Skip to main content
SpringerLink
Log in

Analysis of PROC mutations and clinical features in 22 unrelated families with inherited protein C deficiency

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Currently, limited information is available in the literature regarding the relationships between PROC mutations and clinical features in Chinese individuals. We aimed to characterize severe congenital Protein C deficiency in 22 unrelated Chinese families in a tertiary hospital by analyzing its clinical manifestation, associated risk factors, and gene mutations. We measured protein C activity and antigen levels for all participants, screened them for mutations in the PROC gene, and analyzed the clinical features of each family to identify commonalities and differences. The analysis revealed a total of 75 individuals with PCD and 16 different PROC mutations, including 12 missense mutations and 4 deletion mutations. Among them, 11 who were compound heterozygotes or homozygotes for mutations tended to develop symptoms at a younger age without any clear triggers. In contrast, the remaining 64 individuals who were heterozygotes for mutations often had clear triggers for their symptoms and experienced a milder course of the disease. It is worth noting that the mutation c.565C > T occurred most frequently, being identified in 8 out of 22 families (36%). Our team also reported five novel mutations, including c.742-744delAAG, c.383G > A, c.997G > A, c.1318C > T, and c.833T > C mutations. The identification of five novel mutations adds to the richness of the Human Genome Database. Asymptomatic heterozygotes are not uncommon, and they are prone to develop symptoms with obvious triggers. The evidence presented strongly suggest that asymptomatic individuals with family history of protein C deficiency can benefit from mutational analysis of PROC gene.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

PC:

Protein C

PCD:

Protein C deficiency

VTE:

Venous thromboembolism

PF:

Purpura fulminans

DIC:

Disseminated intravascular

PROC:

Protein C gene

VT:

Venous thrombosis

PE:

Pulmonary embolism

CT:

Computed tomography

DVT:

Deep venous thrombosis

CVST:

Cerebral venous sinus thrombosis

MVT:

Mesenteric venous thrombosis

RSA:

Recurrent spontaneous abortion

SLE:

Systemic lupus erythematosus

PPP:

Platelet-poor plasma

PC:A:

Activity of protein C

PS:A:

Activity of protein S

AT:A:

Activity of antithrombin

PC:Ag:

Protein C antigen

ELISA:

Enzyme-linked immunosorbent assay

PCR:

Polymerase chain reaction

References

  1. Weronska A, Potaczek DP, Oto J et al (2022) A series of 14 polish patients with thrombotic events and PC deficiency-novel c.401–1G>A PROC gene splice site mutation in a patient with aneurysms. Genes (Basel) 13(5):733. https://doi.org/10.3390/genes13050733

    Article  CAS  PubMed  Google Scholar 

  2. Zhu T, Ding Q, Bai X, Wang X et al (2011) 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 96(7):1033–40. https://doi.org/10.3324/haematol.2010.037515

    Article  PubMed  PubMed Central  Google Scholar 

  3. Dahlbäck B (2008) Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood 112(1):19–27. https://doi.org/10.1182/blood-2008-01-077909

    Article  CAS  PubMed  Google Scholar 

  4. Seligsohn U, Lubetsky A (2001) Genetic susceptibility to venous thrombosis. N Engl J Med 344(16):1222–1231. https://doi.org/10.1056/NEJM200104193441607

    Article  CAS  PubMed  Google Scholar 

  5. Alhenc-Gelas M, Plu-Bureau G, Mauge L, Gandrille S, Présot I, GFHT Study Group on Genetic Thrombophilia (2020) Genotype-phenotype relationships in a large french cohort of subjects with inherited protein C deficiency. Thromb Haemost 120(9):1270–1281. https://doi.org/10.1055/s-0040-1714100

    Article  PubMed  Google Scholar 

  6. Winther-Larsen A, Kjaergaard AD, Larsen OH et al (2020) Protein C deficiency; PROC gene variants in a Danish population. Thromb Res 185:153–159. https://doi.org/10.1016/j.thromres.2019.11.027

