Skip to main content
SpringerLink
Log in

Gerinnungsinhibitoren bei Sepsis und disseminierter intravasaler Gerinnung

  • Conference paper
Fachübergreifende Aspekte der Hämostaseologie

Zusammenfassung

Eine grundlegende und für den deutschen Sprachraum prägende Definition der Sepsis geht auf H.Schottmüller zurück [68, 69]. Danach liegt eine Sepsis vor, „wenn sich innerhalb des Körpers ein Herd gebildet hat, von dem konstant oder periodisch pathogene Bakterien in den Blutkreislauf gelangen, und zwar derart, daß durch diese Invasion subjektive und objektive Krankheitserscheinungen ausgelöst werden“. Hiervon abweichend wird die Sepsis in der jüngeren angloamerikanischen Literatur als systemische Entzündungsreaktion auf eine aktive Infektion definiert, klinisch evident durch Fieber, Tachykardie, Tachypnoe und/oder Leukozytose bzw. Leukozytopenie [2]. Bei einer schweren Sepsis („severe sepsis“) treten Zeichen der inadäquaten Organperfusion oder Organdysfunktion wie Hypoxämie, Laktatanstieg, Oligurie oder Bewußtseinsstörungen hinzu [2]. Schwerste Verläufe fuhren zu Schock und Multiorganversagen.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 54.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 69.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literatur

  1. Abbink JJ, Nuijens JH, Eerenberg AJM et al. (1991) Quantification of functional and inactivated a2-macroglobulin in sepsis. Thromb Haemost 65: 32–39

    PubMed  CAS  Google Scholar 

  2. American College of Chest Physicians (1992) Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20: 864–874

    Article  Google Scholar 

  3. Aoki Y, Ohishi R, Takei R et al. (1993) Effects of recombinant human soluble thrombomodulin (rhs-TM) on disseminated intravascular coagulation model in rats with decreased AT III level. Thromb Haemost 69: 736 (abstract)

    Google Scholar 

  4. Asakura H, Jokaji H, Saito M et al. (1991) Plasma levels of soluble thrombomodulin increase in cases of disseminated intravascular coagulation with organ failure. Am J Hematol 38: 281–287

    Article  PubMed  CAS  Google Scholar 

  5. Bajaj MS, Rana SV, Wysolmerski RB, Bajaj SP (1987) Inhibitor of the factor Vila-tissue factor complex is reduced in patients with disseminated intravascular coagulation but not in patients with severe hepatocellular disease. J Clin Invest 79: 1874–1878

    Article  PubMed  CAS  Google Scholar 

  6. Blauhut B, Necek S, Vinazzer H, Bergmann H (1982) Substitution therapy with an antithrombin III concentrate in shock and DIC. Thromb Res 27: 271–278

    Article  PubMed  CAS  Google Scholar 

  7. Blauhut B, Kramar H, Vinazzer H, Bergmann H (1985) Substitution of antithrombin III in shock and DIC. A randomized study. Thromb Res 39: 81–89

    Article  PubMed  CAS  Google Scholar 

  8. Boer JP de, Abbink J J, Brouwer MC et al. (1991) PAI-1 synthesis in the human hepatoma cell line Hep G2 is increased by cytokines — evidence that the liver contributes to acute phase behaviour of PAI-1. Thromb Haemost : 181–185

    PubMed  Google Scholar 

  9. Brandtzaeg P, Sandset PM, Joo GB et al. (1989) The quantitative association of plasma endotoxin, antithrombin, protein C, extrinsic pathway inhibitor and fibrino-peptide A in systemic meningococcal disease. Thromb Res 55: 459–470

    Article  PubMed  CAS  Google Scholar 

  10. Brandtzaeg P, Joo GB, Brusletto B, Kierulf P (1990) Plasminogen activator inhibitor 1 and 2, alpha-2-antiplasmin, plasminogen, and endotoxin levels in systemic meningococcal disease. Thromb Res 57: 271–278

