Thromboembolism in Newborns, Infants and Children

Summary

As in adults, acquired and inherited prothrombotic risk factors increase the risk of thrombosis in neonates, infants and children. Duplex sonography, venography, computed tomography and magnetic resonance imaging can be used to diagnose childhood thromboembolism, but venography is the recommended method to confirm vascular occlusion of the upper venous system. After suffering thrombosis, patients should be screened for factor V G1691A, prothrombin G20210A and MTHFR C677T genotypes, deficiencies of protein C, protein S, and antithrombin, elevation of lipoprotein (a) and fasting homocysteine concentrations (3 to 6 months after thrombotic onset: plasma-based assays). Data interpretation is based on age-dependent reference ranges and the identification of causative gene mutations/polymorphisms with respect to the individual ethnic background. Paediatric treatment protocols for acute thromboembolism, including thrombolytic and anticoagulant therapy, are hampered by the lack of appropriate clinical trials. Thus, recommendations from small-scale studies in paediatric patients and guidelines adapted from adult patient protocols may be helpful in the management of paediatric patients on an individual patient basis.

Key words

Paediatric venous thrombosis - ischaemic stroke - acquired and genetic prothrombotic risk factors - lipoprotein (a) - anticoagulant therapy

• References

• 1 Ehrenforth S, Junker R, Koch HG, Kreuz W, Münchow N, Scharrer I, Nowak-Göttl U. Multicentre evaluation of combined prothrombotic defects with thrombophilia in childhood. Eur J Pediatr 1999; 158: S97-104.
• 2 Andrew M, Paes B, Johnston M. Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol 1990; 12: 95-104.
• 3 Grabowski EF, Carter CA, Ingelfinger JR, Tsukurov O, Conroy N, Abbott WM, Orkin RW. Comparison of tissue factor pathway in human umbilical vein and adult saphenous vein endothelial cells: implications for newborn hemostasis and for laboratory models of endothelial cell function. Pediatr Res 1999; 46: 742-7.
• 4 Ries M, Klinge J, Rauch R. Age-related reference values for activation markers of the coagulation and fibrinolytic systems in children. Thromb Res 1997; 85: 341-4.
• 5 Schwarz HP, Muntean W, Watzke H, Richter B, Griffin JH. Low total protein S antigen but high protein S activity due to decreased c4b-binding protein in neonates. Blood 1988; 71: 562-5.
• 6 Cvirn G, Gallistl S, Muntean W. Effects of antithrombin and protein C on thrombin generation in newborn and adult plasma. Thromb Res 1999; 93: 183-90.
• 7 Andrew M, Schmidt B, Mitchell L, Paes B, Ofosu F. Thrombin generation in newborn plasma is critically dependent on the concentration of prothrombin. Thromb Haemost 1990; 63: 27-30.
• 8 Andrew M, Mitchell L, Vegh P, Ofosu F. Thrombin regulation in children differs from adults in the absence and presence of heparin. Thromb Haemost 1994; 72: 836-42.
• 9 Trusen B, Ries M, Zenker M, Rauh M, Beinder E, Keuper H, Harms D. Whole blood clot lysis in newborns and adults after adding different concentrations of recombinant tissue plasminogen activator (rt-PA). Semin Thromb Haemost 1998; 24: 599-604.
• 10 Ries M, Klinge J, Rauch R, Trusen B, Zenker M, Keuper H, Harms D. In vitro fibrinolysis after adding low doses of plasminogen activators and plasmin generation with and without oxidative inactivation of plasmin inhibitors in newborns and adults. J Pediatr Hematol Oncol 1996; 18: 346-51.
• 11 Ries M, Klinge J, Rauch R, Keuper H, Harms D. The role of alpha 2-antiplasmin in the inhibition of clot lysis in newborns and adults. Biol Neonate 1996; 69: 298-306.
• 12 Siegbahn A, Ruusuvaara L. Age dependence of blood fibrinolytic components and the effects of low-dose oral contraceptives on coagulation and fibrinolysis in teenagers. Thromb Haemost 1988; 60: 361-4.
