PDF herunterladen
Semin Thromb Hemost 2003; 29(4): 349-362
DOI: 10.1055/s-2003-42586
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Protein C Pathway in Infants and Children

Jari Petäjä1 , Marilyn J. Manco-Johnson2
  • 1Head of Neonatology Section Department of Pediatrics Helsinki University Central Hospital Jorvi Hospital Helsinki Finland
  • 2University of Colorado Health Sciences Center, The Children's Hospital, Denver, Colorado
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
30. September 2003 (online)

    Lizenzen und Reprints

ABSTRACT

The protein C pathway comprises a major physiological anticoagulant system. Its major congenital defects, heterozygous deficiencies of protein C and protein S as well as activated protein C resistance due to G1691A mutated factor V (Factor V Leiden), are associated with pediatric venous thromboembolic disease. The protein C pathway is centrally involved in the control of both coagulation and inflammation during sepsis and other inflammatory conditions presenting with disseminated intravascular coagulation. This article reviews the physiology of the protein C pathway with special emphasis on pediatric aspects. Clinical implications of the protein C pathway defects in pediatric venous thromboembolism as well as acquired disturbances of protein C pathway during sepsis are discussed.

KEYWORDS

Protein C - protein S - factor V Leiden - children - newborn infant - venous thrombosis - sepsis

REFERENCES

  • 1 Andrew M, David M, Adams M. et al . Venous thromboembolic complications (VTE) in children: first analyses of the Canadian registry of VTE.  Blood . 1994;  83 1251-1257
    CrossrefPubMedGoogle Scholar
  • 2 Clouse L H, Comp P C. The regulation of hemostasis: the protein C system.  N Engl J Med . 1986;  314 1298-1304
    PubMedGoogle Scholar
  • 3 Griffin J H, Evatt B, Zimmerman T S, Kleiss A J, Wideman C. Deficiency of protein C in congenital thrombotic disease.  J Clin Invest . 1981;  68 1370-1373
    CrossrefPubMedGoogle Scholar
  • 4 Seligsohn U, Berger A, Abead M. et al . Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn.  N Engl J Med . 1984;  310 559-562
    PubMedGoogle Scholar
  • 5 Dreyfus M, Masterson M, David M. et al . Replacement therapy with a monoclonal antibody purified protein C concentrate in newborns with severe congenital protein C deficiency.  Semin Thromb Hemost . 1995;  21 371-381
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 6 Esmon C T. Protein C anticoagulant pathway and its role in controlling microvascular thrombosis and inflammation.  Crit Care Med . 2001;  29(Suppl) S48-51
    PubMedGoogle Scholar
  • 7 Esmon C T, Fletcher Jr T B, Snow T R. Inflammation and coagulation: linked processes potentially regulated through a common pathway mediated by protein C.  Thromb Haemost . 1991;  66 160-165
    PubMedGoogle Scholar
  • 8 Bernard G R, Vincent J L, Laterre P F. et al . Efficacy and safety of recombinant human activated protein C for severe sepsis.  N Engl J Med . 2001;  344 699-709
    CrossrefPubMedGoogle Scholar
  • 9 Giroir B P. Recombinant human activated protein C for the treatment of severe sepsis: is there a role in pediatrics?.  Curr Opin Pediatr . 2003;  15 92-96
    CrossrefPubMedGoogle Scholar
  • 10 Manco-Johnson M J, Knapp-Clevenger R. Recombinant activated protein C (dotrecogin) is effective for purpura fulminans secondary to severe genetic protein C deficiency (in press).  J Pediatr Hematol Oncol. 2003; 
    PubMedGoogle Scholar
  • 11 Schwarz H P, Fischer M, Hopmeier P, Batard M A, Griffin J H. Plasma protein S deficiency in familial thrombotic disease.  Blood . 1984;  64 1297-1300
    PubMedGoogle Scholar
  • 12 Marlar R A, Hassel K L. Protein C and protein S deficiencies. In: Schafer AI, ed. Molecular Mechanisms of Hypercoagulable States New York: RG Landes Co 1997: 79-100