    Article  PubMed  CAS  Google Scholar 

  11. Comp PC, Esmon CT (1991) Regulatory mechanisms in hemostasis: Natural anticoagulants. In: Hoffman R, Benz EJ, Shattil SJ et al. (eds) Hematology. Basic principles and practice. Churchill Livingstone, New York, pp 1243–1251

    Google Scholar 

  12. Chuansumrit A, Manco-Johnson MJ, Hathaway WE (1989) Heparin cofactor II in adults and infants with thrombosis and DIC. Am J Hematol 31: 109–113

    Article  PubMed  CAS  Google Scholar 

  13. Day KC, Hoffman LC, Palmier MO et al. (1990) Recombinant lipoprotein-associated coagulation inhibitor inhibits tissue thromboplastin-induced intravascular coagulation in the rabbit. Blood 76: 1538–1545

    PubMed  CAS  Google Scholar 

  14. Deventer SJH van, Büller HR, ten Cate JW et al. (1990) Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 76: 2520–2526

    PubMed  Google Scholar 

  15. Dofferhoff ASM, Bom VJJ, Vries-Hospers HG de et al. (1992) Patterns of cytokines, plasma endotoxin, plasminogen activator inhibior, and acute-phase proteins during the treatment of severe sepsis in humans. Crit Care Med 20: 185–192

    Article  PubMed  CAS  Google Scholar 

  16. Emeis JJ, Kooistra T (1986) Interleukin 1 and lipopolysaccharide induce an inhibitor of tissue-type plasminogen activator in vivo and in cultured endothelial cells. J Exp Med 163: 1260–1266

    Article  PubMed  CAS  Google Scholar 

  17. Emerson TE, Fournel MA, Leach WJ, Redens TB (1987) Protection against disseminated intravascular coagulation and death by antithrombin III in the Escherichia coli endotoxemic rat. Circ Shock 21: 1–13

    PubMed  CAS  Google Scholar 

  18. Emerson TE, Fournel MA, Redens TB et al. (1989) Efficacy of antithrombin III supplementation in animal models of fulminant Escherichia coli endotoxemia or bacteremia. Am J Med 87 (3B): 27–33

    Article  Google Scholar 

  19. Esmon CT, Taylor FB, Snow Tr (1991) Inflammation and coagulation: Lined processes potentially regulated through a common pathway mediated by protein C. Thromb Haemost 66: 160–165

    PubMed  CAS  Google Scholar 

  20. Fourrier F, Chopin C, Goudemand J et al. (1992) Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 101: 816–823

    Article  PubMed  CAS  Google Scholar 

  21. Fourrier F, Chopin C, Huart JJ et al. (1993) Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Workshop on Disseminated Intravascular Coagulation, Rauischholzhausen, May 12–14, 1993 (Abstract No. 14).

    Google Scholar 

  22. Frank D, Maurin N (1993) Sepsis and septic shock: haemostasis fibrinolysis equilibrium as a prognostic factor and an indicator during therapy. Thromb Haemost 69: 731 (abstract)

    Google Scholar 

  23. Hack CE, Voerman HJ, Eisele B et al. (1992) CI-esterase inhibitor substitution in sepsis. Lancet 1: 378

    Article  Google Scholar 

  24. Hack CE, Ogilvie AC, Eisele B et al. (1993) CI-inhibitor substitution therapy in septic shock and in the vascular leak syndrome induced by high doses of interleukin-2. Intensive Care Med 19: 19–28

    Article  Google Scholar 

  25. Harper PL, Williamson L, Park G et al. (1991) A pilot study of antithrombin replacement in intensive care management: the effects on mortality, coagulation and renal function. Transfusion Med 1: 121–128

    Article  CAS  Google Scholar 

  26. Harper PL, Hermans JM, Carrell RW (1992) Recombinant natural anticoagulants: a review. J Royal Soc Med 85: 407–411

    CAS  Google Scholar 

  27. Heidinger K, Kemkes-Matthes B, Lasch HG (1993) Protein C and S in inflammatory diseases. Thromb Haemost 69: 725 (abstract)