• 13 Andrew M. Developmental hemostasis: Relevance to thromboembolic complications in pediatric patients. Thromb Haemost 1995; 74: 415-25.
• 14 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: 1251-7.
• 15 Schmidt B, Andrew M. Neonatal thrombosis: report of a prospective Canadian and international registry. Pediatrics 1995; 96: 939-43.
• 16 Nowak-Göttl U, von Kries R, Göbel U. Neonatal symptomatic thromboembolism in Germany: two year survey. Arch Dis Child Fetal Neonatal Ed 1997; 76: F163-7.
• 17 Massicotte MP, Dix D, Monagle P, Adams M, Andrew M. Central venous catheter related thrombosis in children: Analysis of the Canadian Registry of venous thromboembolic complications. J Pediatr 1998; 133: 770-6.
• 18 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.
• 19 Vitiello R, McCrindle BW, Nykanen D, Freedom RM, Benson LN. Complications associated with pediatric cardiac catheterization. J Am Coll Cardiol 1998; 32: 1433-40.
• 20 Salonvaara M, Riikonen P, Kekomaki R, Heinonen K. Clinically symptomatic central venous catheter-related deep venous thrombosis in newborns. Acta Paediatr 1999; 88: 642-6.
• 21 Boo NY, Wong NC, Zulkifli SS, Lye MS. Risk factors associated with umbilical vascular catheter-associated thrombosis in newborn infants. J Pediatr Child Health 1999; 35: 460-5.
• 22 Uttenreuther-Fischer MM, Vetter B, Hellmann C, Otting U, Ziemer S, Hausdorf G, Gaedicke G, Kulozik AE. Paediatric thrombo-embolism: the influence of non-genetic factors and the role of activated protein C resistance and protein C deficiency. Eur J Pediatr 1997; 156: 277-81.
• 23 Seixas CA, Hessel G, Ribeiro CC, Arruda VR, Annichino-Bizzacchi JM. Factor V Leiden is not common in children with portal vein thrombosis. Thromb Haemost 1997; 77: 258-61.
• 24 Schwartz DS, Gettner PA, Konstantino MM, Bartley CL, Keller MS, Ehrenkranz RA, Jacobs HC. Umbilical venous catheterization and the risk of portal vein thrombosis. J Pediatr 1997; 131: 760-2.
• 25 Grandas OH, Klar M, Goldman MH, Filston HC. Deep venous thrombosis in the pediatric trauma population: an unusual event: report of three cases. Am Surg 2000; 66: 273-6.
• 26 Kaplan DM, Fliss DM, Peiser Y, Greenberg D, Leiberman A. Internal jugular vein thrombosis in a child due to a “pencil point injury” of the palate. Int J Pediatr Otorhinolaryngol 1998; 44: 183-7.
• 27 Eire PF, Vallejo D, Sastre JL, Villaamil R, Rodriguez MA, Garrido M. An unusual complication of appendicitis in childhood. Eur J Pediatr Surg 1999; 9: 351-2.
• 28 Sifontes MT, Nuss R, Hunger SP, Wilimas J, Jacobson LJ, Manco-Johnson MJ. The factor V Leiden mutation in children with cancer and thrombosis. Br J Haematol 1997; 96: 484-9.
• 29 Mitchell L, Hoogendoorn H, Giles AR, Vegh P, Andrew M. Increased endogenous thrombin generation in children with acute lymphoblastic leukemia: risk of thrombotic complications in L-Asparaginase-induced antithrombin III deficiency. Blood 1994; 83: 386-91.
• 30 Nowak-Göttl U, Wermes C, Junker R, Koch HG, Schobess R, Fleischhack G, Schwabe D, Ehrenforth S. Prospective evaluation of the thrombotic risk in children with acute lymphoblastic leukemia carrying the MTHFR TT677 genotype, the prothrombin G20210A variant, and further prothrombotic risk factors. Blood 1999; 93: 1595-9.
• 31 Kocak U, Gursel T, Ozturk G, Kantarci S. Thrombosis during all-transretinoic acid therapy in a child with acute promyelocytic leukemia and factor VQ 506 mutation. Pediatr Hematol Oncol 2000; 17: 177-80.
