Gene Variations in the Protein C and Fibrinolytic Pathway: Relevance for Severity and Outcome in Pediatric Sepsis

Navin P. Boeddha; Marieke Emonts; Marjon H. Cnossen; Moniek P. de Maat; Frank W. Leebeek; Gertjan J. Driessen; Jan A. Hazelzet

doi:10.1055/s-0036-1597292

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2017; 43(01): 036-047
DOI: 10.1055/s-0036-1597292

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Gene Variations in the Protein C and Fibrinolytic Pathway: Relevance for Severity and Outcome in Pediatric Sepsis

Navin P. Boeddha

¹Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands

²Division of Pediatric Infectious Diseases and Immunology, Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands

,

Marieke Emonts

³Department of Paediatric Infectious Diseases and Immunology, Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

⁴Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom

,

Marjon H. Cnossen

⁵Division of Pediatric Hematology, Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands

,

Moniek P. de Maat

⁶Department of Hematology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

,

Frank W. Leebeek

⁶Department of Hematology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

,

Gertjan J. Driessen

²Division of Pediatric Infectious Diseases and Immunology, Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands

,

Jan A. Hazelzet

⁷Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

› Author Affiliations

Abstract

The host response to infection involves complex interplays between inflammation, coagulation, and fibrinolysis. Deregulation of hemostasis and fibrinolysis are major causes of critical illness and important determinants of outcome in severe sepsis. The hemostatic responses to infection vary widely between individuals, and are in part explained by polymorphisms in genes responsible for the protein C and fibrinolytic pathway. This review gives an overview of genetic polymorphisms in the protein C and fibrinolytic pathway associated with susceptibility and severity of pediatric sepsis. In addition, genetic polymorphisms associated with adult sepsis and other pediatric thromboembolic disorders are discussed, as these polymorphisms might be candidates for future molecular genetic research in pediatric sepsis.

Keywords

genetic polymorphism - protein C - fibrinolysis - sepsis - plasminogen activator inhibitor-1 - thrombin-activatable fibrinolysis inhibitor - thrombosis

