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Disseminated Intravascular Coagulopathy
CHAPTER 124
Disseminated Intravascular Coagulopathy Surbhi Saini, MBBS and Amy L. Dunn, MD Disseminated intravascular coagulopathy (DIC) is defined as: An acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction. International Society on Thrombosis and Haemostasis (ISTH). DIC is a clinicopathological syndrome with variable clinical severity that can range from isolated laboratory abnormalities to massive hemorrhage and/or thrombosis. The systemic activation of dysregulated coagulation, the hallmark of DIC, occurs secondary to a multitude of underlying conditions. Treatment is focused on treating the underlying disease with concurrent replacement of coagulation factors by blood product transfusion.
Pathophysiology: To maintain normal hemostasis, three primary components of the coagulation system—vascular integrity, coagulation factors, and platelets—are very well coordinated to result in a delicate balance between bleeding (anticoagulation) and clotting (procoagulation). Any disruption of this balance can cause DIC. The most common conditions underlying DIC are sepsis and cancer; other less common causes include significant trauma and burns, obstetrical complications (e.g., retained products of conception, placental abruption), large vascular malformations, severe allergic reactions, and envenomation. Any of these conditions can cause a generalized, unregulated activation of the coagulation system leading to widespread thrombin generation and deposition of fibrin-rich microthrombi throughout the circulation. Resultant obstruction of microvasculature causes hypoxic end-organ damage, mainly to the vital organs such as liver, kidney, and brain. Additionally, excessive consumption of endogenous anticoagulant proteins (protein C, protein S, and antithrombin [AT]), and disruption of hemostatic anticoagulant pathways, contributes to the coagulation disarray. This is aggravated by the relative insufficiency of the fibrinolytic system to clear the microthrombi from the circulation. During normal hemostasis, tissue factor (TF) expression is restricted to the surface of cells not exposed to flowing blood (subendothelium, fibroblasts). Microvascular injury exposes TF to circulating FVII, initiating coagulation. In DIC, inflammatory cytokines (TNF-alpha, IL-1, IL-6) induce intravascular monocytes and macrophages to express TF. This intravascular expression of TF initiates exaggerated, pathologic coagulation, ultimately leading to the depletion of coagulation factors, which in turn can predispose to hemorrhage. It is this simultaneous development of pathologic thrombosis and hemorrhage that is the hallmark of DIC. The generation of thrombin also leads Transfusion Medicine and Hemostasis. https://doi.org/10.1016/B978-0-12-813726-0.00124-0 Copyright © 2019 Elsevier Inc. All rights reserved.
749
750
Surbhi Saini, MBBS and Amy L. Dunn, MD
to the exposure of negatively charged phospholipids on the surface of platelets, which plays a role in sustaining thrombin generation, in addition to the platelet microparticles generated by cell damage.
Clinical Manifestations: Clinical presentation of DIC is heterogeneous and to some extent, reflective of the underlying pathophysiology. Severity ranges from isolated laboratory derangements (often referred to as compensated or nonovert DIC) to multiorgan failure and death, indicative of the dynamic nature of DIC. Microvascular occlusion leads to renal, cardiac, central nervous system, and/or pulmonary failure. Digital gangrene and purpura fulminans can occur as a result of widespread skin necrosis. A subset of patients present with primarily hemorrhagic symptoms, most commonly, generalized mucocutaneous bleeding. Mortality rates are high, ranging from 34% to 86%.
