No instant look-up matches.

Search within full reference content by clicking the "SEARCH"

button or pressing enter.

Today
News
Reference
Education
Log Out My Account
Dr. S Triratna

Disseminated Intravascular
Coagulation Treatment & Management

Author: Marcel M Levi, MD; Chief Editor: Emmanuel C Besa, MD more...

Overview

Presentation

DDx

Workup

Treatment

Medication

Updated: Aug 31, 2012

What would you like to print?

Print this section

Print the entire contents of

Approach Considerations

Management of Underlying Disease

Administration of Blood Components and Coagulation Factors

Anticoagulation

Restoration of Anticoagulant Pathways

Investigational Treatments

Consultations

Long-Term Monitoring

Show All

Multimedia Library
Tables
References

Approach Considerations
Treatment 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 However, drotrecogin alfa was withdrawn from the worldwide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.
Next

Management of Underlying Disease

The 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).
Previous
Next

Administration of Blood Components and Coagulation

Factors
Typically, 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.
Platelets
Platelet 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 10 9/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 10 9/L
to 50 109/L are grounds for platelet transfusion (1 or 2 U/kg/day).
Coagulation factors
Previously, 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]
Previous
Next

Anticoagulation
Experimental 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 with
unfractionated 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.
Previous
Next

Restoration of Anticoagulant Pathways

Strategies 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.
Antithrombin
The 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 C
APC 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 inhibitor

The 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 thrombomodulin
rTM 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]
Previous
Next

Investigational Treatments
As 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 observed
to 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]
Previous
Next

Consultations
Consult 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.
Previous
Next

Long-Term Monitoring
Outpatient 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.
Previous
Proceed to Medication
Contributor Information and Disclosures
Author
Marcel 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 Hematology and International 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 Editor
Emmanuel 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: American
Association for Cancer Education, American College of Clinical
Pharmacology, American Federation for Medical Research, American Society of
Clinical Oncology, American Society of Hematology, and New York Academy of
Sciences
Disclosure: Nothing to disclose.
Additional Contributors
Jeffrey L Arnold, MD, FACEP Chairman, Department of Emergency Medicine,
Santa Clara Valley Medical Center
Jeffrey L Arnold, MD, FACEP is a member of the following medical
societies: American Academy of Emergency Medicine and American College of
Physicians
Disclosure: Nothing to disclose.
Joseph U Becker, MD Fellow, Global Health and International Emergency
Medicine, Stanford University School of Medicine
Joseph U Becker, MD is a member of the following medical societies: American
College of Emergency Physicians, Emergency Medicine Residents
Association, Phi Beta Kappa, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine,
Professor of Internal Medicine, Program Director, Emergency Medicine, Case
Medical Center, University Hospitals, Case Western Reserve University School of
Medicine
Barry 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, and Society for Academic
Emergency Medicine
Disclosure: Nothing to disclose.
Steven A Conrad, MD, PhD Chief, Department of Emergency Medicine; Chief,
Multidisciplinary Critical Care Service, Professor, Department of Emergency and
Internal Medicine, Louisiana State University Health Sciences Center
Steven 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,
and Society of Critical Care Medicine
Disclosure: Nothing to disclose.
Brendan R Furlong, MD Clinical Chief, Department of Emergency Medicine,
Georgetown University Hospital
Disclosure: Nothing to disclose.
Mary A Furlong, MD Associate Professor and Program/Residency Director,
Department of Pathology, Georgetown University School of Medicine
Disclosure: Nothing to disclose.
Avishek Kumar, MD Resident Physician, Department of Internal Medicine, St
Michael's Medical Center, Seton Hall University School of Health and Medical
Sciences
Avishek Kumar, MD is a member of the following medical societies: American
Medical Association
Disclosure: Nothing to disclose.

