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    • Novel approaches to the management of disseminated intravascular coagulation Marcel Levi, MD; Evert de Jonge, MD; Tom van der Poll, MD; Hugo ten Cate, MD Objective: Disseminated intravascular coagulation (DIC) is a C–protein S system. Also, impaired fibrin degradation, because of syndrome characterized by systemic intravascular activation of high circulating levels of plasminogen activator inhibitor, type 1, coagulation, leading to widespread deposition of fibrin in the contributes to enhanced intravascular fibrin deposition. circulation. We addressed the issue of whether there is evidence Conclusions: Although the cornerstone of DIC management is that this fibrin deposition contributes to multiple organ failure. We the specific and vigorous treatment of the underlying disorder, also explored the current knowledge on the pathogenesis of DIC strategies aimed at inhibiting coagulation activation may theoret- and reviewed current and future treatment for DIC. ically be justified. Such strategies have been found to be benefi- Data Sources: We searched and reviewed published articles on cial in experimental and initial clinical studies. These strategies, experimental studies of DIC models in animals and clinical studies which follow from our current understanding of the pathophysi- in patients with DIC. ology of DIC, involve inhibition of tissue factor-mediated activa- Data Synthesis: There is ample experimental and clinical evi- tion of coagulation or restoration of physiologic anticoagulant dence that DIC contributes to morbidity and mortality. Recent pathways by means of the administration of antithrombin con- knowledge on important pathogenetic mechanisms that may lead centrate or (activated) protein C concentrate. Although no com- to DIC has resulted in novel preventive and therapeutic ap- plete evidence from controlled clinical trials is available for most proaches to patients with DIC. Although the trigger for the acti- of the proposed therapeutic interventions, these novel strategies vation of the coagulation system may vary depending on the are being studied. (Crit Care Med 2000; 28[Suppl.]:S20 –S24) underlying condition, it is usually mediated by several cytokines. KEY WORDS: disseminated intravascular; sepsis; cytokines; co- Thrombin generation proceeds via the (extrinsic) tissue factor/ agulation; fibrinolysis; antithrombin III; protein C; tissue factor; factor VIIa route and simultaneously occurring depression of tissue factor pathway inhibitor inhibitory mechanisms, such as antithrombin III and the protein D isseminated intravascular co- which may lead to thrombotic occlusion may be accompanied by secondary fibrino- agulation (DIC) is not a dis- of small and midsize vessels. This situa- lysis or inhibited fibrinolysis.” ease or a symptom but a syn- tion may compromise blood supply to Clinical Conditions Associated With drome that is always various organs and may, in conjunction Disseminated Intravascular Coagulation. secondary to an underlying disorder (1, with hemodynamic and metabolic de- DIC may complicate a variety of clinical 2). DIC is characterized by widespread rangements, contribute to multiple or- disorders. Bacterial infection, in particu- activation of blood coagulation, resulting gan failure. Simultaneously, consump- lar, severe sepsis, is the most common in the intravascular formation of fibrin, tion and subsequent exhaustion of entity associated with DIC (1, 3). In addi- platelets and coagulation proteins be- tion, systemic infections with any other cause of the ongoing activation of coag- microorganism, such as viruses and par- ulation may induce severe bleeding com- asites, may lead to DIC. A common patho- From the Department of Vascular Medicine (Drs. Levi and ten Cate), Internal Medicine (Drs. Levi and van plications. In fact, bleeding may be the genetic feature of DIC that is the result of der Poll), Intensive Care (Dr. de Jonge) and the Labo- presenting symptom in a patient with severe infection is the generalized inflam- ratory of Experimental Medicine (Dr. van der Poll), DIC. Hence, a patient with DIC can matory response, characterized by the Academic Medical Center, University of Amsterdam, present with a simultaneously occurring systemic release of cytokines (5). the Netherlands; Department of Internal Medicine (Dr. ten Cate), Slotervaart Hospital, Amsterdam, the Neth- thrombotic and bleeding problem; this Severe trauma is another clinical condi- erlands. obviously complicates the choice of treat- tion frequently associated with DIC (6, 7). A Presented, in part, at the Margaux Conference on ment (3). combination of mechanisms, including re- Critical Illness, Margaux, France, November 11–13, Although there is no general consensus lease of tissue material in the circulation 1999. Adapted from the article “Disseminated intravas- on the definition of DIC, the definition