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
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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.
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