Full Text

References

References
1 Weiss SL, Fitzgerald JC, Pappachan J , et al; Sepsis Prevalence, Outcomes, and Therapies (SPROUT) Study Investigators and Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study. Am J Respir Crit Care Med 2015; 191 (10) 1147-1157
2 Esmon CT. The interactions between inflammation and coagulation. Br J Haematol 2005; 131 (4) 417-430
3 Zeerleder S, Hack CE, Wuillemin WA. Disseminated intravascular coagulation in sepsis. Chest 2005; 128 (4) 2864-2875
4 Levi M, Schultz M, van der Poll T. Sepsis and thrombosis. Semin Thromb Hemost 2013; 39 (5) 559-566
5 Leclerc F, Hazelzet J, Jude B , et al. Protein C and S deficiency in severe infectious purpura of children: a collaborative study of 40 cases. Intensive Care Med 1992; 18 (4) 202-205
6 Macias WL, Nelson DR. Severe protein C deficiency predicts early death in severe sepsis. Crit Care Med 2004; 32 , (5 Suppl): S223-S228
7 Hermans PW, Hibberd ML, Booy R , et al; Meningococcal Research Group. 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Lancet 1999; 354 (9178) 556-560
8 Li L, Nie W, Zhou H, Yuan W, Li W, Huang W. Association between plasminogen activator inhibitor-1 -675 4G/5G polymorphism and sepsis: a meta-analysis. PLoS One 2013; 8 (1) e54883
9 Lorente L, Martín MM, Borreguero-León JM , et al. Sustained high plasma plasminogen activator inhibitor-1 levels are associated with severity and mortality in septic patients. Thromb Res 2014; 134 (1) 182-186
10 Texereau J, Pene F, Chiche JD, Rousseau C, Mira JP. Importance of hemostatic gene polymorphisms for susceptibility to and outcome of severe sepsis. Crit Care Med 2004; 32 , (5 Suppl): S313-S319
11 Arcaroli J, Fessler MB, Abraham E. Genetic polymorphisms and sepsis. Shock 2005; 24 (4) 300-312
12 Jackson CJ, Xue M. Activated protein C--an anticoagulant that does more than stop clots. Int J Biochem Cell Biol 2008; 40 (12) 2692-2697
13 Esmon CT. The protein C pathway. Chest 2003; 124 , (3 Suppl): 26S-32S
14 Castoldi E, Simioni P, Tormene D , et al. Differential effects of high prothrombin levels on thrombin generation depending on the cause of the hyperprothrombinemia. J Thromb Haemost 2007; 5 (5) 971-979
15 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88 (10) 3698-3703
16 Danckwardt S, Gehring NH, Neu-Yilik G , et al. The prothrombin 3'end formation signal reveals a unique architecture that is sensitive to thrombophilic gain-of-function mutations. Blood 2004; 104 (2) 428-435
17 Ruiz-Argüelles GJ, Garcés-Eisele J, Reyes-Núñez V, Ramírez-Cisneros FJ. Primary thrombophilia in Mexico. II. Factor V G1691A (Leiden), prothrombin G20210A, and methylenetetrahydrofolate reductase C677T polymorphism in thrombophilic Mexican mestizos. Am J Hematol 2001; 66 (1) 28-31
18 Varela ML, Adamczuk YP, Forastiero RR , et al. Major and potential prothrombotic genotypes in a cohort of patients with venous thromboembolism. Thromb Res 2001; 104 (5) 317-324
19 Renner W, Köppel H, Hoffmann C , et al. Prothrombin G20210A, factor V Leiden, and factor XIII Val34Leu: common mutations of blood coagulation factors and deep vein thrombosis in Austria. Thromb Res 2000; 99 (1) 35-39
20 Le Cam-Duchez V, Bagan-Triquenot A, Ménard JF, Mihout B, Borg JY. Association of the protein C promoter CG haplotype and the factor II G20210A mutation is a risk factor for cerebral venous thrombosis. Blood Coagul Fibrinolysis 2005; 16 (7) 495-500
21 De Stefano V, Chiusolo P, Paciaroni K , et al. Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients. Blood 1998; 91 (10) 3562-3565
22 Nowak-Göttl U, Sträter R, Heinecke A , et al. Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are risk factors of spontaneous ischemic stroke in childhood. Blood 1999; 94 (11) 3678-3682