Diagnosis: There is no gold standard single test for the diagnosis of DIC. The presence of a triggering condition, clinical signs/symptoms, and supportive laboratory data aids in the diagnosis, and this can be supported by the use of a five-step scoring algorithm developed by the ISTH (Fig. 124.1). This scoring system was designed to assist in diagnosis and to be utilized as a reference standard. Since its inception, it has proven both sensitive and specific for the diagnosis of overt DIC, and increasing scores strongly correlate with patient mortality. The complete blood count is used to assess platelet number and the degree of anemia associated with the underlying illness. In more advanced DIC, the peripheral smear will show evidence of thrombotic microangiopathy (schistocytes, thrombocytopenia, anemia). Varying degrees of thrombocytopenia may be present in DIC; however, thrombocytopenia may also be present as a result of many of the underlying causes of DIC such as malignancy or sepsis. The activated partial thromboplastin time (aPTT) and prothrombin time (PT) are in vitro measurements of the coagulation pathway and can be used to assess factor activation and consumption during DIC. In nearly half of the patients, aPTT and PT would be normal or shortened, reflecting the accelerated thrombin generation phase of DIC. The PT is typically more affected than the PTT in patients with DIC. Fibrinogen levels below 150 mg/dL are typically the result of consumption (e.g., DIC) or decreased production (e.g., liver failure). Levels less than 100 mg/dL significantly increase the risk of bleeding. Fibrinogen is also an acute-phase reactant, and caution must be used when interpreting fibrinogen levels in early DIC, where plasma levels can remain normal or even be elevated. The thrombin time measures the time to conversion of fibrinogen to fibrin. Decreased concentrations of fibrinogen, decreased clearance of fibrin degradation products, and the presence of heparin prolong the thrombin time. Fibrin degradation products (FDPs) are formed when fibrinogen, cross-linked fibrin, and non–cross-linked fibrin are degraded by plasmin. The extent of fibrin formation in DIC can be assessed indirectly by the generation of FDPs. D-dimers are a result of plasmin breakdown of cross-linked fibrin and are proposed by the ISTH as the FDP marker of choice when diagnosing DIC. The D-dimer test has a high negative predictive value but is limited by a low positive predictive value.
751
Disseminated Intravascular Coagulopathy
Does the patient have an underlying disorder known to be associated with overt DIC?
no
yes Order coagulation tests • Platelet count • Prothrombin time • Fibrinogen • Fibrin monomers or degradation products
Do not continue with algorithm
Score coagulation tests • Platelet count o 100,000/ l 0; 100,000/ l 1; 50,000/ l • Prothrombin time prolongation o 3 s 0; 3–6 s 1; 6 s 2 • Fibrinogen o 100 mg/dl 0; 100 mg/dl 1 • Fibrin monomers or degradation products o No increase 0; moderate increase 2, strong increase 3
5 Compatible with overt DIC, repeat scoring daily
2
5 Suggestive of non-overt DIC, repeat next 1–2 days
FIGURE 124.1 Diagnostic algorithm for the diagnosis of disseminated intravascular coagulopathy (DIC).
Levels of the endogenous coagulation inhibitor AT are typically decreased in DIC. Levels less than 80% may be associated with thrombosis. Protein C and S may also be reduced in patients with DIC. The current ISTH criteria concluded that routine testing of these parameters showed no additional value to the 4 test scoring system. However, in selected circumstances, testing may prove beneficial.
Differential Diagnosis: Liver failure and severe vitamin K deficiency can mimic DIC. To distinguish between liver disease and vitamin K deficiency, it is helpful to measure factor V and factor VII levels. In liver disease both factors will be decreased, but in vitamin K deficiency only factor VII will be low. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are also thrombotic microangiopathies but rarely show evidence of consumption of clotting proteins. Heparin-induced
752
Surbhi Saini, MBBS and Amy L. Dunn, MD
thrombocytopenia is characterized by thrombocytopenia and increased risk of thrombosis but is not characterized by clotting protein consumption.
Management: The cornerstone of DIC management is identification and appropriate treatment of the underlying trigger with ongoing supportive care. Management strategies should be individualized and reassessed frequently (Table 124.2). Replacement of consumed coagulation components is often necessary. Table 120.1 shows potential treatment options.
Blood Product Support: There are no randomized clinical trials (RCT) on which to base guidelines for platelet therapy in the setting of DIC. Although it has been hypothesized, there is currently no evidence to support the hypothesis that platelet transfusions may worsen DIC by providing a phospholipid surface for ongoing thrombin generation. Within our practice, we aim to keep the platelet count greater than 20,000/μL in patients at high risk of bleeding and >50,000/μL in the setting of active bleeding or preprocedural hemostasis. The role of fresh frozen plasma (FFP) replacement in DIC has been studied in one small randomized controlled trial in neonates. In that study, plasma and platelet therapy did not show a survival advantage over no therapy or exchange transfusion. Infusion of plasma products or cryoprecipitate (in the setting of severe hypofibrinogenemia) should be considered in the setting of bleeding associated with low fibrinogen levels; however, there is currently no evidence for prophylactic use of plasma support in the absence of bleeding. The goal of fibrinogen replacement is to maintain levels at 100 mg/ dL to prevent or treat bleeding. The use of recombinant factor VIIa is contraindicated in DIC because of its prothrombotic risk.
