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Thrombosis Journal
Published in: Thrombosis Journal 1/2023

Open Access 01-12-2023 | Anticoagulant | Research

Evaluation of prothrombotic risk of two PROC hotspot mutations (Arg189Trp and Lys193del) in Chinese population: a retrospective study

Authors: Lei Li, Jian Li, Xi Wu, Wenman Wu, Qiulan Ding, Baohua Qian, Xuefeng Wang

Published in: Thrombosis Journal | Issue 1/2023

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Abstract

Background

R189W and K193del of protein C (PC) were hotspot mutations in Chinese population with venous thromboembolism (VTE), but almost two-thirds of patients with above mutations coexisting with other genetically or aquiredly prothrombotic risk factors. The aim of this study is to clarify the independent contributions of R189W or K193del to VTE risk.

Methods

490 unrelated patients with a personal history of VTE and 410 healthy participants were enrolled in this study. Data of their demographics, family history, genetic and acquired thrombosis risk factors were collected and statistically analyzed.

Results

PC R189W and K193del were identified in 3/410 (0.7%) and 7/410 (1.7%) healthy controls, and in 27/490 (5.5%) and 43/490 (8.8%) patients with VTE, respectively. Notably, about 70% of these mutant carriers combined with other genetic or acquired thrombophilic factors. After adjustment for age, gender, other inherited and acquired risk factors, we demonstrated that R189W and K193del were associated with 5.781-fold and 4.365-fold increased risk of VTE, respectively, which were significantly lower than the prothrombotic risk of anticoagulant deficiencies induced from rare mutations. Independent R189W or K193del mutation was not associated with earlier first-onset age as well as higher recurrent rate of VTE. However, combination of other genetic or acquired thrombophilic factors had supra-additive effects on those consequences. The more additional risk factors the patients had, the younger first-onset ages and higher risk of recurrence would be.

