The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

Current Concepts
Systemic activation+
of coagulation

D ISSEMINATED I NTRAVASCULAR
C OAGULATION Intravascular+ Depletion of platelets+
deposition of fibrin and coagulation factors
MARCEL LEVI, M.D., AND HUGO TEN CATE, M.D.

Thrombosis of small+ Bleeding

and midsize vessels+

D
ISSEMINATED intravascular coagulation is and organ failure
characterized by the widespread activation
of coagulation, which results in the intravas- Figure 1. The Mechanism of Disseminated Intravascular Coag-
cular formation of fibrin and ultimately thrombotic ulation.
occlusion of small and midsize vessels.1-3 Intravascu- Systemic activation of coagulation leads to widespread intra-
vascular deposition of fibrin and depletion of platelets and co-
lar coagulation can also compromise the blood sup- agulation factors. As a result, thrombosis of small and midsize
ply to organs and, in conjunction with hemodynam- vessels may occur, contributing to organ failure, and there may
ic and metabolic derangements, may contribute to be severe bleeding.
the failure of multiple organs. At the same time, the
use and subsequent depletion of platelets and coag-
ulation proteins resulting from the ongoing coagu-
lation may induce severe bleeding (Fig. 1). Bleeding
may be the presenting symptom in a patient with
disseminated intravascular coagulation, a factor that
TABLE 1. COMMON CLINICAL CONDITIONS
can complicate decisions about treatment. ASSOCIATED WITH DISSEMINATED
INTRAVASCULAR COAGULATION.
ASSOCIATED CLINICAL CONDITIONS
AND INCIDENCE Sepsis
Infectious Disease Trauma
Serious tissue injury
Disseminated intravascular coagulation is an ac- Head injury
Fat embolism
quired disorder that occurs in a wide variety of clin- Cancer
ical conditions, the most important of which are listed Myeloproliferative diseases
in Table 1. Infectious disease, in particular septicemia, Solid tumors (e.g., pancreatic carcinoma, prostatic
carcinoma)
is the most common clinical condition associated Obstetrical complications
with disseminated intravascular coagulation. Although Amniotic-fluid embolism
virtually all microorganisms can cause disseminated Abruptio placentae
Vascular disorders
intravascular coagulation, bacterial infection is most Giant hemangioma (Kasabach–Merritt syndrome)
frequently related to the development of the syn- Aortic aneurysm
Reactions to toxins (e.g., snake venom, drugs, am-
drome. Clinically overt disseminated intravascular co- phetamines)
agulation may occur in 30 to 50 percent of patients Immunologic disorders
with gram-negative sepsis.4-6 Contrary to widely held Severe allergic reaction
Hemolytic transfusion reaction
belief, clinically overt disseminated intravascular co- Transplant rejection
agulation appears to be as common in patients with
gram-positive sepsis as in those with gram-negative
sepsis.7 Triggers of the activation of diffuse coagula-

tion in patients with infections are cell-specific mem-

brane components of the microorganism, such as
From the Department of Vascular Medicine and Internal Medicine, Ac- lipopolysaccharide or endotoxin, or bacterial exo-
ademic Medical Center, University of Amsterdam (M.L., H.C.), and the De-
partment of Internal Medicine, Slotervaart Hospital (H.C.) — both in Am- toxins (e.g., staphylococcal a hemolysin). All these
sterdam. Address reprint requests to Dr. Levi at the Department of Vascular components may induce a generalized inflammatory
Medicine and Internal Medicine, Academic Medical Centre F-4, Meiberg-
dreef 9, 1105 AZ Amsterdam, the Netherlands, or at [email protected].
response, characterized by the activation of the cy-
©1999, Massachusetts Medical Society. tokine network.