Anticoagulant Pathway Therapy: Depletion of anticoagulant proteins such as protein C, protein S, and AT has been postulated to play a role in sustaining DIC, and therefore replacement of these proteins has been explored as a therapeutic option. Over the past decade, evidence has been slowly mounting to support this approach. Subsequently, in a large RCT of recombinant-human activated protein C (rh-APC), adult patients with sepsis treated with rh-APC infusions for 96 hours demonstrated decreased overall mortality at 28 days compared with controls; however, there was a trend toward higher bleeding rates in the treated arm. Subsequent studies have failed to establish a benefit of this therapy in pediatric or adult patients with DIC in less severe sepsis and septic shock, including those with lowered Protein C levels. Smaller, pilot studies have suggested that normalization of serum protein C levels using protein C concentrates (plasma derived, zymogen form) is safe and potentially beneficial. AT concentrates have also been shown, in animal models of sepsis, to improve coagulation and survival rates. However, a double-blind, placebo-controlled, multicenter phase III clinical trial in patients with severe sepsis failed to demonstrate any survival advantage of high-dose AT and was associated with an increased risk of hemorrhage when administered with heparin. A post hoc analysis suggested improved organ failure and mortality rates in patients without heparin and treated early in
Disseminated Intravascular Coagulopathy
753
severe sepsis. Additional trials are needed to clearly define the indications and dosing strategies. Recombinant human soluble thrombomodulin (rhTM) has been shown to decrease thrombin formation by binding to thrombin and acting in complex with activated protein C. This agent has also shown antiinflammatory properties and has been studied in a randomized, double-blind controlled trial of patients with DIC due to malignancy or infection who were randomized to rhTM or low-dose heparin. 66% of patients in the rhTM arm resolved their DIC compared with 50% of patients in the heparin arm. In a subsequent placebo-controlled randomized controlled trial, rhTM failed to show any benefit, and currently, this drug is not available in the United States.
Anticoagulants: Although there are no data to support the routine use of anticoagulants in DIC, with evidence of thromboembolic disease, anticoagulation with heparin, either unfractionated or low-molecular weight, should be considered. Microvascular thrombosis can generally be treated with low-dose heparin, whereas large vessel disease may require full therapeutic dosage. Due consideration should be given to venous thromboembolism (VTE) prophylaxis in acutely ill patients without bleeding and at low risk for bleeding. To date, there are no trials evaluating the clinical usefulness of direct oral anticoagulants in patients with DIC.
Antifibrinolytic Therapy: Hyperfibrinolysis can occur in patients with DIC, particularly in the setting of acute promyelocytic leukemia. This can be recognized by an abnormally short euglobulin clot lysis time, and antifibrinolytic agents such as aminocaproic acid or tranexamic acid may be of use in such a scenario. These agents should be used with caution in the setting of hematuria because of the risk of renal collecting system thrombosis. Suggested dosage and indications for all of the above agents are included in Table 124.1.
TABLE 124.1 International Society on Thrombosis and Hemostasis Diagnostic Algorithm for the Diagnosis of Overt Disseminated Intravascular Coagulopathy (DIC) 1. Risk assessment: Does the patient have an underlying disorder known to be associated with overt DIC? If yes: proceed If no: do not use this algorithm 2. Order global coagulation tests (platelet count, prothrombin time (PT), fibrinogen, D-dimer levels) 3. Score global coagulation test results (i) Platelet count: >100 = 0; <100 = 1; <50 = 2 (ii) Elevated fibrin-related marker (D-dimer, FDPs): no increase = 0; moderate increase = 2; strong increase = 3 (iii) Prolonged prothrombin time: <3 second = 0; 3–6 second = 1; >6 second = 2 (iv) Fibrinogen level: >1.0 g/L = 0; <1.0 g/L = 1 4. Calculate score 5. If >5: compatible with overt DIC; repeat scoring daily If <5: suggestive (not affirmative) for nonovert DIC; repeat next 1–2 days
