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Official reprint from UpToDate


www.uptodate.com 2017 UpToDate

Disseminated intravascular coagulation in infants and children

Authors: Wendy Wong, MD, Bertil Glader, MD, PhD


Section Editor: Donald H Mahoney, Jr, MD
Deputy Editor: Carrie Armsby, MD, MPH

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2017. | This topic last updated: Jan 19, 2016.

INTRODUCTION Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by hemorrhage and microvascular
thrombosis. Endothelial tissue damage from a variety of underlying disorders (eg, sepsis, trauma, and malignancy) activates the coagulation
cascade, which promotes fibrin production and deposition, and consumption of clotting factors. The subsequent consumption of coagulation
factors and platelets, enhanced fibrinolysis, and fibrin deposition result in the clinical picture of DIC of a bleeding diathesis accompanied by
thrombosis that may lead to end organ damage (figure 1 and figure 2).

The etiology, clinical manifestations, diagnosis, and treatment of DIC in infants and children will be reviewed here. DIC in adults is discussed
separately. (See "Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in adults".)

PATHOGENESIS The following is a summary of the pathogenesis of disseminated intravascular coagulation (DIC). A more complete
discussion is found elsewhere. (See "Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in adults", section
on 'Pathogenesis'.)

DIC is a secondary process caused by the systemic activation of the coagulation system by tissue damage from a variety of underlying
diseases (eg, sepsis, trauma, and malignancies) [1]. The activation of the intravascular coagulation system initiates the following processes
(figure 1):

Exposure of blood to procoagulants Tissue damage from the initiating primary disease releases procoagulants into the bloodstream.

Formation of fibrin in the circulation Tissue procoagulants activate hemostasis primarily through the interaction of tissue factor and
Factor VII, which promotes fibrin formation and deposition within the microcirculation.

Fibrinolysis Fibrin formation activates the fibrinolysis pathway, which produces plasmin that cleaves fibrinogen and fibrin, thereby
generating fibrin degradation products (FDPs). FDPs interfere with fibrin polymerization and impair platelet aggregation.

Depletion of clotting factors and platelets Ongoing activation of the coagulation system and fibrin deposition consume clotting factors
and platelets.

End-organ damage Deposition of fibrin into the microcirculation of organs results in tissue ischemia and damage.

Hemolysis Intravascular fibrin strands cause mechanical shearing of red blood cells resulting in microangiopathic hemolytic anemia
(picture 1).

ETIOLOGY Disseminated intravascular coagulation (DIC) occurs in a variety of clinical conditions (table 1). In older infants and children,
the major causes of DIC include sepsis, trauma, and malignancies. In the neonate, DIC is caused primarily by sepsis and perinatal
complications (eg, birth asphyxia).

Older infants and children The following discussion is a summary of the causes of DIC in older infants and children, which are similar to
those seen in adults. The pathogenesis of each of these etiologies is discussed in greater detail elsewhere. (See "Clinical features, diagnosis,
and treatment of disseminated intravascular coagulation in adults", section on 'Causes of DIC'.)

Sepsis Sepsis is the most common cause of DIC in older infants and children. DIC was classically recognized as a complication of
endothelial damage produced by meningococcemia. Viral, rickettsial, fungal, parasitic, and other bacterial infections are also associated with
DIC (table 1). (See "Clinical manifestations of meningococcal infection", section on 'Disseminated intravascular coagulation'.)

Trauma and tissue injury In children, DIC potentially is a serious complication of any major trauma or tissue injury. These include crush
injury, massive burns, extensive surgery, severe hypothermia, heat exhaustion, and shock. In all these cases, release of tissue enzymes and
phospholipids from damaged tissue into the systemic circulation triggers activation of the coagulation system. Brain tissue is a potent
thromboplastin and patients who sustain severe brain injury are especially at risk for DIC.

Malignancy In children with leukemia, laboratory abnormalities in the clotting system are common [2,3]. DIC is rare in children with
acute lymphocytic leukemia, although it has been reported in patients with the uncommon t(17;19) translocation [4]. Patients with acute
promyelocytic leukemia can present with acute hemorrhage due to DIC. In these patients, granules within the blast cells contain
procoagulants that directly trigger the coagulation system [5]. (See "Overview of the complications of acute myeloid leukemia".)

Children with malignancies are often leukopenic and may develop DIC secondary to sepsis.

Miscellaneous Other causes of DIC in children include:

Acute hemolytic transfusion reactions Release of adenosine diphosphate and phospholipids from the hemolyzed red cell activate
platelet and the coagulation system respectively.

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Kasabach Merritt (KM) syndrome Patients with kaposiform hemangioendothelioma, an aggressive form of giant hemangioma, can
develop KM syndrome, a localized form of DIC. The large hemangioma consumes fibrinogen and platelets resulting in thrombocytopenia
and consumptive coagulopathy. (See "Extrinsic nonimmune hemolytic anemia due to mechanical damage: Fragmentation hemolysis and
hypersplenism", section on 'Kasabach Merritt syndrome'.)

Snake and spider bites The venom of some snakes and spiders (eg, rattlesnakes and Russell's viper) can directly activate the
coagulation system and lead to DIC.

Liver disease DIC may be seen in patients with acute or chronic hepatocellular disease including Reye's syndrome [6].

Neonates Newborn infants, particularly preterm infants, are vulnerable to DIC because the anticoagulants (antithrombin and protein C) are
normally low at this age [7-10]. The main causes of DIC include sepsis, birth asphyxia, respiratory distress syndrome (RDS), and necrotizing
enterocolitis (NEC) [11].

Sepsis Neonatal viral infections (eg, rubella, herpes, cytomegalovirus, and enterovirus), systemic candidiasis, and bacterial sepsis (eg,
Group B streptococcus and gram-negative organisms) are causes of neonatal DIC. Perinatal acquired infections (eg, TORCH infections) are
also associated with DIC.

Perinatal conditions Perinatal conditions associated with DIC include complications from pregnancy and delivery that lead to birth
asphyxia, and diseases linked to prematurity [12].

Obstetric complications Obstetric complications resulting in fetal anoxia/birth asphyxia may cause neonatal DIC. These include
abruptio placentae, preeclampsia, eclampsia, and fetal distress during labor.