    Google Scholar 

  28. Hellgren M, Javelin L, Hägnevik K, Blombäck M (1984) Antithrombin III concentrate as adjuvant in DIC treatment. A pilot study in 9 severely ill patients. Thromb Res 35: 459–466

    Article  PubMed  CAS  Google Scholar 

  29. Hesselvik JF, Blombäck M, Brodin B, Maller R (1989) Coagulation, fibrinolysis and kallikrein systems in sepsis: Relation to outcome. Crit Care Med 17: 724–733

    Article  PubMed  CAS  Google Scholar 

  30. Hesselvik JF, Mahn J, Dahlbäck B, Blombäck M (1991) Protein C, protein S and C4b-binding protein in severe infection and septic shock. Thromb Haemost : 126–129

    PubMed  CAS  Google Scholar 

  31. Hinsbergh VWM van, Kooistra T, van de Berg EA et al. (1988) Tumor necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cells in vitro and in rats in vivo. Blood 72: 1467–1473

    PubMed  Google Scholar 

  32. Hoffman M, Pratt CW, Brown RL, Church FC (1989) Heparin cofactor II-proteinase reaction products exhibit neutrophil chemoattractant activity. Blood 73: 1682–1685

    PubMed  CAS  Google Scholar 

  33. Inoue Y, Kohno S, Miyazaki T, Yamaguchi K (1991) Effect of a platelet activating factor antagonist and antithrombin III on septicemia and endotoxemia in rats. Tohoku J Exp Med 163: 175–185

    Article  PubMed  CAS  Google Scholar 

  34. Jordan RE, Nelson RM, Kilpatrick J et al. (1989) Inactivation of human antithrombin by neutrophil elastase. J Biol Chem 264: 10493–10500

    PubMed  CAS  Google Scholar 

  35. Juhan-Vague I, Aillaud MF, Cock F de et al. (1985) The fast-acting inhibitor of tissue plasminogen activator is an acute phase reactant protein. In: Davidson JF, Donati MB, Coccheri S (eds) Progress in fibrinolysis. Churchill Livingstone, Edinburgh p 146

    Google Scholar 

  36. Kaufman N, Page JD, Pixley RA et al. (1991) α2-Makroglobulin-kallikrein complexes detect contact system activation in hereditary angioedema and human sepsis. Blood 77: 2660–2667

    PubMed  CAS  Google Scholar 

  37. Kruithof EKO, Nicoloso G, Bachmann F (1987) Plasminogen activator inhibitor 1: Development of a radioimmunoassay and observations on its plasma concentration during venous occlusion and after platelet aggregation. Blood 70: 1645–1653

    PubMed  CAS  Google Scholar 

  38. Kruithof EKO, Calandra T, Pralong G et al. (1993) Evolution of plasminogen activator inhibitor type 1 in patients with septic shock — correlation with cytokine concentrations. Fibrinolysis 7: 117–121

    Article  Google Scholar 

  39. Laursen B, Mortensen JZ, Frost L, Hansen KB (1981) Disseminated intravascular coagulation in hepatic failure treated with antithrombin III. Thromb Res 22: 701–704

    Article  PubMed  CAS  Google Scholar 

  40. Mammen EF, Miyakawa T, Phillips TF et al. (1985) Human antithrombin concentrates and experimental disseminated intravascular coagulation. Semin Thromb Hemost 11: 373–383

    Article  PubMed  CAS  Google Scholar 

  41. Marlar RA, Endres-Brooks J, Miller C (1985) Serial studies of protein C and its plasma inhibitor in patients with disseminated intravascular coagulation. Blood 66: 59–63

    PubMed  CAS  Google Scholar 

  42. McGuire EA, Tollefsen DM (1987) Activation of heparin cofactor II by fibroblasts and vascular smooth muscle cells. J. Biol Chem 262: 169–173

