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Thromb Haemost 2002; 87(04): 606-613
DOI: 10.1055/s-0037-1613056
Review Article
Schattauer GmbH

Decreased Concentrations of Heparinoids Are Required to Inhibit Thrombin Generation in Plasma from Newborns and Children Compared to Plasma from Adults due to Reduced Thrombin Potential

Anthony K. C. Chan
1   Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada, and McMaster University, Hamilton, Ontario, Canada
,
Leslie R. Berry
1   Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada, and McMaster University, Hamilton, Ontario, Canada
,
Paul T. Monagle
1   Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada, and McMaster University, Hamilton, Ontario, Canada
,
Maureen Andrew
1   Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada, and McMaster University, Hamilton, Ontario, Canada
› InstitutsangabenThis work was supported by project 4 from the Canadian Institutes of Health Research group in developmental lung biology.
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Publikationsverlauf

Received 03. Oktober 2001

Accepted after reversion 14. Dezember 2001

Publikationsdatum:
08. Dezember 2017 (online)

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Summary

Thrombin generation is decreased and delayed in plasma from newborns and children compared to adults. We hypothesized that lower doses of heparinoid anticoagulants are required to give similar thrombin generation in newborn (umbilical cord) and child plasmas compared to that of adults. Thrombin generation was performed in either the absence or presence of unfractionated heparin (UFH), low molecular weight heparin (LMWH) or a covalent antithrombin-heparin complex (ATH). After contact activation and recalcification of each plasma, thrombin activity was measured by periodic sub-sampling into chromogenic substrate. UFH inhibited thrombin generation to a greater extent compared to LMWH in all plasmas. Cord plasma was more sensitive to inhibition and displayed a greater difference in the effectiveness of UFH compared to LMWH than other plasmas. Lower concentrations of UFH and LMWH were required to inhibit thrombin generation in cord and child plasmas compared to adult plasma. In comparison, ATH strongly inhibited thrombin generation in all 3 plasmas. Similar peak thrombin concentrations were observed at lower ATH concentrations (0.1 U/mL) compared to either UFH (0.25 U/mL) or LMWH (0.25 U/mL). As with UFH and LMWH, cord plasma was more sensitive to inhibition by ATH than the other plasmas and lower ATH concentrations inhibited thrombin generation in cord and child plasmas compared to adult plasma. Decreased thrombin generation with heparinoids in cord and child plasmas compared to adult plasma coincided with decreased rates of prothrombin consumption and increased proportion of thrombin- α2-macroglobulin inhibitor complexes. In summary, lower doses of UFH, LMWH or ATH result in similar peak thrombin generation in newborn and child plasmas compared to adult plasma. Cord plasma was the most sensitive to inhibition, with ATH being more effective than UFH or LMWH.

