation, fibrinolytic activation, and inhibitor consumption.
  • Thrombocytopenia is an almost universal finding.
  • Although one would think that the PT and PTT (prothrombin time and partial thromboplastin time) should uniformly be elevated in DIC, this is not the case, with up to 50% of patients having normal values (due to higher circulating levels of clotting factors such as factor Xa and thrombin).
  • Fibrin and fibrinogen degradation products, however, are elevated in 80 – 100% of patients.
    • High FDPs, however, are not specific and can be elevated in any state associated with elevated plasmin levels such as PE/DVT (pulmonary embolism/deep vein thrombosis), liver or renal disease, in patients s/p (status post) surgery, and in women on oral contraceptives.
  • The D-dimer, however, is specific for the presence of fibrin degradation, and is thought to be more sensitive and specific for DIC.
  • Antithrombin levels have become a key test for diagnosing and monitoring therapy in DIC.
    • With thrombin activation, antithrombin is also activated, forming thrombin – antithrombin complexes --> reduced AT levels.
  • The main differential is TTP-HUS (thrombotic thrombocytopenic purpura-hemolytic uremic syndrome), which is associated primarily with thrombocytopenia, and minimal effects on fibrin degradation.
    • The PT and PTT in TTP – HUS are therefore usually normal, and there is little evidence of fibrinolysis and inhibitor consumption.

Differential Diagnosis

(In alphabetical order [6])

Treatment

The underlying cause must be treated initially. Anticoagulants are only given when indicated (development of thrombotic renal complications) as patients with DIC are prone to bleeding. Platelets may be transfused if counts are very low, and fresh frozen plasma may be administered.

DIC results in lower fibrinogen (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, it is only used strictly on indication in intensive care patients.[7]

The prognosis for those with DIC, depending on its cause, is often grim, leading the initials to be known colloquially as "death is coming".[8]

Essentials of DIC Therapy

  • The heterogeneity of DIC has been a major obstacle in the development of controlled prospective trials of therapy.
  • The overall goal of therapy should be to reverse the inciting event, and control the major suspected pathophysiologic process in addition to providing overall supportive care.
  • As micro and macrovascular thrombi are thought to be major contributors to morbidity and mortality, a great deal of attention has focused on anticoagulation, and even thrombolysis.
    • In cases where bleeding is the predominant manifestation, however, inhibition of plasmin may be crucial.
  • Transfusion: FFP (fresh frozen plasma), cryoprecipitate and platelets can be used in patients with severe hemorrhage and hemodynamic compromise as long as ‘the accelerated consumption process is under control’.
    • The feared ‘adding fuel to the fire’ has never been unequivocally proved.

Pharmacotherapy

Acute Pharmacotherapies

  • Heparin is an active inhibitor of thrombin formation and its effects.
    • However, heparin requires AT III in order to produce anticoagulation, and AT III levels are often low in DIC.
    • Additionally platelet factor 4 levels are often elevated in DIC and serve to neutralize heparin.
    • As heparin can induce thrombocytopenia and activate leukocytes and complement, it may not only aggravate bleeding, but possibly induce thrombosis as well.
    • Thus, there is no consensus on its use, though many hematologists would recommend its use as long as there is not excessive clinical bleeding.
  • AT III irreversibly inhibits thrombin and factor Xa.
    • As AT III is reduced in DIC, some authors have suggested that AT III repletion can neutralize excess thrombin and minimize DIC.
    • Recent RTCs in humans have shown a 44% reduction in mortality in patients with DIC who were treated (early) with AT III (this did not reach statistical significance, however).
    • Riewald and Riess recommend that until larger studies are out, AT III should be considered in all patients with DIC and AT III deficiency.
  • Hirudin is a direct thrombin inhibitor that does not require AT III for its anticoagulant activity.
    • It may therefore be even more useful than AT III infusions (studies underway).

Future or Investigational Therapies

  • Phase I trials suggest that infusion of activated protein C may also benefit patients with DIC.
    • The theory is that APC normally inactivates Va and VIIIa, resulting in a decrease in thrombin formation, and promotes fibrinolysis by inactivating plasminogen activator inhibitor.
  • Tissue factor pathway inhibitor has been shown to decrease mortality in baboon models of DIC with E. coli septic shock.
  • Agents such as ASA (aspirin), ticlopidine, dextran and GP IIb/IIIa inhibitors are also being examined with the goal of reducing platelet activation.
  • Currently, if fibrinolysis and hemorrhage appears to be more of a problem than clotting, the only options are antifibrinolytic agents, such as tranexamic acid. However, the risks of microvascular clot formation have limited its use.

References

  1. ↑ Baglin, T., Disseminated intravascular coagulation: diagnosis and treatment, BMJ 1996; 312: 683-686.
  2. ↑ Bick, R.L., Disseminated intravascular coagulation: pathophysiological mechanisms and manifestations, Sem Thromb Hemostasis 1998; 24: 3-18.
  3. ↑ Penner, J.A., Disseminated intravascular coagulation in patients with multiple organ failure of non-septic origin, Sem Thromb Hemostasis 1998, 24: 45-52.
  4. ↑ Riewald, M., Riess, H., Treatment options for clinically recognized disseminated intravascular coagulation, Sem Thromb Hemostasis 1998; 24: 53-59.
  5. ↑ Ledingham, J (2000). Concise Oxford Textbook of Medicine. Oxford University Press. ISBN 0-19-262870-4, Check |isbn= value: invalid character (help). Unknown parameter |coauthors= ignored (help)
  6. ↑ Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:104 ISBN 1591032016
  7. ↑ 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. PMID 15550023.
  8. ↑ Norman K (2004). "Alternative treatments for disseminated intravascular coagulation". Drug News Perspect. 17 (4): 243–50. PMID 15334173.

See also

Template:Hematology Template:SIB


bn:প্রকীর্ণ অন্তর্বাহ তঞ্চন cs:Diseminovaná intravaskulární koagulace de:Disseminierte intravasale Koagulopathie it:Coagulazione intravascolare disseminata no:Disseminert intravaskulær koagulasjon sr:Дисеминована интраваскуларна коагулација


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