    Google Scholar
  • 13 Esmon C T, Esmon N L. Protein C activation.  Semin Thromb Hemost . 1984;  10 122-130
    PubMedGoogle Scholar
  • 14 Broze G J, Miletich J P. Biochemistry and physiology of protein C, protein S, and thrombomodulin. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice; 3rd ed Philadelphia, PA: JB Lippincott 1994: 259-276
    Google Scholar
  • 15 Comp P C, Esmon C T. Generation of fibrinolytic activity by infusion of activated protein C into dogs.  J Clin Invest . 1981;  68 1221-1228
    PubMedGoogle Scholar
  • 16 Sakata Y, Loskutoff D J, Gladson C L, Hekman C M, Griffin J H. Mechanism of protein C-dependent clot-lysis.  Role of plasminogen activator inhibitor. Blood . 1986;  68 1218-1223
    PubMedGoogle Scholar
  • 17 Hanson S R, Griffin J H, Harker L A. et al . Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates.  J Clin Invest . 1993;  92 2003-2012
    PubMedGoogle Scholar
  • 18 Gruber A, Griffin J H. Direct detection of activated protein C in blood from human subjects.  Blood . 1992;  79 2340-2348
    PubMedGoogle Scholar
  • 19 Ilmakunnas M, Petäjä J, Fernández J A. et al . Activation of antithrombotic and anti-inflammatory protein C during reperfusion in clinical liver transplantation.  Transplantation . 2003;  75 467-472
    PubMedGoogle Scholar
  • 20 Heeb M J, Espana F, Griffin J H. Inhibition of and complexation of activated protein C by two major inhibitors in plasma.  Blood . 1989;  73 446-454
    PubMedGoogle Scholar
  • 21 Heeb M J, Gruber A, Griffin J H. Identification of divalent metal ion-dependent inhibition of activated protein C by α2-macroglobulin and α2-antiplasmin in blood and comparison to inhibition of factor Xa, thrombin, and plasmin.  J Biol Chem . 1991;  266 17606-17612
    PubMedGoogle Scholar
  • 22 Fair D S, Revak D J. Quantitation of human protein S in the plasma of normal and warfarin-treated individuals by radioimmunoassay.  Thromb Res . 1984;  36 527-535
    CrossrefPubMedGoogle Scholar
  • 23 Dahlbäck B. Interaction between vitamin K-dependent protein S and the complement component protein, C4b-binding protein. A link between blood coagulation and the complement system.  Semin Thromb Hemost . 1984;  10 139-148
    PubMedGoogle Scholar
  • 24 Walker F. Regulation of activated protein C by protein S. The role of phospholipids in factor Va inactivation.  J Biol Chem . 1981;  256 111-131
    PubMedGoogle Scholar
  • 25 Heeb M J, Mesters R M, Tans G, Rosing J, Griffin J H. Binding of protein S to factor Va associated with inhibition of prothrombinase that is independent of activated protein C.  J Biol Chem . 1993;  268 2872-2877
    PubMedGoogle Scholar
  • 26 Hackeng T M, van't Veer C, Meijers J C, Bouma B N. Human protein S inhibits prothrombinase complex activity on endothelial cells and platelets via direct interactions with factors Va and Xa.  J Biol Chem . 1994;  269 21051-21058
    PubMedGoogle Scholar
  • 27 Salem H H, Esmon N L, Esmon C T, Majerus P W. Effects of thrombomodulin and coagulation factor Va-light chain on protein C activation in vitro.  J Clin Invest . 1984;  73 968-972
    PubMedGoogle Scholar
  • 28 Dahlbäck B. The protein C anticoagulant system: inherited defects as basis for venous thrombosis.  Thromb Res . 1995;  77 1-43
    CrossrefPubMedGoogle Scholar
  • 29 Nicolaes G AF, Dahlbäck B. Factor V and thrombotic disease: description of a Janus-faced protein.  Arterioscler Thromb Vasc Biol . 2002;  22 530-538
    CrossrefPubMedGoogle Scholar
  • 30 Esmon C T, Xu J, Gu J. et al . Endothelial protein C receptor.  Thromb Haemost . 1999;  82 251-258
    PubMedGoogle Scholar
  • 31 Taylor Jr B F, Peer G T, Lockhart M S, Ferrell G, Esmon C T. Endothelial cell protein C receptor plays an important role in protein C activation in vivo.  Blood . 2001;  97 1685-1688
