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Disseminated intravascular coagulation (DIC) in adults:

Evaluation and management
Author: Lawrence LK Leung, MD
Section Editor: Pier Mannuccio Mannucci, MD
Deputy Editor: Jennifer S Tirnauer, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature rev iew current through: Mar 2020. | This topic last updated: Apr 17, 2020.

INTRODUCTION

Disseminated intravascular coagulation (DIC, also called consumption coagulopathy and

defibrination syndrome) is a systemic process with the potential for causing thrombosis and
hemorrhage. It can present as an acute, life-threatening emergency or a chronic, subclinical
process, depending on the degree and tempo of the process and the contribution of morbidities
from the underlying cause. Identifying DIC and the underlying condition responsible for it are
critical to proper management.

This topic discusses the pathogenesis, clinical manifestations, diagnosis, treatment, and
prognosis of DIC in adults. DIC in children and during pregnancy are discussed in detail
separately. (See "Disseminated intravascular coagulation in infants and children" and
"Disseminated intravascular coagulation during pregnancy".)

Separate topic reviews also discuss general approaches to evaluating patients with abnormal
bleeding and unexplained microangiopathic hemolytic anemia and thrombocytopenia. (See
"Approach to the adult with a suspected bleeding disorder" and "Approach to the patient with
suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

PATHOGENESIS

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Intravascular coagulation and fibrinolysis — Normal hemostasis ensures formation of a blood

clot at the site of vessel injury, followed by resolution of the clot to allow tissue repair. There are
multiple feedbacks built into this system to prevent activation of coagulation in the absence of
vessel injury and restrict the clot to the site of injury. (See "Overview of hemostasis".)

In DIC, the processes of coagulation and fibrinolysis become abnormally (and often massively)
activated within the vasculature, leading to ongoing coagulation and fibrinolysis.

A typical sequence of events includes the following (figure 1):

● Procoagulant exposure – Blood is exposed to one or more procoagulants, such as tissue

factor (TF), from which it is normally protected. Sources and components of these
procoagulants depend on the underlying condition. As examples:

• Some bacterial products, such as lipopolysaccharides, can activate coagulation [1].

• In meningococcal sepsis, microparticles containing TF are found in the circulation [2].

• "Cancer procoagulant" is a proteolytic enzyme produced by some mucinous tumors

and placenta that is capable of activating factor X [3,4].

• In trauma, damage to the vascular endothelium and tissues may cause release of
procoagulant enzymes or phospholipids.

• In severe intravascular hemolysis, such as an acute hemolytic transfusion reaction

(AHTR) caused by ABO mismatch, coagulation is activated by a combination of
processes including TF release (likely by monocytes), generation of cytokines including
tumor necrosis factor (TNF) and interleukin 1 (IL-1), and reduced nitric oxide (NO)
function [5].

• In patients with inherited or acquired protein C deficiency, an imbalance between

thrombin generation and fibrinolysis may be responsible for overwhelming normal
mechanisms that protect against inappropriate coagulation.

• Neutrophils may contribute to the formation of neutrophil extracellular traps (NETs),

which have procoagulant properties. (See 'Role of extracellular cell-free DNA and DNA-
binding proteins' below.)

● Coagulation – Activation of the coagulation cascade leads to the production of thrombi

consisting of fibrin and platelets (figure 2). These can occur in the microvasculature and/or
larger vessels. Extensive formation of thrombi in turn leads to consumption of endogenous

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coagulation factors, producing a "consumption coagulopathy"; and of platelets and

anticoagulant factors (eg, protein S, protein C, antithrombin).

● Fibrinolysis – Fibrinolysis is activated at sites of thrombus formation, with generation of

fibrin degradation products (FDP) that, when present in significant amounts, interfere with
both fibrin clot formation and platelet aggregation. (See "Thrombotic and hemorrhagic
disorders due to abnormal fibrinolysis".)

● End organ damage – Tissue or organ damage may result from reduced perfusion,
thrombosis, and/or bleeding. Often, contributions from DIC itself and the condition that
precipitated it are intertwined. Organ failure may result in significant morbidity and mortality.
(See 'Organ dysfunction' below and 'Prognosis' below.)

Other vascular factors that may contribute to the pathogenesis of DIC include endothelial
damage, which can result in the release of procoagulant substances and the loss of endothelial
antithrombotic properties; reduced local blood flow, which slows diffusion of procoagulant and
anticoagulant factors away from the site; and reduced organ perfusion, which may delay hepatic
clearance of coagulation byproducts. Levels of nitric oxide may be reduced, causing increased
vascular tone and enhanced platelet aggregation and activation.

Other blood cells may also participate. As an example, monocytes are known to secrete TF and
von Willebrand factor (VWF) when stimulated by pathogens.

Acidosis and hypothermia may also interfere with appropriate coagulation in the setting of
trauma, resuscitation, or sepsis because the enzymatic functions of the coagulation factors are
pH and temperature-dependent [6].

Role of extracellular cell-free DNA and DNA-binding proteins — Increasing evidence suggests
that damage-associated pattern molecules (DAMPs, also called "alarmins") including cell-free
DNA (cfDNA), extracellular histones, and DNA-binding proteins play a critical role in the
pathogenesis of DIC [7]. DAMPs are released from dying cells or secreted from immune cells in
response to infection or tissue injury. (See "An overview of the innate immune system", section
on 'Interaction of innate and adaptive immunity'.)

Elevated levels of circulating extracellular cfDNA, normally found at approximately 1 mcg/mL in

healthy people, are found in various pathologic conditions including sepsis, trauma, cancer, and
autoimmune diseases, and provide evidence of extensive formation of neutrophil extracellular
traps (NETs). NETs are web-like structures composed of decondensed chromatin coated with a
variety of cellular proteins such as myeloperoxidase, neutrophil elastase, histones, and high
mobility group box 1 protein (HMGB1) that are released from dead or dying neutrophils [8].

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NET formation (NETosis) is a complex and incompletely characterized process in which nuclear
chromatin becomes decondensed and released into the cytoplasm, followed by rupture of the
plasma membrane and expulsion of the cellular contents into the extracellular space. NETosis
accompanies a form of lytic cell death distinct from apoptosis and necrosis. Under normal
conditions, NETosis appears to be a highly regulated component of innate immunity that is
protective against microbial pathogens, but it becomes dysregulated in severe inflammatory
conditions. The cfDNA and other nuclear proteins released during NETosis are cytotoxic and
play an important role in the pathogenesis of DIC.

NETosis is highly procoagulant. It activates the clotting cascade and influences primary and
secondary hemostasis via a number of mechanisms:

● Delivery of tissue factor

● Activation of the contact phase of coagulation by cfDNA
● Cytotoxicity of cfDNA, which activates cell surface Toll-like receptor (TLR9)
● Induction of platelet aggregation by cfDNA
● Proteolytic degradation of anticoagulants such as tissue factor pathway inhibitor (TFPI) via
neutrophil elastase
● Cytotoxicity to endothelial cells from DNA binding proteins that are normally excluded from
the circulation, such as histones and HMGB1

NET formation has been shown to play an important role in the development and propagation of
pathological venous thrombosis [8,9]. An antibody directed at histone proteins has been shown
to reduce sepsis-related mortality in animal models [10].

In a 2015 study involving 199 patients with DIC and 20 healthy controls, elevated plasma levels
of DNA-histone complexes and double-stranded DNA (dsDNA), considered to be in vivo markers
of NETosis, correlated with the severity of coagulopathy in DIC and were independent prognostic
factors [11].

Disruption of the endothelial angiopoietin-tyrosine kinase pathway — The angiopoietin-

tyrosine kinase with immunoglobulin and EGF homology domains (ANG-TIE) pathway is
involved in lymphatic and blood vessel development during embryogenesis and controls
vascular permeability, inflammation, and physiologic and pathologic responses in adult tissues
[12]. Angiopoietins 1 and 2 (ANG1 and ANG2) are ligands that bind to the TIE1 and TIE2 (also
called TEK) receptors, a subfamily of receptor tyrosine kinases on endothelial cells in this cell
signaling pathway. ANG1 is a paracrine ligand expressed by mesenchymal cells and a strong
TIE2 agonist that supports endothelial cell survival, vessel stability, and endothelial barrier
function, whereas ANG2, expressed by endothelial cells and stored in their Weibel-Palade

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bodies, acts as a context-dependent weak TIE2 agonist or antagonist and inhibits the ANG1-
TIE2 signaling axis. Proteomics analysis on plasma samples from septic patients with DIC
showed that the circulating ANG2 level was strongly correlated with traditional DIC markers that
indicate sequelae of DIC and more accurately predicted patient mortality than these markers
[13]. This observation was replicated in a murine endotoxin sepsis model. In that same model,
TIE2 activation normalized the prothrombotic responses in the endothelium by inhibiting
endothelial tissue factor and phosphatidylserine exposure. Disruption of the ANG-TIE2 axis
preceded the development of overt DIC, suggesting that it plays a central role in the
pathogenesis of DIC. Targeting the ANG-TIE2 pathway may have therapeutic potential in the
treatment of sepsis-associated DIC [14].