    PubMed  CAS  Google Scholar 

  43. Mesters RM, Kienast J, Ostermann H, van de Loo J (1993) Tissue factor pathway inhibitor (TFPI) in septicemia: a prospective study in neutropenic patients. Thromb Haemost 69: 1198 (abstract)

    Google Scholar 

  44. Mourik JA van, Lawrence DA, Loskutoff DJ (1984) Purification of an inhibitor of plasminogen activator (antiactivator) synthesized by endothelial cells. J Biol Chem 159: 14914–14921

    Google Scholar 

  45. Novotny WF, Brown SG, Miletich JP et al. (1991) Plasma antigen levels of the lipo- protein-associated coagulation inhibitor in patient samples. Blood 78: 387–393

    PubMed  CAS  Google Scholar 

  46. Nowak-Göttl U, Groll A, Kreuz WD et al. (1992) Behandlung der Verbrauchskoagu- lopathie mit Antithrombin III-Konzentrat bei Kindern mit nachgewiesener Sepsis. Klin Pädiatr 204: 134–140

    Article  PubMed  Google Scholar 

  47. Nuijens JH, Eerenberg-Belmer AJM, Huijbregts CCM et al. (1989) Proteolytic inactivation of plasma Cl-inhibitor in sepsis. J Clin Invest 84: 443–450

    Article  PubMed  CAS  Google Scholar 

  48. Nuijens JH, Abbink JJ, Wachtfogel YT et al. (1992) Plasma elastase at-antitrypsin and lactoferrin in sepsis: evidence for neutrophils as mediators in fatal sepsis. J Lab Clin Med 119: 159–168

    PubMed  CAS  Google Scholar 

  49. Okajima K, Imamura H, Koga S et al. (1990) Treatment of patients with disseminated intravascular coagulation by protein C. Am J Hematol 33: 277–278

    Article  PubMed  CAS  Google Scholar 

  50. Okamoto K, Takaki A, Takeda S et al. (1992) Coagulopathie in disseminated intravascular coagulation due to abdominal sepsis: determination of prothrombin fragment 1+2 and other markers. Haemostasis 22: 17–24

    PubMed  CAS  Google Scholar 

  51. Owen MC, Brennan SO, Lewis JH, Carell RW (1983) Mutation of antitrypsin to antithrombin, alpha-1-antitrypsin Pittsburgh (358 Met-Arg), a fatal bleeding disorder. N Engl J Med 309: 694–698

    Article  PubMed  CAS  Google Scholar 

  52. Páramo JA, Pérez JL, Serrano M, Rocha E (1990) Types 1 and 2 plasminogen activator inhibitor and tumor necrosis factor alpha in patients with sepsis.Thromb Haemost 64: 3–6

    Google Scholar 

  53. Parker KA, Tollefsen DM (1985) The protease specificity of heparin cofactor II. J Biol Chem 260: 3501–3505

    PubMed  CAS  Google Scholar 

  54. Peters M, Fijnvandraat K, Derkx B et al. (1993) Severely reduced protein C levels predict a high mortality in meningococcal shock. Thromb Haemost 69: 1197 (abstract)

    Google Scholar 

  55. Philippé J, Offner F, Declerck PJ et al. (1991) Fibrinolysis and coagulation in patients with infectious disease and sepsis. Thromb Haemost : 291–295

    PubMed  Google Scholar 

  56. Prager RL, Dunn EL, Kirsh MM, Penner JA (1979) Endotoxin-induced intravascular coagulation (DIC) and its therapy. Adv Shock Res 2: 277–287

    PubMed  CAS  Google Scholar 

  57. Pralong G, Calandra T, Glauser MP et al. (1989) Plasminogen activator inhibitor 1: a prognostic marker in septic schock. Thromb Haemost 61: 459–462

    PubMed  CAS  Google Scholar 

  58. Rao LVM, Rapaport SI, Hoang AD (1993) Binding of factor VII a to tissue factor permits rapid antithrombin III/heparin inhibition of factor Villa. Blood 81: 2600–2607