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 CURR ENT CONC EP TS

Severe Trauma Giant Hemangiomas

Another clinical condition frequently associated Giant hemangiomas (the Kasabach–Merritt syn-
with disseminated intravascular coagulation is severe drome) and even large aortic aneurysms may result
trauma, particularly to the brain.1,6,8 A combination in local activation of coagulation.17,18 In patients with
of mechanisms, including the release of fat and phos- these conditions, local activation of coagulation most
pholipids from tissue into the circulation, hemolysis, commonly results in the systemic depletion of local-
and endothelial damage, may promote the systemic ly consumed coagulation factors and platelets, but
activation of coagulation. In addition, there is emerg- activated coagulation factors can reach the systemic
ing evidence that cytokines have a pivotal role in the circulation and cause disseminated intravascular co-
development of disseminated intravascular coagu- agulation. The incidence of clinically overt dissemi-
lation, since the systemic activation patterns of cy- nated intravascular coagulation is 25 percent among
tokines are virtually identical in patients with poly- patients with giant hemangiomas, whereas the inci-
trauma and patients with sepsis.9,10 The incidence of dence is approximately 0.5 to 1 percent among pa-
disseminated intravascular coagulation among patients tients with large aortic aneurysms.18,19
with severe trauma who have a systemic inflammato-
ry response syndrome as a consequence is 50 to 70 Microangiopathic Hemolytic Anemia
percent.6,9 Microangiopathic hemolytic anemias comprise
thrombocytopenic thrombotic purpura, the hemolyt-
Cancer ic–uremic syndrome, chemotherapy-induced micro-
Both solid tumors and hematologic cancers may angiopathic hemolytic anemia, malignant hyperten-
be complicated by disseminated intravascular coagu- sion, and the HELLP syndrome (hemolysis, elevated
lation. Ten to 15 percent of patients with metasta- liver-enzyme levels, and a low platelet count occur-
sized tumors have evidence of disseminated intravas- ring in association with preeclampsia).20 Although
cular coagulation, and the condition is present in some characteristics of microangiopathic hemolytic
approximately 15 percent of patients with acute leu- anemias and the resulting thrombotic occlusion of
kemia.11,12 The mechanism of the derangement of small and midsize vessels may mimic the clinical pic-
the coagulation system in patients with cancer is not ture of disseminated intravascular coagulation, these
clear. However, a number of studies indicate that tis- disorders are a distinct group of diseases. The com-
sue factor, which is expressed on the surface of tumor mon feature of the microangiopathic hemolytic ane-
cells, is involved.13 A distinct form of disseminated mias appears to be endothelial damage, which causes
intravascular coagulation is frequently encountered the adhesion and aggregation of platelets, the forma-
in patients with acute promyelocytic leukemia, which tion of thrombin, and the impairment of fibrinolysis.
is characterized by a severe hyperfibrinolytic state In patients with thrombocytopenic thrombotic pur-
in addition to an activated coagulation system. Al- pura and the hemolytic–uremic syndrome, the ac-
though bleeding is the most common clinical fea- quired deficiency of a protease that cleaves multimers
ture, disseminated thrombosis is found in some pa- of von Willebrand factor leads to the accumulation
tients at autopsy.14 Treatment with all-trans-retinoic of large multimers of this factor.21 A cardinal sign of
acid, however, has drastically reduced the incidence microangiopathic hemolytic anemia is the presence
of severe disseminated intravascular coagulation in of fragmented red cells (schistocytes) in the blood
patients with acute promyelocytic leukemia. smear. Although hemolytic anemia and schistocytes
are also sometimes present in patients with severe
Obstetrical Disorders disseminated intravascular coagulation (because of
Disseminated intravascular coagulation is a classic the presence of intravascular fibrin), these are invari-
complication of obstetrical conditions, such as abrup- able findings in patients with microangiopathic hemo-
tio placentae and amniotic-fluid embolism, occur- lytic anemia.
ring in more than 50 percent of patients with these
conditions.15 Leakage of thromboplastin-like material CLINICAL RELEVANCE AND PROGNOSIS
is likely to cause the systemic activation of coagula- The contribution of disseminated intravascular co-
tion, since amniotic fluid is a potent activator of co- agulation to morbidity and the risk of mortality var-
agulation in vitro and since the degree of placental ies depending on the underlying clinical condition
separation correlates with the extent of disseminated and the intensity of the coagulation disorder. Ob-
intravascular coagulation. Although these obstetrical viously, the seriousness of a severe depletion of
conditions may cause fulminant disseminated intra- platelets and coagulation factors in patients with dif-
vascular coagulation, the disorder is usually short-lived fuse and ongoing bleeding or in patients at high risk
and self-limiting. Preeclampsia can also be compli- for bleeding (e.g., patients recovering from surgery)
cated by disseminated intravascular coagulation, which is indisputable. In addition, several lines of evidence
occurred in 7 percent of consecutive patients with indicate that disseminated intravascular coagulation
severe preeclampsia in one study.16 increases the risk of organ failure and death. First,