put (fat, phospholipids), hemolysis, and endo- cular coagulation: State-of-the-art” presented at the forward by Muller-Berghaus et al. (4) in ¨ thelial damage, may contribute to the sys- XIVth Congress of the International Society of Throm- 1995 may be most appropriate: “Dissemi- temic activation of coagulation (8). In par- bosis and Hemostasis (ISTH), WA 1999 (Thromb nated intravascular coagulation is an ac- ticular, in head trauma patients, local Haemostas 1999; 82:695–705) and “Disseminated intravascular coagulation: Current concepts” (N Engl quired syndrome characterized by the acti- coagulation activation, and systemic coag- J Med 1999; 341:586 –592). vation of intravascular coagulation up to ulation activation are detectable, which Copyright © 2000 by Lippincott Williams & Wilkins intravascular fibrin formation. The process may be understandable in view of the rela- S20 Crit Care Med 2000 Vol. 28, No. 9 (Suppl.)
    • tively large amount of tissue factor in the ders represent a distinct group of diseases combination of consumption resulting cerebral compartment. beyond the scope of this article. from ongoing thrombin generation, deg- Both solid tumors and hematologic Pathogenesis of Disseminated Intra- radation by elastase released from acti- malignancies may be complicated by DIC. vascular Coagulation. In recent years, vated neutrophils, and impaired synthe- The mechanism of the derangement of the mechanisms of the pathologic sys- sis. Low antithrombin III levels in DIC the coagulation system is poorly under- temic fibrin deposition in DIC have be- are associated with increased mortality stood in this situation. However, most come increasingly clear. Enhanced fibrin (20). In addition to the decrease in anti- studies implicate tissue factor, potentially formation is caused by tissue factor- thrombin III, a significant depression of expressed on the surface of tumor cells, mediated thrombin generation and si- the protein C–protein S system may oc- in this process (9). A distinct form of DIC multaneously occurring dysfunction of cur. In models of experimental endotox- is frequently encountered in acute pro- inhibitory mechanisms, such as the anti- emia, down-regulation of thrombomodu- myelocytic leukemia, which is character- thrombin system and the protein C–pro- lin has been demonstrated, resulting in ized by a severe hyperfibrinolytic state on tein S protein system. In addition to en- diminished protein C activity, which may top of an activated coagulation system hanced fibrin formation, fibrin removal is enhance the procoagulant state (21). Tis- (10). Although clinical bleeding predom- impaired because the fibrinolytic system sue factor, the trigger of coagulation, is inates in acute promyelocytic leukemia, is depressed. This impairment of endog- inhibited by tissue factor pathway inhib- disseminated thrombosis is found in enous thrombolysis is caused mainly by itor (TFPI). Administration of recombi- many patients at postmortem examina- high circulating levels of plasminogen ac- nant TFPI to healthy volunteers results in tion. tivator inhibitor, type 1. In a later stage of complete inhibition of endotoxin-induced Acute DIC occurs in obstetrical calam- DIC, fibrinolytic activity may be in- thrombin generation (22). Moreover, in ities such as placental abruption and am- creased and contribute to bleeding. The vivo experiments in lethal baboon models niotic fluid emboli (11). Amniotic fluid derangement of coagulation and fibrino- indicate that TFPI is a potent inhibitor of has been shown to activate coagulation in lysis is mediated by several cytokines, sepsis-related mortality. Whether this ef- vitro, and the degree of placental separa- particularly in DIC associated with infec- fect results solely from impaired clotting tion correlates with the extent of DIC, tious disease but probably also in most activity remains uncertain. In contrast to suggesting that leakage of thromboplas- other clinical conditions associated with other coagulation inhibitors, acquired tin-like material from the placental sys- DIC. deficiencies of TFPI have not been ob- tem is responsible for DIC. The most Activation of Blood Coagulation in served, and DIC is generally associated common obstetrical complication associ- Disseminated Intravascular Coagulation. with only modestly reduced levels, or ated with activation of blood coagulation In all experimental models, thrombin even increased concentrations, of TFPI. is eclampsia and the HELLP (hemolysis, generation is detectable at 3–5 hrs after Experimental models indicate that at elevated liver enzymes, and low platelets) the infusion of microorganisms or endo- the time of maximal activation of coagu- syndrome (12). However, this complica- toxin (14, 15). Several lines of evidence lation, the fibrinolytic system is largely tion is characterized by microangiopathic point to the tissue factor/factor VIIa sys- shut off. Experimental