    CrossrefPubMedGoogle Scholar
  • 32 Laszik Z, Mitro A, Taylor Jr B F. et al . Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway.  Circulation . 1997;  96 3633-3640
    CrossrefPubMedGoogle Scholar
  • 33 Szaba F M, Smiley S T. Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo.  Blood . 2002;  99 1053-1059
    CrossrefPubMedGoogle Scholar
  • 34 Esmon C T. Role of coagulation inhibitors in inflammation.  Thromb Haemost . 2001;  86 51-56
    PubMedGoogle Scholar
  • 35 Yang J, Furie B C, Furie B. The biology of P-selectin glycoprotein ligand-1: its role as a selectin counterreceptor in leukocyte-endothelial and leukocyte-platelet interaction.  Thromb Haemost . 1999;  81 1-7
    PubMedGoogle Scholar
  • 36 Esmon C T. Are natural anticoagulants candidates for modulating the inflammatory response to endotoxin?.  Blood . 2000;  95 1113-1116
    PubMedGoogle Scholar
  • 37 Warr T A, Rao V M, Rapaport S I. Disseminated intravascular coagulation in rabbits induced by administration of endotoxin or tissue factor: effect of anti-tissue factor antibodies and measurement of plasma extrinsic pathway inhibitor activity.  Blood . 1990;  75 1481-1489
    PubMedGoogle Scholar
  • 38 Petäjä J, Pesonen E, Fernández J A. et al . Activated protein C and inflammation in human myocardium after heart surgery.  Am J Hematol . 2001;  67 210-212
    CrossrefPubMedGoogle Scholar
  • 39 White B, Schmidt M, Murphy C. et al . Activated protein C inhibits lipopolysaccharide-induced nuclear translocation of nuclear factor κB(nF-κB) and tumor necrosis factor α (TNFα) production in the THP-1 monocytic cell line.  Br J Haematol . 2000;  110 130-134
    CrossrefPubMedGoogle Scholar
  • 40 Grey S T, Tsuchida A, Hau H, Orthner C L, Salemn H H, Hancock W W. Selective inhibitory effects of the anticoagulant activated protein C on the reponse of human mononuclear phagocytes to LPS, IFN-gamma, or phorbol ester.  J Immunol . 1994;  153 3664-3672
    PubMedGoogle Scholar
  • 41 Shu F, Kobayashi H, Fukudome K, Tsuneyoshi N, Kimoto M, Terao T. Activated protein C suppresses tissue factor expression on U937 cells in the endothelial protein C receptor-dependent manner.  FEBS Lett . 2000;  477 208-212
    CrossrefPubMedGoogle Scholar
  • 42 Andrew M. Developmental hemostasis: relevance to thromboembolic complications in pediatric patients.  Thromb Haemost . 1995;  74 415-425
    PubMedGoogle Scholar
  • 43 Reverdiau-Moalic P, Delahousse B, Body G, Bardos P, Leroy J, Gruel Y. Evolution of blood coagulation activators and inhibitors in the healthy human fetus.  Blood . 1996;  88 900-906
    PubMedGoogle Scholar
  • 44 Andrew M. Hemorrhagic and thrombotic complications in children. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice; 3rd ed Philadelphia, PA: JB Lippincott 1994: 989-1022
    Google Scholar
  • 45 Andrew M, Schmidt B, Mitchell L, Paes B, Ofosu F. Thrombin generation in newborn is critically dependent on the concentration of prothrombin.  Thromb Haemost . 1990;  63 27-30
    PubMedGoogle Scholar
  • 46 Schmidt B, Ofosu F A, Mitchell L, Brooker L A, Andrew M. Anticoagulant effects of heparin in neonatal plasma.  Pediatr Res . 1989;  25 405-408
    PubMedGoogle Scholar
  • 47 Andrew M, Paes J, Johnston M. Development of the hemostatic system in the neonate and young infant.  Am J Pediatr Hematol Oncol . 1990;  12 95-104
    CrossrefPubMedGoogle Scholar
  • 48 Cvirn G, Gallistl S, Muntean W. Effects of antithrombin and protein C on thrombin generation in newborn and adult plasma.  Thromb Res . 1999;  93 183-190
    CrossrefPubMedGoogle Scholar
  • 49 Butenas S, Gissel M T, Mann K G. Tissue factor-initiated thrombin generation in the newborn (Abst).  Blood . 2002;  100 488a
    PubMedGoogle Scholar