Pradyumna D Phatak, MBBS, MD Chair, Division of Hematology and Medical

Oncology, Rochester General Hospital; Clinical Professor of Oncology, Roswell
Park Cancer Institute
Pradyumna D Phatak, MBBS, MD, is a member of the following medical
societies: American Society of Hematology
Disclosure: Novartis Honoraria Speaking and teaching
Ronald A Sacher, MB, BCh, MD, FRCPC Professor, Internal Medicine and
Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic
Health Center
Ronald 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 Blood
Transfusion, International Society on Thrombosis and Haemostasis, and Royal
College of Physicians and Surgeons of Canada
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris
Honoraria Board membership
Hamid Salim Shaaban MD, Fellow in Hematology/ Oncology, Department of
Internal Medicine, Seton Hall University School of Health and Medical Sciences
Hamid Salim Shaaban is a member of the following medical societies: American
College of Physicians
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of
Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug
Reference
Disclosure: Medscape Salary Employment
Charles R Wira, MD Assistant Professor, Department of Surgery, Section of
Emergency Medicine, Yale School of Medicine
Charles R Wira, MD is a member of the following medical societies: American
College of Emergency Physicians, Society for Academic Emergency Medicine,
and Society of Critical Care Medicine
Disclosure: Nothing to disclose.
References

1.

Vincent JL, De Backer D. Does disseminated intravascular coagulation lead

to multiple organ failure?. Crit Care Clin. Jul 2005;21(3):469-77. [Medline].

2.

Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med.

Aug 19 1999;341(8):586-92. [Medline].

3.

[Guideline] Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M. Towards
definition, clinical and laboratory criteria, and a scoring system for
disseminated intravascular coagulation. Thromb Haemost. Nov
2001;86(5):1327-30. [Medline].

4.

Matsuda T. Clinical aspects of DIC--disseminated intravascular

coagulation. Pol J Pharmacol. Jan-Feb 1996;48(1):73-5. [Medline].

5.

Levi M, de Jonge E, van der Poll T. New treatment strategies for

disseminated intravascular coagulation based on current understanding of
the pathophysiology. Ann Med. 2004;36(1):41-9. [Medline].

6.

Branson HE, Katz J, Marble R, Griffin JH. Inherited protein C deficiency

and coumarin-responsive chronic relapsing purpura fulminans in a newborn
infant. Lancet. Nov 19 1983;2(8360):1165-8. [Medline].

7.

Yuen P, Cheung A, Lin HJ, Ho F, Mimuro J, Yoshida N, et al. Purpura

fulminans in a Chinese boy with congenital protein C deficiency. Pediatrics.
May 1986;77(5):670-6. [Medline].

8.

Asherson RA, Espinosa G, Cervera R, Gmez-Puerta JA, Musuruana J,

Bucciarelli S, et al. Disseminated intravascular coagulation in catastrophic
antiphospholipid syndrome: clinical and haematological characteristics of 23
patients. Ann Rheum Dis. Jun 2005;64(6):943-6. [Medline]. [Full Text].

9.

Fourrier F, Chopin C, Goudemand J, Hendrycx S, Caron C, Rime A, et al.

Septic shock, multiple organ failure, and disseminated intravascular
coagulation. Compared patterns of antithrombin III, protein C, and protein S
deficiencies. Chest. Mar 1992;101(3):816-23. [Medline].

10. Gando

S. Disseminated intravascular coagulation in trauma patients. Semin

Thromb Hemost. Dec 2001;27(6):585-92. [Medline].

11. Gando

S, Nakanishi Y, Tedo I. Cytokines and plasminogen activator

inhibitor-1 in posttrauma disseminated intravascular coagulation:
relationship to multiple organ dysfunction syndrome. Crit Care Med. Nov
1995;23(11):1835-42. [Medline].

12. Levi

M. Disseminated intravascular coagulation: What's new?. Crit Care

Clin. Jul 2005;21(3):449-67. [Medline].

13. Franchini

M, Lippi G, Manzato F. Recent acquisitions in the

pathophysiology, diagnosis and treatment of disseminated intravascular
coagulation. Thromb J. Feb 21 2006;4:4. [Medline]. [Full Text].

14. Levi

M. The coagulant response in sepsis. Clin Chest Med. Dec

2008;29(4):627-42, viii. [Medline].

15. Leblebisatan

G, Sasmaz I, Antmen B, Yildizdas D, Kilinc Y. Management of

life-threatening hemorrhages and unsafe interventions in nonhemophiliac
children by recombinant factor VIIa. Clin Appl Thromb Hemost. Feb
2010;16(1):77-82. [Medline].

