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TodayNewsReferenceEducationLog OutMy AccountDr. S TriratnaDisseminated Intravascular CoagulationTreatment & ManagementAuthor: Marcel M Levi, MD; Chief Editor: Emmanuel C Besa, MD more...

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Approach Considerations

Management of Underlying Disease

Administration of Blood Components and Coagulation Factors

Anticoagulation

Restoration of Anticoagulant Pathways

Investigational Treatments

Consultations

Long-Term Monitoring

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Multimedia LibraryTablesReferencesApproach ConsiderationsTreatment of disseminated intravascular coagulation (DIC) is controversial, but treatment guidelines have been published.[33]Monitor vital signs, assess and document extent of hemorrhage and thrombosis, correct hypovolemia, and administer basic hemostatic procedures when indicated. Patients who are stable enough for transfer should be referred expeditiously to centers with appropriate critical care and subspecialty expertise, such as hematology, blood bank, or surgical centers.Treatment should primarily focus on addressing the underlying disorder. DIC can result from several clinical conditions, including sepsis, trauma, obstetric emergencies, and malignancy. Surgical management is limited to primary treatment of certain underlying disorders.Platelet and factor replacement should be directed not at simply correcting laboratory abnormalities but at addressing clinically relevant bleeding or meeting procedural needs. Heparin should be provided to those patients who demonstrate extensive fibrin deposition without evidence of substantial hemorrhage; it is usually reserved for cases of chronic DIC. Heparin is appropriate to treat the thrombosis with DIC. It also has a limited use in acute hemorrhagic DIC in a patient with a self-limited condition of acral cyanosis and digital ischemia.Administration of activated protein C (APC) has shown benefit in subgroups of patients with sepsis who have DIC, with consideration given to the anticoagulant effects of this agent. However, drotrecogin alfa was withdrawn from the worldwide market on October 25, 2011.Recognition of the importance of inflammation in sepsis, coagulation, and DIC is vitally important in directing the development of novel therapeutic strategies.NextManagement of Underlying DiseaseThe management of acute and chronic forms of disseminated intravascular coagulation (DIC) should primarily be directed at treatment of the underlying disorder. Often, the DIC component will resolve on its own with treatment.For example, if infection is the underlying etiology, the appropriate administration of antibiotics and source control is the first line of therapy. As another example, in case of an obstetric catastrophe, the primary approach is to deliver appropriate obstetric care, in which case the DIC will rapidly subside. If the underlying condition causing DIC is not known, a diagnostic workup should be initiated. Most patients with acute DIC require critical care treatment appropriate for the primary diagnosis, occasionally including emergency surgery.A DIC scoring system has been proposed by Bick to assess the severity of the coagulopathy as well as the effectiveness of therapeutic modalities.[1]Clinical and laboratory parameters are measured with regularity (every 8 hours).PreviousNextAdministration of Blood Components and Coagulation FactorsTypically, DIC results in significant reductions in platelet count and increases in coagulation times (prothrombin time [PT] and activated partial thromboplastin time [aPTT]). However, platelet and coagulation factor replacement should not be instituted on the basis of laboratory results alone; such therapy is indicated only in patients with active bleeding and in those requiring an invasive procedure or who are otherwise at risk for bleeding complications.PlateletsPlatelet transfusion may be considered in patients with DIC and severe thrombocytopenia, in particular, in patients with bleeding or in patients at risk for bleeding (eg, in the early postoperative phase or if an invasive procedure is planned).The threshold for transfusing platelets varies. Most clinicians provide platelet replacement in nonbleeding patients if platelet counts drop below 20 109/L, though the exact levels at which platelets should be transfused is a clinical decision based on each patients clinical condition. In some instances, platelet transfusion is necessary at higher platelet counts, particularly if indicated by clinical and laboratory findings.