• 32 Sträter R, Vielhaber H, Kassenböhmer R, von Kries R, Göbel U, Nowak Göttl U. Genetic risk factors of thrombophilia in ischaemic childhood stroke of cardiac origin. A prospective ESPED survey. Eur J Pediatr 1999; 158: S122-5.
• 33 Schlegel N. Thromboembolic risks and complications in nephrotic children. Semin Thromb Hemost 1997; 23: 271-80.
• 34 Fabri D, Belangero VM, Annichino-Bizzachi JM, Arruda VR. Inherited risk factors for thrombophilia in children with nephrotic syndrome. Eur J Pediatr 1998; 157: 939-42.
• 35 Hagstrom JN, Walter J, Bluebond-Langner R, Amatniek JC, Manno CS, High KA. Prevalence of the factor V Leiden mutation in children and neonates with thromboembolic disease. J Pediatr 1998; 133: 777-81.
• 36 Heller C, Schobess R, Kurnik K, Junker R, Günther G, Kreuz W, Nowak Göttl U. Abdominal venous thrombosis in neonates and infants: Role of prothrombotic risk factors – a multicentre case-control study. Br J Haematol 2000; 111: 534-9.
• 37 Schulman H, Hertzog L, Zirkin H, Hertzanu Y. Cerebral sinovenous thrombosis in the idiopathic hypereosinophilic syndrome in childhood. Pediatr Radiol 1999; 29: 595-7.
• 38 Berenson GS, Srinivasan SR, Bao W, Newman WP, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med 1998; 338: 1650-6.
• 39 Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, Chandy M, Dahlbäck B, Ginter EK, Miletich JP, Rosendaal FR, Seligsohn U. Inherited thrombophilia: Part 1. Thromb Haemost 1996; 76: 651-62.
• 40 Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, Chandy M, Dahlbäck B, Ginter EK, Miletich JP, Rosendaal FR, Seligsohn U. Inherited thrombophilia: Part 2. Thromb Haemost 1996; 76: 824-34.
• 41 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-8.
• 42 Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velde PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
• 43 Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, Arzdria G, Boers GHJ, Bromberg IL, Cerone R, Fowler B, Gröbe H, Schmidt H, Schweitzer L. The natural history of homocystinuria due to cystathionine-B-synthase deficiency. Am J Hum Genet 1985; 37: 1-31.
• 44 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-703.
• 45 Seligsohn U, Zivelin A. Thrombophilia as a multigenetic disorder. Thromb Haemost 1997; 78: 297-301.
• 46 Salomon O, Steinberg DM, Zivelin A, Gitel S, Dardik R, Rosenberg N, Berliner S, Inbal A, Many A, Lubetsky A, Varon D, Martinowitz U, Seligsohn U. Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism – Prevalence and risk assessment. Arterioscler Thromb Vasc Biol 1999; 19: 511-8.
• 47 Uterman G. The mysteries of lipoprotein (a). Science 1989; 246: 904-10.
• 48 Berg K, Dahlen G, Frick MH. Lp(a) lipoprotein and pre-beta 1-lipoprotein in patients with coronary heart disease. Clin Genet 1974; 6: 230-5.
• 49 Rader DJ, Hoeg JM, Brewer Jr HB. Quantitation of plasma apolipoproteins in the primary and secondary prevention of coronary artery disease. Ann Intern Med 1994; 120: 1012-25.
• 50 Schaefer EJ, Lamon-Fava S, Jenner JL, McNamara JR, Ordovas JM, Davis CE, Abolafia JM, Lippel K, Levy RI. Lipoprotein (a) levels and risk of coronary heart diseases in men: the Lipid Research Clinics Coronary Primary Prevention Trial. JAMA 1994; 271: 999-1003.
• 51 Assmann G, Schulte H, von Eckardstein A. Hypertriglyceridemia and elevated lipoprotein (a) are risk factors for major coronary events in middle-aged men. Am J Cardiol 1996; 77: 1179-84.