16. Maczewski

M, Duda M, Pawlak W, Beresewicz A. Endothelial protection

from reperfusion injury by ischemic preconditioning and diazoxide involves
a SOD-like anti-O2- mechanism. J Physiol Pharmacol. Sep 2004;55(3):53750. [Medline].

17. Levi

M. Keep in contact: the role of the contact system in infection and

sepsis. Crit Care Med. Nov 2000;28(11):3765-6. [Medline].

18. Sower

LE, Froelich CJ, Carney DH, Fenton JW 2nd, Klimpel GR. Thrombin
induces IL-6 production in fibroblasts and epithelial cells. Evidence for the
involvement of the seven-transmembrane domain (STD) receptor for alphathrombin. J Immunol. Jul 15 1995;155(2):895-901. [Medline].

19. Taylor FB

Jr, Chang A, Ruf W, Morrissey JH, Hinshaw L, Catlett R, et al.

Lethal E. coli septic shock is prevented by blocking tissue factor with
monoclonal antibody. Circ Shock. Mar 1991;33(3):127-34. [Medline].

20. Levi

M, ten Cate H, Bauer KA, van der Poll T, Edgington TS, Bller HR, et
al. Inhibition of endotoxin-induced activation of coagulation and fibrinolysis
by pentoxifylline or by a monoclonal anti-tissue factor antibody in
chimpanzees. J Clin Invest. Jan 1994;93(1):114-20. [Medline]. [Full Text].

21. Carey

MJ, Rodgers GM. Disseminated intravascular coagulation: clinical

and laboratory aspects. Am J Hematol. Sep 1998;59(1):65-73. [Medline].

22. Mesters

RM, Mannucci PM, Coppola R, Keller T, Ostermann H, Kienast J.

Factor VIIa and antithrombin III activity during severe sepsis and septic
shock in neutropenic patients. Blood. Aug 1 1996;88(3):881-6. [Medline].

23. Nawroth

PP, Stern DM. Modulation of endothelial cell hemostatic properties

by tumor necrosis factor. J Exp Med. Mar 1 1986;163(3):740-5. [Medline].
[Full Text].

24. Novotny WF, Brown

SG, Miletich JP, Rader DJ, Broze GJ Jr. Plasma

antigen levels of the lipoprotein-associated coagulation inhibitor in patient
samples.Blood. Jul 15 1991;78(2):387-93. [Medline].

25. Biemond

BJ, Levi M, Ten Cate H, Van der Poll T, Bller HR, Hack CE, et
al. Plasminogen activator and plasminogen activator inhibitor I release
during experimental endotoxaemia in chimpanzees: effect of interventions in
the cytokine and coagulation cascades. Clin Sci (Lond). May
1995;88(5):587-94.[Medline].

26. van

Hinsbergh VW, Kooistra T, van den Berg EA, Princen HM, Fiers W,
Emeis JJ. Tumor necrosis factor increases the production of plasminogen
activator inhibitor in human endothelial cells in vitro and in rats in
vivo. Blood. Nov 1988;72(5):1467-73. [Medline].

27. Mesters

RM, Flrke N, Ostermann H, Kienast J. Increase of plasminogen

activator inhibitor levels predicts outcome of leukocytopenic patients with
sepsis. Thromb Haemost. Jun 1996;75(6):902-7. [Medline].

28. Asakura

H, Ontachi Y, Mizutani T, Kato M, Saito M, Kumabashiri I, et al.

An enhanced fibrinolysis prevents the development of multiple organ failure
in disseminated intravascular coagulation in spite of much activation of
blood coagulation. Crit Care Med. Jun 2001;29(6):1164-8. [Medline].

29. Levi

M. Disseminated intravascular coagulation in cancer patients. Best

Pract Res Clin Haematol. Mar 2009;22(1):129-36. [Medline].

30. Levi

M, van der Poll T, Bller HR. Bidirectional relation between

inflammation and coagulation. Circulation. Jun 8 2004;109(22):2698704. [Medline].

