Disseminated intravascular coagulation in the neonatal period

REVIEW

Abstract Disseminated intravascular coagulation in the neonatal period is a secondary process triggered by a primary disease state. It is a disruption in the hemostatic balance of the coagulation and fibrinolytic systems. This results in a contradictory state of hypercoagulability with systemic microthrombi simultaneously occurring with systemic hemorrhage. The clinical manifestations, treatment, and outcome are largely dependent on the primary disease process. © 2004 Elsevier Inc. All rights reserved.

Disseminated Intravascular Coagulation in the Neonatal Period By Laura Trotter, MSN, RNC, NNP

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isseminated intravascular coagulation (DIC) is a disorder of hemostasis that may occur in the neonatal period as a complication of various other disease processes. Its effects on the newborn, especially a premature or otherwise sick infant, can be particularly devastating. As with many other body systems in the neonate, the hematologic system is immature at birth. As a result, newborns may be at an increased risk for various problems. Bleeding disorders in an infant can be viewed in two categories: inherited or acquired. Inherited disorders include factor deficiencies such as hemophilia, von Willebrand disease, and both autoimmune and alloimmune thrombocytopenias. The most common acquired disorders are vitamin K deficiency, liver disease, and disseminated intravascular coagulation secondary to some underlying cause.1–3 Disseminated intravascular coagulation continues to be a topic of recent discussion due to its prevalence in the sick or premature newborn. DIC is complex and varies in etiology, presentation, diagnosis, and treatment.1– 4

Definition

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isseminated intravascular coagulation is a bleeding disorder characterized by two seemingly opposite conditions. As a caregiver in a neonatal intensive care unit (NICU), it is not uncommon to think first of uncontrolled bleeding at the mention of DIC. This is not incorrect, merely incomplete. DIC is a condition of uncontrolled bleeding, simultaneous with uncontrolled clotting, set into motion by an inappropriate activation and consumption of clotting factors resulting in a hemorrhagic state due to inadequate hemostasis.5

Etiology

From the Medical University of South Carolina, Neonatal ICU, Charleston, SC. Address reprint requests to Laura Trotter, Medical University of South Carolina, Neonatal ICU, 165 Ashley Ave, P.O. Box 250917, Charleston, SC 29425. © 2004 Elsevier Inc. All rights reserved. 1527-3369/04/0404-0000$30.00/0 doi:10.1053/j.nainr.2004.09.003

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IC is not a primary diagnosis, but instead a secondary coagulation disorder that complicates various primary conditions.2,3,6 The range of presentation varies widely with the underlying status of the infant and the severity of the triggering event.1,4 Some of the most common underlying pathologies are asphyxia, sepsis, and respiratory distress syndrome (RDS). It is postulated that the acid– base imbalances and shock that often accompanies these common Newborn and Infant Nursing Reviews, Vol 4, No 4 (December), 2004: pp 176 –180

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neonatal problems cause a release of endotoxins and endothelial damage. These in turn stimulate the pathways of coagulation and fibrinolysis.2

Relevance

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he true incidence of DIC in the newborn is not easily defined by the literature, because DIC may remain undetected until the neonate presents with severe hemorrhaging or the disease is determined at autopsy.2,4,6 Despite evidence that newborns are in a hypercoagulable state,2,7,8 there does not seem to be clear or universally accepted criteria to diagnose DIC in the neonatal ICU. The most frequent causes of DIC, cardiovascular compromise and infection, are very prevalent in this population. Shock and asphyxia, though not as prevalent, are also seen in these fragile patients and initiate the pathway leading to DIC. The disease has been referred to as a “common occurrence” due to the increased susceptibility of these patients as a result of prematurity of antithrombotic functions, an immature reticuloendothelial system, and a tendency to develop acidosis, hypothermia, hypoxia, and shock. While earlier literature states that DIC seems to be frequent in sick neonates, more recent articles discuss the decrease in incidence based on better proactive management and optimal intensive care.8 –10 Regardless of these measures, of all the DIC reported in children, half occurs during the neonatal period.1