23 Martinelli I, Battaglioli T, Razzari C, Mannucci PM. Type and location of venous thromboembolism in patients with factor V Leiden or prothrombin G20210A and in those with no thrombophilia. J Thromb Haemost 2007; 5 (1) 98-101
24 Emmerich J, Rosendaal FR, Cattaneo M , et al; Study Group for Pooled-Analysis in Venous Thromboembolism. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Thromb Haemost 2001; 86 (3) 809-816
25 Ceelie H, Bertina RM, van Hylckama Vlieg A, Rosendaal FR, Vos HL. Polymorphisms in the prothrombin gene and their association with plasma prothrombin levels. Thromb Haemost 2001; 85 (6) 1066-1070
26 Pérez-Ceballos E, Corral J, Alberca I , et al. Prothrombin A19911G and G20210A polymorphisms' role in thrombosis. Br J Haematol 2002; 118 (2) 610-614
27 Martinelli I, Battaglioli T, Tosetto A , et al. Prothrombin A19911G polymorphism and the risk of venous thromboembolism. J Thromb Haemost 2006; 4 (12) 2582-2586
28 Fuentes-Prior P, Iwanaga Y, Huber R , et al. Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex. Nature 2000; 404 (6777) 518-525
29 Boehme MW, Galle P, Stremmel W. Kinetics of thrombomodulin release and endothelial cell injury by neutrophil-derived proteases and oxygen radicals. Immunology 2002; 107 (3) 340-349
30 Takano S, Kimura S, Ohdama S, Aoki N. Plasma thrombomodulin in health and diseases. Blood 1990; 76 (10) 2024-2029
31 Lin SM, Wang YM, Lin HC , et al. Serum thrombomodulin level relates to the clinical course of disseminated intravascular coagulation, multiorgan dysfunction syndrome, and mortality in patients with sepsis. Crit Care Med 2008; 36 (3) 683-689
32 Moore KL, Andreoli SP, Esmon NL, Esmon CT, Bang NU. Endotoxin enhances tissue factor and suppresses thrombomodulin expression of human vascular endothelium in vitro. J Clin Invest 1987; 79 (1) 124-130
33 Hayakawa M, Yamakawa K, Saito S , et al; Japan Septic Disseminated Intravascular Coagulation (JSEPTIC DIC) study group. Recombinant human soluble thrombomodulin and mortality in sepsis-induced disseminated intravascular coagulation. A multicentre retrospective study. Thromb Haemost 2016; 115 (6) 1157-1166
34 Yamakawa K, Aihara M, Ogura H, Yuhara H, Hamasaki T, Shimazu T. Recombinant human soluble thrombomodulin in severe sepsis: a systematic review and meta-analysis. J Thromb Haemost 2015; 13 (4) 508-519
35 Kager LM, Wiersinga WJ, Roelofs JJ , et al. A thrombomodulin mutation that impairs active protein C generation is detrimental in severe pneumonia-derived gram-negative sepsis (melioidosis). PLoS Negl Trop Dis 2014; 8 (4) e2819
36 Cole JW, Roberts SC, Gallagher M , et al; Stroke Prevention in Young Women Study. Thrombomodulin Ala455Val polymorphism and the risk of cerebral infarction in a biracial population: The stroke prevention in young women study. BMC Neurol 2004; 4 (1) 21
37 Faioni EM, Franchi F, Castaman G, Biguzzi E, Rodeghiero F. Mutations in the thrombomodulin gene are rare in patients with severe thrombophilia. Br J Haematol 2002; 118 (2) 595-599
38 Delvaeye M, Noris M, De Vriese A , et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med 2009; 361 (4) 345-357
39 Aleksic N, Folsom AR, Cushman M, Heckbert SR, Tsai MY, Wu KK. Prospective study of the A455V polymorphism in the thrombomodulin gene, plasma thrombomodulin, and incidence of venous thromboembolism: the LITE Study. J Thromb Haemost 2003; 1 (1) 88-94
40 Fan X, Yoshida Y, Honda S , et al. Analysis of genetic and predisposing factors in Japanese patients with atypical hemolytic uremic syndrome. Mol Immunol 2013; 54 (2) 238-246
41 Sipahi T, Pocan H, Akar N. Effect of various genetic polymorphisms on the incidence and outcome of severe sepsis. Clin Appl Thromb Hemost 2006; 12 (1) 47-54
42 Ulu A, Gunal D, Tiras S, Egin Y, Deda G, Akar N. EPCR gene A3 haplotype and elevated soluble endothelial protein C receptor (sEPCR) levels in Turkish pediatric stroke patients. Thromb Res 2007; 120 (1) 47-52