    Article  CAS  PubMed  Google Scholar 

  7. Angchaisuksiri P (2011) Venous thromboembolism in Asia–an unrecognised and under-treated problem? Thromb Haemost 106(4):585–590. https://doi.org/10.1160/TH11-03-0184

    Article  CAS  PubMed  Google Scholar 

  8. Zöller B, Svensson PJ, Dahlbäck B et al (2020) Genetic risk factors for venous thromboembolism. Expert Rev Hematol 13(9):971–981. https://doi.org/10.1080/17474086.2020.1804354

    Article  CAS  PubMed  Google Scholar 

  9. Do MD, Pham DV, Le LP et al (2021) Recurrent PROC and novel PROS1 mutations in Vietnamese patients diagnosed with idiopathic deep venous thrombosis. Int J Lab Hematol 43(2):266–272. https://doi.org/10.1111/ijlh.13345

    Article  PubMed  Google Scholar 

  10. Rojnuckarin P, Settapiboon R, Akkawat B et al (2019) Natural anticoagulant deficiencies in Thais: a population-based study. Thromb Res 178:7–11. https://doi.org/10.1016/j.thromres.2019.03.013

    Article  CAS  PubMed  Google Scholar 

  11. Do MD, Le LGH, Nguyen VT et al (2020) High-resolution HLA Typing of HLA-A, -B, -C, -DRB1, and -DQB1 in Kinh Vietnamese by using next-generation sequencing. Front Genet 30(11):383. https://doi.org/10.3389/fgene.2020.00383

    Article  CAS  Google Scholar 

  12. Martos L, Fernández-Pardo Á, López-Fernández MF, Working Group of the Spanish Society of Thrombosis Haemostasis (SETH) et al (2019) Identification of 58 mutations (26 Novel) in 94 of 109 symptomatic Spanish probands with protein C deficiency. Thromb Haemost 119(9):1409–1418. https://doi.org/10.1055/s-0039-1692440

    Article  PubMed  Google Scholar 

  13. Sirachainan N, Chuansumrit A, Sasanakul W et al (2018) P. R147W in PROC gene is a risk factor of thromboembolism in Thai children. Clin Appl Thromb Hemost 24(2):263–267. https://doi.org/10.1177/1076029617709085

    Article  CAS  PubMed  Google Scholar 

  14. Ding Q, Yang L, Hassanian SM et al (2013) Expression and functional characterisation of natural R147W and K150del variants of protein C in the Chinese population. Thromb Haemost 109(4):614–624. https://doi.org/10.1160/TH12-10-0760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Iijima K, Nakamura A, Kurokawa H et al (2010) A homozygous protein C deficiency (Lys 192 del) who developed venous thrombosis for the first time at adulthood. Thromb Res 125(1):100–101. https://doi.org/10.1016/j.thromres.2009.09.010

    Article  CAS  PubMed  Google Scholar 

  16. Zhou RF, Cai XH, Xie S et al (2006) Molecular mechanism for hereditary protein C deficiency in two Chinese families with thrombosis. J Thromb Haemost 4(5):1154–1156. https://doi.org/10.1111/j.1538-7836.2006.01913.x

    Article  CAS  PubMed  Google Scholar 

  17. Su K, Zhang H, Fang W et al (2018) Protein C deficiency (a novel mutation: ala291Thr) with systemic lupus erythematosus leads to the deep vein thrombosis. Blood Coagul Fibrinolysis 29(8):714–719. https://doi.org/10.1097/MBC.0000000000000778

    Article  CAS  PubMed  Google Scholar 

  18. Deng MY, Liu ZX, Huang HF et al (2016) Two novel compound heterozygous mutations associated with types I and II protein C deficiency with unusual phenotypes. Thromb Res 145:93–99. https://doi.org/10.1016/j.thromres.2016.08.005

    Article  CAS  PubMed  Google Scholar 

  19. Yue Y, Liu S, Han X et al (2019) Pathogenic variants of PROC gene caused type I activity deficiency in a familial Chinese venous thrombosis. J Cell Mol Med 23(10):7099–7104. https://doi.org/10.1111/jcmm.14563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fukushima T, Shimomura Y, Nagaya S et al (2021) A case of treatment with dabigatran for cerebral venous thrombosis caused by hereditary protein C deficiency. Cureus 13(6):e15473. https://doi.org/10.7759/cureus.15473

