Disseminated Intravascular Coagulation in the Newborn William G. Woods, MD; Naomi L. Corman
Luban, MD; Margaret
W.
Hilgartner, MD;
Denis R.
\s=b\ We have reviewed 53 cases of disseminated intravascular coagulation (DIC) in the newborn, including 29 cases that were confirmed at autopsy. Factors predisposing to DIC included maternal
have reviewed the clinical, laboratory, and therapeutic differences in these infants with DIC and compared the differences to outcome.
complications (60%), low Apgar scores (30%), hyaline membrane disease (62%), and sepsis (26%). Diagnostic criteria common to autopsy-proved cases included presence of fibrin degradation products, low factor V activity, a prolonged prothrombin time, and a prolonged partial thromboplastin time and/or thrombocytopenia. There appeared to be no difference in coagulation response or in mortality among patients treated with different therapeutic regimens. Survivors were older gestationally, had higher birth weights, and higher Apgar scores. (Am J Dis Child 133:44-46, 1979)
METHODS
intravascular coagu¬ lation in the newborn is a common occurrence in the intensive care nursery.' The natural history of the disorder, however, has not been well described. Most studies have involved small numbers of patients and have used various clinical and laboratory criteria for diagnosis. Pathologic evidence for DIC generally has been lacking or not evaluated. In our retrospective study, we have attempted to clarify the laboratory profile of DIC in the neonate by corre¬ lating several variables with patholog¬ ic criteria for DIC. Furthermore, we
Disseminated(DIC) period
From the Division of Pediatric Hematology\x=req-\ Oncology, New York Hospital-Cornell Medical Center, New York. Dr Luban is now with Children's Hospital-National Medical Center, Washington, DC; Dr Miller is now with Memorial Sloan-Kettering Cancer Center, New York. Reprint requests to Division of Hematology\x=req-\ Oncology, Children's Hospital Medical Center, 51st and Grove Streets, Oakland, CA 94609 (Dr Woods).
A total of 1,051 infants were admitted to the neonatal intensive care unit of the New York Hospital-Cornell Medical Center dur¬ ing the five-year period from January 1971 to December 1975. Of these, 160 infants, 16% of those admitted, were found to have a bleeding disorder by clinical presenta¬ tion, for example, excessive bleeding from a venipuncture site, or by laboratory data obtained when a coagulopathy was sus¬ pected, for example, in an infant with sepsis. Fifty-three of these 160 infants had laboratory evidence of DIC and are the subject of this report. Twenty-nine of the 53 patients had DIC on postmortem exam¬ ination, using the criteria of Robboy and
colleagues.- Specifically, autopsy-proved cases of DIC showed hemorrhage in several organs plus the presence of fibrin micro¬ thrombi in small vessels. Hemorrhage alone was not considered adequate for pathologic diagnosis of DIC. However, since patients may have clinical DIC with¬ out strict pathologic evidence at autopsy, unconfirmed autopsy cases were included in the total patient population if their coagulation studies showed DIC. For nonautopsy-proved cases of DIC, patients who had abnormal liver enzymes or who had not received vitamin were excluded. Laboratory studies performed by stan¬ dard methods11 on our patients included the determination of prothrombin time (PT), partial thromboplastin time (PTT), throm¬ bin time (TT) "corrected" with addition of normal plasma to demonstrate the pres¬ ence of fibrin degradation products, onestage assays of factors V and VIII, and platelet count. Umbilical catheters, from which blood samples were often obtained, were routinely flushed with a solution that did not contain heparin. Therefore, con-
Miller,
MD
laboratory samples with heparin, and hence invalidation
tamination of exogenous
of the corrected TT test, was not a concern. Abnormal values, selected after review of the laboratory data in pathologically con¬ firmed DIC, were as follows (normal premature values from our laboratory are given in parentheses): PT, >16 seconds (16 seconds); PTT, >85 seconds (60 seconds); TT, >40 seconds (20 seconds) with correc¬ tion to only >30 seconds (18 seconds) with the addition of an equal volume of normal plasma; factor V activity, 1,500 g. Seven of eight had one-minute Apgar scores of 4 or greater. One a
patient had no Apgar scores reported. When comparing survivors and non¬ survivors, maternal and infant
plications
com¬
different except that six of the survivors (67%) had neonatal seizures compared to 18% of the nonsurvivors. This difference may be due to the fact that those infants who possibly had a central nervous system hemorrhage, and survived the were no
DIC, lived long enough sequelae such as seizures.
to
develop
Five of the survivors were followed up at least one year. One had a chronic
seizure disorder, one had microcephaly and developmental delay, and three were developing normally. Two of the three who were doing well had had seizures in the newborn period. Coagulation studies of the survivors were compared to those of the autop¬ sy-proved group (Table 1). Survivor PTs and factor V levels were better than those of the nonsurvivors, whose coagulation values were similar to those having autopsies indicating a possible difference in the degree of
coagulopathy.