Pathophysiology

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o understand the events of DIC, a review of the normal homeostatic process may be beneficial. Hemostasis refers to cessation of bleeding by the physiologic properties of vasoconstriction and coagulation, often initiated by injury to the blood vessel.2,3,11 In a healthy individual, the normal events of hemostasis (vascular constriction, platelet plug formation, and coagulation) must be balanced with the mechanism for breaking down fibrin clots after healing occurs to restore normal blood flow. This is the process of fibrinolysis.2,3,12 When the body experiences an injury to a blood vessel, muscular response to the injury causes the vessel to constrict, decreasing blood flow to the area. The blood is exposed to collagen in the activated vascular endothelium, initiating coagulation. Platelets respond to the site of injury and become activated, releasing substances such as growth factor, adenosine diphosphate, prostaglandins, and fibrin-stabilizing factor. They change their normally smooth surface and shape, and their lipoprotein layer promotes adhesion and aggregation, forming a platelet plug.3 Historically, the clotting cascade has been described as being initiated by either the intrinsic or the extrinsic path-

Fig 1. A brief schematic of the clotting cascade.

way, both of which lead to a common pathway that results in the formation of fibrin.12 The more recent literature no longer separates the two pathways, but instead views the overall process.2,3 Tissue factor is exposed to factor VII, converting it to factor VIIa. In the presence of ionized calcium and phospholipid, this combination activates factor X and factor IX. Factor Xa, along with cofactor Va, is responsible for converting prothrombin to thrombin, a serine protease with important coagulation functions. Thrombin splits fibrinogen to form fibrin monomers, soon converted to fibrin polymers, which, in the presence of factor XIII, forms a stable and cross-linked fibrin clot.7,10 Figure 1 represents the process of coagulation. Once a fibrin clot has been formed, the fibrinolytic system comes into play. Tissue plasminogen activator (tPA) converts plasminogen to plasmin, a serine proteinase, which in turn is responsible for the breakdown of fibrin into fibrin degradation products (FDPs). Specific activators and inhibitors regulate both the coagulation component and the fibrinolytic component. Figure 2 represents fibrinolysis. Together, there is a balance between the two components that maintains the integrity of the system, resulting in normal homeostasis.7,13 DIC disrupts the integrity of the system, resulting in a combined hemostatic defect consisting of a reduction in certain procoagulants, anticoagulants, and components of the fibrinolytic system.13 The underlying disease process often results in endothelial damage, which causes the release of cytokines such as interleukins 1, 6, and 8, platelet activating factor, and tumor necrosis factor. Tissue factor activity is increased in response to certain cytokines. Through the normal mechanisms of the coagulation pathway, this increased activity favors the overproduction of thrombin.2,4 Sepsis is the most frequent cause of DIC in the neo-

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Fig 2. A brief schematic of the fibrinolytic process. tPA/tissue plasminogen activator; FDPs/fibrin degradation products.

nate.6 In bacterial sepsis, particularly with gram-negative organisms, it is believed that the endotoxins released into the bloodstream trigger tissue thromboplastin, which combines with factor VII and leads to stimulation of the coagulation pathway. Cardiovascular compromise or shock often accompanies severe sepsis in these patients, causing further endothelial damage and thereby also triggering the pathway. In sepsis caused by a viral pathogen, coagulation may begin by circulating antigen–antibody complexes that activate factor XII. Fibrinolytic activity may also be inhibited by the production of interleukin-1 or tissue necrosis factor.9 Hypoxemia, shock, and acidosis are all consequences of birth asphyxia. The mechanism related to initiating coagulation and fibrinolysis in this case is not only the release of tissue factor from the hypoxic injury to the endothelium, but also the breakdown of red blood cells leading to the production of tPA. Tissue factor combines with factor VII to form factor X and potentiates the production of prothrombin to thrombin and fibrinogen to fibrin. At the same time, tPA acts on plasminogen to convert to plasmin to breakdown fibrin. These simultaneous actions are in excess of the normal response, leading to overuse of coagulation products. For this reason, DIC has been called a consumption coagulopathy.1,2 In RDS, the mechanisms of DIC are similar to sepsis and asphyxia. Hypoxia and acidosis again lead to the increase in tissue factor activity. However, in this condition, intraalveolar and intravascular fibrin deposits resulting from the overstimulation of the pathway are likely to contribute to severe respiratory insufficiency, which is responsible for inactivating considerable amounts of surfactant and worsening the disease process.9,14 In any of these situations, the excessive formation of clots will have several detrimental consequences. Deple-