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

histologic studies have shown that signs of ischemia Defects in Inhibitors of Coagulation
and necrosis are related to the deposition of fibrin in All major physiologic anticoagulants — antithrom-
the vasculature of organs in patients with dissemi- bin III, protein C, and tissue factor–pathway inhib-
nated intravascular coagulation.22 Second, the amel- itor — appear to be affected in patients with dissem-
ioration of experimentally induced disseminated in- inated intravascular coagulation. Plasma levels of
travascular coagulation in animals decreases the risk antithrombin III, the most important inhibitor of
of organ failure and, in some cases, death.23,24 In a thrombin, are markedly reduced as a result of the
large number of clinical studies, the occurrence of dis- ongoing coagulation, degradation by elastase released
seminated intravascular coagulation appeared to be from activated neutrophils, and impaired synthesis of
associated with an unfavorable outcome and was an antithrombin III.24,32
independent predictor of mortality. Prospective clin- A marked impairment of the protein-C system
ical studies have shown that the development of dis- may further compromise the regulation of activated
seminated intravascular coagulation in patients with coagulation. This reduction in the activity of the
sepsis or severe trauma roughly doubles the risk of protein-C system is caused by a combination of im-
death.6,10,25 In spite of the apparent association be- paired protein synthesis, a cytokine-mediated decrease
tween disseminated intravascular coagulation and the in the activity of endothelial thrombomodulin, and
risk of death, however, it remains uncertain to what a decline in the level of the free fraction of protein S
extent intravascular fibrin or coagulation proteases are (the essential cofactor of protein C).33,34
the critical factors in determining the clinical course, Tissue factor, the trigger of coagulation in dissem-
rather than just the consequences of a more severe inated intravascular coagulation, is inhibited by tis-
systemic inflammatory response. sue factor–pathway inhibitor. Although no acquired
PATHOGENESIS
deficiency or functional defect of tissue factor–path-
way inhibitor has been identified in patients with
Recent studies in patients with disseminated intra- disseminated intravascular coagulation, there is evi-
vascular coagulation and in animal models have large- dence that the inhibitor does not regulate tissue fac-
ly clarified the pathogenetic pathways of the disor- tor activity sufficiently in such patients.23
der. The systemic formation of fibrin results from
increased generation of thrombin, the simultaneous Fibrinolytic Defect
suppression of physiologic anticoagulation mecha- Studies in animal models of disseminated intravas-
nisms, and the delayed removal of fibrin as a conse- cular coagulation indicate that the fibrinolytic system
quence of impaired fibrinolysis (Fig. 2). is largely suppressed at the time of maximal activa-
As is true for almost all systemic inflammatory re- tion of coagulation. This inhibition is caused by a
sponses, the derangement of coagulation and fibri- sustained increase in the plasma level of plasminogen-
nolysis in disseminated intravascular coagulation is activator inhibitor type 1, the principal inhibitor of
mediated by several proinflammatory cytokines.26,27 the fibrinolytic system.28,35 Clinical studies have con-
The principal mediator of the activation of coagula- firmed that suppression of fibrinolysis is mediated
tion appears to be interleukin-6. Tumor necrosis fac- by plasminogen-activator inhibitor type 1 and show
tor a indirectly influences the activation of coagula- that although there is some fibrinolytic activity in re-
tion because of its effects on interleukin-6, and it is sponse to the formation of fibrin, the level of this ac-
the pivotal mediator of the dysregulation of the tivity is too low to counteract the systemic deposi-
physiologic anticoagulation pathways and the fibri- tion of fibrin.6,10,36
nolytic defect.
DIAGNOSIS
Generation of Thrombin There is no single laboratory test that can estab-
Systemic generation of thrombin in animal models lish or rule out the diagnosis of disseminated intra-
of disseminated intravascular coagulation was shown vascular coagulation. However, a combination of test
to be mediated exclusively by the extrinsic pathway results in a patient with a clinical condition known
involving tissue factor and activated factor VIIa. In- to be associated with disseminated intravascular co-
hibition of tissue factor or factor VIIa totally sup- agulation can be used to diagnose the disorder with
pressed the endotoxin-induced generation of throm- reasonable certainty in most cases.37 In clinical prac-
bin, whereas interference in the intrinsic pathway of tice the disorder can be diagnosed on the basis of the
coagulation did not affect the activation of coagula- following findings: an underlying disease known to
tion.28-30 The exact source of tissue factor is not always be associated with disseminated intravascular coagu-
clear. Tissue factor may be expressed on mononuclear lation; an initial platelet count of less than 100,000
cells in response to proinflammatory cytokines,31 but per cubic millimeter or a rapid decline in the platelet
the role of the expression of tissue factor on vascular count; prolongation of clotting times, such as the
endothelial cells in disseminated intravascular coag- prothrombin time and the activated partial-throm-
ulation remains to be elucidated. boplastin time; the presence of fibrin-degradation

