AUTHOR INFORMATION

Section 1 of 12

Authored by Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP, Assistant Professor of Pediatric Hematology-Oncology, Department of Pediatrics, Children's Hospital at Albany Medical Center

Coauthored by 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

Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP, is a member of the following medical societies: American Academy of Pediatrics, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Royal College of Physicians

Edited by 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, Associate Professor, Department of Pediatrics, 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; and Robert J Arceci, MD, PhD, King Fahd Professor, Division of Pediatric Oncology, Johns Hopkins University School of Medicine

Author's Email:	Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP
Editor's Email:	Gary R Jones, MD

eMedicine Journal, October 17 2006, VOLUME 7, Number 10

INTRODUCTION

Section 2 of 12

Background: Consumptive 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.

Pathophysiology: Central 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.

Frequency:

• In the US: The true incidence of DIC is unknown.

• Internationally: The incidence of DIC among hospitalized children in Turkey was around 1%.

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%. DIC-related mortality due to acute promyelocytic leukemia has declined since the introduction of all trans-retinoic acid.

Race: No predilection for any race is known.

Sex: No predilection for either sex is known.

Age: DIC occurs at any age.

CLINICAL

Section 3 of 12

History: As 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.

• Obtain appropriate historical facts, as follows:


• • History of fevers

  • Behavior changes

  • Feeding patterns

  • Urine output

  • Sick contacts

  • Recent travel
  
  
  
• Obtain a birth history, including these details:


• • Pregnancy course

  • Prenatal testing

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

  • Immediate postnatal course, especially neonatal illnesses

  • Sepsis evaluation

  • Antibiotic therapy
  
  
  
• Obtain other history, as follows:


• • Recent illness

  • Recent bruising

  • Fatigue

  • Frequent infections

  • Weight loss

  • 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 past venipuncture sites to severe life-threatening hemorrhage.

  • Coexisting signs of thrombosis and bleeding may be present.
  
  
  
  • Purpura fulminans is severe, extensive hemorrhage into the skin associated with fever and hypotension. It may be caused by infections such as meningococcemia or by protein C deficiency. Cutaneous purpuric or hemorrhagic lesions develop and spread rapidly, which may progress to frank gangrene (see Image 1).
  
  
  
  • 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 they 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


• • 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


• • Placental abruption
  
  
  
  • Amniotic fluid embolism
  
  
  
  • Intrauterine fetal demise
  
  
  
• Malignancies


• • Acute leukemia - Promyelocytic (M3), myelomonocytic (M4), monocytic (M5), lymphoblastic (T cell), and lymphoblastic (Philadelphia-chromosome positive)
  
  
  
  • Metastatic tumors - Neuroblastoma, alveolar rhabdomyosarcoma
  
  
  
• Collagen vascular disorders


• • Systemic lupus erythematosus
  
  
  
  • Juvenile rheumatoid arthritis
  
  
  
• Trauma


• • Massive head trauma
  
  
  
  • Burn injuries
  
  
  
  • Major surgery
  
  
  

DIFFERENTIALS

Section 4 of 12

Fulminant Hepatic Failure
Hemolytic-Uremic Syndrome
Hemorrhagic Disease of Newborn

Other Problems to be Considered:

Postbypass pump syndrome
Posttransfusion purpura
Thrombotic thrombocytopenic purpura

WORKUP

Section 5 of 12

Lab Studies:

• Screening


• • Perform screening tests in all patients, followed by confirmatory tests if necessary. Changes in values are important. For example, a decline in the platelet count of >20% is a poor prognostic factor.

  • The CBC with smear review frequently reveals several findings suggestive of DIC. Thrombocytopenia is an almost universal finding, whereas the smear often shows decreased platelet size, schistocytes, and helmet cells (see Image 2).
  
  
  
  • The prothrombin time (PT) and the activated partial thromboplastin time (aPTT) are usually prolonged on screening tests for coagulation dysfunction. However, the results may be normal in an individual in the early phase of DIC.
  
  
  
  • Test for fibrin or fibrinogen degradation products and D-dimers may be helpful. Because of the rapid generation of fibrin and breakdown of cross-linked fibrin polymers, levels of fibrin and fibrinogen breakdown products are usually elevated in persons with DIC. Although sensitive, these tests are not specific.
  
  
  
• Levels of factors V, VII, IX, X, and XIII; fibrinogen; antithrombin III; alpha2-antiplasmin; plasminogen; and fibronectin are decreased.



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

  DIC Scoring System

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



• The worse the coagulation defect, the worse the outcome. The following findings indicate a poor prognosis:


• • PT >20 sec
  
  
  
  • Platelet count <60 X 10⁹/L
  
  
  
• The following clinical syndromes also indicate a poor prognosis:


• • Multiorgan dysfunction
  
  
  
  • Acute respiratory distress syndrome
  
  
  

Other Tests:

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

TREATMENT

Section 6 of 12

Medical Care: The most important concept in 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.



• Important supportive measures include ventilatory support, volume support, and pressor support if the patient is hypotensive 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.

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 and 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.
  
  
  
• Blood-bank specialists
  • Treatment of patients may involve blood products.

  • Blood bank specialists can provide resource advice on treatment decisions.



• Critical care specialist


• • 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.
  
  
  
• 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.

MEDICATION

Section 7 of 12

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.

Drug Category: Anticoagulants -- 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 -- 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) -- 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

Drug Category: Blood products -- 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 -- 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) -- 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 -- 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

Drug Category: Coagulation inhibitors -- 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) -- 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) -- 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

Drug Category: Coagulation factors -- Coagulation factors may be required to control bleeding secondary to DIC.