[57]In actively bleeding patients, platelet levels from 20 109/L to 50 109/L are grounds for platelet transfusion (1 or 2 U/kg/day).Coagulation factorsPreviously, concerns have been expressed regarding the possibility that coagulation factor replacement therapy might add fuel to the fire of consumption; however, this has never been established in research studies.[58]It is generally considered that cryoprecipitate and coagulation factor concentrates should not routinely be used as replacement therapy in DIC, because they lack several specific factors (eg, factor V). Additionally, worsening of the coagulopathy via the presence of small amounts of activated factors is a theoretical risk. Specific deficiencies in coagulation factors, such as fibrinogen, can be corrected by administration of cryoprecipitate or purified fibrinogen concentrate in conjuction with fresh frozen plasma administration.Data suggest that the consumption-induced deficiency of coagulation factors can be partially rectified by administering large quantities of fresh frozen plasma (FFP), particularly in patients with an international normalized ratio (INR) higher than 2.0, a 2-fold or greater prolongation of the aPTT, or a fibrinogen level below 100 mg/dL.[59]The suggested starting dose is 15 mg/kg.[33]Repeated measurement of global clotting tests (eg, aPTT and PT) might be useful for monitoring the coagulation defect. In case of a (relative) vitamin K deficiency in the face of consumption, administration of vitamin K may be required.[12, 5, 13]PreviousNextAnticoagulationExperimental studies have suggested that heparin can at least partly inhibit the activation of coagulation in cases of sepsis and other causes of DIC.[60]However, a beneficial effect of heparin on clinically important outcome events in patients with DIC has not yet been demonstrated in controlled clinical trials. Moreover, antithrombin, the primary target of heparin activity, is markedly decreased in DIC, which means that the effectiveness of heparin therapy will be limited without concomitant replacement of antithrombin.Furthermore, there are well-founded concerns with respect to anticoagulating DIC patients who are already at high risk for hemorrhagic complications. It is generally agreed that therapeutic doses of heparin are indicated in cases of obvious thromboembolic disease or where fibrin deposition predominates (eg, purpura fulminans or acral ischemia).[61, 62, 63]The use of heparin in chronic DIC where there is preponderance of coagulation without consumption coagulopathy is well established.[64]In other patients with acryl cyanosis and digital ischemia and DIC, heparin can be safely administered at lower doses. A dose of 4-5 U/kg constant infusion without a 80-U/kg bolus is a safe means to deliver heparin to the DIC without increasing the bleeding risk.Enoxaparin has been used for treatment and prophylaxis of chronic DIC in specific clinical situations. In a multicenter, cooperative, double-blinded trial from Japan that compared the low-molecular-weight heparin (LMWH) dalteparin withunfractionated heparin, the former was associated with a decreased bleeding tendency and reduced organ failure.[62]One randomized clinical trial showed LMWH to be superior for reducing 28-day mortality in patients with severe sepsis.[65]Patients with DIC may benefit from prophylaxis to prevent venous thromboembolism, which will not be achieved with standard low-dose subcutaneous heparin. Theoretically, the most logical anticoagulant agent to use in DIC is directed against tissue factor activity.PreviousNextRestoration of Anticoagulant PathwaysStrategies for restoring anticoagulant pathways have primarily involved administration of antithrombin concentrate or recombinant human APC, though tissue factor (TF) pathway inhibitor (TFPI) and recombinant thrombomodulin (rTM) have also been studied.AntithrombinThe antithrombin pathway, an important inhibitor of coagulation in normal patients, is largely depleted and incapacitated in acute DIC. As a result, several studies have evaluated the utility of antithrombin replacement in DIC. Most have demonstrated benefit in terms of improving laboratory values and even organ function.