Compensatory changes — DIC is a dynamic process. The acuity and magnitude of ongoing
intravascular coagulation determine whether consumption of coagulation factors and platelets
can be compensated adequately by ongoing synthesis of coagulation factors and generation of
new platelets in the bone marrow. The two ends of the spectrum between inadequate and
adequate compensation are sometimes referred to as acute and chronic DIC.

● Acute DIC – Acute (decompensated) DIC can develop when blood is exposed to large
amounts of tissue factor (or other procoagulant substances) over a brief period of time, with
significant generation of thrombin. This leads to rapid consumption of coagulation factors
that outpaces their production. The fibrin degradation products (FDPs) that are generated in
turn disrupt normal fibrin polymerization and fibrinogen binding to platelet surface αIIbβ3
(GPIIbIIIa), thus interfering with both fibrin clot formation and platelet aggregation, and
effectively operating as pathological anticoagulant and anti-platelet agents.

The consumption coagulopathy, combined with the high concentration of FDPs, leads to the
severe bleeding diathesis seen in decompensated DIC, and accounts for the clinical
observation that supportive therapy with Fresh Frozen Plasma (FFP) and platelet
transfusions by themselves are generally insufficient to completely correct the bleeding
diathesis. Clotting times become prolonged and the potential for clinically important
bleeding increases [15]. Acute DIC is typically seen in settings such as sepsis, trauma, or
acute promyelocytic leukemia. (See 'Acute DIC' below.)

● Chronic DIC – Chronic (compensated) DIC can develop when blood is continuously or
intermittently exposed to smaller amounts of tissue factor (or other procoagulant
substances). Coagulation factors and platelets are consumed, but production is able to
compensate, and the liver is able to clear the FDPs. Clotting times may be normal, and
thrombocytopenia may be mild or absent. Thrombosis generally predominates over

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bleeding, although many patients are asymptomatic with laboratory-only evidence of

increased thrombin generation and fibrinolysis [16]. Chronic DIC is typically seen in patients
with advanced malignancy, especially pancreatic, gastric, ovarian, and brain tumors. (See
'Chronic DIC' below and "Pathogenesis of the hypercoagulable state associated with
malignancy".)

DIC versus other TMAs — DIC is associated with microvascular thrombi that contain fibrin as
well as platelets.

In contrast, some of the other thrombotic microangiopathies (TMAs), such as thrombotic

thrombocytopenic purpura (TTP) and complement-mediated hemolytic uremic syndrome (HUS),
are characterized by platelet-rich microthrombi without significant fibrin clot formation or
consumption coagulopathy. Thus, other TMAs generally present with thrombocytopenia and
normal coagulation studies.

In some cases, other TMAs are caused by clearly defined endothelial defects:

● TTP is caused by deficiency of the ADAMTS13 protease, which results in accumulation of

very long von Willebrand factor multimers on the endothelial surface that are capable of
binding platelets. (See "Pathophysiology of acquired TTP and other primary thrombotic
microangiopathies (TMAs)", section on 'TTP pathogenesis'.)

● Complement-mediated HUS is thought to be caused by complement-induced damage to

the endothelium. (See "Complement-mediated hemolytic uremic syndrome in children".)

These endothelial defects may promote platelet adherence and activation without exposing the
blood to large amounts of procoagulant substances.

Both DIC and other TMAs can produce microangiopathic hemolytic anemia (MAHA),
characterized by schistocytes on the peripheral blood smear (picture 1). Schistocytes are formed
as red blood cells (RBCs) pass through fibrin strands and microthrombi and become
mechanically sheared (picture 2). The extent of microangiopathic hemolysis is often greater in
TTP and complement-mediated HUS than it is in DIC.

CAUSES OF DIC

DIC does not occur in isolation. A number of underlying conditions are responsible for initiating
and propagating the process (table 1) [6].

Common causes of DIC include the following:

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● Sepsis from a variety of organisms (bacterial, fungal, viral, and parasitic).

In a series of 183 consecutive individuals admitted to the hospital with 2019-2020

coronavirus disease (COVID-19) pneumonia (median age, 54 years), coagulation testing
revealed evidence of overt DIC (using the ISTH criteria) in only one patient who survived,
versus 15 patients (71 percent) who died [17]. The median time from admission to
development of DIC was four days (range, 1 to 12 days).

● Malignancy, especially acute promyelocytic leukemia, mucinous tumors (eg, pancreatic,

gastric, ovarian), and brain tumors.

● Trauma, especially to the central nervous system.

● Obstetrical complications, including preeclampsia, retained dead fetus, acute fatty liver of
pregnancy.

● Intravascular hemolysis, often due to acute hemolytic transfusion reaction (AHTR) in the
setting of ABO incompatible transfusion, but also in other forms of hemolysis such as in
severe malaria [18].

The relative frequency of causes has been illustrated by two large case series, which found the
most common causes of DIC to be infection, malignancy, and trauma/surgery, each accounting
for approximately 10 to 20 percent of cases depending on the study [19,20].

Additional causes are seen less often, but may be considered if none of the above conditions
are obviously present, or in certain clinical settings [6,21]. These include:

● Heat stroke
● Crush injuries
● Amphetamine overdose
● Insertion of a peritovenous shunt
● Fat embolism
● Vascular abnormalities, including aortic aneurysm and Kaposiform hemangioendothelioma
● Rattlesnake or other viper bite (considered by some to be another type of coagulopathy
and/or thrombotic microangiopathy other than DIC) [22]
● Hereditary protein C deficiency
● Acute solid organ transplant rejection
● Catastrophic antiphospholipid antibody syndrome (APS)

These conditions are discussed in detail in separate topic reviews.

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EPIDEMIOLOGY

DIC is seen in approximately 1 percent of admissions to tertiary care hospitals. In a series of

123,231 patients admitted to university hospitals in Japan, 1286 were diagnosed with DIC (1
percent) [23]. These data may underestimate the incidence of mild, subclinical, or transient DIC.
In contrast, the incidence of DIC may be lower in lower acuity settings.

The incidence of DIC in specific medical conditions is illustrated by the following examples:

● Cancer – DIC is seen in a significant number of patients with cancer. Malignancies most
likely to cause DIC include acute promyelocytic leukemia, pancreatic cancer, and other
mucin-producing solid tumors such as gastric, prostate, breast, and ovarian cancer [24]. In
a cohort of 1117 patients with various solid tumor malignancies, DIC was diagnosed in 76
(6.8 percent) [25]. Significant risk factors for the development of DIC included age >60 years
(odds ratio [OR] 5.1), male sex (OR 4.3), breast cancer (OR 4.0), tumor necrosis (OR 3.4),
and advanced stage disease (OR 2.6).

● Infection – DIC is common in patients with bacterial sepsis, with increasing likelihood
related to the severity of the systemic inflammatory response. In a series of 35 patients who
met criteria for systemic inflammatory response syndrome for four or more consecutive
days, DIC was seen in 29 (83 percent) [26]. (See "Sepsis syndromes in adults:
Epidemiology, definitions, clinical presentation, diagnosis, and prognosis".)

● Trauma – In a review of 136 patients with severe trauma, 42 had DIC (31 percent) [27].
Series of patients with head trauma have reported DIC in approximately 40 percent [28,29].

● Obstetrical complications – The incidence of DIC in patients with obstetrical complications

ranges from 20 percent in patients with hemolysis, elevated liver function tests, and low
platelets (HELLP syndrome) to 66 percent in patients with amniotic fluid embolism [30,31].
These and other obstetrical conditions associated with DIC are discussed in detail
separately. (See "Disseminated intravascular coagulation during pregnancy".)