754
Surbhi Saini, MBBS and Amy L. Dunn, MD
TABLE 124.2 Management Guidelines for Disseminated Intravascular Coagulopathy (DIC) Product
Dose
Indication
Aminocaproic acid
100 mg/kg PO every 6 hour 33.3 mg/kg/hour IV
DIC associated with hyper fibrinolytic states
Cryoprecipitate or fibrinogen concentrate
1 unit per 10 kg of body weight
Clinically relevant bleeding; fibrinogen < 100 mg/dL unresponsive to FFP
Fresh frozen plasma
15–30 cc/kg
Clinically relevant bleeding; INR ≥2; 1.5-fold prolongation of aPTT; fibrinogen < 100 mg/dL; peri-op hemostasis for invasive procedures
Heparin
500 IU/hour (no loading dose) 5–10 IU/kg/hour low dose
DIC with evidence of ongoing thrombin generation unresponsive to conventional measures
Platelet product
Per domestic transfusion guidelines
Maintain plts > 20 × 109/L; plts > 50 × 109/L with major bleeding; periop hemostasis for invasive procedures
Further Reading Abraham, E., Laterre, P. F., Garg, R., Levy, H., Talwar, D., Trzaskoma, B. L., et al. (2005). Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med, 353(13), 1332–1341. Baratto, F., Michielan, F., Meroni, M., Dal Palu, A., Boscolo, A., & Ori, C. (2008). Protein C concentrate to restore physiological values in adult septic patients. Intensive Care Med, 34(9), 1707–1712. Bernard, G. R., Vincent, J. L., Laterre, P. F., LaRosa, S. P., Dhainaut, J. F., Lopez-Rodriguez, A., et al. (2001). Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med, 344(10), 699–709. Decembrino, L., D’Angelo, A., Manzato, F., Solinas, A., Tumminelli, F., De Silvestri, A., et al. (2010). Protein C concentrate as adjuvant treatment in neonates with sepsis-induced coagulopathy: A pilot study. Shock, 34(4), 341–345. Eid, A., Wiedermann, C. J., & Kinasewitz, G. T. (2008). Early administration of highdose antithrombin in severe sepsis: Single center results from the KyberSept-trial. Anesth Analg, 107(5), 1633–1638. Gando, S., Saitoh, D., Ogura, H., Mayumi, T., Koseki, K., Ikeda, T., et al. (2008). Natural history of disseminated intravascular coagulation diagnosed based on the newly established diagnostic criteria for critically ill patients: Results of a multicenter, prospective survey. Crit Care Med, 36(1), 145–150. Hoffman, M., & Dargaud, Y. (2012). Mechanisms and monitoring of bypassing agent therapy. J Thromb Haemost, 10(8), 1478–1485. Levi, M., de Jonge, E., & van der Poll, T. (2001). Rationale for restoration of physiological anticoagulant pathways in patients with sepsis and disseminated intravascular coagulation. Crit Care Med, 29(7 Suppl.), S90–S94. Levi, M., & Meijers, J. C. (2011). Dic: Which laboratory tests are most useful. Blood Rev, 25(1), 33–37.
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Ranieri, V. M., Thompson, B. T., Barie, P. S., Dhainaut, J. F., Douglas, I. S., Finfer, S., et al. (2012). Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med, 366(22), 2055–2064 Epub 2012/05/24. Singh, B., Hanson, A. C., Alhurani, R., Wang, S., Herasevich, V., Cartin-Ceba, R., et al. (2013). Trends in the incidence and outcomes of disseminated intravascular coagulation in critically ill patients (2004-2010): A population-based study. Chest, 143(5), 1235–1242. Squizzato, A., Hunt, B. J., Kinasewitz, G. T., Wada, H., Ten Cate, H., Thachil, J., et al. (2016). Supportive management strategies for disseminated intravascular coagulation. An international consensus. Thromb Haemost, 115(5), 896–904. Taylor, F. B., Jr., Toh, C. H., Hoots, W. K., Wada, H., & Levi, M. (2001). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost, 86(5), 1327–1330. Toh, C. H., & Downey, C. (2005). Back to the future: Testing in disseminated intravascular coagulation. Blood Coagul Fibrinolysis, 16(8), 535–542. Umemura, Y., Yamakawa, K., Ogura, H., Yuhara, H., & Fujimi, S. (2016). Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: A meta-analysis of randomized controlled trials. J Thromb Haemost, 14(3), 518–530. Warren, B. L., Eid, A., Singer, P., Pillay, S. S., Carl, P., Novak, I., et al. (2001). Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: A randomized controlled trial. JAMA, 286(15), 1869–1878. Yamakawa, K., Aihara, M., Ogura, H., Yuhara, H., Hamasaki, T., & Shimazu, T. (2015). Recombinant human soluble thrombomodulin in severe sepsis: A systematic review and meta-analysis. J Thromb Haemost, 13(4), 508–519.