• 52 Soulat T, Loyau S, Baudoin V, Maisonneuve L, Hurtaud-Roux MF, Schlegel N, Loirat C, Anglès-Cano E. Effect of individual plasma Lipoprotein(a) variations in vivo on its competition with plasminogen for fibrin and cell binding – An in vitro study using plasma from children with idiopathic nephrotic syndrome. Arterioscler Thromb Vasc Biol 2000; 20: 575-84.
• 53 Nowak-Göttl U, Junker R, Hartmeier M, Koch HG, Münchow N, Assmann G, von Eckardstein A. Increased lipoprotein (a) is an important risk factor for venous thromboembolism in childhood. Circulation 1999; 100: 743-8.
• 54 Nowak-Göttl U, Sträter R, Heinecke A, Junker R, Koch HG, Schuierer G, von Eckardstein A. Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin and methylenetetrahydrofolate reductase are risk factors of ischaemic stroke in childhood. Blood 1999; 94: 3678-82.
• 55 Von Depka Prondzinski M, Nowak-Göttl U, Eisert R, Dieterich C, Barthels M, Scharrer I, Ganser A, Ehrenforth S. Increased lipoprotein (a) levels as an independent risk factor for venous thromboembolism. Blood 2000; 96: 3364-8.
• 56 Formstone CJ, Hallam PJ, Tuddenham EG, Voke J, Layton M, Nicolaides K, Hann IM, Cooper DV. Severe perinatal thrombosis in double and triple heterozygous offspring of a family segregating two independent protein S mutations and a protein C mutation. Blood 1996; 87: 3731-7.
• 57 Brenner B, Zivelin A, Lanir N, Greengard JS, Griffin JH, Seligsohn U. Venous thromboembolism associated with double heterozygosity for R506Q mutation of factor V and for T298M mutation of protein C in a large family of a previously described homozygous protein C deficient newborn with massive thrombosis. Blood 1996; 88: 877-80.
• 58 Kosch A, Junker R, Kurnik K, Schobess R, Günther G, Koch HG, Nowak Göttl U. Prothrombotic risk factors in children with spontaneous venous thrombosis and their asymptomatic parents: a family study. Thromb Res 2000; 99: 531-7.
• 59 Salafia CM, Vintzileos AM, Silberman L, Bantham KF, Vogel CA. Placental pathology of idiopathic intrauterine growth retardation at term. Am J Perinatol 1992; 9: 179-84.
• 60 De Wolf F, Carreras LO, Moerman P, Vermylen J, Van Assche A, Renaer M. Decidual vasculopathy and extensive placental infarction in a patient with repeated thromboembolic accidents, recurrent foetal loss, and lupus anticoagulant. Am J Obstet Gynecol 1982; 142: 829-34.
• 61 Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, Fait G, Lessing JB. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340: 9-13.
• 62 Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemost 1999; 82: 6-9.
• 63 Dizon-Townson DS, Meline L, Nelson LM, Varner M, Ward K. Fetal carriers of the factor V Leiden are prone to miscarriage and placental infarction. Am J Ostet Gynecol 1997; 177: 402-5.
• 64 Berg K, Roald B, Sande H. High Lp(a) lipoprotein level in maternal serum may interfere with placental circulation and cause fetal growth retardation. Clin Genet 1994; 46: 52-6.
• 65 Göpel W, Kim D, Gortner L. Prothrombotic mutations as a risk factor for preterm birth. Lancet 1999; 353: 1411-2.
• 66 Verspyck E, Le Camp-Duchez V, Gravier A, Descargues G, Marpeau L, Borg JY. Small for gestational age infant in association with maternal prothrombin gene variant (nt 20210A). Eur J Obstet Gynecol Reprod Biol 1999; 83: 143-4.
• 67 Vries de LS, Eken P, Groenendaal F, Rademacher KJ, Hoogervorst B, Bruinse HW. Antenatal onset of haemorrhagic and/or ischaemic lesions in preterm infants: prevalence and associated obstetric variables. Arch Dis Child Fetal Neonatal Ed 1998; 78: F51-6.
• 68 Ment LR, Duncan CC, Ehrenkranz RA. Perinatal cerebral infarction. Ann Neurol 1984; 16: 559-68.