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 C URR ENT CONC EP TS

Tissue factor+
+ factor VIIa

Cytokines

Factor IXa+ Factor Xa+

(+ factor VIII) (+ factor V) Plasminogen

Plasminogen+
activators X
Factor IIa+ Low levels of antithrombin III
(thrombin) PAI-1 Plasmin
Impaired function of+
protein-C system
Fibrinogen Fibrin Insufficient TFPI Fibrin FDPs

Impairment of+
Generation of thrombin+ anticoagulation+ Suppression of+
mediated by tissue factor pathways fibrinolysis by PAI-1

Formation+ Inadequate removal+

of fibrin of fibrin

Thrombosis of small+
and midsize vessels
Figure 2. Pathogenetic Pathways Involved in Disseminated Intravascular Coagulation.
In patients with disseminated intravascular coagulation, fibrin is formed as a result of the generation of thrombin mediated by tissue
factor. Tissue factor, expressed on the surface of activated mononuclear cells and endothelial cells, binds and activates factor VII.
The complex of tissue factor and factor VIIa can activate factor X directly (black arrows) or indirectly (white arrows) by means of
activated factor IX and factor VIII. Activated factor X, in combination with factor V, can convert prothrombin (factor II) to thrombin
(factor IIa). Simultaneously, all three physiologic means of anticoagulation — antithrombin III, protein C, and tissue factor–pathway
inhibitor (TFPI) — are impaired. The resulting intravascular formation of fibrin is not balanced by adequate removal of fibrin because
endogenous fibrinolysis is suppressed by high plasma levels of plasminogen-activator inhibitor type 1 (PAI-1). The high levels of
PAI-1 inhibit plasminogen-activator activity and consequently reduce the rate of formation of plasmin. The combination of increased
formation of fibrin and inadequate removal of fibrin results in disseminated intravascular thrombosis. FDPs denotes fibrin-degra-
dation products.

products in plasma; and low plasma levels of coagu- ant. In fact, clinical studies have shown that a finding
lation inhibitors, such as antithrombin III. of hypofibrinogenemia is useful diagnostically only in
A low initial platelet count and, particularly, a very severe cases of disseminated intravascular coag-
progressive drop in the platelet count are sensitive, ulation. Measurement of selected inhibitors of coag-
though not specific, signs of disseminated intravas- ulation, including antithrombin III or protein C, may
cular coagulation and may indicate ongoing throm- provide useful prognostic information.25,32 Tests for
bin-induced activation and use of platelets. Pro- fibrin-degradation products or D-dimers may be help-
longed clotting times may reflect the depletion of ful to differentiate disseminated intravascular coagu-
coagulation factors, a possibility that can be substan- lation from other conditions that are associated with
tiated by the measurement of one or two selected a low platelet count or prolonged clotting times.38
coagulation factors. Measurements of plasma coagu- It may be difficult to differentiate between severe
lation factors may reveal other coagulation abnormal- liver disease and disseminated intravascular coagula-
ities, such as a deficiency of vitamin K. tion, since the two disorders have the same character-
Measurement of plasma fibrinogen has often been istic laboratory abnormalities. Circumstantial findings
advocated, but plasma fibrinogen levels may remain such as portal hypertension, which is indicative of
in the normal range despite considerable coagulation liver disease, or an underlying condition known to be
activity, because this protein is an acute-phase react- associated with disseminated intravascular coagula-

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

A B

Figure 3. Blood Smear (Panel A) and Kidney-Biopsy Specimen (Panel B) from a Patient with Disseminated Intravascular
Coagulation.
In Panel A, the arrows indicate typical fragmented red cells (schistocytes). In Panel B, intravascular fibrin is present in
a small arteriole (arrow). Courtesy of Jan J. Weening, M.D., Amsterdam. (Panel A: hematoxylin and eosin, ¬500; Panel B:
Jones methenamine silver, ¬300.)