    PubMed  CAS  Google Scholar 

  59. Rapaport SI (1991) The extrinsic pathway inhibitor: A regulator of tissue factor- dependent blood coagulation. Thromb Haemost 66: 6–15

    PubMed  CAS  Google Scholar 

  60. Redens TB, Leach WJ, Bogdanoff DA, Emerson TE (1988) Synergistic protection from lung damage by combining antithrombin-III and arproteinase inhibitor in the E. coli endotoxemic sheep pulmonary dysfunction model. Circ Shock 26: 15–26

    CAS  Google Scholar 

  61. Redens TB, Emerson TE (1989) Antithrombin III treatment limits disseminated intravascular coagulation in endotoxemia. Circ Shock 28: 49–58

    PubMed  CAS  Google Scholar 

  62. Rivard GE, David M, Farrell C et al. (1993) Treatment of purpura fulminans in meningococcemia with protein C concentrate. Thromb Heamost 69: 1198 (abstract)

    Google Scholar 

  63. Sakata Y, Curriden S, Lawrence D et al. (1985) Activated protein C stimulates the fibrinolytic activity of cultured endothelial cells and decreases antiactivator activity. Proc Natl Acad Sci USA 82: 1121–1125

    Article  PubMed  CAS  Google Scholar 

  64. Sandset PM, Roise O, Aasen AO, Abildgard U (1989) Extrinsic pathway inhibitor in postoperative/posttraumatic septicemia: increased levels in fatal cases. Haemostasis 19: 189–195

    PubMed  CAS  Google Scholar 

  65. Sandset PM, Warn-Cramer BJ, Maki SL, Rapaport SI (1991) Immunodepletion of extrinsic pathway inhibitor sensitizes rabbits to endotoxin-induced intravascular coagulation and the generalized Shwartzman reaction. Blood 78: 1496–1502

    PubMed  CAS  Google Scholar 

  66. Sandset PM, Abildgaard U (1991) Extrinsic pathway inhibitor — the key to feedback control of blood coagulation initiated by tissue thromboplastin. Haemostasis 21: 219–239

    PubMed  CAS  Google Scholar 

  67. Sandset PM; Warn-Cramer BJ, Rao LVM et al. (1991) Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: evidence supporting a physiologic role for EPI as a natural anticoagulant. Proc Natl Acad Sci USA 88: 708–712

    Article  PubMed  CAS  Google Scholar 

  68. Schipper HG, Jenkins CSP, Kahlé LH, ten Cate JW (1978) Antithrombin-III trans-fusion in disseminated intravascular coagulation. Lancet 1: 854–856

    Article  PubMed  CAS  Google Scholar 

  69. Schottmüller H (1914) Wesen und Behandlung der Sepsis. Verh Dtsch Ges Inn Med 31: 257

    Google Scholar 

  70. Schuster HP (1989) Sepsis als Ursache des Multiorganversagens. Definition, Pathophysiologic und diagnostische Parameter. Anästh Intensivther Notfallmed 24: 206–211

    Article  PubMed  CAS  Google Scholar 

  71. Seitz R, Wolf M, Egbring R et al. (1987) Participation and interactions of neutrophil elastase in haemostatic disorders of patients with severe infections. Eur J Haematol 38: 231–240

    Article  PubMed  CAS  Google Scholar 

  72. Seitz R, Wolf M, Egbring R, Havemann K (1989) The disturbance of hemostasis in septic shock: role of neutrophil elastase and thrombin, effects of antithrombin III and plasma substitution. Eur J Haematol 43: 22–28

    Article  PubMed  CAS  Google Scholar 

  73. Sprengers ED, Princen HMG, Kooistra T, Hinsbergh VWM van (1985) Inhibition of plasminogen activators by conditioned medium of human hepatocytes and hepatoma cell line Hep G2. J Lab Clin Med 105: 751–758