[51, 66, 67, 68]To date, however, large-scale randomized trials have failed to demonstrate any mortality benefit in patients treated with antithrombin concentrate.Most of the randomized controlled trials involved patients with sepsis or septic shock. In the later clinical trials, very high doses of antithrombin concentrate were used to attain supraphysiologic plasma levels. A series of relatively small trials showed a modest reduction in mortality in antithrombin-treated patients. However, in none of the trials did the effect reach statistical significance.A large-scale multicenter, randomized controlled trial to directly address this issue showed no significant reduction in mortality of septic patients who were treated with antithrombin concentrate. In this trial, 2114 patients with severe sepsis and associated organ failure were included. Surprisingly, subgroup analyses indicated some benefit in patients who did not receive concomitant heparin, but this observation needs prospective validation.In another study that evaluated the effects of antithrombin in 23 patients with DIC diagnosed on the basis of the Japanese Association for Acute Medicine (JAAM)criteria (a newly developed diagnostic algorithm for critical illness), patients were treated with either high-dose (60 IU/kg/day; 12 patients) or low-dose (30 IU/kg/day; 11 patients) antithrombin concentrates for 3 days.[69]On day 0, the patients backgrounds and antithrombin activity were identical in the 2 groups.[69]However, on day 7, the JAAM DIC score and PT ratio were significantly improved in comparison with those on day 0. However, mortality at 28 days and interaction within the administered antithrombin doses showed no differences.[69]There were also no differences in the time course of the platelet counts, coagulation and fibrinolytic markers, and DIC scores in the 2 groups.[69]The authors concluded that the effects of antithrombin on prognosis and coagulation and fibrinolytic parameters are independent of the doses administered in patients who have DIC associated with the systemic inflammatory response syndrome (SIRS) or sepsis.Activated protein CAPC is an important regulator of coagulation. It deactivates factor VIIIa and factor Va and also has a role in activating protease-activated receptor 1 (PAR-1), which has an inhibitory effect on inflammation and apoptosis.[59]In studies of patients with sepsis who had associated organ failure, APC has been shown to reduce mortality and improve organ function.The PROWESS study (Human Recombinant Activated Protein C Worldwide Evaluation in Sepsis) documented reductions in 28-day mortality and improved organ function in APC-treated patients, despite an increase in the overall number of bleeding complications.[70, 71]These results were confirmed by the ENHANCE trial, which also suggested that APC might be more effective when administered earlier.[72]A retrospective, subgroup analysis of the PROWESS study demonstrated a lower mortality among patients treated with APC who met criteria for DIC with a modified DIC scoring system.[73]Other studies of APC in patients with a low risk of death from sepsis have failed to show an effect, suggesting that APC may be most useful in severely ill patients.[74]Drotrecogin alfa was withdrawn from the worldwide market October 25, 2011. In the PROWESS-SHOCK clinical trial, drotrecogin alfa failed to demonstrate a statistically significant reduction in 28-day all-cause mortality in patients with severe sepsis and septic shock. Trial results observed a 28-day all-cause mortality of 26.4% in patients treated with activated drotrecogin alfa compared with 24.2% in the placebo group of the study.A nonrandomized comparison between heparin and APC in patients with DIC showed more rapid resolution of DIC with the latter, though the study was too small to demonstrate effects on organ failure and mortality.Related to the use of APC is the use of protein C concentrate to treat coagulation abnormalities in adult patients with sepsis. A study found protein C concentrate to be safe and useful in restoring coagulation and hematologic parameters; however, further study is required, and prospective evaluation of its safety and efficacy are indicated.