Protein C pathway in infants and children

Seminars in Thrombosis and Hemostasis

Volumn 29, Issue 4, 2003, Pages 349-361

  Petäjä, Jari ^a   Manco Johnson, Marilyn J ^b  

^a JORVI HOSPITAL   (Finland)

^b UNIVERSITY OF COLORADO   (United States)

Author keywords

Children; Factory V Leiden; Newborn infant; Protein C; Protein S; Sepsis; Venous thrombosis

Indexed keywords

ACTIVATED PROTEIN C; ALPHA 1 ANTITRYPSIN; ALPHA 2 MACROGLOBULIN; ANTITHROMBIN; BLOOD CLOTTING FACTOR 5 LEIDEN; BLOOD CLOTTING FACTOR 5A; BLOOD CLOTTING FACTOR 8A; PHOSPHOLIPID ANTIBODY; PROTEIN C; PROTEIN S; THROMBIN; THROMBOMODULIN; TISSUE FACTOR PATHWAY INHIBITOR; TUMOR NECROSIS FACTOR ALPHA;

ACTIVATED PROTEIN C RESISTANCE; ANTICOAGULATION; CHILD DEVELOPMENT; CHILDHOOD DISEASE; DISSEMINATED INTRAVASCULAR CLOTTING; FULMINATING PURPURA; HEMOSTASIS; HUMAN; INFLAMMATION; MATERNAL DISEASE; PRIORITY JOURNAL; PROTEIN C DEFICIENCY; PROTEIN S DEFICIENCY; REVIEW; SEPSIS; THROMBOEMBOLISM; THROMBOPHILIA; VEIN THROMBOSIS;

BLOOD COAGULATION; CHILD; FEMALE; HUMANS; INFANT, NEWBORN; INFLAMMATION; PREGNANCY; PREGNANCY COMPLICATIONS, HEMATOLOGIC; PROTEIN C; PROTEIN C DEFICIENCY; SEPSIS; VENOUS THROMBOSIS;

EID: 0042866016     PISSN: 00946176     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-2003-42586     Document Type: Review

References (142)