31. Altieri

DC. Molecular cloning of effector cell protease receptor-1, a novel

cell surface receptor for the protease factor Xa. J Biol Chem. Feb 4
1994;269(5):3139-42. [Medline].

32. Camerer

E, Huang W, Coughlin SR. Tissue factor- and factor X-dependent

activation of protease-activated receptor 2 by factor VIIa. Proc Natl Acad
Sci U S A. May 9 2000;97(10):5255-60. [Medline]. [Full Text].

33. Levi

M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and
management of disseminated intravascular coagulation. British Committee
for Standards in Haematology. Br J Haematol. Apr 2009;145(1):2433. [Medline].

34. Sawamura A,

Hayakawa M, Gando S, Kubota N, Sugano M, Wada T, et al.

Disseminated intravascular coagulation with a fibrinolytic phenotype at an
early phase of trauma predicts mortality. Thromb Res. Nov 2009;124(5):60813. [Medline].

35. Sivula

M, Pettil V, Niemi TT, Varpula M, Kuitunen AH.

Thromboelastometry in patients with severe sepsis and disseminated

intravascular coagulation.Blood Coagul Fibrinolysis. Sep 2009;20(6):41926. [Medline].

36. Sawamura A,

Hayakawa M, Gando S, Kubota N, Sugano M, Wada T, et al.

Application of the Japanese Association for Acute Medicine disseminated
intravascular coagulation diagnostic criteria for patients at an early phase of
trauma. Thromb Res. Dec 2009;124(6):706-10. [Medline].

37. Zhu YJ,

Huang XK. Relationship between disseminated intravascular

coagulation and levels of plasma thrombinogen segment 1+2, D-dimer, and
thrombomodulin in patients with multiple injuries. Chin J Traumatol. Aug
2009;12(4):203-9. [Medline].

38. Duchesne JC,

Islam TM, Stuke L, Timmer JR, Barbeau JM, Marr AB, et al.
Hemostatic resuscitation during surgery improves survival in patients with
traumatic-induced coagulopathy. J Trauma. Jul 2009;67(1):33-7; discussion
37-9. [Medline].

39. Siegal T, Seligsohn

U, Aghai E, Modan M. Clinical and laboratory aspects

of disseminated intravascular coagulation (DIC): a study of 118
cases. Thromb Haemost. Feb 28 1978;39(1):122-34. [Medline].

40. Wada

H, Mori Y, Shimura M, Hiyoyama K, Ioka M, Nakasaki T, et al. Poor

outcome in disseminated intravascular coagulation or thrombotic
thrombocytopenic purpura patients with severe vascular endothelial cell
injuries. Am J Hematol. Jul 1998;58(3):189-94. [Medline].

41. Takashima A,

Shirao K, Hirashima Y, Takahari D, Okita NT, Nakajima TE,

et al. Sequential chemotherapy with methotrexate and 5-fluorouracil for
chemotherapy-naive advanced gastric cancer with disseminated
intravascular coagulation at initial diagnosis. J Cancer Res Clin Oncol. Feb
2010;136(2):243-8. [Medline].

42. Bick

RL. Disseminated intravascular coagulation: objective clinical and

laboratory diagnosis, treatment, and assessment of therapeutic
response. Semin Thromb Hemost. 1996;22(1):69-88. [Medline].

43. Horan

JT, Francis CW. Fibrin degradation products, fibrin monomer and

soluble fibrin in disseminated intravascular coagulation. Semin Thromb
Hemost. Dec 2001;27(6):657-66. [Medline].

44. Leung

L. Clinical features, diagnosis, and treatment of disseminated

intravascular coagulation in adults. UpToDate [serial online]. Available at .
Available at http://www.utdol.com.

45. Spero

JA, Lewis JH, Hasiba U. Disseminated intravascular coagulation.

Findings in 346 patients. Thromb Haemost. Feb 29 1980;43(1):2833. [Medline].

46. Olson

JD, Kaufman HH, Moake J, O'Gorman TW, Hoots K, Wagner K, et

al. The incidence and significance of hemostatic abnormalities in patients
with head injuries. Neurosurgery. Jun 1989;24(6):825-32. [Medline].