Treatment of the survivors is listed in Table 4. Two patients survived DIC without specific treatment. Both had well-substantiated clinical DIC with thrombocytopenia, low activity of fac¬ tor V, and presence of fibrin degrada¬ tion products. COMMENT
Disseminated intravascular coagu¬ lation in the newborn is a clinical phenomenon described within the past decade.4-5 One early report placed some emphasis on pathologic correla¬ tion with clinical presentation.6 Subse¬ quent reports have differed over how best to make the diagnosis7-8 without utilizing pathologic data. Unlike DIC in the adult8 or older child, DIC in the newborn period is more difficult to diagnose clinically because of the normally prolonged coagulation val¬ We have ues of premature infants.1" evaluated the laboratory data in those children with DIC confirmed at autop¬ sy, using cases where hemorrhage and thrombosis were present, and have found criteria that appear to be common to all cases and that cannot be confused with normal values for premature infants. Evaluation of our patients shows the importance of obstetrical compli¬ cations and low Apgar scores in the development of DIC. Other reports have emphasized the role of sepsis,812 hyaline membrane disease,'1 dissemi¬ nated herpes simplex infection," and necrotizing enterocolitis15 in the de¬ velopment of DIC, and our study confirms these roles. Virtually any "
added stress to these infants can be sufficient to cause tissue necrosis, release of thromboplastin, intravascu¬ lar coagulation with rapid consump¬ tion of factors that cannot be replaced adequately, and hemorrhage. Our sur¬ vivors were gestationally older, larg¬ er, and had better Apgar scores; this emphasizes the vulnerability of the high-risk, stressed premature infant.
In our retrospective study, overt bleeding was the primary reason for doing tests of coagulation. The fact
that the children were evaluated after the possible onset of the active consumption of coagulation factors may have contributed to the high mortality. Determination of PT, PTT, platelet count, and any readily avail¬ able rapid test for fibrin degradation products should be performed on any infant suspected of having DIO We utilize the TT with correction because it provides two important facts: the relative level of fibrinogen in the absence of heparin, and the presence of fibrin degradation products when the TT does not return to normal with the addition of normal plasma. Nine¬ ty-three percent of our patients in this study had an abnormal TT that did not correct. Determination of the levels of fibrin degradation products can be a lengthy process. A method of determining fibrin degradation prod¬ ucts unaffected by heparin (Reptilase time) may be helpful in high-risk nurseries where heparin is routinely used to keep umbilical catheters patent or for therapy for DIC. If available, the determination of factor V levels would be useful. Determina¬ tions of factor VIII level should not be relied on to make the diagnosis of DIC. Vitamin should be given to all infants and liver disease ruled out. Several patients were not included in our study because these procedures had not been done routinely. No difference in response or surviv¬ al could be determined in comparing various modalities in the treatment of DIC. There are several reports of small series that advocate the use of
heparin,12 exchange transfusion,16 or no specific therapy.17 The use of replacement factors, especially pro¬ thrombin complex, has not been recommended in the past7 because of
the danger of thrombotic complica¬ tions. In our study, newborns treated with fresh frozen plasma or concen¬ trated factors alone did as well as the other infants. Three of our survivors were so treated. No thrombotic com¬ plications were detected. A controlled,
prospective study, utilizing early diag¬ nosis before bleeding occurs and comparing various forms of therapy,
is necessary before recommendations can be made regarding optimum ther¬ apy. This investigation was supported in part by grant from the Children's Blood Foundation.