bacteremia and hemolytic anemia with secondary tem as pivotal in the initiation of throm- changes in the coagulation system, a sit- bin generation. First, experiments in hu- endotoxemia result in a rapid increase in uation that is related to, but clearly dis- mans with endotoxemia or in humans fibrinolytic activity, likely because of the tinct from, DIC. infused with the proinflammatory cyto- release of plasminogen activators from Vascular disorders, such as large aor- kine tumor necrosis factor (TNF) did not endothelial cells. This profibrinolytic re- tic aneurysms or giant hemangiomas show any change in markers for activa- sponse is followed almost immediately by (Kasabach-Merritt syndrome), may result tion of the contact system (16). Similarly, a suppression of fibrinolytic activity re- in local activation of coagulation (13). inhibition of the contact system did not sulting from a sustained increase in Activated coagulation factors can ulti- prevent activation of coagulation in bac- plasma levels of plasminogen activator mately “overflow” to the systemic circu- teremic baboons (17). Furthermore, ab- inhibitor, type 1 (23). lation and cause DIC, but the systemic rogation of the tissue factor/factor VIIa Cytokines. The derangement of coag- depletion of coagulation factors and pathway by monoclonal antibodies specif- ulation and fibrinolysis is mediated by platelets as a result of local consumption ically directed against tissue factor or fac- several proinflammatory cytokines, such is more common. This may result in a tor VIIa activity resulted in complete in- as TNF- , interleukin (IL)-1, and IL-6. clinical condition that is hardly distin- hibition of thrombin generation in The principal mediator of coagulation ac- guishable from DIC. endotoxin-challenged chimpanzees and tivation in DIC appears to be IL-6 (24). Microangiopathic hemolytic anemia prevented DIC and mortality in baboons TNF- indirectly influences the activa- represents a group of disorders: throm- that were infused with Escherichia coli tion of coagulation because of its effects bocytopenic thrombotic purpura, hemo- (18, 19). on IL-6, and TNF- is the pivotal media- lytic uremic syndrome, chemotherapy- Suppression of Physiologic Anticoag- tor of the dysregulation of the physiologic induced microangiopathic hemolytic ulant Pathways and Impaired Fibrinoly- anticoagulant pathways and the fibrino- anemia, malignant hypertension, and the sis. Impaired function of various natural lytic defect (25). Anti-inflammatory cyto- HELLP syndrome (12). Although some regulating pathways of coagulation acti- kines, such as IL-10, may modulate the characteristics of microangiopathic he- vation may contribute to fibrin forma- activation of coagulation, as it was shown molytic anemia and the resulting throm- tion. Plasma levels of the most important that administration of recombinant IL-10 botic occlusion of small and midsize ves- inhibitor of thrombin, antithrombin III, to humans completely abrogated the sels leading to organ failure may mimic are usually markedly reduced in septic endotoxin-induced effects on coagulation the clinical picture of DIC, these disor- patients. This reduction is caused by a (26). Crit Care Med 2000 Vol. 28, No. 9 (Suppl.) S21
    • Diagnosis of Disseminated Intravas- sial. These controversies arise from the I cular Coagulation in Routine Clinical lack of properly conducted clinical trials Settings. There is no single test to accu- on DIC treatment because of the com- t is well established rately diagnose DIC in an individual pa- plexity of DIC’s clinical presentation, its that the cornerstone tient. However, a combination of a clini- variable and unpredictable course, and its cal condition that may be complicated by either subtle or catastrophic clinical con- of disseminated intra- DIC with a number of laboratory results sequences. Besides, the clinical picture of will establish the presence of DIC with an a patient with widespread thrombotic vascular coagulation treat- acceptable level of certainty. Some novel deposition in small vessels of various or- laboratory tests (such as assays for solu- gans on the one hand and bleeding be- ment is the specific and vig- ble fibrin) will be available soon and may cause of consumption and subsequent de- orous treatment of the help in the diagnosis; however, most of pletion of platelets and coagulation the newer tests are currently available in factors on the other hand does not di- underlying disorder. In some specialized laboratories only. In these cir- rectly guide the physician to specific cumstances, a diagnosis of DIC may be therapies. Despite these complicating cir- cases, the disseminated in- made by a combination of platelet count, cumstances, it is well established that the measurement of global clotting times cornerstone of DIC treatment is the spe- travascular coagulation will (activated partial thromboplastin time cific