Disseminated intravascular coagulation in infants and children

INTRODUCTION — Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by excessive systemic activation of coagulation, resulting in both hemorrhage and thrombosis. DIC can progress rapidly into life-threatening multiorgan failure; thus, identifying the underlying etiology is paramount to management.

The etiology, clinical manifestations, diagnosis, and treatment of DIC in infants and children will be reviewed here. DIC in adults and in pregnancy is discussed separately. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Disseminated intravascular coagulation (DIC) during pregnancy: Clinical findings, etiology, and diagnosis".)

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

Under normal hemostatic conditions, clot formation and resolution are tightly regulated. In DIC, dysregulated activation of the coagulation system results in a consumptive coagulopathy and microvascular thrombosis. DIC is always a secondary process caused by a variety of underlying disorders (eg, sepsis, trauma, or malignancy), which can cause endothelial tissue damage and procoagulant exposure [1]. This activates the coagulation cascade, which promotes fibrin production and deposition and consumption of clotting factors. The subsequent consumption of coagulation factors and platelets, inhibition of natural anticoagulants and fibrinolysis, and fibrin deposition result in the clinical picture of DIC: a bleeding diathesis accompanied by microvascular thrombosis that often leads to end-organ damage (figure 1 and figure 2).

DIC can be summarized into the following processes (figure 1):

●Intravascular activation of coagulation – Tissue damage from the initiating underlying disease releases procoagulants into the bloodstream, resulting in intravascular activation of coagulation. Examples of procoagulants include lipopolysaccharides from bacteria, phospholipids from damaged vascular endothelium, or the formation of neutrophil extracellular traps.

●Formation of fibrin in the circulation – Tissue procoagulants activate hemostasis primarily through the interaction of tissue factor and factor VII, thereby promoting fibrin formation and deposition within the microcirculation.

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

●Consumption of clotting factors and platelets – Ongoing activation of the coagulation system and fibrin deposition consume clotting factors and platelets.

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

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

ETIOLOGY — DIC occurs in a variety of clinical conditions (table 1).

Etiologies that can occur at any age — The broad categories of causes of DIC in children and in adults are similar (table 1), but there are some nuanced differences.

Sepsis — Sepsis is the most common cause of DIC in infants and children. DIC was classically recognized as an extreme complication of endothelial damage produced by meningococcemia. (See "Clinical manifestations of meningococcal infection", section on 'Disseminated intravascular coagulation'.)

A wide variety of viral, rickettsial, fungal, parasitic, and bacterial infections can be associated with DIC (table 1).

DIC is a recognized complication of coronavirus disease of 2019 (COVID-19) in adults, and it has been described in children with COVID-19-related multisystem inflammatory syndrome in children (MIS-C). (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis" and "COVID-19: Hypercoagulability".)

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. Congenital infections (TORCH infections) are also associated with DIC. In addition to exposure of procoagulant-triggering DIC, hypotensive shock from sepsis and the ensuing hypoperfusion contributes to endothelial damage and further propagates DIC. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates" and "Overview of TORCH infections".)

Trauma and tissue injury — In children, DIC can be a 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. (See "Severe traumatic brain injury (TBI) in children: Initial evaluation and management" and "Trauma management: Approach to the unstable child", section on 'Blood products'.)

Malignancy — In children with leukemia, laboratory abnormalities in the clotting system are common both at presentation and as a result of induction chemotherapy [2,3]. DIC constitutes a medical emergency in acute promyelocytic leukemia because, if left untreated, it is the major cause of morbidity and mortality. The granules within the acute promyelocytic leukemia blast cells contain procoagulants that directly trigger the coagulation system [4]. DIC can also complicate solid tumors and acute lymphoblastic leukemia and has been reported in patients with the uncommon t(17;19) translocation [5]. (See "Acute myeloid leukemia: Overview of complications".)

Other etiologies — Other uncommon causes of DIC include:

●Acute hemolytic transfusion reactions – Release of adenosine diphosphate and phospholipids from the hemolyzed red cell activate platelet and the coagulation system, respectively. (See "Hemolytic transfusion reactions".)

●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. (See "Snakebites worldwide: Clinical manifestations and diagnosis" and "Diagnostic approach to the patient with a suspected spider bite: An overview".)

