Thrombolysis in Newborns and Infants

Thromb Haemost 1999; 82 (Suppl.): 112–6

© 1999 Schattauer Verlag, Stuttgart

Thrombolysis in Newborns and Infants U. Nowak-Göttl 1, K. Auberger 2, S. Halimeh 3, R. Junker 4, J. Klinge 5, W. D. Kreuz 6, M. Ries 5, N. Schlegel 7 From the Departments of Paediatrics, University Children Hospital 1 Münster, 2 Munich, 3 Hanover, 5 Erlangen and 6 Frankfurt, 4 Institute of Clinical Chemistry and Laboratory Medicine, University of Münster, Germany, 7 Biological Haematological Department, Hopital Robert Debré, Paris, France

Key words

Thrombolysis, heparin, infancy, intracranial haemorrhage Summary

This review analyses literature reports from 1970 to 1998 assessing the use of streptokinase (SK), urokinase (UK) or recombinant tissuetype plasminogen activator (rt-PA) for thrombolytic therapy in neonates and infants. From 1970 to 1998 182 infants were reported to have received SK (n = 54; 29.5%), UK (n = 41; 22.5%) or rt-PA (n = 87; 48%). During thrombolytic therapy no concomitant heparin administration or low dose heparin therapy (5 U/kg/h) were recorded. To perform reocclusion prophylactics heparin was reinitiated at the end of thrombolytic therapy usually in the recommended dosage of 20 U/ kg/h. The overall thrombolytic patency rate in neonates varied from 39% to 86%. Besides bleeding from local puncture sites or recent catheterisation sites (10.4%), pulmonary embolism was reported in 1.1% of the 182 infants. Major bleeding complications, i.e. pulmonary bleeding (0.6%), gastrointestinal bleeding (0.6%) or intraventricular haemorrhage (IVH 2.7%) are rarely reported side effects and only 2 thrombolysis related deaths due to haemorrhage were mentioned. Bleedings reported in the central nervous system (n = 4) mainly occurred in preterm infants (n = 3). In conclusion, data of this preliminary analysis suggest that there is no big difference (p = 0.09; 2-test) in the efficacy rate between the 3 thrombolytic agents used in the first year of life. In each case an assessment must be made with respect to the relative benefit conferred by thrombolytic therapy in preventing organ or limb damage versus the potential side effects, costs and inconvenience for the childhood patient. Controlled prospective multicentre studies on thrombolytic therapy in neonates and infants are recommended to evaluate patency rates and adverse effects for the different thrombolytic agents used.

auto-immune diseases, renal diseases, the use of central lines, trauma or surgery, resulting in increased thrombin generation with subsequent fibrin and/or thrombus formation are being increasingly recognised during infancy and childhood (1-3). Besides the underlying diseases known to trigger early thrombotic onset during infancy, evidence is given that established prothrombotic risk factors, such as the factor V G1691A mutation and further deficiencies within the protein C pathway may influence strongly the occurrence of thrombosis during childhood (4, 5). However, due to the special properties of the haemostatic system in infancy and childhood, clinical manifestation of thromboembolism occurs in less than 5% of affected children compared with approximately 40% of adults (1). Within the entire childhood population, neonates are at the greatest risk of thromboembolic complications, and the incidence of vascular accidents decreases significantly after the first year of life with a second peak during puberty and adolescence (1). Although heparin has been the mainstay of therapy for children with deep venous or renal venous thrombosis it fails in the majority of cases to prevent valvular damage in the deep veins and kidney shrinking (6-10). Since thrombolytic therapy is increasingly used in life threatening situations to safe organs or limbs in new-borns and infants with aortic clots secondary to umbilical catheters, femoral artery thrombosis following retrograde cardiac catheterisation, renal venous thrombosis and vascular accidents of other sites, this review is focused on literature reports from 1970 to 1998 assessing the use of streptokinase (SK), urokinase (UK) or recombinant tissue-type plasminogen activator (rt-PA) for thrombolytic therapy of arterial or venous thrombosis in neonates and infants; reports dealing with thrombolysis of blocked catheters were not included in this review. Medline Search

From 1970 to 1998 182 neonates and infants were reported to have received SK (n = 54; 29.5%), UK (n = 41; 22.5%) or rt-PA (n = 87; 48%) respectively.