Disseminated Intravascular Coagulopathy Surbhi Saini, MBBS and Amy L. Dunn, MD Disseminated intravascular coagulopathy (DIC) is defined as: An acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction. International Society on Thrombosis and Haemostasis (ISTH). DIC is a clinicopathological syndrome with variable clinical severity that can range from isolated laboratory abnormalities to massive hemorrhage and/or thrombosis. The systemic activation of dysregulated coagulation, the hallmark of DIC, occurs secondary to a multitude of underlying conditions. Treatment is focused on treating the underlying disease with concurrent replacement of coagulation factors by blood product transfusion.
Pathophysiology: To maintain normal hemostasis, three primary components of the coagulation system—vascular integrity, coagulation factors, and platelets—are very well coordinated to result in a delicate balance between bleeding (anticoagulation) and clotting (procoagulation). Any disruption of this balance can cause DIC. The most common conditions underlying DIC are sepsis and cancer; other less common causes include significant trauma and burns, obstetrical complications (e.g., retained products of conception, placental abruption), large vascular malformations, severe allergic reactions, and envenomation. Any of these conditions can cause a generalized, unregulated activation of the coagulation system leading to widespread thrombin generation and deposition of fibrin-rich microthrombi throughout the circulation. Resultant obstruction of microvasculature causes hypoxic end-organ damage, mainly to the vital organs such as liver, kidney, and brain. Additionally, excessive consumption of endogenous anticoagulant proteins (protein C, protein S, and antithrombin [AT]), and disruption of hemostatic anticoagulant pathways, contributes to the coagulation disarray. This is aggravated by the relative insufficiency of the fibrinolytic system to clear the microthrombi from the circulation. During normal hemostasis, tissue factor (TF) expression is restricted to the surface of cells not exposed to flowing blood (subendothelium, fibroblasts). Microvascular injury exposes TF to circulating FVII, initiating coagulation. In DIC, inflammatory cytokines (TNF-alpha, IL-1, IL-6) induce intravascular monocytes and macrophages to express TF. This intravascular expression of TF initiates exaggerated, pathologic coagulation, ultimately leading to the depletion of coagulation factors, which in turn can predispose to hemorrhage. It is this simultaneous development of pathologic thrombosis and hemorrhage that is the hallmark of DIC. The generation of thrombin also leads Transfusion Medicine and Hemostasis. https://doi.org/10.1016/B978-0-12-813726-0.00124-0 Copyright © 2019 Elsevier Inc. All rights reserved.
749
750
Surbhi Saini, MBBS and Amy L. Dunn, MD
to the exposure of negatively charged phospholipids on the surface of platelets, which plays a role in sustaining thrombin generation, in addition to the platelet microparticles generated by cell damage.
Clinical Manifestations: Clinical presentation of DIC is heterogeneous and to some extent, reflective of the underlying pathophysiology. Severity ranges from isolated laboratory derangements (often referred to as compensated or nonovert DIC) to multiorgan failure and death, indicative of the dynamic nature of DIC. Microvascular occlusion leads to renal, cardiac, central nervous system, and/or pulmonary failure. Digital gangrene and purpura fulminans can occur as a result of widespread skin necrosis. A subset of patients present with primarily hemorrhagic symptoms, most commonly, generalized mucocutaneous bleeding. Mortality rates are high, ranging from 34% to 86%.