a
References 1. Boyd JF: Disseminated fibrin thromboembolism among neonates dying more than 48 hours after birth. J Clin Pathol 22:663-671, 1969. 2. Robboy SJ, Colman RW, Minna JD: Pathology of disseminated intravascular coagulation (DIC). Hum Pathol 3:327-343, 1972. 3. Hilgartner MW, Miller DR: The effect of cyanate on the clotting proteins and platelet function. Proc Soc Exp Biol Med 149:5-9, 1975. 4. Leissring JC, Vorlicky LN: Disseminated intravascular coagulation in a neonate. Am J Dis Child 115:100-106, 1968. 5. Edson JR, Blaese RM, White JG, et al: Defibrination syndrome in an infant born after abruptio placentae. J Pediatr 72:342-346, 1968. 6. Hathaway WE, Mull MM, Pechet GS: Disseminated intravascular coagulation in the newborn. Pediatrics 43:233-240, 1969. 7. Abildgaard CF: Recognition and treatment of intravascular coagulation. J Pediatr 74:163\x=req-\ 176, 1969. 8. Whaun JM, Oski FA: Experience with disseminated intravascular coagulation in a children's hospital. Can Med Assoc J 107:963-967, 1972. 9. Colman RW, Robboy SJ, Minna JD: Disseminated intravascular coagulation (DIC): An approach. Am J Med 52:679-689, 1972. 10. Sell EJ, Corrigan JJ: Platelet counts, fibrinogen concentrations and factor V and factor VIII levels in healthy infants according to gestational age. J Pediatr 82:1028-1032, 1973. 11. Karpatkin M: Diagnosis and management of disseminated intravascular coagulation. Pediatr Clin North Am 18:23-37, 1971. 12. Corrigan JJ, Jordan CM: Heparin therapy in septicemia with disseminated intravascular coagulation. N Engl J Med 283:778-782, 1970. 13. Margolis CZ, Orzalesi MM, Schwartz AD: Disseminated intravascular coagulation in the respiratory distress syndrome. Am J Dis Child 125:324-326, 1973. 14. Miller DR, Hanshaw JB, O'Leary DS, et al: Fatal disseminated herpes simplex virus infection and hemorrhage in the neonate: Coagulation studies in a case and a review. J Pediatr 76:409\x=req-\ 415, 1970. 15. Frantz ID, L'Heureux P, Engel RR, et al: Necrotizing enterocolitis. J Pediatr 86:259-263, 1975. 16. Gross S, Melhorn DK: Exchange transfusion with citrated whole blood for disseminated intravascular coagulation. J Pediatr 78:415-419,
1971. 17.
Corrigan JJ, Jordan CM, Bennett BB: Disseminated intravascular coagulation in septic shock. Am J Dis Child 126:629-632, 1973.
Luban, MD; Margaret
W.
Hilgartner, MD;
Denis R.
\s=b\ We have reviewed 53 cases of disseminated intravascular coagulation (DIC) in the newborn, including 29 cases that were confirmed at autopsy. Factors predisposing to DIC included maternal
have reviewed the clinical, laboratory, and therapeutic differences in these infants with DIC and compared the differences to outcome.
complications (60%), low Apgar scores (30%), hyaline membrane disease (62%), and sepsis (26%). Diagnostic criteria common to autopsy-proved cases included presence of fibrin degradation products, low factor V activity, a prolonged prothrombin time, and a prolonged partial thromboplastin time and/or thrombocytopenia. There appeared to be no difference in coagulation response or in mortality among patients treated with different therapeutic regimens. Survivors were older gestationally, had higher birth weights, and higher Apgar scores. (Am J Dis Child 133:44-46, 1979)
METHODS
intravascular coagu¬ lation in the newborn is a common occurrence in the intensive care nursery.' The natural history of the disorder, however, has not been well described. Most studies have involved small numbers of patients and have used various clinical and laboratory criteria for diagnosis. Pathologic evidence for DIC generally has been lacking or not evaluated. In our retrospective study, we have attempted to clarify the laboratory profile of DIC in the neonate by corre¬ lating several variables with patholog¬ ic criteria for DIC. Furthermore, we
Disseminated(DIC) period
From the Division of Pediatric Hematology\x=req-\ Oncology, New York Hospital-Cornell Medical Center, New York. Dr Luban is now with Children's Hospital-National Medical Center, Washington, DC; Dr Miller is now with Memorial Sloan-Kettering Cancer Center, New York. Reprint requests to Division of Hematology\x=req-\ Oncology, Children's Hospital Medical Center, 51st and Grove Streets, Oakland, CA 94609 (Dr Woods).
