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Semin Thromb Hemost 2003; 29(4): 349-362
DOI: 10.1055/s-2003-42586
DOI: 10.1055/s-2003-42586
Protein C Pathway in Infants and Children
Weitere Informationen
Publikationsverlauf
Publikationsdatum:
30. September 2003 (online)
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
- 2 Clouse L H, Comp P C. The regulation of hemostasis: the protein C system. N Engl J Med . 1986; 314 1298-1304
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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;
- 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
- 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
MissingFormLabel
- 13 Esmon C T, Esmon N L. Protein C activation. Semin Thromb Hemost . 1984; 10 122-130
- 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
MissingFormLabel
- 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
- 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
- 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
- 18 Gruber A, Griffin J H. Direct detection of activated protein C in blood from human subjects. Blood . 1992; 79 2340-2348
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 28 Dahlbäck B. The protein C anticoagulant system: inherited defects as basis for venous thrombosis. Thromb Res . 1995; 77 1-43
- 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
- 30 Esmon C T, Xu J, Gu J. et al . Endothelial protein C receptor. Thromb Haemost . 1999; 82 251-258
- 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
- 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
- 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
- 34 Esmon C T. Role of coagulation inhibitors in inflammation. Thromb Haemost . 2001; 86 51-56
- 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
- 36 Esmon C T. Are natural anticoagulants candidates for modulating the inflammatory response to endotoxin?. Blood . 2000; 95 1113-1116
- 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
- 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
- 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
- 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
- 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
- 42 Andrew M. Developmental hemostasis: relevance to thromboembolic complications in pediatric patients. Thromb Haemost . 1995; 74 415-425
- 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
- 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
MissingFormLabel
- 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
- 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
- 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
- 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
- 49 Butenas S, Gissel M T, Mann K G. Tissue factor-initiated thrombin generation in the newborn (Abst). Blood . 2002; 100 488a
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 64 Takano S, Kimura S, Ohodama S. et al . Plasma thrombomodulin in health and disease. Blood . 1990; 79 837-838
- 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
- 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
- 67 Boldt J, Knothe C, Schindler E. et al . Thrombomodulin in pediatric cardiac surgery. Ann Thorac Surg . 1994; 57 1584-1589
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 84 Miletich J, Sherman L, Broze G. Absence of thrombosis with heterozygous protein C deficiency. N Engl J Med . 1987; 317 991-996
- 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
- 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
- 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
- 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
- 89 Josephson C, Nuss R, Jacobson L. et al . The varicella autoantibody syndrome. Pediatr Res . 2001; 50 345-352
- 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
- 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
- 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
- 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
- 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
- 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
- 96 Clark P, Walker I D. The phenomenon known as acquired activated protein C resistance. Br J Haematol . 2001; 115 767-773
- 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
- 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
- 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
- 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
- 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
- 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
- 103 Ireland H, Kunz G, Kyriakoulis K. et al . Thrombomodulin gene mutations in myocardial infarction. Circulation . 1997; 96 15-18
- 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
- 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
- 106 Lane D A, Mannucci P M, Bauer K A. et al . Inherited thrombophilia: part 1. Thromb Haemostas . 1996; 76 651-662
- 107 Lane D A, Mannucci P M, Bauer K A. et al . Inherited thrombophilia: part 2. Thromb Haemostas . 1996; 76 824-834
- 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
- 109 Nowak-Göttl U, Kosch A, Schegel N. Thromboembolism in newborns, infants and children. Thromb Haemost . 2001; 86 464-474
- 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
- 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
- 112 Manco-Johnson M J. Disorders of hemostasis in childhood: risk factors for venous thromboembolism. Thromb Haemost . 1997; 78 710-714
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 120 Roberts D, Schwartz R S. Clotting and hemorrhage in the placenta. A delicate balance. N Engl J Med . 2002; 347 57-59
- 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
- 122 Sood R, Weiler H. The blood coagulation regulator thrombomodulin modulates proliferation and cell death of placental cells (Abst). Blood . 2002; 100 693a
- 123 Göpel W, Kim D, Gortner L. Prothrombotic mutations as a risk factor for preterm birth. Lancet . 1999; 353 1411-1412
- 124 Petäjä J, Hiltunen L, Fellman V. Increased risk of intraventricular hemorrhage in newborn infants with thrombophilia. Pediatr Res . 2001; 49 643-646
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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