and vigorous treatment of the un- completely resolve within and prothrombin time), measurement of derlying disorder. In some cases, the DIC antithrombin III and/or one or two clot- will completely resolve within hours after hours after the resolution of ting factors, and a test for fibrin degrada- the resolution of the underlying condi- tion products (2). It should be empha- tion (for example, DIC induced by placen- the underlying condition. sized that serial coagulation tests are tal abruption and amniotic fluid embo- generally more helpful than single labo- lism). In other cases (for example, DIC in ratory results in establishing the diagno- patients with sepsis and a systemic in- sis of DIC. A reduction in the platelet flammatory response syndrome), DIC tients with DIC. However, a beneficial count or a clear downward trend at sub- may be present for a number of days, effect of heparin on clinically important sequent measurements is a sensitive (al- even after proper treatment for the un- outcome events in patients with DIC has though not specific) sign of DIC. The derlying condition has been initiated. In never been demonstrated in controlled prolongation of global clotting times may these patients, supportive measures to clinical trials (29, 30). Also, the safety of reflect the consumption and depletion of manage the DIC may be necessary. heparin treatment is debatable in DIC various coagulation factors, which may Briefly, these interventions may consist patients who are prone to bleeding. On be further substantiated by the measure- of plasma and platelet substitution ther- the other hand, most patients with DIC ment of one or two selected coagulation apy, anticoagulant strategies, or adminis- should receive adequate prophylaxis to factors. However, the accuracy of one- tration of physiologic coagulation inhib- prevent venous thromboembolism (31); stage clotting assays in patients with DIC itors. this may be achieved with low-dose hep- has been contested. Plasma and Platelet Substitution arin. In view of this, there is a case for Measurement of antithrombin III has Therapy. Low levels of platelets and co- administering subcutaneous heparin or the additional advantage of specifically agulation factors may increase the risk of perhaps even intravenous low-dose hepa- assessing the consumption of the most bleeding. However, plasma or platelet rin to patients with DIC. Higher doses of important inhibitor of thrombin. Mea- substitution therapy should not be insti- heparin should be reserved for patients surement of fibrinogen has often been tuted on the basis of laboratory results with clinically overt thromboembolism advocated but, in fact, is usually not very alone; such therapy is indicated only in or extensive fibrin deposition, like pur- helpful for diagnosing DIC. Fibrinogen patients with active bleeding and in those pura fulminans or acral ischemia (30). acts as an acute-phase reactant, and de- requiring an invasive procedure or other- Theoretically, the most logical antico- spite ongoing consumption, plasma lev- wise at risk for bleeding complications agulant to use in DIC is one directed els can remain well within the normal (27). The suggestion that administration against tissue factor activity. Recently, a range for a long period. In a consecutive of blood components might add “fuel to potent and specific inhibitor of the ter- series of patients, the sensitivity of a low the fire” has, in fact, never been proven in nary complex between tissue factor/factor fibrinogen level for the diagnosis of DIC clinical or experimental studies (1). The VIIa and factor Xa has been developed was only 28% and hypofibrinogenemia efficacy of treatment with plasma or (33). This agent, rNAPc2, is derived from was detected only in very severe cases of platelets has not been proven in random- the family of nematode anticoagulant DIC. Tests for fibrin degradation products ized controlled trials but appears to be a proteins, which were originally isolated (such as dimerized plasmin fragment D) rational therapy in bleeding patients or in from hematophagous hookworm nema- may be helpful to differentiate DIC from patients at risk for bleeding who have a todes. At present, rNAPc2 is being inves- other conditions that may be associated significant depletion of these elements. tigated in phase II/III clinical studies, in- with a low platelet count and prolonged Anticoagulants. Experimental studies cluding a study in DIC patients. clotting times. have shown that heparin can at least Coagulation Inhibitor Concentrates. Current and Future Treatment of Dis- partly inhibit the activation of coagula- Because antithrombin III is one of the seminated Intravascular Coagulation. tion in sepsis and other causes of DIC most important physiologic inhibitors of Several issues in the proper management (28). Success using heparin has been coagulation and antithrombin III treat- of patients with DIC remain controver- claimed in uncontrolled case series of pa- ment showed promising results in animal S22 Crit Care Med 2000 Vol. 28, No. 9 (Suppl.)