43 Vassiliou AG, Maniatis NA, Kotanidou A , et al. Endothelial protein C receptor polymorphisms and risk of severe sepsis in critically ill patients. Intensive Care Med 2013; 39 (10) 1752-1759
44 Kinasewitz GT, Yan SB, Basson B , et al; PROWESS Sepsis Study Group. Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569]. Crit Care 2004; 8 (2) R82 –R90
45 de Kleijn ED, de Groot R, Hack CE , et al. Activation of protein C following infusion of protein C concentrate in children with severe meningococcal sepsis and purpura fulminans: a randomized, double-blinded, placebo-controlled, dose-finding study. Crit Care Med 2003; 31 (6) 1839-1847
46 Bernard GR, Vincent JL, Laterre PF , et al; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344 (10) 699-709
47 Kalil AC, LaRosa SP. Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression. Lancet Infect Dis 2012; 12 (9) 678-686
48 Spek CA, Poort SR, Bertina RM, Reitsma PH. Determination of the allelic and haplotype frequencies of three polymorphisms in the promoter region of the human protein C gene. Blood Coagul Fibrinolysis 1994; 5 (2) 309-311
49 Spek CA, Koster T, Rosendaal FR, Bertina RM, Reitsma PH. Genotypic variation in the promoter region of the protein C gene is associated with plasma protein C levels and thrombotic risk. Arterioscler Thromb Vasc Biol 1995; 15 (2) 214-218
50 Binder A, Endler G, Rieger S , et al; Central European Meningococcal Genetic Study Group. Protein C promoter polymorphisms associate with sepsis in children with systemic meningococcemia. Hum Genet 2007; 122 (2) 183-190
51 Walley KR, Russell JA. Protein C -1641 AA is associated with decreased survival and more organ dysfunction in severe sepsis. Crit Care Med 2007; 35 (1) 12-17
52 Chen QX, Wu SJ, Wang HH , et al. Protein C -1641A/-1654C haplotype is associated with organ dysfunction and the fatal outcome of severe sepsis in Chinese Han population. Hum Genet 2008; 123 (3) 281-287
53 Russell JA, Wellman H, Walley KR. Protein C rs2069912 C allele is associated with increased mortality from severe sepsis in North Americans of East Asian ancestry. Hum Genet 2008; 123 (6) 661-663
54 Zhang YJ, Miao YF, Cheng KB, Yue J, Tan XY, Liu JM. Protein C polymorphism and susceptibility to PTE in China. Blood Coagul Fibrinolysis 2012; 23 (8) 693-699
55 Schwarz HP, Fischer M, Hopmeier P, Batard MA, Griffin JH. Plasma protein S deficiency in familial thrombotic disease. Blood 1984; 64 (6) 1297-1300
56 Sheth SB, Carvalho AC. Protein S and C alterations in acutely ill patients. Am J Hematol 1991; 36 (1) 14-19
57 Kimura R, Honda S, Kawasaki T , et al. Protein S-K196E mutation as a genetic risk factor for deep vein thrombosis in Japanese patients. Blood 2006; 107 (4) 1737-1738
58 Kinoshita S, Iida H, Inoue S , et al. Protein S and protein C gene mutations in Japanese deep vein thrombosis patients. Clin Biochem 2005; 38 (10) 908-915
59 Liu W, Yin T, Okuda H , et al. Protein S K196E mutation, a genetic risk factor for venous thromboembolism, is limited to Japanese. Thromb Res 2013; 132 (2) 314-315
60 Draxler DF, Medcalf RL. The fibrinolytic system-more than fibrinolysis?. Transfus Med Rev 2015; 29 (2) 102-109
61 Cesarman-Maus G, Hajjar KA. Molecular mechanisms of fibrinolysis. Br J Haematol 2005; 129 (3) 307-321
62 Rijken DC, Abdul S, Malfliet JJ, Leebeek FW, Uitte de Willige S. Compaction of fibrin clots reveals the antifibrinolytic effect of factor XIII. J Thromb Haemost 2016; 14 (7) 1453-1461
63 Sakata Y, Curriden S, Lawrence D, Griffin JH, Loskutoff DJ. Activated protein C stimulates the fibrinolytic activity of cultured endothelial cells and decreases antiactivator activity. Proc Natl Acad Sci U S A 1985; 82 (4) 1121-1125