tion may help in differentiating the two disorders. underlying cause is predestined to fail. Supportive
Also, the coagulation abnormalities resulting from measures may be necessary, although firm evidence
uncomplicated liver disease usually tend to be stable on which to base management is scarce, and there is
rather than to worsen progressively. In patients with no consensus regarding the optimal treatment or sup-
disseminated intravascular coagulation, the blood portive strategy. A patient with disseminated intra-
smear may contain schistocytes, and histologic analy- vascular coagulation who has diffuse bleeding from
sis of organ-biopsy tissue may reveal the deposition various sites at presentation will need different sup-
of fibrin in small or midsize vessels (Fig. 3). portive treatment from what is appropriate for a pa-
More specialized, but not generally available, lab- tient with thrombotic obstruction of the vasculature
oratory tests that are useful in the diagnosis of dis- and subsequent multiorgan failure.
seminated intravascular coagulation include the meas-
Anticoagulants
urement of soluble fibrin and sensitive assays that
can measure the generation of thrombin, such as as- Theoretically, interruption of coagulation should
says for the detection of prothrombin activation frag- be of benefit in patients with disseminated intravas-
ment F1+2 or thrombin–antithrombin complexes.39,40 cular coagulation. Indeed, experimental studies have
The sensitivity and specificity of these assays for the shown that heparin can partially inhibit the activa-
diagnosis of disseminated intravascular coagulation tion of coagulation in cases that are related to sepsis
range from 80 to 90 percent, but although they may or other causes. Adequate prophylaxis is also needed
be helpful in complicated clinical situations, they are to eliminate the risk of venous thromboembolism.
usually not essential in general clinical practice. Heparin has been shown to have a beneficial effect
in small, uncontrolled studies of patients with dissem-
MANAGEMENT inated intravascular coagulation, but not in controlled
The cornerstone of the management of dissemi- clinical trials.41,42 Although the safety of heparin in
nated intravascular coagulation is the treatment of patients with disseminated intravascular coagulation
the underlying disorder. Treatment of disseminated who are prone to bleeding has often been debated,
intravascular coagulation without treatment of the clinical studies have not shown that treatment with

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 C URR ENT CONC EP TS

heparin significantly increased the incidence of bleed- intravascular coagulation and sometimes improvement
ing complications. Taken together, these findings sug- in organ function.45-47 In the more recent trials, very
gest that treatment with heparin is probably useful high doses of antithrombin III concentrate were used
in patients with disseminated intravascular coagula- (up to 150 percent of normal), and the favorable ef-
tion, particularly those with clinically overt thrombo- fect in these trials seems to be more distinct. Some
embolism or extensive deposition of fibrin, as occurs trials showed a modest reduction in mortality in pa-
with purpura fulminans or acral ischemia. Patients tients treated with antithrombin III, but this effect
with disseminated intravascular coagulation are usual- did not reach statistical significance.
ly given relatively low doses of heparin (300 to 500 U A meta-analysis of the trials with adequate study
per hour) as a continuous infusion. Low-molecular- methods showed a reduction in mortality from 56
weight heparin may also be used as an alternative to percent to 44 percent (odds ratio for death, 0.63; 95
unfractionated heparin.43 percent confidence interval, 0.39 to 1.0).48 At present,
Novel, antithrombin III–independent inhibitors a large randomized, controlled multicenter trial with
of thrombin, such as desirudin and related com- supraphysiological dosing of antithrombin III in pa-
pounds, might be more effective than heparin, and tients with sepsis is being conducted and the outcome
