Pediatrics

Disseminated Intravascular Coagulation (DIC)

OVERVIEW: What every practitioner needs to know

Are you sure your patient has disseminated intravascular coagulation? What are the typical findings for this disease?

The most common symptom of Disseminated Intravascular coagulation (DIC) is excessive and/or prolonged bleeding. This can be particularly apparent from venipuncture sites. In other patients, purpura or petechiae are the presenting symptoms. In severe cases of DIC, severe hemorrhage and clotting can lead to life threatening symptoms, including intracranial hemorrhage, necrosis of digits or limbs, or organ failure.

What other disease/condition shares some of these symptoms?

Other diseases that activate the clotting system share symptoms with DIC. These include immune thrombocytopenic purpura (ITP), hemolytic uremic syndrome (HUS), Kassebach Merrit syndrome (KMS), and liver failure.

Patients with ITP have increased bruising and bleeding associated with very low platelet counts, often below 10,000. Coagulation studies are normal as there is not activation consumption of factors in the clotting cascade. ITP is usually self-limited in children.

HUS is a consumptive coagulopathy that is difficult to differentiate from DIC. HUS can be caused by congenital or aquired deficiencies in the ADAMST3 von Willebrand Factor cleaving protease leading to hyperactivity of von Willebrand factor, or from abnormalities in proteins involved in protecting the kidneys from the effects of complement. Patients with HUS can present with infectious diarrhea and renal failure, and also can present with seizures or other neurological symptoms associated with clotting in the brain.

In Kassebach Merrit Syndrome consumptive coagulopathy is associated with large hemagiomas, often found in the liver. Platelets and clotting factors are consumed within the hemangioma. In liver failure, coagulopathy is due to reduced synthesis of coagulation factors and thrombopoietin production rather than consumption.

What caused this disease to develop at this time?

DIC is usually preceded by damage to endothelium from any number of causes (Table I). This results in the release of tissue factor and the activation of the clotting cascade; which leads to the formation of thrombosis in small vessels, reduction of levels of clotting factors, and ultimately bleeding and tissue necrosis. The key to treating DIC is identifying the underlying cause.

Table I.

Causes of DIC
Underlying Cause Catalyst for DIC
Septic Shock Endotoxin associated with bacterial, fungal, ricketssial, and parasitic infection
Trauma Crush injuries lead to the release of tissue factor
Massive Burns Tissue injury leads to the release of tissue factor
Brain Injury Tissue injury leads to the release of tissue factor
Pregnancy Complications Obstretrical complications such as a retained fetus or abruptio placentae cause release of tissue factor
Malignancy Acute leukemia, particularly promyelocytic leukemia and leukemia with t(17;19), is associated with the development of DIC
Acute Hemolytic Transfusion Reactions Hemolysis release phospholipids from erythrocyte walls which trigger the coagulation cascade
Snake and Spider Bites Venom from snakes and spiders can activate the coagulation cascade leading to DIC
Hepatic Failure Liver failure associated with hepatic necrosis can lead to DIC through release of tissue factor and other procoagulants

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Laboratory studies that can suggest a diagnosis of DIC include a complete blood count with differential, a prothrombin time, partial thromboplastin time, fibrinogen level, fibrin degradation products (FDPs), and D-Dimers.

DIC is suggested when a complete blood count with differential shows thrombocytopenia and anemia with a normal leukocyte count. Schistocytes (red cell fragments) on the peripheral blood smear are the result of shearing of erythrocytes from fibrin strands in small blood vessels. Schistocytes are seen in approximately 50% of cases of DIC.

Patients with DIC will present with both the PT and PTT prolonged due to decreased levels of coagulation factors in both the intrinsic and extrinsic pathways in a Protime and Partial Thromboplastin Time study. Fibrinogen levels are frequently low in patients with DIC. However, because fibrinogen is an acute phase reactant, it can be elevated in patients with DIC associated with a chronic inflammatory disorder. A fibrinogen level of 300 mg/dl, while normal, may be lower than normal in a patient with a baseline high fibrinogen due to chronic inflammation.