  • 50 Cvirn G, Gallisti S, Leschnik B, Muntean W. Low tissue factor pathway inhibitor (TFPI) together with low antithrombin allows sufficient thrombin generation in neonates.  J Thromb Haemost . 2003;  1 263-268
    CrossrefPubMedGoogle Scholar
  • 51 Karpatkin M, Mannucci P M, Bhogal M, Vigano S, Nardi M. Low protein C in the neonatal period.  Br J Haematol . 1986;  62 137-142
    PubMedGoogle Scholar
  • 52 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
  • 53 Fernández J A, Estelles A, Gilabert J, Espana F, Aznar J. Functional and immunologic protein S in normal pregnant women and in full-term newborns.  Thromb Haemost . 1989;  61 474-478
    PubMedGoogle Scholar
  • 54 Melissari E, Nicolaides K H, Scully M F, Kakkar V V. Protein S and C4b-binding protein in fetal and neonatal blood.  Br J Haematol . 1988;  70 199-203
    PubMedGoogle Scholar
  • 55 Nardi M, Karpatkin M. Prothrombin and protein C in early childhood: normal adult levels are not achieved until the fourth year of life.  J Pediatr . 1986;  109 843-845
    PubMedGoogle Scholar
  • 56 Schmidt B, Mitchell L, Ofosu F, Andrew M. Alpha2-macroglobulin is an important progressive inhibitor of thrombin in neonatal and infant plasma.  Thromb Haemost . 1989;  62 1074-1077
    PubMedGoogle Scholar
  • 57 Schmidt B, Gillie P, Mitchell L, Andrew M, Caco C, Roberts R. A placebo-controlled randomized trial of antithrombin therapy in neonatal respiratory distress syndrome.  Am J Respir Crit Care Med . 1998;  158 470-476
    CrossrefPubMedGoogle Scholar
  • 58 Greffe B S, Marlar R A, Manco-Johnson M. Neonatal protein C: molecular composition and distribution in normal term infants.  Thromb Res . 1989;  56 91-98
    CrossrefPubMedGoogle Scholar
  • 59 Manco-Johnson M, Spedale S, Peters M. et al . Identification of a unique form of protein C in the ovine fetus: developmentally linked transition to the adult form.  Pediatr Res . 1995;  37 365-372
    CrossrefPubMedGoogle Scholar
  • 60 Fernández J A, Hackeng T M, Kojima K, Griffin J H. The carbohydrate moiety of factor V modulates inactivation by activated protein C.  Blood . 1997;  89 4348-4354
    PubMedGoogle Scholar
  • 61 Petäjä J, Fernández J A, Fellman V, Griffin J H. Upregulation of the antithrombotic protein C pathway at birth.  Pediatr Hematol Oncol . 1998;  15 489-499
    PubMedGoogle Scholar
  • 62 Fernández J A, Espana F, Gilabert J. et al . Decreased levels of protein C inhibitor during pregnancy and puerperium.  Rev Iberoamer Tromb Hemost . 1991;  4 189-192
    PubMedGoogle Scholar
  • 63 Malm J, Bennhagen R, Holmberg L, Dahlbäck B. Plasma concentrations of C4b-binding protein and vitamin K-dependent protein S in term and preterm infants: low levels of protein S-C4b-binding protein complexes.  Br J Haematol . 1988;  68 445-449
    PubMedGoogle Scholar
  • 64 Takano S, Kimura S, Ohodama S. et al . Plasma thrombomodulin in health and disease.  Blood . 1990;  79 837-838
    PubMedGoogle Scholar
  • 65 Menashi S, Aurousseau M H, Gozin D. et al . High levels of circulating thrombomodulin in human foetuses and children.  Thromb Haemost . 1999;  81 906-909
    PubMedGoogle Scholar
  • 66 Knöfler R, Hofmann S, Weissbach G. et al . Molecular markers of the endothelium, the coagulation and the fibrinolytic systems in healthy newborns.  Semin Thromb Hemost . 1998;  24 453-461
    PubMedGoogle Scholar
  • 67 Boldt J, Knothe C, Schindler E. et al . Thrombomodulin in pediatric cardiac surgery.  Ann Thorac Surg . 1994;  57 1584-1589
    PubMedGoogle Scholar
  • 68 Healy A M, Rayburn H B, Rosenberg R D, Weiler H. Absence of the blood-clotting regulator thrombomodulin causes embryonic lethality in mice before development of a functional cardiovascular system.  Proc Natl Acad Sci USA . 1995;  92 850-854
    PubMedGoogle Scholar