experimental studies have had promising results. of this trial will help determine the place of antithrom-
However, there have not yet been any controlled bin III treatment in sepsis and disseminated intravas-
clinical trials of these drugs in patients with dissem- cular coagulation. In the meantime, antithrombin III
inated intravascular coagulation, and the relatively treatment may be considered as a supportive thera-
high risk of bleeding associated with the use of these peutic option in patients with severe disseminated
compounds may be a limiting factor. intravascular coagulation, although the substantial
costs of this treatment may be a limiting factor.
Platelets and Plasma
Low levels of platelets and coagulation factors may Antifibrinolytic Agents
cause serious bleeding or may increase the risk of Antifibrinolytic treatment is effective in patients
bleeding in patients who require an invasive proce- with bleeding, but the use of these agents in patients
dure. In such patients, the efficacy of treatment with with disseminated intravascular coagulation is gener-
platelet concentrate and plasma has clearly been ally not recommended. Since the deposition of fibrin
shown.11,44 There is no evidence to support the use in this disorder appears to be due in part to insuffi-
of prophylactic administration of platelets or plasma cient fibrinolysis, further inhibition of the fibrinolytic
to patients with disseminated intravascular coagula- system would not seem to be appropriate. A clear
tion who are not bleeding and who are not at high exception might be made in the case of patients with
risk for bleeding. It may be necessary to administer primary or secondary hyperfibrinolysis, such as those
large volumes of plasma (up to 6 units per 24 hours) with the coagulopathy associated with acute promy-
to ameliorate or correct the coagulation defect. Treat- elocytic leukemia and some patients with dissemi-
ment with coagulation-factor concentrates may over- nated intravascular coagulation in association with
come the need for large infusions of plasma, but cancer. In such patients, antifibrinolytic treatment has
their use in patients with disseminated intravascular controlled the coagulopathy.49
coagulation is generally not advocated because the
concentrates may be contaminated with traces of ac- FUTURE THERAPEUTIC OPTIONS
tivated coagulation factors, which could exacerbate A logical therapeutic intervention would be direct-
the coagulation disorder. Also, these concentrates con- ed against tissue-factor activity. One such inhibitor,
tain only selected coagulation factors, whereas pa- recombinant nematode anticoagulant protein c2, a
tients with disseminated intravascular coagulation potent and specific inhibitor of the complex formed
usually have a deficiency of all coagulation factors. by tissue factor and factor VIIa with factor Xa, has
recently been developed and is currently being eval-
Concentrates of Coagulation Inhibitors uated in a clinical study.50 Administration of recom-
Restoration of physiologic pathways of anticoagu- binant tissue factor–pathway inhibitor may also block
lation might be an appropriate aim of therapy. Anti- tissue-factor activity in endotoxin-induced activation
thrombin III is one of the most important natural of coagulation (de Jonge E, et al.: unpublished data).
inhibitors of coagulation, and patients with dissem- This possibility is now being evaluated in clinical trials.
inated intravascular coagulation almost invariably have In view of the impairment of the protein-C system
an acquired deficiency of antithrombin. The admin- in patients with disseminated intravascular coagula-
istration of this inhibitor in supraphysiologic concen- tion, supplementation with (activated) protein C may
trations reduced sepsis-related mortality in animals.24 be beneficial,51 as was true in an animal model of the
Several controlled clinical trials, mostly in patients disorder.52 Adequately controlled clinical trials of
with sepsis or with septic shock, have shown benefi- protein-C concentrates are currently being initiated
cial effects in terms of improvement of disseminated or are under way.