Conditions associated with prematurity DIC is associated with necrotizing enterocolitis (NEC) and respiratory distress syndrome
(RDS), both of which are seen more frequently in premature infants. In patients with NEC, ischemic bowel tissue releases tissue factor,
which activates the coagulation system. Patients with severe RDS are also at risk for DIC presumably due to tissue damage from
hypoxia. Autopsy studies in preterm infants with RDS have demonstrated fibrin deposition not only in the lungs but also the liver and
kidney [13]. (See "Clinical features and diagnosis of necrotizing enterocolitis in newborns".)

Miscellaneous Rare causes of neonatal DIC include hypothermia and massive hemolysis, such as seen in Rh incompatibility.

Congenital disorders Congenital homozygous deficiency of protein C and S can present in the neonatal period with DIC and purpura
fulminans, while neonates who have large hemangiomas can develop Kasabach Merritt syndrome. (See "Extrinsic nonimmune hemolytic
anemia due to mechanical damage: Fragmentation hemolysis and hypersplenism", section on 'Kasabach Merritt syndrome' and "Protein C
deficiency", section on 'Neonatal purpura fulminans'.)

CLINICAL MANIFESTATIONS Although the clinical spectrum and causes of disseminated intravascular coagulation (DIC) are variable in
infants and children, the pathophysiology is the same, with an overwhelmed hemostatic system that is unable to compensate for the ongoing
consumption of clotting factors and platelets. In these patients, clinical bleeding and microthrombosis occur, and coagulation tests are often
abnormal.

Clinical findings vary depending on the severity of DIC. In mild cases, bleeding may only be noted at venipuncture sites, but in other cases
there may be severe hemorrhage and thrombosis with end-organ damage to the kidney, liver, lung, central nervous system (CNS), and
extremities. Hemorrhage is the most common presentation followed by skin manifestations of purpura and acral gangrene (purpura
fulminans).

In neonates, the most common sites of bleeding are the gastrointestinal tract and venipuncture sites [14]. In severe cases, intrapulmonary and
intraventricular hemorrhages occur. Risk factors for DIC in neonates include prematurity, low birth weight, and low Apgar scores (calculator 1)
[12].

LABORATORY FINDINGS Laboratory findings in DIC are classified based upon the pathologic process:

Consumption of coagulation factors and platelets


Increased fibrin formation
Increased fibrinolysis

Consumption Tests that show consumption of clotting factors and platelets include the following (figure 2):

Platelet count Thrombocytopenia (platelet count <100,000/microL) usually is present in patients with DIC. On the peripheral smear,
platelets are large, suggesting a destructive process (picture 1).

Prothrombin time (PT) The PT is prolonged in 50 to 75 percent of cases [15]. A prolonged PT reflects a reduction in the activity of the
extrinsic and common coagulation pathways.

Activated partial thromboplastin time (aPTT) The aPTT is prolonged in 50 to 60 percent of cases [15]. A prolonged aPTT reflects a
reduction in the activity of the intrinsic and common coagulation pathways.

Factor V and VIII levels Both Factor V (common coagulation pathway) and factor VIII (intrinsic pathway) are decreased (figure 2).

Some patients with DIC will have a normal PT and aPTT as noted above. This may be due to circulating activated clotting factors such as
thrombin and factor Xa [15].

Fibrin formation Studies indicative of fibrin formation include:

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Fibrinogen When the fibrinogen concentration is low, it is consistent with a diagnosis of DIC due to its consumption in the formation of
fibrin. However, fibrinogen is not a sensitive test for DIC because it is also an acute phase reactant. When the concentration is normal, it
may represent a significant decrease in a patient whose fibrinogen level should be higher because of the inflammation from his/her
underlying disease.

Thrombin time Thrombin time is prolonged when the fibrinogen concentration is low. FDPs also impair fibrin formation, thereby
prolonging the thrombin time.

Microangiopathic hemolytic anemia Microangiopathic changes on the peripheral smear are suggestive of DIC and are due to
mechanical shearing of red blood cells by intravascular fibrin strands (picture 1).

Fibrinolysis DIC is unlikely if there is no evidence of fibrinolysis as indicated by the following:

Fibrin degradation products (FDPs) FDPs are products of plasmin degradation of fibrinogen and fibrin [15]. They are present in 85 to
100 percent of patients with DIC. However FDPs are not a specific test, since they are also present in patients who have systemic lupus
erythematous, necrotizing enterocolitis, thrombotic events from causes other than DIC, and in some individuals taking oral
contraceptives.

D-dimer D-dimer is a neoantigen produced when cross-linked fibrin is degraded by plasmin. It is elevated in 90 percent of patients with
DIC and is more specific than FDPs [15].

Other studies DIC is also characterized by decreased levels of antithrombin, and protein C and S, which lead to impairment of the
anticoagulant pathway. Despite the decreased concentration of these anticoagulants, their measurement generally is not helpful in clinical
management.

There are several other tests for DIC that may prove to be helpful but are not widely available or used.

Procoagulant activation Commercial assays are available to measure markers of procoagulant activation such as prothrombin
fragment 1.2, fibrinopeptide A and fibrinopeptide B, and thrombin-antithrombin (TAT) complexes.

Fibrinolysis Fibrinolysis can be detected by elevated levels of plasmin and plasmin-antiplasmin (PAP) complex.

Neonates In neonates, establishing normal values for clotting factors and coagulation tests have been hampered by:

Changes in concentration of coagulation factors and coagulation test values with gestational and postnatal age.

Difficulties in obtaining adequate control groups of healthy preterm and term infants.

Normal ranges for coagulation tests and concentrations of specific clotting factors have been reported for full-term infants and preterm infants
(>30 weeks gestation) from birth to six months postnatal age (table 2 and table 3) [9,10]. These values are based upon studies that included
72 term infants [9], 70 preterm infants born at 34 to 36 weeks gestational age (GA), and 67 infants born at 30 to 33 weeks GA [10]. In
extremely preterm infants (GA <27 weeks), factor V and VIII are higher than vitamin K-dependent clotting factors. The level of vitamin
K-dependent factors also increases with increasing gestational age [16].

When interpreting coagulation tests in neonates, it is imperative to recognize the differences in the normal values of coagulation tests between
the neonatal and adult patient [7]. As an example, aPTT is normally prolonged in term infants at birth compared to adults (mean values, 42.9
11.6 versus 33.5 6.8 sec, respectively) [9]. This difference is even greater in the preterm infant (mean value for infants 30 to 36 weeks
gestation, 53.6 26.1) [10]. The aPTT in both preterm and term infants decreases to adult values by six months of age.

