How I Treat

How I treat disseminated intravascular coagulation

Marcel Levi1,2 and Marie Scully2,3
1
Department of Medicine, 2Cardiometabolic Program, National Institute of Health Research, University College London Hospitals/University College London
Biomedical Research Centre, and 3Department of Hematology, University College London Hospitals NHS Trust, London, United Kingdom

Disseminated intravascular coagulation (DIC) is a condition characterized by systemic activation of coagulation, po-
tentially leading to thrombotic obstruction of small and midsize vessels, thereby contributing to organ dysfunction.
At the same time, ongoing consumption of platelets and coagulation proteins results in thrombocytopenia and low

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concentrations of clotting factors, which may cause profuse hemorrhagic complications. DIC is always secondary to an
underlying condition, such as severe infections, solid or hematologic malignancies, trauma, or obstetric calamities.
A reliable diagnosis of DIC can be made through simple scoring algorithms based on readily available routine he-
mostatic parameters. The cornerstone of supportive treatment of this coagulopathy is management of the underlying
condition. Additionally, administration of heparin may be useful, and restoration of physiological anticoagulants has
been suggested, but has not been proven successful in improving clinically relevant outcomes so far. In patients with
major bleeding or at risk for hemorrhagic complications, administration of platelet concentrates, plasma, or coagulation
factor concentrates should be considered. (Blood. 2018;131(8):845-854)

Introduction More common is the occurrence of thrombosis in small and

midsize vessels contributing to organ failure in patients with DIC,
A variety of disorders, including severe sepsis, systemic in-
with reported ranges from 10% to 15% in patients with cancer or
flammatory conditions, trauma, and malignant disease, will lead
trauma and up to 40% in patients with sepsis, although these
to activation of the coagulation system. In many cases, this
estimates may not be very precise.13,14
coagulation will not result in clinical complications and will not
even be identified by routine laboratory tests, but can only be
A variety of organs in patients with DIC show intravascular fibrin
detected when sensitive molecular markers for activation of
deposition at pathological examination related to the clinical
coagulation pathways are used.1 However, if the activation dysfunction of the organs.15 Experimental DIC in animals causes
of coagulation is sufficiently strong, consumption of platelets intra- and extravascular fibrin deposition in the kidneys, lungs,
and coagulation proteins may become visible through prolonga- liver, and brain, and amelioration of the hemostatic defect im-
tion of routine clotting tests and increasing thrombocytopenia. proves organ failure and, in some cases, mortality.15,16 In addi-
Systemic activation of coagulation in its most extreme form tion, DIC has been shown to be an independent and relatively
is known as disseminated intravascular coagulation (DIC). DIC strong predictor of organ dysfunction and mortality in critically ill
is classically characterized by the simultaneous occurrence of patients.9,17 In patients with sepsis and DIC, mortality is almost
widespread vascular clot deposition, compromising an adequate 2 times higher as compared with patients who do not have DIC.
blood supply to various organs, and thereby contributing to organ
failure.2-5 Due to ongoing activation of the coagulation system and After a general introduction on the settings in which DIC may occur
other factors, such as impaired synthesis and increased degra- and a brief overview of current insights into the pathogenesis of
dation of coagulation proteins and protease inhibitors, exhaustion DIC, we will use 4 clinical cases to highlight the main clinical di-
of factors and platelets may occur, potentially resulting in profuse lemmas encountered when managing DIC in clinical practice.
bleeding from various sites. In addition, high levels of fibrin
degradation products may affect platelet function and fibrin cross-
linking and thereby further contribute to the bleeding tendency.6,7 Clinical settings
It should be emphasized that DIC is not a disease in itself, but is
Extreme bleeding may dominate the clinical picture in patients always secondary to an underlying condition that causes the
with DIC; however, this occurs in only a minority of patients.3 The activation of coagulation. The disorders most frequently asso-
incidence of major bleeding (ie, intracranial, intrathoracic, or ciated with DIC are listed in Table 1.
intra-abdominal bleeding, or bleeding requiring transfusion) in
patients with DIC was 5% to 12% in previous studies.8,9 Patients About 35% of cases of severe sepsis may be complicated by
with DIC and a platelet count of ,50 3 109/L have a four- to DIC.15,18 Classically, infection with Gram-negative microorgan-
fivefold higher risk for bleeding as compared with patients with a isms has been associated with DIC; however, the incidence
higher platelet count.10-12 of DIC in patients with Gram-positive infections is similar.19