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

Dr. Levi is an Investigator of the Royal Dutch Academy of Arts and Sci- 27. Levi M, van der Poll T, ten Cate H, van Deventer SJH. The cytokine-
ences. Dr. ten Cate is a Clinical Established Investigator of the Netherlands mediated imbalance between coagulant and anticoagulant mechanisms in
Heart Foundation. sepsis and endotoxemia. Eur J Clin Invest 1997;27:3-9.
28. Levi M, ten Cate H, Bauer KA, et al. Inhibition of endotoxin-induced
REFERENCES activation of coagulation and fibrinolysis by pentoxifylline or by a mono-
clonal anti-tissue factor antibody in chimpanzees. J Clin Invest 1994;93:
1. Marder VJ, Feinstein DI, Francis CW, Colman RW. Consumptive 114-20.
thrombohemorrhagic disorders. In: Colman RW, Hirsh J, Marder VJ, Salz- 29. Taylor FB Jr, Chang A, Ruf W, et al. Lethal E. coli septic shock is pre-
man EW, eds. Hemostasis and thrombosis: basic principles and clinical vented by blocking tissue factor with monoclonal antibody. Circ Shock
practice. 3rd ed. Philadelphia: J.B. Lippincott, 1994:1023-63. 1991;33:127-34.
2. Bone RC. Modulators of coagulation: a critical appraisal of their role in 30. Pixley RA, De La Cadena R, Page JD, et al. The contract system con-
sepsis. Arch Intern Med 1992;152:1381-9. tributes to hypotension but not disseminated intravascular coagulation in
3. Müller-Berghaus G, ten Cate H, Levi MM. Disseminated intravascular lethal bacteremia: in vivo use of a monoclonal anti-factor XII antibody to
coagulation. In: Verstraete M, Fuster V, Topol EJ, eds. Cardiovascular block contact activation in baboons. J Clin Invest 1993;92:61-8.
thrombosis: thrombocardiology and thromboneurology. 2nd ed. Philadel- 31. Østerud B, Flaegstad T. Increased tissue thromboplastin activity in
phia: Lippincott-Raven, 1998:781-801. monocytes of patients with meningococcal infection: related to an un-
4. Thijs LG, de Boer JP, de Groot MCM, Hack CE. Coagulation disorders favourable prognosis. Thromb Haemost 1983;49:5-7.
in septic shock. Intensive Care Med 1993;19:Suppl 1:S8-S15. 32. Mesters RM, Mannucci PM, Coppola R , Keller T, Ostermann H, Kie-
5. Baglin T. Disseminated intravascular coagulation: diagnosis and treat- nast J. Factor VIIa and antithrombin III activity during severe sepsis and
ment. BMJ 1996;312:683-7. septic shock in neutropenic patients. Blood 1996;88:881-6.
6. Gando S, Kameue T, Nanzaki S, Nakanishi Y. Disseminated intravascu- 33. Conway EM, Rosenberg RD. Tumor necrosis factor suppresses tran-
lar coagulation is a frequent complication of systemic inflammatory re- scription of the thrombomodulin gene in endothelial cells. Mol Cell Biol
sponse syndrome. Thromb Haemost 1996;75:224-8. 1988;8:5588-92.
7. Bone RC. Gram-positive organisms and sepsis. Arch Intern Med 1994; 34. Taylor FB, Chang A, Ferrell G, et al. C4b-binding protein exacerbates
154:26-34. the host response to Escherichia coli. Blood 1991;78:357-63.
8. Hulka F, Mullins RJ, Frank EH. Blunt brain injury activates the coagu- 35. Suffredini AF, Harpel PC, Parrillo JE. Promotion and subsequent in-
lation process. Arch Surg 1996;131:923-8. hibition of plasminogen activator after administration of intravenous endo-
9. Roumen RMH, Hendriks T, van der Ven-Jongekrijg J, et al. Cytokine toxin to normal subjects. N Engl J Med 1989;320:1165-72.
patterns in patients after major vascular surgery, hemorrhagic shock, and 36. Nossel HL. Relative proteolysis of the fibrinogen B beta chain by
severe blunt trauma: relation with subsequent adult respiratory distress syn- thrombin and plasmin as a determinant of thrombosis. Nature 1981;291:
drome and multiple organ failure. Ann Surg 1993;6:769-76. 165-7.
10. Gando S, Nakanishi Y, Tedo I. Cytokines and plasminogen activator 37. Bick RL. Disseminated intravascular coagulation: objective clinical and
inhibitor-1 in posttrauma disseminated intravascular coagulation: relation- laboratory diagnosis, treatment, and assessment of therapeutic response.
ship to multiple organ dysfunction syndrome. Crit Care Med 1995;23: Semin Thromb Hemost 1996;22:69-88.
1835-42. 38. Bick RL, Baker WF. Diagnostic efficacy of the D-dimer assay in dis-
11. Colman RW, Rubin RN. Disseminated intravascular coagulation due seminated intravascular coagulation (DIC). Thromb Res 1992;65:785-90.
to malignancy. Semin Oncol 1990;17:172-86. 39. Wada H, Wakita Y, Nakase T, et al. Increased plasma-soluble fibrin
12. Sarris AH, Kempin S, Berman E, et al. High incidence of disseminated monomer levels in patients with disseminated intravascular coagulation.
intravascular coagulation during remission induction of adult patients with Am J Hematol 1996;51:255-60.
acute lymphoblastic leukemia. Blood 1992;79:1305-10. 40. Bauer KA, Rosenberg RD. The pathophysiology of the prethrombotic
13. Contrino J, Hair G, Kreutzer DL, Rickles FR. In situ detection of ex- state in humans: insights gained from studies using markers of hemostatic