Physiologic levels of factors V, VIII, and fibrinogen in term infants are similar to those in adults and can serve as diagnostic markers for DIC in
this age group [7]. In preterm infants, fibrinogen concentration is low and D-dimer is commonly present without DIC, limiting their value in the
diagnosis of DIC. In addition, neonates have relatively decreased amounts of plasma due to their higher hematocrit levels and therefore it is
imperative that the correct anticoagulant to plasma ratio is obtained in the blood specimens to ensure accurate testing.

DIAGNOSIS The diagnosis of overt disseminated intravascular coagulation (DIC) is based upon clinical findings of hemorrhage and
microthrombi in patients with predisposing medical conditions and abnormal coagulation studies.

Laboratory evaluation Although laboratory studies are used to support the diagnosis, there is no single test that is sensitive or specific
enough to assure a definite diagnosis [17]. A reasonable panel of coagulation studies to establish the diagnosis includes:

Complete blood count (CBC)


Prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
D-dimer level
Fibrinogen level
Factor V and VIII levels

Adding to the challenge of establishing the diagnosis, every patient with DIC does not have positive findings consistent with DIC in all
laboratory studies. The most helpful tests clinically are those that indicate the presence of fibrinolysis (eg, FDPs and D-dimers). D-dimer is a
more specific test for DIC than FDPs. The latex agglutination assay for D-dimer is commonly used and is one of the more reliable tests. In
addition, decreased levels of factors V and VIII help substantiate the diagnosis of DIC.

Serial measurements of coagulation parameters are more informative than laboratory measurements performed at a single timepoint. As an
example, a prothrombin time, which is in the upper normal range but is significantly longer than an earlier measurement, reflects the

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consumptive process of DIC and not a normal hemostatic state. Serial measurements of platelet counts that document a downward trend are
a sensitive but not specific sign for DIC [18].

Scoring systems Various scoring systems have been developed to assist in diagnosing DIC. These scoring systems have been validated
largely in adult patients and there are limited data available in pediatric patients.

International Society on Thrombosis and Haemostasis The International Society on Thrombosis and Haemostasis (ISTH) scoring
system is one of the most widely used methods. It assesses patients with an underlying medical condition known to be associated with
DIC (table 1) and is based upon readily available global coagulation tests (platelet count, FDPs, PT, and fibrinogen) (table 4) [19]. Scores
are dependent on the degree of abnormality measured by each test (eg, a platelet count <50,000/microL is scored higher than
<100,000/microL).

The ISTH scoring system has been validated in adult patients and has been found to correlate with mortality and morbidity risk [20,21].
Limited pediatric data suggest that this scoring system also performs reasonably well in pediatric patients [22,23].

Japanese Association for Acute Medicine The Japanese Association for Acute Medicine (JAAM) scoring system for DIC is similar to
the ISTH system in that it uses the same four laboratory parameters (platelet count, FDPs, PT, and fibrinogen) (table 5) [24,25]. However,
the JAAM scoring system places more attention on trends in platelet counts rather than a single measurement. In a multicenter
prospective study, the JAAM scoring system had better prognostic value compared with the ISTH system in predicting adverse outcomes
in adult patients with severe sepsis [26]. The JAAM scoring system has not been validated in pediatric patients.

Neonates Similar to older patients, the diagnosis of DIC in the neonate relies on abnormal global coagulation tests in the appropriate
clinical setting [27]. However, it is more difficult to establish the diagnosis of DIC in these neonates. Testing is limited because the volume of
blood required may be difficult to obtain in the neonate. In addition, the interpretation of these studies in the neonate is challenging as the
hemostatic system is still in a state of flux at birth with physiologic alterations of coagulation and fibrinolysis. As a result, the diagnosis of DIC
in the neonate may rely more heavily on the patient's clinical manifestations than on laboratory studies. The recognition of the underlying
condition rather than establishing the diagnosis of DIC is more important as the most important therapeutic intervention is to treat the
underlying disorder. (See 'Neonates' above and 'Treatment' below.)

DIFFERENTIAL DIAGNOSIS The differential diagnosis for disseminated intravascular coagulation (DIC) is broad and includes those
diseases that present with bleeding. The laboratory evaluation, however, usually differentiates DIC from these other diseases. (See "Approach
to the child with bleeding symptoms".)

Thrombocytopenia and normal coagulation tests In children, the main cause of destructive thrombocytopenia is immune
thrombocytopenia (ITP). It is differentiated from DIC as patients with ITP have normal coagulation tests. In contrast to patients with DIC who
may be ill-appearing, the vast majority of patients with ITP are well appearing apart from findings of petechiae and ecchymoses. (See
"Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis".)

Hemolytic uremic syndrome (HUS), like DIC, presents with thrombocytopenia and microangiopathic hemolytic anemia. Although in most
patients with HUS, PT and aPTT are normal, severe cases may have abnormal coagulation tests. In these patients, the history and clinical
setting are important to differentiate between the two conditions. (See "Clinical manifestations and diagnosis of Shiga toxin-producing
Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children".)

Causes of thrombocytopenia in children are reviewed in detail separately. (See "Causes of thrombocytopenia in children".)

Neonate In the neonate, causes of consumptive thrombocytopenia without evidence of other coagulation abnormalities include:

Alloimmune neonatal thrombocytopenia


Maternal idiopathic thrombocytopenia
Renal vein thrombosis
Bacterial and viral infections

Causes of thrombocytopenia in neonates are reviewed in detail separately. (See "Causes of neonatal thrombocytopenia".)

Abnormal coagulation tests and normal platelet count There are many conditions that present with bleeding and have abnormal PT
and aPTT but a normal platelet count. These include genetic disorders of specific clotting factor deficiency (eg, Hemophilia due to factors VIII
and IX deficiency), and are discussed elsewhere. (See "Approach to the child with bleeding symptoms", section on 'Normal initial testing'.)

Hepatic failure and vitamin K deficiency have similar clinical findings as those with DIC but have normal platelet counts. Bleeding from the
latter is often seen in neonates who do not receive prophylactic vitamin K at birth.

Normal coagulation tests and platelet count Children with disorders of platelet function (eg, Glanzmann thrombasthenia), factor XIII
deficiency, and fibrinolytic pathway defects (eg, plasminogen activator inhibitor, PAI-1, deficiency) can present with bleeding diathesis but their
screening coagulation tests and platelet counts will be normal.

