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Screening children with thrombosis for thrombophilic proteins. Cui bono?

2003; Elsevier BV; Volume: 1; Issue: 5 Linguagem: Inglês

10.1046/j.1538-7836.2003.00159.x

1538-7933

A. H. Sutor,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

In 1988, when we planned a conference on thromboembolic events in childhood, it was considered an extraordinarily rare subject. Surprisingly, however, a 1990 survey in West Germany revealed thromboembolic events in 188 children, an incidence of 1.9 per 100 000 children per year [1Sutor A.H. Bruhn H.D. Schreiber R. Seifried E. Weißbach G. Thrombosen im Kindesalter.Hämostaseologie. 1992; 12: 82-93Crossref Google Scholar]. At this conference, many of the conditions in Table 1 were already identified as risks for thromboembolic events, except for thrombophilic proteins which were mentioned in only three case reports of purpura fulminans. Today the incidence for venous thromboembolic events (VTEs) is similar [2Van Ommen C.H. Heijboer H. Buller H.R. Hirasing R.A. Heijmans H.S. Peters M. Venous thromboembolism in childhood: a prospective two-year registry in the Netherlands.J Pediatr. 2001; 139: 676-81Abstract Full Text Full Text PDF PubMed Scopus (524) Google Scholar], but reports focus mainly on its association with thrombophilic proteins.Table 1Risk conditions and laboratory factors for thromboembolic events (TE). Compiled from [5Kosch A. Von Kries R. Nowak-Göttl U. Thrombosen im Kindesalter.Monatsschr Kinderheilk. 2000; 148: 387-97Crossref Google Scholar, 14Richardson M.W. Allen G.A. Monahan P.E. Thrombosis in children: current perspective and distinct challenges.Thromb Haemost. 2002; 88: 900-11Crossref PubMed Google Scholar, 17Mannucci P.M. The measurement of multifactorial thrombosis.Thromb Haemost. 2002; 88: 1-2Crossref PubMed Google Scholar, 19Manco-Johnson M.J. Grabowski E.F. Hellgreen M. Kemahli A.S. Massicotte M.P. Muntean W. Peters M. Nowak-Göttl U. Laboratory testing for thrombophilia in children: on behalf of the subcommittee for perinatal and pediatric thrombosis of the scientific and standardization committee of the international society of thrombosis and haemostasis.Thromb Hemost. 2002; 88: 155-6Crossref PubMed Scopus (0) Google Scholar, 30Sutor A.H. Uhl M. Diagnosis of thromboembolic disease during infancy and childhood.Sem Thromb Hemostas. 1997; 23: 237-46Crossref PubMed Google Scholar]Family/own historyIatrogenic risks; diseaseLaboratory screeningFamily historyIatrogenic risksThrombophilic proteinsVTE, MI, stroke < 40 yearsCVLs, shunts, stentsFV Leiden (G1691A)*Genetic, DNA-based.VTE on unusual locations: (hepatic, mesenterial, sinus)Cardiac valvesFII (G 20210A)*Genetic, DNA-based.Recurrent TECatheterizationMTHFR (677TT)*Genetic, DNA-based. (and) fasting homocysteinePurpura fulminansSurgery, even minor (16)↓ Protein C†Genetic or acquired. ↑, high; ↓, low. VTE, venous thromboembolism; IUGR, intrauterine growth retardation; MI, myocardial infarction; HIT, heparin-induced thrombocytopenia; OAC, oral anticoagulants; CVL, central venous line; CDG, carbohydrate-deficient glycoprotein; HELPP, hemolysis, elevated liver enzymes, low platelets; MTHFR, methylenetetrahydrofolate reductase. in neonatal periodParenteral nutrition↓ Protein S†Genetic or acquired. ↑, high; ↓, low. VTE, venous thromboembolism; IUGR, intrauterine growth retardation; MI, myocardial infarction; HIT, heparin-induced thrombocytopenia; OAC, oral anticoagulants; CVL, central venous line; CDG, carbohydrate-deficient glycoprotein; HELPP, hemolysis, elevated liver enzymes, low platelets; MTHFR, methylenetetrahydrofolate reductase. with varicellaMedications↓ Antithrombin†Genetic or acquired. ↑, high; ↓, low. VTE, venous thromboembolism; IUGR, intrauterine growth retardation; MI, myocardial infarction; HIT, heparin-induced thrombocytopenia; OAC, oral anticoagulants; CVL, central venous line; CDG, carbohydrate-deficient glycoprotein; HELPP, hemolysis, elevated liver enzymes, low platelets; MTHFR, methylenetetrahydrofolate reductase. with septicemiaOral contraceptivesF VIII†Genetic or acquired. ↑, high; ↓, low. VTE, venous thromboembolism; IUGR, intrauterine growth