    Article  PubMed  PubMed Central  Google Scholar 

  21. Yu T, Dai J, Liu H et al (2012) Homozygous protein C deficiency with late onset venous thrombosis: identification and in vitro expression study of a novel Pro275Ser mutation. Pathology 44(4):348–353. https://doi.org/10.1097/PAT.0b013e328353a218

    Article  CAS  PubMed  Google Scholar 

  22. Tang L, Lu X, Yu JM et al (2012) PROC c.574_576del polymorphism: a common genetic risk factor for venous thrombosis in the Chinese population. J Thromb Haemost 10(10):2019–26. https://doi.org/10.1111/j.1538-7836.2012.04862.x

    Article  CAS  PubMed  Google Scholar 

  23. Reitsma PH, Bernardi F, Doig RG et al (1995) 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 73(5):876–89

    Article  CAS  PubMed  Google Scholar 

  24. Tsay W, Shen MC (2004) R147W mutation of PROC gene is common in venous thrombotic patients in Taiwanese Chinese. Am J Hematol 76(1):8–13. https://doi.org/10.1002/ajh.20043

    Article  CAS  PubMed  Google Scholar 

  25. Cheng X, Wang M, Jiang M et al (2016) A protein C and plasminogen compound heterozygous mutation and a compound heterozygote of protein C in two related Chinese families. Blood Coagul Fibrinolysis 27(7):838–844. https://doi.org/10.1097/MBC.0000000000000579

    Article  CAS  PubMed  Google Scholar 

  26. Marlar RA, Neumann A (1990) Neonatal purpura fulminans due to homozygous protein C or protein S deficiencies. Semin Thromb Hemost 16(4):299–309. https://doi.org/10.1055/s-2007-1002683

    Article  CAS  PubMed  Google Scholar 

  27. Di Minno MN, Ambrosino P, Ageno W et al (2015) Natural anticoagulants deficiency and the risk of venous thromboembolism: a meta-analysis of observational studies. Thromb Res 135(5):923–932. https://doi.org/10.1016/j.thromres.2015.03.010

    Article  CAS  PubMed  Google Scholar 

  28. Mahmoodi BK, Brouwer JL, Ten Kate MK et al (2010) A prospective cohort study on the absolute risks of venous thromboembolism and predictive value of screening asymptomatic relatives of patients with hereditary deficiencies of protein S, protein C or antithrombin. J Thromb Haemost 8(6):1193–1200. https://doi.org/10.1111/j.1538-7836.2010.03840.x

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We express our gratitude to the patient and her family members for their cooperation. The authors declare that they have no interests that could be perceived as posing a conflict or bias.

Funding

We acknowledge the support provided by the Wenzhou Basic Medical and Health Science and Technology Project (Y20210111) and the Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province (2022E10022) for this work.

Author information

Authors and Affiliations

  1. Department of Laboratory Medicine, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China

    Fei Xu, Ke Zhang, Qiyu Xu, Longying Ye, Manlin Zeng, Yanhui Jin, Mingshan Wang & Lihong Yang

Authors
  1. Fei Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ke Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qiyu Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Longying Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Manlin Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yanhui Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mingshan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lihong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors have made significant contributions to the study's conception and design, data acquisition, analysis and interpretation, as well as to the drafting and critical revision of the manuscript for important intellectual content. Furthermore, all authors have provided their final approval for the submitted version of the article.

Corresponding author

Correspondence to Lihong Yang.

Ethics declarations

Conflicts of interest

The authors declare no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, F., Zhang, K., Xu, Q. et al. Analysis of PROC mutations and clinical features in 22 unrelated families with inherited protein C deficiency. Ann Hematol 103, 645–652 (2024). https://doi.org/10.1007/s00277-023-05487-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-023-05487-w

Keywords

Search

Navigation