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Thromb Haemost 1992; 68(03): 325-330
DOI: 10.1055/s-0038-1656374
Original Article
Schattauer GmbH Stuttgart

Fibrin Clot Lysis by Thrombolytic Agents Is Impaired in Newborns due to a Low Plasminogen Concentration

M Andrew
The Departments of Pediatrics and Medicine, McMaster University Health Sciences Centre, Chedoke-McMaster Hospitals, Hamilton, Ontario, Canada
,
L Brooker
The Departments of Pediatrics and Medicine, McMaster University Health Sciences Centre, Chedoke-McMaster Hospitals, Hamilton, Ontario, Canada
,
M Leaker
The Departments of Pediatrics and Medicine, McMaster University Health Sciences Centre, Chedoke-McMaster Hospitals, Hamilton, Ontario, Canada
,
B Paes
The Departments of Pediatrics and Medicine, McMaster University Health Sciences Centre, Chedoke-McMaster Hospitals, Hamilton, Ontario, Canada
,
J Weitz
The Departments of Pediatrics and Medicine, McMaster University Health Sciences Centre, Chedoke-McMaster Hospitals, Hamilton, Ontario, Canada
› Author Affiliations
Further Information

Publication History

Received 08 August 1991

Accepted after revision 09 April 1992

Publication Date:
04 July 2018 (online)

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Summary

Although thrombolytic drugs have been extensively used in adults, there is sparse information on their effectiveness in newborns whose fibrinolytic system differs significantly from adults. The purpose of this study was to determine if low plasma levels of plasminogen in cord plasma limited the therapeutic effectiveness of thrombolytic agents. Urokinase (UK), streptokinase (SK) and tissue plasminogen activator (TPA) were compared for their ability to lyse washed 125I-labelled adult or cord fibrin clots suspended in cord or adult plasma. 125I-labelled fibrin clots were prepared by recalcifying cord or adult plasma spiked with labelled fibrinogen and then placed into cord or adult plasma which contained either saline or differing amounts of a specific thrombolytic agent. After a 60 min incubation, the remaining 125I-fibrin in clots released 125I-fibrin fragments, and concentrations of fibrinogen, α2-antiplasmin, and plasminogen in the bathing plasma were measured and compared to starting values. Cord fibrin clots were more resistant than adult fibrin clots to all thrombolytic drugs tested (p <0.001). On average, the cord system retained 27% more 125I-fibrin in clots, and released 32% less 125I-fibrin fragments into plasma. Fibrinogenolysis was also decreased in cord plasmas compared to adult plasmas. The degree of fibrinolysis and fibrinogenolysis in cord plasma increased to adult values when plasminogen concentrations were increased in the bathing plasma. Thus, cord fibrin clots have an impaired response to thrombolytic agents secondary to low levels of plasminogen. We speculate that the clinical response of newborns to thrombolytic agents is also impaired and will not be enhanced by increasing doses of thrombolytic agents but may be enhanced by increasing the concentration of plasminogen.

 