TREATMENT Disseminated intravascular coagulation (DIC) is a serious complication of the underlying primary disease. As a result,
successful treatment of DIC is dependent on identifying and treating the underlying cause, thereby removing the triggering factors implicated
in the DIC process. In some cases, successful treatment of the underlying cause will lead to resolution of DIC. In others, despite vigorous
therapy directed towards the primary disease, coagulation abnormalities persist resulting in significant hemorrhage and/or thrombosis with
organ damage. These patients have a high rate of mortality, and as a result, commonly receive DIC supportive therapy.

There is no consensus on how supportive therapy should be used due to the paucity of data. In general, supportive care is divided into
component replacement and anticoagulation therapy. Treatment is individualized based upon a patient's age, severity of clinical symptoms,

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underlying primary disorder, and overall clinical status.

Replacement therapy There have been no randomized controlled trials to study the efficacy of platelet, fresh frozen plasma (FFP), or
cryoprecipitate transfusions in children or adults with DIC. Nevertheless, the use of these agents seems rational in patients with significant
bleeding due to thrombocytopenia and clotting factor consumption [28].

Our approach for replacement therapy in patients with DIC is as follows:

Replacement therapy should not be routinely given to correct coagulation tests or to address mild clinical signs of bleeding (eg, a few
petechiae or positive guaiac test) [5].

Replacement therapy is indicated in patients with clinically significant bleeding symptoms (eg, melena or prolonged bleeding from
venipuncture sites) or who are at high risk for bleeding because of an impending invasive procedure.

The goal of replacement therapy is to reduce or stop significant bleeding. Although replacement therapy should not be used to normalize
laboratory tests (which often is impossible), a reasonable guide for the judicious use of blood components in the setting of clinically
significant bleeding includes maintaining platelet counts >50,000/microL and fibrinogen concentration >100 mg/dL (1 mol/L) [29].

Clotting factors can be replaced by either FFP or cryoprecipitate. FFP provides both procoagulant and anticoagulant proteins and is
administered every 12 to 24 hours at a dose of 10 to 15 mL/kg per infusion. Cryoprecipitate has higher concentrations of factor VIII and
fibrinogen, and can be used to correct hypofibrinogenemia. It is administered every 6 hours as needed at a dose of 10 mL/kg per infusion.
Platelet transfusions are administered with a goal of maintaining the platelet counts >50,000/microL.

Repeat transfusions may be necessary. The theoretical concern of replacement therapy increasing thrombotic risk by "adding fuel to the fire"
has not been demonstrated [15], and should not dissuade the clinician from administering replacement therapy to control significant bleeding.
Clinicians should monitor for volume overload in patients who receive factor replacement.

Anticoagulation Anticoagulation therapy can be divided into administration of extrinsic anticoagulants (ie, heparin) or restoration of
endogenous anticoagulant proteins (ie, antithrombin).

Heparin Heparin has a very limited role in the management of DIC. In adults with DIC, heparin is sometimes used in treatment doses for
patients with predominantly thrombotic manifestations and without bleeding, or in prophylactic doses for critically ill patients without bleeding
[27]. In children, it is our practice to administer heparin only to patients with life-threatening or symptomatic thrombi (eg, acral ischemia or skin
infection) without clinical bleeding. Heparin is contraindicated in patients with central nervous system (CNS) injury or liver failure. (See
"Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in adults", section on 'Prevention/treatment of
thrombosis'.)

Except for the unusual patients described above, heparin is generally avoided for patients with DIC because of its potential to exacerbate
bleeding, and because there are no controlled trials that demonstrate a benefit in children or adults with DIC. In the past, heparin was
routinely used in patients with clinically overt thrombosis and potential end-organ failure, but there is little evidence that its use improved organ
dysfunction.

If the clinical decision is made to administer therapeutic doses of heparin, continuous infusion of unfractionated heparin is probably the best
choice because of the risk of bleeding. The starting dose of unfractionated heparin should be lower at 5 to 10 units/kg per hour, by constant
intravenous infusion. For children with DIC, loading doses generally should not be used. Low molecular weight heparin (LMWH) has been
used in adults with DIC but there are no data to assess its effectiveness in children with sepsis. In children, anti-factor Xa levels should be
monitored during treatment with either unfractionated heparin or LMWH. (See "Diagnosis and treatment of venous thrombosis and
thromboembolism in infants and children", section on 'Unfractionated heparin' and "Diagnosis and treatment of venous thrombosis and
thromboembolism in infants and children", section on 'LMW heparin'.)

Anticoagulant restoration The levels of both antithrombin and protein C are decreased in DIC. It is reasonable to think that
administration of these anticoagulants may have a beneficial effect in management as restoration of these proteins may reduce
microthrombus formation. In addition to fresh frozen plasma, which provides anticoagulant and procoagulant factors, there are specific protein
C and antithrombin concentrates.

Human protein C concentrate Protein C concentrate is not biologically active on administration; it is converted to the activated form in
vivo. Its clinical utility is limited to very specific disorders:

Congenital protein C deficiency Human protein C concentrate is effective for prophylaxis and treatment of venous thrombosis and
purpura fulminans in patients with severe congenital protein C deficiency. (See "Management of thrombosis in the newborn", section
on 'Neonatal purpura fulminans'.)

Severe sepsis and purpura fulminans Limited evidence suggests that human protein C concentrate may be effective in selected
patients with severe sepsis and purpura fulminans. In a randomized, placebo-controlled, dose-finding study in 40 children with
severe meningococcal sepsis with purpura fulminans, administration of protein C concentrate yielded increased plasma levels of
activated protein C, improvement of coagulation defects, and no adverse reaction. However, this study was underpowered to detect
survival outcome [30]. A European retrospective study of 94 pediatric patients with sepsis (mainly meningococcemia) reported that
patients given protein C concentrate had clinical improvement of DIC, with lower amputation and skin graft rates, and without an
increased risk of bleeding compared with historic controls [31]. These preliminary data are encouraging and supportive for a potential
role of protein C concentrates in severe DIC with sepsis. However, more data on safety and efficacy of protein C concentrates are
needed before it can be recommended for treatment of DIC. (See "Septic shock in children: Ongoing management after
resuscitation", section on 'Treat disseminated intravascular coagulation'.)