tion of clotting factors and platelets will occur, resulting in uncontrolled hemorrhage. The fibrin deposits may also cause damage to red blood cells as they circulate by, resulting in a microangiopathic hemolytic anemia.12 Microthrombi, as well as septic emboli, can be distributed throughout the circulation, with a potential for inducing ischemic injury and organ damage. As fibrinolysis begins, excessive plasmin yields fibrin degradation products, whose anticoagulant function contributes to the tendency for bleeding. Plasmin also activates the complement system, which causes further damage to RBCs and platelets. This destruction releases phospholipids with procoagulant properties that stimulate clot formation, starting the cycle over again. In this sense, DIC is a contradictory state of extreme clotting and bleeding.

Evaluation and Diagnosis

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he clinical manifestations of DIC and their time of onset can be variable. The infant will first show signs of the underlying disease process, and then may progress to subtle clues or major signs of DIC. These infants are already sick, probably requiring ventilatory support and possibly cardiovascular support as well. As expected, bleeding is typically an initial presentation. An infant who continues to bleed after laboratory draws or venipuncture should raise suspicion. Hemorrhage can range from oozing of an umbilical line or wound to frank blood in the mouth, nose, or orogastric or endotracheal tube indicating a major gastrointestinal or pulmonary bleed. The most severe presentation may be a change in vital signs, especially hypothermia, and level of consciousness that would represent an intraventricular hemorrhage.10,15–17 In addition, the systemic coagulation and bleeding may also present as petechiae, purpura, ecchymoses, or hematomas. Ischemic damage related to thrombosis could manifest as cyanosis, as well as specific organ failure, depending on the site of the clot. Laboratory diagnosis of DIC can be complex in the sick or preterm neonate due to already “abnormal” results compared with adult values. The most common tests used to evaluate coagulation and fibrinolysis are platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen levels, and FDPs in some institutions, or D-dimers in others. Platelet counts and fibrinogen levels are relatively consistent with adult values, with thrombocytopenia defined as a platelet count ⬍ 100,000/ mm3 and an abnormal fibrinogen level considered ⬍150 mg/dL. Both Taeusch and Ballard3 and Christensen2 utilize values published in the American Journal of Pediatric Hematology and Oncology in 1990 by Paes and Johnston to define reference values for coagulation tests in neonates based on gestational and postnatal age. PT and APTT

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Table 1. Mean Coagulation Values in Fetuses and Full-Term Infants

Parameter PT APTT

24–29 Week Fetus

30–38 Week Fetus

Term Newborn

32.2 154.0

22.6 108.4

16.7 44.3

PT, prothrombin time; APTT, activated partial thromboplastin time. Adapted from Reverdiau-Moalic et al.19