●Liver disease – DIC may be seen in patients with acute or chronic hepatocellular disease, including Reye syndrome [6]. (See "Acute liver failure in children: Etiology and evaluation".)

Etiologies unique to pediatric patients — Specific considerations in the pediatric populations include:

Protein C and S deficiency — In patients with homozygous protein C or S deficiency, an imbalance between thrombin generation and fibrinolysis results in the presentation of neonatal purpura fulminans at birth. (See "Protein C deficiency" and "Protein S deficiency".)

Kasabach-Merritt syndrome — Patients with kaposiform hemangioendothelioma, an aggressive form of giant hemangioma, can develop Kasabach-Merritt syndrome, a localized form of DIC. The large hemangioma consumes fibrinogen and platelets, resulting in thrombocytopenia and consumptive coagulopathy. (See "Tufted angioma, kaposiform hemangioendothelioma (KHE), and Kasabach-Merritt phenomenon (KMP)" and "Non-immune (Coombs-negative) hemolytic anemias in adults", section on 'Fragmentation'.)

Other etiologies in 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 neonatal DIC include sepsis, perinatal asphyxia, respiratory distress syndrome (RDS), and necrotizing enterocolitis (NEC) [11].

●Perinatal complications – Complications resulting in perinatal asphyxia may cause neonatal DIC. These include placental abruption, preeclampsia, eclampsia, fetal distress during labor, and neonatal sepsis. (See "Perinatal asphyxia in term and late preterm infants" and "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates".)

●Conditions associated with prematurity – In neonates 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 [12]. (See "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis" and "Neonatal necrotizing enterocolitis: Clinical features and diagnosis".)

●Miscellaneous – Rare causes of neonatal DIC include hypothermia and massive hemolysis, such as seen in Rh incompatibility. (See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management".)

CLINICAL MANIFESTATIONS — Although the clinical spectrum and causes of 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 more severe cases, there may be extensive hemorrhage and thrombosis with end-organ damage to the kidney, liver, lung, extremities, and central nervous system. 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 [13]. In severe cases, intrapulmonary and intraventricular hemorrhages occur. Risk factors for DIC in neonates include prematurity, low birth weight, and low Apgar scores [14].

DIC can also occur in a chronic form due to continuous exposure to small amounts of a procoagulant, such as in the example of malignancy. In chronic DIC, production compensates for the consumptive coagulopathy and thrombosis tends to be the prevailing presentation, rather than hemorrhage.

LABORATORY FINDINGS — Laboratory abnormalities in DIC are consequences of the following pathologic process:

●Consumption of platelets and coagulation factors

●Increased fibrin formation

●Increased fibrinolysis

The range of laboratory abnormalities seen in DIC are described in the following sections. Not all affected patients have all of these abnormalities. Performing a comprehensive evaluation that includes all of these tests is generally not necessary to make the diagnosis. (See 'Laboratory evaluation' below.)

Platelet and clotting factor consumption — Laboratory evidence of consumption of clotting factors and platelets includes (figure 2):

●Decreased platelet count – Thrombocytopenia (platelet count <100,000/microL) usually is present in patients with DIC. Serial measurements of platelet counts documenting a downward trend are a sensitive but not specific sign for DIC [15].

●Prolonged prothrombin time (PT) – The PT is prolonged in 50 to 75 percent of cases [16]. A prolonged PT reflects a reduction in the activity of the extrinsic and common coagulation pathways.

●Prolonged activated partial thromboplastin time (aPTT) – The aPTT is prolonged in 50 to 60 percent of cases [16]. A prolonged aPTT reflects a reduction in the activity of the intrinsic and common coagulation pathways.

●Decreased 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 adequate compensation or circulating activated clotting factors such as thrombin and factor Xa [16].

Fibrin formation — Laboratory findings indicative of fibrin formation include:

●Decreased 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 or her underlying disease.

●Increased thrombin time – Thrombin time is prolonged when the fibrinogen concentration is low. Fibrin degradation products (FDPs) also impair fibrin formation, thereby prolonging the thrombin time.

Fibrinolysis — The diagnosis of DIC generally requires evidence of fibrinolysis, as indicated by the following:

●Elevated 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 [16]. The latex agglutination assay for D-dimer is commonly used and is one of the more reliable tests.