Introduction

Numerous clinical and environmental conditions, such as peripartal asphyxia, foetal diabetes, dehydration, septicaemia, malignant diseases,

Correspondence to: Prof. Dr. Ulrike Nowak-Göttl, Westfälische WilhelmsUniversität, Department of Paediatrics, Paediatric Haematology and Oncology, Albert-Schweitzer-Straße 33, D-48149 Münster, Germany – Tel +49 251 8347783; Fax: +49 251 8347828; E-mail: [email protected]

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Localisation and Thrombolytic Therapy of Thrombosis in Neonates and Infants

As recently recorded in the Canadian and German thrombosis registries (2, 3) thrombotic complications related to cardiac catheterisation, central venous lines or umbilical catheters account for 77% of children (n = 140) receiving thrombolytic therapy in this age group. Tables 1-4 summarize the literature data of thrombolytic therapy for femoral arterial thrombosis following cardiac catheterisation (Table 1), aortic

Nowak-Göttl et al.: Thrombolysis in Infancy

Table 1 Thrombolytic therapy for femoral arterial thrombosis following cardiac catheterisation, right atrial and left atrial thrombosis. SK, streptokinase; UK, urokinase; rt-PA, recombinant tissue-type plasminogen activator; BL, bleeding; PE, pulmonary embolism

thrombosis (Table 2), renal venous thrombosis (Table 3) and vascular accidents of different sites (Table 4). There was a gradual shift from the use of SK in the 1970s to the use of UK since the mid 1980s and to rt-PA in the 1990s, and a wide range of doses were used for all 3 thrombolytic agents administered locally or systemically respectively. Interestingly, during thrombolytic therapy no concomitant heparin administration (11, 13, 14, 21, 22, 26-36, 38, 42, 43, 45, 48, 50-52, 54, 56) or low dose heparin therapy (5 IU/kg/h) (16-18, 25, 44, 46, 47, 49, 55) were recorded. To perform reocclusion prophylactics heparin was reinitiated at the end of thrombolytic therapy usually in the recommended dosage of 20 IU/kg/h (57). Patency Rate

Patency rate and median/range age of neonates and infants requiring thrombolytic therapy with respect to thrombotic localisation are shown in Fig. 1. Whereas the overall thrombolytic patency rate in neonates with aortic thromboses reached only 39% (9 out of 23), in patients with thrombosis of different sites the overall patency rate was 58% (50 out of 86) and 86.5% (45 out of 52) in the cardiac group. In addition, with respect to the thrombolytic agent used the overall patency and failure rate is shown in Fig. 2. Taken into account the fact that cases in this

study are mainly recorded from case reports or small series and the difficulty to compare thrombosis of different sizes and locations with respect to the thrombolytic therapy performed, data of this preliminary analysis suggest that there is no great difference (p = 0.09; 2-test) in the efficacy rate between the 3 thrombolytic agents used in the first year of life. Adverse Effects and Outcome

Besides bleeding from local puncture sites or recent catheterisation sites (n = 19; 10.4%), pulmonary embolism was reported in two (1.1%) of the 182 infants reported (13-15, 18, 22, 28, 44, 48-50, 54- 56). Major bleeding complications, i.e. pulmonary bleeding (n = 1; 0.6%), gastrointestinal bleeding (n = 1; 0.6%) or intraventricular haemorrhage (IVH n = 5; 2.7%) are rarely reported site effects (38, 45, 48, 56); only 2 thrombolysis-related deaths due to haemorrhage were mentioned (29, 45). However, the bleedings reported in the central nervous system (n = 4) mainly occurred in preterm infants (n = 3), who due to their prematurity are at high risk to develop spontaneous IVHs. The fourth reported IVH leading to death occurred in a term infant with birth asphyxia treated with rt-PA despite severe thrombocytopenia (45). In addition, spontaneous amputation of four toes (n = 1; 0.6%) was record-

Table 2 Thrombolytic therapy for aortic thrombosis. SK, streptokinase; UK, urokinase; rt-PA, recombinant tissue-type plasminogen activator. PE, pulmonary embolism; ARF, acute renal failure; IVH, intraventricular haemorrhage

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Table 3 Thrombolytic therapy for renal venous thrombosis. SK, streptokinase; UK, urokinase; rt-PA, recombinant tissue-type plasminogen activator. BE, bleeding; ARF, acute renal failure