47. Conway

EM, Rosenberg RD. Tumor necrosis factor suppresses transcription

of the thrombomodulin gene in endothelial cells. Mol Cell Biol. Dec
1988;8(12):5588-92. [Medline]. [Full Text].

48. Faust

SN, Levin M, Harrison OB, Goldin RD, Lockhart MS, Kondaveeti S,

et al. Dysfunction of endothelial protein C activation in severe
meningococcal sepsis. N Engl J Med. Aug 9 2001;345(6):408-16. [Medline].

49. Downey

C, Kazmi R, Toh CH. Novel and diagnostically applicable

information from optical waveform analysis of blood coagulation in
disseminated intravascular coagulation. Br J Haematol. Jul 1997;98(1):6873. [Medline].

50. Dempfle

CE. The use of soluble fibrin in evaluating the acute and chronic
hypercoagulable state. Thromb Haemost. Aug 1999;82(2):67383. [Medline].

51. Levi

M, de Jonge E, van der Poll T, ten Cate H. Disseminated intravascular

coagulation. Thromb Haemost. Aug 1999;82(2):695-705. [Medline].

52. Carr

JM, McKinney M, McDonagh J. Diagnosis of disseminated

intravascular coagulation. Role of D-dimer. Am J Clin Pathol. Mar
1989;91(3):280-7.[Medline].

53. Levi

M, Meijers JC. DIC: which laboratory tests are most useful. Blood Rev.
Jan 2011;25(1):33-7. [Medline].

54. Lin

SM, Wang YM, Lin HC, Lee KY, Huang CD, Liu CY, et al. Serum
thrombomodulin level relates to the clinical course of disseminated
intravascular coagulation, multiorgan dysfunction syndrome, and mortality
in patients with sepsis. Crit Care Med. Mar 2008;36(3):683-9. [Medline].

55. Bakhtiari

K, Meijers JC, de Jonge E, Levi M. Prospective validation of the

International Society of Thrombosis and Haemostasis scoring system for
disseminated intravascular coagulation. Crit Care Med. Dec
2004;32(12):2416-21. [Medline].

56. Gando

S, Saitoh D, Ogura H, Mayumi T, Koseki K, Ikeda T, et al. 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. Jan 2008;36(1):14550. [Medline].

57. Levi

M, Opal SM. Coagulation abnormalities in critically ill patients. Crit

Care. 2006;10(4):222. [Medline]. [Full Text].

58. Alving

B, Spivak J, Deloughery T. Consultative hematology: Hemostasis

and transfusion issues in surgery and critical care medicine. Hematology.
1998;320-42.

59. Wada

H, Asakura H, Okamoto K, Iba T, Uchiyama T, Kawasugi K, et al.

Expert consensus for the treatment of disseminated intravascular coagulation
in Japan. Thromb Res. Jan 2010;125(1):6-11. [Medline].

60. Pernerstorfer T, Jilma

B, Eichler HG, Aull S, Handler S, Speiser W. Heparin

lowers plasma levels of activated factor VII. Br J Haematol. Jun
1999;105(4):1127-9. [Medline].

61. Feinstein

DI. Diagnosis and management of disseminated intravascular

coagulation: the role of heparin therapy. Blood. Aug 1982;60(2):2847. [Medline].

62. Sakuragawa

N, Hasegawa H, Maki M, Nakagawa M, Nakashima M.

Clinical evaluation of low-molecular-weight heparin (FR-860) on
disseminated intravascular coagulation (DIC)--a multicenter co-operative
double-blind trial in comparison with heparin. Thromb Res. Dec 15
1993;72(6):475-500.[Medline].

63. Pernerstorfer T, Hollenstein

U, Hansen J, Knechtelsdorfer M, Stohlawetz P,

Graninger W, et al. Heparin blunts endotoxin-induced coagulation
activation.Circulation. Dec 21-28 1999;100(25):2485-90. [Medline].

64. Majumdar

G. Idiopathic chronic DIC controlled with low-molecular-weight

heparin. Blood Coagul Fibrinolysis. Jan 1996;7(1):97-8. [Medline].

65. Levi

M, Levy M, Williams MD, Douglas I, Artigas A, Antonelli M, et al.