  • 69 Weiler-Guettler H, Christie P D, Beeler D L. et al . A targeted point mutation in thrombomodulin generates viable mice with a prothrombotic state.  J Clin Invest . 1998;  101 1983-1991
    CrossrefPubMedGoogle Scholar
  • 70 Petäjä J, Pesonen E, Fernández J A, Vento A, Rämö O J, Griffin J H. Cardiopulmonary bypass and activation of antithrombotic plasma protein C.  J Thorac Cardiovasc Surg . 1999;  118 422-431
    PubMedGoogle Scholar
  • 71 Manco-Johnson M, Abshire T C, Jacobson L J. et al . Severe neonatal protein C deficiency: prevalence and thrombotic risk.  J Pediatr . 1991;  119 793-798
    PubMedGoogle Scholar
  • 72 Branson H E, Marble R, Katz J, Griffin J H. Inherited protein C deficiency and coumarin-responsive chronic relapsing purpura fulminans in a newborn.  Lancet . 1983;  2 1165-1168
    PubMedGoogle Scholar
  • 73 Marlar R, Montgomery R, Broekmans A W, and the Working Party. Diagnosis and treatment of homozygous protein C deficiency: report of the Working Party on Homozygous Protein C and Protein S Deficiency, International Committee on Thrombosis and Haemostasis.  J Pediatr . 1989;  114 528-534
    PubMedGoogle Scholar
  • 74 Mahasandana C, Suvatte V, Chuansumrit A. et al . Homozygous protein S deficiency in an infant with purpura fulminans.  J Pediatr . 1990;  117 750-753
    CrossrefPubMedGoogle Scholar
  • 75 Marlar R A, Neumann A. Neonatal purpura fulminans due to homozygous protein C or protein S deficiencies.  Semin Thromb Hemost . 1990;  16 299-309
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 76 Pipe S W, Schmaier A H, Nichols W C, Ginsburg D, Bozynski M, Castle V. Neonatal purpura fulminans in association with factor V R506Q mutation.  J Pediatr . 1996;  128 706-709
    PubMedGoogle Scholar
  • 77 Adcock D M, Brozna J, Marlar R A. Proposed classification and pathologic mechanisms of purpura fulminans and skin necrosis.  Semin Thromb Hemost . 1990;  16 333-340
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 78 Hartman K, Manco-Johnson M J, Rawlings J S, Bowen D R, Marlar R A. Homozygous protein C deficiency: early treatment with warfarin.  Am J Pediatr Hematol Oncol . 1989;  11 395-401
    PubMedGoogle Scholar
  • 79 Monagle P, Newall F, Ignjatovic V, Sharkaar S, Campbell J, Savoia H. Homozygous protein C deficiency: subcutaneous protein C replacement is effective as salvage or maintenance therapy (Abst).  Blood . 2002;  100 267a
    PubMedGoogle Scholar
  • 80 Dreyfus M, Magny J F, Bridey F. et al . Treatment of homozygous protein C deficiency and neonatal purpura fulminans with a purified protein C concentrate.  N Engl J Med . 1991;  325 1565-1568
    CrossrefPubMedGoogle Scholar
  • 81 Reitsma P H, Bernardi F, Doig R G. et al . Protein C deficiency: a data base of mutations, 1995 update.  Thromb Haemost . 1995;  73 876-889
    PubMedGoogle Scholar
  • 82 Tuddenham E GD, Takase T, Thomas A E. et al . Homozygous protein C deficiency with delayed onset of symptoms at 7 to 10 months.  Thromb Res . 1989;  53 475-484
    CrossrefPubMedGoogle Scholar
  • 83 Monagle P, Andrew M, Halton J. et al . Homozygous protein C deficiency: description of a new mutation and successful treatment with low-molecular-weight heparin.  Thromb Haemost . 1998;  79 756-761
    PubMedGoogle Scholar
  • 84 Miletich J, Sherman L, Broze G. Absence of thrombosis with heterozygous protein C deficiency.  N Engl J Med . 1987;  317 991-996
    CrossrefPubMedGoogle Scholar
  • 85 Tait R C, Walker I D, Reisma P H. et al . Prevalence of protein C deficiency in the healthy population.  Thromb Haemost . 1995;  73 87-93
    PubMedGoogle Scholar
  • 86 Bucciarelli P, Rosendaal F R, Tripodi A. et al . Risk of venous thromboembolism and clinical manifestations in carriers of antithrombin, protein C, protein S deficiency, or activated protein C resistance. A multicenter collaborative family study.  Arterioscler Thromb Vasc Biol . 1999;  19 1026-1033