Drug Name	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.
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

FOLLOW-UP

Section 8 of 12

Further Inpatient Care:

• Because most children with DIC are critically ill, serial monitoring of laboratory values is necessary. CBC, PT and aPTT, D-dimers, and fibrinogen measurements should be repeated frequently.



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

Further Outpatient Care:

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

In/Out Patient Meds:

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



• Patients with chronic DIC may benefit from treatment with LMWH on an outpatient basis. Although these agents are not labeled for use in children, 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.

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Failure to look for purpura in a febrile child, and to recognize it as a possible sign of DIC, could lead to an adverse outcome.



• Recognizing and treating the underlying cause are important. DIC in meningococcemia and pneumococcemia is fulminant, and patients with these conditions should rapidly be given antibiotics and immediately transferred to a tertiary center.

TEST QUESTIONS

Section 10 of 12

CME Question 1: An ambulance crew brings a 4-year-old girl to the emergency department. She is obtunded and has scattered reddish-purple skin lesions, which do not blanch. Her vital signs are as follows: temperature 103.2°F, heart rate 150 bpm, blood pressure 70/50 mm Hg, and respiratory rate 30 breaths per minute. The patient bleeds profusely from venipuncture sites, and disseminated intravascular coagulation (DIC) is suspected. Which laboratory values best support the diagnosis of DIC?

A: Platelet count 200 X 10⁹/L, prothrombin time (PT) 12.6 seconds, activated partial thromboplastin time (aPTT) 20 sections, fibrinogen level 200 mg/dL, and fibrin split products normal
B: Platelet count 10 X 10⁹/L, PT 12.6 seconds, aPTT 20 seconds, fibrinogen 200 mg/dL, and fibrin split products normal
C: Platelet count 80 X 10⁹/L, PT 12.6 seconds, aPTT 20 seconds, fibrinogen 200 mg/dL, and fibrin split products elevated
D: Platelet count 40 X 10⁹/L, PT 19.6 seconds, aPTT 30 seconds, fibrinogen 100 mg/dL, and fibrin split products markedly elevated
E: None of the above

The correct answer is D: This patient presents with the clinical picture of meningococcemia, which is frequently complicated with a form of DIC termed purpura fulminans. Because an underlying disorder known to cause DIC is clinically suspected, use of the DIC score is appropriate. For item D, the score is > 5 with a platelet count <50 X 10⁹/L, a PT prolonged by > 6 seconds, fibrinogen level <100 mg/dL and markedly elevated level of fibrin split products. The DIC score is sensitive and specific for diagnosing DIC if the patient has a condition known to cause DIC.

CME Question 2: A teenage girl with a deep venous thrombosis had a family history of several individuals with deep vein thrombosis and a half-sibling who developed disseminated intravascular coagulation (DIC) at birth. What was the most likely cause for neonatal DIC in her half-sibling?

A: Homozygous protein C deficiency
B: Cystic fibrosis
C: Factor VIII deficiency
D: Heterozygous protein C deficiency
E: None of the above

The correct answer is A: Homozygous protein C deficiency results in DIC in the neonatal period. Although critically ill patients with cystic fibrosis may develop DIC, mutations of the cystic fibrosis transmembrane regulator do not predispose individuals to DIC. After the neonatal period, patients with heterozygous protein C deficiency may be most likely to develop DIC in response to sepsis or severe trauma, but their greatest risk is deep venous thrombosis.

Pearl Question 1 (T/F): Acute disseminated intravascular coagulation (DIC) is a consumptive coagulopathy characterized by shock, thrombotic tendency, and simultaneous or subsequent bleeding tendency; however, the cause of DIC is usually unknown.

The correct answer is False: DIC is always secondary to an underlying illness, and identifying that disorder is crucial. The common categories of illness causing DIC include infection, obstetric emergencies, trauma, malignancies, and collagen vascular disorders.

Pearl Question 2 (T/F): CBC determination and a review of the peripheral smear are the single tests to diagnose disseminated intravascular coagulation (DIC).

The correct answer is False: No single test is diagnostic for DIC, though the CBC and peripheral smear provide useful information. Diagnosis of DIC involves a combination of a typical clinical picture with supporting laboratory results, including a decreased platelet count, a prolonged prothrombin time, and decreased levels of fibrinogen and elevated fibrin split products.

Pearl Question 3 (T/F): A child can have disseminated intravascular coagulation (DIC) and appear asymptomatic.

The correct answer is True: In the special case of compensated or chronic DIC, a child can have DIC and appear asymptomatic. This occurs in children with vascular malformations, malignancy, or other chronic activators of the coagulation cascade.

Pearl Question 4 (T/F): All patients with disseminated intravascular coagulation (DIC) should receive heparin.

The correct answer is False: The use of anticoagulants such as heparin may be appropriate in a subgroup of patients with DIC, but it is not currently recommended for all patients. The key remains supportive care, with removal of the underlying cause. The use of other agents, such as recombinant activated protein C, should be considered in severe DIC secondary to sepsis.

PICTURES

Section 11 of 12

Caption: Picture 1. Purpura fulminans.
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Caption: Picture 2. Peripheral blood of a child with disseminated intravascular coagulation demonstrates thrombocytopenia and many schistocytes (Wright stain, original magnification X1000)
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BIBLIOGRAPHY

Section 12 of 12

• Arbuthnot C, Wilde JT: Haemostatic problems in acute promyelocytic leukaemia. Blood Rev 2006 Jun 3;[Medline].
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