Table 4 Thrombolytic therapy for thrombosis of different sites. SK, streptokinase; UK, urokinase; rt-A, tissue-type plasminogen activator. BE, bleeding; IVH, intraventricular bleeding; GI, gastointestinal

Fig. 1 Complete patency rate achieved with streptokinase (SK), urokinase (UK) and recombinant tissue-type plasminogen activator (rt-PA) in neonates after retrograde cardiac catherisation and cardiac heart disease (CHD), thrombosis of the aorta, renal venous thrombosis and in patients with vascular accidents at different sites

ed (35), and renal atrophy following complete or partial patency or acute renal failure in 4 cases respectively (29, 43-45) . Conclusions

The cases included in this review are mainly enrolled from case reports or very small case series. Based on a strong publication bias expected, it is very difficult to draw any conclusions, especially concerning patency rate and adverse effects. 114

Fig. 2 Complete patency, partial patency and failure rate in neonatal thrombosis using streptokinase (SK), urokinase (UK) or recombinant tissue type plasminogen activator (rt-PA). No difference is observed with respect to the three agents used

However, the management of neonates and infants with life threatening thrombosis possibly leading to organ or limb damage comprises acute thrombotic treatment, e.g. thrombolytic therapy. After carefully evaluation of absolute contraindications, i.e. major surgery during the last 10 days, history of severe bleeding (intracranial, pulmonary or gastrointestinal), peripartal asphyxia (brain damage), uncontrolled arterial hypertension and severe thrombocytopenia, thrombolytic therapy may be started on an individual patient basis. Since preterm infants due to their immaturity and concomitant medical problems are at a higher

Nowak-Göttl et al.: Thrombolysis in Infancy

risk to develop spontaneous IVH, thrombolytic therapy should be discussed only in life threatening vascular accidents. The three thrombolytic agents used for systemic thrombolysis SK (bolus: 2000 IU/kg; maintenance: 2000 IU/kg/h 6-12 h), UK (bolus: 4400 IU/kg; maintenance: 4400 IU/kg/h, 6-12 h) or rt-PA (bolus 0.1 mg/kg: maintenance: 0.9 mg/kg, 3-6 h) – all mediate their activities by converting endogenous plasminogen into plasmin (57). The interaction between thrombolytic therapy and heparin during thrombolysis has not been precisely evaluated in neonates and infants. Since there is no evidence from the literature reported here that thrombolytic therapy along with concomitant heparin (20 IU/kg/h) is more effective compared with no heparin or low-dose heparin (5 IU/kg/h), thrombolytic therapy should be performed without heparin or, at least low-dose heparin until controlled clinical data in neonates and infants are available. Since plasminogen concentrations are physiologically reduced during the neonatal period and secondary to many diseases in infancy (58, 59), a reduced thrombolytic efficacy may occur during thrombolysis with the above mentioned agents. Thus, besides monitoring thrombolytic therapy with PT, aPTT, fibrinogen and D-Dimer, evidence is given that plasminogen measurements should be included in the monitoring during thrombolytic therapy in neonates and infants; in addition, until safe plasminogen concentrates are available low plasminogen levels could be safely increased with fresh frozen plasma. However, the possible risk of enhancing the thrombotic process by administration of fresh frozen plasma should be carefully evaluated in each individual childhood patient (25). Thrombus formation that has been present for several days may be resistant to thrombolytic therapy (49, 51). Thus, when there are no objective radiological changes within the clot over a 6-7 days’ period using an appropriate dosage of a thrombolytic agent therapy should be stopped. However, in each case an assessment must be made with respect to the relative benefit conferred by thrombolytic therapy in preventing organ or limb damage versus the potential side effects, costs and inconvenience for the childhood patient. Controlled prospective multicentre studies on thrombolytic therapy in neonates and infants are recommended to evaluate patency rates and adverse effects for the different thrombolytic agents used. Acknowledgement The authors thank Susan Griesbach for editing this manuscript.