[75]Tissue factor pathway inhibitorThe TFPI mechanism of coagulation inhibition has received attention as a potential therapy in sepsis-associated DIC. Indeed, initial results from animal studies have been very promising in demonstrating the ability of TFPI to arrest DIC and to prevent the mortality and end-organ damage witnessed in untreated animals.[76]However, a large phase III trial of TFPI in humans with DIC did not show any mortality benefit.[77]Recombinant thrombomodulinrTM can be used for treatment of DIC in cases of severe sepsis and hematopoietic malignancy. Thrombomodulin binds with thrombin, and the resulting complex allows the conversion of protein C to APC. Additionally, thrombomodulin can also bind high-mobility group B (HBGM-1), which inhibits the inflammatory process.[59]rTM has shown beneficial effects on DIC parameters and clinical outcome in initial trials.[78]It was evaluated in a randomized controlled study involving 234 subjects and was found to yield significantly improved control of DIC in comparison with unfractionated heparin, particularly with respect to the control of persistent bleeding diathesis.[79]PreviousNextInvestigational TreatmentsAs understanding of the inflammatory and coagulation derangements in DIC has improved, the range of therapeutic considerations has broadened.Treatment modalities focused on the tissue factor (TF)-VIIa complex include inactivated factor VII and recombinant nematode anticoagulant peptide (NAPc2), a member of the nematode family of anticoagulant proteins (NAPs) and an inhibitor of the complex between TF, factor VIIa, and factor Xa. NAPc2 has been observedto inhibit coagulation activation in a primate model of sepsis.[5, 13]Other research has used antibodies against TF-VIIa in animal trials, with promising results.[13]Recombinant factor VIIa (rVIIa) has also been demonstrated to be useful in cases of severe bleeding, as is seen in DIC.[13]However, given its procoagulant effect rVIIa, the risks and benefits in patients with DIC should be carefully considered before administration. Further, antifibrinolytic agents, such as -aminocaproic acid or tranexamic acid, can also be considered in patients with DIC in which bleeding predominates. These agents should always be administered with heparin to arrest their prothrombotic effects.[13, 80]Recognition of the importance of inflammation in both sepsis and DIC has led to further investigation of inhibitors of inflammation. In a murine model, researchers showed that antiselectin antibodies and heparin blocked leukocyte and platelet adhesion.[81]Similarly, focus has been placed on interleukin (IL)10, an anti-inflammatory cytokine that may have effects on coagulation activation. Initial studies of IL-10 have shown promise in preventing coagulation activation associated with endotoxemia.[82]Other researchers have targeted p38 mitogen activated protein kinase (MAPK), an important element in intracellular signaling responsible for inflammatory responses. Inhibition of MAPK has been shown to reduce coagulation activation, fibrinolysis, and endothelial activation in endotoxemia.[83]PreviousNextConsultationsConsult a hematologist for assistance with diagnosis and management if the clinical picture is suggestive of DIC. Consult a transfusion specialist or a blood bank; determine the availability of general and specialized blood products that may be necessary for the acute management of fulminant DIC. Consult a critical care specialist if multiple organ failure is present.Early consultation is indicated for this complicated, life-threatening condition. Obtain other subspecialty consultations as indicated by the patients primary diagnosis.PreviousNextLong-Term MonitoringOutpatient medications may include antiplatelet agents for those with low-grade DIC, antibiotics appropriate to the primary diagnosis, or both. Patients who recover from acute DIC should follow up with their primary care provider or a hematologist. Patients with low-grade or chronic DIC may be treated by a hematologist on an outpatient basis after initial assessment and stabilization. Patients with chronic DIC and cancer can be managed by subcutaneous heparin or low molecular weight heparin.PreviousProceed toMedicationContributor Information and DisclosuresAuthorMarcel M Levi, MD Dean, Academic Medical Center, University of Amsterdam, The Netherlands