Keywords

Heparin - thrombin - anticoagulant - newborn - plasma
 

  • References

  • 1 Andrew M, Michelson AD, Bovill T, Leaker M, Massicotte MP, Marzinotto V, Brooker LA. The prevention and treatment of thrombembolic disease in children: A need for thrombophilia programs. J Pediatr Hematol/Oncol 1997; 19: 7-22.
    CrossrefPubMedGoogle Scholar
  • 2 Andrew M, Massicotte MP, deVeber G, Leaker M, David M, Brown A, Adams M, Chan AKC. 1997. 1-800-NO-CLOTS: A quaternary care solution to a new tertiary care disease: Childhood thrombophilia. Thromb Haemost 1997; 77 (Suppl.) 727.
    PubMedGoogle Scholar
  • 3 Dix D, Andrew M, Marzinotto V, Charpentier K, Bridge S, Monagle P, deVeber 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.
    CrossrefPubMedGoogle Scholar
  • 4 Michelson AD, Bovill E, Monagle P, Andrew M. Antithrombotic therapy in children. Chest 1998; 114: 748S-69S.
    CrossrefPubMedGoogle Scholar
  • 5 Randolph AG, Cook DJ, Gonzalez CA, Andrew M. Benefit of heparin in peripheral venous and arterial catheters: Systematic review and metaanalysis of randomized controlled trials. BMJ 1998; 316: 969-75.
    CrossrefPubMedGoogle Scholar
  • 6 Andrew M, Michelson AD, Bovill E, Leaker M, Massicotte MP. Guidelines for antithrombotic therapy in pediatric patients. J Pediatr 1998; 132: 575-88.
    CrossrefPubMedGoogle Scholar
  • 7 Marzinotto V, Leaker M, Massicotte MP, Andrew M. Childhood thrombophilia programs: An approach to the prevention and treatment of thromboembolic disease in pediatric patients. In: Managing Oral Anticoagulation. Ansell JE, Oertel LB, Wittkowsky AK. eds. Gaithersburg: Aspen Publishers Inc; 1996: 1-22.
    Google Scholar
  • 8 Streif W, Andrew M, Marzinotto V, Massicotte MP, Julian J, Mitchell L. Analysis of warfarin therapy in pediatric patients: A prospective cohort study of 319 patients. Blood 1999; 94: 3007-14.
    CrossrefPubMedGoogle Scholar
  • 9 Massicotte P, Brooker L, Marzinotto V, Andrew M. Oral Anticoagulation Therapy in Children. In: Oral Anticoagulants. Hirsh J, Poller L. eds. London: Edwards Arnold (Hodder & Stoughton); 1996: 216-27.
    Google Scholar
  • 10 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, Silva 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: 763-6.
    CrossrefPubMedGoogle Scholar
  • 11 Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood 1992; 80: 1998-2005.
    PubMedGoogle Scholar
  • 12 Chan AK, Leaker M, Burrows FA, Williams WG, Gruenwald CE, Whyte L, Adams M, Brooker LA, Adams H, Mitchell L, Andrew M. Coagulation and fibrinolytic profile of paediatric patients undergoing cardiopulmonary bypass. Thromb Haemost 1997; 77: 270-7.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 13 Manco-Johnson M. Disorders of hemostasis in childhood: risk factors for venous thromboembolism. Thromb Haemost 1997; 78: 710-4.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 14 David M, Manco-Johnson M, Andrew M. Diagnosis and treatment of venous thromboembolism in children and adolescents. On behalf of the Subcommittee on Perinatal Haemostasis of the Scientific and Standardization Committee of the ISTH. Thromb Haemost 1995; 74: 791-2.
    PubMedGoogle Scholar
  • 15 Xu L, Delorme M, Berry L, Ofosu F, Mitchell L, Paes B, Andrew M. Alpha-2-macroglobulin remains as important as antithrombin III for thrombin regulation in cord plasma in the presence of endothelial cell surfaces. Pediatr Res 1995; 37: 373-8.
    CrossrefPubMedGoogle Scholar
  • 16 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.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 17 Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, Castle V, Powers P. Development of the human coagulation system in the healthy premature infant. Blood 1988; 72: 1651-7.
    PubMedGoogle Scholar
  • 18 Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, Powers P. Development of the human coagulation system in the full-term infant. Blood 1987; 70: 165-72.
    PubMedGoogle Scholar
  • 19 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.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 20 Schmidt B, Mitchell L, Ofosu F, Andrew M. Alpha-2-macroglobulin is an important progressive inhibitor of thrombin in neonatal and infant plasma. Thromb Haemost 1989; 62: 1074-7.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 21 Mitchell L, Piovella F, Ofosu F, Andrew M. Alpha-2-macroglobulin may provide protection from thromboembolic events in antithrombin III deficient children. Blood 1991; 78: 2299-304.
    PubMedGoogle Scholar
  • 22 Johnston M, Zipursky A. Microtechnology for the study of the blood coagulation system in newborn infants. Can J Med Tech 1980; 42: 159-64.
    PubMedGoogle Scholar
  • 23 Schmidt B, Ofosu FA, Mitchell L, Brooker LA, Andrew M. Anticoagulant effects of heparin in neonatal plasma. Pediatr Res 1989; 25: 405-8.
    CrossrefPubMedGoogle Scholar
  • 24 Berry L, Andrew M, Post M, Ofosu F, O’Brodovich H. A549 lung epithelial cell line synthesize anticoagulant molecules on the cell surface, matrix, and in conditioned media. Am J Resp Cell Mol Biol 1991; 04: 338-46.
    CrossrefPubMedGoogle Scholar
  • 25 Chan AK, Berry L, O’Brodovich H, Klement P, Mitchell M, Baranowski B, Monagle P, Andrew M. Covalent antithrombin-heparin complexes with high anticoagulant activity: Intravenous, subcutaneous and intratracheal administration. J Biol Chem 1997; 272: 22111-7.