retardation; MI, myocardial infarction; HIT, heparin-induced thrombocytopenia; OAC, oral anticoagulants; CVL, central venous line; CDG, carbohydrate-deficient glycoprotein; HELPP, hemolysis, elevated liver enzymes, low platelets; MTHFR, methylenetetrahydrofolate reductase.Skin necrosis after OACCorticosteroids↑ Lipoprotein (a)Prenatal historyAsparaginaseAntiphospholipid antibodies (including cardiolipin)Repeated IUGRHeparin (HIT)(↑FI, IX, XI, ↓plasminogen ?)Repeated abortionsCoagulation factor concentratesHypercoagulation markersMaternal diabetesDisease/conditiond-Dimers (23)Pre-eclampsiaShock-syndromesEndogenous thrombin potentials (17)HELPP syndromeMalignancyVT during pregnancySepticemia, meningitisMalformationsImmobilization, even short (16)Anal atresiaTrauma, even minor, burnsPorencephalyNephrotic syndromeCardiac diseaseCDG syndromeSystemic lupus erythematodesRheumatoid arthritisCrohn's disease, ulcerative colitisKawasaki syndromeKasabach–Merritt syndromeDiabetesDehydrationSickle cell anemiaPrematurityAsphyxia (hypoxemia)HypertensionVascular malformations/damagePolycythemiaAtmospheric conditions (31)* Genetic, DNA-based.† Genetic or acquired. ↑, high; ↓, low. VTE, venous thromboembolism; IUGR, intrauterine growth retardation; MI, myocardial infarction; HIT, heparin-induced thrombocytopenia; OAC, oral anticoagulants; CVL, central venous line; CDG, carbohydrate-deficient glycoprotein; HELPP, hemolysis, elevated liver enzymes, low platelets; MTHFR, methylenetetrahydrofolate reductase. Open table in a new tab In this issue, Revel-Vilk et al. [3Revel-Vilk S. Chan A. Bauman M. Massicotte P. Prothrombotic conditions in an unselected cohort of children with venous thromboembolic disease.J Thromb Haemost. 2003; 1: 915-21Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar] from Canada conclude that (i) the major risk factors for VTEs in children are central venous lines (CVLs) and/or other medical conditions; (ii) thrombophilic proteins do not contribute significantly to the pathogenesis of VTEs in neonates and children; and (iii) the results do not justify screening all children with VTEs for thrombophilic proteins. This contrasts with the recommendation of the German thrombophilia study group that children with VTEs should be tested comprehensively for genetic and acquired thrombophilic proteins [4Ehrenfort S. Junker R. Koch H.G. Kreuz W. Münchow N. Scharrer I. Nowak-Göttl U. Multicentre evaluation of combined prothrombotic defects associated with thrombophilia in childhood.Eur J Pediatr. 1999; 158: S97-104Crossref PubMed Google Scholar, 5Kosch A. Von Kries R. Nowak-Göttl U. Thrombosen im Kindesalter.Monatsschr Kinderheilk. 2000; 148: 387-97Crossref Google Scholar, 6Nowak-Göttl U. Junker R. Hartmeier M. Koch H.G. Münchow N. Assmann G. Von Eckardstein A. Increased lipoprotein (a) is an important risk factor for venous thromboembolism in childhood.Circulation. 1999; 100: 743-8Crossref PubMed Google Scholar, 7Nowak-Göttl Junker R. Kreuz W. Von Eckardstein A. Kosch A. Nohe N. Schobess R. Ehrenfort S. Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors.Blood. 2001; 97: 858-62Crossref PubMed Scopus (224) Google Scholar, 8Nowak-Göttl U. Kosch A. Schlegel N. Thromboembolism in newborns, infants and children.Thromb Haemost. 2001; 86: 464-74Crossref PubMed Scopus (0) Google Scholar]. The conflicting opinions result from striking differences in the following data gleaned by the two groups: incidence of thrombophilic proteins (13% in Canadian children with VTEs vs. 57–78% found in Germany); median age (2.3 months vs. 6 years, reflecting the higher proportion of newborns and infants in the Canadian study); proportion of spontaneous VTEs, i.e. without underlying medical condition (6.4% vs. 60%; 79% of German cases had thrombophilic proteins). In the Canadian study, older children with spontaneous VTEs also were found to have a high prevalence of thrombophilic proteins (60%, in contrast to only 10% in older children with non-spontaneous VTEs). Among the 18 (= 10.5%) Canadian cases that recurred (12 of them while on anticoagulant therapy), thrombophilic proteins were present only in two. Surprisingly, the results of the Netherlands thrombophilia registry are closer to the Canadian results than to those of neighboring Germany [2Van Ommen C.H. Heijboer H. Buller H.R. Hirasing R.A. Heijmans H.S. Peters M. Venous thromboembolism in childhood: a prospective two-year registry in the Netherlands.J Pediatr. 