  • References

  • 1 Schmidt B, Zipursky A. Thrombotic disease in newborn infants. Clin Perinatol 1984; 11: 461-488
    CrossrefPubMedGoogle Scholar
  • 2 Schmidt B, Andrew M. Neonatal thrombotic disease: Prevention, diagnosis and treatment. J Pediatr 1988; 113: 407-410
    CrossrefPubMedGoogle Scholar
  • 3 Barnard DR, Hathaway WE. Neonatal thrombosis. Am J Pediatr Hematol/Oncol 1979; 1: 235-244
    CrossrefPubMedGoogle Scholar
  • 4 O’Neill JA, Neblett WW III, Born ML. Management of major thromboembolic complications of umbilical artery catheters. J Pediatr Surg 1981; 16: 972-978
    CrossrefPubMedGoogle Scholar
  • 5 Neal WA, Reynolds JW, Jarvis CW, Willians HJ. Umbilical artery catheterization: Demonstration of arterial thrombosis by aortography. Pediatrics 1972; 50: 06-13
    PubMedGoogle Scholar
  • 6 Goetzman BW, Stadalnik RC, Bogren HG, Blankenship WK, Ikeda RM, Thayer J. Thrombotic complications of umbilical artery catheters: A clinical and radiographic study. Pediatrics 1975; 56: 374-379
    PubMedGoogle Scholar
  • 7 Olinsky A, Aitken FG, Isdale JM. Thrombus formation after umbilical arterial catheterization: An angiographic study. S Afr Med J 1975; 49: 1467-1470
    PubMedGoogle Scholar
  • 8 Mokrohisky ST, Levine R, Blumhagen JD, Wesenberg RL, Simmons MA. Low positioning of umbilical artery catheters increases associated complications in newborn infants. N Engl J Med 1978; 299: 561-564
    CrossrefPubMedGoogle Scholar
  • 9 Saia OS, Rubatelli FF, d’Elia RD, Marigo A, Perale R, Audino G, Lagarjolli G, Zanardo Y, Cantarutti F. Clinical and aortographic assessment of the complications of arterial catheterization. Eur J Pediatr 1978; 128: 169-179
    CrossrefPubMedGoogle Scholar
  • 10 Wesstrom G, Finnstrom O, Stenport G. Umbilical artery catheterization in newborns. I. Thrombosis in relation to catheter type and position. Acta Paediatr Scand 1979; 68: 575-581
    PubMedGoogle Scholar
  • 11 Gilhooly JT, Lindenberg JA, Reynolds JW. Survey of umbilical catheter practices. Clin Res 1987; 34: 142A
    PubMedGoogle Scholar
  • 12 Verstraete M, Collen D. Thrombolytic therapy in the eighties. Blood 1986; 67: 1529-1541
    CrossrefPubMedGoogle Scholar
  • 13 Marder VJ, Sherry S. Thrombolytic therapy: Current status (Part I). N Engl J Med 1988; 318: 1512-1520
    CrossrefPubMedGoogle Scholar
  • 14 Marder VJ, Sherry S. Thrombolytic therapy: Current status (Part II). N Engl J Med 1988; 318: 1585-1593
    CrossrefPubMedGoogle Scholar
  • 15 Corrigan JJ, Allen HD, Jeter M, Malone JM. Aortic thrombosis in a neonate: Failure of urokinase thrombolytic therapy. Am J Pediatr Hematol/Oncol 1982; 4: 243-247
    PubMedGoogle Scholar
  • 16 Delaplane D, Scott JP, Riggs TW, Silverman BL, Hung CE. Urokinase therapy for a catheter related right atrial thrombus. J Pediatr 1982; 100: 149-152
    CrossrefPubMedGoogle Scholar
  • 17 Vailas GN, Brouillette RT, Scott JP, Shkolnik A, Conway J, Wiringa K. Neonatal aortic thrombosis: Recent experience. J Pediatr 1986; 109: 101-108
    CrossrefPubMedGoogle Scholar
  • 18 Wessel DL, Keane JF, Fellows KE, Robichaud H, Lock JE. Fibrinolytic therapy for femoral arterial thrombosis after cardiac catheterization in infants and children. Am J Cardiol 1986; 58: 347-351
    CrossrefPubMedGoogle Scholar
  • 19 Pangiglione G, Marasini M, Ribaldone D, Silvestri G, Tuo P, Garello-Canton L. Right atrial thrombosis in two premature infants: Successful treatment with urokinase and heparin. Eur Heart J 1986; 7: 1086-1089
    CrossrefPubMedGoogle Scholar
  • 20 Emani A, Saldanha R, Knupp C, Kodroff M. Failure of systemic thrombolytic and heparin therapy in the treatment of neonatal aortic thrombosis. Pediatrics 1987; 79: 773-777
    PubMedGoogle Scholar
  • 21 Sadiq HF, Devaskar S, Keenan WJ, Weber TR. Broviac catheterization in low weight infants: Incidence and treatment of associated complications. Crit Care Med 1987; 15: 47-50
    CrossrefPubMedGoogle Scholar
  • 22 Griffin MP, Casta A. Successful urokinase therapy for superior vena cava syndrome in premature infant. Am J Dis Child 1988; 142: 1267-1268
    PubMedGoogle Scholar
  • 23 Strife JL, Ball Jr WS, Towbin R, Keller MS, Dillon T. Arterial occlusion in neonates: use of fibrinolytic therapy. Radiology 1988; 166: 395-400
    CrossrefPubMedGoogle Scholar
  • 24 Kennedy LA, Drummond WH, Knight ME, Williams JL, Millsaps MM. Successful thrombolysis by tissue plasminogen activator in neonatal aortic thrombosis. Pediatr Res 1989; 15: A391
    PubMedGoogle Scholar