64 Mosnier LO, Bouma BN. Regulation of fibrinolysis by thrombin activatable fibrinolysis inhibitor, an unstable carboxypeptidase B that unites the pathways of coagulation and fibrinolysis. Arterioscler Thromb Vasc Biol 2006; 26 (11) 2445-2453
65 Gando S. Role of fibrinolysis in sepsis. Semin Thromb Hemost 2013; 39 (4) 392-399
66 Raum D, Marcus D, Alper CA, Levey R, Taylor PD, Starzl TE. Synthesis of human plasminogen by the liver. Science 1980; 208 (4447) 1036-1037
67 Petersen TE, Martzen MR, Ichinose A, Davie EW. Characterization of the gene for human plasminogen, a key proenzyme in the fibrinolytic system. J Biol Chem 1990; 265 (11) 6104-6111
68 Ichinose A, Espling ES, Takamatsu J , et al. Two types of abnormal genes for plasminogen in families with a predisposition for thrombosis. Proc Natl Acad Sci U S A 1991; 88 (1) 115-119
69 Dolan G, Greaves M, Cooper P, Preston FE. Thrombovascular disease and familial plasminogen deficiency: a report of three kindreds. Br J Haematol 1988; 70 (4) 417-421
70 Sartori MT, Patrassi GM, Theodoridis P, Perin A, Pietrogrande F, Girolami A. Heterozygous type I plasminogen deficiency is associated with an increased risk for thrombosis: a statistical analysis in 20 kindreds. Blood Coagul Fibrinolysis 1994; 5 (6) 889-893
71 Brandt JT. Plasminogen and tissue-type plasminogen activator deficiency as risk factors for thromboembolic disease. Arch Pathol Lab Med 2002; 126 (11) 1376-1381
72 Shigekiyo T, Kanazuka M, Aihara K , et al. No increased risk of thrombosis in heterozygous congenital dysplasminogenemia. Int J Hematol 2000; 72 (2) 247-252
73 Syrovets T, Lunov O, Simmet T. Plasmin as a proinflammatory cell activator. J Leukoc Biol 2012; 92 (3) 509-519
74 Donmez-Demir B, Celkan T, Sarper N , et al. Novel plasminogen gene mutations in Turkish patients with type I plasminogen deficiency. Blood Coagul Fibrinolysis 2016; 27 (6) 637-644
75 Raum D, Marcus D, Alper CA. Genetic polymorphism of human plasminogen. Am J Hum Genet 1980; 32 (5) 681-689
76 Klammt J, Kobelt L, Aktas D , et al. Identification of three novel plasminogen (PLG) gene mutations in a series of 23 patients with low PLG activity. Thromb Haemost 2011; 105 (3) 454-460
77 Kłak M, Anäkkälä N, Wang W , et al. Tranexamic acid, an inhibitor of plasminogen activation, aggravates staphylococcal septic arthritis and sepsis. Scand J Infect Dis 2010; 42 (5) 351-358
78 Levin EG, del Zoppo GJ. Localization of tissue plasminogen activator in the endothelium of a limited number of vessels. Am J Pathol 1994; 144 (5) 855-861
79 Kooistra T, Schrauwen Y, Arts J, Emeis JJ. Regulation of endothelial cell t-PA synthesis and release. Int J Hematol 1994; 59 (4) 233-255
80 Rånby M. Studies on the kinetics of plasminogen activation by tissue plasminogen activator. Biochim Biophys Acta 1982; 704 (3) 461-469
81 Mondino A, Blasi F. uPA and uPAR in fibrinolysis, immunity and pathology. Trends Immunol 2004; 25 (8) 450-455
82 Goldhaber SZ, Haire WD, Feldstein ML , et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet 1993; 341 (8844) 507-511
83 Ouriel K, Veith FJ, Sasahara AA ; Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators. A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. N Engl J Med 1998; 338 (16) 1105-1111
84 Winkler F, Kastenbauer S, Koedel U, Pfister HW. Role of the urokinase plasminogen activator system in patients with bacterial meningitis. Neurology 2002; 59 (9) 1350-1355
85 Philippé J, Offner F, Declerck PJ , et al. Fibrinolysis and coagulation in patients with infectious disease and sepsis. Thromb Haemost 1991; 65 (3) 291-295
86 Philippé J, Dooijewaard G, Offner F, Turion P, Baele G, Leroux-Roels G. Granulocyte elastase, tumor necrosis factor-alpha and urokinase levels as prognostic markers in severe infection. Thromb Haemost 1992; 68 (1) 19-23