    CrossrefPubMedGoogle Scholar
  • 87 Koster R, Rosendaal F R, Briët E. et al . Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis. Leiden Thrombophilia Study.  Blood . 1995;  85 2756-2761
    PubMedGoogle Scholar
  • 88 Zöller B, de Frutos G P, Dahlbäck B. Evaluation of the relationship between protein S and C4b-binding protein isoforms in hereditary protein S deficiency demonstrating type I and type III deficiencies to be phenotypic variants of the same genetic disease.  Blood . 1995;  85 3524-3531
    PubMedGoogle Scholar
  • 89 Josephson C, Nuss R, Jacobson L. et al . The varicella autoantibody syndrome.  Pediatr Res . 2001;  50 345-352
    CrossrefPubMedGoogle Scholar
  • 90 Kurugol Z, Vardar F, Ozkinay F, Kavakli K, Ozkinay C. Lupus anticoagulant and protein S deficiency in otherwise healthy children with acute varicella infection.  Acta Paediatr . 2000;  89 1186-1189
    CrossrefPubMedGoogle Scholar
  • 91 Dahlbäck B, Carlsson M, Svensson P J. 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 1004-1008
    CrossrefPubMedGoogle Scholar
  • 92 Bertina R M, Koeleman B PC, Koster T. et al . Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature . 1994;  369 64-67
    CrossrefPubMedGoogle Scholar
  • 93 Greengard J S, Sun X, Xu X, Fernandez J A, Griffin J H, Evatt B. Activated protein C resistance caused by Arg506Gln mutation in factor Va.  Lancet . 1994;  343 1361-1362
    PubMedGoogle Scholar
  • 94 Voorberg J, Roelse J, Koopman R. et al . Association of idiopathic venous thromboembolism with single point mutation at Arg506 of factor V.  Lancet . 1994;  343 1535-1536
    CrossrefPubMedGoogle Scholar
  • 95 Petäjä J, Griffin J H. Activated protein C resistance: what have we learned now that the dust has settled?.  Ann Med . 1997;  29 469-472
    PubMedGoogle Scholar
  • 96 Clark P, Walker I D. The phenomenon known as acquired activated protein C resistance.  Br J Haematol . 2001;  115 767-773
    CrossrefPubMedGoogle Scholar
  • 97 Pötzsch B, Kawamura H, Preissner K T, Schmidt M, Seelig C, Müller-Berghaus G. Acquired protein C dysfunction but not decreased activity of thrombomodulin is a possible marker of thrombophilia in patients with lupus anticoagulant.  J Lab Clin Med . 1995;  125 56-65
    PubMedGoogle Scholar
  • 98 Male C, Mitchell L, Julian J. et al . Acquired activated protein C resistance is associated with lupus anticoagulants and thrombotic events in pediatric patients with systemic lupus erythematosus.  Blood . 2001;  97 844-849
    CrossrefPubMedGoogle Scholar
  • 99 Esmon N L, Safa O, Smirnov M D, Esmon C T. Antiphospholipid antibodies and the protein C pathway.  J Autoimmun . 2000;  15 221-225
    CrossrefPubMedGoogle Scholar
  • 100 Soria J M, Almasy L, Souto J C. et al . A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility.  Blood . 2003;  101 163-167
    CrossrefPubMedGoogle Scholar
  • 101 Öhlin A K, Marlar R A. The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease.  Blood . 1995;  85 330-336
    PubMedGoogle Scholar
  • 102 Norlund L, Holm J, Zöller B. et al . A common thrombomodulin amino acid polymorphism is associated with myocardial infarction.  Thromb Haemost . 1997;  77 248-251
    PubMedGoogle Scholar
  • 103 Ireland H, Kunz G, Kyriakoulis K. et al . Thrombomodulin gene mutations in myocardial infarction.  Circulation . 1997;  96 15-18
    PubMedGoogle Scholar
  • 104 Martinelli I, Mannucci P M, De Stefano V. et al . Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families.  Blood . 1998;  92 2353-2358
    PubMedGoogle Scholar
  • 105 Tormene D, Simioni P, Prandoni P. et al . The incidence of venous thromboembolism in thrombophilic children: a prospective cohort study.  Blood . 2002;  100 2403-2405
    CrossrefPubMedGoogle Scholar