Diagnosis: There is no gold standard single test for the diagnosis of DIC. The presence of a triggering condition, clinical signs/symptoms, and supportive laboratory data aids in the diagnosis, and this can be supported by the use of a five-step scoring algorithm developed by the ISTH (Fig. 124.1). This scoring system was designed to assist in diagnosis and to be utilized as a reference standard. Since its inception, it has proven both sensitive and specific for the diagnosis of overt DIC, and increasing scores strongly correlate with patient mortality. The complete blood count is used to assess platelet number and the degree of anemia associated with the underlying illness. In more advanced DIC, the peripheral smear will show evidence of thrombotic microangiopathy (schistocytes, thrombocytopenia, anemia). Varying degrees of thrombocytopenia may be present in DIC; however, thrombocytopenia may also be present as a result of many of the underlying causes of DIC such as malignancy or sepsis. The activated partial thromboplastin time (aPTT) and prothrombin time (PT) are in vitro measurements of the coagulation pathway and can be used to assess factor activation and consumption during DIC. In nearly half of the patients, aPTT and PT would be normal or shortened, reflecting the accelerated thrombin generation phase of DIC. The PT is typically more affected than the PTT in patients with DIC. Fibrinogen levels below 150 mg/dL are typically the result of consumption (e.g., DIC) or decreased production (e.g., liver failure). Levels less than 100 mg/dL significantly increase the risk of bleeding. Fibrinogen is also an acute-phase reactant, and caution must be used when interpreting fibrinogen levels in early DIC, where plasma levels can remain normal or even be elevated. The thrombin time measures the time to conversion of fibrinogen to fibrin. Decreased concentrations of fibrinogen, decreased clearance of fibrin degradation products, and the presence of heparin prolong the thrombin time. Fibrin degradation products (FDPs) are formed when fibrinogen, cross-linked fibrin, and non–cross-linked fibrin are degraded by plasmin. The extent of fibrin formation in DIC can be assessed indirectly by the generation of FDPs. D-dimers are a result of plasmin breakdown of cross-linked fibrin and are proposed by the ISTH as the FDP marker of choice when diagnosing DIC. The D-dimer test has a high negative predictive value but is limited by a low positive predictive value.
751
Disseminated Intravascular Coagulopathy
Does the patient have an underlying disorder known to be associated with overt DIC?
no
yes Order coagulation tests • Platelet count • Prothrombin time • Fibrinogen • Fibrin monomers or degradation products
Do not continue with algorithm
Score coagulation tests • Platelet count o 100,000/ l 0; 100,000/ l 1; 50,000/ l • Prothrombin time prolongation o 3 s 0; 3–6 s 1; 6 s 2 • Fibrinogen o 100 mg/dl 0; 100 mg/dl 1 • Fibrin monomers or degradation products o No increase 0; moderate increase 2, strong increase 3
5 Compatible with overt DIC, repeat scoring daily
2
5 Suggestive of non-overt DIC, repeat next 1–2 days
FIGURE 124.1 Diagnostic algorithm for the diagnosis of disseminated intravascular coagulopathy (DIC).
Levels of the endogenous coagulation inhibitor AT are typically decreased in DIC. Levels less than 80% may be associated with thrombosis. Protein C and S may also be reduced in patients with DIC. The current ISTH criteria concluded that routine testing of these parameters showed no additional value to the 4 test scoring system. However, in selected circumstances, testing may prove beneficial.
Differential Diagnosis: Liver failure and severe vitamin K deficiency can mimic DIC. To distinguish between liver disease and vitamin K deficiency, it is helpful to measure factor V and factor VII levels. In liver disease both factors will be decreased, but in vitamin K deficiency only factor VII will be low. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are also thrombotic microangiopathies but rarely show evidence of consumption of clotting proteins. Heparin-induced
752
Surbhi Saini, MBBS and Amy L. Dunn, MD
thrombocytopenia is characterized by thrombocytopenia and increased risk of thrombosis but is not characterized by clotting protein consumption.
Management: The cornerstone of DIC management is identification and appropriate treatment of the underlying trigger with ongoing supportive care. Management strategies should be individualized and reassessed frequently (Table 124.2). Replacement of consumed coagulation components is often necessary. Table 120.1 shows potential treatment options.
Blood Product Support: There are no randomized clinical trials (RCT) on which to base guidelines for platelet therapy in the setting of DIC. Although it has been hypothesized, there is currently no evidence to support the hypothesis that platelet transfusions may worsen DIC by providing a phospholipid surface for ongoing thrombin generation. Within our practice, we aim to keep the platelet count greater than 20,000/μL in patients at high risk of bleeding and >50,000/μL in the setting of active bleeding or preprocedural hemostasis. The role of fresh frozen plasma (FFP) replacement in DIC has been studied in one small randomized controlled trial in neonates. In that study, plasma and platelet therapy did not show a survival advantage over no therapy or exchange transfusion. Infusion of plasma products or cryoprecipitate (in the setting of severe hypofibrinogenemia) should be considered in the setting of bleeding associated with low fibrinogen levels; however, there is currently no evidence for prophylactic use of plasma support in the absence of bleeding. The goal of fibrinogen replacement is to maintain levels at 100 mg/ dL to prevent or treat bleeding. The use of recombinant factor VIIa is contraindicated in DIC because of its prothrombotic risk.