87 Jern C, Ladenvall P, Wall U, Jern S. Gene polymorphism of t-PA is associated with forearm vascular release rate of t-PA. Arterioscler Thromb Vasc Biol 1999; 19 (2) 454-459
88 Valle-Garay E, Montes AH, Corte JR, Meana A, Fierer J, Asensi V. tPA Alu (I/D) polymorphism associates with bacterial osteomyelitis. J Infect Dis 2013; 208 (2) 218-223
89 Ladenvall P, Wall U, Jern S, Jern C. Identification of eight novel single-nucleotide polymorphisms at human tissue-type plasminogen activator (t-PA) locus: association with vascular t-PA release in vivo. Thromb Haemost 2000; 84 (2) 150-155
90 Li JF, Lin Y, Yang YH , et al. Fibrinogen A(alpha) Thr312Ala polymorphism specifically contributes to chronic thromboembolic pulmonary hypertension by increasing fibrin resistance. PLoS One 2013; 8 (7) e69635
91 Dosne AM, Dupuy E, Bodevin E. Production of a fibrinolytic inhibitor by cultured endothelial cells derived from human umbilical vein. Thromb Res 1978; 12 (3) 377-387
92 Kawano T, Morimoto K, Uemura Y. Urokinase inhibitor in human placenta. Nature 1968; 217 (5125) 253-254
93 Scott RW, Bergman BL, Bajpai A , et al. Protease nexin. Properties and a modified purification procedure. J Biol Chem 1985; 260 (11) 7029-7034
94 Pollack MM, Ruttimann UE, Getson PR. Pediatric risk of mortality (PRISM) score. Crit Care Med 1988; 16 (11) 1110-1116
95 Binder A, Endler G, Müller M, Mannhalter C, Zenz W ; European Meningococcal Study Group. 4G4G genotype of the plasminogen activator inhibitor-1 promoter polymorphism associates with disseminated intravascular coagulation in children with systemic meningococcemia. J Thromb Haemost 2007; 5 (10) 2049-2054
96 Geishofer G, Binder A, Müller M , et al; Central European Meningococcal Genetic Study Group. 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene in children with systemic meningococcaemia. Eur J Pediatr 2005; 164 (8) 486-490
97 Haralambous E, Hibberd ML, Hermans PWM, Ninis N, Nadel S, Levin M. Role of functional plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism in susceptibility, severity, and outcome of meningococcal disease in Caucasian children. Crit Care Med 2003; 31 (12) 2788-2793
98 Sapru A, Hansen H, Ajayi T , et al. 4G/5G polymorphism of plasminogen activator inhibitor-1 gene is associated with mortality in intensive care unit patients with severe pneumonia. Anesthesiology 2009; 110 (5) 1086-1091
99 Yende S, Angus DC, Ding J , et al; Health ABC Study. 4G/5G plasminogen activator inhibitor-1 polymorphisms and haplotypes are associated with pneumonia. Am J Respir Crit Care Med 2007; 176 (11) 1129-1137
100 Komitopoulou A, Platokouki H, Kapsimali Z , et al. Mutations and polymorphisms in genes affecting haemostasis components in children with thromboembolic events. Pathophysiol Haemost Thromb 2006; 35 (5) 392-397
101 Mansilha A, Araújo F, Severo M, Sampaio SM, Toledo T, Albuquerque R. Genetic polymorphisms and risk of recurrent deep venous thrombosis in young people: prospective cohort study. Eur J Vasc Endovasc Surg 2005; 30 (5) 545-549
102 Balcerzyk A, Żak I, Emich-Widera E , et al. The plasminogen activator inhibitor-1 gene polymorphism in determining the risk of pediatric ischemic stroke--case control and family-based study. Neuropediatrics 2011; 42 (2) 67-70
103 Komitopoulou A, Platokouki H, Kapsimali Z, Pergantou H, Adamtziki E, Aronis S. Mutations and polymorphisms in genes affecting hemostasis proteins and homocysteine metabolism in children with arterial ischemic stroke. Cerebrovasc Dis 2006; 22 (1) 13-20
104 Lynch JK, Han CJ, Nee LE, Nelson KB. Prothrombotic factors in children with stroke or porencephaly. Pediatrics 2005; 116 (2) 447-453
105 Nowak-Göttl U, Sträter R, Kosch A , et al; Childhood Stroke Study Group. The plasminogen activator inhibitor (PAI)-1 promoter 4G/4G genotype is not associated with ischemic stroke in a population of German children. Eur J Haematol 2001; 66 (1) 57-62