© 2018 by The American Society of Hematology blood® 22 FEBRUARY 2018 | VOLUME 131, NUMBER 8 845
Table 1. Clinical conditions most frequently associated with DIC

Condition Examples Impact of precipitating condition

Severe infectious diseases Gram-positive or -negative organisms, Thrombosis may contribute to organ failure
malaria, hemorrhagic fevers (eg acute kidney failure)14,18

Malignancy Solid tumors (eg, adenocarcinomas) Primarily thrombotic consequences/VTE23

Acute promyelocytic leukemia or monocytic Severe thrombocytopenia and factor
leukemia deficiency may lead to bleeding21

Trauma Multitrauma Primary feature is acute bleeding, followed by

Brain injury thrombosis24,26
Burns

Obstetrical complications Abruptio placentae Profuse bleeding in combination with

Amniotic fluid embolism thrombotic complications27,28

Vascular malformations Kasabach-Merrit syndrome Bleeding primarily with severe

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Giant hemangiomas thrombocytopenia and
Other vascular malformations hypofibrinogenaemia3
Large aortic aneurysms

Severe immunologic reactions Transfusion reaction

Heat stroke Thrombotic features more common than

bleeding

Post–cardiopulmonary resuscitation Thrombosis is a greater risk than bleeding

VTE, venous thromboembolism.

Systemic infections with other microorganisms, including fungi correlates with the extent of DIC, suggesting that leakage of
or parasites may lead to DIC as well.19 For example, high par- tissue factor from the placental system into the maternal cir-
asitemia, primarily of Falciparum malaria, may be associated with culation is responsible for the occurrence of DIC.
DIC and high mortality.20 Factors involved in the development of
DIC complicating infections are microbial membrane constitu- For other underlying conditions (Table 1), DIC is a relatively in-
ents, such as lipopolysaccharide or lipoteichoic acid, or exo- frequent complication. In most situations, the severity of the as-
toxins (eg, Staphylococcal a-toxin), evoking a strong immune sociated systemic inflammatory response in combination with
response and release of cytokines. specific circumstances, such as concomitant infections, will de-
termine whether severe systemic coagulation activation will occur.
Both hematological malignancies and solid tumors may be
complicated by DIC due to the expression of procoagulant
factors by tumor cells.21 The incidence of DIC in cancer is not
Pathogenetic pathways
The most important mechanisms leading to the pathological
precisely known and may depend on the diagnostic criteria
derangement of coagulation in DIC have been clarified. The
used; however, some series, in particular in patients with me-
initiation and propagation of procoagulant pathways with si-
tastasized adenocarcinoma or lymphoproliferative disease,
multaneous impairment of natural anticoagulant systems and
report an incidence of up to 20% in consecutive cases.22 The
suppression of endogenous fibrinolysis as a result of systemic
risk of thrombosis is greater than bleeding, and in severe cases,
inflammatory activation are leading to platelet activation and
thromboembolism in conjunction with bleeding can be seen.23 fibrin deposition.15,29 Important mediators that regulate these
processes are cytokines, such as interleukin-1 (IL-1) and IL-6 and
Severe trauma is another clinical condition commonly associated tumor necrosis factor-a (TNF-a). In addition, recent studies point
with DIC.2,24 Systemic cytokine patterns in patients with severe to a prominent role of intravascular webs (neutrophil extracellular
trauma have been shown to be virtually identical to those of traps) consisting of denatured DNA from damaged cells and
septic patients.25 In addition, release of tissue material (such as entangling neutrophils, platelets, fibrin, and cationic proteins,
tissue thromboplastin, in particular in patients with head trauma) such as histones, in the development of thrombus deposition.30
into the circulation and endothelial disruption may contribute
to the systemic activation of coagulation. It may be difficult Thrombin generation in DIC is initiated through the tissue factor/
to differentiate DIC from the coagulopathy due to massive blood factor VII(a) pathway that activates downstream coagulation
loss and the dilutional coagulopathy as a result of massive factors.31 Tissue factor may be expressed by activated mono-
transfusion or infusion of large volumes of crystalloids that may cytes, but also by vascular endothelial cells or cancer cells.
occur in the first hours after major trauma.26 Besides inflammation causing procoagulant effects, the activa-
tion of coagulation also modulates inflammation (Figure 1).
In obstetric calamities, such as placental abruption and amni-
otic fluid emboli, acute and fulminant DIC may occur.27,28 The In DIC, all physiological anticoagulant pathways are function-
degree of placental separation in patients with abruptio placentae ally impaired.15 Firstly, a marked imbalance of TFPI function in