●Elevated FDPs – FDPs are products of plasmin degradation of fibrinogen and fibrin [16]. 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 (NEC), or thrombotic events from causes other than DIC and in some individuals taking oral contraceptives.

Peripheral blood smear — The peripheral blood smear may show evidence of microangiopathic hemolytic anemia with schistocytes, helmet cells, and large platelets, suggesting a destructive process (picture 1 and picture 2). However, these findings tend to be less pronounced in DIC than in other thrombotic microangiopathies such as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS). (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

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.

Other tests for DIC that are not widely available or not routinely used include markers of procoagulant activation (eg, prothrombin fragment 1.2, fibrinopeptide A and fibrinopeptide B, and thrombin-antithrombin complexes) and measures of fibrinolysis (eg, elevated levels of plasmin and plasmin-antiplasmin complex).

Coagulation tests in neonates — Special consideration needs to be taken in the interpretation of coagulation tests for the neonate. 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) [9,10,17]. 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 GA [18].

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 with 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 and 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]. Preterm infants commonly have low fibrinogen concentration and elevated D-dimer in the absence of DIC, limiting the value of these tests for diagnosing DIC in this population. 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 DIC is based upon a combination of clinical findings (eg, bleeding and/or microthrombi in a patient with a predisposing medical condition) and abnormal coagulation studies.

Laboratory evaluation — We suggest the following panel of tests to evaluate for DIC:

●Complete blood count

●Review of the peripheral blood smear

●Prothrombin time (PT) and international normalized ratio (INR)

●Activated partial thromboplastin time (aPTT)

●D-dimer level

●Fibrinogen level

However, patients with DIC may not have positive findings in all laboratory studies and no single test is sensitive or specific enough to definitively establish the diagnosis [19]. The most clinically helpful tests are those that indicate the presence of fibrinolysis (eg, D-dimer). Serial measurements of coagulation parameters are more informative than a single assessment.

While not routinely required for the diagnosis, decreased levels of factors V and VIII help substantiate the diagnosis of DIC in uncertain cases. Factor VIII levels can be used to distinguish DIC from coagulopathy associated with severe liver disease. Factor VIII is not produced by hepatocytes and thus is often low in DIC and increased or normal in liver disease. (See "Hemostatic abnormalities in patients with liver disease", section on 'Liver disease versus DIC'.)

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 (ISTH) – The 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), as summarized in the table (table 4) [20]. 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). 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 related ISTH sepsis-induced coagulopathy (SIC) score is a newer tool to assess patients with suspected DIC as a consequence of sepsis. The ISTH SIC score is determined by the degree of thrombocytopenia (2 points if <100/microL; 1 point if ≥100 to <150/microL), degree of PT prolongation (2 points for INR >1.4; 1 point for INR >1.2 to ≤1.4), and severity of organ dysfunction (measured using the Sequential Organ Failure Assessment [SOFA] score; 2 points for SOFA ≥2; 1 point for SOFA of 1) [21]. An ISTH SIC score ≥5 is consistent with sepsis-related DIC. A limitation of this tool in pediatric practice is that it relies on the SOFA score. While the SOFA score is widely used in adult patients and is included in the consensus definition of sepsis in adults, there are fewer data on its use in children. An age-adjusted pediatric SOFA score (pSOFA) has been developed and validated in pediatric patients [22,23]. However, pSOFA is not included in the definition of pediatric sepsis. This is discussed separately. (See "Sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Pediatric versus adult definitions'.)

●Japanese Association for Acute Medicine (JAAM) – The 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.

Both the ISTH and JAAM DIC scoring systems have been validated in adult patients and have been found to correlate with mortality and morbidity risk [26-28]. Limited pediatric data suggest that these scoring systems perform reasonably well in pediatric patients, though data in neonates are lacking [29-31]. Despite the lack of robust data, the ISTH and JAAM DIC scoring systems are often used in the pediatric intensive care unit setting. These scoring systems provide objective tools for assessing the likelihood of DIC, and they have prognostic value in patients with overt DIC. Disadvantages include their complexity and limited ability to capture asymptomatic or "non-overt" DIC.