106 Calabrò RS, La Spina P, Serra S , et al. Prevalence of prothrombotic polymorphisms in a selected cohort of cryptogenic and noncryptogenic ischemic stroke patients. Neurol India 2009; 57 (5) 636-637
107 Kathiresan S, Gabriel SB, Yang Q , et al. Comprehensive survey of common genetic variation at the plasminogen activator inhibitor-1 locus and relations to circulating plasminogen activator inhibitor-1 levels. Circulation 2005; 112 (12) 1728-1735
108 Laine O, Joutsi-Korhonen L, Mäkelä S , et al. Polymorphisms of PAI-1 and platelet GP Ia may associate with impairment of renal function and thrombocytopenia in Puumala hantavirus infection. Thromb Res 2012; 129 (5) 611-615
109 Bouton MC, Boulaftali Y, Richard B, Arocas V, Michel JB, Jandrot-Perrus M. Emerging role of serpinE2/protease nexin-1 in hemostasis and vascular biology. Blood 2012; 119 (11) 2452-2457
110 Vaughan PJ, Cunningham DD. Regulation of protease nexin-1 synthesis and secretion in cultured brain cells by injury-related factors. J Biol Chem 1993; 268 (5) 3720-3727
111 Guttridge DC, Lau AL, Cunningham DD. Protease nexin-1, a thrombin inhibitor, is regulated by interleukin-1 and dexamethasone in normal human fibroblasts. J Biol Chem 1993; 268 (25) 18966-18974
112 Abdul S, Leebeek FW, Rijken DC, Uitte de Willige S. Natural heterogeneity of α2-antiplasmin: functional and clinical consequences. Blood 2016; 127 (5) 538-545
113 Kager LM, Weehuizen TA, Wiersinga WJ , et al. Endogenous α2-antiplasmin is protective during severe gram-negative sepsis (melioidosis). Am J Respir Crit Care Med 2013; 188 (8) 967-975
114 Dalli J, Norling LV, Montero-Melendez T , et al. Microparticle alpha-2-macroglobulin enhances pro-resolving responses and promotes survival in sepsis. EMBO Mol Med 2014; 6 (1) 27-42
115 de Boer JP, Creasey AA, Chang A , et al. Alpha-2-macroglobulin functions as an inhibitor of fibrinolytic, clotting, and neutrophilic proteinases in sepsis: studies using a baboon model. Infect Immun 1993; 61 (12) 5035-5043
116 Humphries SE, Cook M, Dubowitz M, Stirling Y, Meade TW. Role of genetic variation at the fibrinogen locus in determination of plasma fibrinogen concentrations. Lancet 1987; 1 (8548) 1452-1455
117 Danesh J, Lewington S, Thompson SG , et al; Fibrinogen Studies Collaboration. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA 2005; 294 (14) 1799-1809
118 Manocha S, Russell JA, Sutherland AM, Wattanathum A, Walley KR. Fibrinogen-beta gene haplotype is associated with mortality in sepsis. J Infect 2007; 54 (6) 572-577
119 Biswas A, Tiwari AK, Ranjan R , et al. Prothrombotic polymorphisms, mutations, and their association with pediatric non-cardioembolic stroke in Asian-Indian patients. Ann Hematol 2009; 88 (5) 473-478
120 Camilleri RS, Cohen H. No association between pulmonary embolism or deep vein thrombosis and the -455G/A beta-fibrinogen gene polymorphism. Blood Coagul Fibrinolysis 2005; 16 (3) 193-198
121 van Hylckama Vlieg A, Rosendaal FR. High levels of fibrinogen are associated with the risk of deep venous thrombosis mainly in the elderly. J Thromb Haemost 2003; 1 (12) 2677-2678
122 Standeven KF, Grant PJ, Carter AM, Scheiner T, Weisel JW, Ariëns RA. Functional analysis of the fibrinogen Aalpha Thr312Ala polymorphism: effects on fibrin structure and function. Circulation 2003; 107 (18) 2326-2330
123 Kovar FM, Marsik C, Jilma B , et al. The fibrinogen -148 C/T polymorphism influences inflammatory response in experimental endotoxemia in vivo. Thromb Res 2007; 120 (5) 727-731
124 Rubattu S, Speranza R, Ferrari M , et al. A role of TNF-alpha gene variant on juvenile ischemic stroke: a case-control study. Eur J Neurol 2005; 12 (12) 989-993
125 Foley JH, Kim PY, Mutch NJ, Gils A. Insights into thrombin activatable fibrinolysis inhibitor function and regulation. J Thromb Haemost 2013; 11 (Suppl. 01) 306-315
