eMedicine Specialties > Pediatrics: General Medicine > Hematology

Consumption Coagulopathy

Author: Jennifer Boden Cerone, MD, Resident Physician, Department of Pediatrics, The Children's Hospital at Albany Medical Center
Coauthor(s): Vikramjit S Kanwar, MD, MBA, MRCP(UK), FAAP, Associate Professor of Pediatric Hematology and Oncology, Department of Pediatrics, Albany Medical Center; Faculty, Alden March Bioethics Institute; Richard H Sills, MD, Professor of Pediatrics, Upstate Medical University
Contributor Information and Disclosures

Updated: Jan 6, 2009

Introduction

Background

Consumptive 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

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.² 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.³

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.⁴

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.⁵  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.⁶  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.⁷

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.⁸  

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.

Frequency

United States

The incidence of DIC is unknown.

International

The incidence of DIC among hospitalized children in Turkey is around 1%.⁹  The incidence of DIC in Japan is 1.72% among hospitalized patients.¹⁰  

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%.

Race

No predilection for any race is known.

Sex

No predilection for either sex is known.

Age

DIC occurs at any age.

Clinical

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 is severe, extensive hemorrhage into the skin associated with fever and hypotension. 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 (see Media file 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 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

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