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Basic Discussion of DIC DIC is characterized by excess thrombin generation with activation of the fibrinolytic system, which results in degradation of clotting factors and platelet membrane glycoproteins. Consumption of coagulation factors may occur in severe cases. SX: Causes of DIC:
2. Events that complicate & propagate DIC: shock, complement pathway activation Conditions Associated With Disseminated Intravascular Coagulation
Diagnosis:
During DIC, plasmin is generated through the direct release of t-PA from perturbed or damaged endothelial cells. This is accompanied by plasminogen consumption, depletion of a2-antiplasmin (the specific inhibitor of plasmin), and the generation of circulating fibrinogen/fibrin degradation products (FDP and Fdp, respectively) and D-dimers from degraded cross-linked fibrin . Plasmin also inactivates factor VIII and degrades vWF.
TREATMENT OF DIC - is necessarily
individualized Very rarely, heparin resistance is encountered if AT-III levels are
markedly decreased; in these circumstances, replenishment of AT-III
levels with AT-III concentrates might be useful, although adequate
prospective, controlled studies have not been conducted to confirm this
premise. REF: More advanced discussion of DIC The most important coagulopathy in Intensive Care Medicine is acute Disseminated Intravascular Coagulation ( DIC ). This is basically a state of increased propensity for clot formation triggered by a variety of stimuli related to such diverse disorders as sepsis, endothelial cell damage ( heat stroke, shock ), obstetrical complications ( abruptio placenta, amniotic fluid embolism ) and neoplasias. There may be clinical and laboratory evidence of hipercoagulability, but in acute cases, consumptive coagulopathy with hemorrhagic manifestations may predominate. The normal response to tissue damage is a contained explosion of thrombin generation at the site of injury, which results in coagulation of blood on the surface of damaged microvessels and stops blood loss. In DIC, an unregulated thrombin explosion causes release of free thrombin into the circulation. Widespread microvascular thrombosis produces tissue ischemia and organ damage. In an attempt to maintain vascular patency, excess plasmin is generated so that systemic fibrinogenolysis as well as local fibrinolysis occurs. It is the generation of free thrombin and plasmin within the circulation that leads to the clinical features of DIC, with thrombin and plasmin responsible for the thrombotic and hemorrhagic manifestations, respectively. The diagnosis and treatment of this syndrome require an understanding of its pathophysiology, awareness of the disorders that can trigger it and its early recognition. The endothelium acts like a fire extinguisher. Functional healthy endothelium concentrates antithrombin molecules on its surface and express thrombomodulin molecules. If thrombin is generated next to healthy endothelium, it is either captured and neutralized by antithrombin or binds to thrombomodulin, which alters its substrate specificity so radically that it is no longer capable of converting fibrinogen to fibrin. Instead, thrombomodulin bound thrombin activates the natural anticoagulant protein C system, which rapidly dismantles the fire. Thus, endothelial bound antithrombin and and the protein CA system are the extinguishers. When thrombin is generated at the site of tissue damage, there is no intact endothelium and thus no extinguisher, and explosive thrombin generation causes blood to clot. As the thrombin explosion spreads, it eventually meets intact healthy endothelium outside the area of tissue damage. The explosion is then rapidly ended by the extinguishing properties described above. Hence, the thrombin generation is contained at the site of tissue damage. DIC occurs when this antagonist systems of coagulation and anticoagulation are not balanced. Any component of the fire may be present in excess or the extinguishers may be damaged or rapidly used up, allowing the thrombin explosion to spread uncontrolled throughout the circulation. The endothelium may be disrupted so that tissue factor is released from tissue damaged by trauma, ischemia, infections, excessive metabolic stress, heat, chemicals, tumors or activation of the complement cascade. Alternatively, white blood cells may release tissue factor into the circulation in response to endotoxins, immune complexes or cancer cells. Snake venoms are capable of activating many components of the hemostatic system. Also, cytokine action may be critical to the development of DIC in many diseases. For example, TNF and Interleukin 1 can elicit production of tissue factor by endothelial cells and monocytes while simultaneously reducing the expression of thrombomodulin. Thus, when there is an inflammatory reaction, the hemostatic balance is shifted towards coagulation and away from anticoagulation. Acute DIC is usually associated with infections, the commonest cause. About 10-20% of patients with gram negative sepsis have evidence of DIC, but gram positive organisms may also be responsible, particularly in patients with hyposplenism. Systemic fungal infections, malaria, hemorrhagic fevers, herpes and influenza viruses are other recognized causes. The other causes of acute DIC are shown in Table 1.
Chronic DIC is usually associated with carcinomatosis, retained dead fetus syndrome or an aneurysm or hemangioma. Adenocarcinoma is a common cause. Recurrent deep venous thrombosis is a particular feature of this disease ( Trousseau's syndrome ), and reccurence may be prevented by heparin but typically not by warfarin. Carcinoma may cause DIC by invasion of tissues and release of tissue factor, activation of leucocytes, secretion of tissue factor and direct activation of the prothrombinase complex. Localized chronic DIC occurs in patients with aortic aneurysms, hemangiomas ( Kasabach-Merrit syndrome ) or empyema. The local generation of thrombin and plasmin may be so great that coagulation factors and platelets are depleted, leading to a systemic hypocoagulable state and hemorrhagic complications indistinguishable from true DIC. The diagnosis of this syndrome is essentially clinical, with laboratory tests providing confirmatory evidence. A pathological degree of bleeding in a sick patient should alert doctors to the possibility of DIC. Depending on the relative rates of formation and breakdown of fibrin, the syndrome may be assymptomatic or cause severe bleeding or thrombosis, or both. Microvascular thrombosis is the primary mechanism in most cases, and end organ failure is a major cause of death. Table 2 shows clinical characteristics and its pathophysiological basis.