Marcel M Levi, MD is a member of the following medical societies:American Society of HematologyandInternational Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.Coauthor(s)Alvin H Schmaier, MD Robert W Kellermeyer Professor of Hematology/Oncology, Case Western Reserve University School of Medicine; Chief, Division of Hematology/Oncology, University Hospitals Case Medical Center

Alvin H Schmaier, MD is a member of the following medical societies:American Federation for Medical Research,American Heart Association,American Society for Clinical Investigation,American Society of Hematology,Association of American Physicians,Central Society for Clinical Research, andInternational Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.Chief EditorEmmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies:AmericanAssociation for Cancer Education,American College of Clinical Pharmacology,American Federation for Medical Research,American Society of Clinical Oncology,American Society of Hematology, andNew York Academy of Sciences

Disclosure: Nothing to disclose.Additional ContributorsJeffrey L Arnold, MD, FACEPChairman, Department of Emergency Medicine, Santa Clara Valley Medical CenterJeffrey L Arnold, MD, FACEP is a member of the following medical societies:American Academy of Emergency MedicineandAmerican College of PhysiciansDisclosure: Nothing to disclose.Joseph U Becker, MDFellow, Global Health and International Emergency Medicine, Stanford University School of MedicineJoseph U Becker, MD is a member of the following medical societies:American College of Emergency Physicians,Emergency Medicine Residents Association,Phi Beta Kappa, andSociety for Academic Emergency MedicineDisclosure: Nothing to disclose.Barry E Brenner, MD, PhD, FACEPProfessor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, Case Medical Center, University Hospitals, Case Western Reserve University School of MedicineBarry E Brenner, MD, PhD, FACEP is a member of the following medical societies:Alpha Omega Alpha,American Academy of Emergency Medicine,American College of Chest Physicians,American College of Emergency Physicians,American College of Physicians,American Heart Association,American Thoracic Society,Arkansas Medical Society,New York Academy of Medicine,New York Academy of Sciences, andSociety for Academic Emergency MedicineDisclosure: Nothing to disclose.Steven A Conrad, MD, PhDChief, Department of Emergency Medicine; Chief, Multidisciplinary Critical Care Service, Professor, Department of Emergency and Internal Medicine, Louisiana State University Health Sciences CenterSteven A Conrad, MD, PhD is a member of the following medical societies:American College of Chest Physicians, American College of Critical Care Medicine,American College of Emergency Physicians,American College of Physicians,International Society for Heart and Lung Transplantation,Louisiana State Medical Society,Shock Society,Society for Academic Emergency Medicine, andSociety of Critical Care MedicineDisclosure: Nothing to disclose.Brendan R Furlong, MDClinical Chief, Department of Emergency Medicine, Georgetown University HospitalDisclosure: Nothing to disclose.Mary A Furlong, MDAssociate Professor and Program/Residency Director, Department of Pathology, Georgetown University School of MedicineDisclosure: Nothing to disclose.Avishek Kumar, MDResident Physician, Department of Internal Medicine, St Michael's Medical Center, Seton Hall University School of Health and Medical SciencesAvishek Kumar, MD is a member of the following medical societies:American Medical AssociationDisclosure: Nothing to disclose.Pradyumna D Phatak, MBBS, MDChair, Division of Hematology and Medical Oncology, Rochester General Hospital; Clinical Professor of Oncology, Roswell Park Cancer InstitutePradyumna D Phatak, MBBS, MD, is a member of the following medical societies:American Society of HematologyDisclosure: Novartis Honoraria Speaking and teachingRonald A Sacher, MB, BCh, MD, FRCPCProfessor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health CenterRonald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies:American Association for the Advancement of Science,American Association of Blood Banks,American Clinical and Climatological Association,American Society for Clinical Pathology,American Society of Hematology,College of American Pathologists, International Society of BloodTransfusion,International Society on Thrombosis and Haemostasis, andRoyal College of Physicians and Surgeons of CanadaDisclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membershipHamid Salim ShaabanMD, Fellow in Hematology/ Oncology, Department of Internal Medicine, Seton Hall University School of Health and Medical SciencesHamid Salim Shaaban is a member of the following medical societies:American College of PhysiciansDisclosure: Nothing to disclose.Francisco Talavera, PharmD, PhDAdjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug ReferenceDisclosure: Medscape Salary EmploymentCharles R Wira, MDAssistant Professor, Department of Surgery, Section of Emergency Medicine, Yale School of MedicineCharles R Wira, MD is a member of the following medical societies:American College of Emergency Physicians,Society for Academic Emergency Medicine, andSociety of Critical Care MedicineDisclosure: Nothing to disclose.ReferencesVincent JL, De Backer D. Does disseminated intravascular coagulation lead to multiple organ failure?.Crit Care Clin. Jul 2005;21(3):469-77.[Medline].