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Activated protein C concentrate Recombinant activated protein C (aPC, drotrecogin alfa) is not recommended for treatment of DIC or
other coagulation disorders, and is no longer available. Although beneficial effects of this drug were initially reported in patients with
sepsis, further randomized studies in adults and children failed to show benefit [32]. Furthermore, there appears to be a risk for bleeding
complications in infants younger than two months of age, as suggested by a systematic review of five randomized trials [33]. Drotrecogin
alfa was voluntarily removed from the world market in 2011. (See "Investigational and ineffective therapies for sepsis", section on
'Ineffective therapies'.)

Antithrombin In children, there are minimal data on the use of antithrombin [34]. In adults, data suggest that antithrombin proved no
benefit in patients with severe sepsis or shock. Antithrombin should not be used until further studies demonstrate that it is effective and
safe. (See "Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in adults", section on 'Treatment'.)

Investigational therapy Recombinant human soluble thrombomodulin (Recomodulin: Asahi Kasei Pharma, Tokyo, Japan), a new
agent which inactivates coagulation by binding to thrombin and activates protein C, is being investigated in patients with DIC [35,36]. A
phase III clinical trial in Japanese patients greater than 15 years of age with DIC from infection or malignancy, showed promising results
in comparison to heparin therapy [37].

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

SUMMARY AND RECOMMENDATIONS

Disseminated intravascular coagulation (DIC) is an acquired syndrome due to activation of the coagulation system by a variety of
underlying disorders (eg, sepsis, trauma, and malignancy) (table 1). (See 'Pathogenesis' above and 'Etiology' above.)

Clinical manifestations vary depending on the ability of the hemostatic system to compensate for the ongoing depletion of coagulation
factors and platelets. (See 'Clinical manifestations' above.)

The diagnosis of DIC is based upon clinical findings of hemorrhage and microthrombi in patients with predisposing underlying conditions,
and abnormal coagulation tests. No single test can be used to confirm the diagnosis. Laboratory values must be evaluated in aggregate,
and serial testing is more informative than single measurements. Scoring systems have been developed to assist in diagnosing DIC
(table 4 and table 5). When evaluating neonates, it is important to recognize that neonatal values of laboratory tests used to establish the
diagnosis of DIC differ considerably from adult values (table 2 and table 3). (See 'Diagnosis' above and 'Neonates' above.)

The differential diagnosis for DIC is broad and includes diseases that present with bleeding. The laboratory evaluation usually
differentiates DIC from other causes of bleeding in children. (See 'Differential diagnosis' above.)

A major principle in the management of DIC in pediatric patients is treatment of the underlying primary disease. In patients with clinically
significant bleeding, we recommend the administration of replacement therapy with platelets and coagulation factors (Grade 1C). (See
'Treatment' above.)

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REFERENCES

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8. Kreuz W, Veldmann A, Fischer D, et al. Neonatal sepsis: a challenge in hemostaseology. Semin Thromb Hemost 1999; 25:531.
9. Andrew M, Paes B, Milner R, et al. Development of the human coagulation system in the full-term infant. Blood 1987; 70:165.
10. Andrew M, Paes B, Milner R, et al. Development of the human coagulation system in the healthy premature infant. Blood 1988; 72:1651.
11. Veldman A, Fischer D, Nold MF, Wong FY. Disseminated intravascular coagulation in term and preterm neonates. Semin Thromb
Hemost 2010; 36:419.

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12. Woods WG, Luban NL, Hilgartner MW, Miller DR. Disseminated intravascular coagulation in the newborn. Am J Dis Child 1979; 133:44.
13. GAJL-PECZALSKA K. PLASMA PROTEIN COMPOSITION OF HYALINE MEMBRANE IN THE NEWBORN AS STUDIES BY
IMMUNOFLUORESCENCE. Arch Dis Child 1964; 39:226.
14. Buchanan GR. Coagulation disorders in the neonate. Pediatr Clin North Am 1986; 33:203.
15. Bick RL. Disseminated intravascular coagulation current concepts of etiology, pathophysiology, diagnosis, and treatment. Hematol Oncol
Clin North Am 2003; 17:149.
16. Poralla C, Traut C, Hertfelder HJ, et al. The coagulation system of extremely preterm infants: influence of perinatal risk factors on
coagulation. J Perinatol 2012; 32:869.
17. Favaloro EJ. Laboratory testing in disseminated intravascular coagulation. Semin Thromb Hemost 2010; 36:458.
18. Akca S, Haji-Michael P, de Mendona A, et al. Time course of platelet counts in critically ill patients. Crit Care Med 2002; 30:753.
19. Taylor FB Jr, Toh CH, Hoots WK, et al. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated
intravascular coagulation. Thromb Haemost 2001; 86:1327.
20. Bakhtiari K, Meijers JC, de Jonge E, Levi M. Prospective validation of the International Society of Thrombosis and Haemostasis scoring
system for disseminated intravascular coagulation. Crit Care Med 2004; 32:2416.
21. Toh CH, Hoots WK, SSC on Disseminated Intravascular Coagulation of the ISTH. The scoring system of the Scientific and
Standardisation Committee on Disseminated Intravascular Coagulation of the International Society on Thrombosis and Haemostasis: a
5-year overview. J Thromb Haemost 2007; 5:604.
22. Khemani RG, Bart RD, Alonzo TA, et al. Disseminated intravascular coagulation score is associated with mortality for children with
shock. Intensive Care Med 2009; 35:327.
23. Soundar EP, Jariwala P, Nguyen TC, et al. Evaluation of the International Society on Thrombosis and Haemostasis and institutional
diagnostic criteria of disseminated intravascular coagulation in pediatric patients. Am J Clin Pathol 2013; 139:812.
24. Gando S, Iba T, Eguchi Y, et al. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for
critically ill patients: comparing current criteria. Crit Care Med 2006; 34:625.
25. Gando S, Saitoh D, Ogura H, et al. Natural history of disseminated intravascular coagulation diagnosed based on the newly established
diagnostic criteria for critically ill patients: results of a multicenter, prospective survey. Crit Care Med 2008; 36:145.
26. Gando S, Saitoh D, Ogura H, et al. A multicenter, prospective validation study of the Japanese Association for Acute Medicine
disseminated intravascular coagulation scoring system in patients with severe sepsis. Crit Care 2013; 17:R111.
27. Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British
Committee for Standards in Haematology. Br J Haematol 2009; 145:24.
28. Williams MD, Chalmers EA, Gibson BE, Haemostasis and Thrombosis Task Force, British Committee for Standards in Haematology.
The investigation and management of neonatal haemostasis and thrombosis. Br J Haematol 2002; 119:295.
29. Franchini M, Manzato F. Update on the treatment of disseminated intravascular coagulation. Hematology 2004; 9:81.
30. de Kleijn ED, de Groot R, Hack CE, et al. Activation of protein C following infusion of protein C concentrate in children with severe
meningococcal sepsis and purpura fulminans: a randomized, double-blinded, placebo-controlled, dose-finding study. Crit Care Med
2003; 31:1839.
31. Veldman A, Fischer D, Wong FY, et al. Human protein C concentrate in the treatment of purpura fulminans: a retrospective analysis of
safety and outcome in 94 pediatric patients. Crit Care 2010; 14:R156.
32. Nadel S, Goldstein B, Williams MD, et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised
controlled trial. Lancet 2007; 369:836.
33. Mart-Carvajal AJ, Sol I, Lathyris D, Cardona AF. Human recombinant activated protein C for severe sepsis. Cochrane Database Syst
Rev 2011; :CD004388.
34. Hanada T, Abe T, Takita H. Antithrombin III concentrates for treatment of disseminated intravascular coagulation in children. Am J
Pediatr Hematol Oncol 1985; 7:3.
35. Ogawa E, Yagasaki H, Kato M, et al. Successful treatment of disseminated intravascular coagulation in a child with acute myelogenous
leukaemia using recombinant thrombomodulin. Br J Haematol 2010; 149:911.
36. Shirahata A, Mimuro J, Takahashi H, et al. Postmarketing Surveillance of Recombinant Human Soluble Thrombomodulin
(Thrombomodulin ) in Pediatric Patients With Disseminated Intravascular Coagulation. Clin Appl Thromb Hemost 2014; 20:465.
37. Saito H, Maruyama I, Shimazaki S, et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated
intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 2007; 5:31.