Fibrin degradation products (FDPs) are the result of the breakdown of fibrinogen and fibrin when cleaved by plasmin. FDPs are seen in most patients with DIC but are also seen in other disorders such as systemic lupus erythematosis. D-Dimers are the result of the breakdown of crosslinked fibrin by plasmin. D-dimers are seen in most patients with DIC and are more specific than elevated FDPs.

Would imaging studies be helpful? If so, which ones?

Imaging studies have limited utility in diagnosing DIC but could be helpful in determining the cause of DIC. For instance, imaging of the brain demonstrating stroke or injury, pelvic imaging showing a retained fetus, or abdominal imaging showing inflamed bowel, could be helpful in determining the source of damaged tissue that can trigger DIC. Choice of imaging should be determine by the clinical picture.

Confirming the diagnosis

One should suspect DIC when abnormalities in the following labs are noted: CBC, PT, PTT, Fibrinogen, D-Dimer.

Patient with falling platelets or thrombocytopenia, falling fibrinogen or hypofibrinogenemia, elevated PT/PTT, elevated d-dimer all supportive of DIC.

Schystocytes are seen on peripheral smear in around 50% of cases due to sheering in the small blood vessels.

If you are able to confirm that the patient has disseminated intravascular coagulation, what treatment should be initiated?

Treatments should be focused on treating the underlying cause of DIC. Reducing the generation of tissue factor or other procoagulants by treating the underlying disorder is key to treating DIC.

It is generally unnecessary to replace clotting factors or platelets in a patient with DIC unless the patient is acutely hemorrhaging. Acute hemorrhage can be treated with platelet transfusions and replacement of clotting factors with fresh frozen plasma and cryoprecipitate. FFP replaces both pro and anticoagulant proteins whereas cryoprecipitate has higher levels of factor VIII and fibrinogen. FFP is dosed 10 ml/kg every 12 to 24 hours and cryoprecipitate is dosed 10 ml/kg every 6 hours. Replacement therapy should aim to keep platelets > 50,000/microliter and fibrinogen levels > 100.

Some centers advocate using low dose heparin to reduce the effect of microthrombosis on end organs. Other centers have used recombinant protein C or antithrombin 3 to limit the level of microthrombosis and end organ damage. Patients should be monitored closely for signs of occult bleeding such as abdominal distension or the Cushing's triad. Gastrointestinal and intracranial hemorrhage are common causes of mortality in patients with DIC.

What are the adverse effects associated with each treatment option?

Replacement of clotting factors and platelets can lead to significant fluid overload, particularly in patients with renal failure. Platelet transfusions are associated with transfusion related infections, severe allergic reactions, and alloimmunization.

What are the possible outcomes of disseminated intravascular coagulation?

The prognosis depends on the underlying cause of the DIC. The outcome is generally favorable provided the underlying source of the DIC can be successfully treated. In the past it has been suggested that treating symptomatic DIC with replacement therapy can lead to worsening DIC due to "throwing fuel on the fire". However, more recent studies have not supported this.

What causes this disease and how frequent is it?

DIC is caused by severe infection/sepsis, head injury, pulmonary embolism/fat embolism, amphetamines, obstetrical complications/abruptio placentae/retained fetus, hemolytic transfusion reaction, immunological disorders such as systemic lupus erythmatosis, malignancy (i.e., promyelocytic leukemia), spider/snake bites, and transplant rejection.

DIC is rare but has been estimated to occur in 1/100 to 1/1000 hospital admissions. Cases of mild DIC are probably missed because it is not suspected. Bleeding is a more common manifestation of DIC than clotting. In one series, bleeding occurred in approximately 50% whereas clotting occurred in 5%.

How do these pathogens/genes/exposures cause the disease?

DIC is caused by tissue damage leading to the release of tissue factor. Activated tissue factor leads to the activation of the coagulation cascade and thromboin generation. This ultimately leads to the production of fibrin. However, fibrinolysis is not balanced due to the presence of high levels of plasminogen activator inhibiro. This leads to inadequate removal of fibrin leading to disseminated intravenouascular thrombosis, in addition to increased tendency to bleed. The anticoagulation system is simultaneously activated, including activation of antithrombin III, protein C, and the tissue factor pathway inhibitor.

Other clinical manifestations that might help with diagnosis and management.

