EDUCATIONAL COMMENTARY DISSEMINATED INTRAVASCULAR COAGULATION

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1 EDUCATIONAL COMMENTARY DISSEMINATED INTRAVASCULAR COAGULATION Educational commentary is provided through our affiliation with the American Society for Clinical Pathology (ASCP). To obtain FREE CME/CMLE credits click on Earn CE Credits under Continuing Education on the left side of the screen. LEARNING OBJECTIVES Upon completion of this exercise, the participant should be able to briefly explain the mechanisms involved in disseminated intravascular coagulation (DIC). list coagulation tests that are useful in diagnosis and monitoring this disorder and the expected results. describe the underlying conditions and symptoms associated with DIC. describe new tests that may become helpful in the diagnosis of DIC in the future. Disseminated intravascular coagulation (DIC) is often described as clotting causing bleeding or consumptive coagulopathy. In this syndrome, the coagulation system is activated by an abnormal event that triggers excess thrombin formation and activation of the fibrinolytic system. The coagulation factors and platelets are then consumed, owing to the formation of intravascular clots and resulting in bleeding, thrombosis, or both. General Aspects DIC is an acquired disorder and not considered a primary disease; it is a complication of various underlying conditions. Septicemia, complications of pregnancy, neoplasms, massive tissue injury, vascular injury, extensive burns, and severe toxic or immunologic reactions are all conditions that may trigger DIC. 1 The most common underlying condition is septicemia, in which microorganisms release cell membrane components (e.g., lipopolysaccharides and endotoxins) or bacterial exotoxins (e.g., staphylococcal hemolysin) that initiate a generalized inflammatory response and release cytokines that activate the coagulation system. In the same manner, other conditions that trigger DIC activate the coagulation system by causing cellular damage and release of tissue factor, leading to activation of inflammatory pathways. Excess thrombin is generated via the extrinsic coagulation pathway. 1 In complications of pregnancy, amniotic fluid acts as a thromboplastin to activate coagulation pathways. 2 Symptoms of DIC are often masked by the symptoms of the underlying disease. Bleeding usually begins abruptly and from several sites. Simultaneously, small blood vessels become occluded by strands of fibrin, which may lead to organ failure. In this case, renal failure, liver failure, or respiratory failure may be accompanied by venous thromboembolism.

2 Cases of DIC may be divided into two categories: acute, or uncompensated, and chronic, or compensated. Most cases of DIC fall into the acute category; in which bleeding is usually sudden and severe. About 10% to 20% of cases are deemed chronic, which typically manifests with thrombosis. In chronic cases, the usual hemostatic mechanisms tend to compensate for loss of coagulation factors because the stimulus is much weaker. 2 Laboratory Evaluation DIC is diagnosed primarily based on the patient s history and clinical symptoms. Laboratory testing is used to confirm the diagnosis, although no single laboratory test is sufficient to diagnose DIC. A battery of screening tests is usually ordered first, including platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen level, and D-dimer. The expected results of these tests in patients with DIC are listed in Table 1. The PT and APTT are prolonged, owing to a decrease in the amount of coagulation factors. These factors are consumed by the formation of tiny clots in the blood vessels. The fibrinogen level may be decreased, owing to the same mechanism, and in severe cases, the fibrinogen level may drop as low as 10 to 15 mg/dl. However, fibrinogen is not always a reliable indicator of DIC because, as an acute-phase reactant protein, its levels often rise in conditions that cause inflammation. Therefore, if the patient has such a condition, the fibrinogen level may not be as low as expected and could even be normal. A negative D-dimer result can be useful to rule out DIC; however, a positive result does not specifically confirm DIC; it merely confirms that coagulation activation has taken place. Evaluation of a stained blood smear may also be helpful. Schistocytes are often seen on the blood smear in DIC owing to the fragmenting of the red blood cells as they attempt to circulate through vessels occluded with tiny clots. 2 Table 1. Routine Laboratory Tests and Expected Results in DIC Test Expected Result Reference Range* Platelet count Decreased 150, ,000/µL PT Prolonged s APTT Usually prolonged s Fibrinogen level Decreased mg/dl D-dimer Increased <250 ng/l (<1.37 nmol/l) Blood smear Schistocytes N/A APTT indicates activated partial thromboplastin time; NA, not applicable; PT, prothrombin time. *Source: McKenzie SB, Williams JL. Clinical Laboratory Hematology. 2 nd ed. Upper Saddle River, New Jersey: Pearson Education Inc; It is important to diagnose DIC as soon as possible and to monitor the progress using the same laboratory tests. The screening tests listed in Table 1 are readily available in most coagulation