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GRAPHICS

Pathophysiology of the clinical manifestations of disseminated


intravascular coagulation

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Intrinsic, extrinsic, and common coagulation pathways

Schematic representation of the intrinsic (in red), extrinsic (in blue), and
common (in green) coagulation pathways. Contact factors include prekallikrein
and high molecular weight kininogen (HMWK). In the clinical laboratory, the
intrinsic (and common) pathway is assessed by the activated partial
thromboplastin time (aPTT) and the extrinsic (and common) pathway by the
prothrombin time (PT). The thrombin time (TT) assesses the final step in the
common pathway, the conversion of fibrinogen to fibrin, following the addition of
exogenous thrombin. Fibrin is crosslinked through the action of factor XIII,
making the final fibrin clot insoluble in 5 Molar urea or monochloroacetic acid.
This latter function is not tested by the PT, aPTT, or TT.

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Peripheral smear in microangiopathic hemolytic anemia


showing presence of schistocytes

Peripheral blood smear from a patient with a microangiopathic hemolytic anemia


with marked red cell fragmentation. The smear shows multiple helmet cells
(arrows) and other fragmented red cells (small arrowhead); microspherocytes
are also seen (large arrowheads). The platelet number is reduced; the large
platelet in the center (dashed arrow) suggests that the thrombocytopenia is due
to enhanced destruction.

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 70851 Version 8.0

Normal peripheral blood smear

High-power view of a normal peripheral blood smear. Several platelets


(arrows) and a normal lymphocyte (arrowhead) can also be seen. The red
cells are of relatively uniform size and shape. The diameter of the normal red
cell should approximate that of the nucleus of the small lymphocyte; central
pallor (dashed arrow) should equal one-third of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).

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Causes of disseminated intravascular coagulation in children

Infection
Bacteria - Meningococcus, Gram positive and negative bacterial sepsis

Virus - Human immunodeficiency virus, Varicella-zoster, cytomegalovirus (CMV), Dengue fever, Ebola virus

Fungal - Candida, Aspergillus

Rickettsia - Rocky Mountain Spotted fever

Malaria

Injury
Brain injury

Crush injury

Massive burns

Extensive surgery

Malignancy
Acute promyelocytic leukemia

Acute lymphoblastic leukemia

Microangiopathic disorders
Giant hemangioma - Kasabach-Merritt syndrome

Gastrointestinal disease
Acute and chronic liver disease

Reye syndrome

Neonatal causes
Birth asphyxia

Respiratory distress syndrome

Meconium aspiration

Amniotic fluid aspiration

Necrotizing enterocolitis

Congenital infections - Neonatal CMV, Herpes simplex virus, bacterial or fungal infections

Congenital thrombotic disorders


Homozygous deficiencies of proteins C and S

Antithrombin III deficiency

Courtesy of Wendy Wong, MD and Bertil Glader MD, PhD.

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Reference values for coagulation tests in the healthy full-term infant during the first 6 months of life

Tests Day 1 (n) Day 5 (n) Day 30 (n) Day 90 (n) Day 180 (n) Adult (n)

PT (s) 13.0 1.43 (61)* 12.4 1.46 (77)* 11.8 1.25 (67)* 11.9 1.15 (62)* 12.3 0.79 (47)* 12.4 0.78 (29)

APTT (s) 42.9 5.80 (61) 42.6 8.62 (76) 40.4 7.42 (67) 37.1 6.52 (62)* 35.5 3.71 (47)* 33.5 3.44 (29)

TCT (s) 23.5 2.38 (58)* 23.1 3.07 (64) 24.3 2.44 (53)* 25.1 2.32 (52)* 25.5 2.86 (41)* 25.0 2.66 (19)

Fibrinogen (g/L) 2.83 0.58 (61)* 3.12 0.75 (77)* 2.70 0.54 (67)* 2.43 0.68 (60)* 2.51 0.68 (47)* 2.78 0.61 (29)

II (U/mL) 0.48 0.11 (61) 0.63 0.15 (76) 0.68 0.17 (67) 0.75 0.15 (62) 0.88 0.14 (47) 1.08 0.19 (29)

V (U/mL) 0.72 0.18 (61) 0.95 0.25 (76) 0.98 0.18 (67) 0.90 0.21 (62) 0.91 0.18 (47) 1.06 0.22 (29)