846 blood® 22 FEBRUARY 2018 | VOLUME 131, NUMBER 8 LEVI and SCULLY
 Inflammatory
cells

Toll-like PAR 1,3,4 PAR 2

receptor-4

Fibrinogen to fibrin
conversion

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Thrombin Shut down of
generation fibrinolysis

Tissue factor-mediated Pro-inflammatory

coagulation activation cytokines and chemokines

Activated Impairment of natural

Fibrin-platelet
clot
platelet P-selectin anticoagulant pathways

Platelet-vessel Mononuclear
wall interaction cells
Vascular endothelium

Figure 1. Mononuclear cells express tissue factor resulting in thrombin generation and subsequent fibrinogen to fibrin conversion, which, in combination with
increased platelet vessel wall interaction and activation of platelets, contribute to microvascular clot formation. P-selectin released from activated platelets further
upregulates tissue factor expression. Binding of fibrin to Toll-like receptor 4 and activated coagulation proteases to specific protease activated receptors (PARs) on inflammatory
cells (dotted lines) modulates inflammation through the additional release of proinflammatory cytokines. Cytokines also play a key role in the suppression of endogenous
fibrinolysis and impairment of physiological anticoagulant pathways, such as the APC pathway.

relation to the increased tissue factor–dependent activation of blood pressure was 100/60 mm Hg, heart rate was 120 beats per
coagulation has been described.32 In addition, significant impair- minute (regular), respiratory rate was 28 breaths per minute, and
ment of the protein C system may further compromise adequate temperature was 38.1°C. Arterial blood gas analysis showed
regulation of thrombin generation. This is caused by a cytokine- a PaO2 of 8.4 kPa (63 mmHg) and oxygen saturation of 84%
mediated downregulation of thrombomodulin expression on en- while on 5 L supplemental oxygen. Laboratory analysis showed
dothelial cells in combination with decreased synthesis of protein a hemoglobin concentration of 6.8 mmol/L (11.0 g/dL), a leu-
C and a fall in the concentration of the free fraction of protein S kocyte count of 9.2 3 109/L with 7.7 3 109/L neutrophils,
(the essential cofactor of protein C), together resulting in reduced a remarkable left shift and some schistocytes in the blood smear,
activation of protein C.33 Lastly, plasma levels of antithrombin, the a creatinine concentration of 212 mmol/L (2.4 mg/dL), a bilirubin
most prominent inhibitor of thrombin and factor Xa, are signifi- concentration of 18 mmol/L (1.2 mg/dL), a lactic acid concen-
cantly reduced in DIC due to a combination of consumption, tration of 3.3 mmol/L (30 mg/dL), and a bicarbonate concen-
degradation by elastase from activated neutrophils, and impaired tration of 18 mmol/L. The patient was intubated and ventilated,
synthesis.34 In addition, the endogenous fibrinolytic system is achieving an oxygen saturation of 98%, and hemodynamically
largely shut off as a result of a sustained rise in the plasma level stabilized with crystalloids and IV administration of dopamine. He
of plasminogen activator inhibitor-1 (PAI-1), the principal inhibitor
was further treated with broad spectrum antibiotics and con-
of plasminogen activation and plasmin generation.2
tinues subcutaneous heparin prophylaxis.

Routine coagulation tests showed a platelet count of 98 3 109/L

Patient 1: diagnosis of DIC in a (152 3 109/L the day before), a prothrombin time (PT) of
68-year-old critically ill man 17 seconds (normal, ,12 seconds), which equals an international
A 68-year-old man was admitted to the intensive care unit be- normalized ratio (INR) of 1.4, an activated partial thromboplastin time
cause of respiratory failure 3 days after a hemicolectomy. His () of 43 seconds (normal, ,28 seconds), a D-dimer concentration of