3 laboratories. A scoring system was developed by the International Society for Thrombosis and Hemostasis (ISTH) and published in 2001 (Table 2). A five-year evaluation published in 2005 confirmed that a score of five or more can reliably identify overt DIC with a sensitivity of 91% and a specificity of 97%. 1 ISTH also recommended that the score be calculated daily to assess the severity and course of the syndrome. Scoring systems such as this one provide an objective measurement of DIC but must be used carefully along with clinical symptoms and treatment of the underlying disease. 1 TABLE 2. ISTH Scoring System for DIC Parameter Overt DIC* Non-overt DIC Platelet count, x10 9 /L >100 = 0 <50 = 2 >100 = 0 Rising = -1 Falling = 1 Prothrombin Time, No. of seconds prolonged over reference range < 3s = 0 >3 but <6 = 1 >6 = 2 <3 = 0 Falling = -1 Rising = 1 Fibrinogen level, mg/dl >100 = 0 Not included Fibrin-related marker, such as D- dimer No increase = 0 Moderate increase = 2 Strong increase = 3 Normal = 0 Raised = 1 Falling = -1 Rising = 1 DIC indicates disseminated intravascular coagulation; ISTH, International Society for Thrombosis and Hemostasis. *Overt DIC = stressed but decompensated hemostatic system. Non-overt DIC = stressed but compensated hemostatic system. Source: Favaloro EJ. Laboratory testing in disseminated intravascular coagulation. Semin Thromb Hemost. 2010;36: Other Laboratory Tests Levels of natural anticoagulants, such as antithrombin and protein C, are frequently decreased in patients with DIC and may provide information as to prognosis. Decreased levels of these coagulation inhibitors were reported in 40% to 60% of critically ill patients and in 90% of patients with DIC. 3 A level of antithrombin less than 50% of normal may indicate more severe disease and increased mortality in

4 patients with DIC due to sepsis. 1 Laboratory values of these natural inhibitors can provide valuable information in the diagnosis and monitoring of DIC in some patients but these tests are not available in all laboratories. According to the ISTH, these additional tests provide no added value to the four tests used in the scoring system. Low levels of antithrombin and protein C are not specific for DIC; they can also be associated with liver disease or other acquired causes. 1 New Tests In addition to the platelet count, other platelet parameters may be used in the future to assist in the diagnosis of DIC. Some hematology instruments are able to identify reticulated platelets, measured as an immature platelet fraction. These are newly released platelets that contain residual RNA. A recent study showed that an increase in reticulated platelets correlated with the diagnosis of overt DIC and with the ISTH score. Also the presence of reticulated platelets correlated with increased fibrin degradation products and showed better mortality prediction than the platelet count. 1 Because DIC involves activation of the inflammatory process, analysis of inflammatory biomarkers such as C-reactive protein, interleukin-6, interleukin-8, tumor necrosis factor-α, procalcitonin, and the lipoprotein-binding protein may have increased use in the future. Some may prove to be very helpful in the diagnosis and management of DIC. 1,3 The APTT test is being used in a new way to assist in the diagnosis of DIC. Waveform analysis makes use of the pattern created by the change in percent transmittance over time during the APTT clotting process. Some instruments allow visualization and assessment of the clotting process through this waveform plot. An abnormal clotting pattern has been correlated with a biphasic waveform in critically ill patients with DIC. The prevalence of the abnormal pattern was observed in 87% of patients with septic DIC as diagnosed by the ISTH score. 1 The presence of a biphasic waveform has been shown to precede a clinical diagnosis of DIC using standard methods by at least 18 hours. 4 The waveform analysis may be a promising, inexpensive, and rapid test in the diagnosis of DIC, especially in patients with severe sepsis; however, it is not yet available in all laboratories. Molecular markers that are more sensitive for coagulation activation are usually insufficiently specific. Currently tests for markers are not available in most settings for daily clinical care. 3 Therapy Eliminating the underlying cause of DIC, if possible, is the first goal of treatment. Hemostasis is a delicate balance between bleeding and clotting, which makes it difficult and sometimes controversial to treat patients with this syndrome. Treatment with platelet transfusions and plasma components is primarily based on clinical symptoms, not laboratory test results. Platelet transfusions may be considered for

5 patients with platelet counts less than 50,000/µL who are actively bleeding or at high risk for bleeding. 5 If the patient has a prolonged PT and APTT, fresh frozen plasma may be helpful, but it is usually reserved for those with active bleeding or those who require a surgical procedure. If thrombosis is the primary problem, therapeutic doses of heparin may be considered. If there is also a high risk for bleeding in these patients, unfractionated heparin is recommended, owing to its short half-life and reversibility. 5 Conclusion DIC is a complicated series of events that abnormally activate the coagulation and fibrinolytic systems to cause potentially life-threatening bleeding or thrombosis. Underlying conditions that can trigger DIC include sepsis, abnormal pregnancy, and massive tissue injury. The primary therapy involves treatment of the underlying condition. Laboratory testing is an important component of the diagnostic process, but no single test available at this time can definitively diagnose DIC. Laboratory testing is used along with clinical signs and symptoms and identification of the underlying disease. A battery of four common laboratory tests, PT, APTT, fibrinogen, and platelet count, is recommended to assist in the diagnosis. The ISTH scoring system using these four test results has been shown to be useful. New tests on the horizon that may prove useful in the diagnosis of DIC are the APTT waveform analysis, reticulated platelets, and analysis of biomarkers. Molecular methods are also being developed but lack specificity at this time. References 1. Favaloro EJ. Laboratory testing in disseminated intravascular coagulation. Semin Thromb Hemost.2010;36: Carpenter S, Kirby B. Disorders of secondary hemostasis. In: McKenzie SB, Williams JL. Clinical Laboratory Hematology, 2nd ed. Upper Saddle River, New Jersey: Pearson Education Inc; 2011: Levi M, Meijers JC. DIC: which laboratory tests are most useful. Blood Rev.2011;25: Mair G, Dunhill S, Tiplady C. Prognostic implications of a biphasic waveform for APTT analysis in a district general hospital. Int J Lab Hematol. 2008;30: Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Hematology. Br J Haematol. 2009;145(1): ASCP 2011