Establishing the diagnosis — DIC is a clinical and laboratory diagnosis, based on findings of coagulopathy and/or fibrinolysis in the appropriate setting (eg, infection, trauma, malignancy). No single laboratory test can accurately confirm or eliminate the diagnosis. Often, it is more important to recognize the underlying condition than it is to firmly establish the diagnosis of DIC because the most important therapeutic intervention is to treat the underlying disorder. (See 'Management' below.)

We consider the diagnosis of DIC to be established if all the following criteria are met:

●The patient has an underlying condition that predisposes them to DIC (eg, infection, trauma, malignancy) (table 1)

●Laboratory testing is consistent with DIC (ie, thrombocytopenia plus coagulation factor consumption [prolonged PT and aPTT, low fibrinogen] and fibrinolysis [elevated D-dimer])

●No other etiology for these findings has been identified

Clinical evidence of bleeding or thrombosis are supportive of the diagnosis but are not required for diagnosis.

Neonates — Similar to older infants and children, the diagnosis of DIC in the neonate relies on abnormal global coagulation tests in the appropriate clinical setting [16]. However, it is more difficult to establish the diagnosis of DIC in neonates. Testing is often 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 since 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. However, it is generally more important to recognize the underlying condition than it is to firmly establish the diagnosis of DIC because the most important therapeutic intervention is to treat the underlying disorder. (See 'Coagulation tests in neonates' above and 'Management' below.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for DIC is broad and includes other diseases associated with bleeding symptoms, abnormal coagulation tests, and/or thrombocytopenia. The history, clinical setting, and laboratory evaluation usually differentiate DIC from other causes. The diagnostic approach to the child presenting with bleeding symptoms is summarized in the algorithm and reviewed in detail separately (algorithm 1). (See "Approach to the child with bleeding symptoms".)

●Hepatic failure – Hepatic failure can manifest with decreased fibrinogen and increased prothrombin time (PT) and partial thromboplastin time (PTT) due to the reduced synthetic function of the liver. These findings are similar to the laboratory findings of DIC, but the platelet count is typically normal. If the specific coagulation factors are tested, factor VIII will remain elevated in hepatic failure but depleted in DIC since it is the one coagulation factor made outside of the liver. (See "Acute liver failure in children: Management, complications, and outcomes", section on 'Coagulopathy'.)

●Vitamin K deficiency – Vitamin K is essential for the activation of coagulation factors II, VII, IX, and X. Vitamin K deficiency is associated with increased PT and PTT levels, similar to the laboratory findings of DIC, but the platelet count typically is normal in vitamin K deficiency. If the specific factors are tested, non-vitamin K-dependent factors, such as factors V and VIII, will remain intact in vitamin K deficiency but are depleted in DIC. (See "Overview of vitamin K", section on 'Vitamin K deficiency'.)

●Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) – The thrombotic microangiopathies (TMA) such as TTP (TMA resulting from severe ADAMTS13 deficiency) and HUS (Shiga toxin-mediated TMA) are associated with thrombocytopenia and microangiopathic changes on the peripheral blood smear. However, TTP and HUS are unlikely to have elevated PT and PTT because they are not consumptive coagulopathies. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

●Immune thrombocytopenia – In children, the main cause of destructive thrombocytopenia is immune thrombocytopenia. In contrast with DIC, patients with immune thrombocytopenia are typically otherwise well-appearing and coagulation tests are normal. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis".)

●Neonatal thrombocytopenia – In the neonate, causes of consumptive thrombocytopenia include alloimmune neonatal thrombocytopenia, maternal idiopathic thrombocytopenia, renal vein thrombosis, and infections. Causes of thrombocytopenia in neonates are reviewed in detail separately. (See "Neonatal thrombocytopenia: Etiology".)

●Other thrombocytopenias – Other causes of thrombocytopenia in children are summarized in the table (table 6). The diagnostic approach to the child presenting with thrombocytopenia is reviewed in detail separately. (See "Approach to the child with unexplained thrombocytopenia" and "Causes of thrombocytopenia in children".)

MANAGEMENT

Treat the underlying condition — DIC is a serious complication of the underlying primary disease. The most important principle in managing a child with DIC is to identify and treat 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. DIC supportive therapy is appropriate for such patients. However, the risk of mortality and morbidity in severely affected patients remains high.