Conclusions

As the most frequent mutations for PC deficiency in Chinese population, both R189W and K193del mutations had limited independent contributions to VTE development compared with other rare mutations in PROC gene, but may act in concert with other genetic defects or acquired thrombotic risk factors to produce the final severe phenotype.
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Literature
1.
Connors JM. Thrombophilia Testing and venous thrombosis. N Engl J Med. 2017;377(23):2298.PubMed
2.
Campello E, Spiezia L, Adamo A, Simioni P. Thrombophilia, risk factors and prevention. Expert Rev Hematol. 2019;12(3):147–58.CrossRefPubMed
3.
Middeldorp S. Inherited thrombophilia: a double-edged sword. Hematology Am Soc Hematol Educ Program. 2016; 2016(1):1–9.
4.
Stevens SM, Woller SC, Bauer KA, Kasthuri R, Cushman M, Streiff M, et al. Guidance for the evaluation and treatment of hereditary and acquired thrombophilia. J Thromb Thrombolysis. 2016;41(1):154–64.CrossRefPubMedPubMedCentral
5.
Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A. 1993;90(3):1004–8.CrossRefPubMedPubMedCentral
6.
Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369(6475):64–7.CrossRefPubMed
7.
Zöller B, Svensson PJ, Dahlbäck B, Lind-Hallden C, Hallden C, Elf J. Genetic risk factors for venous thromboembolism. Expert Rev Hematol. 2020;13(9):971–81.CrossRefPubMed
8.
Favaloro EJ. Genetic testing for Thrombophilia-Related genes: observations of testing patterns for factor V Leiden (G1691A) and Prothrombin Gene Mutation (G20210A). Semin Thromb Hemost. 2019;45(7):730–42.CrossRefPubMed
9.
Miyawaki Y, Suzuki A, Fujita J, Maki A, Okuyama E, Murata M, et al. Thrombosis from a prothrombin mutation conveying antithrombin resistance. N Engl J Med. 2012;366(25):2390–6.CrossRefPubMed
10.
Wu X, Li L, Ding Q, Wang X, Wu F, Wu W. Screening and functional exploration of prothrombin Arg596 related mutations in Chinese venous thromboembolism patients. J Clin Pathol. 2018;71(7):614–9.CrossRefPubMed
11.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24.CrossRefPubMedPubMedCentral
12.
Angchaisuksiri P. Venous thromboembolism in Asia–an unrecognised and under-treated problem? Thromb Haemost. 2011;106(4):585–90.PubMed
13.
Miyata T, Sato Y, Ishikawa J, Okada H, Takeshita S, Sakata T, 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(1):14–8.CrossRefPubMed
14.
Shen MC, Lin JS, Tsay W. Protein C and protein S deficiencies are the most important risk factors associated with thrombosis in Chinese venous thrombophilic patients in Taiwan. Thromb Res. 2000;99(5):447–52.CrossRefPubMed
15.
Tang L, Wang HF, Lu X, Jian XR, Jin B, Zheng H, et al. Common genetic risk factors for venous thrombosis in the Chinese population. Am J Hum Genet. 2013;92(2):177–87.CrossRefPubMedPubMedCentral
16.
Tang L, Guo T, Yang R, Mei H, Wang H, Lu X, et al. Genetic background analysis of protein C deficiency demonstrates a recurrent mutation associated with venous thrombosis in Chinese population. PLoS ONE. 2012;7(4):e35773.CrossRefPubMedPubMedCentral
17.
Ding Q, Yang L, Hassanian SM, Rezaie AR. Expression and functional characterisation of natural R147W and K150del variants of protein C in the Chinese population. Thromb Haemost. 2013;109(4):614–24.CrossRefPubMedPubMedCentral
18.
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(1):53–8.CrossRefPubMed
19.
Li L, Wu X, Wu W, Ding Q, Cai X, Wang X. Clinical manifestation and mutation spectrum of 53 unrelated pedigrees with Protein S Deficiency in China. Thromb Haemost. 2019.
20.
Faul F, Erdfelder E, Lang A-G, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39(2):175–91.CrossRefPubMed
21.
Salzano A, Arcopinto M, Marra AM, Bobbio E, Esposito D, Accardo G, et al. Klinefelter syndrome, cardiovascular system, and thromboembolic disease: review of literature and clinical perspectives. Eur J Endocrinol. 2016;175(1):R27–40.CrossRefPubMed
22.
Tsay W, Shen MC. R147W mutation of PROC gene is common in venous thrombotic patients in Taiwanese Chinese. Am J Hematol. 2004;76(1):8–13.CrossRefPubMed
23.
Mather T, Oganessyan V, Hof P, Huber R, Foundling S, Esmon C, et al. The 2.8 a crystal structure of gla-domainless activated protein C. EMBO J. 1996;15(24):6822–31.CrossRefPubMedPubMedCentral
24.
Mesters RM, Heeb MJ, Griffin JH. A novel exosite in the light chain of human activated protein C essential for interaction with blood coagulation factor va. Biochemistry. 1993;32(47):12656–63.CrossRefPubMed
25.
Yamashita A, Zhang Y, Sanner MF, Griffin JH, Mosnier LO. C-terminal residues of activated protein C light chain contribute to its anticoagulant and cytoprotective activities. J Thromb Haemost. 2020;18(5):1027–38.CrossRefPubMedPubMedCentral
26.
Funk DM. Coagulation assays and anticoagulant monitoring. Hematology Am Soc Hematol Educ Program. 2012; 2012:460–465.
27.
Ireland H, Bayston T, Thompson E, Adami A, Gonçalves C, Lane DA, et al. Apparent heterozygous type II protein C deficiency caused by the factor V 506 arg to gln mutation. Thromb Haemost. 1995;73(4):731–2.CrossRefPubMed
28.
Marlar RA, Gausman JN. Laboratory testing issues for protein C, protein S, and antithrombin. Int J Lab Hematol. 2014;36(3):289–95.CrossRefPubMed
29.
Faioni EM, Hermida J, Rovida E, Razzari C, Asti D, Zeinali S, et al. Type II protein C deficiency: identification and molecular modelling of two natural mutants with low anticoagulant and normal amidolytic activity. Br J Haematol. 2000;108(2):265–71.CrossRefPubMed
30.
Reitsma PH, Bernardi F, Doig RG, Gandrille S, Greengard JS, Ireland H, et al. Protein C deficiency: a database of mutations, 1995 update. On behalf of the Subcommittee on plasma coagulation inhibitors of the Scientific and Standardization Committee of the ISTH. Thromb Haemost. 1995;73(5):876–89.CrossRefPubMed
31.
Sirachainan N, Chuansumrit A, Sasanakul W, Yudhasompop N, Mahaklan L, Vaewpanich J, et al. R147W in PROC Gene is a risk factor of Thromboembolism in Thai Children. Clin Appl Thromb Hemost. 2018;24(2):263–7.CrossRefPubMed
32.
Tang L, Lu X, Yu JM, Wang QY, Yang R, Guo T, et al. PROC c.574_576del polymorphism: a common genetic risk factor for venous thrombosis in the Chinese population. J Thromb Haemost. 2012;10(10):2019–26.CrossRefPubMed
33.
Noguchi K, Nakazono E, Tsuda T, Jin X, Sata S, Miya M, et al. Plasma phenotypes of protein S Lys196Glu and protein C Lys193del variants prevalent among young Japanese women. Blood Coagul Fibrinolysis. 2019;30(8):393–400.CrossRefPubMedPubMedCentral
34.
Miyata T, Sakata T, Yasumuro Y, Okamura T, Katsumi A, Saito H, et al. Genetic analysis of protein C deficiency in nineteen Japanese families: five recurrent defects can explain half of the deficiencies. Thromb Res. 1998;92(4):181–7.CrossRefPubMed
35.
Tsuda H, Noguchi K, Oh D, Bereczky Z, Lee LH, Kang D, et al. Racial differences in protein S Tokushima and two protein C variants as genetic risk factors for venous thromboembolism. Res Pract Thromb Haemost. 2020;4(8):1295–300.CrossRefPubMedPubMedCentral
36.
37.
Parakh RS, Sabath DE. Venous thromboembolism: role of the clinical laboratory in diagnosis and management. J Appl Lab Med. 2019;3(5):870–82.CrossRefPubMed
38.
McCormack T, Harrisingh MC, Horner D, Bewley S. Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing. BMJ. 2020;369:m1565.CrossRefPubMed
39.
40.
Kinoshita S, Iida H, Inoue S, Watanabe K, Kurihara M, Wada Y, et al. Protein S and protein C gene mutations in Japanese deep vein thrombosis patients. Clin Biochem. 2005;38(10):908–15.
41.
Wang Z, Wang T, Chang J, Li H, Wang C, Li Y, et al. Genetic association of PROC variants with pulmonary embolism in Northern Chinese Han population. Springerplus. 2016;5:147.
Metadata
Title
Evaluation of prothrombotic risk of two PROC hotspot mutations (Arg189Trp and Lys193del) in Chinese population: a retrospective study
Authors
Lei Li
Jian Li
Xi Wu
Wenman Wu
Qiulan Ding
Baohua Qian
Xuefeng Wang
Publication date
01-12-2023
Publisher
BioMed Central
Keyword
Anticoagulant
Published in
Thrombosis Journal / Issue 1/2023
Electronic ISSN: 1477-9560
DOI
https://doi.org/10.1186/s12959-023-00548-6

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