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7.5 mg/mL (normal, ,0.5 mg/mL), and a fibrinogen concentration Table 2. Scoring algorithm for the diagnosis of DIC
of 3.5 g/L (normal, 1-3 g/L).
Platelet count, 3109/L
Comments about patient 1 .100 5 0
,100 5 1
This critically ill patient with multiple organ failure and a
,50 5 2
clinical suspicion of sepsis showed clear signs of a coa-
gulopathy, characterized by a low platelet count, prolonged Level of fibrin markers (eg D-dimer, fibrin degradation products)
global coagulation tests, and increased D-dimer. These lab- No increase 5 0
oratory abnormalities may be compatible with DIC, however, Increased but ,5x upper limit of normal 5 2
some differential diagnostic considerations need to be taken Strong increase ($5x upper limit of normal) 5 3
into account.
Prolonged prothrombin time*
Sepsis per se is clearly associated with thrombocytopenia, and ,3 s 5 0
the severity of sepsis correlates with the reduction in platelet $3 s but ,6 s 5 1
count.35 The principal factors that contribute to thrombocyto- $6s52
penia in patients with sepsis are impaired platelet production,
Fibrinogen level

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increased consumption or destruction, or sequestration of
.1.0 g/L 5 0
platelets in the spleen or along the endothelial surface. In ad-
#1.0 g/L 5 1
dition, in a considerable number of patients with sepsis, marked
hemophagocytosis may occur. This pathologic process consists
This scoring system is only appropriate in patients with an underlying disorder that can be
of active phagocytosis of megakaryocytes and other hemato- associated with DIC. A score of $5 points is compatible with DIC. Note that if the score is
poietic cells by monocytes and macrophages, hypothetically ,5, consider repeating after 1 to 2 days.43
*If prothrombin time values are only available as INRs, an INR value of .1.3 or .1.5 will
due to stimulation with high levels of macrophage colony- generate 1 or 2 points, respectively (assuming the International Sensitivity Index value of
stimulating factor (M-CSF).36 Platelet activation, consumption, the thromboplastin reagents used is close to 1).
and destruction may also occur at the vascular surface as a
result of extensive endothelial cell–platelet interaction in sepsis,
which may differentially occur in vascular beds of various organs.37 degradation, such as D-dimer or fibrin degradation prod-
These mechanisms alone, however, do not explain a prolongation ucts.42 Coagulation proteins with a marked acute phase
of coagulation times. behavior, such as factor VIII or fibrinogen, are usually not de-
creased or may even increase. One of the often-advocated
The presence of thrombocytopenia and schistocytes in the laboratory tests for the diagnosis of DIC, fibrinogen, is therefore
blood film may point in the direction of a thrombotic micro- not a very good marker for DIC, except in very severe cases,
angiopathy, such as thrombotic thrombocytopenic purpura or although sequential measurements can give some insight.
hemolytic-uremic syndrome. However, these syndromes are Dynamic changes in coagulation factors and platelets may
typically accompanied by normal clotting times and normal or add important information. A significant drop in platelet count
only slightly elevated D-dimer.38 Schistocytes may also be seen (as illustrated in this case), a lengthening duration of clotting
in patients with DIC as a result of enhanced platelet-vessel assays, or an increase in fibrin split products, even still within
wall interaction and the formation of microvascular thrombotic the normal range, can indicate an early stage of developing
obstruction, causing mechanical damage to erythrocytes. In- DIC.9
terestingly, patients with severe sepsis and DIC may have re-
duced ADAMTS-13 levels (presumably due to consumption There is no single laboratory test with sufficient accuracy for the
as a result of the large amount of von Willebrand factor diagnosis of DIC. For the diagnosis of DIC, a simple scoring
multimers released from perturbed endothelial cells), causing system (Table 2, Figure 2) has been developed by the In-
some overlap between DIC and thrombotic microangiopathy.39 ternational Society on Thrombosis and Hemostasis.43,44 The
Raised von Willebrand factor levels and the related reduced score can be calculated based on routinely available laboratory
ADAMTS 13 levels are associated with worse outcomes in severe tests (ie, platelet count, prothrombin time, a fibrin-related
DIC.40 marker [usually D-dimer], and fibrinogen). Prospective studies
have shown that the sensitivity of the DIC score is 93%, and
Another differential diagnostic consideration for the thrombo- the specificity is 98%.17,45 The severity of DIC according to this
cytopenia in this case may be heparin-induced thrombocyto- scoring system is a strong predictor for mortality in sepsis.46
penia (HIT).41 It is likely that our patient was treated with Similar scoring systems and diagnostic guidance have been
subcutaneous heparin for some days as perioperative throm- developed and extensively evaluated in Japan, Italy, and the
bosis prophylaxis. Patients with HIT may present with arterial and United Kingdom.47-49 The major difference between the inter-
venous thrombosis, which may explain a high D-dimer result. national and Japanese scoring systems seems to be a slightly
However, HIT is not associated with abnormal global coag- higher sensitivity of the Japanese algorithm, although this may
ulation times. be due to different patient populations, because Japanese series
typically include relatively large numbers of patients with he-
Taken together, DIC is the most probable explanation for the matological malignancies.
coagulopathy in this patient. Patients with DIC have a low or
rapidly decreasing platelet count, prolonged global coagu- In our patient, the platelet count (1 point), prolongation of the PT
lation tests, low plasma levels of coagulation factors and (1 point), and strongly increased D-dimer (3 points) led to a score
inhibitors, and increased markers of fibrin formation and/or of 5 points, compatible with a diagnosis of DIC.