126 Henry M, Aubert H, Morange PE , et al. Identification of polymorphisms in the promoter and the 3′ region of the TAFI gene: evidence that plasma TAFI antigen levels are strongly genetically controlled. Blood 2001; 97 (7) 2053-2058
127 Emonts M, de Bruijne EL, Guimarães AH , et al. Thrombin-activatable fibrinolysis inhibitor is associated with severity and outcome of severe meningococcal infection in children. J Thromb Haemost 2008; 6 (2) 268-276
128 Zeerleder S, Schroeder V, Hack CE, Kohler HP, Wuillemin WA. TAFI and PAI-1 levels in human sepsis. Thromb Res 2006; 118 (2) 205-212
129 Kremer Hovinga JA, Franco RF, Zago MA, Ten Cate H, Westendorp RG, Reitsma PH. A functional single nucleotide polymorphism in the thrombin-activatable fibrinolysis inhibitor (TAFI) gene associates with outcome of meningococcal disease. J Thromb Haemost 2004; 2 (1) 54-57
130 Muszbek L, Bagoly Z, Bereczky Z, Katona E. The involvement of blood coagulation factor XIII in fibrinolysis and thrombosis. Cardiovasc Hematol Agents Med Chem 2008; 6 (3) 190-205
131 Sakata Y, Aoki N. Significance of cross-linking of alpha 2-plasmin inhibitor to fibrin in inhibition of fibrinolysis and in hemostasis. J Clin Invest 1982; 69 (3) 536-542
132 Valnickova Z, Enghild JJ. Human procarboxypeptidase U, or thrombin-activable fibrinolysis inhibitor, is a substrate for transglutaminases. Evidence for transglutaminase-catalyzed cross-linking to fibrin. J Biol Chem 1998; 273 (42) 27220-27224
133 Ariëns RA, Lai TS, Weisel JW, Greenberg CS, Grant PJ. Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms. Blood 2002; 100 (3) 743-754
134 Ariëns RA, Philippou H, Nagaswami C, Weisel JW, Lane DA, Grant PJ. The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure. Blood 2000; 96 (3) 988-995
135 Kovar FM, Marsik CL, Jilma B , et al. The inflammatory response is influenced by FXIII VAL 34 LEU polymorphism in a human LPS model. Wien Klin Wochenschr 2009; 121 (15-16) 515-519
136 Zeerleder S, Schroeder V, Lämmle B, Wuillemin WA, Hack CE, Kohler HP. Factor XIII in severe sepsis and septic shock. Thromb Res 2007; 119 (3) 311-318
137 Egbring R, Schmidt W, Fuchs G, Havemann K. Demonstration of granulocytic proteases in plasma of patients with acute leukemia and septicemia with coagulation defects. Blood 1977; 49 (2) 219-231
138 Holst FG, Hemmer CJ, Foth C, Seitz R, Egbring R, Dietrich M. Low levels of fibrin-stabilizing factor (factor XIII) in human Plasmodium falciparum malaria: correlation with clinical severity. Am J Trop Med Hyg 1999; 60 (1) 99-104
139 Härtel C, König I, Köster S , et al. Genetic polymorphisms of hemostasis genes and primary outcome of very low birth weight infants. Pediatrics 2006; 118 (2) 683-689
140 Van Hylckama Vlieg A, Komanasin N, Ariëns RA , et al. Factor XIII Val34Leu polymorphism, factor XIII antigen levels and activity and the risk of deep venous thrombosis. Br J Haematol 2002; 119 (1) 169-175
141 Kopyta IA, Emich-Widera E, Balcerzyk A , et al. Polymorphisms of genes encoding coagulation factors II, V, VII, and XIII in relation to pediatric ischemic stroke: family-based and case-control study. Neurologist 2012; 18 (5) 282-286
142 Franco RF, Reitsma PH, Lourenço D , et al. Factor XIII Val34Leu is a genetic factor involved in the etiology of venous thrombosis. Thromb Haemost 1999; 81 (5) 676-679
143 Davila S, Wright VJ, Khor CC , et al; International Meningococcal Genetics Consortium. Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease. Nat Genet 2010; 42 (9) 772-776
144 Rautanen A, Mills TC, Gordon AC , et al; ESICM/ECCRN GenOSept Investigators. Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study. Lancet Respir Med 2015; 3 (1) 53-60

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