• 69 Kraus FT, Acheen VI. Fetal thrombotic vasculopathy in the placenta: cerebral thrombi and infarcts, coagulopathies, and cerebral palsy. Hum Pathol 1999; 30: 759-69.
• 70 Debus O, Koch HG, Kurlemann G, Straeter R, Vielhaber H, Weber P, Nowak-Göttl U. Factor V Leiden and genetic defects of thrombophilia in childhood porencephaly. Arch Dis Child Fetal Neonatal Ed 1998; 78: F121-4.
• 71 Govaert P, Matthys E, Zecic A, Roelens F, Oostra A, Vanzieleghem B. Perinatal cortical infarction within middle cerebral artery trunks. Arch Dis Child Fetal Neonatal Ed 2000; 82: F59-63.
• 72 DeVeber G, Monagle P, Chan A, MacGregor D, Curtis R, Lee S, Vegh P, Adams M, Marzinotto V, Leaker M, Massicotte P, Lillicrap D, Andrew M. Prothrombotic disorders in infants and children with cerebral thromboembolism. Arch Neurol 1998; 55: 1539-43.
• 73 Vielhaber H, Ehrenforth S, Koch HG, Scharrer I, van der Werf N, Nowak Göttl U. Cerebral venous thrombosis in infancy and childhood: role of genetic and acquired risk factors of thrombophilia. Eur J Pediatr 1998; 157: 555-60.
• 74 Nuss R, Hays T, Manco-Johnson M. Childhood thrombosis. Pediatrics 1995; 96: 291-4.
• 75 Mocan H, Beattie TJ, Murphy AV. Renal venous thrombosis in infancy: long-term follow-up. Pediatr Nephrol 1991; 5: 45-9.
• 76 Bökenkamp A, von Kries R, Nowak-Göttl U, Göbel U, Hoyer PF. Neonatal renal venous thrombosis in Germany between 1992 and 1994: epidemiology, treatment and outcome. Eur J Pediatr 2000; 159: 44-8.
• 77 Becker S, Heller C, Gropp F, Scharrer I, Kreuz W. Thrombophilic disorders in children with cerebral infarction. Lancet 1998; 352: 1756-7.
• 78 Ganesan V, Kelsey H, Cookson J, Osborn A, Kirkham FJ. Activated protein C resistance in childhood stroke. Lancet 1996; 347: 260.
• 79 Riikonen RS, Vahtera EM, Kekomäki RM. Physiological anticoagulants and activated protein C resistance in childhood stroke. Acta Paediatr 1996; 85: 242-4.
• 80 Zenz W, Bodo Z, Plotho J, Streif W, Male C, Bernert G, Rauter L, Ebetsberger G, Kaltenbrunner K, Kurnik P, Lischka A, Paky F, Ploier R, Höfler G, Mannhalter C, Muntean W. Factor V Leiden and prothrombin gene G20210A variant in children with ischaemic stroke. Thromb Haemost 1998; 80: 763-6.
• 81 McColl MD, Chalmers EA, Thomas A, Sproul A, Healey C, Rafferty I, McWilliam R, Eunson P. Factor V Leiden, prothrombin 20210GA and the MTHFR C677T mutations in childhood stroke. Thromb Haemost 1999; 81: 690-4.
• 82 Van Beynum IM, Smeitink JA, den Heijer M, te Poele Pothoff MT, Blom HJ. Hyperhomocysteinemia: a risk for ischemic stroke in children. Circulation 1999; 99: 2070-2.
• 83 Kenet G, Sadetzki S, Murad H, Martinowitz U, Rosenberg N, Gitel S, Rechavi G, Inbal A. Factor V Leiden and antiphospholipid antibodies are significant risk factors for ischemic stroke in children. Stroke 2000; 31: 1283-8.
• 84 Günther G, Junker R, Sträter R, Schobess R, Kurnik K, Heller C, Kosch A, Nowak-Göttl U. Symptomatic ischemic stroke in full-term neonates: Role of acquired and genetic prothrombotic risk factors. Stroke 2000; 31: 2437-41.