848 blood® 22 FEBRUARY 2018 | VOLUME 131, NUMBER 8 LEVI and SCULLY
 Clinical suspicion of DIC
- Underlying condition known to be associated with DIC
- Low/decreasing platelet count and/or prolonged global clotting
assays (PT, aPTT)

Use DIC scoring algorithm

Score <5: no DIC, consider repeating

after 1-2 days

Score ≥ 5: compatible with DIC

Treat the underlying condition

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Active bleeding or need to No major bleeding Overt thrombo-embolism and/
undergo invasive procedure or thrombosis or organ failure related to clot
formation (e.g. purpura fulminans)
- Platelet transfusion to keep - Prophylactic
platelet count > 30-50x109/L (LMW) heparin - Therapeutic anticoagulant
treatment (e.g. unfractionated
- Plasma and/or factor heparin i.v.)
concentrate administration
to keep PT < 3 sec. - (Restoration of natural anticoagulant
prolonged and keep pathways under evaluation in clinical
fibrinogen > 1.5 g/L studies)

- Vitamin K suppletion in case

of (suspected) vitamin K
deficiency

- Antifibrinolytic treatment in
case of excessive
hyperfibrinolysis

Figure 2. Flowchart for the diagnostic and therapeutic management of DIC. LMW, low molecular weight.

Patient 2: a 63-year-old woman with DIC present with a platelet count of ,150 3 109/L, and in . 10% of
patients, the platelet count is ,75 3 109/L, most importantly
or coagulopathy related to liver disease? caused by sequestration of platelets in the enlarged spleen,
A 63-year-old woman, with long-standing alcohol abuse, pre- reduced levels of thrombopoietin, and consumption.50,51 In
sented with decompensated liver cirrhosis. At physical exami- addition, plasma levels of almost all coagulation factors (except
nation, the most prominent signs were hepatic encephalopathy, factor VIII and von Willebrand factor) are low, as the liver is
jaundice, splenomegaly, and ascites. Laboratory test results the most important site of coagulation protein synthesis. The
showed a hemoglobin concentration of 7.0 mmol/L (11.3 g/dL), combination of thrombocytopenia and low levels of coagulation
a leukocyte count of 7.9.2 3 109/L, a platelet count of 88 3 109/L factors was traditionally interpreted as a hypocoagulable state
(1 week before admission, 84 3 109/L), a bilirubin concentration and associated with a high risk of bleeding. However, recent
of 84 mmol/L (1.2 mg/dL), and an albumin concentration of 28 g/L. insights point to a rebalanced hemostatic system in patients with
Coagulation tests reveal a PT of 17 seconds (normal, ,12 seconds), chronic liver failure, as low levels of natural coagulation inhibitors
an aPTT of 52 seconds (normal, ,28 seconds), a D-dimer con- may balance low levels of coagulation factors and the reduced
centration of 1.0 mg/mL (normal, ,0.5 mg/mL), and a fibrinogen platelet count may be offset by high levels of von Willebrand
concentration of 2.1 g/L (normal, 1-3 g/L). The question is whether factor.52,53
these coagulation abnormalities are due to liver failure-related
coagulopathy or DIC, secondary to an infection. The differential diagnosis between the coagulopathy of liver
disease and DIC is challenging as many laboratory abnormalities
Comments on patient 2 point in the same direction. Even more complex situations may
In patients with severe hepatic failure, several changes in co- occur when the coagulopathy of liver disease is complicated
agulation may occur. More than 75% of patients with cirrhosis by DIC, as patients with severe liver disease may present with