A total of 1,051 infants were admitted to the neonatal intensive care unit of the New York Hospital-Cornell Medical Center dur¬ ing the five-year period from January 1971 to December 1975. Of these, 160 infants, 16% of those admitted, were found to have a bleeding disorder by clinical presenta¬ tion, for example, excessive bleeding from a venipuncture site, or by laboratory data obtained when a coagulopathy was sus¬ pected, for example, in an infant with sepsis. Fifty-three of these 160 infants had laboratory evidence of DIC and are the subject of this report. Twenty-nine of the 53 patients had DIC on postmortem exam¬ ination, using the criteria of Robboy and
colleagues.- Specifically, autopsy-proved cases of DIC showed hemorrhage in several organs plus the presence of fibrin micro¬ thrombi in small vessels. Hemorrhage alone was not considered adequate for pathologic diagnosis of DIC. However, since patients may have clinical DIC with¬ out strict pathologic evidence at autopsy, unconfirmed autopsy cases were included in the total patient population if their coagulation studies showed DIC. For nonautopsy-proved cases of DIC, patients who had abnormal liver enzymes or who had not received vitamin were excluded. Laboratory studies performed by stan¬ dard methods11 on our patients included the determination of prothrombin time (PT), partial thromboplastin time (PTT), throm¬ bin time (TT) "corrected" with addition of normal plasma to demonstrate the pres¬ ence of fibrin degradation products, onestage assays of factors V and VIII, and platelet count. Umbilical catheters, from which blood samples were often obtained, were routinely flushed with a solution that did not contain heparin. Therefore, con-
Miller,
MD
laboratory samples with heparin, and hence invalidation
tamination of exogenous
of the corrected TT test, was not a concern. Abnormal values, selected after review of the laboratory data in pathologically con¬ firmed DIC, were as follows (normal premature values from our laboratory are given in parentheses): PT, >16 seconds (16 seconds); PTT, >85 seconds (60 seconds); TT, >40 seconds (20 seconds) with correc¬ tion to only >30 seconds (18 seconds) with the addition of an equal volume of normal plasma; factor V activity, 1,500 g. Seven of eight had one-minute Apgar scores of 4 or greater. One a
patient had no Apgar scores reported. When comparing survivors and non¬ survivors, maternal and infant
plications
com¬
different except that six of the survivors (67%) had neonatal seizures compared to 18% of the nonsurvivors. This difference may be due to the fact that those infants who possibly had a central nervous system hemorrhage, and survived the were no
DIC, lived long enough sequelae such as seizures.
to
develop
Five of the survivors were followed up at least one year. One had a chronic
seizure disorder, one had microcephaly and developmental delay, and three were developing normally. Two of the three who were doing well had had seizures in the newborn period. Coagulation studies of the survivors were compared to those of the autop¬ sy-proved group (Table 1). Survivor PTs and factor V levels were better than those of the nonsurvivors, whose coagulation values were similar to those having autopsies indicating a possible difference in the degree of
coagulopathy.
Treatment of the survivors is listed in Table 4. Two patients survived DIC without specific treatment. Both had well-substantiated clinical DIC with thrombocytopenia, low activity of fac¬ tor V, and presence of fibrin degrada¬ tion products. COMMENT
Disseminated intravascular coagu¬ lation in the newborn is a clinical phenomenon described within the past decade.4-5 One early report placed some emphasis on pathologic correla¬ tion with clinical presentation.6 Subse¬ quent reports have differed over how best to make the diagnosis7-8 without utilizing pathologic data. Unlike DIC in the adult8 or older child, DIC in the newborn period is more difficult to diagnose clinically because of the normally prolonged coagulation val¬ We have ues of premature infants.1" evaluated the laboratory data in those children with DIC confirmed at autop¬ sy, using cases where hemorrhage and thrombosis were present, and have found criteria that appear to be common to all cases and that cannot be confused with normal values for premature infants. Evaluation of our patients shows the importance of obstetrical compli¬ cations and low Apgar scores in the development of DIC. Other reports have emphasized the role of sepsis,812 hyaline membrane disease,'1 dissemi¬ nated herpes simplex infection," and necrotizing enterocolitis15 in the de¬ velopment of DIC, and our study confirms these roles. Virtually any "
added stress to these infants can be sufficient to cause tissue necrosis, release of thromboplastin, intravascu¬ lar coagulation with rapid consump¬ tion of factors that cannot be replaced adequately, and hemorrhage. Our sur¬ vivors were gestationally older, larg¬ er, and had better Apgar scores; this emphasizes the vulnerability of the high-risk, stressed premature infant.