    • models of DIC, the use of antithrombin M, et al (Eds): DIC: Pathogenesis, Diagnosis 18. Levi M, ten Cate H, Bauer KA, et al: Inhibiton III concentrates in patients with DIC has and Therapy of Disseminated Intravascular of endotoxin-induced activation of coagula- been studied relatively intensively. There Fibrin Formation. Amsterdam, Elsevier Sci- tion and fibrinolysis by pentoxifylline or by a are a number of controlled clinical trials ence Publishers BV, 1993 monoclonal anti-tissue factor antibody in a 5. Levi M, van der Poll T, ten Cate H, et al: The chimpanzee model. J Clin Invest 1994; 93: on the use of antithrombin concentrates cytokine-mediated imbalance between coag- 114 –120 in DIC patients, mostly patients with sep- ulant and anticoagulant mechanisms in sep- 19. Biemond BJ, Levi M, ten Cate H, et al: Com- sis and/or septic shock. All trials show sis and endotoxemia. Eur J Clin Invest 1997; plete inhibition of endotoxin-induced coagu- some improvement in DIC score, short- 27:3–9 lation activation in chimpanzees with a ening of DIC duration, or even improve- 6. Bick RL: Disseminated intravascular coagu- monoclonal antibody to factor VII/VIIa. ment in organ function. The more recent lation: A common complication of trauma Thromb Haemostas 1995; 73:223–228 clinical trials used very high doses of an- and shock. In: The Traumatized Patient. Bor- 20. Fourrier F, Chopin C, Goudemand J, et al: tithrombin concentrate to attain supra- ris LC, Lassen MR, Bergqvist D (Eds). New Septic shock, multiple organ failure, and dis- physiologic plasma levels, and the bene- York, Romer Grafik, 1992, pp 33–53 seminated intravascular coagulation: Com- ficial results in these trials seem to be 7. Gando S, Kameue T, Nanzaki S, et al: Dis- pared patterns of antithrombin III, protein C, seminated intravascular coagulation is a fre- and protein S deficiencies. Chest 1992; 101: more distinct. Some trials showed a mod- quent complication of systemic inflamma- 816 – 823 est reduction in mortality in antithrombin- tory response syndrome. Thromb Haemostas 21. Conway EM, Rosenberg RD: Tumor necrosis treated patients; this effect did not reach 1996; 75:224 –228 factor suppresses transcription of the throm- statistical significance. However, if one 8. Roumen JMH, Hendriks T, van der Ven J, et bomodulin gene in endothelial cells. Mol Cell performs a meta-analysis of the effect of al: Cytokine patterns in patients after major Biol 1988; 8:5588 –5592 antithrombin III treatment on mortality vascular surgery, hemorrhagic shock, and se- 22. de Jonge E, Dekkers PEP, Creasey AA, et al: in the trials, a statistically significant re- vere blunt trauma. Ann Surg 1993; Tissue factor pathway inhibitor (TFPI) dose- duction in mortality (from 47% to 32%) 6:769 –776 dependently inhibits coagulation activation is observed (odds ratio, 0.59; 95% confi- 9. Contrino J, Hair G, Kreutzer D, et al: In situ without influencing the fibrinolytic and cy- dence interval, 0.39 – 0.87) (34 –37). It is detection of expression of tissue factor in tokine response during human endotoxemia. vascular endothelial cells: Correlation with Blood 2000; 95:1124 –1129 not clear from the literature which pa- the malignant phenotype of human breast 23. Biemond BJ, Levi M, ten Cate H, et al: En- tients will benefit most from antithrom- tissue. Nat Med 1996; 2:209 –215 dotoxin-induced activation and inhibition of bin III treatment in terms of clinically 10. Falanga A, Consonni R, Marchetti M, et al: the fibrinolytic system: Effects of various in- important outcomes (such as mortality Cancer procoagulant and tissue factor are terventions in the cytokine and coagulation or organ failure). differently modulated by all-trans-retinoic cascades in experimental endotoxemia in Depression of the protein C system acid in acute promyelocytic leukemia cells. chimpanzees. Clin Sci 1995; 88:587–594 may contribute significantly to the patho- Blood 1998; 92:143–151 24. van der Poll T, Levi M, Hack CE, et al: Elim- physiology of DIC, and clinical observa- 11. Martin JN, Stedman CM: Imitators of pre- ination of interleukin 6 attenuates coagula- tions suggest that this is associated with a eclampsia and HELLP syndrome. Obstet tion activation in experimental endotoxemia fatal outcome. Hence, supplementation Gynecol Clin North Am 1991; 18:181–198 in chimpanzees. J Exp Med 1994; 179: of protein C may benefit patients with 12. Ruggenenti P, Lutz J, Remuzzi G: Pathogen- 1253–1259 esis and treatment of thrombotic microangi- 25. van der Poll T, Levi M, van Deventer SJH, et DIC. A favorable effect of administration opathy. Kidney Int 1997; 58:S97–S101 al: Differential effects of anti-tumor necrosis of protein C concentrate in experimental 13. 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