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infectious complications (such as bacterial peritonitis) or leakage be rational therapy in bleeding patients or in patients at risk for
of endotoxin from the intestinal compartment that may elicit hemorrhage with a significant deficiency of these hemostatic
DIC. However, in most cases, the coagulopathy of liver disease factors. The use of large volumes of plasma may be required
can eventually be distinguished from the presence of DIC.54 to restore normal levels of coagulation factors. Coagulation
Helpful clues may be that, in contrast to patients with DIC, in factor concentrates, such as prothrombin complex concen-
severe liver disease, the (low) platelet count is usually stable, and trate, may overcome this impediment, but these agents may
fibrin degradation products (such as D-dimer) are only mildly lack important factors (eg, factor V). Previously, the use of
elevated due to the simultaneous presence of fibrinolytic acti- prothrombin complex concentrates was thought to aggravate
vation and impairment in this condition.55-57 In addition, clinical the coagulopathy in DIC due to small traces of activated
signs, such as the presence of splenomegaly and ascites, may factors in the concentrate. It is, however, not very likely that
indicate that liver disease rather than DIC is the cause of the this is still the case for the currently available concentrates.
coagulopathy. In the case presented, the DIC score was Specific deficiencies in coagulation factors, such as fibrinogen,
4 (suggestive of no DIC), and, in combination with the clinical may be corrected by administration of purified coagulation
signs and symptoms, a diagnosis of coagulopathy due to severe factor concentrates. Vitamin K must be remembered as a
liver failure was made. useful non–blood product alternative to correcting vitamin K–
dependent factors and will work within 4 to 6 hours after a

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dose.
Patient 3: supportive treatment in a
Experimental studies have shown that heparin can at least partly
63-year-old man with sepsis and DIC inhibit the activation of coagulation in DIC.60 However, a clini-
A 63-year-old man presented with severe cholangiosepsis cally relevant effect of heparin in patients with DIC has never
due to an obstructive stone in the common bile duct. He been unequivocally demonstrated in controlled clinical trials,
was in shock, respiratory insufficient, and developed acute although indirect evidence is accumulating that heparin might
renal failure. Blood cultures were positive for Klebsiella be of benefit.61,62 In addition, there are several studies showing
pneumoniae. that all critically ill patients need adequate prophylaxis for ve-
nous thromboembolism, usually with (low–molecular-weight)
Coagulation analysis showed a platelet count of 48 3 109/L, a PT heparin.63 Therapeutic doses of heparin are indicated in pa-
of 19 seconds (normal, ,12 seconds), which equals an INR of tients with clinically overt thromboembolism and may be con-
1.6, an aPTT of 39 seconds (normal, ,28 seconds), a D-dimer sidered in cases of extensive thrombotic manifestations, such as
concentration of 5.5 mg/mL (normal, ,0.5 mg/mL), and a fi- in purpura fulminans or acral ischemia.
brinogen concentration of 2.8 g/L (normal, 1-3 g/L). Based on
these findings, the DIC score was 6 and a diagnosis of DIC was Restoration of the levels of physiological anticoagulants in DIC
established. may be a rational approach and has been extensively evalu-
ated.34 Based on successful preclinical studies, the use of
Awaiting endoscopic retrograde cholangiopancreatography anti-thrombin concentrates has been evaluated in randomized
and restoration of bile duct patency, the patient was treated controlled trials in patients with severe sepsis. All trials have
with vasopressors, intubation, and mechanical ventilation, shown some beneficial effect in terms of improvement of
and antibiotic treatment was started. The question is what laboratory parameters or even improvement in organ function.
would be the most appropriate (supportive) treatment of the An international multicenter, randomized controlled trial with
coagulopathy. an anti-thrombin concentrate, however, did not demonstrate
a significant reduction in mortality of septic patients.64 In-
Comments about patient 3 terestingly, post-hoc subgroup analyses of this study indicated
The keystone in the management of DIC is adequate treatment some benefit in patients who did not receive concomitant
of the underlying disorder. If the condition causing the DIC is heparin and in those with the most severe coagulopathy.65
properly dealt with (in the example of the case with bile duct Recent propensity-adjusted retrospective data from Japan
drainage and antibiotics), the coagulopathy will spontaneously demonstrated a significant advantage of anti-thrombin–treated
resolve. However, in some situations, adjunctive supportive treat- patients with severe infection and DIC.66,67 However, these
ment aimed at the coagulation system will be required, because observations require prospective validation.
the coagulopathy may proceed for a while even after adequate
treatment of the underlying condition has been initiated Adjunctive therapy with activated protein C (APC) has also
(Figure 2).42,58,59 been widely studied. A phase III trial of APC concentrate
in patients with sepsis was prematurely terminated because
Low levels of platelets and coagulation factors may increase of a significant reduction of mortality in these patients.68
the risk of bleeding, in particular in postoperative patients or Notably, patients with overt DIC benefited most from this
those planned to undergo an invasive intervention. However, treatment.46 However, after a series of negative trials in specific
plasma or platelet substitution therapy should not be in- populations of patients with severe sepsis, meta-analyses of
stituted on the basis of laboratory results alone; it is indicated published studies concluded that the basis for treatment with
only in patients with active hemorrhage and in those requiring APC was lacking.69 In addition, there was ambiguity regarding
an invasive procedure or who are otherwise at risk for bleed- the hemorrhagic risk of APC in patients with severe sepsis.
ing complications.48,58 The presumed efficacy of treatment The last large placebo-controlled trial in patients with severe
with plasma, fibrinogen, cryoprecipitate, or platelets is not sepsis and septic shock was prematurely stopped due to the
underpinned by randomized controlled trials, but appears to absence of any significant advantage of APC.70 Subsequently,