2001; 139: 676-81Abstract Full Text Full Text PDF PubMed Scopus (524) Google Scholar]. The difference in the results can be partially explained by methodological differences. The Canadian study from a single institution may have been better informed of individual patients' situations, thus detecting more underlying medical conditions than the multicenter German study. Racial differences also may have contributed, since immigrants may have very different prevalences of inheritable thrombophilic proteins. Factor V Leiden, for example, is almost never found in those from Africa and East Asia but affects up to 14% of the Eastern Mediterranean population [9Irani-Hakime N. Tamim H. Kreidy R. Almawi W.Y. The prevalence of factor V R506Q mutation-Leiden among apparently healthy Lebanese.Am J Hematol. 2000; 65: 45-9Crossref PubMed Scopus (0) Google Scholar]. In addition, the role of thrombophilic protein risk factors is not straightforward: The concentration of lipoprotein(a) [Lp(a)] can be altered by asparaginase and by inflammation, which are known risk factors for VTEs. In uremic patients high concentrations of Lp(a) are related to activated rather than impaired fibrinolysis [10Korte W. Greiner J. Feldges A. Riesen W. Increased lipoprotein (a) levels are not a steady prothrombotic defect.Blood. 2001; 96: 1993-4Crossref Scopus (14) Google Scholar, 11Gatica A. Panes O. Tagle R. Pereira J. Mezzano D. High plasma levels of lipoprotein (a) in uremic patients are related to markers of inflammation, and to activated, not impaired fibrinolysis.Thromb Haemost. 2002; 88: 688-9Crossref PubMed Scopus (2) Google Scholar]. Factor V Leiden is thrombophilic in older children but, paradoxically, may cause bleeding in those born prematurely [12Petäjä J. Hiltunen L. Fellman V. Increased risk of intraventricular hemorrhage in preterm infants with thombophilia.Pediatr Res. 2000; 49: 643-6Crossref Scopus (68) Google Scholar]. It is conceivable that non-familial reduced levels of protein C, protein S, and antithrombin found several months after thromboembolic events are markers and not the cause of ongoing thrombophilia. Diagnostic criteria can also affect the results reported. For example, among 60 children with leukemia only one had clinical features of thromboembolism, but 29% had radiographic evidence [13Male C. Chait P. Ginsberg J.S. Hanna K. Andrew M. Halton J. Andreson R. McCusker P. Wu J. Abshire T. Cherrick I. Mahoney D. Mitchell L. Comparison of venography and ultrasound for the diagnosis of asymptomatic deep vein thrombosis in the upper body in children. Results of the PARKAA Study.Thromb Haemost. 2002; 87: 593-8Crossref PubMed Google Scholar]. Cui bono? Neonates with purpura fulminans, an acute and potentially lethal syndrome, and those with spontaneous large vessel thrombosis certainly benefit from screening for thrombophilic proteins, since protein C (or, in single reports, protein S or antithrombin) is always absent and treatment is available. Older children with purpura fulminans associated with septicemia might also benefit from screening for similar reasons [14Richardson M.W. Allen G.A. Monahan P.E. Thrombosis in children: current perspective and distinct challenges.Thromb Haemost. 2002; 88: 900-11Crossref PubMed Google Scholar]. Screening may benefit children with spontaneous or recurrent VTEs, as they may have multiple thrombophilic proteins whose recognition would allow more rational prophylaxis or treatment [7Nowak-Göttl Junker R. Kreuz W. Von Eckardstein A. Kosch A. Nohe N. Schobess R. Ehrenfort S. Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors.Blood. 2001; 97: 858-62Crossref PubMed Scopus (224) Google Scholar]. In children with VTEs and a positive family history, screening for thrombophilia might also be of benefit to relatives, since knowledge of the carrier state might prevent some prenatal complications (Table 1). The vast majority of childhood VTEs are non-spontaneous [14Richardson M.W. Allen G.A. Monahan P.E. Thrombosis in children: current perspective and distinct challenges.Thromb Haemost. 