CLINICAL MANIFESTATIONS

COVID-19-associated abnormalities — Patients with coronavirus disease 2019 (COVID-19)

have been reported to have a number of clinical and laboratory abnormalities that suggest a
form of sepsis coagulopathy, although the mechanisms and risk factors for these changes are
not well-characterized.

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Observations from case reports and retrospective series, including a series of 183 consecutive
patients from Wuhan, China, suggest the following changes may occur [17,32-34]:

● Prolonged PT and aPTT

● Increased D-dimer
● High fibrinogen
● Thrombocytopenia

Guidance on managing the coagulopathy is presented below. (See 'COVID-19-specific

management' below.)

Acute versus chronic DIC — Acute and chronic DIC (also called decompensated and
compensated DIC, respectively) represent two ends of a pathogenic balance between
coagulation factor and platelet consumption, and their production. (See 'Intravascular
coagulation and fibrinolysis' above.)

These pathogenic differences translate into differences in clinical and laboratory findings as well
(table 2). (See 'Laboratory abnormalities' below.)

Acute and chronic DIC may both be associated with bleeding and/or thrombosis, along with their
sequelae in affected organs. However, acute DIC is much more likely to present with bleeding,
due to consumption of fibrinogen and other procoagulant factors and the disruption of normal
fibrin formation and platelet function by the large amount of fibrin degradation products; whereas
chronic DIC is more likely to present with thromboembolic complications because production of
procoagulant factors keeps pace with ongoing generation of thrombi. (See 'Bleeding and
thrombosis' below.)

Acute DIC — Findings consistent with acute DIC include the following, although none of
these findings are highly specific for DIC (table 2):

● Recent history of trauma, sepsis, malignancy (especially acute promyelocytic leukemia), or

ABO-incompatible blood transfusion
● Bleeding, especially oozing from sites of trauma, catheters, or drains
● Thrombocytopenia
● Prolonged PT and aPTT
● Low plasma fibrinogen
● Elevated plasma D-dimer
● Abnormalities of other coagulation testing
• Increased thrombin time
• Reduced levels of procoagulant factors such as factors VII, X, V, and II (prothrombin)

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• Reduced levels of coagulation inhibitors such as antithrombin (AT), protein C, and

protein S [35]
● Microangiopathic changes on peripheral blood smear (picture 1 and picture 3)

In one series of 118 patients with acute DIC, the main clinical manifestations included the
following [19]:

● Bleeding (64 percent)

● Renal dysfunction (25 percent)
● Hepatic dysfunction (19 percent)
● Respiratory dysfunction (16 percent)
● Shock (14 percent)
● Thromboembolism (7 percent)
● Central nervous system involvement (2 percent)

Chronic DIC — The following findings are consistent with chronic DIC, although none of these
findings are highly specific (table 2):

● History of malignancy, especially pancreatic, gastric, ovarian, or brain tumors

● Venous or arterial thromboembolism, especially without another clear precipitating factor
● Mild or no thrombocytopenia
● Normal or mildly prolonged PT and aPTT
● Normal or even slightly elevated plasma fibrinogen
● Elevated plasma D-dimer
● Microangiopathic changes on peripheral blood smear (picture 1 and picture 3)

Many patients with chronic DIC in the setting of malignancy are asymptomatic, with laboratory-
only evidence of low-grade coagulation and fibrinolysis.

Bleeding and thrombosis — Common bleeding manifestations include petechiae;

ecchymoses; and blood oozing from wound sites, intravenous lines, catheters, mucosal
surfaces. Patients who develop DIC after surgical procedures may also accumulate blood in
serous cavities. The bleeding can be life-threatening if it involves the gastrointestinal tract, lungs,
or central nervous system. Bleeding is more likely to occur in acute DIC, but patients with chronic
DIC can also have bleeding.

Common thromboembolic manifestations of DIC include venous thromboembolism (VTE) and

arterial thrombosis with tissue or organ ischemia. Thrombosis is more likely to occur in chronic
DIC, in the setting of solid tumors, but patients with acute DIC can also have thromboembolic
complications.

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In addition to venous and arterial thrombosis, patients with chronic DIC in the setting of
malignancy can also develop non-bacterial thrombotic endocarditis (marantic endocarditis,
Libman-Sacks endocarditis, verrucous endocarditis) and superficial migratory thrombophlebitis
(Trousseau's syndrome). (See "Anticoagulation therapy for venous thromboembolism (lower
extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy" and
"Nonbacterial thrombotic endocarditis".)

An exception to the association of malignancy with chronic DIC is acute promyelocytic leukemia,
in which patients frequently present with acute DIC (or develop it after initiation of cytotoxic
chemotherapy). Life-threatening hemorrhage can result, with a high risk of early hemorrhagic
death. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic
leukemia in adults", section on 'Coagulopathy and APL'.)

Thromboembolic findings can also occur in patients with malignancy who do not have DIC, due
to other causes of hypercoagulability such as chemotherapeutic or biologic agents, indwelling
central venous catheters, and/or surgery. This subject is discussed in detail separately. (See
"Pathogenesis of the hypercoagulable state associated with malignancy" and "Risk and
prevention of venous thromboembolism in adults with cancer", section on 'Incidence and risk
factors'.)

Organ dysfunction — DIC can lead to organ dysfunction due to a variety of mechanisms
including vascular thrombosis, hemorrhage, and hypoperfusion. This may be especially
concerning in individuals with underlying organ dysfunction or organ damage caused by their
underlying condition.

● Renal failure – Acute renal failure occurs in 25 to 40 percent of patients with acute DIC.

● Hepatic dysfunction – Jaundice from hepatic dysfunction is common in DIC. Preexisting

liver failure can exacerbate DIC by impairing hepatic production and/or clearance of clotting
factors.

● Acute lung injury – Pulmonary hemorrhage with hemoptysis and dyspnea may result from
damage to the pulmonary vascular endothelium. Pulmonary microthrombi may contribute to
lung injury; this may be especially concerning in patients with acute respiratory distress
syndrome (ARDS) due to their underlying condition. (See "Acute respiratory distress
syndrome: Clinical features, diagnosis, and complications in adults".)

● Neurologic dysfunction – A number of neurologic abnormalities can occur in patients with

DIC. These include coma, delirium, and transient focal neurologic symptoms. Microthrombi,
hemorrhage, and hypoperfusion all may contribute.

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● Adrenal failure – Waterhouse-Friderichsen syndrome is a form of adrenal insufficiency that

can result from adrenal hemorrhage or infarction. (See "Clinical manifestations of
Staphylococcus aureus infection in adults" and "Clinical manifestations of meningococcal
infection" and "Causes of primary adrenal insufficiency (Addison's disease)".)

Purpura fulminans — Purpura fulminans is a rare, life-threatening condition characterized by

DIC, with extensive tissue thrombosis and hemorrhagic skin necrosis. A classic presentation of
purpura fulminans is as retiform purpura with branched or angular purpuric lesions (picture 4
and picture 5 and picture 6 and picture 7 and picture 8).

Many patients with this condition have inherited protein C deficiency (homozygous or compound
heterozygous deficiency). Presentation in early infancy is common, but older patients are also
occasionally seen. In contrast, heterozygous protein C deficiency with venous thromboembolism
typically does not have DIC as a component of its pathogenesis. (See "Management of
thrombosis in the newborn", section on 'Neonatal purpura fulminans' and "Protein C deficiency",
section on 'Neonatal purpura fulminans'.)

Purpura fulminans may also occur in the setting of severe acquired protein C deficiency, such as
may occur in patients with severe meningococcal infections. (See "Clinical manifestations of
meningococcal infection", section on 'Purpura fulminans'.)

Laboratory abnormalities — Laboratory findings of DIC may include the following:

● Prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT)
(table 2). Prolonged PT will lead to increase in the international normalized ratio (INR) for
the PT. These abnormalities are more typical of acute than chronic DIC.

● Hypofibrinogenemia, which is more common with acute than chronic DIC. Importantly,
patients with sepsis, malignancy, and other inflammatory conditions may have markedly
increased production of fibrinogen since fibrinogen functions as an acute phase reactant;
thus, a plasma fibrinogen level within the normal range may represent a substantial
consumption (and a significant abnormality) for that patient despite being in the normal
range.

● Increased D-dimer, which is seen in both acute and chronic DIC.