VII (U/mL) 0.66 0.19 (60) 0.89 0.27 (75) 0.90 0.24 (67) 0.91 0.26 (62) 0.87 0.20 (47) 1.05 0.19 (29)

VIII (U/mL) 1.00 0.39 (60)* 0.88 0.33 (75)* 0.91 0.33 (67)* 0.79 0.23 (62)* 0.73 0.18 (47) 0.99 0.25 (29)

vWF (U/mL) 1.53 0.67 (40) 1.40 0.57 (3) 1.28 0.59 (40) 1.18 0.44 (40) 1.07 0.45 (46) 0.92 0.33 (29)

IX (U/mL) 0.53 0.19 (59) 0.53 0.19 (75) 0.51 0.15 (67) 0.67 0.23 (62) 0.86 0.25 (47) 1.09 0.27 (29)

X (U/mL) 0.40 0.14 (60) 0.49 0.15 (76) 0.59 0.14 (67) 0.71 0.18 (62) 0.78 0.20 (47) 1.06 0.23 (29)

XI (U/mL) 0.38 0.14 (60) 0.55 0.16 (74) 0.53 0.13 (67) 0.69 0.14 (62) 0.86 0.24 (47) 0.97 0.15 (29)

XII (U/mL) 0.53 0.20 (60) 0.47 0.18 (75) 0.49 0.16 (67) 0.67 0.21 (62) 0.77 0.19 (47) 1.08 0.28 (29)

PK (U/mL) 0.37 0.16 (45) 0.48 0.14 (51) 0.57 0.17 (48) 0.73 0.16 (46) 0.86 0.15 (43) 1.12 0.25 (29)

HMW-K (U/mL) 0.54 0.24 (47) 0.74 0.28 (63) 0.77 0.22 (50)* 0.82 0.32 (46)* 0.82 0.23 (48)* 0.92 0.22 (29)

XIIIa (U/mL) 0.79 0.26 (44) 0.94 0.25 (49)* 0.93 0.27 (44)* 1.04 0.34 (44)* 1.04 0.29 (41)* 1.05 0.25 (29)

XIIIb (U/mL) 0.76 0.23 (44) 1.06 0.37 (47)* 1.11 0.36 (45)* 1.16 0.34 (44)* 1.10 0.30 (41)* 0.97 0.20 (29)

Plasminogen (CTA, 1.95 0.35 (44) 2.17 0.38 (60) 1.98 0.36 (52) 2.48 0.37 (44) 3.01 0.40 (47) 3.36 0.44 (29)
U/mL)

All factors except fibrinogen and plasminogen are expressed as units per milliliter where pooled plasma contains 1.0 U/mL. Plasminogen units are
those recommended by the Committee on Thrombolytic Agents (CTA). AU values are expressed as mean 1 SD.

VIII: factor VIII procoagulant.


* Values that do not differ statistically from the adult values.
These measurements are skewed because of a disproportionate number of high values. The lower limit that excludes the lower 2.5th percentile of the
population has been given in the respective figure. The lower limit for factor VIII was 0.50 U/mL at all time points for the infant.

Reprinted from: Andrew, M, Paes, B, Milner, R, et al. Development of the Human Coagulation System in the Full-Term Infant. Blood 1987; 70:165. Copyright
American Society of Hematology.

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Reference values for coagulation tests in healthy premature infants (30 to 36 weeks gestation) during first
6 months of life

Day 1 Day 5 Day 30 Day 90 Day 180 Adult


Tests
M B M B M B M B M B M B

PT (s) 13 (10.6-16.2)* 12.5 (10-15.3)* 11.8 (10-13.6)* 12.3 (10-14.6)* 12.5 (10-15)* 12.4 (10.8-13.9)

APTT (s) 53.6 (27.5-79.4) 50.5 (26.9-74.1) 44.7 (26.9-62.5) 39.5 (28.3-50.7) 37.5 (21.7-53.3)* 33.5 (26.6-40.3)

TCT (s) 24.8 (19.2-30.4)* 24.1 (18.8-29.4)* 24.4 (18.8-29.9)* 25.1 (19.4-30.8)* 25.2 (18.9-31.5)* 25 (19.7-30.3)

Fibrinogen 2.43 (1.5-3.73)* 2.80 (1.6-4.18)* 2.54 (1.5-4.14)* 2.46 (1.5-3.52)* 2.28 (1.5-3.6) 2.78 (1.56-4)
(g/L)

II (u/mL) 0.45 (0.2-0.77) 0.57 (0.29-0.85) 0.57 (0.36-0.95) 0.68 (0.3-1.06) 0.87 (0.51-1.23) 1.08 (0.7-1.46)

V (U/mL) 0.88 (0.41-1.44)* 1 (0.46-1.54) 1.02 (0.48-1.56) 0.99 (0.59-1.39) 1.02 (0.58-1.46) 1.06 (0.62-1.5)

VII (U/mL) 0.67 (0.21-1.13) 0.84 (0.3-1.38) 0.83 (0.21-1.45) 0.87 (0.31-1.43) 0.99 (0.47-1.51)* 1.05 (0.67-1.43)

VIII (U/mL) 1.11 (0.5-2.13)* 1.15 (0.53-2.05)* 1.11 (O.50- 1.06 (0.58-1.88)* 0.99 (0.5-1.87)* 0.99 (0.5-1.49)
l.99)*

vWF (U/mL) 1.36 (0.78-2.1) 1.33 (0.72-2.19) 1.36 (0.66-2.16) 1.12 (0.75-l.84)* 0.98 (0.54-1.58)* 0.92 (0.5-1.58)

IX (U/mL) 0.35 (0.19-0.65) 0.42 (0.14-0.74) 0.44 (0.13-0.80) 0.59 (0.25-0.93) 0.81 (0.5-1.2) 1.09 (0.55-1.63)

X (U/mL) 0.41 (0.11-0.71) 0.51 (0.19-0.83) 0.56 (0.2-0.92) 0.67 (0.35-0.99) 0.77 (0.35-1.19) 1.06 (0.7-1.52)

XI (U/mL) 0.3 (0.08-0.52) 0.41 (0.13-0.69) 0.43 (0.15-0.71) 0.59 (0.25-0.93) 0.78 (0.46-1.1) 0.97 (0.67-1.27)

XII (U/mL) 0.38 (0.1-0.66) 0.39 (0.09-0.69) 0.43 (0.11-0.75) 0.61 (0.15-1.07) 0.82 (0.22-1.42) 1.08 (0.52-1.64)