  • 106 Lane D A, Mannucci P M, Bauer K A. et al . Inherited thrombophilia: part 1.  Thromb Haemostas . 1996;  76 651-662
    PubMedGoogle Scholar
  • 107 Lane D A, Mannucci P M, Bauer K A. et al . Inherited thrombophilia: part 2.  Thromb Haemostas . 1996;  76 824-834
    PubMedGoogle Scholar
  • 108 Pabinger I, Schneider B. Thrombotic risk in hereditary antithrombin III, protein C or protein S deficiency. A cooperative, retrospective study for the Gesellschaft für Thrombose-und Hämostaseforschung (GTH) Study Group on Natural Inhibitors.  Arterioscler Thromb Vasc Biol . 1996;  16 742-748
    CrossrefPubMedGoogle Scholar
  • 109 Nowak-Göttl U, Kosch A, Schegel N. Thromboembolism in newborns, infants and children.  Thromb Haemost . 2001;  86 464-474
    PubMedGoogle Scholar
  • 110 Gunther G, Junker R, Sträter R. et al . Symptomatic ischemic stroke in full-term neonates: role of acquired and genetic prothrombotic risk factors.  Stroke . 2000;  31 2437-2471
    PubMedGoogle Scholar
  • 111 Petäjä J, Lundström U, Sairanen H, Marttinen E, Griffin J H. Central venous thrombosis after cardiac surgery in children.  J Thorac Cardiovasc Surg . 1996;  112 883-889
    PubMedGoogle Scholar
  • 112 Manco-Johnson M J. Disorders of hemostasis in childhood: risk factors for venous thromboembolism.  Thromb Haemost . 1997;  78 710-714
    PubMedGoogle Scholar
  • 113 Nuss R, Hays T, Chudgar U, Manco-Johnson M. Antiphospholipid antibodies and coagulation regulatory protein abnormalities in children with pulmonary emboli.  J Pediatr Hematol Oncol . 1997;  19 202-207
    CrossrefPubMedGoogle Scholar
  • 114 Nowak-Göttl U, Koch H G, Aschka I. et al . Resistance to activated protein C (APCR) in children with venous or arterial thromboembolism.  Br J Haematol . 1996;  92 992-998
    CrossrefPubMedGoogle Scholar
  • 115 Nowak-Göttl U, Junker R, Kreuz W. et al . Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors.  Blood . 2001;  97 858-862
    CrossrefPubMedGoogle Scholar
  • 116 Streif W, Andrew M, Marzinotto V. et al . Analysis of warfarin therapy in paediatric patients: a prospective cohort study of 319 patients.  Blood . 1999;  94 3007-3014
    PubMedGoogle Scholar
  • 117 Nowak-Göttl U, Wermes C, Junker R. et al . Prospective evaluation of the thrombotic risk in children with acute lymphoblastic leukemia carrying the MTHFR TT 677 genotype, the prothrombin G20210A variant, and further prothrombotic risk factors.  Blood . 1999;  93 1595-1599
    PubMedGoogle Scholar
  • 118 Preston F E, Rosendaal F R, Walker I D. et al . Increased fetal loss in women with heritable thrombophilia.  Lancet . 1996;  348 913-916
    CrossrefPubMedGoogle Scholar
  • 119 Kupferminc M J, Eldor A, Steinman N. et al . Increased frequency of genetic thrombophilia in women with complications of pregnancy.  N Engl J Med . 1999;  340 9-13
    CrossrefPubMedGoogle Scholar
  • 120 Roberts D, Schwartz R S. Clotting and hemorrhage in the placenta. A delicate balance.  N Engl J Med . 2002;  347 57-59
    CrossrefPubMedGoogle Scholar
  • 121 Infante-Rivard C, Rivard G, Yotov W. et al . Absence of association of thrombophilia polymorphisms with intrauterine growth restriction.  N Engl J Med . 2002;  347 19-25
    CrossrefPubMedGoogle Scholar
  • 122 Sood R, Weiler H. The blood coagulation regulator thrombomodulin modulates proliferation and cell death of placental cells (Abst).  Blood . 2002;  100 693a
    PubMedGoogle Scholar
  • 123 Göpel W, Kim D, Gortner L. Prothrombotic mutations as a risk factor for preterm birth.  Lancet . 1999;  353 1411-1412
    CrossrefPubMedGoogle Scholar
  • 124 Petäjä J, Hiltunen L, Fellman V. Increased risk of intraventricular hemorrhage in newborn infants with thrombophilia.  Pediatr Res . 2001;  49 643-646
    PubMedGoogle Scholar