Prophylactic heparin in patients with severe sepsis treated with drotrecogin
alfa (activated). Am J Respir Crit Care Med. Sep 1 2007;176(5):48390. [Medline].

66. Baudo

F, Caimi TM, de Cataldo F, Ravizza A, Arlati S, Casella G, et al.

Antithrombin III (ATIII) replacement therapy in patients with sepsis and/or
postsurgical complications: a controlled double-blind, randomized,
multicenter study. Intensive Care Med. Apr 1998;24(4):336-42. [Medline].

67. Fourrier F, Jourdain

M, Tournoys A. Clinical trial results with antithrombin

III in sepsis. Crit Care Med. Sep 2000;28(9 Suppl):S38-43. [Medline].

68. Eisele

B, Lamy M, Thijs LG, Keinecke HO, Schuster HP, Matthias FR, et al.
Antithrombin III in patients with severe sepsis. A randomized, placebocontrolled, double-blind multicenter trial plus a meta-analysis on all

randomized, placebo-controlled, double-blind trials with antithrombin III in

severe sepsis. Intensive Care Med. Jul 1998;24(7):663-72. [Medline].
69. Sawamura A,

Gando S, Hayakawa M, Hoshino H, Kubota N, Sugano M.

Effects of antithrombin III in patients with disseminated intravascular
coagulation diagnosed by newly developed diagnostic criteria for critical
illness. Clin Appl Thromb Hemost. Oct 2009;15(5):561-6. [Medline].

70. Dhainaut

JF, Laterre PF, Janes JM, Bernard GR, Artigas A, Bakker J, et al.
Drotrecogin alfa (activated) in the treatment of severe sepsis patients with
multiple-organ dysfunction: data from the PROWESS trial. Intensive Care
Med. Jun 2003;29(6):894-903. [Medline].

71. Vincent

JL, Angus DC, Artigas A, Kalil A, Basson BR, Jamal HH, et al.
Effects of drotrecogin alfa (activated) on organ dysfunction in the
PROWESS trial. Crit Care Med. Mar 2003;31(3):834-40. [Medline].

72. Vincent

JL, Bernard GR, Beale R, Doig C, Putensen C, Dhainaut JF, et al.

Drotrecogin alfa (activated) treatment in severe sepsis from the global openlabel trial ENHANCE: further evidence for survival and safety and
implications for early treatment. Crit Care Med. Oct 2005;33(10):226677. [Medline].

73. Dhainaut

JF, Yan SB, Joyce DE, Pettil V, Basson B, Brandt JT, et al.
Treatment effects of drotrecogin alfa (activated) in patients with severe
sepsis with or without overt disseminated intravascular coagulation. J
Thromb Haemost. Nov 2004;2(11):1924-33. [Medline].

74. [Best

Evidence] Abraham E, Laterre PF, Garg R, Levy H, Talwar D,

Trzaskoma BL, et al. Drotrecogin alfa (activated) for adults with severe
sepsis and a low risk of death. N Engl J Med. Sep 29 2005;353(13):133241. [Medline].

75. Baratto

F, Michielan F, Meroni M, Dal Pal A, Boscolo A, Ori C. Protein C

concentrate to restore physiological values in adult septic patients. Intensive
Care Med. Sep 2008;34(9):1707-12. [Medline].

76. Abraham E.

Tissue factor inhibition and clinical trial results of tissue factor

pathway inhibitor in sepsis. Crit Care Med. Sep 2000;28(9 Suppl):S31-3.
[Medline].

77. Abraham E,

Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez AL, et al.

Efficacy and safety of tifacogin (recombinant tissue factor pathway
inhibitor) in severe sepsis: a randomized controlled trial. JAMA. Jul 9
2003;290(2):238-47. [Medline].

78. Yamakawa

K, Fujimi S, Mohri T, Matsuda H, Nakamori Y, Hirose T, et al.

Treatment effects of recombinant human soluble thrombomodulin in

patients with severe sepsis: a historical control study. Crit Care.

2011;15(3):R123. [Medline]. [Full Text].
79. Saito

H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Ohno R, et al.

Efficacy and safety of recombinant human soluble thrombomodulin (ART123) in disseminated intravascular coagulation: results of a phase III,
randomized, double-blind clinical trial. J Thromb Haemost. Jan
2007;5(1):31-41.[Medline].