While many laboratory tests are available to detect excess thrombin and plasmin generation, only a few simple tests are required to confirm the diagnosis. Thrombocytopenia due to thrombin generation is an almost universal finding in acute DIC. Production of platelets by the bone marrow is increased, but platelet survival is so short that severe thrombocytopenia is common. Global tests of the capacity to generate thrombin may show prolonged prothrombin times ( PT ) and activated partial thromboplastin times ( aPTT ) because of consumptive deficiency of coagulation factors. However, PT and aPTT are prolonged in only 70% and 50% of patients, respectively. Similarly, fibrinogen concentrations are low in less than half of patients. All these tests reflect excess thrombin generation. Excess plasmin generation is reflected by elevated plasma levels of fibrin and fibrinogen degradation products ( FDP ), with abnormal concentrations being found in 85% of patients. It is important to remember that high concentrations of FDP are not specific for DIC, occurring after surgery, in patients with hematomas and liver or renal failure. So, when in doubt, a D-dimer test is useful, as it is specific for fibrin degradation and thus indicate that thrombosis occurred before fibrinolysis, thereby distinguishing DIC from primary fibrinolysis. Examination of a blood film may reveal red cell fragmentation ( Schistocytes ) in approximately 50% of patients. The mechanism is unknown, and its presence does not help to elucidate the cause of DIC. Considerable fragmentation with moderate to severe thrombocytopenia but only mildly abnormal coagulation tests raises the possibility of Thrombotic Thrombocytopenic Purpura or Hemolytic Uremic Syndrome rather than DIC. Other laboratory tests important in the context of a patient with suspected DIC are liver and renal function tests, blood cultures and tests of antibiotic sensitivity. Arterial blood gases analysis may be complicated by severe hemorrhage, and respiratory function should be assessed by pulse oximetry when feasible. The key step in management is therapy of the condition predisposing to the hipercoagulable state. The condition will not resolve until the trigger mechanism is removed, and death is often the result of the underlying disease in these critical patients. They may be treated with blood components to replace depleted coagulation factors ( although, in theory, it may temporarily " feed the fire " ), platelets and natural inhibitors of plasmin and thrombin in an attempt to reduce bleeding while the underlying problem is being corrected ( antibiotics, fetal delivery, aneurysm surgery ... ). Unfortunately, the optimal regimen for treatment with blood components and the absolute indications for anticoagulant and antifibrinolytic treatments are unknown. We should keep in mind that critically ill patients may develop a coagulopathy because of vitamin K deficiency, and 10 mg of vitamin K should be given in two consecutive days before coagulopathy is attributed exclusively to DIC. Patients with DIC can also become vitamin K depleted because of its increased use, and its administration to these patients will replenish stores. Some doctors also give folic acid in order to prevent acute folate deficiency and impaired platelet production. Although laboratory parameters are essential for guiding management, the decision to start replacing blood components is determined by whether the patient is bleeding and whether an invasive procedure is required. If there is no bleeding and no procedure is required then no replacement is not indicated. If either is positive, then an attempt to restore hemostatic capacity by replacing platelets and coagulation factors ( fresh frozen plasma or cryoprecipitate ) is indicated, always assessing its effects on laboratory parameters to determine whether further treatment is required. Platelet concentrates should be given at a dose of 1 donor unit / 10 kg body weight when the platelet count is below 50.000. Fresh frozen plasma contains more fibrinogen than cryoprecipitate as well all the coagulant factors and natural anticoagulants such as antithrombin and protein C. It should be given at a dose of 15 ml / kg. If fresh frozen plasma cannot maintain the fibrinogen concentration above 0.5g / L, then cryoprecipitate can be given as well. The indications for treatment with heparin and the dose required are not established. There is no conclusive evidence that it reduces morbidity or mortality in acute DIC. All that can be concluded about the role of heparin is that while some patients seem to benefit, it should be used with extreme caution and at a low dose. When it is used, a dose of 1.000 U / hour or 15 U / Kg / h by continuous infusion has been recommended as there are no data on dose responses and the coagulopathy makes it extremely difficult to monitor the treatment. Patients with cancer and large vessel thrombosis should receive conventional doses of heparin to maintain an aPTT at twice normal, as this can be extremely beneficial. Heparin treatment may relatively ineffective because it requires antithrombin for anticoagulant activity, and this is usually reduced in DIC. Direct thrombin inhibitors may be more effective as they do not require antithrombin. Recombinant Hirudin reduced thrombin activity in DIC, but clinical benefits has not yet been evaluated. Infusion of concentrates of natural thrombin inhibitors such as antithrombin or protein C has been attempted, with an apparent reduction in mortality associated with resolution of DIC, indicating that a randomized trial is justified to determine if and when it is indicated. Plasmin inhibitors such as Tranexamic acid or Aprotonin are generally considered to be contraindicated because of the increased risk of end-organ damage from microvascular thrombosis. However, they are occasionally given when patients continue to bleed despite treatment with blood components. Lastly, Gabexate Mesylate, a synthetic inhibitor of serine proteases ( including thrombin and plasmin ), seemed to improve the severity of DIC in a retrospective study, but has not yet been examined in controlled trials. In conclusion, DIC is a clinical syndrome confirmed by laboratory tests. As it is usually seen in the context of critically ill patients it carries a high mortality rate. To make things worse, we don't actually know how and even when or if it should be treated. What we discussed above is the best evidence we have today, even though it is scarce. Hopefully, better understanding of the influence of cytokines on coagulation may lead to new treatments for DIC, specially when it is associated with infections or carcinoma. Also, as therapy for sepsis is improved, less cases of DIC are expected, so that we have good reasons to be optimistic and continue research on this topic, which is one of the most challenging issues in the Intensive Care field.
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