References 1. Andrew M. Developmental hemostasis: Relevance to thromboembolic complications in pediatric patients. Thromb Haemost 1995; 74: 415-25. 2. Schmidt B, Andrew M. Neonatal thrombosis: Report of a prospective Canadian and International registry. Pediatrics 1995; 96: 939-43. 3. Nowak-Göttl U, Kries von R, Göbel U. Neonatal symptomatic thromboembolism in Germany: two year survey. Arch Dis Child 1997; 76: F163-7. 4. Nowak-Göttl U, Koch HG, Aschka I, Kohlhase B, Vielhaber H, Kurlemann G, Oleszuk-Raschke K, Kehl HG, Jürgens H, Schneppenheim R. Resistance to activated protein C (APCR) in children with venous or arterial thromboembolism. Brit J Haematol 1996; 92, 992-6. 5. Nowak-Göttl U, Dübbers A, Kececioglu D, Koch HG, Kotthoff S, Runde J, Vielhaber H. Factor V Leiden, protein C and lipoprotein (a) in catheter related thrombosis in childhood – a prospective study. J Pediatr 1997; 131: 608-12.

6. Andrew M, David M, Adams M, Ali K, Anderson R, Barnard D, Bernstein M, Brisson L, Cairney B, DeSai D, Grant R, Israels S, Jardine L, Luke B, Massicotte P, Silva M. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian registry of VTE. Blood 1994; 83: 1251-57. 7. Jobin J, O`Regan S, Demay G, Mongeau JG, Robitaille P. Neonatal renal vein thrombosis-long-term follow-up after conservative management. Clin Nephrol 1982; 17: 36-40. 8. Mocan H, Beattie TJ, Murphy AV. Renal venous thrombosis in infancy: long-term follow-up. Pediatr Nephrol 1991; 5: 45-9. 9. Keidan I, Lotan D, Gazit G, Boichis H, Reichman B, Linder N. Early neonatal renal venous thrombosis: long-term outcome. Acta Padiatr 1994; 83: 1225-7. 10. Nuss R, Hays T, Manco-Johnson M. Efficacy and safety of heparin anticoagulation for neonatal renal vein thrombosis. J Ped Hematol Oncol 1994; 16: 127-31. 11. Prichard SL, Culham JAG, Rogers PJC. Low-dose fibrinolytic therapy in infants. J Pediatr 1985; 106: 594-8. 12. Wessel DL, Keane JF, Fellows KE, Robichand H, Lock JE. Fibrinolytic therapy for femoral arterial thrombosis after cardiac catherisation in infants and children. Am J Cardiol 1986; 58: 347-51. 13. Ino T, Benson LN, Freedom RM, Barker GA, Aipursky A, Rowe RD.Thrombolytic therapy for femoral artery thrombosis after pediatric cardiac catheterisation. Am Heart J 1988; 115: 633-9. 14. Brus F, Witsenburg M, Hofhuis WJD, Hazelzet JA, Hess J. Streptokinase treatment for femoral artery thrombosis after cardiac catheterisation in infants and children. Br Heart J 1990; 63: 291-4. 15. Zenz W, Muntean W, Beitzke A, Zobel G, Riccabona M, Gamillscheg A. Tissue plasminogen activator (alteplase) treatment for femoral artery thrombosis after cardiac catheterisation in infants and children. Br Heart J 1993; 70: 382-5. 16. Ries M, Singer H, Hofbeck M. Thrombolysis of a modified Blalock-Taussig shunt with recombinant tissue plasminogen activator in a newborn infant with pulmonary atresia and ventricular septal defect. Br Heart J 1994; 72: 201-2. 17. Ries M, Singer H, Hofbeck M, Klinge J, Wild F, Vogel P. Systemische und lokale Thrombolyse bei Kindern mit angeborenen Herzfehlern. Monatsschr Kinderheilkd 1994; 142: 205-8. 18. Vielhaber H, Kohlhase B, Koch HG, Kehl HG, Fliedner M, Kececioglu D, Kehrel B, Veltmann H, Vogt J, Nowak-Göttl U. Flush heparin during cardiac catheterization prevents long-term coagulations activation in children without APC-Resistance – preliminary results. Thromb Res 1996; 81: 651-6. 19. Delaplane D, Scott JP, Riggs TW, Silverman BL, Hunt CK. Urokinase therapy for a catheter-related right atrial thrombus. J Pediatr 1982; 100: 149-52. 20. Pongiglione G, Marasini M, Ribaldone D, Silvestri G, Tuo P, GarelloCantoni L. Right atrial thrombosis in two premature infants: sucessful treatment with urokinase and heparin. Eur Heart J 1986; 7: 1086-9. 21. Zureikat GY, Martin GR, Silverman NH, Newth CJ. Urokinase therapy for a catheter-related right atrial thrombus and pulmonary embolism in a 2-month-old infant. Pediatr Pulmonol 1986; 2: 303-6. 22. Suarez CR, Ow EP, Lambert GH, Anderson CL, Purewal NS. Urokinase therapy for a central venous catheter thrombosis. Am J Hematol 1989; 31: 269-72. 23. Jolly N, Kaul UA, Khallilullah M. Right atrial thrombus over eustachian valves – sucessful lysis with streptokinase. Int J Cardiol 1991; 30: 354-6. 24. Overmeire van B, Reempts van PJ, Acker van KJ. Intracardiac thrombus formation with rapidly progressive heart failure in the neonate: treatment with tissue type plasminogen activator. Arch Dis Child 1992; 67: 443-5. 25. Kehl HG, Kececioglu D, Vielhaber H, Kotthoff S, Weyand M, Jorch G, Vogt J, Nowak-Göttl U. Left atrial thrombus in a 10-month-old boy – successful thrombolysis with recombinant tissue-type plasminogen activator after open-heart surgery: review of the literature. Intensive Care Med 1996; 22: 968-71.