2002; 88: 900-11Crossref PubMed Google Scholar, 15Monagle P, Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest; 119 (Suppl. 1): 344S–70S.Google Scholar] and the value of screening every case for thrombophilic proteins is not known [15Monagle P, Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest; 119 (Suppl. 1): 344S–70S.Google Scholar]. In addition, risk factors not related to thrombophilic proteins outnumber those of thrombophilic proteins (Table 1). CVLs bear a very high risk, but even minor events such as short periods of immobilization (short illness, minor surgery or injuries) may treble the risk of VTEs [16Eekhoff E.M. Rosendaal F.R. Vandenbroucke J.P. Minor events and the risk of deep venous thrombosis.Thromb Haemost. 2000; 83: 408-11Crossref PubMed Google Scholar] and the actual risk of developing VTEs is more than the simple sum of each relative risk [17Mannucci P.M. The measurement of multifactorial thrombosis.Thromb Haemost. 2002; 88: 1-2Crossref PubMed Google Scholar]. In adults, thrombophilic protein results are less predictive of recurrence risk than clinical circumstances with the presence of continuing risk factors being a very strong predictor [18Baglin T. Greaves M. Rebuttal: is a nihilistic approach to thrombophilia screening justified?.Thromb Haemost. 2002; 88: 700-1Crossref PubMed Scopus (11) Google Scholar]. Presently there is disagreement between recent published recommendations on screening for thrombophilic proteins in children with thromboembolic events [8Nowak-Göttl U. Kosch A. Schlegel N. Thromboembolism in newborns, infants and children.Thromb Haemost. 2001; 86: 464-74Crossref PubMed Scopus (0) Google Scholar, 14Richardson M.W. Allen G.A. Monahan P.E. Thrombosis in children: current perspective and distinct challenges.Thromb Haemost. 2002; 88: 900-11Crossref PubMed Google Scholar, 15Monagle P, Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest; 119 (Suppl. 1): 344S–70S.Google Scholar, 19Manco-Johnson M.J. Grabowski E.F. Hellgreen M. Kemahli A.S. Massicotte M.P. Muntean W. Peters M. Nowak-Göttl U. Laboratory testing for thrombophilia in children: on behalf of the subcommittee for perinatal and pediatric thrombosis of the scientific and standardization committee of the international society of thrombosis and haemostasis.Thromb Hemost. 2002; 88: 155-6Crossref PubMed Scopus (0) Google Scholar]. How can we move forward? Extrapolation from the large experience in adults is problematic because the situation in children (especially newborns) is quite different and, in addition, experts in adult thromboembolic events are divided into ‘screenists’ and ‘nihilists’[18Baglin T. Greaves M. Rebuttal: is a nihilistic approach to thrombophilia screening justified?.Thromb Haemost. 2002; 88: 700-1Crossref PubMed Scopus (11) Google Scholar, 20Hunt B.J. Shannon M. Bevan D. Murday V. Is a nihilistic attitude to thrombophilia screening justified?.Thromb Haemost. 2002; 87: 918Crossref PubMed Scopus (7) Google Scholar]. The ritual plea for further research on more patients is appropriate but cannot deliver a speedy solution. Huge difficulties exist in recruiting a sufficient number of children with VTEs and coordinating and performing the study as outlined by Massicotte [21Massicotte M.P. Low-molecular-weight heparin therapy in children.J Pediatr Hematol Oncol. 2001; 23: 189-94Crossref PubMed Scopus (0) Google Scholar]. On the other hand, we need reliable information in this age group in order to minimize the damage of affected individuals [14Richardson M.W. Allen G.A. Monahan P.E. Thrombosis in children: current perspective and distinct challenges.Thromb Haemost. 2002; 88: 900-11Crossref PubMed Google Scholar, 15Monagle P, Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest; 119 (Suppl. 1): 344S–70S.Google Scholar, 22Marzinotto A. Choi M. Massicotte P. Chan A.K. Andrew M. Post-thrombotic syndrome in children with previous deep vein thrombosis.Thromb Haemost. 