DISSEMINATED INTRAVASCULAR COAGULATION
• Disseminated intravascular coagulation (DIC) occurs in the presence of a life-threatening underlying illness and is characterized by systemic pathologic activation of the coagulation system.
• Symptoms may be secondary to either the underlying disease or to DIC, the most common manifestation being a bleeding diathesis.
• A combination of clinical and laboratory findings aid in making an accurate diagnosis.
• Depending on the underlying condition, laboratory abnormalities can vary. The most common laboratory findings are thrombocytopenia, elevated fibrin degradation products, elevated D-dimer assay, prolonged prothrombin time, prolonged activated partial thromboplastin time, low fibrinogen, and microangiopathic hemolytic anemia.
• A validated objective scoring system for the diagnosis of overt DIC based solely on laboratory data is available.
• Prompt and efficacious treatment of the underlying condition is crucial.
• Aggressive supportive care measures are required.
• Platelet and factor replacement with fresh frozen plasma and cryoprecipitate may be indicated.
• Anticoagulation with heparin is used for selected cases.
• Activated protein C concentrates (drotrecogin alfa [Xigris]) are useful in disseminated intravascular coagulation secondary to severe sepsis.
Disseminated intravascular coagulation (DIC) is an acquired clinicopathologic syndrome that typically occurs as a consequence of a serious underlying condition. It is characterized by systemic activation of the coagulation system. This process initiates a cascade of events that includes the formation of fibrin clots and microthrombi with secondary end-organ ischemia and failure and concomitant consumption of coagulation factors and platelets that can result in hemorrhagic manifestations.
DIC is a secondary thrombohemorrhagic phenomenon that occurs as a consequence of a multitude of disorders that pathologically activate and dysregulate the intravascular coagulation system. The most common causes are sepsis, cancer, and trauma. DIC is estimated to occur in approximately 1% of hospitalized patients, but it may be present in up to 30% to 50% of those with severe sepsis. DIC carries a high morbidity and mortality risk, usually depending on the severity of the underlying disease and the degree of the hematologic and thrombotic manifestations. Mortality rates have been reported to range from 31% to as high as 86% in some series. Advanced age is associated with a worse outcome.
The main factor for the occurrence of DIC is the presence of a life- threatening underlying condition that abnormally activates the coagulation process. Severe sepsis (bacterial, viral, fungal) is the major cause. Additionally, serious trauma, especially head trauma, has a high correlation with DIC. Several pregnancy complications have also been implicated in the pathogenesis of DIC. Box 1 summarizes the most common causes.
|Underlying Conditions in Disseminated Intravascular Coagulation|
• Other organisms
Trauma and tissue damage
• Crush injury
• Heat stroke
• Acute promyelocytic leukemia
• Solid tumors
• Abruptio placentae
• Amniotic fluid embolism
Protein C and S deficiencies (purpura fulminans) Kasabach-Merritt syndrome
Severe hemolytic transfusion reactions
Toxin exposures (snake and spider bites)
The most common initiating event in DIC is the exposure of blood to tissue factor, which can be secondary to vascular endothelial damage or to activation of tissue factor by circulating monocytes in response to inflammatory cytokines. As a result, this aberrant exposure to tissue factor produces increased amounts of thrombin. In DIC, thrombin generation becomes so excessive that it cannot be counterregulated by the natural antithrombotic pathways, such as tissue factor pathway inhibitor and antithrombin III. Because thrombin activates fibrin, these events create a widespread systemic deposition of fibrin, thus stimulating the formation of microthrombi and end-organ ischemia and damage.
Thrombin promotes the release of tissue plasminogen activator from damaged endothelium. This phenomenon causes a secondary activation of the fibrinolytic pathway, generating fibrin degradation products that in turn interfere with fibrin polymerization and have a deleterious effect on platelet aggregation.
There is generalized consumption of fibrinogen, platelets, and coagulation factors (II, V, VIII), thus promoting bleeding. Coagulation inhibitors such as protein C also get depleted, further impairing the capacity to control the thrombotic manifestations. DIC can also induce a secondary microangiopathic hemolytic anemia, mostly due to intravascular fibrin causing mechanical damage and fragmentation of red blood cells.
Symptoms may be secondary to either the underlying disease or to DIC. The most common manifestation is that of a bleeding diathesis. A patient might initially have excessive oozing from venipuncture sites or mucosal surfaces, but more severe hemorrhages can also occur. Both venous and arterial thrombosis are seen in DIC and can manifest with secondary organ damage. Other signs include renal, hepatic, and neurologic impairment. Pulmonary hemorrhage and acute respiratory distress syndrome have been reported in severe cases. Table 1 summarizes the most common symptomatology in DIC.
Clinical Symptoms in DIC
|Sign or Symptom Incidence (%)|
No single test is diagnostic for DIC, but rather a combination of clinical and laboratory findings can aid in making an accurate diagnosis. Depending on the underlying condition, laboratory abnormalities can vary. However, the most common findings, in decreasing order of frequency, are thrombocytopenia, elevated fibrin degradation products or D-dimers, prolonged prothrombin time (PT), prolonged activated partial thromboplastin time (aPTT), and low fibrinogen. Thrombocytopenia occurs in 98% of patients with DIC, and the platelet count is less than 50,000 per microliter in 50% of them, making this an extremely sensitive, though nonspecific, marker. The PT and aPTT are prolonged in 75% and 60% of patients, respectively, reflecting the degree of consumption of coagulation factors.