115


26. Bhat R, Fischer E, Doshi U, Raza S, Sepehri B, Flangigan P, Vidyasagar D. Neonatal abdominal aortic thrombosis. Crit Care Med 1981; 9: 858-61. 27. Rao S, Chow-Thug E, Flangigan D. Urokinase therapy in newborn infants with aortoiliac thrombosis. In: Mannucci DM, Dàngelo A, eds. Urokinase: Basic and clinical aspects. Orlando, Fla: Academic Press 1982: p 215-21. 28. Corrigan JJ Jr, Jeter M, Allen HD, Malone JM. Aortic thrombosis in a neonate: failure of urokinase thrombolytic therapy. Am J Pediatr Hematol Oncol 1982; 4: 243-7. 29. Le Blanc JG, Culham JA, Chan KW, Patterson MW, Tipple M, Sandor GG. Treatment of grafts and major vessel thrombosis with low dose streptokinase in children. Ann Thorac Surg 1986; 41: 630-5. 30. Vailas GN, Brouillette RT, Scott JP, Shkolnik A, Conway J, Wiringa K. Neonatal aortic thrombosis: Recent experience. J Pediatr 1986; 109: 101-8. 31. Emami A, Saidanha R, Knupp C, Kodroff M. Failure of systemic thrombolytic and heparin therapy in treatment of neonatal aortic thrombosis. Pediatrics 1987; 79: 773-7. 32. Kirk CR, Bhrolchain NC, Quereshi SA. Streptokinase for aortic thrombosis. Arch Dis Child 1988; 65: 1086-7. 33. Strife JL, Ball WS, Towbin R, Keller MS, Dillon T. Arterial occlusion in neonates: useof fibrinolytic therapy. Radiology 1988; 166: 395-00. 34. Reznik VM, Anderson J, Griswold WR, Segall ML, Murphy JL, Mendoza SA. Successful fibrinolytic treatment of arterial thrombosis and hypertension in a cocaine-exposed neonate. Pediatrics 1989; 84: 735-8. 35. Kennedy LA, Drummond WH, Knight ME, Millsaps MM, Williams JL. Successful treatment of neonatal aortic thrombosis with tissue plasminogen activator. J Pediatr 1990; 116: 798-801. 36. Ahluwalia JS, Kelsall AWR, Diederich S, Rennie JM. Successful treatment of aortic thrombosis after umbilical catheterization with tissue plasminogen activator. Acta Paediatr 1994; 83: 1215-7. 37. Berger C, Francoise M, Durand C, Sandre D, Gouyon JB. Utilisation de l` activateur du plasminogène dans le traitment des thromboses aortiques du nouveau-né. Arch Pediatr 1994; 1: 1014-8. 38. Deeg KH, Wölfel D, Rupprecht TH. Diagnosis of neonatal aortic thrombosis by colour coded Doppler sonography. Pediatr Radiol 1992; 22: 62-3. 39. Demarquez JL, Tavernier J, Babin JP. Thrombose de la veine rénale chez le nouveau-né. Arch Fr Pediatr 1975; 32: 381-8. 40. Velin P, Dupont D, Messa J, Kubar J. Thrombose veineuse rénale bilatérale néonatale et infection à Salmonella ibadan. Arch Fr Pediatr 1987; 44: 287-9. 41. Griffin MP, Casta A. Successful urokinase therapy for superior vena cava syndromes in a premature infant. Am J Dis Child 1986; 142: 267-8. 42. Rogers PCJ, Silva MP, Carter JEJ, Wadsworth LD. Renal vein thrombosis and response to therapy in a newborn due to protein C deficiency. Eur J Pediatr 1989; 149: 124-5. 43. Duncan BW, Adzick NS, Longaker MT, Edwards JR, Nelson RM, Koerper MA. In tero arterial embolism from renal vein thrombosis with successful postnatal thrombolytic therapy. J Ped Surg 1991; 26: 741-3.

