The clinical investigator

, Volume 70, Issue 6, pp 529–534 | Cite as

Acquired protein S deficiency

  • B. Kemkes-Matthes
Molecular Medicine Review


Hereditary deficiencies of coagulation inhibitors like antithrombin 111, protein C and protein S lead to an enhanced incidence of thromboembolic complications. Recently, acquired deficiencies of protein S were described in several disease states in which thromboembolic complications frequently occur. These acquired protein S deficiencies reach — in part — the extent realised by hereditary protein S deficiency. Thus, acquired protein S deficiencies seem to be one source of thromboembolic complications occurring in nephrotic syndrome, acute phase reactions, malignancy and pregnancy. In this presentation disease states accompanied by acquired protein S deficiency and the mechanisms leading to these alterations are discussed.

Key words

Acquired protein S deficiency Thrombosis 



antithrombin III


C4b-binding protein


disseminated intravascular coagulation


systemic lupus erythematosus


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bezeaud A, Venisse L, Conard J, Horellou MH, Salomon JL, Lebaleur A, Samama M, Guillin MC (1987) Déficit héréditaire en protéine S et thromboses veineuses récidivantes. Presse Med 16:1895–1897Google Scholar
  2. 2.
    Boerger LM, Morris PC, Thurnau GR, Esmon CT, Comp PC (1987) Oral contraceptives and gender affect protein S status. Blood 69:692–694Google Scholar
  3. 3.
    Böttiger LE, Boman G, Eklund G, Westerholm B (1980) Oral contraceptives and thromboembolic disease: effects of lowering oestrogen content. Lancet 1:1099–1101Google Scholar
  4. 4.
    Broekmans AW, Bertina RM, Loeliger EA, Hofmann V (1983) Protein C and the development of skin necrosis during anticoagulant therapy. Thromb Haemost 49:244Google Scholar
  5. 5.
    Broekmans AW, Bertina RM, Reinalda-Poot J, Engesser L, Muller HP, Lceuw JA, Michiels JJ, Brommer EJP, Briet E (1985) Hereditary protein S deficiency and venous thrombo-embolism. A study in three Dutch families. Thromb Haemost 37:273–277Google Scholar
  6. 6.
    Chafa O, Fischer AM, Meriane F, Chellali F, Rahal S, Sternberg C, Benabadji M (1989) A new case of “type II” inherited protein S deficiency. Br J Haematol 73:501–505Google Scholar
  7. 7.
    Cole MS, Minifee PK, Wolma FJ (1988) Coumarin necrosis — a review of the literature. Surgery 103:271–277Google Scholar
  8. 8.
    Comp PC (1984) Animal studies on protein C physiology. Semin Thromb Haemost 10:149–153Google Scholar
  9. 9.
    Comp PC, Esmon CT (1981) Generation of fibrinolytic activity by infusion of activated protein C into dogs. J Clin Invest 68:1221–1228Google Scholar
  10. 10.
    Comp PC, Nixon RR, Cooper MR, Esmon CT (1984) Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 74:2082–2088Google Scholar
  11. 11.
    Comp PC, Doray D, Patton D, Esmon CT (1986) An abnormal plasma distribution of protein S occurs in functional protein S deficiency. Blood 67:504–508Google Scholar
  12. 12.
    Comp PC, Thurnau GR, Welsh J, Esmon CT (1986) Functional and immunologic protein S levels are decreased during pregnancy. Blood 68:881–885Google Scholar
  13. 13.
    Conlan MG, Haire WD (1989) Low protein S in essential thrombocythemia with thrombosis. Am J Hematol 32:88–93Google Scholar
  14. 14.
    Dahlbäck B (1984) Interaction between vitamin K-dependent protein S and the complement protein, C4b-binding protein. Semin Thromb Hemost 10:139–148Google Scholar
  15. 15.
    D'Angelo A, Vigano-D'Angelo S, Esmon CT, Comp PC (1988) Acquired deficiencies of protein S. J Clin Invest 81:1445–1454Google Scholar
  16. 16.