● Thrombocytopenia, which is seen more typically with acute than chronic DIC. The platelet
count is typically mildly to moderately reduced; platelet counts below 20,000/microL are less
commonly seen.

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● Microangiopathic hemolytic anemia (MAHA), with schistocytes and helmet cells seen on the
peripheral blood smear (picture 3 and picture 1). These changes may be less pronounced
than those seen in other thrombotic microangiopathies such as thrombotic
thrombocytopenic purpura (TTP). Severe anemia due to microangiopathic hemolysis is
uncommon, although most of the underlying conditions responsible for DIC can cause
anemia due to other mechanisms (eg, bone marrow suppression, anemia of chronic
disease/inflammation). MAHA can be seen in both acute and chronic DIC.

Plasma histone-DNA complexes and cell-free DNA levels are elevated in DIC, but their clinical
value remains to be determined.

Of note, many of the laboratory abnormalities used to support a diagnosis of DIC are present in
normal pregnancy, as discussed in detail separately. (See "Disseminated intravascular
coagulation during pregnancy".)

DIAGNOSTIC EVALUATION

DIC may be suspected in an individual with generalized oozing from multiple intravenous
catheter sites or other signs of bleeding, or occasionally in an individual with unexplained
thrombosis. Most individuals with DIC have an obvious underlying condition associated with DIC
such as sepsis or malignancy, but occasionally DIC is the presenting finding for these
conditions.

DIC is a clinical and laboratory diagnosis, based on findings of coagulopathy and/or fibrinolysis
in the appropriate setting (eg, sepsis, malignancy). No single laboratory test can accurately
confirm or eliminate the diagnosis.

Findings such as thrombocytopenia, low fibrinogen, and elevated D-dimer are considered to be
relatively sensitive for the diagnosis but not specific; however data from clinical trials addressing
sensitivity and specificity are lacking. Some of the other causes of these findings are discussed
below. (See 'Differential diagnosis' below.)

In patients for whom an underlying condition known to be associated with DIC is obvious, the
laboratory evaluation typically includes a complete blood count, review of the peripheral blood
smear, and screening tests of coagulation (eg, prothrombin time [PT], activated partial
thromboplastin time [aPTT], fibrinogen, and D-dimer). For patients without bleeding or
thrombosis, the PT and aPTT may be done first, and fibrinogen and D-dimer done only in those
with prolonged PT and aPTT. For patients with bleeding or thrombosis, it is appropriate to obtain

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all of these tests simultaneously. The International Society of Thrombosis and Haemostasis has
developed a scoring system to be applied to individuals with an underlying disorder associated
with DIC, which incorporates laboratory features including the PT, platelet count, fibrinogen level,
and D-dimer; this scoring system has been validated but is not widely used [36,37].

Testing is often repeated serially to determine if coagulation and fibrinolysis are worsening or
improving. The frequency of testing depends on the severity of clinical findings. Daily or even
twice-daily testing may be appropriate in an acutely ill patient with active bleeding or thrombosis;
less frequent testing may be reasonable in a patient with laboratory-only findings.

For patients with findings suggestive of DIC who do not have an obvious underlying cause, the
evaluation for DIC is conducted simultaneously with the evaluation for the underlying condition
responsible for ongoing coagulation, as well as the evaluation for other possible causes of
bleeding, thrombosis, and laboratory abnormalities. (See 'Causes of DIC' above and 'Differential
diagnosis' below.)

We consider the diagnosis of acute DIC to be established if the patient has laboratory evidence
of thrombocytopenia, coagulation factor consumption (eg, prolonged PT, aPTT; low fibrinogen),
and fibrinolysis (eg, increased D-dimer), as long as another etiology for these findings does not
become apparent. Bleeding or thrombosis are supportive of the diagnosis if present but are not
required for diagnosis.

We consider the diagnosis of chronic DIC confirmed if the patient has evidence of fibrinolysis
(eg, increased D-dimer) in the absence of another etiology, such as VTE, in an appropriate
clinical setting. Typically, this implies the presence of malignancy, although certain other causes,
such as a vascular lesion, may be present. Chronic DIC in a patient with malignancy does not
necessarily imply the need for a clinical intervention; management is guided by the clinical
setting and treatment goals for the individual patient. (See 'Causes of DIC' above.)

Of note, we do not test for chronic DIC routinely in patients with malignancy. We reserve this
testing for patients with evidence of unexpected bleeding or thromboembolic complications, and
prior to initiating anticoagulant therapy. We also do not test for chronic DIC preoperatively in a
patient with cancer if the PT, aPTT, and platelet count are normal.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of DIC includes other conditions associated with bleeding and
hypercoagulability, and other causes of microangiopathic hemolytic anemia (MAHA) and

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thrombocytopenia. Some conditions, such as liver failure, can be either a cause of DIC or a
consequence of DIC. In such cases, the diagnosis of the other condition does not eliminate the
possibility of DIC, and vice versa.

● Severe liver disease – Liver disease severe enough to impair the hepatic synthesis of
coagulation factors can cause a severe coagulopathy. Like DIC, severe liver disease is
associated with reductions in both procoagulant and anticoagulant factors as well as
thrombocytopenia; patients can have bleeding or thrombosis. The coagulation factor
reductions and thrombocytopenia in severe liver disease are often caused by a combination
of hypersplenism and thrombopoietin (TPO) deficiency, since the liver is the primary site of
TPO synthesis. Unlike DIC, patients with severe liver disease typically present with a known
source of liver injury (eg, acute hepatitis, alcoholic cirrhosis) and abnormal liver function
tests, although transaminases may appear to normalize if liver synthetic function is severely
impaired. Some clinicians consider factor VIII levels to be helpful because factor VIII is not
produced by hepatocytes and thus is often low in DIC and high in severe liver disease. (See
"Hemostatic abnormalities in patients with liver disease".)

● Heparin-induced thrombocytopenia (HIT) – HIT is a potentially life-threatening complication

of heparin exposure due to an autoantibody to platelet factor four epitope created by heparin
binding to platelets; rare cases of HIT in the absence of heparin exposure have also been
reported. Like DIC, patients with HIT can have thrombosis (due to platelet activation by the
HIT antibody and/or the underlying condition for which they were receiving heparin) and
bleeding (due to heparin or the non-heparin anticoagulant used to treat HIT). Unlike DIC,
patients with HIT typically have recent heparin exposure and a positive laboratory testing for
heparin-PF4 antibodies (HIT antibodies); and patients with HIT do not have global
coagulation abnormalities, with the exception of abnormalities caused by their anticoagulant
or increased D-dimer associated with thromboembolism. (See "Clinical presentation and
diagnosis of heparin-induced thrombocytopenia".)

● Thrombotic thrombocytopenic purpura (TTP) or other thrombotic microangiopathy (TMA)

– TTP and other TMAs (eg, drug-induced TMA [DITMA], hemolytic uremic syndrome [HUS])
present with MAHA and thrombocytopenia due to platelet consumption in microvascular
thrombi. Like DIC, patients may be acutely ill, thrombocytopenic, and have schistocytes on
the peripheral blood smear. Unlike DIC, patients with TTP, DITMA, or HUS have normal
coagulation testing because microvascular thrombi in these conditions are primarily
platelet-rich and fibrin-poor thrombi, and are not associated with consumption coagulopathy
(ie, the PT, aPTT, fibrinogen, and D-dimer are normal in TTP and other TMAs) (table 3). A
rare exception may be a patient with a TMA that leads to organ ischemia and in turn causes

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DIC. Also, unlike DIC, patients with TTP and other TMAs tend to have more severe
microangiopathic changes on the blood smear, and other laboratory abnormalities specific
to the type of TMA (eg, ADAMTS13 activity level <10 percent in TTP; complement
abnormalities in complement-mediated HUS, positive stool studies in Shiga toxin-mediated
HUS). (See "Approach to the patient with suspected TTP, HUS, or other thrombotic
microangiopathy (TMA)" and "Acquired TTP: Clinical manifestations and diagnosis" and
"Drug-induced thrombotic microangiopathy".)

A list of causes of an elevated D-dimer is included in the table (table 4). A more extensive
discussion of other possible causes of abnormal coagulation testing is also presented
separately. (See "Clinical use of coagulation tests".)

TREATMENT

Treat the underlying cause — DIC is a process of ongoing thrombin generation and fibrinolysis,
and resolution of these abnormalities depends on elimination of the stimulus for these
processes.