values, which reflect depletion of clotting factors, are higher in infants than adults. It is noteworthy that these values are for healthy infants; therefore the values seen in DIC are likely to be even further elevated. According to Paes and Johnston, on the fifth day of life, PT is prolonged if ⬎15.3 seconds in term and preterm infants, whereas APTT is prolonged if ⬎ 59.8 seconds in a term infant and ⬎ 74.1 seconds in a preterm infant. Elevated FDPs and D-dimers, which indicate increased fibrinolysis, are ⬎10 or ⬎0.5 mg/mL, respectively. Table 1 displays mean PT and APTT values as measured in fetuses and term newborn infants. Laboratory evaluation of DIC may also include thrombin ⫹ antithrombin III complex (TAT) and plasmin ⫹ antiplasmin (PAP) values. Elevations in these values represent activation of the coagulation and fibrinolytic systems and their generation of thrombin or plasmin and could be considered sufficient biochemical evidence of DIC.4,13 Assays for specific clotting factors can confirm the diagnosis of DIC, but are not frequently performed. There are references in current literature to faster methods for diagnosis. The Simpli RED D-dimer test is a quicker test that could make it possible to diagnose DIC within 15 minutes after blood drawing at any hospital in which an automatic cell counter is available.5 Thromboelastography (TEG) produces a tracing that evaluates the entire coagulation cycle from platelet activation to clot breakdown,12 including how fast the clot forms and how strong it is. Even with these newer techniques, the care provider of an infant with uncontrolled bleeding and abnormal coagulation tests must still eliminate other possible causes. The differential diagnosis for DIC should include hemorrhagic disease of the newborn and severe liver disease. A careful history of the delivery can uncover the possibility of vitamin K deficiency related to not receiving the prophylactic dose at birth. The liver is the site of synthesis of all clotting factors except factor VIII; therefore in liver disease there will be prolonged values due to a lack of factor production. Transfusing the patient with fresh frozen plasma and monitoring the PT and PTT can exclude liver disease. The values will normalize somewhat, then grad-

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ually become prolonged as the body uses the factors provided by the transfusion. In contrast, if the patient is in DIC, there will not be the expected normalizing of laboratory values, because the body is consuming the factors as fast as it is receiving them.17

Treatment

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he basis for treatment of DIC in the neonatal period is contingent on the underlying disease process that initiates this disrupted hemostasis. Early recognition and intervention will help to improve outcomes, but only if the primary problem is corrected as well. To this end, supportive measures based on the infant’s clinical status are of the utmost importance. If infection is identified as the precipitating factor, appropriate antibiotic treatment and dosing is vital. In infants with RDS, exogenous surfactant may be beneficial. These patients will need careful maintenance of their respiratory and cardiovascular systems, often requiring ventilator assistance and pressor support. Diligent monitoring of blood gasses will dictate changes to correct hypoxia, hypercapnia, and acidosis. Vital signs and physical assessment skills determine the need for vasopressor drips and medications. Fluid and electrolyte balance and nutritional support as tolerated is important as always in this population. Interventions specific to the disease process of DIC include attentive monitoring for any additional signs of bleeding from the gastrointestinal, pulmonary, renal, and neurological systems. Avoid any intramuscular injections or invasive procedures that may cause trauma or bleeding. Limit venipuncture, and place a central line to avoid heelsticks for the frequent examination of laboratory values such as complete blood counts and coagulation studies. In the infant that is actively bleeding, the results of these studies will direct replacement therapy with the recommended blood components. Transfusions of platelets and fresh frozen plasma (FFP), which contains all of the clotting factors, are the most frequently used. Cryoprecipitate, with its high concentration of factor VIII and fibrinogen can also be used, but with caution, as it can also be thrombogenic. Packed red blood cell transfusions are indicated to correct hypovolemia or anemia. If a specific factor deficiency is known, concentrates may be transfused as well.1,10,14,16 In the most severe cases of DIC, a double volume exchange transfusion may be indicated. Although this is a rare treatment, probably due to the associated complications and no definitive data, there are several benefits supporting this concept. Not only are clotting factors replaced at adult content levels, but fibrin degradation products are removed as well. The adult hemoglobin can im-

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prove oxygen delivery, and fluid overload from multiple transfusions can be avoided.3,6,8 Anticoagulant therapy is controversial in treating DIC. For example, there is currently a debate concerning antithrombin III concentrate and its efficacy in this situation. AT III is a natural anticoagulant that inhibits thrombin and is important in mediating the predominant antithrombotic effect of heparin.18,19 In DIC, AT III is consumed, and deficiency impairs the clearance of activated coagulation factors. Clinical trials of AT III concentration are not yet definitive, but most studies have shown improvement in coagulation values and a shortened duration of DIC.19 Heparin is also being considered for beneficial usage in DIC, but few studies have focused on neonates as of yet.