    CrossrefPubMedGoogle Scholar
  • 26 Colman RW, Marder VJ, Salzman EW, Hirsh J. Overview of hemostasis. In: Hemostasis and Thrombosis Principles and Clinical Practice. Colman R, Hirsh J, Marder V, Salzman E. eds. Philadelphia: JB Lippincott Company; 1987: 3-8.
    Google Scholar
  • 27 Ofosu FA, Sie P, Modi GJ, Fernandez F, Buchanan MR, Blajchman MA, Boneu B, Hirsh J. The inhibition of thrombin-dependent positive-feedback reactions is critical to the expression of the anticoagulant effect of heparin. Biochem J 1987; 243: 579-88.
    CrossrefPubMedGoogle Scholar
  • 28 Ofosu FA, Hirsh J, Esmon CT, Modi GJ, Smith LM, Anvari N, Buchanan MR, Fenton JW, Blajchman MA. Unfractionated heparin inhibits thrombincatalysed amplification reactions of coagulation more efficiently than those catalysed by factor Xa. Biochem J 1989; 257: 143-50.
    CrossrefPubMedGoogle Scholar
  • 29 Ofosu FA, Fenton JW, Maraganore J, Blajchman MA, Yang X, Smith LM, Anvari N, Buchanan MR, Hirsh J. Inhibition of the amplification reactions of blood coagulation by site-specific inhibitors of alpha-thrombin. Biochem J 1992; 283: 893-7.
    CrossrefPubMedGoogle Scholar
  • 30 Blombäck B, Blombäck M. The molecular structure of fibrinogen. Ann NY Acad Sci 1972; 202: 77-97.
    CrossrefPubMedGoogle Scholar
  • 31 Harmon JT, Jamieson GA. Platelet activation by α-thrombin is a receptormediated event. In: Bioregulatory Functions of Thrombin. Walz D, Fenton J, Shuman M. eds. New York: The New York Academy of Sciences; 1986: 387-95.
    Google Scholar
  • 32 Michelson AD. Platelet activation by thrombin can be directly measured in whole blood through the use of the peptide GPRP and flow cytometry: methods and clinical applications. Blood Coag Fibrinol 1994; 05: 121-31.
    CrossrefPubMedGoogle Scholar
  • 33 Martinuzzo ME, Maclouf J, Carreras LO, Levy-Toledano S. Antiphospholipid antibodies enhance thrombin-induced platelet activation and thromboxane formation. Thromb Haemost 1993; 70: 667-71.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 34 Puri RN. Phospholipase A2: its role in ADP- and thrombin-induced platelet activation mechanisms. Int J Biochem Cell Biol 1998; 30: 1107-22.
    CrossrefPubMedGoogle Scholar
  • 35 Rao LV, Ezban M. Active site-blocked activated factor VII as an effective antithrombotic agent: mechanism of action. Blood Coag Fibrinol 2000; 11: S135-S143.
    CrossrefPubMedGoogle Scholar
  • 36 Vietti TJ, Murphy TP, James JA, Pritchard JA. Observation on the prophylactic use of vitamin K in the newborn. J Pediatr 1960; 56: 343-6.
    CrossrefPubMedGoogle Scholar
  • 37 Oliver JA, Monroe DM, Roberts HR, Hoffman M. Thrombin activates factor XI on activated platelets in the absence of factor XII. Arterioscler Thromb Vasc Biol 1999; 19: 170-7.
    CrossrefPubMedGoogle Scholar
  • 38 Vieira A, Berry L, Ofosu F, Andrew M. Heparin sensitivity and resistance in the neonate: an explanation. Thromb Res 1991; 63: 85-98.
    CrossrefPubMedGoogle Scholar
  • 39 Shah JK, Mitchell LG, Paes B, Ofosu FA, Schmidt B, Andrew M. Thrombin inhibition is impaired in plasma of sick neonates. Pediatr Res 1992; 31: 391-5.
    CrossrefPubMedGoogle Scholar
  • 40 Hoylaerts M, Owen WG, Collen D. Involvement of heparin chain length in the heparin catalyzed inhibition of thrombin by antithrombin III. J Biol Chem 1984; 259: 5670-7.
    PubMedGoogle Scholar
  • 41 Massicotte P, Marzinotto V, Adams M, Vegh P, Brooker L, Andrew M. Enhanced thrombin regulation during warfarin therapy in children compared to adults. Thromb Haemost 1998; 80: 570-4.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 42 Berry L, Stafford A, Fredenburgh J, O’Brodovich H, Mitchell L, Weitz J, Andrew M, Chan AK. Investigation of the anticoagulant mechanisms of a covalent antithrombin-heparin complex. J Biol Chem 1998; 273: 34730-6.
    CrossrefPubMedGoogle Scholar
  • 43 Streif W, Monagle P, South M, Leaker M, Andrew M. Spontaneous arterial thrombosis in children. J Pediatr 1999; 134: 110-2.
    CrossrefPubMedGoogle Scholar
  • 44 Schmidt B, Andrew M. Neonatal thrombotic disease: prevention, diagnosis and therapy. J Pediatr 1988; 113: 407-10.
    CrossrefPubMedGoogle Scholar
  • 45 Xu L, Delorme M, Berry L, Ofosu F, Mitchell L, Paes B, Andrew M. Alpha-2-macroglobulin remains as important as ATIII for thrombin regulation in cord plasma in the presence of endothelial cell surfaces. Pediatr Res 1995; 37: 1-6.
    CrossrefPubMedGoogle Scholar
  • 46 Andrew M, Berry L, O’Brodovich H. Thrombin inhibition by fetal distal lung epithelium is different in fetal and adult plasma. Am J Resp Cell Mol Biol 1994; 11: 35-41.
    CrossrefPubMedGoogle Scholar
  • 47 Weitz JI. Low molecular weight heparins. N Engl J Med 1997; 337: 688-98.
    CrossrefPubMedGoogle Scholar
  • 48 Kuijer PMM, Prins MH, Buller HR. Low molecular weight heparins: treatment of venous thromboembolism. In: Advances in therapeutic agents in thrombosis and thrombolysis. Sashara AA, Loscalzo J. eds. New York: M Dekker; 1997: 129-47.
    Google Scholar
  • 49 Jeske W, Lojewski B, Walenga JM, Hoppensteadt D, Ahsan A, Fareed J. Biochemical and pharmacological profile of low molecular weight heparin (LU 47311, Clivarin). Sem Thromb Hemostas 1993; 19: 229-40.
    PubMedGoogle Scholar