Thus, a major principle in the management of DIC is treatment of the underlying cause in order
to eliminate the stimulus for ongoing coagulation and thrombosis. (See 'Causes of DIC' above.)

Supportive measures — The need for additional supportive measures is individualized for each
patient. Examples include the following:

● Hemodynamic and/or ventilatory support – (see "Evaluation and management of suspected

sepsis and septic shock in adults" and "Septic shock in children: Rapid recognition and
initial resuscitation (first hour)")

● Aggressive hydration for acute hemolytic transfusion reaction – (see "Hemolytic transfusion
reactions", section on 'Acute hemolytic reactions')

● Red blood cell transfusion for severe bleeding – (see "Indications and hemoglobin
thresholds for red blood cell transfusion in the adult", section on 'Acute bleeding')

Role of systemic therapies — In general, systemic therapies, such as pro-hemostatic or

anticoagulant agents, are not used prophylactically to prevent bleeding or thrombosis. However,
patients are closely monitored for bleeding and thrombotic complications, and these
complications are treated promptly if they occur. (See 'Prevention/treatment of bleeding' below
and 'Prevention/treatment of thrombosis' below.)

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Our approach is largely based on observational studies and our own experience; there are very
few randomized trials to guide therapy in DIC. The management recommendations presented
here are largely consistent with a consensus document from the British Committee for
Standards in Haematology (BCSH) task force in hemostasis and thrombosis and other
international consensus documents [6,38,39].

Prevention/treatment of bleeding — Patients with DIC are at risk of bleeding due to

thrombocytopenia and depletion of coagulation factors. However, it is not possible to reliably
predict which patients will have bleeding. (See 'Pathogenesis' above.)

We do not routinely use prophylactic administration of platelets and coagulation factors in

patients who are not bleeding or who are not at high risk of bleeding, as long as the platelet
count is ≥10,000/microL. This practice is based on the lack of evidence that bleeding can be
prevented by these therapies; the likely transient nature of DIC if the underlying cause is
addressed; and the concomitant increased risk of thrombosis in DIC. One international
consensus group suggested using a platelet count threshold of 20,000/microL in the absence
of bleeding [38].

However, treatment is justified in patients who have serious bleeding, are at high risk for
bleeding (eg, after surgery), or require invasive procedures. Importantly, appropriate treatment for
bleeding should not be withheld for fear of "fueling the fire."

● Patients with serious bleeding or need for urgent/emergent surgery and a platelet count
<50,000/microL should be given platelet transfusions. Typically, we give one to two units of
random donor platelets per 10 kg of body weight, or one single donor apheresis unit daily.
Thresholds for specific surgical procedures are presented separately. The increase in
platelet count may be less than expected due to ongoing platelet consumption. (See
"Clinical and laboratory aspects of platelet transfusion therapy", section on 'TTP or HIT' and
"Clinical and laboratory aspects of platelet transfusion therapy", section on 'Preparation for
an invasive procedure'.)

● Patients with a platelet count <10,000/microL should be given platelet transfusions due to
the increased risk of spontaneous bleeding. This degree of thrombocytopenia is rare in
DIC, with the exception of acute promyelocytic leukemia or other conditions associated with
severe bone marrow dysfunction.

● Patients with serious bleeding and a significantly prolonged prothrombin time (PT) or
activated partial thromboplastin time (aPTT), or a fibrinogen level <50 mg/dL and serious
bleeding, should receive coagulation factor replacement. Options include Fresh Frozen

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Plasma (FFP), related plasma products such as Plasma Frozen Within 24 Hours After
Phlebotomy (PF24), or cryoprecipitate. Cryoprecipitate provides a good source of fibrinogen
with significantly less volume load than FFP or PF24 (table 5). (See "Clinical use of plasma
components".)

The specific threshold for transfusion and amount of the product given are individualized to
the specific clinical setting and other patient factors such as volume status and severity of
bleeding. As an example, the following may be appropriate:

• If the plasma fibrinogen level is <100 mg/dL, we administer cryoprecipitate to increase

it to >100 mg/dL.

• If the plasma fibrinogen level is >100 mg/dL and the PT or aPTT remains significantly
elevated, we administer FFP or PF24. The goal is to reduce bleeding, not to normalize
the coagulation tests. Dosing is provided in the table (table 5).

We do not use antithrombin to treat bleeding in DIC. This practice is based on a trial that
randomly assigned 2314 patients with sepsis to antithrombin or placebo and found no
difference in mortality [40]. There was an increase in bleeding in patients who also received
heparin in this study. A randomized trial testing recombinant thrombomodulin in sepsis-
associated DIC also failed to show any benefit over placebo [41]. (See "Investigational and
ineffective therapies for sepsis", section on 'Ineffective therapies'.)

Of note, the administration of antifibrinolytic agents such as tranexamic acid (TXA), epsilon-
aminocaproic acid (EACA) or aprotinin is generally contraindicated since blockade of the
fibrinolytic system may increase the risk of thrombotic complications [42]. However, these agents
may be appropriate in patients who have severe bleeding associated with a hyperfibrinolytic
state [6].

There are no data regarding the use of prothrombin complex concentrates (PCC) in DIC. In the
author's opinion, PCCs are also contraindicated in DIC, since administration may trigger more
thrombotic complications in the setting of an already hypercoagulable state.

Prevention/treatment of thrombosis — Patients with DIC are at risk of thrombosis because

of ongoing stimulation of coagulation, mediated by continuous exposure to tissue factor,
thrombin, or other procoagulant substances. (See 'Pathogenesis' above.)

Thrombosis appears to be more common (although still rare overall) with certain infectious
causes of DIC such as severe malaria or dengue virus infection. In those cases, thrombosis
can be life- or limb-threatening. Digital gangrene of the fingers or toes has been reported

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[43-46]. Treatment with heparin in such cases is appropriate, although there are no major trials
addressing the efficacy or administration of anticoagulants in this setting. (See "Heparin and
LMW heparin: Dosing and adverse effects".)

Despite the risk of thrombosis, there is little evidence to support the use of prophylactic
anticoagulation in patients with acute or chronic DIC, with the exception of the perioperative
period or during a hospital admission for an acute medical illness, as done for patients without
DIC. In contrast, anticoagulation is generally appropriate for VTE treatment, with indications
similar to individuals without DIC.

Separate topic reviews discuss subjects related to the treatment and prevention of VTE:

● Indications for prophylactic anticoagulation – (See "Prevention of venous thromboembolic

disease in acutely ill hospitalized medical adults" and "Prevention of venous
thromboembolic disease in adult nonorthopedic surgical patients".)

● Anticoagulation in patients with cancer who have a venous or arterial thromboembolism –

(See "Anticoagulation therapy for venous thromboembolism (lower extremity venous
thrombosis and pulmonary embolism) in adult patients with malignancy" and "Nonbacterial
thrombotic endocarditis".)

● Anticoagulation in individuals with thrombocytopenia – (See "Anticoagulation in individuals

with thrombocytopenia".)

● Alternatives to anticoagulation in individuals with contraindications – (See "Overview of the

treatment of lower extremity deep vein thrombosis (DVT)", section on 'Patients with
contraindications to anticoagulation'.)

As noted, mild to moderate thrombocytopenia from DIC (eg, platelet count 50,000 to
150,000/microL) is not a contraindication to anticoagulation for VTE or arterial thromboembolism
(table 6).

Monitoring of anticoagulation in DIC may be complicated because coagulation testing may show
baseline elevation in the prothrombin time (PT) or activated partial thromboplastin time (aPTT).
Institution-specific guidelines, such as use of heparin levels and/or prolongation above
baseline, should be used [47].

Purpura fulminans/protein C deficiency — Patients with homozygous protein C deficiency or

acquired protein C deficiency (eg, due to meningococcemia) may develop purpura fulminans.
(See 'Purpura fulminans' above.)

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Patients with purpura fulminans, including adults, appear to benefit from the administration of
protein C concentrate [26,48-51]. In one series of 12 patients with purpura fulminans so treated,
none died despite a predicted mortality rate of 60 to 80 percent [26]. Intravenous dosing is 100
IU/kg as an initial bolus followed by 50 IU/kg every six hours until D-dimer normalizes or shows
a decreasing trend [51]. (See "Approach to the patient with retiform (angulated) purpura", section
on 'Recognition of life-threatening emergencies' and "Treatment and prevention of
meningococcal infection".)