    De Boer K, Cate JW ten, Sturk A, Borm JJJ, Treffers PE (1989) Enhanced thrombin generation in normal and hypertensive pregnancy. Am J Obstet Gynecol 160:95–100Google Scholar
  17. 17.
    De Fouw NJ, Hinsbergh VWM van, Jong YF de, Haverkate F, Bertina RM (1987) The interaction of activated protein C and thrombin with the plasminogen activator inhibitor released from human endothelial cells. Thromb Haemost 57:176–182Google Scholar
  18. 18.
    Engesser L, Broekmans AW, Brier E, Brommer EJP, Bertina RM (1987) Hereditary protein S deficiency: clinical manifestations. Ann Int Med 106:677–682Google Scholar
  19. 19.
    Esmon CT (1983) Protein C: biochemistry, physiology, and clinical implications. Blood 62:1155–1158Google Scholar
  20. 20.
    Esmon CT, Esmon NL (1984) Protein C activation. Semin Thromb Haemost 10:122–130Google Scholar
  21. 21.
    Esmon NL, Owen WG, Esmon CT (1982) Isolation of a membrane-bound cofactor for thrombin-catalyzed activation of protein C. J Biol Chem 257:859–864Google Scholar
  22. 22.
    Fair DS, Marlar RA, Levin EG (1986) Human endothelial cells synthesize protein S. Blood 67:1168–1171Google Scholar
  23. 23.
    Fernández JA, Estellés A, Gilabert J, Espana F, Aznar J (1989) Functional and immunologic protein S in normal pregnant women and in full-term newborns. Thromb Haemost 61:474–478Google Scholar
  24. 24.
    Freyssinet J-M, Cazenave J-P (1987) Lupus-like anticoagulants, modulation of the protein C pathway and thrombosis. Thromb Haemost 58:679–681Google Scholar
  25. 25.
    Gerstmann BB, Piper JM, Tomita DK, Ferguson WJ, Stadel BV, Lundin FE (1991) Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease. Am J Epidemiol 133:32–37Google Scholar
  26. 26.
    Gilabert J, Fernandez JA, Espana F, Aznar J, Estelles A (1988) Physiological coagulation inhibitors (protein S, protein C and antithrombin III) in severe preeclamptic states and in users of oral contraceptives. Thromb Res 49:319–329Google Scholar
  27. 27.
    Gips H (1986) Endokrinologie der Schwangerschaft. In: Künzel W, Wulf KH (eds) Klinik der Frauenheilkunde und Geburtshilfe, vol 4. Die normale Schwangerschaft. Urban & Schwarzenberg, Munich, pp 351–371Google Scholar
  28. 28.
    Gladson CL, Schleef RR, Binder BR, Loskutoff DJ, Griffin JH (1989) A comparison between activated protein C and des-1–41-light chain-activated protein C in reactions with type 1 plasminogen activator inhibitor. Blood 74:173–181Google Scholar
  29. 29.
    Gonzalez R, Alberca I, Vicente V (1985) Protein C levels in late pregnancy, postpartum and in women on oral contraceptives. Thromb Res 39:637–640Google Scholar
  30. 30.
    Grimaudo V, Gueissaz F, Hauert J, Sarraj A, Kruithof EKO, Bachmann F (1989) Necrosis of skin induced by coumarin in a patient deficient in protein S. Br Med J 298:233–234Google Scholar
  31. 31.
    Heeb MJ, Mosher D, Griffin JH (1989) Activation and complexation of protein C and cleavage and decrease of protein S in plasma of patients with intravascular coagulation. Blood 73:455–461Google Scholar
  32. 32.
    Heidinger K, Kemkes-Matthes B, Matthes KJ (1991) Veränderungen antikoagulatorisch wirksamer Plasmaproteine bei entzündlichen Erkrankungen. Klin Wochenschr 69 [Suppl XXIII]:130Google Scholar
  33. 33.
    Hesselvik JF, Malm J, Dahlbäck B, Blombäck M (1991) Protein C, protein S and C4b-binding protein in severe infection and septic shock. Thromb Haemost 65:126–129Google Scholar
  34. 34.
    Hillarp A, Dahlbäck B (1987) The protein S-binding site localized to the central core of C4b-binding protein. J Biol Chem 262:11300–11307Google Scholar
  35. 35.
    Hillarp A, Hessing M, Dahlbäck B (1989) Protein S binding in relation to the subunit composition of human C4b-binding protein. FEBS Lett 259:53–56Google Scholar