PK (U/mL) 0.33 (0.09-0.57) 0.45 (0.26-0.75) 0.59 (0.31-0.87) 0.79 (0.37-1.21) 0.78 (0.4-1.16) 1.12 (0.62-1.62)

HMWK 0.49 (0.09-0.89) 0.62 (0.24-1) 0.64 (0.16-1.12) 0.78 (0.32-1.24) 0.83 (0.41-1.25)* 0.92 (0.5-1.36)
(U/mL)

XIIIa 0.7 (0.32-1.08) 1.01 (0.57-1.45)* 0.99 (0.51-1.47)* 1.13 (0.71-1.55)* 1.13 (0.65-1.61)* 1.05 (0.55-1.55)
(U/mL)

XIIIb 0.81 (0.35-1.27) 1.1 (0.68-1.58)* 1.07 (0.57-1.57)* 1.21 (0.75-1.67) 1.15 (0.67-1.63) 0.97 (0.57-1.37)
(U/mL)

Plasminogen 1.7 (1.12-2.48) 1.91 (1.21-2.61) 1.81 (1.09-2.53) 2.38 (1.58-3.18) 2.75 (1.91-3.59) 3.36 (2.48-4.24)
(CTA, U/mL)

All factors except fibrinogen and plasminogen are expressed as U/mL, where pooled plasma contains 1.0 U/mL. Plasminogen units are those
recommended by the Committee on Thrombolytic Agents (CTA). All values are given as a mean (m) followed by lower and upper boundary
encompassing 95 percent of the population (B). Between 40 and 96 samples were assayed for each value for newborns.

PT: prothrombin time; APTT: activated partial thromboplastin time; TCT: thrombin clotting time; vWF: von Willebrand factor; PK: prekallikrein; HMWK: high
molecular weight kininogen.
* Values indistinguishable from those of adults.
Measurements are skewed owing to a disproportionate number of high values. Lower limit which excludes the lower 2.5 percent of the population is given (B).
Values different from those of full term infants.

Reprinted from: Andrew M, Paes B, Milner R, et al. Development of the Human Coagulation System in the Healthy Premature Infant. Blood 1988; 72:1651.
Copyright 1988 The American Society of Hematology.

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International Society on Thrombosis and Haemostasis (ISTH) scoring system for disseminated
intravascular coagulation (DIC)

1. Risk assessment: Does the patient have an underlying disorder known to be associated with overt DIC?*

If yes, proceed.
If no, do not use this scoring system.

2. Obtain the following laboratory tests:

Platelet count
Fibrin-related markers (eg, fibrin degradation products [FDPs], soluble fibrin monomers, D-dimer )
Prothrombin time (PT)
Fibrinogen

3. Assign score for each laboratory parameter: Score:

Platelet count (per microL):

>100,000 0

50,000 to 100,000 1

<50,000/microL = 2

Fibrin-related markers (eg, FDPs, D-dimer ):

No increase 0

Moderate increase 2

Strong increase 3

PT:

Prolonged <3 seconds 0

Prolonged 3 to 6 seconds 1

Prolonged >6 seconds 2

Fibrinogen level:

>100 mg/dL (>1.0 g/L) 0

<100 mg/dL (>100 g/L) 1

4. Calculate total score: Add individual scores for each laboratory parameter.

5. Score interpretation:

5: Compatible with overt DIC. Repeat scoring daily.


<5: Suggestive (not affirmative) for non-overt DIC. Repeat in 1 to 2 days.

* Causes of DIC in children include infection, trauma, burns, malignancy, acute and chronic liver disease (including Reye syndrome), microangiopathic disorders
(eg, Kasabach-Merritt syndrome), and congenital thrombotic disorders (eg, homozygous deficiencies of protein C and S, antithrombin III deficiency). Additional
causes in neonates include birth asphyxia, respiratory distress syndrome, meconium aspiration, amniotic fluid aspiration, necrotizing enterocolitis.
Although D-dimer is not explicitly included in this scoring system, elevated D-dimer is a strong indicator of fibrinolysis and is more specific than FDPs.

Reproduced with permission from: Taylor FB, Toh CH, Hoots WK, et al. Towards definition, Clinical and Laboratory Criteria, and a Scoring System for
Disseminated Intravascular Coagulation. Thromb Haemost 2001; 86:1327. Copyright 2001 Schattauer GmbH.

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Japanese Association for Acute Medicine (JAAM) scoring system for disseminated intravascular
coagulation (DIC)

Score

SIRS criteria met*:

3 1

0 to 2 0

Platelet count (per microL):

<80 or >50% decrease within 24 hours 3

81 to 120 or 30 to 50% decreased within 24 hours 1

120 0

Prothrombin time (PT):

INR 1.2 1

INR <1.2 0

Fibrinogen level (mg/dL):

<35 1

35 0

Fibrin/fibrinogen degradation products (mcg/mL):

25 3

10 to 24 1

<10 0

Score interpretation: DIC is diagnosed if total score is 4.

JAAM: Japanese Association for Acute Medicine; DIC: disseminated intravascular coagulation; SIRS: systemic inflammatory response syndrome; PT:
prothrombin time; INR: international normalized ratio.
* SIRS criteria include abnormal (high or low) core temperature, tachycardia, tachypnea, and abnormal (high or low) leukocyte count. For details of SIRS
criteria, refer to UpToDate topic reviews on sepsis and SIRS in adult and pediatric patients.

Additional information from:


1. Gando S, Saitoh D, Ogura H, et al. Natural history of disseminated intravascular coagulation diagnosed based on the newly established diagnostic criteria
for critically ill patients: results of a multicenter, prospective survey. Crit Care Med 2008; 36:145.
From: Gando S, Iba T, Eguchi Y, et al. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients:
comparing current criteria. Crit Care Med 2006; 34:625. DOI: 10.1097/01.CCM.0000202209.42491.38. Copyright 2006 Society of Critical Care Medicine.
Reproduced with permission from Lippincott Williams & Wilkins. Unauthorized reproduction of this material is prohibited.

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Contributor Disclosures
Wendy Wong, MD Nothing to disclose Bertil Glader, MD, PhD Nothing to disclose Donald H Mahoney, Jr, MD Nothing to disclose Carrie
Armsby, MD, MPH Nothing to disclose

Contributor disclosures are reviewed 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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