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 LH, Comp PC. The regulation of hemostasis: the protein C system. N Engl J Med 1986;314:1298-1304
3. Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, 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 CT. Protein C anticoagulant pathway and its role in controlling microvascular thrombosis and inflammation. Crit Care Med 2001;29(Suppl):S48-51
7. Esmon CT, Fletcher BT Jr, Snow TR. Inflammation and coagulation: linked processes potentially regulated through a common pathway mediated by protein C. Thromb Haemost 1991;66:160-165
8. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709
9. Giroir BP. 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 MJ, Knapp-Clevenger R. Recombinant activated protein C (dotrecogin) is effective for purpura fulminans secondary to severe genetic protein C deficiency. J Pediatr Hematol Oncol 2003; (in press)
11. Schwarz HP, Fischer M, Hopmeier P, Batard MA, Griffin JH. Plasma protein S deficiency in familial thrombotic disease. Blood 1984;64:1297-1300
12. Marlar RA, Hassel KL. Protein C and protein S deficiencies. In: Schafer AI, ed. Molecular Mechanisms of Hypercoagulable States. New York: RG Landes Co; 1997:79-100
13. Esmon CT, Esmon NL. Protein C activation. Semin Thromb Hemost 1984;10:122-130
14. Broze GJ, Miletich JP. 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
15. Comp PC, Esmon CT. Generation of fibrinolytic activity by infusion of activated protein C into dogs. J Clin Invest 1981;68:1221-1228
16. Sakata Y, Loskutoff DJ, Gladson CL, Hekman CM, Griffin JH. Mechanism of protein C-dependent clot-lysis. Role of plasminogen activator inhibitor. Blood 1986;68:1218-1223
17. Hanson SR, Griffin JH, Harker LA, 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 JH. Direct detection of activated protein C in blood from human subjects. Blood 1992;79:2340-2348
19. Ilmakunnas M, Petäjä J, Fernández JA, et al. Activation of antithrombotic and anti-inflammatory protein C during reperfusion in clinical liver transplantation. Transplantation 2003;75:467-472
20. Heeb MJ, Espana F, Griffin JH. Inhibition of and complexation of activated protein C by two major inhibitors in plasma. Blood 1989;73:446-454
21. 2-antiplasmin in blood and comparison to inhibition of factor Xa, thrombin, and plasmin. J Biol Chem 1991;266:17606-17612
22. Fair DS, Revak DJ. 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 MJ, Mesters RM, Tans G, Rosing J, Griffin JH. 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 TM, van't Veer C, Meijers JC, Bouma BN. 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 HH, Esmon NL, Esmon CT, Majerus PW. 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 GAF, Dahlbäck B. Factor V and thrombotic disease: description of a Janus-faced protein. Arterioscler Thromb Vasc Biol 2002;22:530-538
30. Esmon CT, Xu J, Gu J, et al. Endothelial protein C receptor. Thromb Haemost 1999;82:251-258
31. Taylor FB Jr, Peer GT, Lockhart MS, Ferrell G, Esmon CT. 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 FB Jr, 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 FM, Smiley ST. Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo. Blood 2002;99:1053-1059
34. Esmon CT. Role of coagulation inhibitors in inflammation. Thromb Haemost 2001;86:51-56
35. Yang J, Furie BC, 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 CT. Are natural anticoagulants candidates for modulating the inflammatory response to endotoxin? Blood 2000;95:1113-1116
37. Warr TA, Rao VM, Rapaport SI. 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 JA, 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 ST, Tsuchida A, Hau H, Orthner CL, Salemn HH, Hancock WW. 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
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 FA, Mitchell L, Brooker LA, 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 MT, Mann KG. Tissue factor-initiated thrombin generation in the newborn. Blood 2002;100:488a (Abst)
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 PM, 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 JA, 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 KH, Scully MF, Kakkar VV. 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. 2-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 BS, Marlar RA, 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 JA, Hackeng TM, Kojima K, Griffin JH. The carbohydrate moiety of factor V modulates inactivation by activated protein C. Blood 1997;89:4348-4354
61. Petäjä J, Fernández JA, Fellman V, Griffin JH. Upregulation of the antithrombotic protein C pathway at birth. Pediatr Hematol Oncol 1998;15:489-499
62. Fernández JA, 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 MH, 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 AM, Rayburn HB, Rosenberg RD, 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 PD, Beeler DL, 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 JA, Vento A, Rämö OJ, Griffin JH. Cardiopulmonary bypass and activation of antithrombotic plasma protein C. J Thorac Cardiovasc Surg 1999;118:422-431
71. Manco-Johnson M, Abshire TC, Jacobson LJ, et al. Severe neonatal protein C deficiency: prevalence and thrombotic risk. J Pediatr 1991;119:793-798
72. Branson HE, Marble R, Katz J, Griffin JH. 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 AW, 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 RA, Neumann A. Neonatal purpura fulminans due to homozygous protein C or protein S deficiencies. Semin Thromb Hemost 1990;16:299-309
76. Pipe SW, Schmaier AH, Nichols WC, Ginsburg D, Bozynski M, Castle V. Neonatal purpura fulminans in association with factor V RS06Q mutation. J Pediatr 1996;128:706-709
77. Adcock DM, Brozna J, Marlar RA. Proposed classification and pathologic mechanisms of purpura fulminans and skin necrosis. Semin Thromb Hemost 1990;16:333-340
78. Hartman K, Manco-Johnson MJ, Rawlings JS, Bowen DR, Marlar RA. 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. Blood 2002;100:267a (Abst)
80. Dreyfus M, Magny JF, 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 PH, Bernardi F, Doig RG, et al. Protein C deficiency: a data base of mutations, 1995 update. Thromb Haemost 1995;73:876-889
82. Tuddenham EGD, Takase T, Thomas AE, 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 RC, Walker ID, Reisma PH, et al. Prevalence of protein C deficiency in the healthy population. Thromb Haemost 1995;73:87-93
86. Bucciarelli P, Rosendaal FR, 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 FR, 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 PG, 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 PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993;90:1004-1008
92. Bertina RM, Koeleman BPC, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64-67
93. 506Gln mutation in factor Va. Lancet 1994;343:1361-1362
94. 506 of factor V. Lancet 1994;343:1535-1536
95. Petäjä J, Griffin JH. Activated protein C resistance: what have we learned now that the dust has settled? Ann Med 1997;29:469-472
96. Clark P, Walker ID. The phenomenon known as acquired activated protein C resistance. Br J Haematol 2001;115:767-773
97. Pötzsch B, Kawamura H, Preissner KT, 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 NL, Safa O, Smirnov MD, Esmon CT. Antiphospholipid antibodies and the protein C pathway. J Autoimmun 2000;15:221-225
100. Soria JM, Almasy L, Souto JC, 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 AK, Marlar RA. 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 PM, 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 DA, Mannucci PM, Bauer KA, et al. Inherited thrombophilia: part 1. Thromb Haemostas 1996;76:651-662
107. Lane DA, Mannucci PM, Bauer KA, 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 JH. Central venous thrombosis after cardiac surgery in children. J Thorac Cardiovasc Surg 1996;112:883-889
112. Manco-Johnson MJ. 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 HG, 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 FE, Rosendaal FR, Walker ID, et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996;348:913-916
119. Kupferminc MJ, 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 RS. 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. Blood 2002;100:693a (Abst)
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 DG, 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 JC, 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 OP. 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 JW. 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 GE, David M, Farrell C, Schwarz HP. Treatment of purpura fulminans in meningococcemia with protein C concentrate. J Pediatr 1995;126:646-652
134. Westendrop RG, Langermans JA, Huizinga TW, Verwij CL, Sturk A. Genetic influence of cytokine production in meningococcal disease. Lancet 1997;349:1912-1913
135. Hermans PW, Hibberd ML, 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 RG, Hottenga JJ, Slagboom PE. Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock. Lancet 1999;354:561-563
137. Hyytiäinen S, Syrjälä, Fellman V, Heilkinheimo M, Petäjä J. Fresh frozen plasma reduces thromin formation in newborn infants. J Thromb Haemostas 2003;1:1189-1194
138. 506Gln 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 PM, 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 MJ, Grabowski EF, Hellgren M, et al. Laboratory testing for thrombophilia in pediatric patients. Thromb Haemost 2002;88:155-156