Download PDF
Thromb Haemost 2019; 119(03): 449-460
DOI: 10.1055/s-0038-1677031
Stroke, Systemic or Venous Thromboembolism
Georg Thieme Verlag KG Stuttgart · New York

Clinical Manifestation and Mutation Spectrum of 53 Unrelated Pedigrees with Protein S Deficiency in China

Lei Li   *
1   State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
,
Xi Wu   *
2   Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
,
Wenman Wu
2   Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
3   Collaborative Innovation Center of Hematology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
,
Qiulan Ding
2   Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
3   Collaborative Innovation Center of Hematology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
,
Xiaohong Cai
4   Department of Blood Transfusion, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
,
Xuefeng Wang
2   Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
3   Collaborative Innovation Center of Hematology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
› Author Affiliations
Funding This study was supported by the General Program of National Natural Science Foundation of China (81570114, 81570115, 81770135), and the National Key Research and Development Program of China (2016YFC0905100).
Further Information

Publication History

14 June 2018

21 November 2018

Publication Date:
22 January 2019 (online)

   Permissions and Reprints

Abstract

Protein S (PS) deficiency is associated with a 10-fold increased risk of venous thromboembolism (VTE), but its diagnosis is quite difficult and complicated. In this study, we identified 53 unrelated pedigrees with PS deficiency in China. Data of their clinical characteristics and laboratory examinations were collected. Genetic analysis of PROS1 including direct sequencing, copy number variant detection and messenger ribonucleic acid analysis was performed in probands and related family members. Of these 53 probands, 52.8% (28/53) experienced multi-site and/or recurrent thrombotic episodes, mainly manifested as deep venous thrombosis and/or pulmonary embolism (82.7%). Additional risk factors of VTE were observed in 39.6% (21/53) probands who exhibited a significantly higher rate of recurrent VTE compared with those not, in which 7 probands were complicated by anti-phospholipid syndrome. Most probands and family members exhibited quantitative PS deficiency with impairment of both activated protein C and tissue factor pathway inhibitor cofactor activities. Note that 87.2% (34/39) PROS1 detectable mutation rate was obtained through comprehensive phenotypic and genetic analysis. A total of 36 PROS1 causative mutations including 16 novel mutations were identified in 48 probands, whereas no PROS1 mutations were detected in the other 5 probands. Three hotspot mutations (Glu67Ala, Arg561Trp and Tyr560*) were identified in the Chinese population for the first time. This article provides a framework for correlating the clinical pathogenesis of PS deficiency to genetic backgrounds in the Chinese population.

Keywords

protein S deficiency - PROS1 - mutation spectrum - venous thromboembolism

* These authors contributed equally to this work.


Supplementary Material

 

  • References

  • 1 Dahlbäck B. The tale of protein S and C4b-binding protein, a story of affection. Thromb Haemost 2007; 98 (01) 90-96
    Thieme ConnectPubMedSearch in Google Scholar
  • 2 Rezende SM, Simmonds RE, Lane DA. Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex. Blood 2004; 103 (04) 1192-1201
    CrossrefPubMedSearch in Google Scholar
  • 3 Walker FJ. Regulation of activated protein C by a new protein. A possible function for bovine protein S. J Biol Chem 1980; 255 (12) 5521-5524
    CrossrefPubMedSearch in Google Scholar
  • 4 De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood 1996; 87 (09) 3531-3544
    CrossrefPubMedSearch in Google Scholar
  • 5 Hackeng TM, Rosing J. Protein S as cofactor for TFPI. Arterioscler Thromb Vasc Biol 2009; 29 (12) 2015-2020
    CrossrefPubMedSearch in Google Scholar
  • 6 Ndonwi M, Broze Jr G. Protein S enhances the tissue factor pathway inhibitor inhibition of factor Xa but not its inhibition of factor VIIa-tissue factor. J Thromb Haemost 2008; 6 (06) 1044-1046
    CrossrefPubMedSearch in Google Scholar
  • 7 Buchanan GS, Rodgers GM, Ware Branch D. The inherited thrombophilias: genetics, epidemiology, and laboratory evaluation. Best Pract Res Clin Obstet Gynaecol 2003; 17 (03) 397-411
    CrossrefPubMedSearch in Google Scholar
  • 8 Angchaisuksiri P. Venous thromboembolism in Asia--an unrecognised and under-treated problem?. Thromb Haemost 2011; 106 (04) 585-590
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 ten Kate MK, van der Meer J. Protein S deficiency: a clinical perspective. Haemophilia 2008; 14 (06) 1222-1228
    PubMedSearch in Google Scholar
  • 10 Margaglione M, Grandone E. Population genetics of venous thromboembolism. A narrative review. Thromb Haemost 2011; 105 (02) 221-231
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 Maurissen LF, Castoldi E, Simioni P, Rosing J, Hackeng TM. Thrombin generation-based assays to measure the activity of the TFPI-protein S pathway in plasma from normal and protein S-deficient individuals. J Thromb Haemost 2010; 8 (04) 750-758
    CrossrefPubMedSearch in Google Scholar
  • 12 Castoldi E, Maurissen LF, Tormene D. , et al. Similar hypercoagulable state and thrombosis risk in type I and type III protein S-deficient individuals from families with mixed type I/III protein S deficiency. Haematologica 2010; 95 (09) 1563-1571
    CrossrefPubMedSearch in Google Scholar
  • 13 Marlar RA, Gausman JN. Protein S abnormalities: a diagnostic nightmare. Am J Hematol 2011; 86 (05) 418-421
    CrossrefPubMedSearch in Google Scholar
  • 14 Dahlbäck B. C4b-binding protein: a forgotten factor in thrombosis and hemostasis. Semin Thromb Hemost 2011; 37 (04) 355-361
    Thieme ConnectPubMedSearch in Google Scholar
  • 15 Pintao MC, Garcia AA, Borgel D. , et al. Gross deletions/duplications in PROS1 are relatively common in point mutation-negative hereditary protein S deficiency. Hum Genet 2009; 126 (03) 449-456
    CrossrefPubMedSearch in Google Scholar
  • 16 Cooper PC, Goodeve AC, Beauchamp NJ. Quality in molecular biology testing for inherited thrombophilia disorders. Semin Thromb Hemost 2012; 38 (06) 600-612
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 García de Frutos P, Fuentes-Prior P, Hurtado B, Sala N. Molecular basis of protein S deficiency. Thromb Haemost 2007; 98 (03) 543-556
    Thieme ConnectPubMedSearch in Google Scholar
  • 18 The Human Gene Mutation Database. Available at: http://www.hgmd.cf.ac.uk/ac/gene.php?gene=PROS1
    PubMed
  • 19 Lanke E, Johansson AM, Hillarp A. , et al. Co-segregation of the PROS1 locus and protein S deficiency in families having no detectable mutations in PROS1. J Thromb Haemost 2004; 2 (11) 1918-1923
    CrossrefPubMedSearch in Google Scholar
  • 20 Alhenc-Gelas M, Plu-Bureau G, Horellou MH, Rauch A, Suchon P. ; GEHT genetic thrombophilia group. PROS1 genotype phenotype relationships in a large cohort of adults with suspicion of inherited quantitative protein S deficiency. Thromb Haemost 2016; 115 (03) 570-579
    Thieme ConnectPubMedSearch in Google Scholar
  • 21 Yin T, Takeshita S, Sato Y. , et al. A large deletion of the PROS1 gene in a deep vein thrombosis patient with protein S deficiency. Thromb Haemost 2007; 98 (04) 783-789
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Yoo JH, Kim HJ, Maeng HY. , et al. Hereditary protein S deficiency from a novel large deletion mutation of the PROS1 gene detected by multiplex ligation-dependent probe amplification (MLPA). Thromb Res 2009; 123 (05) 793-795
    CrossrefPubMedSearch in Google Scholar
  • 23 Ding Q, Shen W, Ye X, Wu Y, Wang X, Wang H. Clinical and genetic features of protein C deficiency in 23 unrelated Chinese patients. Blood Cells Mol Dis 2013; 50 (01) 53-58
    CrossrefPubMedSearch in Google Scholar
  • 24 Heit JA. Thrombophilia: common questions on laboratory assessment and management. Hematology (Am Soc Hematol Educ Program) 2007; 127-135
    PubMedSearch in Google Scholar
  • 25 Connors JM. Thrombophilia testing and venous thrombosis. N Engl J Med 2017; 377 (23) 2298
    PubMedSearch in Google Scholar
  • 26 Miyakis S, Lockshin MD, Atsumi T. , et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4 (02) 295-306
    CrossrefPubMedSearch in Google Scholar
  • 27 Hemker HC, Giesen P, AlDieri R. , et al. The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability. Pathophysiol Haemost Thromb 2002; 32 (5-6): 249-253
    CrossrefPubMedSearch in Google Scholar
  • 28 Zhang X, Xu Y, Liu D. , et al. A modified multiplex ligation-dependent probe amplification method for the detection of 22q11.2 copy number variations in patients with congenital heart disease. BMC Genomics 2015; 16: 364
    CrossrefPubMedSearch in Google Scholar
  • 29 Zhu T, Ding Q, Bai X. , et al. Normal ranges and genetic variants of antithrombin, protein C and protein S in the general Chinese population. Results of the Chinese Hemostasis Investigation on Natural Anticoagulants Study I Group. Haematologica 2011; 96 (07) 1033-1040
    CrossrefPubMedSearch in Google Scholar
  • 30 Wang WB, Fu QH, Ding QL. , et al. Characterization of molecular defect of 13387-9delG mutated antithrombin in inherited type I antithrombin deficiency. Blood Coagul Fibrinolysis 2005; 16 (02) 149-155
    CrossrefPubMedSearch in Google Scholar
  • 31 Margini C, Berzigotti A. Portal vein thrombosis: the role of imaging in the clinical setting. Dig Liver Dis 2017; 49 (02) 113-120
    CrossrefPubMedSearch in Google Scholar
  • 32 Miyata T, Sato Y, Ishikawa J. , et al. Prevalence of genetic mutations in protein S, protein C and antithrombin genes in Japanese patients with deep vein thrombosis. Thromb Res 2009; 124 (01) 14-18
    CrossrefPubMedSearch in Google Scholar
  • 33 Chen TY, Su WC, Tsao CJ. Incidence of thrombophilia detected in southern Taiwanese patients with venous thrombosis. Ann Hematol 2003; 82 (02) 114-117
    CrossrefPubMedSearch in Google Scholar
  • 34 Angchaisuksiri P, Atichartakarn V, Aryurachai K. , et al. Risk factors of venous thromboembolism in Thai patients. Int J Hematol 2007; 86 (05) 397-402
    CrossrefPubMedSearch in Google Scholar
  • 35 Kyrle PA, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Eichinger S. The risk of recurrent venous thromboembolism in men and women. N Engl J Med 2004; 350 (25) 2558-2563
    CrossrefPubMedSearch in Google Scholar
  • 36 Rabinovich A, Kahn SR. The postthrombotic syndrome: current evidence and future challenges. J Thromb Haemost 2017; 15 (02) 230-241
    CrossrefPubMedSearch in Google Scholar
  • 37 McGehee WG, Klotz TA, Epstein DJ, Rapaport SI. Coumarin necrosis associated with hereditary protein C deficiency. Ann Intern Med 1984; 101 (01) 59-60
    PubMedSearch in Google Scholar
  • 38 Goldberg SL, Orthner CL, Yalisove BL, Elgart ML, Kessler CM. Skin necrosis following prolonged administration of coumarin in a patient with inherited protein S deficiency. Am J Hematol 1991; 38 (01) 64-66
    CrossrefPubMedSearch in Google Scholar
  • 39 Ames PR, Tommasino C, Iannaccone L, Brillante M, Cimino R, Brancaccio V. Coagulation activation and fibrinolytic imbalance in subjects with idiopathic antiphospholipid antibodies--a crucial role for acquired free protein S deficiency. Thromb Haemost 1996; 76 (02) 190-194
    Thieme ConnectPubMedSearch in Google Scholar
  • 40 Combemale P, Amiral J, Estival JL, Dupin M, Chouvet B, Berruyer M. Cutaneous necrosis revealing the coexistence of an antiphospholipid syndrome with acquired protein S deficiency, factor V Leiden and hyperhomocysteinemia. Eur J Dermatol 2002; 12 (03) 278-282
    PubMedSearch in Google Scholar
  • 41 Reyes-Iglesias Y, Ortiz AA, Goitía DM, Meléndez R. Coexistence of primary antiphospholipid syndrome and protein S deficiency in a Hispanic man with ischemic stroke. South Med J 1998; 91 (03) 296-298
    CrossrefPubMedSearch in Google Scholar
  • 42 Lijfering WM, Mulder R, ten Kate MK, Veeger NJ, Mulder AB, van der Meer J. Clinical relevance of decreased free protein S levels: results from a retrospective family cohort study involving 1143 relatives. Blood 2009; 113 (06) 1225-1230
    CrossrefPubMedSearch in Google Scholar
  • 43 Tang L, Jian XR, Hamasaki N. , et al. Molecular basis of protein S deficiency in China. Am J Hematol 2013; 88 (10) 899-905
    CrossrefPubMedSearch in Google Scholar
  • 44 Suleiman L, Négrier C, Boukerche H. Protein S: a multifunctional anticoagulant vitamin K-dependent protein at the crossroads of coagulation, inflammation, angiogenesis, and cancer. Crit Rev Oncol Hematol 2013; 88 (03) 637-654
    CrossrefPubMedSearch in Google Scholar
  • 45 Alshaikh NA, Rosing J, Thomassen MCLGD, Castoldi E, Simioni P, Hackeng TM. New functional assays to selectively quantify the activated protein C- and tissue factor pathway inhibitor-cofactor activities of protein S in plasma. J Thromb Haemost 2017; 15 (05) 950-960
    CrossrefPubMedSearch in Google Scholar
  • 46 Fernandes N, Mosnier LO, Tonnu L, Heeb MJ. Zn2(+) -containing protein S inhibits extrinsic factor X-activating complex independently of tissue factor pathway inhibitor. J Thromb Haemost 2010; 8 (09) 1976-1985
    CrossrefPubMedSearch in Google Scholar
  • 47 Johansson AM, Hillarp A, Säll T, Zöller B, Dahlbäck B, Halldén C. Large deletions of the PROS1 gene in a large fraction of mutation-negative patients with protein S deficiency. Thromb Haemost 2005; 94 (05) 951-957
    Thieme ConnectPubMedSearch in Google Scholar
  • 48 Rezende SM, Lane DA, Mille-Baker B, Samama MM, Conard J, Simmonds RE. Protein S Gla-domain mutations causing impaired Ca(2+)-induced phospholipid binding and severe functional protein S deficiency. Blood 2002; 100 (08) 2812-2819
    CrossrefPubMedSearch in Google Scholar
  • 49 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 (04) 1737-1738
    CrossrefPubMedSearch in Google Scholar
  • 50 Duchemin J, Gandrille S, Borgel D. , et al. The Ser 460 to Pro substitution of the protein S alpha (PROS1) gene is a frequent mutation associated with free protein S (type IIa) deficiency. Blood 1995; 86 (09) 3436-3443
    CrossrefPubMedSearch in Google Scholar