In our retrospective study, overt bleeding was the primary reason for doing tests of coagulation. The fact
that the children were evaluated after the possible onset of the active consumption of coagulation factors may have contributed to the high mortality. Determination of PT, PTT, platelet count, and any readily avail¬ able rapid test for fibrin degradation products should be performed on any infant suspected of having DIO We utilize the TT with correction because it provides two important facts: the relative level of fibrinogen in the absence of heparin, and the presence of fibrin degradation products when the TT does not return to normal with the addition of normal plasma. Nine¬ ty-three percent of our patients in this study had an abnormal TT that did not correct. Determination of the levels of fibrin degradation products can be a lengthy process. A method of determining fibrin degradation prod¬ ucts unaffected by heparin (Reptilase time) may be helpful in high-risk nurseries where heparin is routinely used to keep umbilical catheters patent or for therapy for DIC. If available, the determination of factor V levels would be useful. Determina¬ tions of factor VIII level should not be relied on to make the diagnosis of DIC. Vitamin should be given to all infants and liver disease ruled out. Several patients were not included in our study because these procedures had not been done routinely. No difference in response or surviv¬ al could be determined in comparing various modalities in the treatment of DIC. There are several reports of small series that advocate the use of
heparin,12 exchange transfusion,16 or no specific therapy.17 The use of replacement factors, especially pro¬ thrombin complex, has not been recommended in the past7 because of
the danger of thrombotic complica¬ tions. In our study, newborns treated with fresh frozen plasma or concen¬ trated factors alone did as well as the other infants. Three of our survivors were so treated. No thrombotic com¬ plications were detected. A controlled,
prospective study, utilizing early diag¬ nosis before bleeding occurs and comparing various forms of therapy,
is necessary before recommendations can be made regarding optimum ther¬ apy. This investigation was supported in part by grant from the Children's Blood Foundation.
a
References 1. Boyd JF: Disseminated fibrin thromboembolism among neonates dying more than 48 hours after birth. J Clin Pathol 22:663-671, 1969. 2. Robboy SJ, Colman RW, Minna JD: Pathology of disseminated intravascular coagulation (DIC). Hum Pathol 3:327-343, 1972. 3. Hilgartner MW, Miller DR: The effect of cyanate on the clotting proteins and platelet function. Proc Soc Exp Biol Med 149:5-9, 1975. 4. Leissring JC, Vorlicky LN: Disseminated intravascular coagulation in a neonate. Am J Dis Child 115:100-106, 1968. 5. Edson JR, Blaese RM, White JG, et al: Defibrination syndrome in an infant born after abruptio placentae. J Pediatr 72:342-346, 1968. 6. Hathaway WE, Mull MM, Pechet GS: Disseminated intravascular coagulation in the newborn. Pediatrics 43:233-240, 1969. 7. Abildgaard CF: Recognition and treatment of intravascular coagulation. J Pediatr 74:163\x=req-\ 176, 1969. 8. Whaun JM, Oski FA: Experience with disseminated intravascular coagulation in a children's hospital. Can Med Assoc J 107:963-967, 1972. 9. Colman RW, Robboy SJ, Minna JD: Disseminated intravascular coagulation (DIC): An approach. Am J Med 52:679-689, 1972. 10. Sell EJ, Corrigan JJ: Platelet counts, fibrinogen concentrations and factor V and factor VIII levels in healthy infants according to gestational age. J Pediatr 82:1028-1032, 1973. 11. Karpatkin M: Diagnosis and management of disseminated intravascular coagulation. Pediatr Clin North Am 18:23-37, 1971. 12. Corrigan JJ, Jordan CM: Heparin therapy in septicemia with disseminated intravascular coagulation. N Engl J Med 283:778-782, 1970. 13. Margolis CZ, Orzalesi MM, Schwartz AD: Disseminated intravascular coagulation in the respiratory distress syndrome. Am J Dis Child 125:324-326, 1973. 14. Miller DR, Hanshaw JB, O'Leary DS, et al: Fatal disseminated herpes simplex virus infection and hemorrhage in the neonate: Coagulation studies in a case and a review. J Pediatr 76:409\x=req-\ 415, 1970. 15. Frantz ID, L'Heureux P, Engel RR, et al: Necrotizing enterocolitis. J Pediatr 86:259-263, 1975. 16. Gross S, Melhorn DK: Exchange transfusion with citrated whole blood for disseminated intravascular coagulation. J Pediatr 78:415-419,
1971. 17.
Corrigan JJ, Jordan CM, Bennett BB: Disseminated intravascular coagulation in septic shock. Am J Dis Child 126:629-632, 1973.
