You are in: eMedicine Specialties > Pediatrics: General Medicine > Hematology Consumption CoagulopathyArticle Last Updated: Oct 17, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP, Associate Professor of Pediatric Hematology-Oncology, Department of Pediatrics, Albany Medical Center; Faculty, Alden March Bioethics Institute Vikramjit S Kanwar is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and Royal College of Physicians of the United Kingdom Coauthor(s): Paul J Galardy, MD, Instructor, Department of Pediatrics, Massachusetts General Hospital for Children and Harvard Medical School; Eric Grabowski, MD, ScD, Director of Cardiovascular Thrombosis Laboratory, Massachusetts General Hospital for Children; Associate Professor, Department of Pediatrics, Division of Hematology-Oncology, Harvard Medical School Editors: Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Gary D Crouch, MD, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Associate Professor, Uniformed Services University of the Health Sciences; Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University; Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Department of Oncology, Division of Pediatric Oncology, Johns Hopkins University School of Medicine Author and Editor Disclosure Synonyms and related keywords: disseminated intravascular coagulation, DIC, excess production of thrombin INTRODUCTIONSection 2 of 11
  BackgroundConsumptive coagulopathy, better known as disseminated intravascular coagulation (DIC), is a disorder characterized by abnormally increased activation of procoagulant pathways, resulting in intravascular fibrin deposition and decreased levels of hemostatic components. Although chronic DIC can be asymptomatic, acute DIC results in intravascular thrombosis formation that can lead to tissue hypoxia, multiorgan dysfunction, and death. PathophysiologyCentral to the process of DIC is the excess production of thrombin. 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 it 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 a variety of stimuli may induce leukocytes and endothelial cells to express TF. TF has a prominent role in the pathophysiology of DIC. 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. 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. Other sources of thromboplastic activity, or direct activation of factor X, include certain snake venoms. Many malignancies may release cancer procoagulant (CP) and TF. For example, in acute promyelocytic leukemia, CP and TF are contained in multiple granules in the myeloblasts and are responsible for the DIC that complicates the early course of this disease. Endothelial cells, monocytes, and other cells produce and secrete a natural inhibitor of TF, ie, TF pathway inhibitor (TFPI). Activity balance of TF and TFPI determine overall activity of the extrinsic pathway. Levels of TFPI are increased in DIC, but when clinical DIC develops, the TF-TFPI ratio increases to the point that the extrinsic pathway is activated. Resolution of DIC results in a normalization of this ratio. Intrinsic (contact) pathway Although the TF pathway is believed to be primary in the initiation of DIC, many instances exist in which the intrinsic pathway contributes to the pathophysiology of DIC. 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 Shock and DIC may accompany severe hemolytic transfusion reactions. Immune complexes that form in such instances activate complement and initiate coagulation. Interestingly, nonimmune hemolysis does not initiate coagulation. Exposure of lipids normally residing on the internal face of the erythrocyte plasma membrane also 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. Fibrinolysis Unregulated generation of thrombin and deposition of fibrin provide a strong stimulus for 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. FrequencyUnited StatesThe true incidence of DIC is unknown. InternationalThe incidence of DIC among hospitalized children in Turkey was around 1%. Mortality/MorbidityThe 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%. DIC-related mortality due to acute promyelocytic leukemia has declined since the introduction of all trans-retinoic acid. RaceNo predilection for any race is known. SexNo predilection for either sex is known. AgeDIC occurs at any age. CLINICALSection 3 of 11
HistoryAs with most areas of pediatrics, tailor the history to the age of the child. Important historical aspects are the presence or suspected presence of any known predisposing conditions. 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. Highly suspect infection.
PhysicalClinical manifestations depend on whether the onset is acute or chronic.
CausesDIC has numerous causes from conditions in many organ systems. The abbreviated list below emphasizes the pediatric causes of DIC.
DIFFERENTIALSSection 4 of 11
Fulminant Hepatic Failure Hemolytic-Uremic Syndrome Hemorrhagic Disease of Newborn
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| 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 = not applicable.
The most important concept in DIC is that it is a secondary manifestation of an underlying disorder.
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.
Every effort is made to remove the underlying cause, but further management of childhood DIC then varies. Little or no evidence suggests that replacement blood products exacerbate the problem, and these should be used as needed. The role of heparin is controversial, but may be beneficial in purpura fulminans. Relatively new agents, such as activated protein C and recombinant factor VIIa, are expensive and often hard to access. Their value in childhood DIC remains unproven.