Anticoagulant Pathway Therapy: Depletion of anticoagulant proteins such as protein C, protein S, and AT has been postulated to play a role in sustaining DIC, and therefore replacement of these proteins has been explored as a therapeutic option. Over the past decade, evidence has been slowly mounting to support this approach. Subsequently, in a large RCT of recombinant-human activated protein C (rh-APC), adult patients with sepsis treated with rh-APC infusions for 96 hours demonstrated decreased overall mortality at 28 days compared with controls; however, there was a trend toward higher bleeding rates in the treated arm. Subsequent studies have failed to establish a benefit of this therapy in pediatric or adult patients with DIC in less severe sepsis and septic shock, including those with lowered Protein C levels. Smaller, pilot studies have suggested that normalization of serum protein C levels using protein C concentrates (plasma derived, zymogen form) is safe and potentially beneficial. AT concentrates have also been shown, in animal models of sepsis, to improve coagulation and survival rates. However, a double-blind, placebo-controlled, multicenter phase III clinical trial in patients with severe sepsis failed to demonstrate any survival advantage of high-dose AT and was associated with an increased risk of hemorrhage when administered with heparin. A post hoc analysis suggested improved organ failure and mortality rates in patients without heparin and treated early in
Disseminated Intravascular Coagulopathy
753
severe sepsis. Additional trials are needed to clearly define the indications and dosing strategies. Recombinant human soluble thrombomodulin (rhTM) has been shown to decrease thrombin formation by binding to thrombin and acting in complex with activated protein C. This agent has also shown antiinflammatory properties and has been studied in a randomized, double-blind controlled trial of patients with DIC due to malignancy or infection who were randomized to rhTM or low-dose heparin. 66% of patients in the rhTM arm resolved their DIC compared with 50% of patients in the heparin arm. In a subsequent placebo-controlled randomized controlled trial, rhTM failed to show any benefit, and currently, this drug is not available in the United States.
Anticoagulants: Although there are no data to support the routine use of anticoagulants in DIC, with evidence of thromboembolic disease, anticoagulation with heparin, either unfractionated or low-molecular weight, should be considered. Microvascular thrombosis can generally be treated with low-dose heparin, whereas large vessel disease may require full therapeutic dosage. Due consideration should be given to venous thromboembolism (VTE) prophylaxis in acutely ill patients without bleeding and at low risk for bleeding. To date, there are no trials evaluating the clinical usefulness of direct oral anticoagulants in patients with DIC.
Antifibrinolytic Therapy: Hyperfibrinolysis can occur in patients with DIC, particularly in the setting of acute promyelocytic leukemia. This can be recognized by an abnormally short euglobulin clot lysis time, and antifibrinolytic agents such as aminocaproic acid or tranexamic acid may be of use in such a scenario. These agents should be used with caution in the setting of hematuria because of the risk of renal collecting system thrombosis. Suggested dosage and indications for all of the above agents are included in Table 124.1.
TABLE 124.1 International Society on Thrombosis and Hemostasis Diagnostic Algorithm for the Diagnosis of Overt Disseminated Intravascular Coagulopathy (DIC) 1. Risk assessment: Does the patient have an underlying disorder known to be associated with overt DIC? If yes: proceed If no: do not use this algorithm 2. Order global coagulation tests (platelet count, prothrombin time (PT), fibrinogen, D-dimer levels) 3. Score global coagulation test results (i) Platelet count: >100 = 0; <100 = 1; <50 = 2 (ii) Elevated fibrin-related marker (D-dimer, FDPs): no increase = 0; moderate increase = 2; strong increase = 3 (iii) Prolonged prothrombin time: <3 second = 0; 3–6 second = 1; >6 second = 2 (iv) Fibrinogen level: >1.0 g/L = 0; <1.0 g/L = 1 4. Calculate score 5. If >5: compatible with overt DIC; repeat scoring daily If <5: suggestive (not affirmative) for nonovert DIC; repeat next 1–2 days
754