• 85 Heller C, Becker S, Scharrer I, Kreuz W. Prothrombotic risk factors in childhood stroke and venous thrombosis. Eur J Pediatr 1999; 158: S117-21.
• 86 Andrew M, Michelson AD, Bovill E, Leaker M, Massicotte MP. Guidelines for antithrombotic therapy in pediatric patients. J Pediatr 1998; 132: 575-88.
• 87 Ginsberg JS, Kearon C, Douketis J, Turpie AG, Brill-Edwards P, Stevens P, Panju A, Patel A, Crowther M, Andrew M, Massicotte P, Hirsh J, Weitz JL. The use of D-dimer testing and impedance plethysmographic examination in patients with clinical indications of deep vein thrombosis. Arch Int Med 1997; 157: 1077-81.
• 88 Worth LL, Hoots WK. Development of a subdural vein thrombosis following aggressive factor VII replacement for postnatal intracranial haemorrhage in a homozygous factor VII-deficient infant. Haemophilia 1998; 4: 757-61.
• 89 Escuriola Ettingshausen C, Martinez Saguer I, Kreuz W. Portal vein thrombosis in a patient with severe haemophilia A and F V G1691A mutation during continuous infusion of F VIII after intramural jejunal bleeding – successful thrombolysis under heparin therapy. Eur J Pediatr 1999; 158: S180-2.
• 90 Manco-Johnson MJ, Abshire TC, Jacobson LG, Marlar RA. Severe neonatal protein C deficiency: prevalence and thrombotic risk. J Pediatr 1991; 119: 793-8.
• 91 Manco-Johnson MJ, Nuss R, Key N, Moertel C, Jacobson L, Meech S, Weinberg A, Lefkowitz J. Lupus anticoagulant and protein S deficiency in children with postvaricella purpura fulminans or thrombosis. J Pediatr 1996; 128: 319-23.
• 92 Nowak-Göttl U, Koch HG, Aschka I, Kohlhase B, Vielhaber H, Kurlemann G, Oleszcuk-Raschke K, Kehl HG, Jürgens H, Schneppenheim R. Resistance to activated protein C (APCR) in children with venous or arterial thromboembolism. Br J Haematol 1996; 92: 992-8.
• 93 Sifontes MT, Nuss R, Jacobson LJ, Griffin JH, Manco-Johnson MJ. Thrombosis in otherwise well children with the factor V Leiden mutation. J Pediatr 1996; 128: 324-8.
• 94 Aschka I, Aumann V, Bergmann F, Budde U, Eberl W, Eckhof-Donovan S, Krey S, Nowak-Göttl U, Schobess R, Sutor AH, Wendisch J, Schneppenheim R. Prevalence of factor V Leiden in children with thromboembolism. Eur J Pediatr 1996; 155: 1009-14.
• 95 Lawson SE, Butler D, Enayat MS, Williams MD. Congenital thrombophilia and thrombosis: a study in a single centre. Arch Dis Child 1999; 81: 176-8.
• 96 Junker R, Koch HG, Auberger K, Münchow N, Ehrenforth S, Nowak Göttl U. Prothrombin G20210A gene mutation and further prothrombotic risk factors in childhood thrombophilia. Arterioscler Thromb Vasc Biol 1999; 19: 2568-72.
• 97 Schobess R, Junker R, Auberger K, Münchow N, Burdach S, Nowak Göttl U. Factor V G1691A and prothrombin G20210A in childhood spontaneous venous thrombosis – evidence of an age-dependent thrombotic onset in carriers of factor V G1691A and prothrombin G20210A mutation. Eur J Pediatr 1999; 158: S105-8.
• 98 Bonduel M, Hepner M, Sciuccati G, Torres AF, Pieroni G, Frontroth JP. Prothrombotic abnormalities in children with venous thromboembolism. J Pediatr Hematol Oncol 2000; 22: 66-72.
• 99 Rees DC. The population genetics of factor V Leiden (Arg 506 Gln). Review. Br J Haematol 1996; 95: 579-86.
• 100 Häusler M, Duque D, Merz U, Mertens R, Mühler E, Hörnchen H. The clinical outcome after inferior vena cava thrombosis in early infancy. Eur J Pediatr 1999; 158: 416-20.