116

44. Nowak-Göttl U, Schwabe D, Schneider W, Schlösser R, Kreuz W. Thrombolysis with recombinant tissue-type plasminogen activator in renal venous thrombosis. Lancet 1992; 340; 1105. 45. Farnoux C, Camard O, Pinquier D, Hurtaud-Roux MF, Sebag G, Schlegel N, Beaufils F. Recombinant tissue-type plasminogen activator therapy of thrombosis in 16 neonates. J Pediatr 1998; 133: 137-4. 46. Schmidt B, Wais U, Fürste HO, Pringesheim W. Successful non-surgical treatment with urokinase and low-dose heparin. Helv Paediat Acta 1982; 37: 483-8. 47. Breviere GM, Vaksmann G, Francart C, Rey C, Dupuis C. Traitement par l`urokinase des thromboses artérielles systémiques du nouveau-né. Arch Mal Coeur 1989; 82: 771-7. 48. Levy M, Benson LN, Burrows PS, Bentur Y, Strong DK, Smith J, Johnson D, Jacobson S, Koren G. Tissue plasminogen activator for the treatment of thromboembolism in infants and children. J Pediatr 1991; 118: 467-72. 49. Nowak-Göttl U, Kreuz WD, Schwabe D, Linde R, Kornhuber B. Thrombolysis with rt-PA in children suffering from arterial or venous thrombosis. Klin Pädiatr 1991; 203: 359-62. 50. Doyle E, Britto J, Freemann J, Munro D, Morton NS. Thrombolysis with low dose tissue plasminogen activator. Arch Dis Child 1992; 67: 1483-4. 51. Rayan CA, Andrew M. Failure of thrombolytic therapy in four children with extensive thromboses. AJDC 1992; 146: 187-93. 52. Rehan VK, Cronin CMG, Bowman JM. Neonatal portal vein thrombosis successfully treated by regional streptokinase infusion. Eur J Pediatr 1994; 153: 456-9. 53. Gebara BM, Goetting MG, Wang AM. Dural sinus thrombosis complicating subclavian vein catheterization: treatment with local thrombolysis. Pediatrics 1995; 95: 138-40. 54. Wever MLG, Liem KD, Geven WB, Tank RB. Urokinase therapy in neonates with catheter related central venous thrombosis. Thromb Haemost 1995; 73: 180-5. 55. Schwabe D, Schlösser R, Auberger K, Kries von R, Nowak-Göttl U. Thrombolyse bei Neugeborenen und Säuglingen. Eine multizentrische Pilotstudie. Hämostaseologie 1996; 16: 236-8. 56. Weiner GM, Castle VP, DiPietro MA, Faix RG. Successful treatment of neonatal arterial thromboses with recombinant tissue plasminogen activator. J Pediatr 1998; 133: 133-6. 57. Andrew M, Michelson AD, Bovill E, Leaker M, Massicotte MP. Guidelines for antithrombotic therapy in pediatric patients. J Pediatr 1998; 123: 575-88. 58. Corrigan JJ Jr, Sluth J, Jeter M, Lox C. Newborn`s fibrinolytic mechanism: components and plasmin generation. Am J Hematol 1989; 32: 237-8. 59. Andrew M, Brooker L, Leaker M, Paes B, Weitz J. Fibrin clot lysis by thrombolytic agents is impaired in newborns due to a low plasminogen concentration. Thromb Haemost 1992; 68: 325-30.