Because the deregulated generation of thrombin is the central problem, many physicians use anticoagulants. However, in individuals with acute DIC, the coagulation defect is complex, and the value of anticoagulants in a patient with bleeding is uncertain. Low-molecular-weight heparin (LMWH) may be used in persons with chronic DIC.
| Drug Name | Heparin |
|---|---|
| Description | 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. |
| Adult Dose | 5-10 U/kg/h IV without bolus; adjust to response |
| Pediatric Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity; bleeding; decide use of heparin in DIC on individual basis |
| Interactions | Drugs that interfere with platelet function (eg, acetylsalicylic acid, NSAIDs, acetaminophen, penicillins, cephalosporins, nitrates, nitroprusside, psychotropic drugs) may increase risk of bleeding; digoxin, nicotine, tetracycline, and antihistamines may decrease effects |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | May increase bleeding in DIC; in neonates, preservative-free heparin recommended to avoid possible toxicity (gasping syndrome) due to benzyl alcohol (preservative); caution in severe hypotension and shock; monitor for bleeding in peptic ulcer disease |
| Drug Name | Enoxaparin (Lovenox) |
|---|---|
| Description | Clinical benefit of LMWH primarily seen in chronic DIC. |
| Adult Dose | Not established |
| Pediatric Dose | No studies in pediatric DIC; therefore, appropriate dosing difficult to determine For anticoagulation in deep venous thrombosis (DVT) treatment, DVT prophylaxis, or treatment of thrombosis after resolution of DIC: 1-2 mg/kg/d SC divided bid; target antifactor-Xa activity (heparin level) for DVT treatment is 0.5-1 U/mL |
| Contraindications | Documented hypersensitivity; profuse bleeding |
| Interactions | Drugs that interfere with platelet function (eg, acetylsalicylic acid, NSAIDs, acetaminophen, penicillins, cephalosporins, nitrates, nitroprusside, psychotropic drugs) |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | May increase bleeding in DIC |
Theoretical reasons suggest that blood products should not be used. However, in practice, almost all hematologists administer blood product for supportive care in children with severe DIC. The goal is to replace fibrinogen, depleted coagulation factors, and platelets.
| Drug Name | Platelets |
|---|---|
| Description | 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. |
| Adult Dose | 1 random-donor U/10 kg when platelet count is <50,000 X 109/L Many institutions use apheresis-derived platelets; 1 apheresis U of platelets is approximately equivalent to 6 random-donor platelet U |
| Pediatric Dose | 1 random donor U IV raises platelet count 10-12 X 109/L Neonates: 0.1 U/kg IV raises platelet count 30 X 109/L Infants: 2 U IV minimum Toddlers: 3 U IV minimum Children: 4 U IV minimum Adolescents: 6-8 U IV minimum Many institutions use apheresis-derived platelets from single donor; 1 apheresis U of platelets is approximately equivalent to 6 random-donor platelet U |
| Contraindications | As with all products derived from whole blood, benefits of platelet transfusion must be balanced with risks of transfusion reactions and infection; perform transfusion with great caution in known immunoglobulin A (IgA) deficiency |
| Interactions | Avoid coadministration with antiplatelet agents or drugs that may cause thrombocytopenia; administer in IV line dedicated to blood products to avoid incompatibility with drugs |
| Pregnancy | A - Safe in pregnancy |
| Precautions | Product should be CMV safe and leukoreduced; platelets should be irradiated for patients <6 wk and those with primary (ie, inherited) or secondary (ie, HIV, postchemotherapy, bone marrow transplantation) immunodeficiency; multiple transfusions may sensitize patients to platelet antigens |
| Drug Name | Fresh-frozen plasma (FFP) |
|---|---|
| Description | Considered first-line blood product in patients with bleeding from unknown etiology. In general, no data support use in DIC. |
| Adult Dose | 16 mL/kg IV when aPTT ratio >1.5 |
| Pediatric Dose | 10-15 mL/kg IV increase levels of all coagulation factors by 10-20%; in ongoing consumption, repeat q8h |
| Contraindications | As with all products derived from whole blood, benefits of transfusion must be balanced with risks of transfusion reactions and infection |
| Interactions | Administer in IV line dedicated to blood products to avoid incompatibility with drugs |
| Pregnancy | A - Safe in pregnancy |
| Precautions | Volume overload may be a concern in neonates or patients on fluid restrictions |
| Drug Name | Cryoprecipitate |
|---|---|
| Description | Contains high concentrations of factor VIII, von Willebrand factor, fibrinogen, and fibronectin. In DIC, main use is to increase fibrinogen levels in patients with hypofibrinogenemia. Some suggest use only in patients with DIC that is self-limited, resolving, or controlled with heparin. Concern is that no HIV-inactivated products are available. |
| Adult Dose | 1 U raises fibrinogen by 6-8 mg/dL |
| Pediatric Dose | One half pack/kg increases factor VIII by 80-100% and fibrinogen by 200-250 mg/dL; consider repeat infusion on basis of laboratory assessment and patient's condition |
| Contraindications | Uncontrolled DIC |
| Interactions | Administer in IV line dedicated to blood products to avoid incompatibility with drugs |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Thrombosis in some adults |
Antithrombin III is an alpha2-globulin and is the major endogenous inhibitor of thrombin. It inactivates thrombin, plasmin, and other serine proteases of coagulation (eg, factors VIIa, IXa, Xa, XIa, and XIIa), which, in turn, inhibit coagulation. Drotrecogin alfa elicits antithrombotic effect by inhibiting factors VA and VIIIa. In additional, it exerts an anti-inflammatory effect.