• 101 Monagle P, Adams M, Mahoney M, Ali K, Barnard D, Bernstein M, Brisson L, David M, Desai S, Scully MF, Halton J, Israels S, Jardine L, Leaker M, McCusker P, Silvia M, Wu J, Anderson R, Andrew M, Massicotte MP. Outcome of pediatric thromboembolic disease: a report from the Canadian childhood thrombophilia registry. Pediatr Res 2000; 47: 63-6.
• 102 Streif W, Andrew M, Marzinotto V, Massicotte P, Chan AK, Julian JA, Mitchell L. Analysis of Warfarin therapy in pediatric patients: A prospective cohort study of 319 patients. Blood 1999; 94: 3007-14.
• 103 Nowak-Göttl U, Junker R, Kreuz W, von Eckardstein A, Kosch A, Nohe N, Schobess R, Ehrenforth S. Risk of recurrent thrombosis in children with combined prothrombotic risk factors. Blood 2001; 97: 858-62.
• 104 Prandoni P, Lensing AW, Prins MR. Long-term outcomes after deep venous thrombosis of the lower extremities. Vas Med 1998; 3: 57-60.
• 105 Stefano de V, Martinelli I, Mannucci PM, Paciaroni K, Chiusolo P, Casorelli I, Rossi E, Leone G. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med 1999; 341: 801-6.
• 106 Marlar RA, Montgommery RR, Broekmans AW. Diagnosis and treatment of homozygous protein C deficiency. Report of the Working Party of Homozygous Protein C Deficiency of the Subcommittee on Protein C and Protein S. International Committee on Thrombosis and Haemostasis. J Pediatr 1989; 114: 528-34.
• 107 Dreyfus M, Magny JF, Bridey F, Schwarz HP, Planche C, Dehan M, Tchernia G. Treatment of homozygous protein C deficiency and neonatal purpura fulminans with purified protein C concentrate. N Engl J Med 1991; 325: 1565-8.
• 108 Massicotte P, Adams M, Marzinotto V, Brooker LA, Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study. J Pediatr 1996; 128: 313-8.
• 109 Dix D, Andrew M, Marzinotto V, Charpentier K, Bridge S, Monagle P, de Veber G, Leaker M, Chan AK, Massicotte MP. The use of low molecular weight heparin in pediatric patients: a prospective cohort study. J Pediatr 2000; 136: 439-45.
• 110 Kirk CR, Qureshi SA. Streptokinase in the management of arterial thrombosis in infancy. Int J Cardiol 1989; 25: 15-20.
• 111 Nowak-Göttl U, Schwabe D, Schneider W, Schlösser R, Kreuz W. Thrombolysis with recombinant tissue-type plasminogen activator in renal venous thrombosis in infancy. Lancet 1992; 340: 1105.
• 112 Wever ML, Liem KD, Geven WB, Tanke RB. Urokinase therapy in neonates with catheter related central venous thrombosis. Thromb Haemost 1995; 73: 180-5.
• 113 Farnoux C, Camard O, Pinquier D, Hurtaud-Roux MF, Sebag G, Schlegel N, Beaufils F. Recombinant tissue-type plasminogen activator herapy of thrombosis in 16 neonates. J Pediatr 1998; 133: 137-40.
• 114 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.
• 115 Nowak-Göttl U, Auberger K, Halimeh S, Junker R, Klinge J, Kreuz WD, Ries M, Schlegel N. Thrombolysis in newborns and infants. Thromb Haemost 1999; 82: S112-6.
• 116 Manco-Johnson MJ, Nuss R, Hays T, Krupski W, Drose J, Manco-Johnson ML. Combined thrombolytic and anticoagulant therapy for venous thrombosis in children. J Pediatr 2000; 136: 446-53.
• 117 Massicotte P, Leaker M, Marzinotto V, Adams M, Freedom R, Williams W, Vegh P, Berry L, Shah B, Andrew M. Enhanced thrombin regulation during warfarin therapy in children compared to adults. Thromb Haemost 1998; 80: 570-4.