pression of tissue factor in vascular endothelial cells: correlation with the system activation. Blood 1987;70:343-50.
malignant phenotype of human breast disease. Nat Med 1996;2:209-15. 41. Corrigan JJ Jr. Heparin therapy in bacterial septicemia. J Pediatr 1977;
14. Falanga A, Consonni R , Marchetti M, et al. Cancer procoagulant and 91:695-700.
tissue factor are differently modulated by all-trans-retinoic acid in acute 42. Feinstein DI. Diagnosis and management of disseminated intravascular
promyelocytic leukemia cells. Blood 1998;92:143-51. coagulation: the role of heparin therapy. Blood 1982;60:284-7.
15. Weiner CP. The obstetric patient and disseminated intravascular coag- 43. Sakuragawa N, Hasegawa H, Maki M, Nakagawa M, Nakashima M.
ulation. Clin Perinatol 1986;13:705-17. Clinical evaluation of low-molecular-weight heparin (FR-860) on dissemi-
16. Sibai BM, Spinnato JA, Watson DL, Hill GA, Anderson GD. Pregnancy nated intravascular coagulation (DIC) — a multicenter co-operative double-
outcome in 303 cases with severe preeclampsia. Obstet Gynecol 1984;64: blind trial in comparison with heparin. Thromb Res 1993;72:475-500.
319-25. 44. Feinstein DI. Treatment of disseminated intravascular coagulation.
17. Szlachetka DM. Kasabach-Merritt syndrome: a case review. Neonatal Semin Thromb Hemost 1988;14:351-62.
Netw 1998;17(1):7-15. [Erratum, Neonatal Netw 1998;17(3):21.] 45. Fourrier F, Chopin C, Huart JJ, Runge I, Caron C, Goudemand J.
18. Aboulafia DM, Aboulafia ED. Aortic aneurysm-induced disseminated Double-blind, placebo-controlled trial of antithrombin III concentrates in
intravascular coagulation. Ann Vasc Surg 1996;10:396-405. septic shock with disseminated intravascular coagulation. Chest 1993;104:
19. Kazmers A, Jacobs L, Perkins A, Lindenauer SM, Bates E. Abdominal 882-8.
aortic aneurysm repair in Veterans Affairs medical centers. J Vasc Surg 46. Baudo F, Caimi TM, de Cataldo F, et al. Antithrombin III (ATIII)
1996;23:191-200. replacement therapy in patients with sepsis and/or postsurgical complica-
20. Ruggenenti P, Lutz J, Remuzzi G. Pathogenesis and treatment of tions: a controlled double-blind, randomized, multicenter study. Intensive
thrombotic microangiopathy. Kidney Int Suppl 1997;58:S97-S101. Care Med 1998;24:336-42.
21. Furlan M, Robles R, Galbusera M, et al. Von Willebrand factor–cleaving 47. Eisele B, Lamy M, Thijs LG, et al. Antithrombin III in patients with
protease in thrombotic thrombocytopenic purpura and the hemolytic–ure- severe sepsis: a randomized placebo-controlled, double-blind multicenter
mic syndrome. N Engl J Med 1998;339:1578-84. trial plus meta-analysis on all randomized, placebo-controlled, double-
22. Regoeczi E, Brain MC. Organ distribution of fibrin in disseminated blind trials with antithrombin III in severe sepsis. Intensive Care Med
intravascular coagulation. Br J Haematol 1969;17:73-81. 1998;24:663-72.
23. Creasey AA, Chang ACK, Feigen L, Wun TC, Taylor FB Jr, Hinshaw 48. Levi M, de Jonge E, van der Poll T, ten Cate H. Disseminated intra-
LB. Tissue factor pathway inhibitor reduces mortality from Escherichia coli vascular coagulation: state of the art 1999. Thromb Haemost (in press).
septic shock. J Clin Invest 1993;91:2850-6. 49. Avvisati G, ten Cate JW, Buller HR, Mandelli F. Tranexamic acid for con-
24. Kessler CM, Tang Z, Jacobs HM, Szymanski LM. The suprapharma- trol of haemorrhage in acute promyelocytic leukaemia. Lancet 1989;2:122-4.
cological dosing of antithrombin concentrate for Staphylococcus aureus- 50. Bergum P, Cruikshank A, Maki S, Ruf W, Vlasuk G. The potent, factor
induced disseminated intravascular coagulation in guinea pigs: substantial X(a)-dependent inhibition by rNAPc 2 of factor VIIa (FVIIa)/tissue factor
reduction in mortality and morbidity. Blood 1997;89:4393-401. involves the binding of its cofactor to a exosite on FVII, followed by oc-
25. Fourrier F, Chopin C, Goudemand J, et al. Septic shock, multiple organ cupation of the active site. Blood 1998;92:Suppl 1:669a. abstract.
failure, and disseminated intravascular coagulation: compared patterns of 51. Smith OP, White B, Vaughan D, et al. Use of protein-C concentrate,
antithrombin III, protein C, and protein S deficiencies. Chest 1992;101: heparin, and haemodiafiltration in meningococcus-induced purpura fulmi-
816-23. nans. Lancet 1997;350:1590-3.
26. van der Poll T, Büller HR, ten Cate H, et al. Activation of coagulation 52. Taylor FB Jr, Chang A, Esmon CT, D’Angelo A, Vigano-D’Angelo S,
after administration of tumor necrosis factor to normal subjects. N Engl J Blick KE. Protein C prevents the coagulopathic and lethal effects of
Med 1990;322:1622-7. Escherichia coli infusion in the baboon. J Clin Invest 1987;79:918-25.

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