The administration of FFP as a source of protein C is more difficult because of the short half-life
of protein C in the plasma. Two to three units of FFP may be administered approximately every
six hours if tolerated.

In contrast, protein C deficiency without purpura fulminans is not an indication for using protein
C concentrate.

Protein C concentrate should not be confused with recombinant activated protein C, a product
that was evaluated for sepsis and withdrawn from the market in 2011 due to lack of efficacy. (See
"Investigational and ineffective therapies for sepsis", section on 'Ineffective therapies'.)

COVID-19-specific management — Individuals with coronavirus disease 2019 (COVID-19) have

a number of coagulation abnormalities that appear to be associated with adverse prognosis.

There are no high-quality data to guide management. Acknowledging this lack of evidence, we
agree with interim guidance from the International Society of Thrombosis and Haemostasis
(ISTH), which advises the following [52]:

● Monitor coagulation parameters (PT, aPTT, D-dimer, fibrinogen) and platelet count as a
means of assessing clinical status and prognosis, which may impact decision-making
about level of care and investigational therapies.

● Use prophylactic dose low molecular weight (LMW) heparin (or unfractionated heparin if
LMW heparin is not available) for individuals admitted to the hospital unless
contraindicated. LMW heparin is known to reduce the risk of VTE and may have
antiinflammatory properties.

In a retrospective study of 449 individuals with severe COVID-19, enoxaparin (40 to 60 mg

once daily) appeared to be associated with improved survival, especially in those with a
high D-dimer [34]. However, the survival difference was only seen in a subset of individuals
with a high sepsis-induced coagulopathy score (28-day mortality 40 percent with heparin
versus 64 percent without) or a high D-dimer. In those with a high D-dimer, with the

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magnitude of benefit increased with each multiple of the upper limit of normal, and the
reduced mortality became statistically significant at six times the upper limit of normal (33
versus 52 percent). LMW heparin was not associated with lower 28-day mortality in the
cohort as a whole.

● Treat VTE with anticoagulation, similar to individuals without COVID-19 [39].

● Treat bleeding with transfusions and hemostatic products as needed, similar to individuals
without COVID-19 [39]. However, it should be noted that fibrinogen is often increased in
COVID-19 and supplementation with fibrinogen may not be needed.

Management of coagulation abnormalities in patients with COVID-19 receiving extracorporeal

membrane oxygenation (ECMO) is discussed separately. (See "Coronavirus disease 2019
(COVID-19): Critical care issues", section on 'Additional options' and "Extracorporeal membrane
oxygenation (ECMO) in adults".)

RESOLUTION OF ABNORMALITIES

Unlike bleeding from other causes, such as administration of an anticoagulant, DIC does not
resolve immediately once the inciting factor is corrected. Resolution generally requires
synthesis of coagulation factors, which are produced at different rates; clearance of
anticoagulant factors and fibrin degradation products from the circulation, which depend on
hepatic function; and production of new platelets from the bone marrow, which may take several
days. (See "Overview of hemostasis" and "Megakaryocyte biology and the production of
platelets".)

The laboratory abnormalities associated with DIC will usually begin to improve within a few days
after the inciting trigger is removed or terminated. Resolution of these abnormalities may take
longer if significant liver damage is present, because the liver is the major site of coagulation
factor synthesis and clearance.

Renal failure generally does not interfere with the resolution of DIC unless there is a component
of hepatorenal syndrome or if the kidneys are a major site of thrombosis.

PROGNOSIS

The mortality of DIC is highly dependent on the degree of coagulation impairment as well as the
treatability of the underlying condition. A marked reduction in antithrombin levels at the onset of

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septic shock may be a sensitive marker of unfavorable prognosis, presumably by permitting

persistence of the procoagulant state [35,53]. (See 'Diagnostic evaluation' above.)

The reported mortality rate ranges from 40 to 80 percent in patients with severe sepsis, trauma,
or burns [19,27-29,54-56].

Risk factors for death include increasing age and the severity of the organ dysfunction and
hemostatic abnormalities [6,19,21,57-61]. It is not clear, however, if the poor outcome in sepsis
and trauma reflects the effects of DIC or the consequences of the systemic inflammatory
response. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation,
diagnosis, and prognosis".)

In one study, the median survival of patients with cancer was lower in those with concomitant
DIC versus those without DIC, regardless of the stage of the malignancy (early stage tumors: 16
versus 44 months; advanced stage tumors: 9 versus 14 months) [25].

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."
The Basics patient education pieces are written in plain language, at the 5 th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given condition.
These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are written at the 10 th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topic (see "Patient education: Disseminated intravascular coagulation (The

Basics)")

SUMMARY AND RECOMMENDATIONS

● Common causes of disseminated intravascular coagulation (DIC) include sepsis,

malignancy, and trauma, as well as obstetrical complications and hemolysis from acute
hemolytic transfusion reaction. Additional causes are seen less often but may be

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considered if none of the above conditions are obviously present. (See 'Causes of DIC'
above and "Disseminated intravascular coagulation during pregnancy" and "Hemolytic
transfusion reactions", section on 'Acute hemolytic reactions'.)

● In DIC, the processes of coagulation and fibrinolysis become abnormally (and often
massively) activated within the vasculature, leading to ongoing coagulation and fibrinolysis.
A variety of initiating procoagulants may contribute, including tissue factor (TF), bacterial
products, microparticles, and cell-free DNA (cfDNA) and DNA binding proteins from
neutrophil extracellular traps (NETs). Disruption of the endothelial angiopoietin-TIE2
signaling pathway also plays a central role in the pathogenesis of DIC. (See 'Intravascular
coagulation and fibrinolysis' above and 'Role of extracellular cell-free DNA and DNA-binding
proteins' above and 'Disruption of the endothelial angiopoietin-tyrosine kinase pathway'
above.)

● Acute and chronic DIC represent two ends of a pathogenic balance between coagulation
factor and platelet consumption, and their production (table 2). (See 'Compensatory
changes' above and 'Acute versus chronic DIC' above.)

• Acute DIC generally is seen in patients with a history of sepsis, malignancy (especially
acute promyelocytic leukemia), or ABO-incompatible blood transfusion. Clinical findings
include bleeding; thrombocytopenia; prolonged PT and aPTT; low plasma fibrinogen;
elevated plasma D-dimer; and microangiopathic changes on peripheral blood smear
(picture 1), although none of these are highly specific. (See 'Acute DIC' above.)

• Chronic DIC generally is seen in patients with a history of malignancy, especially

pancreatic, gastric, ovarian, or brain tumors; venous or arterial thromboembolism; mild
or no thrombocytopenia; normal or mildly prolonged PT and aPTT; normal or slightly
elevated plasma fibrinogen; and elevated plasma D-dimer. (See 'Chronic DIC' above.)

● DIC is a clinical and laboratory diagnosis, based on findings of coagulopathy and/or

fibrinolysis in the appropriate setting (figure 1). No single laboratory test can accurately
confirm or eliminate the diagnosis. (See 'Diagnostic evaluation' above.)

● The differential diagnosis of DIC includes other conditions associated with bleeding and
hypercoagulability, such as severe liver disease or heparin-induced thrombocytopenia (HIT),
and other causes of microangiopathic hemolytic anemia (MAHA) and thrombocytopenia
such as thrombotic thrombocytopenic purpura (TTP). A list of causes of an elevated D-dimer
is included in the table (table 4). (See 'Differential diagnosis' above.)

● A major principle in the management of DIC is treatment of the underlying cause in order to

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eliminate the stimulus for ongoing coagulation and thrombosis. (See 'Treat the underlying
cause' above.)

● For patients who are not bleeding, we do not routinely use prophylactic transfusion of
platelets and coagulation factors, as long as the platelet count is ≥10,000/microL. One
international consensus group suggested using a platelet count threshold of 20,000/microL
in the absence of bleeding. However, treatment is justified in patients who have serious
bleeding, are at high risk for bleeding, or require invasive procedures. Platelets and/or
plasma products should not be withheld in these settings for fear of "fueling the fire." In
contrast, the administration of antifibrinolytic agents, such as tranexamic acid (TXA),
epsilon-aminocaproic acid (EACA), or aprotinin, is generally contraindicated. (See
'Prevention/treatment of bleeding' above.)