850 blood® 22 FEBRUARY 2018 | VOLUME 131, NUMBER 8 LEVI and SCULLY
the manufacturer of APC has withdrawn the product from the These patients may present with a severe and sometimes life-
market. threatening bleeding tendency. The hemorrhagic tendency
is a consequence of DIC with consumption of coagulation
A promising intervention that is currently being evaluated is factors and platelets in combination with striking hyperfibrino-
recombinant soluble thrombomodulin. Preclinical experimental lysis. Hyperfibrinolysis can be diagnosed by low levels of plas-
sepsis studies have demonstrated that soluble thrombomodulin minogen and a2-antiplasmin, low levels of fibrinogen (due to
is capable of ameliorating the derangement of coagulation plasmin-mediated fibrinogenolysis), and excessively high levels
and may improve organ dysfunction.71,72 Recombinant soluble of fibrin degradation products (eg, D-dimer).78 Further analysis
thrombomodulin was evaluated in a phase II/III clinical study in may reveal remarkably low levels of factor VIII and factor V (which
750 patients with sepsis and DIC.73 Twenty-eight-day mortality are both degraded by plasmin), which is in contrast to more
was 17.8% in the thrombomodulin group and 21.6% in the conventional types of DIC, where plasma levels of factor VIII are
placebo group. The encouraging results with soluble throm- usually relatively preserved.
bomodulin were confirmed by retrospective data in large series
of Japanese patients and are being prospectively investigated The coagulopathy associated with acute promyelocytic leukemia
in a currently ongoing multicenter phase III trial.74 is caused by the expression of tissue factor and cancer pro-
coagulant on leukemic cells in combination with increased