  • 25 Andrew M, Paes B, Milner R, Johnston M, Powers P, Tollefsen DM. The development of the human coagulation system in the fullterm infant. Blood 1987; 70: 165-172
    PubMedGoogle Scholar
  • 26 Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, Castle V, Powers P. Development of the coagulation system in the healthy premature infant. Blood 1988; 72: 1651-1657
    CrossrefPubMedGoogle Scholar
  • 27 Andrew M, Paes B, Johnston M. Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol/Oncol 1990; 12: 095-104
    CrossrefPubMedGoogle Scholar
  • 28 Ambrus CM, Ambrus JL, Choi TS, Jung O, Mirand EA, Bartfay-Szabo A. The fibrinolysin system and its relationship to disease in the newborn. Am J Pediatr Hematol/Oncol 1979; 1: 251-260
    CrossrefPubMedGoogle Scholar
  • 29 Corrigan JJ. Neonatal thrombosis and the thrombolytic system: Pathophysiology and therapy. Am J Pediatr Hematol/Oncol 1988; 10: 83-91
    CrossrefPubMedGoogle Scholar
  • 30 Corrigan JJ, Sleeth JJ, Jeter M, Lox CD. Newborn’s fibrinolytic mechanism: Components and plasmin generation. Am J Hematol 1989; 32: 273-278
    CrossrefPubMedGoogle Scholar
  • 31 Morselli PL, Franco-Morselli R, Bossi L. Clinical pharmacokinetics in newborns and infants, age-related differences and therapeutic implication. Clin Pharm 1980; 5: 485-527
    CrossrefPubMedGoogle Scholar
  • 32 Straughn W, III Wagner RH. A simple method for preparing fibrinogen. Thromb Diath Haemorrh 1966; 6: 198-206
    PubMedGoogle Scholar
  • 33 Ikeno LC, Bowen BM, Der M. Commercial production of 125I-fibrinogen for injection. J Radioanal Chem 1981; 65: 179-188
    CrossrefPubMedGoogle Scholar
  • 34 Deutsch DG, Mertz ET. Plasminogen: Purification from human plasma by affinity chromatography. Science 1970; 170: 1095-1096
    CrossrefPubMedGoogle Scholar
  • 35 Friberger P, Knos M, Gustavsson S, Aurell L, Claeson G. Methods for determination of plasmin, antiplasmin and plasminogen by means of substrate S-2251. Haemostasis 1978; 7: 138-145
    PubMedGoogle Scholar
  • 36 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-246
    CrossrefPubMedGoogle Scholar
  • 37 Weitz JI, Berry L, Ginsberg J. Soluble fibrin degradation products potentiate tissue plasminogen activator-induced fibrinogen proteolysis. J Clin Invest 1991; 87: 1080-1092
    PubMedGoogle Scholar
  • 38 Sabovic M, Lijnen HR, Keber D, Collen D. Correlation between progressive adsorption of plasminogen to blood clots and their sensitivity to lysis. Thromb Haemostas 1990; 64: 450-454
    PubMedGoogle Scholar
  • 39 Sabovic M, Lijnen HR, Keber D, Collen D. Effect of retraction on the lysis of hyman clots with fibrin specific and non-fibrin specific plasminogen activities. Thromb Haemostas 1989; 62: 1083-1087
    PubMedGoogle Scholar
  • 40 Suarez CR, Menendez CE, Walenga JM, Fareed J. Neonatal and maternal hemostasis: Value of molecular markers in the assessment of hemostatic status. Semin Thromb Haemostas 1984; 10 (4) 280-284
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Andrew M, O’Brodovich H, Mitchell L. Fetal lam coagulation during normal birth. Am J Hematol 1988; 28: 116-118
    CrossrefPubMedGoogle Scholar
  • 42 Reverdiau-Moalic P, Gruel Y, Delahausse B, Rupin A, Huart MC, Body G, Leroy J. Comparative study of the fibrinolytic system in human fetuses and in pregnant women. Thromb Res 1991; 61: 489-499
    CrossrefPubMedGoogle Scholar
  • 43 Estelles A, Aznar J, Gilabert J, Parrilla JJ. Dysfunctional plasminogen in fullterm newborns. Pediatr Res 1980; 14: 1180-1185
    CrossrefPubMedGoogle Scholar
  • 44 Al Hilali MM, Gilliver BE. Physiological activation of plasminogen in full term newborn infants. J Clin Pathol 1984; 37: 1264-1267
    CrossrefPubMedGoogle Scholar
  • 45 Benavent A, Estelles A, Aznar J, Martinez-Sales V, Gilabert J, Fornas E. Dysfunctional plasminogen in full term newborn – study active site plasmin. Thromb Haemostas 1984; 51: 67-70
    PubMedGoogle Scholar
  • 46 Edelberg JM, Enghild JJ, Pizzo SV, Gonzales-Gronow M. Neonatal plasminogen displays altered cell surface binding and activation kinetics. Correlation with increased glycosylation of the protein. J Clin Invest 1990; 86: 106-112
    PubMedGoogle Scholar
  • 47 Galanakis DK, Mossesson MW. Evaluation of the role of in vivo proteolysis (fibrinogenolysis) in prolonging the thrombin time of human umbilical cord fibrinogen. Blood 1976; 48: 109-118
    PubMedGoogle Scholar
  • 48 Gralnick HR, Gilveber H, Abrams E. Dysfibrinogenemia associated with hepatoma. Increased carbohydrate content of the fibrinogen molecule. N Engl J Med 1978; 299: 221-226
    PubMedGoogle Scholar