  36. 36.
    Huisveld IA, Hospers JEH, Meijers JCM, Starkenburg AE, Erich WBM, Bouma BN (1987) Oral contraceptives reduce total protein S, but not free protein S. Thromb Res 45:109–114Google Scholar
  37. 37.
    Jeffries WS, Bochner F (1991) Thromboembolism and its management in pregnancy. Med J Aust 155:253–258Google Scholar
  38. 38.
    Jespersen J, Gram J, Bertina RM (1989) The risk of thrombosis in hereditary protein S deficiency in a Scandinavian family. Fibrinolysis 3:37–40Google Scholar
  39. 39.
    Jorens PG, Hermanns CR, Haber I, Kockx MM, Vermylen J, Parizel GA (1990) Acquired protein C and S deficiency, inflammatory bowel disease and cerebral arterial thrombosis. Blut 61:307–310Google Scholar
  40. 40.
    Keeling DM, Campbell SJ, Mackie IJ, Machin SJ, Isenberg DA (1990) Total and free protein S in systemic lupus erythematosus. Thromb Res 60:237–240Google Scholar
  41. 41.
    Kemkes-Matthes B, Matthes KJ (1985) Zusammenhänge zwischen Gerinnungsfaktoren und anderen Plasmaproteinen bei chronischen Lebererkrankungen. Med Welt 36:1223–1227Google Scholar
  42. 42.
    Kemkes-Matthes B, Matthes KJ (1988) Protein S bei Lebererkrankungen. Klin Wochenschr 66 [Suppl XIII]:64Google Scholar
  43. 43.
    Kemkes-Matthes B, Matthes KJ (1989) Veränderungen antikoagulatorisch wirksamer Plasmaproteine bei Lebererkrankungen. Zeitschr Gastroenterol XXVII:37Google Scholar
  44. 44.
    Kemkes-Matthes B, Matthes KJ (1990) Beziehungen zwischen Protein S und C4b-Bindungsprotein bei akuten und chronischen Lebererkrankungen. Med Welt 41:923–926Google Scholar
  45. 45.
    Kemkes-Matthes B, Heinrich D, Dapper F, Lasch HG (1988) Kumarinnekrose bei Protein C-Mangel. Med Welt 39:72–75Google Scholar
  46. 46.
    Kemkes-Matthes B, Matthes KJ, Pralle H (1988) Protein S bei metastasierten Carcinomen und Lymphomen. Klin Wochenschr 66 [Suppl XIII]:269Google Scholar
  47. 47.
    Kemkes-Matthes B, Matthes KJ, Pralle H (1989) Protein S in pulmonary and intestinal cancer patients. Thromb Haemost 62:273Google Scholar
  48. 48.
    Kemkes-Matthes B, Pralle H, Matthes KJ (1989) Protein S — Zusammenhänge zwischen Thromboseneigung und Metastasierung bei Karzinompatienten. Klin Wochenschr 67 [Suppl XVI]:165Google Scholar
  49. 49.
    Kemkes-Matthes B, Plusczyk T, Lasch HG (1992) Coagulation inhibitors in pulmonary cancer patients. Thromb Res (manuscript submitted)Google Scholar
  50. 50.
    Madden RM, Gill JC, Marlar RA (1990) Protein C and protein S levels in two patients with acquired purpura fulminans. Br J Haematol 75:112–117Google Scholar
  51. 51.
    Malm J, Laurell M, Dahlbäck B (1988) Changes in the plasma levels of vitamin K-dependent proteins C and S and of C4b-binding protein during pregnancy and oral contraception. Br J Haematol 68:437–443Google Scholar
  52. 52.
    Manucci PM, Vigano S (1982) Deficiencies of protein C, an inhibitor of blood coagulation. Lancet II:463–466Google Scholar
  53. 53.
    McGehee WG, Klotz TA, Epstein DJ, Rapaport SI (1984) Coumarin necrosis associated with hereditary protein C deficiency. Ann Int Med 100: 59–60Google Scholar
  54. 54.
    Melis GB, Fruzzetti F, Ricci C, Carmassi F, Fioretti P (1988) Oral contraceptives and venous thromboembolic disease: the effect of the oestrogen dose. Maturitas [Suppl] 1:131–139Google Scholar
  55. 55.
    Melissari E, Kakkar VV (1988) The effects of oestrogen administration on the plasma free protein S and C4b-binding protein. Thromb Res 49:489–495Google Scholar
  56. 56.
    Michiels JJ, Stibbe J, Bettina R, Broekmans A (1987) Effectiveness of long oral anticoagulation treatment in preventing venous thrombosis in hereditary protein S deficiency. Br Med J 295:641–643Google Scholar