Petechiae and purpura can be another manifestation of DIC. They can be the initial presenting symptoms in DIC due to meningococcemia or in newborns with homozygous protein C deficiency.

What complications might you expect from the disease or treatment of the disease?

DIC can lead to end organ damage due to poor perfusion. This includes damage to organs, skin necrosis, or necrosis of extremities. DIC can also lead to life threatening bleeding.

Are additional laboratory studies available; even some that are not widely available?

Factor V and Factor VIII levels will be low in DIC. Thrombin time is increased in DIC. Fibrin degradation products are elevated as a result of plasmin degradation of fibrin.

In coagulopathy due to liver failure, factor VIII levels are normal (not produced in the liver).

Although fibrin degradation products are elevated in the vast majority of patients with DIC, they are also elevated in other disorders such as lupus.

Elevated lactic acid dehydrogenase and decreased haptoglobin can demonstrate intravascular hemolysis.

How can disseminated intravascular coagulation be prevented?

Because DIC is not a primary disorder but rather secondary to other disorders, there are no specific ways to prevent DIC.

What is the evidence?

Most research in DIC is focused on adults. The papers below, however, are particularly relevant to recent advances in the understanding of DIC and how they pertain to children.

Oren, H, Cingoz, I, Duman, M, Yilmaz, S, Irken, G. "Disseminated intravascular coagulation in pediatric patients: clinical and laboratory features and prognostic factors influencing the survival". Pediatr Hematol Oncol.. vol. 22. 2005. pp. 679-688.

(A large retrospective study of pediatric patient with DIC in Turkey. High mortality rates were seen in patients with DIC and multi-organ system failure or acute respiratory distress syndrome. Discussion has a nice review of DIC in children.)

Chiaretti, A, Pezzotti, P, Mestrovic, J. "The influence of hemocoagulative disorders on the outcome of children with head injury". Pediatr Neurosurg.. vol. 34. 2001. pp. 131-137.

(This paper shows a correlation between the presence of DIC and death in children who have head injury.)

Khemani, RG, Bart, RD, Alonzo, TA, Hatzakis, G, Hallam, D, Newth, CJ. "Disseminated intravascular coagulation score is associated with mortality for children with shock". Intensive Care Med.. vol. 35. 2009. pp. 327-333.

(This study correlates degree of DIC using a DIC score with poor outcome (death) in children.)

Binder, A, Endler, G, Muller, M, Mannhalter, C, Zenz, W. "4G4G genotype of the plasminogen activator inhibitor-1 promoter polymorphism associates with disseminated intravascular coagulation in children with systemic meningococcemia". J Thromb Haemost.. vol. 5. 2007. pp. 2049-2054.

(This paper ties a specific polymorphism in PAI-1 to DIC, demonstrating that some individuals are predictably prone to develop DIC due to genetic factors.)

Goldenberg, NA, Manco-Johnson, MJ. "Protein C deficiency". Haemophilia.. vol. 14. 2008. pp. 1214-1221.

(An excellent review of protein C deficiency, which can predispose patients to develop DIC particularly in the neonatal period.)

Higuchi, T, Toyama, D, Hirota, Y. "Disseminated intravascular coagulation complicating acute lymphoblastic leukemia: a study of childhood and adult cases". Leuk Lymphoma.. vol. 46. 2005. pp. 1169-1176.

(This study from Japan mentions that DIC is seen in 5% of children with acute lymphoblastic leukemia, but is more prevalent later in induction therapy. Coagulation disorders are common during ALL therapy due to the use of asparaginase which diminishes the production of both pro and anticoagulant proteins.)

Mazoyer, E, Enjolras, O, Laurian, C, Houdart, E, Drouet, L. "Coagulation abnormalities associated with extensive venous malformations of the limbs: differentiation from Kasabach-Merritt syndrome". Clin Lab Haematol.. vol. 24. 2002. pp. 243-251.

(A reminder that vascular malformations can be associated with DIC.)

Ongoing controversies regarding etiology, diagnosis, treatment

While focus on treating the underlying cause of DIC and using replacement therapy to treat active bleeding are widely accepted treatments for DIC, the use of new agents such as recombinant activated protein C are controversial and have not been widely studied in children.

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