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expression of annexin II, causing excessive plasminogen acti-
Patient 4: a 48-year-old woman with acute vation and fibrinolysis.79,80 Release of nonspecific proteases from
granules in the leukemia cells may further contribute to the
promyelocytic leukemia and severe DIC degradation of both fibrin and fibrinogen.
A 48-year-old female presented with severe persisting epistaxis.
She also reported gingival bleeding and widespread ecchymosis Management of patients who present with acute promyelocytic
for 1 week and unusually severe menorrhagia. Laboratory analysis leukemia and DIC consists of supportive treatment with platelet
showed a hemoglobin concentration of 5.5 mmol/L (8.9 g/dL), a transfusion (aiming at a platelet count of .30-50 3 109/L), fresh
leukocyte count of 21.7 3 109/L, with 90% (19.5 3 109/L) pro- frozen plasma, and fibrinogen concentrate (guided by the
myelocytes, 4% (0.9 3 109/L) myelocytes, 3% (0.7 3 109/L) fibrinogen concentration in the patient’s plasma) and should
metamyelocytes, and 2% (0.4 3 109/L) neutrophils, and a platelet be maintained throughout remission induction and disappear-
count of 56 3 109/L. The bone marrow contained few blast-like ance of the coagulopathy.81 In addition, invasive procedures,
cells with scant granules and 72% promyelocytes with Auer such as biopsies or IV line placement, should be avoided as
rods. Immunophenotyping showed expression of CD9, CD13, much as possible. In view of the high risk of bleeding and the
and CD33 and was negative for CD34. Fluorescence in situ lack of evidence from clinical studies, the use of heparin is not
hybridization of the bone marrow aspirate revealed a t(15;17) advocated. Before the introduction of all-trans retinoic acid
translocation and the PML-RARa fusion gene was confirmed by and arsenic trioxide in the therapy of acute promyelocytic
reverse transcriptase polymerase chain reaction, all compatible leukemia, adjunctive treatment with fibrinolysis inhibitors
with a diagnosis of acute promyelocytic leukemia (M3 subtype of (such as tranexamic acid) was shown to be beneficial in small
acute myeloid leukemia [AML-M3], according to the French– clinical trials.82 However, with these modern treatment mo-
American–British classification). dalities, the coagulopathy quickly subsides and inhibition of
fibrinolysis is usually not necessary anymore and may even
Coagulation analysis revealed a PT of 20 seconds (normal, be harmful in view of the prothrombotic features of retinoic
,12 seconds), which equals an INR of 1.7, an aPTT of acid.83
59 seconds (normal, ,28 seconds), a D-dimer concentration
of 10 mg/mL (normal, ,0.5 mg/mL), and a fibrinogen concen-
tration of 0.8 g/L (normal, 1-3 g/L). The plasma levels Final considerations
of plasminogen and a2-antiplasmin were 68% (normal, 80%- Although the understanding of DIC and its underlying path-
120%) and 43% (normal, 80%-100%), respectively. Taken to- ogenetic pathways has increased in recent decades, some
gether, these results indicate the presence of DIC in combination important questions regarding the proper management of this
with marked hyperfibrinolysis. coagulopathy remain. Current therapeutic interventions are
mostly supportive and only partly effective, at best resulting
Comments about patient 4 in an amelioration of the derangement of coagulation or more
There is ample evidence for a procoagulant state in virtually all rapid resolution of DIC; however, they have not been proven to
patients with advanced malignant disease. This may eventually result in an improvement of clinically relevant outcomes, such as
lead to venous thromboembolism or evolve into DIC.75 DIC can organ failure or mortality. Because there is increasing circum-
be diagnosed in up to 15% of consecutive patients presenting stantial evidence that heparin may be beneficial in patients with
with acute leukemia, in particular acute lymphoblastic leukemia, DIC, a randomized controlled trial of heparin in this situation is
and some reports indicate that the incidence of DIC in acute urgently wanted.
leukemia patients might further increase during remission in-
duction with chemotherapy.76 Better supportive treatment of DIC may also benefit from
advances in early patient identification and risk stratification.
A special manifestation of DIC may occur in some patients with Hypothetically, assays specifically aimed at the assessment of
advanced adenocarcinoma, but more frequently in patients endothelial cell perturbation in combination with early stage
with acute promyelocytic leukemia (AML-M3) and monocytic systemic coagulopathy would be helpful to recognize high-
leukemias (eg, the M5 subunit of AML) at the time of diagnosis.77 risk patients and would facilitate early (and thereby potentially

DISSEMINATED INTRAVASCULAR COAGULATION blood® 22 FEBRUARY 2018 | VOLUME 131, NUMBER 8 851
more efficacious) intervention. In addition, genetic variation may Authorship
play a role in the individual propensity to develop DIC and the Contribution: M.L. and M.S. designed the outline of the paper, reviewed
severity of the coagulopathy.84 Gene mutations and polymor- the literature, and wrote the paper.
phisms have been demonstrated to affect hemostatic changes in
DIC. Septic mice with heterozygous protein C deficiency due to Conflict-of-interest disclosure: The authors declare no competing financial
a 1-allele targeted disruption of the protein C gene presented interests.
with more severe DIC and associated inflammatory response.85
ORCID profiles: M.L., 0000-0002-2212-5299; M.S., 0000-0002-2443-6517.
The presence of factor V Leiden heterozygosity has been as-
sociated with the incidence and outcome of DIC in patients with Correspondence: Marcel Levi, Department of Medicine, University
sepsis.86 In addition, the functional 4G/5G polymorphism in the College London Hospitals NHS Trust, 250 Euston Rd, London NW1 2PG,
PAI-1 gene affected plasma levels of PAI-1 and was related to United Kingdom; e-mail: [email protected].
clinical outcome of meningococcal sepsis and DIC.87 A better
understanding of the influence of genomic variation in the
host response leading to DIC could be helpful in identifying Footnote
patients that are more susceptible to severe coagulopathy Submitted 11 October 2017; accepted 17 December 2017. Prepublished
and eventually tailoring treatment to the most vulnerable online as Blood First Edition paper, 18 December 2017; DOI 10.1182/

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patients. blood-2017-10-804096.

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