    PubMed  CAS  Google Scholar 

  74. Suffredini AF, Harpel PC, Parillo JE (1989) Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. N Engl J Med 320: 1165–1172

    Article  PubMed  CAS  Google Scholar 

  75. Taylor FB, Emerson TE, Jordan R et al. (1988) Antithrombin III prevents the lethal effects of Escherichia coli infusion in baboons. Circ Shock 26: 227–235

    PubMed  CAS  Google Scholar 

  76. Tollefsen DM, Pestka CA, Monafo WJ (1983) Activation of heparin cofactor II by dermatan sulfate. J Biol Chem 258: 6713–6716

    PubMed  CAS  Google Scholar 

  77. Tollefsen DM, Pestka CA (1985) Heparin cofactor II activity in patients with disseminated intravascular coagulation and hepatic failure. Blood 66: 769–774

    PubMed  CAS  Google Scholar 

  78. Tran TH, Duckert F (1984) Heparin cofactor II determination — levels in normals and patients with hereditary antithrombin III deficiency and disseminated intravascular coagulation. Thromb Haemost 52: 112–116

    PubMed  CAS  Google Scholar 

  79. Triantaphyllopoulos DC (1984) Effects of human antithrombin III on mortality and blood coagulation induced in rabbits by endotoxin. Thromb Haemost 51: 232–235

    PubMed  CAS  Google Scholar 

  80. Vinazzer H (1989) Therapeutic use of antithrombin III in shock and disseminated intravascular coagulation. Semin Thromb Haemost 15: 347–352

    Article  CAS  Google Scholar 

  81. Voss R, Matthias FR, Borkowski G, Reitz D (1990) Activation and inhibition of fibrinolysis in septic patients in an internal intensive care unit. Br J Haematol 75: 99–105

    Article  PubMed  CAS  Google Scholar 

  82. Wada H, Ohiwa M, Kaneko T et al. (1992) Plasma thrombomodulin as a marker of vascular disorders in thrombotic thrombocytopenic purpura and disseminated intravascular coagulation. Am J Hematol 39: 20–24

    Article  PubMed  CAS  Google Scholar 

  83. Warr TA, Rao LVM, Rapaport SI (1989) Human plasma extrinsic pathway inhibitor activity: II. Plasma levels in disseminated intravascular coagulation and hepatocellular disease. Blood 74: 994–998

    PubMed  CAS  Google Scholar 

  84. Wieding JU, Eisinger G, Köstering H (1989) Diagnostik der disseminierten intravasalen Gerinnung: Aussagekraft von löslichem Fibrin, D-Dimeren und Fibrin(ogen)- Spaltprodukten. Klin Wochenschr 67: 764–773

    Article  PubMed  CAS  Google Scholar 

  85. Witt W, Fredrich M, Wydro R, Morser J (1993) Antithrombotic effects of recombinant soluble human thrombomodulin analogues in animal models of tissue-factor and thrombin induced DIC, Workshop on Disseminated Intravascular Coagulation, Rauischholzhausen, May 12–14 (Abstract No. 39)

    Google Scholar 

Download references

Authors
  1. J. Kienast
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. Ostermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Mesters
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Klinik für Anaesthesiologie, Universität Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Deutschland

    E. Martin

  2. Innere Medizin I Universitätsklinik, Universität Heidelberg, Bergheimer Straße 58, 69115, Heidelberg, Deutschland

    P. P. Nawroth

Rights and permissions

Reprints and permissions

Copyright information

© 1994 Springer-Verlag Berlin Heidelberg

About this paper

Cite this paper

Kienast, J., Ostermann, H., Mesters, R. (1994). Gerinnungsinhibitoren bei Sepsis und disseminierter intravasaler Gerinnung. In: Martin, E., Nawroth, P.P. (eds) Fachübergreifende Aspekte der Hämostaseologie. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-93561-9_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-93561-9_3

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-58054-6

  • Online ISBN: 978-3-642-93561-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation