Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 2.1 (5-Year IF – 2.0)
Journal Citation Indicator (JCI) (2023) – 0.4
Scopus CiteScore – 3.7 (CiteScore Tracker – 4.3)
Index Copernicus  – 171.00; MNiSW – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2013, vol. 22, nr 4, July-August, p. 459–467

Publication type: editorial article

Language: English

Protein C and Protein S Deficiency – Practical Diagnostic Issues

Niedobór białka C i białka S – praktyczne problemy diagnostyczne

Ewa Wypasek1,2,A,B,C,D, Anetta Undas1,2,A,C,E,F

1 The John Paul II Hospital, Kraków, Poland

2 Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland

Streszczenie

Białko C (protein C, PC) i białko S (protein S, PS) to zależne od witaminy K glikoproteiny będące naturalnymi inhibitorami krzepnięcia krwi. Proteolityczna aktywacja PC przez trombinę zachodzi na powierzchni komórek śródbłonka w obecności trombomoduliny i śródbłonkowego receptora PC. Aktywne PC (APC) z udziałem kofaktora, którym jest PS, w obecności fosfolipidów i wapnia, degraduje czynnik Va i FVIIIa przez ich cięcie w specyficznych resztach argininowych. Niedobory PC i PS są podłożem występowania i nawrotów żylnej choroby zakrzepowozatorowej (ż.ch.z.z.). Niedobory PC/PS są dziedziczone w sposób autosomalny dominujący i w większości przypadków pochodzą z heterozygotycznych mutacji typu zmiany sensu (odpowiednio: 78 i 63%). Heterozygotyczny niedobór PC występuje u 6% rodzin z trombofilią, u 3% pacjentów, z pierwszym epizodem zakrzepicy żył głębokich oraz u 0,2–0,3% osób zdrowych. Niedobór PS pojawia się częściej niż niedobór PC, a jego występowanie szacuje się na mniej niż 0,5% w zdrowej populacji europejskiej i 2–12% u pacjentów z zakrzepicą. U około 75% pacjentów z niedoborem PC występuje niedobór typu I, a u 95% pacjentów z niedoborem PS rozwija się typ I i typ III niedoboru. Diagnostyka niedoborów PC i PS jest trudna ze względu na występowanie wielu czynników fazy przedi analitycznej wpływających na stężenia PC i PS. Analiza molekularna genów PC i PS (odpowiednio: PROC i PROS1) obejmuje ich bezpośrednie sekwencjonowanie genów, a w przypadku wyniku negatywnego stosuje się metodę multipleksowej amplifikacji sondy zależnej od ligacji (multiplex ligation-dependent probe amplification, MLPA). Pacjenci z małymi stężeniami PC i PS oraz mutacją w genach PROC lub PROS1 w połączeniu z innymi genetycznymi i środowiskowymi czynnikami sprzyjającymi zakrzepicy są narażeni na zwiększone ryzyko nawracających epizodów zakrzepowo-zatorowych, co jest wskazaniem do stosowania przewlekłej antykoagulacji.

Key words

protein C, protein S, deficiency, venous thromboembolism, mutation.

Słowa kluczowe

białko C, białko S, niedobór, zakrzepica żylna, mutacja.

References (47)

  1. Esmon CT: The protein C pathway. Chest 2003, 124, 26S–32S.
  2. Dahlbäck B: Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood 2008, 112, 19–27.
  3. Dahlback B: Inhibition of protein Ca cofactor function of human and bovine protein S by C4b-binding protein. J Biol Chem 1986, 261, 12022–12027.
  4. Hackeng TM, van’t Veer C, Meijers JCM, Bouma BN: Human protein S inhibits prothrombinase complex activity on endothelial cells via a direct interaction of protein S with factor Va and Xa. Evidence for an activated protein C independant anticoagulant function of protein S in plasma. J Biol Chem 1994, 269, 21051–21058.
  5. Hackeng T, Sere KM, Tans G, Rosing J: Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. Proc Natl Acad Sci 2006, 103, 3106–3111.
  6. Griffin JH, Zlokovic BV, Mosnier LO: Protein C anticoagulant and cytoprotective pathways. Int J Hematol 2012, 95, 333–345.
  7. Dahlbäck B, Villoutreix BO: regulation of blood coagulation by the protein C anticoagulant pathway: novel insights into structure-function relationships and molecular recognition. Arterioscler Thromb Vasc Biol 2005, 25, 1311–1320.
  8. Mosnier LO, Zlokovic BV, Griffin JH: The cytoprotective protein C pathway. Blood 2007, 109, 3161–3172.
  9. Cheng T, Liu D, Griffin JH, Fernández JA, Castellino FJ, Rosen ED, Fukudome K, Zlokovic BV: Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med 2003, 9, 338–342.
  10. 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.
  11. Comp PC, Esmon CT: recurrent venous thromboembolism in patients with a partial deficiency of protein S. N Engl J Med 1984, 311, 1525–1528.
  12. Haemostasis and Thrombosis Task Force, British Committee for Standards in Haematology Investigation and management of heritable thrombophilia. Br J Haematol 2001, 114, 512–528.
  13. Caspers M, Pavlova A, Driesen J, Harbrecht U, Klamroth R, Kadar J, Fischer R, Kemkes-Matthes B, Oldenburg J: Deficiencies of antithrombin, protein C and protein S – practical experience in genetic analysis of a large patient cohort. Thromb Haemost 2012, 108, 247–57.
  14. Bereczky Z, Kovács KB, Muszbek L: Protein C and protein S deficiencies: similarities and differences between two brothers playing in the same game. Clin Chem Lab Med 2010, 48, S53–66.
  15. Goldenberg NA, Manco-Johnson MJ: Protein C deficiency. Haemophilia 2008, 14, 1214–1221.
  16. Estelles A, Garcia-Plaza I, Dasi A, Aznar J, Duart M, Sanz G, Pérez-Requejo JL, Espana F, Jimenez C, Abeledo G: Severe inherited “homozygous” protein C deficiency in a newborn infant. Thromb Haemost 1984, 52, 53–56.
  17. Reitsma PH, Poort SR, Bernardi F, Gandrille S, Long GL, Sala N, Cooper DN: Protein C deficiency: a database of mutations. For the Protein C & S Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 1993, 69, 77–84.
  18. Mackie I, Cooper P, Lawrie A, Kitchen S, Gray E, Laffan M: British Committee for Standards in Haematology: Guidelines on the laboratory aspects of assays used in haemostasis and thrombosis. Int J Lab Hematol 2013, 35, 1–13.
  19. García de Frutos P, Fuentes-Prior P, Hurtado B, Sala N: Molecular basis of protein S deficiency. Thromb Haemost 2007, 98, 543–556.
  20. Borgel D, Duchemin J, Alhenc-Gelas M, Matheron C, Aiach M, Gandrille S: Molecular basis for protein S hereditary deficiency: genetic defects observed in 118 patients with type I and type IIa deficiencies. The French Network on Molecular Abnormalities responsible for Protein C and Protein S Deficiencies. J Lab Clin Med 1996, 128, 218–227.
  21. Mulder R, Tichelaar VY, Lijfering WM, Kluin-Nelemans HC, Mulder AB, Meijer K: Decreased free protein S levels and venous thrombosis in the acute setting, a case-control study. Thromb res 2011, 128, 501–502.
  22. Bissuel F, Berruyer M, Causse X, Dechavanne M, Trepo C: Acquired protein S deficiency: correlation with advanced disease in HIV-1-infected patients. J Acquir Immune Defic Syndr 1992, 5, 484–489.
  23. Regnault V, Boehlen F, Ozsahin H, Wahl D, de Groot PG, Lecompte T, de Moerloose P: Anti-protein S antibodies following a varicella infection: detection, characterization and influence on thrombin generation. J Thromb Haemost 2005, 3, 243–249.
  24. Lind-Halldén C, Dahlen A, Hillarp A, Zöller B, Dahlbäck B, Halldén C: Small and large ProS1 deletions but no other types of rearrangements detected in patients with protein S deficiency. Thromb Haemost 2012, 108, 94–100.
  25. Pintao MC, Garcia AA, Borgel D, Alhenc-Gelas M, Spek CA, de Visser MC, Gandrille S, Reitsma PH: Gross deletions/duplications in ProS1 are relatively common in point mutation negative hereditary protein S deficiency. Hum Genet 2009, 126, 449–456.
  26. ten Kate MK, van der Meer J: Protein S deficiency: a clinical perspective. Haemophilia 2008, 14, 1222–1228.
  27. Kimura R, Kokubo Y, Miyashita K, Otsubo R, Nagatsuka K, Otsuki T, Sakata T, Nagura J, Okayama A, Minematsu K, Naritomi H, Honda S, Sato K, Tomoike H, Miyata T: Polymorphisms in vitamin K-dependent gamma-carboxylation-related genes influence interindividual variability in plasma protein C and protein S activities in the general population. Int J Hematol 2006, 84, 387–397.
  28. Aiach M, Nicaud V, Alhenc-Gelas M, Gandrille S, Arnaud E, Amiral J, Guize L, Fiessinger JN, Emmerich J: Complex association of protein C gene promoter polymorphism with circulating protein C levels and thrombotic risk. Arterioscler Thromb Vasc Biol 1999, 19, 1573–1576.
  29. Lipe B, Ornstein DL: Deficiencies of natural anticoagulants, protein C, protein S, and antithrombin. Circulation 2011, 124, e365–368.
  30. Brouwer JL, Lijfering WM, Ten Kate MK, Kluin-Nelemans HC, Veeger NJ, van der Meer J: High long-term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C or antithrombin. Thromb Haemost 2009, 101, 93–99.
  31. Brouwer JL, Veeger NJ, Kluin-Nelemans HC, van der Meer J: The pathogenesis of venous thromboembolism: evidence for multiple interrelated causes. Ann Intern Med 2006, 145, 807–815.
  32. Vossen CY, Conard J, Fontcuberta J, Makris M, van der Meer FJ, Pabinger I, Palareti G, Preston FE, Scharrer I, Souto JC, Svensson P, Walker ID, Rosendaal FR: risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCoT). J Thromb Haemost 2005, 3, 459–464.
  33. Goldhaber SZ, Piazza G: optimal duration of anticoagulation after venous thromboembolism. Circulation 2011, 123, 664–667.
  34. Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ: Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003, 348, 1425–1434.
  35. Monagle P, Andrew M, Halton J, Marlar R, Jardine L, Vegh P, Johnston M, Webber C, Massicotte MP: Homozygous protein C deficiency: description of a new mutation and successful treatment with low molecular weight heparin. Thromb Haemost 1998, 79, 756–761.
  36. Manco-Johnson MJ, Knapp-Clevenger R: Activated protein C concentrate reverses purpura fulminans in severe genetic protein C deficiency. J Pediatr Hematol oncol 2004, 26, 25–27.
  37. Nadel S, Goldstein B, Williams MD, Dalton H, Peters M, Macias WL, Abd-Allah SA, Levy H, Angle R, Wang D, Sundin DP, Giroir B: rEsearching severe Sepsis and organ dysfunction in children: a gLobal perspective (rESoLVE) study group. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet 2007, 369, 836–843.
  38. Sayin MR, Akpinar I, Karabag T, Aydin M, Dogan SM, Cil C: Left main coronary artery thrombus resulting from combined protein C and S deficiency. Intern Med 2012, 51, 3041–3044.
  39. Sadiq A, Ahmed S, Karim A, Spivak J, Mattana J: Acute myocardial infarction: a rare complication of protein C deficiency. Am J Med 2001, 110, 414.
  40. Mahmoodi BK, Brouwer JL, Veeger NJ, van der Meer J: Hereditary deficiency of protein C or protein S confers increased risk of arterial thromboembolic events at a young age: results from a large family cohort study. Circulation 2008, 118, 1659–1667.
  41. Baglin T, Gray E, Greaves M, Hunt BJ, Keeling D, Machin S, Mackie I, Makris M, Nokes T, Perry D, Tait RC, Walker I, Watson H: Clinical guidelines for testing for heritable thrombophilia. Br J Haematol 2010, 149, 209–220.
  42. Heit JA: Thrombophilia: common questions on laboratory assessment and management. Hematology Am Soc Hematol Educ Program 2007, 127–135.
  43. Wypasek E, Pankiw-Bembenek O, Potaczek DP, Alhenc-Gelas M, Trebacz J, Undas A: A missense mutation G109r in the ProC gene associated with type I protein C deficiency in a young Polish man with acute myocardial infarction. Int J Cardiol 2013, May 2.
  44. Wypasek E, Alhenc-Gelas M, Undas A: First report of a large ProS1 deletion from exon 1 through 12 detected in Polish patients with deep-vein thrombosis. Thromb res 2013, Mar 6.
  45. Bertina RM, Ploos van Amstel HK, van Wijngaarden A, Coenen J, Leemhuis MP, Deutz-Terlouw PP, van der Linden IK, Reitsma PH: Heerlen polymorphism of protein S, an immunologic polymorphism due to dimorphism of residue 460. Blood 1990, 76, 538–548.
  46. Giri TK, Yamazaki T, Sala N, Dahlba¨ck B, de Frutos PG: Deficient APC-cofactor activity of protein S Heerlen in degradation of factor Va Leiden: a possible mechanism of synergism between thrombophilic risk factors. Blood 2000, 96, 523–531.
  47. Wypasek E, Potaczek PD, Alhenc-Gelas M, Undas A: Heerlen polymorphism associated with type III protein S deficiency and factor V mutation in a Polish patient with deep vein thrombosis. Blood Coagul Fibrinolysis (in press).
© Wroclaw Medical University