Low fibrinogen is another marker for DIC, but its sensitivity has been reported to be as low as 28%. This may be due in part to the fact that fibrinogen is an inflammatory marker and may be falsely elevated in some conditions that cause DIC. Fibrin degradation products and D- dimers are elevated owing to the increased activation of the fibrinolytic pathway. The D-dimer assay has been shown to be more specific for DIC than the measurement of fibrin degradation In addition, the thrombin time may be elevated secondary to the increase in fibrin degradation products as well as to the hypofibrinogenemia. Measurement of anticoagulant proteins such as antithrombin III and protein C can demonstrate decreased levels in DIC, but there are limitations owing to the lack of availability of these assays in most centers. In addition, a review of the blood smear can reveal fragmented red blood cells in cases where DIC has caused a microangiopathic hemolytic anemia.
An objective scoring system for the diagnosis of overt DIC based solely on laboratory data has been established by the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis (Box 2). It has been demonstrated to have a sensitivity of 91% and a specificity of 97% and to be an independent prognostic factor for mortality. Following the guidelines of the scoring system, patients with sepsis and DIC have been shown to have a mortality of 43%, as compared to only 27% for those without DIC.
|Scoring System for Overt Disseminated Intravascular Coagulation|
|1. Risk assessment: Does the patient have an underlying disorder known to be associated with overt DIC?
• Yes: Proceed
• No: Do not use this algorithm
2. Order global coagulation tests (platelet count, fibrin markers, PT, fibrinogen).
3. Score results.
• Platelet count: >100 = 0, <100 =1, <50 = 2
• Elevated fibrin markers such as D-dimers or FDP: No increase = 0, moderate increase = 2, strong increase = 3
• Prolonged PT: <3 sec = 0, >3 sec but <6 sec = 1, >6 sec = 2
• Fibrinogen level: >1 g/L = 0, <1 g/L = 1
4. Calculate score:
• ≥5: compatible with overt DIC. Repeat score daily.
• <5: Suggestive (not conclusive) for nonovert DIC. Repeat score in next 1 or 2 days.
Abbreviations: DIC = disseminated intravascular coagulation; FDP = fibrin degradation product; PT = prothrombin time.
To control DIC, the precipitating disease needs to be treated vigorously and promptly. Additionally, aggressive supportive care measures, usually in an intensive care setting, are of utmost importance. In some cases this can indeed be enough. In other instances, a more specific treatment approach, such as replacing platelets or coagulation factor, may be necessary. This should not be based on laboratory parameters alone but rather on the clinical scenario and whether there is active bleeding, thrombosis, or organ dysfunction.
Platelet transfusions in nonbleeding patients are not usually indicated. They should be reserved for patients with a count of <50,000/µL and active bleeding or those who are perceived to be at an increased risk for bleeding, for example, in a preoperative or postoperative setting. A higher platelet count may be desired in specific situations, such as neurotrauma. Platelet support may also be considered in nonbleeding patients if the count is significantly low (<20,000–30,000/mL).
The same rule applies to factor replacement with fresh frozen plasma. For patients without active bleeding, fresh frozen plasma is rarely indicated. However, in patients with a prolongation of the PT and aPTT and bleeding, or those perceived to be at an increased risk for bleeding or who are undergoing an invasive procedure, fresh frozen plasma should be considered. If the fibrinogen level is significantly low (<1 g/L), cryoprecipitate may be administered.
The use of anticoagulant therapy with heparin in patients with DIC has been controversial. Its use can potentiate the bleeding risks.
However, heparin should be considered in cases where thrombosis predominates and is likely to lead to severe tissue injury. For example, heparin or other anticoagulant therapy should be given in the presence of dermal or acral ischemia that might rapidly progress to gangrene, as occurs in purpura fulminans and in some types of bacteremia. Indeed, anticoagulation has been demonstrated to reduce mortality from 90% to 18% in patients with purpura fulminans. Other instances in which heparin may be of benefit include DIC related to metastatic cancers, aortic aneurysms, retained dead fetus syndrome, and acute promyelocytic leukemias that are unresponsive to initial standard therapy. In addition, heparin therapy may be indicated in the presence of large vessel clots or in cases where intensive replacement of blood products alone has not been effective.
Replacement of anticoagulant factors, including administration of activated protein C (drotrecogin alfa [Xigris] and antithrombin concentrates (Thrombate III, ATryn),1 is another strategy that has been evaluated. Clinical studies have shown a survival advantage for patients with severe sepsis and DIC using activated protein C, but there was a minor increased risk of bleeding (3.5% versus 2% in placebo), and caution should be exercised in this regard. After several clinical trials studying its potential efficacy in DIC, antithrombin administration has not been demonstrated to decrease mortality.
Antifibrinolytic therapy is usually contraindicated in DIC because of its risk of promoting thrombosis, but it may be considered in patients with severe bleeding whose primary process is a hyperfibrinolytic state. Agents include aminocaproic acid (Amicar) and tranexamic acid (Cyklokapron).1
Potential treatment agents undergoing trials include recombinant thrombomodulin, recombinant tissue factor pathway inhibitor, activated factor VII (Novoseven), and recombinant nematode anticoagulant protein c2.
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1 Not FDA approved for this indication.
1 Not FDA approved for this indication