| Drug Name | Antithrombin III (ATnativ, Thrombate III) |
|---|---|
| Description | 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. |
| Adult Dose | 3000-6000 U/d IV q12h or qd Total U = (desired level - initial level) (0.6 X total body weight in kg) IV q8h with desired level >125% loading dose of 100 U/kg IV over 3 h followed by continuous infusion of 100 U/kg/d |
| Pediatric Dose | No standard achieved for dosing in DIC; dosages include 250 U IV q8h Neonates: 40-60 U/kg/d along with heparin 200 U/kg/d) 120-250 U/kg/d IV continuous infusion; goal is to achieve antithrombin III levels of 100-120% |
| Contraindications | Documented hypersensitivity |
| Interactions | Enhances anticoagulant effect of heparin |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Despite measures to remove infectious agents from human product, may transmit disease or contain unknown infectious agents |
| Drug Name | Drotrecogin alfa (Xigris) |
|---|---|
| Description | Recombinant human activated protein C. 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. |
| Adult Dose | 24 mcg/kg/h IV continuous infusion for 96 h; ideally start within 48 h of onset of sepsis |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; increased risk of bleeding (eg, active internal bleeding, recent hemorrhagic stroke, recent intraspinal or intracranial surgery, recent or current trauma, epidural catheter, intracranial neoplasm, cerebral herniation, severe head trauma) |
| Interactions | None reported; coadministration with drugs that affect hemostasis may increase risk of bleeding (eg, warfarin, heparin, thrombolytics, glycoprotein IIb/IIIa inhibitors) |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Bleeding most common serious adverse effect; caution in conditions that increase risk of bleeding: international normalized ratio (INR) >3; concurrent therapeutic heparin >15 U/kg/h; within 6 wk of GI bleeding episode; within 3 d of thrombolytic therapy, within 7 d of administration of platelet inhibitors; within 3 mo of ischemic stroke, intracranial arteriovenous malformation or aneurysm, known bleeding diathesis, or chronic severe hepatic disease; stop infusion if clinically significant bleeding occurs |
Coagulation factors may be required to control bleeding secondary to DIC.
| Drug Name | Recombinant coagulation factor VIIa (NovoSeven) |
|---|---|
| Description | 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. |
| Adult Dose | 60-120 mcg/kg IV bolus; may repeat after 2-6 h prn |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Coadministration with activated prothrombin complex concentrates (ie, FEIBA, Autoplex T) or prothrombin complex concentrates (eg, AlphaNine, BeneFix) may increase risk of thrombosis |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Monitor for signs of thrombosis or activation of coagulation system; thrombotic events may increase in advanced atherosclerotic disease, crush injury, sepsis, or DIC |
| Media file 1: Purpura fulminans. | |
 | View Full Size Image | Media type: Photo |
| Media file 2: Peripheral blood of a child with disseminated intravascular coagulation demonstrates thrombocytopenia and many schistocytes (Wright stain, original magnification X1000) | |
 | View Full Size Image | Media type: Photo |
Consumption Coagulopathy excerpt
Article Last Updated: Oct 17, 2006