Surbhi Saini, MBBS and Amy L. Dunn, MD
TABLE 124.2 Management Guidelines for Disseminated Intravascular Coagulopathy (DIC) Product
Dose
Indication
Aminocaproic acid
100 mg/kg PO every 6 hour 33.3 mg/kg/hour IV
DIC associated with hyper fibrinolytic states
Cryoprecipitate or fibrinogen concentrate
1 unit per 10 kg of body weight
Clinically relevant bleeding; fibrinogen < 100 mg/dL unresponsive to FFP
Fresh frozen plasma
15–30 cc/kg
Clinically relevant bleeding; INR ≥2; 1.5-fold prolongation of aPTT; fibrinogen < 100 mg/dL; peri-op hemostasis for invasive procedures
Heparin
500 IU/hour (no loading dose) 5–10 IU/kg/hour low dose
DIC with evidence of ongoing thrombin generation unresponsive to conventional measures
Platelet product
Per domestic transfusion guidelines
Maintain plts > 20 × 109/L; plts > 50 × 109/L with major bleeding; periop hemostasis for invasive procedures
Further Reading Abraham, E., Laterre, P. F., Garg, R., Levy, H., Talwar, D., Trzaskoma, B. L., et al. (2005). Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med, 353(13), 1332–1341. Baratto, F., Michielan, F., Meroni, M., Dal Palu, A., Boscolo, A., & Ori, C. (2008). Protein C concentrate to restore physiological values in adult septic patients. Intensive Care Med, 34(9), 1707–1712. Bernard, G. R., Vincent, J. L., Laterre, P. F., LaRosa, S. P., Dhainaut, J. F., Lopez-Rodriguez, A., et al. (2001). Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med, 344(10), 699–709. Decembrino, L., D’Angelo, A., Manzato, F., Solinas, A., Tumminelli, F., De Silvestri, A., et al. (2010). Protein C concentrate as adjuvant treatment in neonates with sepsis-induced coagulopathy: A pilot study. Shock, 34(4), 341–345. Eid, A., Wiedermann, C. J., & Kinasewitz, G. T. (2008). Early administration of highdose antithrombin in severe sepsis: Single center results from the KyberSept-trial. Anesth Analg, 107(5), 1633–1638. Gando, S., Saitoh, D., Ogura, H., Mayumi, T., Koseki, K., Ikeda, T., et al. (2008). Natural history of disseminated intravascular coagulation diagnosed based on the newly established diagnostic criteria for critically ill patients: Results of a multicenter, prospective survey. Crit Care Med, 36(1), 145–150. Hoffman, M., & Dargaud, Y. (2012). Mechanisms and monitoring of bypassing agent therapy. J Thromb Haemost, 10(8), 1478–1485. Levi, M., de Jonge, E., & van der Poll, T. (2001). Rationale for restoration of physiological anticoagulant pathways in patients with sepsis and disseminated intravascular coagulation. Crit Care Med, 29(7 Suppl.), S90–S94. Levi, M., & Meijers, J. C. (2011). Dic: Which laboratory tests are most useful. Blood Rev, 25(1), 33–37.
Disseminated Intravascular Coagulopathy
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Ranieri, V. M., Thompson, B. T., Barie, P. S., Dhainaut, J. F., Douglas, I. S., Finfer, S., et al. (2012). Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med, 366(22), 2055–2064 Epub 2012/05/24. Singh, B., Hanson, A. C., Alhurani, R., Wang, S., Herasevich, V., Cartin-Ceba, R., et al. (2013). Trends in the incidence and outcomes of disseminated intravascular coagulation in critically ill patients (2004-2010): A population-based study. Chest, 143(5), 1235–1242. Squizzato, A., Hunt, B. J., Kinasewitz, G. T., Wada, H., Ten Cate, H., Thachil, J., et al. (2016). Supportive management strategies for disseminated intravascular coagulation. An international consensus. Thromb Haemost, 115(5), 896–904. Taylor, F. B., Jr., Toh, C. H., Hoots, W. K., Wada, H., & Levi, M. (2001). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost, 86(5), 1327–1330. Toh, C. H., & Downey, C. (2005). Back to the future: Testing in disseminated intravascular coagulation. Blood Coagul Fibrinolysis, 16(8), 535–542. Umemura, Y., Yamakawa, K., Ogura, H., Yuhara, H., & Fujimi, S. (2016). Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: A meta-analysis of randomized controlled trials. J Thromb Haemost, 14(3), 518–530. Warren, B. L., Eid, A., Singer, P., Pillay, S. S., Carl, P., Novak, I., et al. (2001). Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: A randomized controlled trial. JAMA, 286(15), 1869–1878. Yamakawa, K., Aihara, M., Ogura, H., Yuhara, H., Hamasaki, T., & Shimazu, T. (2015). Recombinant human soluble thrombomodulin in severe sepsis: A systematic review and meta-analysis. J Thromb Haemost, 13(4), 508–519.