Outcomes

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s with the treatment of DIC, the prognosis and outcomes are essentially dependent on the primary disease process. Historically, most infants with DIC have died. Avery and coworkers1 report that the underlying disease and the ischemic damage caused by the cardiovascular collapse and DIC result in high mortality rates. In infants with DIC who experience severe bleeding, mortality rates are reported to 60 to 80%.6 However, other literature now states that the majority of infants with DIC survive due to the advances in neonatal medicine and its supportive care.2,10

Conclusion

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isseminated intravascular coagulation is not an uncommon occurrence in the neonatal period, and its effects can be devastating. It is a secondary process set off by an underlying disease state that results in an imbalance of the coagulation system and the fibrinolytic system. This disruption in hemostasis leads to microthrombi distribution throughout the circulation concurrent with systemic hemorrhaging, and resulting in end organ dysfunction. The evaluation, clinical manifestations, treatment, and outcome are largely dependent on the primary diagnosis, but include monitoring coagulation studies, replacing deficient

clotting factors in the actively bleeding infant, and supportive care. Early recognition and intervention by the caregivers in the NICU can dramatically enhance the overall survival of these critically ill infants.

References 1. Avery GB, Fletcher MA, MacDonald MG: Neonatology: Pathophysiology and Management of the Newborn (ed 5). Philadelphia, PA, Lippincott, Williams, and Wilkins, 1999 2. Christensen RD: Hematologic Problems of the Neonate. Philadelphia, PA, WB Saunders Company, 2000 3. Taeusch HW, Ballard RA: Avery’s Diseases of the Newborn (ed 7). Philadelphia, PA, WB Saunders Company, 1998 4. Bick RL: Disseminated intravascular coagulation: Current concepts of etiology, pathophysiology, diagnosis, and treatment. Hematol Oncol Clin North Am 17:149 –176, 2003 5. Shirahata A, Shirakawa Y, Murakami C: Diagnosis of DIC in very low birth weight infants. Semin Thromb Hemost 24:467– 471, 1998 6. Kuehl J: Neonatal disseminated intravascular coagulation. J Perinat Neonat Nurs 11:69 –77, 1997 7. Manco-Johnson M, Nuss R: Hemostasis in the neonate. NeoReviews 1:191–194, 2000 8. Suzuki S, Morishita S: Hypercoagulability and DIC in high-risk infants. Semin Thromb Hemost 24:463– 466, 1998 9. Mautone A, Giordano P, Montagna O, et al: Coagulation and fibrinolytic systems in the ill preterm newborn. Acta Paediatr 86:1100 – 1104, 1997 10. Nuss R, Manco-Johnson M: Bleeding disorders in the neonate. NeoReviews, 1:196 –199, 2000 11. Spitzer A: Intensive Care of the Fetus and Neonate. St. Louis, MO, Mosby, 1996 12. Arafeh JMR: Disseminated intravascular coagulation in pregnancy: An update. J Perinat Neonat Nurs 11:30 – 45, 1997 13. Aronis S, Platokouki H, Photopoulos S, et al: Indications of coagulation and/or fibrinolytic system activation in healthy and sick very-low-birth-weight neonates. Biol Neonate 74:337–344, 1998 14. Monagle P, Andrew M: Coagulation Disorders in the Newborn, in Hansen TN, McIntosh N (eds): Current Topics in Neonatology Number 4. Philadelphia, PA, WB Saunders, 2000 15. Gobel BH: Disseminated intravascular coagulation. Semin Oncol Nurs 15:174 –182, 1999 16. Journeycake JM, Buchanan GR: Coagulation disorders. Pediatr Rev 24:83–90, 2003 17. Polin RA, Spitzer AR: Fetal and Neonatal Secrets. Philadelphia, PA, Hanley and Belfus 2001 18. Bucur SZ, Levy JH, Despotis GJ, et al: Uses of antithrombin III concentrate in congenital and acquired deficiency states. Transfusion 38:481– 493, 1998 19. Reverdiau-Moalic P, Delahousse B, Bardos G, et al: Evolution of blood coagulation activators and inhibitors in the healthy human fetus. Blood 88:900 –906, 1996