● There is little evidence to support the use of anticoagulation in patients with acute or chronic
DIC, with the exceptions of prophylaxis during the perioperative period or a hospital
admission for an acute medical illness, and treatment of venous or arterial
thromboembolism. Patients with purpura fulminans appear to benefit from the
administration of protein C concentrate. (See 'Prevention/treatment of thrombosis' above
and "Anticoagulation therapy for venous thromboembolism (lower extremity venous
thrombosis and pulmonary embolism) in adult patients with malignancy" and "Nonbacterial
thrombotic endocarditis".)

● Laboratory abnormalities associated with DIC usually begin to improve within a few days
after the inciting trigger is removed or terminated. Resolution of these abnormalities may
take longer if significant liver damage is present. (See 'Resolution of abnormalities' above.)

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systemic inflammatory response syndrome predict organ dysfunctions after trauma:

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harmonization of the recommendations from three guidelines. J Thromb Haemost 2013.

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coagulation (DIC). Hematology Am Soc Hematol Educ Program 2009; :240.

48. Dreyfus M, Magny JF, Bridey F, et al. Treatment of homozygous protein C deficiency and
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49. Rintala E, Seppälä OP, Kotilainen P, et al. Protein C in the treatment of coagulopathy in
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52. https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.14810 (Accessed on April 13, 2020).

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Topic 1306 Version 38.0

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GRAPHICS

Pathogenesis of disseminated intravascular coagulation

Tex t in blue refers to pathophy s iologic proc es s es ; tex t in green denotes

as s oc iated laboratory abnormalities . R efer to U pToD ate topic s on dis s eminated
intrav as c ular c oagulation for additional details .

NET: neutrophil extracellular trap; PT: prothrombin time; aPTT: activated partial thromboplastin
time; FDPs: fibrin degradation products; dsDNA: double-stranded DNA; MAHA: microangiopathic
hemolytic anemia.

Graphic 98047 Version 3.0

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Coagulation cascade overview

T his s c hematic s hows a rev is ed v ers ion of the c oagulation c as c ade

that emphas izes the importanc e of pathway s for hemos tas is in v iv o.
T is s ue fac tor ex pos ed at a wound interac ts with fac tor V I I a and
initiates c lotting by two pathway s : (1 ) ac tiv ation of fac tor X to X a (ie,
the ex trins ic ten- as e c omplex ) and (2 ) c onv ers ion of fac tor I X to I X a,
whic h ac tiv ates fac tor X to X a (ie, the intrins ic ten- as e c omplex ).
P athway s 1 and 2 are equally important.
I n a third pathway (3 ), thrombin als o ac tiv ates fac tor X I to X I a, whic h
c an lead to further generation of fac tor I X a; it s erv es as an
amplific ation pathway required during s ev ere hemos tatic c hallenges .
C oagulation fac tors are s hown as R oman numerals . O nly the ac tiv ated
forms (with the s uffix " a" ) are s hown in this diagram for s implic ity.
T hrombin is fac tor I I a.

Graphic 90873 Version 9.0

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Peripheral smear in microangiopathic hemolytic

anemia showing presence of schistocytes

P eripheral blood s mear from a patient with a mic roangiopathic

hemoly tic anemia with mark ed red c ell fragmentation. T he s mear
s hows multiple helmet c ells (arrows ) and other fragmented red c ells
(s mall arrowhead); mic ros pheroc y tes are als o s een (large
arrowheads ). T he platelet number is reduc ed; the large platelet in the
c enter (das hed arrow) s ugges ts that the thromboc y topenia is due to
enhanc ed des truc tion.

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 70851 Version 8.0

Normal peripheral blood smear

H igh- power v iew of a normal peripheral blood s mear. S ev eral

platelets (arrowheads ) and a normal ly mphoc y te (arrow) c an als o
be s een. T he red c ells are of relativ ely uniform s ize and s hape. T he
diameter of the normal red c ell s hould approx imate that of the
nuc leus of the s mall ly mphoc y te; c entral pallor (das hed arrow)
s hould equal one- third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 59683 Version 5.0

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Genesis of the schistocyte

T his s c anning elec tron mic rophotograph s hows a red blood c ell (white
arrow) about to be " guillotined" by a fibrin s trand (y ellow arrow),
produc ed as a res ult of intrav as c ular c oagulation. T his res ults in the
formation of a fragmented red blood c ell, termed a s c his toc y te or
" helmet c ell."

From Bull BS, Kuhn IN: The production of schistocytes by fibrin strands (a scanning
electron microscope study). Blood 1970; 35:104. Copyright American Society of
Hematology, used by permission.

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Major causes of disseminated intravascular coagulation

Events that initiate DIC

Septicemia - Gram negative and Gram positive

Crush injury or complicated surgery

Severe head injury

Cancer procoagulant (Trousseau's syndrome)

Acute leukemia, especially promyelocytic

Complications of pregnancy

Amniotic fluid embolism

Abruptio placentae

HELLP syndrome

Eclampsia and severe preeclampsia

Septic abortion

Amphetamine overdose

Giant hemangioma (Kasabach-Merritt syndrome)

Abdominal aortic aneurysm

Peritoneovenous shunt

Acute hemolytic transfusion reaction (ABO incompatibility)

Paroxysmal nocturnal hemoglobinuria

Snake and viper venoms

Liver disease

Fulminant hepatic failure

Reperfusion after liver transplantation

Heat stroke

Burns

Purpura fulminans

Events that complicate and propagate DIC

Shock

Complement pathway activation

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Coagulation parameters in acute and chronic disseminated intravascular

coagulation

A cute (decompensated) Chronic (compensated)

Parameter
DIC DIC

Platelet count Reduced Variable

Prothrombin time (PT) Prolonged Normal

Activated partial thromboplastin time Prolonged Normal

(aPTT)

Thrombin time Prolonged Normal to slightly prolonged

Plasma fibrinogen Reduced Normal to elevated

Plasma factor V Reduced Normal

Plasma factor VIII Reduced Normal

Fibrin degradation products Elevated Elevated

D-dimer Elevated Elevated

I n c hronic D I C , the thrombin time is more s ens itiv e than P T or aP T T to the effec ts of inc reas ed
D - dimer and fibrin degradation produc ts .

DIC: disseminated intravascular coagulation.

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Helmet cells in microangiopathic hemolytic anemia

P eripheral s mears from two patients with mic roangiopathic hemoly tic
anemia, s howing a number of red c ell fragments (ie, s c his toc y tes ), s ome
of whic h tak e the form of c ombat (arrow), bic y c le (arrowhead), or football
(s hort arrow) " helmets ." M ic ros pheroc y tes are als o s een (das hed arrows ),
along with a nuc leated red c ell (thic k arrow).

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 50715 Version 5.0

Normal peripheral blood smear

H igh- power v iew of a normal peripheral blood s mear. S ev eral

platelets (arrowheads ) and a normal ly mphoc y te (arrow) c an als o
be s een. T he red c ells are of relativ ely uniform s ize and s hape. T he
diameter of the normal red c ell s hould approx imate that of the
nuc leus of the s mall ly mphoc y te; c entral pallor (das hed arrow)
s hould equal one- third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 59683 Version 5.0

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Purpura fulminans

A large, retiform, purpuric les ion is pres ent on the leg. P urpura fulminans is
c harac terized by the pres enc e of ex tens iv e purpura.

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.

Graphic 57103 Version 5.0

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Purpura fulminans

S harply demarc ated, purpuric les ions were pres ent in this patient with
purpura fulminans .

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights

reserved.

Graphic 53920 Version 5.0

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Acute meningococcemia

S k in les ions in ac ute meningoc oc c emia c an begin as papules but

quic k ly progres s to petec hiae and purpura. A s s een here, the purpuric
les ions c an c oales c e.

Courtesy of Charles V Sanders. (The Skin and Infection: A Color Atlas and Text,
Sanders CV, Nesbitt, LT Jr [Eds], Williams & Wilkins, Baltimore, 1995).

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Acral purpura in disseminated intravascular coagulation

M ultiple purpuric les ions are pres ent on the hand of this patient with
dis s eminated intrav as c ular c oagulation. S ev eral les ions ex hibit a retiform
s hape.

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.

Graphic 74453 Version 7.0

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Retiform purpura in disseminated intravascular

coagulation

Wides pread retiform purpura are pres ent in this patient with dis s eminated
intrav as c ular c oagulation.