80. Levi

M. Current understanding of disseminated intravascular

coagulation. Br J Haematol. Mar 2004;124(5):567-76. [Medline].

81. Norman

KE, Cotter MJ, Stewart JB, Abbitt KB, Ali M, Wagner BE, et al.
Combined anticoagulant and antiselectin treatments prevent lethal
intravascular coagulation. Blood. Feb 1 2003;101(3):921-8. [Medline].

82. Pajkrt

D, van der Poll T, Levi M, Cutler DL, Affrime MB, van den Ende A,
et al. Interleukin-10 inhibits activation of coagulation and fibrinolysis during
human endotoxemia. Blood. Apr 15 1997;89(8):2701-5. [Medline].

83. Branger

J, van den Blink B, Weijer S, Gupta A, van Deventer SJ, Hack CE,
et al. Inhibition of coagulation, fibrinolysis, and endothelial cell activation
by a p38 mitogen-activated protein kinase inhibitor during human
endotoxemia. Blood. Jun 1 2003;101(11):4446-8. [Medline].

Diagnostic 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 Coagulation

Type
Infectious

Cause
Bacterial (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)

Malignancy

Hematologic (eg, acute myelocytic leukemia)

Metastatic (eg, mucin-secreting adenocarcinoma)

Obstetric

Placental abruption

Amniotic fluid embolism

Acute fatty liver of pregnancy

Eclampsia

Trauma

Burns

Motor vehicle accidents

Snake envenomation

Transfusion

Hemolytic reactions

Transfusion

Other

Liver 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 Coagulation

Type
Malignancies Solid tumors

Cause

Leukemia

Obstetric

Retained dead fetus syndrome

Retained products of conception

Hematologic
Vascular

Myeloproliferative syndromes
Rheumatoid arthritis

Raynaud disease

Cardiovascular Myocardial infarction

Inflammatory Ulcerative colitis

Crohn disease

Sarcoidosis

Localized DIC Aortic aneurysms

Giant hemangioma (Kasabach-Merritt syndrome)

Acute renal allograft rejection

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

Patients
Features

Affected Patients, %
Bleeding
64%
Renal dysfunction
25%
Hepatic dysfunction
19%
Respiratory dysfunction
16%
Shock
14%
Central nervous system dysfunction 2%

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

Score

SIRS criteria

>3
0-2
Platelet count ( 109/L)
< 80 or >50 % decrease within 24 hours
>80 and < 120 or >30% decrease within 24 hours
>120
Prothrombin time (value of patient/normal value)
>1.2
< 1.2
Fibrin/FDPs (mg/L)
>25
>10 and < 25
< 10
Diagnosis

1
0
3
1
0
1
0
3
1
0
DIC

4 points or more

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.

View Table List

Read more about Disseminated Intravascular Coagulation on Medscape
Related Reference Topics

Purpura Fulminans

Consumption
Coagulopathy

Related News and Articles

Evaluation of the International Society on Thrombosis

and Haemostasis and Institutional Diagnostic Criteria
of Disseminated Intravascular Coagulation in Pediatric
Patients

Fibrin and FibrinogenDegradation Products

A Randomized, Double-Blind, Placebo-Controlled,

Phase 2b Study to Evaluate the Safety and Efficacy of
Recombinant Human Soluble Thrombomodulin, ART123, in Patients With Sepsis and Suspected
Disseminated Intravascular Coagulation

FDA Clears Tretten for Coagulation Factor XIII

Deficiency

Medscape Reference 2011 WebMD, LLC

About Medscape

Privacy Policy

Terms of Use

WebMD

MedicineNet

eMedicineHealth

RxList

WebMD Corporate

Help

All material on this website is protected by copyright, Copyright 1994-2014 by

WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site
is designed primarily for use by qualified physicians and other medical
professionals. The information contained herein should NOT be used as a
substitute for the advice of an appropriately qualified and licensed physician or
other health care provider. The information provided here is for educational and
informational purposes only. In no way should it be considered as offering medical
advice. Please check with a physician if you suspect you are ill.

Close