2001; : POC962Google Scholar]. While awaiting the guidance of new data, we should make the very best of the limited information already available to us. Rather than making conflicting recommendations, it would be more helpful if representatives of national thrombophilia registries were to meet and share their precious data on all known children with thrombotic disorders. Re-evaluation of risk factors other than thrombophilic proteins (columns 1 and 2, Table 1) and of the prognostic value of hypercoagulation markers [17Mannucci P.M. The measurement of multifactorial thrombosis.Thromb Haemost. 2002; 88: 1-2Crossref PubMed Google Scholar, 23Prins M.H. Marchiori A. Risk of recurrent venous thromboembolism: expanding the frontier.Thromb Haemost. 2002; 87: 1-3Crossref PubMed Scopus (18) Google Scholar, column 3, Table 1], might help us to move on from the rigidity of current guidelines regarding duration of anticoagulation (which vary widely from 3 months to several years) to more rational schemes. These might be tailored to the individual to give appropriate prophylaxis whilst limiting side effects such as bleeding, osteoporosis, heparin-induced thrombophilia, and, lest it be forgotten, the trauma of repeated venepunctures [21Massicotte M.P. Low-molecular-weight heparin therapy in children.J Pediatr Hematol Oncol. 2001; 23: 189-94Crossref PubMed Scopus (0) Google Scholar, 24Severin T. Sutor A.H. Heparin-induced thrombocytopenia in pediatrics.Sem Thromb Hemostas. 2001; 27: 293-300Crossref PubMed Scopus (0) Google Scholar]. Collaboration with obstetricians is necessary because of the strong association between pre-eclampsia, prothrombotic disorders, and neonatal venous sinus thrombosis and the interaction of maternal and fetal prothrombotic risk factors contributing to prenatal conditions as listed in Table 1[25Hunt R.W. Badawi N. Laing S. Lam A. Pre-eclampsia: a predisposing factor for neonatal venous sinus thrombosis?.Pediatr Neurol. 2001; 25: 242-6Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 26Von Kries R. Junker R. Oberle D. Kosch A. Nowak-Göttl U. Foetal growth restriction in children with prothrombotic risk factors.Thromb Haemost. 2001; 86: 1012-6Crossref PubMed Google Scholar]. Another challenge is to study in kidney transplant recipients the role of genetic thrombophilic protein in delayed graft function, acute rejection and long-term graft dysfunction [27Hocher B. Slowinski T. Hauser I. Vetter B. Fritschel L. Bachert D. Kulozik A. Neumayer H.H. Association of factor V Leiden mutation with delayed graft function, acute rejection episodes and long-term graft dysfunction in kidney transplant recipients.Thromb Haemost. 2002; 87: 194-8Crossref PubMed Scopus (41) Google Scholar]. In seeking to prevent childhood thrombotic events, it is essential to address the risk of CVLs, which account for most events in neonates and infants [2Van Ommen C.H. Heijboer H. Buller H.R. Hirasing R.A. Heijmans H.S. Peters M. Venous thromboembolism in childhood: a prospective two-year registry in the Netherlands.J Pediatr. 2001; 139: 676-81Abstract Full Text Full Text PDF PubMed Scopus (524) Google Scholar, 3Revel-Vilk S. Chan A. Bauman M. Massicotte P. Prothrombotic conditions in an unselected cohort of children with venous thromboembolic disease.J Thromb Haemost. 2003; 1: 915-21Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 15Monagle P, Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest; 119 (Suppl. 1): 344S–70S.Google Scholar, 21Massicotte M.P. Low-molecular-weight heparin therapy in children.J Pediatr Hematol Oncol. 2001; 23: 189-94Crossref PubMed Scopus (0) Google Scholar]. Besides applying strict indications for CVL use, the search for thrombophobic material for their manufacture (and that of stents and cardiac valves) must continue and put into practice, since they may prevent not only thromboembolic events but infections as well [28Herrmann R. Schmidmaier G. Merkl B. Resch A. Hahnel I. Stemberger A. Alt E. Antithrombogenic coating of stents using a biodegradable drug delivery technology.Thromb Haemost. 1999; 82: 51-7Crossref PubMed Scopus (55) Google Scholar, 29Pierce C.M. Wade A. Mock Q. Heparin-bonded central venous lines reduce thrombotic and infective complications in critically ill children.Intensive Care Medical. 2000; 26: 927-72Crossref Scopus (163) Google Scholar].