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PreviousNextDiagnostic algorithm for the diagnosis of overt disseminated intravascular coagulation.Coagulation pathway.Table 1. Causes of Acute (Hemorrhagic) Disseminated Intravascular Coagulation

Table 2. Causes of Chronic Disseminated Intravascular Coagulation

Table 3. Main Features of Disseminated Intravascular Coagulation in Series of 118 Patients

Table 4. Japanese Association for Acute Medicine (JAAM) Scoring System for DIC

Table 1. Causes of Acute (Hemorrhagic) Disseminated Intravascular CoagulationTypeCause

InfectiousBacterial (eg, gram-negative sepsis, gram-positive infections, rickettsial)



Viral (eg, HIV, cytomegalovirus [CMV], varicella-zoster virus [VZV], and hepatitis virus)



Fungal (eg,Histoplasma)



Parasitic (eg, malaria)

MalignancyHematologic (eg, acute myelocytic leukemia)



Metastatic (eg, mucin-secreting adenocarcinoma)

ObstetricPlacental abruption



Amniotic fluid embolism



Acute fatty liver of pregnancy



Eclampsia

TraumaBurns



Motor vehicle accidents



Snake envenomation

TransfusionHemolytic reactions



Transfusion

OtherLiver disease/acute hepatic failure*



Prosthetic devices



Shunts (Denver or LeVeen)



Ventricular assist devices

*Some do not classify this as DIC; rather, it is liver disease with reduced blood coagulation factor synthesis and reduced clearance of activate products of coagulation.

Table 2. Causes of Chronic Disseminated Intravascular CoagulationTypeCause

MalignanciesSolid tumors



Leukemia

ObstetricRetained dead fetus syndrome



Retained products of conception

HematologicMyeloproliferative syndromes

VascularRheumatoid arthritis



Raynaud disease

CardiovascularMyocardial infarction

InflammatoryUlcerative colitis



Crohn disease



Sarcoidosis

Localized DICAortic aneurysms



Giant hemangioma (Kasabach-Merritt syndrome)



Acute renal allograft rejection

Table 3. Main Features of Disseminated Intravascular Coagulation in Series of 118 PatientsFeaturesAffected Patients, %

Bleeding64%

Renal dysfunction25%

Hepatic dysfunction19%

Respiratory dysfunction16%

Shock14%

Central nervous system dysfunction2%

Table 4. Japanese Association for Acute Medicine (JAAM) Scoring System for DICClinical conditions that should be ruled out

Thrombocytopenia



Dilution and abnormal distribution



Massive blood loss, massive infusion



ITP, TTP-HUS, HIT, HELLP syndrome



Disorders of hematopoiesis



Liver disease



Hypothermia



Spurious laboratory results

Diagnostic algorithm for SIRS

Temperature >38C or < 36C



Heart rate >90 beats/min



Respiratory rate >20 breaths/min or PaCO2< 32 mm Hg (< 4.3 kPa)



WBC count >12,000 cells/L, < 4000 cells/ L, or 10% immature (band) forms

Diagnostic algorithm



SIRS criteria

Score

>31

0-20

Platelet count( 109/L)

< 80 or >50 % decrease within 24 hours3

>80 and < 120 or >30% decrease within 24 hours1

>1200

Prothrombin time (value of patient/normal value)

>1.21

< 1.20

Fibrin/FDPs (mg/L)

>253

>10 and < 251

< 100

Diagnosis



4 points or more

DIC

DIC = disseminated intravascular coagulation; FDP = fibrin degradation product; HELLP = hemolysis, elevated liver enzymes, low platelet count; HIT = heparin-induced thrombocytopenia; HUS = hemolytic uremic syndrome; ITP = idiopathic thrombocytopenic purpura; PaCO2= partial pressure of carbon dioxide in arterial blood; SIRS = systemic inflammatory response syndrome; TTP = thrombotic thrombocytopenic purpura; WBC = white blood cell.

PreviousNextView Table ListRead more about Disseminated Intravascular Coagulation on MedscapeRelated Reference TopicsPurpura Fulminans

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