Supportive therapy — Data to guide the use of supportive therapy in infants and children with DIC are limited, and consensus is lacking. In general, the intervention used most frequently for supportive care is component replacement (ie, platelet, fresh frozen plasma [FFP], or cryoprecipitate transfusions); the use of anticoagulation therapy is more limited. Treatment is individualized based upon a patient's age, severity of clinical symptoms, underlying primary disorder, and overall clinical status.

Replacement therapy — There have been no randomized controlled trials evaluating the efficacy of platelet, 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.

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

●Indications – Replacement therapy is indicated in patients with DIC who have clinically significant bleeding symptoms or who are at high risk for bleeding because of an impending invasive procedure. Examples of clinically significant bleeding may include gastrointestinal bleeding (not merely a positive guaiac test), prolonged bleeding from venipuncture sites, prolonged epistaxis, or prolonged bleeding after suctioning the endotracheal tube.

●Goals – The aim of replacement therapy is to reduce or stop significant bleeding, not to normalize laboratory tests (which often is impossible). Reasonable goals for the judicious use of blood components in the setting of clinically significant bleeding include maintaining platelet counts >50,000/microL and fibrinogen concentrations >100 mg/dL (1 mol/L) [32,33].

●Choice of replacement products – 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, von Willebrand factor, and fibrinogen and can be used to correct hypofibrinogenemia. It is administered every six 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 – Repeat transfusions may be necessary. The theoretical concern of replacement therapy increasing thrombotic risk by "adding fuel to the fire" has not been demonstrated [16] 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. The exception to this is for patients with Kasabach-Merrit syndrome, in which platelet transfusions are thought to exacerbate bleeding and swelling of the tumors, presumably due to intratumoral trapping and activation of platelets. The risks and benefits of platelet transfusion should be carefully weighted, especially if the tumor is in a critical location such as the airway or neurovascular space.

Anticoagulation — Therapeutic anticoagulation has a very limited role in the management of pediatric DIC. In our practice, we administer anticoagulant therapy (typically with unfractionated heparin [UFH]) only to patients with life-threatening or symptomatic thrombosis (eg, acral ischemia) who lack clinically significant bleeding. Therapeutic heparin should not be administered to patients with recent severe traumatic brain injury or liver failure.

In infants and children with DIC, heparin is generally avoided (with the exception of the rare patient with life-threatening or symptomatic thrombosis) because of its potential to exacerbate bleeding and because there are no compelling data demonstrating a benefit of heparin therapy 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 this improved organ dysfunction.

The use of heparin in pediatric patients differs from practice in adults, in which therapeutic heparin may be used for patients with predominantly thrombotic manifestations without bleeding, or for prophylaxis in critically ill patients without bleeding [16]. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Prevention/treatment of thrombosis'.)

If the clinical decision is made to administer therapeutic doses of heparin, continuous intravenous infusion of UFH is preferred because it allows for finely tuned titration and can be quickly turned off should bleeding occur. The starting dose of UFH should be lower than is typically used for treatment of thromboembolic disease (we typically start the continuous intravenous infusion at 5 to 10 units/kg per hour). 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 DIC. In children, anti-factor Xa levels should be monitored during treatment with either UFH or LMWH. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Unfractionated heparin' and "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Low molecular weight heparin'.)

Unproven and ineffective therapies — The levels of endogenous anticoagulants (eg, antithrombin and protein C) are decreased in DIC. It has been suggested that administration of these anticoagulants may reduce microthrombus formation and improve outcomes in patients with DIC. However, the available data suggest that these interventions are either not effective or their effectiveness is limited to very select clinical settings.

●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 "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Treatment'.)

●Human protein C concentrate – Protein C concentrate is not used routinely in management of DIC. Its clinical utility is limited to patients who present with purpura fulminans in the setting of one of the following conditions, which are discussed in greater detail separately:

•Neonatal purpura fulminans due to congenital protein C deficiency (see "Neonatal thrombosis: Management and outcome", section on 'Neonatal purpura fulminans')

•Purpura fulminans due to severe meningococcal infection (see "Treatment and prevention of meningococcal infection", section on 'Protein C concentrate')

●Activated protein C concentrate – Recombinant activated protein C (drotrecogin alfa) is not recommended for treatment of DIC or other coagulation disorders and is no longer available. Drotrecogin alfa was voluntarily removed from the world market in 2011. (See "Investigational and ineffective pharmacologic therapies for sepsis", section on 'Ineffective therapies'.)