  57. 57.
    Moreb J, Kitchens CS (1989) Acquired functional protein S deficiency, cerebral venous thrombosis, and coumarin skin necrosis in association with antiphospholipid syndrome: report of two cases. Am J Med 87:207–210Google Scholar
  58. 58.
    Odegaard B, Mann K (1987) Proteolysis of factor Va by factor Xa and activated protein C. J Biol Chem 262:11233–11238Google Scholar
  59. 59.
    Ogura M, Tanabe N, Nishioka J, Suzuki K, Saito H (1987) Biosynthesis and secretion of functional protein S by a human megakaryoblastic cell line (MEG-01). Blood 70:301–306Google Scholar
  60. 60.
    Sack GH, Levin J, Bell W (1977) Trousseau's syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic, and therapeutic features. Medicine 56:1–37Google Scholar
  61. 61.
    Saeki T, Hirose S, Nukatsuda M, Kusunoki Y, Nagasawa S (1989) Evidence that C4b-binding protein is an acute phase protein. Biochem Biophys Res Commun 164:1446–1451Google Scholar
  62. 62.
    Sakata Y, Loskutoff DJ, Gladson CL, Hekman CM, Griffin JH (1986) Mechanism of protein C-dependent clot lysis: role of plasminogen activator inhibitor. Blood 68:1218–1223Google Scholar
  63. 63.
    Saleh AA, Bottoms SF, Welch RA, Ali AM, Mariona FG, Mammen EF (1987) Preeclampsia, delivery, and the hemostatic system. Am J Obstet Gynecol 157:331–336Google Scholar
  64. 64.
    Schved JF, Gris JC, Sarlat C, Amiral J, Brun S, Brunschwig C, Petris I, Lassonery M (1990) Study of quantitative modifications of the plasma protein S system components in nonacute inflammatory syndromes. Nouv Rev Hematol 32:271–276Google Scholar
  65. 65.
    Takahashi H, Takewaki W, Wada K, Shibata A (1989) Plasma protein S in disseminated intravascular coagulation, liver disease, collagen disease, diabetes mellitus, and under oral anti-coagulant therapy. Clin Chim Acta 182:195–208Google Scholar
  66. 66.
    Taylor FB Jr, Lockhart MS (1985) A new function for activated protein C: activated protein C prevents inhibition of plasminogen activators by release from mononuclear leucocytes-platelet suspensions stimulated by phorbol diester. Thromb Res 37:155–164Google Scholar
  67. 67.
    Troy K, Essex D, Rand J, Lema M, Cuttner J (1991) Protein C and S levels in acute leukemia. Am J Hematol 37:159–162Google Scholar
  68. 68.
    Tsakiris DA, Settas L, Makris PE, Marbet GA (1990) Lupus anticoagulant-antiphospholipid antibodies and thrombophilia. Relation to protein C-protein S-thrombomodulin. J Rheumatol 17:785–789Google Scholar
  69. 69.
    Vigano-D'Angelo S, D'Angelo A, Kaufman CE, Sholer C, Esmon CT, Comp PC (1987) Protein S deficiency occurs in the nephrotic syndrome. Ann Int Med 107:42–47Google Scholar
  70. 70.
    Walker FJ (1984) Protein S and the regulation of activated protein C. Semin Thromb Hemost 10:131–138Google Scholar
  71. 71.
    Walker FJ, Chavin SL Fay PJ (1987) Inactivation of factor VIII by activated protein C and protein S. Arch Biochem Biophys 252:322–328Google Scholar
  72. 72.
    Warwick R, Hutton RA, Goff L, Letsky E, Heard M (1989) Changes in protein C and free protein S during pregnancy and following hysterectomy. J R Soc Med 82:591–594Google Scholar
  73. 73.
    Wyshock E, Caldwell M, Crowley JP (1988) Deep venous thrombosis, inflammatory bowel disease, and protein S deficiency. Am J Clin Pathol 90:633–635Google Scholar
  74. 74.
    Zoppi M, Furlan M, Brun del Re G, Wuillemin W, Lämmle B (1990) Decreased free protein S levels in polycythemia vera. Thromb Haemost 64:177–178Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • B. Kemkes-Matthes
    • 1
  1. 1.Zentrum für Innere Medizin der Justus Liebig Universität GießenGießen

Personalised recommendations