Consumption Coagulopathy 

Updated: Aug 24, 2017
Author: Alexander Gozman, MD; Chief Editor: Robert J Arceci, MD, PhD 

Overview

Background

Consumption coagulopathy, better known as disseminated intravascular coagulation (DIC), is characterized by abnormally increased activation of procoagulant pathways. This results in intravascular fibrin deposition and decreased levels of hemostatic components, including platelets, fibrinogen, and other clotting factors. Although chronic DIC can be asymptomatic, acute DIC results in bleeding and intravascular thrombus formation that can lead to tissue hypoxia, multiorgan dysfunction, and death.[1, 2]

Pathophysiology

The excess production of thrombin is central to the process of DIC. In addition to the conversion of fibrinogen to fibrin, thrombin has numerous other effects relative to the coagulation cascade. Thrombin contributes to the activation of factors V, VIII, and XIII (fibrin-stabilizing factor) and has an activating effect on platelets. Modulation of anticoagulant molecules also occurs by means of a thrombin-dependent mechanism. This mechanism includes generation of activated protein C and protein S and the activation of tissue-type plasminogen activator (tPA), with subsequent inhibition of activated factors V and VIII, plasminogen activator inhibitor-1 (PAI-1), and thrombin-activated fibrinolysis inhibitor (TAFI).

Tissue factor–dependent (extrinsic) pathway

Tissue factor (TF), or thromboplastin, is the primary activating moiety for the extrinsic pathway of coagulation. TF binds to factor VII and converts factor VII to factor VIIa. The resultant dimeric TF–factor VIIa complex then activates factors X and IX. TF is also a principal activator of factor IX. TF is expressed by cells of the subendothelium (smooth muscle cells, fibroblasts), whereas various stimuli may induce leukocytes and endothelial cells to express TF.

TF has a prominent role in the pathophysiology of DIC.[3] Production of TF is increased in infection. Endotoxin, tumor necrosis factor (TNF), interleukin-1 (IL-1), and other inflammatory mediators induce expression of TF in endothelial cells and monocytes, where only small amounts are normally expressed. Some evidence suggests that in sepsis-related DIC, TF and procoagulant-laden microparticles (MPs) are present in the circulation.[4]

Excessive release of TF is the primary mechanism involved in DIC resulting from trauma, especially head injury, and obstetric complications, which include intrauterine fetal demise, amniotic fluid embolism, and placental abruption. In trauma, tissue damage leads to release of TF and other tissue thromboplastins. Because of the rich TF content of brain tissue, massive head injuries are often complicated by DIC, and recent data suggest that brain trauma releases procoagulant-rich microparticles.[5]

Many malignancies are associated with cancer-derived procoagulants (CDP). TF is expressed on subcellular membrane vesicles termed plasma MPs. The procoagulant activity of these MPs was increased in patients in overt DIC with an underlying malignancy.[6] In acute promyelocytic leukemia (APL), CDP and TF are contained in multiple granules in the myeloblasts, which are responsible for the DIC commonly seen when chemotherapy results in leukemic cell lysis.[7] The use of differentiating agents in APL has significantly reduced this complication.

An uncommon source of thromboplastic activity is snake venom; some snake bites can lead to direct activation of factor X and hemorrhagic DIC.

Endothelial cells, monocytes and other cells produce and secrete a natural inhibitor of TF (ie, TF pathway inhibitor [TFPI]). The balance between TF and TFPI determines overall activity of the extrinsic pathway. Levels of TFPI are increased early in DIC; however, when overt DIC develops, the TF-to-TFPI ratio increases to the point that the extrinsic pathway is activated. Resolution of DIC results in a normalization of this ratio.[8]

Intrinsic (contact) pathway

Although the TF pathway is believed to be primary in the initiation of DIC, several instances in which the intrinsic pathway contributes to the pathophysiology of DIC are observed. Factor XII activation occurs in response to endotoxin, antigen-antibody complexes, fatty acids from fat embolism, burns, and extracorporeal circulation. In addition, factor XIIa leads to the activation of the complement system and generation of bradykinin. Increased levels of bradykinin may be responsible for hypotension observed in many forms of DIC.

Miscellaneous

Hypotensive shock and DIC may accompany severe hemolytic transfusion reactions. Immune complexes that form in such instances activate complement and initiate coagulation. Exposure of lipids normally residing on the internal surface of the erythrocyte plasma membrane may be involved in activation of the coagulation cascade.

Anticoagulant proteins C and S and antithrombin III also play a role in DIC. Congenital homozygous deficiencies of proteins C and S may result in neonatal DIC. Low levels of antithrombin III are noted during DIC, and infusion of antithrombin III concentrate may aid in the recovery from DIC.

The Ashwell receptor is a transmembrane glycoprotein on the vascular cell surface of hepatocytes. This receptor is involved in the clearance of prothrombotic factors and may mitigate sepsis-related DIC.[9]

Fibrinolysis

Unregulated generation of thrombin and deposition of fibrin provide a strong stimulus to the fibrinolytic system. Whether fibrinolysis is a primary or secondary event is uncertain, but most believe that the fibrinolytic system is activated in response to the initiation of coagulation. In response to thrombin generation and endothelial injury, tPA is released from the endothelium. The continued activity of the fibrinolytic system contributes to the consumption of coagulation factors and to development of the hemorrhagic diathesis.

Epidemiology

Frequency

United States

The incidence of DIC is unknown.

International

The incidence of DIC among hospitalized children in Turkey is around 1%.[10] The incidence of DIC in Japan is 1.72% among hospitalized patients.[11]

Mortality/Morbidity

The DIC mortality rate varies depending on the underlying disorder and on the availability of supportive care. The overall mortality rate for children with sepsis-related DIC is 13-40%. In developing countries, this rate can exceed 90%.

A Korean study, by Sohn et al, found that among patients with primary postpartum hemorrhage presenting to an emergency department, 22.4% of whom had overt DIC, the rate of major adverse events in women with DIC versus those without it were 96.5% and 44.4%, respectively.[12]

Race

No predilection for any race is known.

Sex

No predilection for either sex is known.

Age

DIC occurs at any age.

Prognosis

A study by Chi and Ikezoe found that the median survival period in patients with non-Hodgkin lymphoma (NHL) and DIC was significantly less than in patients with NHL without DIC. The study, which involved 161 patients with NHL, 18 of whom were also diagnosed with DIC, found that the median length of survival in patients with DIC was 176 days, versus 2430 days in those without DIC, with the difference still being significant after the investigators adjusted for age, performance status, Ann Arbor stage, international prognostic index, and liver function panels. The study found worse liver function panels in patients with DIC, including with regard to values for bilirubin, aminotransferases, serum cholinesterase, and albumin, than in patients without DIC.[13]

 

Presentation

History

The history should be tailored to the age of the child. Important historical aspects in disseminated intravascular coagulation (DIC) are the presence or suspected presence of any known predisposing conditions, especially sepsis. With meningococcal and pneumococcal sepsis, the prodrome may be limited, and the first indication of problems may be a purpuric rash with fever and hypotension.

Obtain appropriate historical facts, as follows:

  • History of fever

  • Behavior changes: Alterations in mental status may be indicative of CNS infection, an encephalopathic condition, or CNS insult such as thrombosis, hemorrhage, or infarction.

  • Feeding patterns: Alteration of feeding patterns may indicate illness in the infant or nonverbal child.

  • Urine output, as a measure of hydration status as well as cardiovascular and renal function

  • Sick contacts, exposure to potential bacterial or viral agents that are known causes of DIC in the pediatric population

  • Recent travel, exposure to fungal or parasitic agents endemic to particular areas

Obtain a birth history, including the following:

  • Perinatal course (eg, placental abruption or eclampsia)

  • Prenatal testing

  • Neonatal risk factors of sepsis (eg, premature rupture of membranes, maternal fever, fetal tachycardia, maternal group B streptococcal status, perinatal antibiotic therapy)

  • Immediate postnatal course, especially neonatal illnesses

  • Sepsis evaluation

  • Antibiotic therapy

Obtain other history, as follows:

  • Recent illness

  • Recent bruising - Indicates an underlying hematologic disorder

  • Fatigue

  • Frequent infections

  • Weight loss - May indicate the presence of underlying chronic illness or malignancy

  • Menstrual history - To evaluate likelihood of pregnancy in female adolescents

  • Use of any legal or illegal drugs

  • Family history suggestive of an inherited thrombotic disorder or cancer syndrome

  • Chronic illnesses, including malignancy, vascular malformations (eg, Kasabach-Merritt syndrome, Klippel-Trenaunay syndrome), and inherited or acquired immunodeficiencies

Physical

Clinical manifestations depend on whether the onset is acute or chronic.

Acute onset (Minutes to days)

The patient's general appearance is frequently toxic.

The clinical picture is commonly one of bleeding with signs of shock out of proportion to the amount of blood loss, with poor perfusion, cold extremities, and poor tone in the neonate.

Bleeding may range in severity from petechiae, purpura, subconjunctival or mucosal hemorrhages and extravasation from past venipuncture or surgical sites, to severe life-threatening hemorrhage.

Coexisting signs of bleeding and thrombosis may be present.

Purpura fulminans (see the image below) is severe, extensive hemorrhage into the skin associated with fever and hypotension.

Purpura fulminans. Purpura fulminans.

It may be caused by infections, such as meningococcemia and varicella, or by protein C deficiency. Cutaneous purpuric or hemorrhagic lesions rapidly develop and spread and may progress to frank gangrene.

In addition to these signs, renal, hepatic, pulmonary, or CNS manifestations often accompany DIC. Most patients are critically ill.

The clinical appearance of each patient heavily depends on the underlying cause.

In many instances, determining if clinical manifestations are a result of DIC or an underlying disorder is difficult.

Chronic onset (Days to weeks)

Patients with specific underlying disorders may develop a chronic form of DIC.

Chronic onset occurs in children with large vascular malformations and in women with intrauterine fetal demise, chronic inflammation, and certain forms of malignancy (eg, acute promyelocytic leukemia, metastatic alveolar rhabdomyosarcoma). These patients have a low, constant rate of thrombin formation that does not outstrip the body's ability to compensate.

Patients with chronic DIC may not have obvious clinical manifestations. Patients may develop slowly resolving ecchymoses or have prolonged bleeding from internal or cutaneous wounds.

Causes

DIC has numerous causes from conditions in many organ systems. The abbreviated list below emphasizes the pediatric causes of DIC.

Infections, as follows:

  • Bacterial - Meningococcemia, sepsis, and others

  • Rickettsial -Rocky Mountain spotted fever and others

  • Viral - Herpes simplex, hepatitis, cytomegalovirus (CMV), varicella, and others

  • Fungal -Aspergillus infection, histoplasmosis, and others

  • Parasitic -Malaria, trypanosomiasis, and others

Obstetric complications, as follows[14] :

  • Placental abruption

  • Amniotic fluid embolism

  • Intrauterine fetal demise

Malignancies, as follows:

  • Acute leukemia - Promyelocytic (M3), myelomonocytic (M4), monocytic (M5), lymphoblastic (T cell), and lymphoblastic (Philadelphia-chromosome positive)

  • Metastatic tumors -Neuroblastoma, alveolar rhabdomyosarcoma

Collagen vascular disorders, as follows:

  • Systemic lupus erythematosus

  • Juvenile rheumatoid arthritis

Trauma, as follows:

  • Massive head trauma

  • Burn injuries

  • Major surgery

 

DDx

 

Workup

Laboratory Studies

Screening

No single test or combination of tests is adequate to diagnose disseminated intravascular coagulation (DIC).[15] Perform screening tests in all patients, such as platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time, and fibrin degradation products or soluble fibrin monomers. Additional tests that may be useful in aiding in the diagnosis include antithrombin III levels, protein C, D-dimer, fibrinogen, measurements of specific coagulation factors such as factor V and VIII, and plasminogen activator inhibitor type I (PAI-1). Clinical judgment in conjunction with these tests provide a means of working towards a diagnosis of DIC, although no single test results alone are confirmatory.[16]

Thrombocytopenia is an almost universal finding, and the CBC count with smear review may reveal findings suggestive of DIC, such as increased platelet size, schistocytes (see the image below), and helmet cells.

Peripheral blood of a child with disseminated intr Peripheral blood of a child with disseminated intravascular coagulation demonstrates thrombocytopenia and many schistocytes (Wright stain, original magnification X 1000).

The PT and the aPTT are usually prolonged on screening tests but may be normal in an individual in the early phase of DIC ("nonovert DIC").

Fibrin or fibrinogen degradation products and D-dimers are usually elevated due to the rapid generation of fibrin and breakdown of cross-linked fibrin polymers. Although sensitive, these tests are not specific.

Fibrinogen levels are often decreased, as is antithrombin III.

The International Society on Thrombosis and Hemostasis (ISTH) DIC scoring system can help in diagnosis.[17] In the presence of an underlying cause, key tests are performed, and the results are scored as shown in the Table below. A total score of 5 or greater is diagnostic of DIC.

Table. DIC Scoring System (Open Table in a new window)

Measure

Score

0

1

2

3

Platelet count

>100 X 109/L

< 100 X 109/L

< 50 X 109/L

NA

PT prolongation, s

0-3

3-6

6

NA

Fibrinogen level (mg/dL)

>100

< 100

NA

NA

Fibrin split products

NA

NA

+

+++

The most important prognostic factor is the ability to correct the underlying cause and arrest the ongoing derangement of the coagulation system.

A similar scoring system proposed by the Japanese Ministry of Health and Welfare (JMHW) in 1979 used more specific criteria. They numerically categorized the extent of fibrin degradation product, included underlying disease and clinical symptoms as part of the overall scoring system; whereas underlying disease is an essential component in the ISTH system.[11] The ISTH system is useful for predicting overt DIC.

The ISTH DIC scoring system does not precisely define the extent of the increase in fibrin split products or which marker is being measured. Specifying these fibrin products as either D-dimers or soluble fibrin monomers and clearly defining numerical parameters of these products within the scoring system makes the score a more powerful prognostic indicator.[18, 19]

In a retrospective study evaluating prognostic factors influencing mortality in pediatric patients with DIC, multiorgan dysfunction syndrome, acute respiratory distress syndrome, and cardiovascular and respiratory system dysfunction were associated with increased mortality.[10]

A new scoring system used in the pediatric ICU at Texas Children's Hospital used sequential measurement of the same laboratory values along with the clinical condition of the patient to determine if overt DIC is present. This scoring system proved to be more sensitive than ISTH system.[20]

Other Tests

Because DIC is not the primary disease but a manifestation of underlying illness, diagnosing the initiating disorder is crucial.

 

Treatment

Medical Care

The most important concept in disseminated intravascular coagulation (DIC) is that it is a secondary manifestation of an underlying disorder.

The most important therapeutic maneuver is treating the initiating disorder. Without this, supportive measures ultimately fail.

Shock is a frequent underlying factor, and important supportive measures include ventilatory support, volume support, and pressor support as well as close monitoring of neurologic and renal function. Dialysis may be needed.

Surgical Care

Involve a pediatric surgeon, as the underlying disorder indicates.

Surgical complications may include thrombotic occlusion of an artery with imminent loss of limb or organ function, bleeding, or compartment syndrome.

DIC can result in bleeding at any surgical site.

Consultations

DIC is a complex pediatric disease that is best treated in tertiary care centers by using a multidisciplinary approach. Involving many services may be appropriate.

Hematologist-oncologist

Treatment involves complex decisions regarding differential diagnosis and treatment options.

Involve a pediatric hematologist early.

If DIC is thought to be secondary to malignancy, a pediatric oncologist can expedite diagnosis.

Intensivist

Most children with DIC are critically ill and require monitoring available in the pediatric ICU.

Many children develop shock and respiratory failure and require ventilatory support.

Blood bank specialist

Treatment of patients may involve blood products.

Blood bank specialists can provide resource advice on treatment decisions.

Infectious disease specialist

Many children with DIC have underlying sepsis that requires aggressive management.

Nephrologist

Renal derangement is not uncommon because thrombosis and shock interfere with renal perfusion.

Neurologist

DIC may cause neurologic symptoms related to CNS thrombosis, infarction, or hemorrhage.[21]

 

Medication

Medication Summary

Every effort is made to remove the underlying cause, but further management of childhood disseminated intravascular coagulation (DIC) varies. No evidence suggests that replacement blood products exacerbate the problem, and these should be aggressively used to provide hemostasis. The role of heparin is controversial, but it may be beneficial in purpura fulminans.

Activated protein C and protein C products have shown promising results in sepsis-related DIC. Protein C replacement therapy has been shown to lead to increased activated protein C levels, resolution of coagulopathy, and correction of hemostasis.[22, 23, 24, 25] Similarly, recombinant factor VIIa has also been successfully used in a small sample of neonates with DIC, and larger studies are awaited.[26, 27] However, these products are expensive and difficult to obtain, and their benefit in childhood DIC remains unproven.

Despite promising initial pilot studies, a randomized, double-blind, placebo-controlled trial (RESOLVE [REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspectiVE]) of activated drotrecogin alfa (Xigris) in 477 pediatric patients with severe sepsis showed no decrease in mortality.[28]

Drotrecogin alfa (Xigris) was withdrawn from the worldwide market October 25, 2011. In the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS)-SHOCK clinical trial, drotrecogin alfa failed to demonstrate a statistically significant reduction in 28-day all-cause mortality in patients with severe sepsis and septic shock. Trial results observed a 28-day all-cause mortality rate of 26.4% in patients treated with activated drotrecogin alfa compared with 24.2% in the placebo group of the study.

Blood products

Class Summary

Blood products are administered for supportive care in children with severe DIC. The goal is to replace platelets, depleted coagulation factors, and fibrinogen.

Platelets

In patients with DIC, platelet activity may be abnormal because of fibrin or fibrinogen degradation products. Therefore, consider platelet transfusions at a platelet count of 50 X 109/L, especially for patients who are intubated and have lines inserted. Most institutions use apheresis-derived platelets administered at 10ml/kg over 1 hour.

Fresh-frozen plasma (FFP)

Considered first-line blood product in patients with bleeding from unknown etiology. Although long-term benefit is uncertain in DIC, it is routine practice to administer FFP to correct the PTT once it exceeds 1.5-2 times normal.

Cryoprecipitate

Contains high concentrations of factor VIII, von Willebrand factor, fibrinogen, and fibronectin. In DIC, main use is to correct hypofibrinogenemia (

Anticoagulants

Class Summary

In acute DIC, the value of intravenous heparin is uncertain, but it may be used in purpura fulminans. Low-molecular-weight heparin (LMWH) may be used in patients with chronic DIC. No randomized controlled trials have been performed to prove the value for heparin in DIC in adult settings, such as peripartum DIC.[29]

Heparin

Cofactor for antithrombin III; activating stops production of thrombin. Useful in chronic DIC but less effective in acute DIC. aPTT cannot be used to monitor levels of anticoagulation. Some monitor heparin levels. Target heparin levels 0.35-0.7 U/mL with antifactor-Xa method.

Enoxaparin (Lovenox)

Clinical benefit of LMWH primarily seen in chronic DIC.

Thrombomodulin alfa

While the recombinant product is available in Japan and Europe, it is not routinely used in the United States, and its benefit in pediatric DIC is uncertain

Coagulation inhibitors

Class Summary

Antithrombin III and drotrecogin alfa (recombinant human-activated protein C) both have an antithrombotic effect, but their benefit in sepsis-related childhood DIC remains anecdotal. In the PROWESS-SHOCK trial, administration of recombinant human APC was not shown to improve mortality, and therefore, the drug was withdrawn from the worldwide market on October 25, 2011.

Antithrombin III (ATnativ, Thrombate III)

Concentrate has been used to treat adults with severe DIC resulting from sepsis. Infusion speeds resolution and reduces multiorgan dysfunction. Studies relatively small, and few have involved children. Some recommend use only with concurrent heparin therapy.

Drotrecogin alfa (Xigris)

October 25, 2011: Withdrawn from worldwide market. Recombinant human activated protein C. Was indicated to reduce mortality in patients with severe sepsis associated with acute organ dysfunction and at high risk of death. Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial showed a significant decrease in mortality in patients with sepsis and DIC treated with activated protein C. Exerts antithrombotic effect by inhibiting factors Va and VIIIa. Has indirect profibrinolytic activity by inhibiting PAI-1 and limiting formation of activated thrombin-activatable-fibrinolysis-inhibitor. May exert anti-inflammatory effect by inhibiting human TNF production by monocytes, blocking leukocyte adhesion to selectins, and limiting thrombin-induced inflammatory responses within microvascular endothelium.

Coagulation factors

Class Summary

Recombinant factor VII may help reduce active bleeding, but its benefit in childhood DIC remains anecdotal.

Recombinant coagulation factor VIIa (NovoSeven)

Indicated for hemophilia with inhibitors refractory to routine therapy and for congenital factor VII deficiency. Used off label for uncontrolled bleeding secondary to trauma or DIC and refractory to usual measures. Recombinant activated factor VII complexes with TF to activate factors IX and X, which converts prothrombin to thrombin.

 

Follow-up

Further Outpatient Care

Follow-up care with subspecialists may be required depending on the patient's underlying disorder and clinical course.

Further Inpatient Care

Because most children with disseminated intravascular coagulation (DIC) are critically ill, serial monitoring of laboratory values is necessary. CBC count, prothrombin time (PT) and activated partial thromboplastin time (aPTT), D-dimers, and fibrinogen measurements should be frequently repeated.

Organ involvement and concurrent illness dictate the need for additional laboratory studies.

Inpatient & Outpatient Medications

The patient's underlying disorder and clinical course dictate the medications required at discharge.

Patients with chronic DIC may benefit from treatment with low molecular weight heparin (LMWH) on an outpatient basis. Recommended dosages are 1-1.5 mg/kg given subcutaneously every 12 hours.

Transfer

Transfer pediatric patients to tertiary care centers with a pediatric ICU and subspecialists.