●Investigational therapy – Recombinant human soluble thrombomodulin (ART-123), an agent which inactivates coagulation by binding to thrombin and activating protein C, is an investigational treatment for DIC [35,36]. The SCARLET trial (Sepsis Coagulopathy Asahi Recombinate LE Thrombomodulin), a randomized trial in adults with sepsis-related DIC, did not detect a significant difference in 28-day mortality in patients treated with ART-123 versus placebo [37]. An earlier clinical trial in Japanese patients >15 years of age with DIC from infection or malignancy showed promising results with ART-123 in comparison with heparin therapy [38]. Further studies are needed before ART-123 can be recommended for clinical use. (See "Investigational and ineffective pharmacologic therapies for sepsis", section on 'Ineffective therapies'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Thrombotic diseases in infants and children".)

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 6^th 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 12^th 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 email 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

●Pathogenesis and etiology – Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by hemorrhage and microvascular thrombosis. It results from activation of the coagulation system (figure 1) caused by a variety of underlying disorders (eg, sepsis, trauma, and malignancy) (table 1). (See 'Pathogenesis' above and 'Etiology' above.)

●Clinical manifestations – Clinical manifestations vary depending on the ability of the hemostatic system to compensate for the ongoing depletion of coagulation factors and platelets. In mild cases, bleeding may only be noted at venipuncture sites, but in more severe cases, there may be extensive hemorrhage and thrombosis, with end-organ damage to the kidney, liver, lung, extremities, and central nervous system. (See 'Clinical manifestations' above.)

●Laboratory evaluation – In children with suspected DIC, we suggest the following panel of tests to establish the diagnosis (see 'Laboratory evaluation' above):

•Complete blood count

•Review of the peripheral blood smear

•Prothrombin time (PT)

•Activated partial thromboplastin time (aPTT)

•D-dimer level

•Fibrinogen level

●Diagnosis – The diagnosis of DIC is based upon a combination of clinical findings (eg, bleeding and microthrombi in a patient with a predisposing medical condition) and abnormal coagulation studies. No single test confirms 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). (See 'Diagnosis' above.)

•Establishing the diagnosis – We consider the diagnosis of DIC to be established if all the following criteria are met (see 'Establishing the diagnosis' above):

-Patient has an underlying condition that predisposes them to DIC (eg, infection, trauma, malignancy) (table 1)

-Laboratory testing is consistent with DIC (ie, thrombocytopenia plus coagulation factor consumption [prolonged PT and aPTT, low fibrinogen] and fibrinolysis [elevated D-dimer])

-No other etiology for these findings has been identified

•Neonates – 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 'Coagulation tests in neonates' above and 'Neonates' above.)

●Differential diagnosis – The differential diagnosis for DIC is broad and includes diseases that present with bleeding, coagulopathy, and/or thrombocytopenia (algorithm 1 and table 6). The laboratory evaluation usually differentiates DIC from other causes of bleeding in children. (See 'Differential diagnosis' above.)

●Management – Key aspects of management include (see 'Management' above):

•Treating the underlying condition – The most important principle in managing a child with DIC is to identify and treat the underlying cause, thereby removing the triggering factors implicated in the DIC process. (See 'Treat the underlying condition' above.)

•Replacement therapy – In patients with clinically significant bleeding, we recommend the administration of replacement therapy with platelet transfusion and/or coagulation factors (fresh frozen plasma [FFP] or cryoprecipitate) (Grade 1C). The aim of replacement therapy is to reduce or stop significant bleeding, not to normalize laboratory tests. Repeat transfusions may be necessary. The theoretical concern of replacement therapy increasing thrombotic risk by "adding fuel to the fire" has not been demonstrated and should not dissuade the clinician from administering replacement therapy to control significant bleeding. Patients who require a considerable volume of replacement therapy should be monitored for signs of volume overload. (See 'Replacement therapy' above.)

•Limited role of anticoagulation – Therapeutic anticoagulation has a very limited role in the management of DIC in infants and children. (See 'Anticoagulation' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Wendy Wong, MD, and Bertil Glader, MD, who contributed to earlier versions of this topic review.