  • 125 Göpel W, Gortner L, Kohlman T, Schultz C, Möller J. Low prevalence of large intraventricular haemorrhage in very-low-birth-weight infants carrying the factor V Leiden or prothrombin G20210 mutation.  Acta Paediatr . 2001;  90 1021-1024
    CrossrefPubMedGoogle Scholar
  • 126 Tommiska V, Heinonen K, Ikonen S. et al . A national short-term follow-up study of extremely-low-birth-weight infants born in Finland in 1996-1997.  Pediatrics . 2001;  107 E2
    CrossrefPubMedGoogle Scholar
  • 127 Wahl D G, Guillemin E, deMaistre E, Perret C, Lecompte T, Thibaut G. Risk of venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus: a meta analysis.  Lupus . 1997;  6 467-473
    CrossrefPubMedGoogle Scholar
  • 128 Reverter J C, Tassies D, Font J. et al . Hypercoagulable state in patients with antiphospholipid syndrome is related to high induced tissue factor expression on monocytes and to low free protein S.  Arterioscler Thromb Vasc Biol . 1996;  16 1319-1326
    PubMedGoogle Scholar
  • 129 Leclerc F, Hazelzet J, Jude B. et al . Protein C and S deficiency in severe infectious purpura of children. A collaborative study of 40 patients.  Intensive Care Med . 1992;  18 202-205
    CrossrefPubMedGoogle Scholar
  • 130 White B, Livingstone W, Murphy C, Hodgson A, Rafferty M, Smith O P. An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia.  Blood . 2000;  96 3719-3724
    PubMedGoogle Scholar
  • 131 Fijnvandraat K, Peters M, Derkx B, van Deventer S, ten Cate W J. Endotoxin induced coagulation activation and protein C reduction in meningococcal septic shock.  Prog Clin Biol Res . 1994;  388 247-254
    PubMedGoogle Scholar
  • 132 Fijnvandraat K, Derkx B, Peters M. et al . Coagulation activation and tissue necrosis in meningococcal septic shock: severely reduced protein C levels predict a high mortality.  Thromb Haemost . 1995;  73 15-20
    PubMedGoogle Scholar
  • 133 Rivard G E, David M, Farrell C, Schwarz H P. Treatment of purpura fulminans in meningococcemia with protein C concentrate.  J Pediatr . 1995;  126 646-652
    PubMedGoogle Scholar
  • 134 Westendrop R G, Langermans J A, Huizinga T W, Verwij C L, Sturk A. Genetic influence of cytokine production in meningococcal disease.  Lancet . 1997;  349 1912-1913
    CrossrefPubMedGoogle Scholar
  • 135 Hermans P W, Hibberd M L, Booy R. et al . 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease: Meningococcal Research Group.  Lancet . 1999;  354 556-560
    CrossrefPubMedGoogle Scholar
  • 136 Westendorp R G, Hottenga J J, Slagboom P E. Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock.  Lancet . 1999;  354 561-563
    CrossrefPubMedGoogle Scholar
  • 137 Hyytiäinen S, Syrjälä, Fellman V, Heikinheimo M, Petäjä J. Fresh frozen plasma reduces thromin formation in newborn infants.  J Thromb Haemostas . 2003;  1 1189-1194
    PubMedGoogle Scholar
  • 138 Simioni P, Prandoni P, Lensing A WA. et al . The risk of recurrent venous thromboembolism in patients with an Arg506Gln mutation in the gene for factor V (factor V Leiden).  N Engl J Med . 1997;  336 399-403
    CrossrefPubMedGoogle Scholar
  • 139 Eichinger S, Pabinger I, Stumpflen A. et al . The risk of recurrent venous thromboembolism in patients with and without factor V Leiden.  Thromb Haemost . 1997;  77 624-628
    PubMedGoogle Scholar
  • 140 Lindmarker P, Schulman S, Sten-Linder M. et al . The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene.  Thromb Haemost . 1999;  81 684-689
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 141 Stefano de V, Martinelli I, Mannucci P M. et al . 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;  341 801-806
    CrossrefPubMedGoogle Scholar
  • 142 Manco-Johnson M J, Grabowski E F, Hellgren M. et al . Laboratory testing for thrombophilia in pediatric patients.  Thromb Haemost . 2002;  88 155-156
    PubMedGoogle Scholar