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.

Graphic 61719 Version 6.0

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Laboratory diagnosis of abnormal fibrinolysis

Primary
Test DIC TTP
hyperfibrinolysis

Platelet count Normal Decreased Decreased

Fibrinogen Decreased Decreased Normal

FDP Increased Increased Normal

D-dimer Increased Increased Normal

Antithrombin Normal Decreased Normal

Schistocytes Absent Present Present

Plasma clotting times* Normal or prolonged Prolonged Normal

Euglobulin lysis time Shortened Shortened Normal

ADAMTS13 level Normal Normal ¶ Low (usually <10

percent) Δ

R efer to U pToD ate topic s on dis orders of fibrinoly s is , D I C , and T T P for additional details .

DIC: disseminated intravascular coagulation; TTP: thrombotic thrombocytopenic purpura; FDP: fibrinogen degradation
products; ADAMTS13: von Willebrand factor-cleaving protease (a disintegrin and metalloproteinase with a thrombospondin
type 1 motif, member 13).
* Clotting times include the prothrombin time with international normalized ratio (PT/INR) and the activated partial
thromboplastin time (aPTT).
¶ May be reduced when bacterial sepsis is present.
Δ A normal plasma ADAMTS13 level does not exclude the diagnosis of TTP.

Modified with permission from: Rocha E, Paramo JA, Montes R, Panizo C. Acute generalized, widespread bleeding.
Diagnosis and management. Haematologica 1998; 83:1024. Copyright © 1998 Ferrata Storti Foundation.

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Disorders associated with increased plasma levels of fibrin D-dimer

Arterial thromboembolic disease

Myocardial infarction

Stroke

Acute limb ischemia

Atrial fibrillation

Intracardiac thrombus

Venous thromboembolic disease

Deep vein thrombosis

Pulmonary embolism

Disseminated intravascular coagulation

Preeclampsia and eclampsia

Abnormal fibrinolysis; use of thrombolytic agents

Cardiovascular disease, congestive failure

Severe infection/sepsis/inflammation

Surgery/trauma (eg, tissue ischemia, necrosis)

Systemic inflammatory response syndrome

Vaso-occlusive episode of sickle cell disease

Severe liver disease (decreased clearance)

Malignancy

Renal disease

Nephrotic syndrome (eg, renal vein thrombosis)

Acute renal failure

Chronic renal failure and underlying cardiovascular disease

Normal pregnancy
Venous malformations

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Blood components: Indications and dosing in adults

Component (volume) Contents Indications and dose

Whole blood (1 unit = 500 RBCs, platelets, Rarely required. May be appropriate when massive bleeding
mL) plasma requires transfusion of more than 5 to 7 units of RBCs
(increasingly used in early trauma management).

RBCs in additive solution (1 RBCs Anemia, bleeding. The increase in hemoglobin from 1 unit of
unit = 350 mL) RBCs will be approximately 1 g/dL; the increase in hematocrit
will be approximately 3 percentage points.

FFP or other plasma product* All soluble plasma Bleeding or expected bleeding (eg, emergency surgery) in
(1 unit = 200 to 300 mL) proteins and clotting individuals with deficiencies of multiple coagulation factors
factors (eg, DIC, liver disease, massive transfusion, anticoagulation
with warfarin or warfarin overdose if not corrected by vitamin
K and/or PCC, depending on the clinical setting); therapeutic
plasma exchange in TTP. FFP may be used to manage
bleeding in individuals with isolated factor deficiencies (most
often factor V) if a factor concentrate or recombinant factor is
not available. In the rare event that FFP is used to replace a
clotting factor, the dose is 10 to 20 mg/kg. This dose will
raise the level of any factor, including fibrinogen, by close to
30%, which is typically sufficient for hemostasis.

Cryoprecipitate, also Fibrinogen; factors Bleeding or expected bleeding with low fibrinogen: The
called "cryo" (1 unit = 10 to VIII and XIII; VWF increase in plasma fibrinogen from 1 unit of Cryoprecipitate
20 mL) per 10 kg body weight will be approximately 50 mg/dL.
Bleeding or expected bleeding in individuals with deficiencies
of factor XIII or factor VIII (hemophilia A) if a recombinant
product or factor concentrate is unavailable.
Bleeding or expected bleeding in individuals with VWD if
DDAVP (desmopressin) is ineffective and recombinant VWF or
a VWF concentrate is unavailable.
Cryoprecipitate is generally provided in pools containing 5
units, and most patients receive one to two pools.

Platelets (derived from whole Platelets The platelet count increase from 5 to 6 units of whole blood-
blood or apheresis) (1 unit of derived platelets or 1 unit of apheresis platelets will be
apheresis platelets or a 5 to 6 approximately 30,000/microL in an average-sized adult.
unit pool of platelets from
whole blood = 200 to 300
mL)

R efer to U pToD ate topic s on thes e produc ts and on s pec ific c onditions for details of us e. F rozen
blood produc ts (F F P, C ry oprec ipitate) tak e 1 0 to 3 0 minutes to thaw. I t may tak e the s ame amount
of time to perform an unc omplic ated c ros s matc h.

RBCs: red blood cells; FFP: Fresh Frozen Plasma; DIC: disseminated intravascular coagulation; PCC: prothrombin complex
concentrate; TTP: thrombotic thrombocytopenic purpura; VWF: von Willebrand factor; VWD: von Willebrand disease.
* Other plasma products include Plasma Frozen Within 24 Hours After Phlebotomy (PF24) or Thawed Plasma. PF24 may be
used interchangeably with FFP for all of the indications listed above, with the exceptions of factor VIII deficiency or protein
C deficiency, which are treated with recombinant products or plasma-derived factor concentrates. In the rare event that
specific factor concentrates are unavailable and these deficiencies must be treated with a plasma product, FFP should be
used. Thawed Plasma may be used interchangeably with FFP for all of the indications listed above, with the exception of
factor VIII deficiency without access to factor VIII concentrates, in which FFP should be used; or factor V deficiency, in
which FFP or PF24 should be used.

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Possible contraindications to anticoagulation

Possible contraindication Factors to consider

Active, clinically significant bleeding Site and degree of bleeding (eg, nosebleeds and menses generally are not a
contraindication; active intracerebral bleeding is almost always an
absolute contraindication); interval since bleeding stopped

Severe bleeding diathesis Nature, severity, and reversibility of bleeding diathesis

Severe thrombocytopenia (platelet Absolute platelet count, platelet count trend, and platelet function (eg, some
count <50,000/microL) individuals with ITP and a platelet count in the range of 30,000 to 50,000
may tolerate anticoagulation if needed)

Major trauma Site and extent of trauma, time interval since event (eg, for a patient with a
mechanical heart valve it may be appropriate to anticoagulate sooner after
trauma than a patient with a lesser indication)

Invasive procedure or obstetric Type of procedure and associated bleeding risk, interval between procedure
delivery (recent, emergency, or and anticoagulation
planned)

Previous intracranial hemorrhage Time interval since hemorrhage and underlying cause (eg, trauma or
uncontrolled hypertension)

Intracranial or spinal tumor Site and type of tumor, other comorbidities

Neuraxial anesthesia Interval since spinal/epidural puncture or catheter removal, other alternatives
for anesthesia. Traumatic procedures are more concerning.

Severe, uncontrolled hypertension Absolute blood pressure and blood pressure trend

T his lis t does not tak e the plac e of c linic al judgment in dec iding whether or not to adminis ter an
antic oagulant. I n any patient, the ris k of bleeding from an antic oagulant mus t be weighed agains t the
ris k of thrombos is and its c ons equenc es . T he greater the thromboembolic ris k , the greater the
toleranc e for the pos s ibility of bleeding and for s hortening the time interv al between an epis ode of
bleeding and antic oagulant initiation. R efer to U pToD ate topic s on the s pec ific indic ation for the
antic oagulant and the s pec ific pos s ible c ontraindic ation for dis c us s ions of thes e ris k s .

ITP: immune thrombocytopenia.

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Contributor Disclosures
Law rence LK Leung, MD Nothing to disclose Pier Mannuccio Mannucci, MD Speaker's Bureau: Novo
Nordisk; Bayer; Kedrion Biopharma [Hemophilia, coagulation disorders (Human coagulation factor
VIII)]. Jennifer S Tirnauer, MD Nothing to disclose

Contributor disclosures are review ed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy

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