Clinical Analysis and Mental Health Survey of Hemophilia Carriers: a Cross-sectional Study

Abstract

Objective

Hemophilia carriers (HCs), who are heterozygous for mutations in the clotting factor VIII/clotting factor IX gene (F8 or F9), may have a wide range of clotting factor levels, from very low, similar to afflicted males, to the upper limit of normal, and may experience mental health issues. The purpose of this study was to provide genetic information on mothers of hemophilia patients and to understand the clotting factor activity and phenotype of HCs. Additionally, we aimed to investigate the mental health status of HCs in China.

Methods

A total of 127 hemophilia mothers, including 93 hemophilia A (HA) mothers and 34 hemophilia B (HB) mothers, were enrolled in this study. Long distance PCR, multiplex PCR, and Sanger sequencing were used to analyze mutations in F8 or F9. Coagulation factor activity was detected by a one-stage clotting assay. The Symptom Checklist 90 (SCL-90, China/Mandarin version) was given to HCs at the same time to assess their mental health.

Results

A total of 90.6% of hemophilia mothers were diagnosed genetically as carriers, with inversion in intron 22 and missense mutations being the most common mutation types in HA and HB carriers, respectively. The median clotting factor level in carriers was 0.74 IU/mL (ranging from 0.09 to 1.74 IU/mL) compared with 1.49 IU/mL (ranging from 0.93 to 1.89 IU/mL) in noncarriers, of which 14.3% of HCs had clotting factor levels of 0.40 IU/mL or below. A total of 53.8% (7/13) of HA carriers with low clotting factor levels (less than 0.50 IU/mL) had a history of bleeding, while none of the HB carriers displayed a bleeding phenotype. The total mean score and the global severity index of the SCL-90 for surveyed HCs were 171.00 (±60.37) and 1.78 (±0.59), respectively. A total of 67.7% of the respondents had psychological symptoms, with obsessive-compulsive disorder being the most prevalent and severe. The pooled estimates of all nine factors were significantly higher than those in the general population (P<0.05).

Conclusions

The detection rate of gene mutations in hemophilia mothers was 90.6%, with a median clotting factor level of 0.74 IU/mL, and 14.3% of HCs had a clotting factor level of 0.40 IU/mL or below. A history of bleeding was present in 41.2% of HCs with low clotting factor levels (less than 0.50 IU/mL). Additionally, given the fragile mental health status of HCs in China, it is critical to develop efficient strategies to improve psychological well-being.

Keywords

hemophilia A / hemophilia B / mutation / carrier / mental health

References

[1] DolanG, BensonG, DuffyA, et al.. Haemophilia B: Where are we now and what does the future hold?. Blood Rev, 2018, 32(1): 52-60

[2] BerntorpE, FischerK, HartD P, et al.. Haemophilia. Nat Rev Dis Primers, 2021, 7(1): 45

[3] PlugI, Mauser-BunschotenE P, Brocker-VriendsA H, et al.. Bleeding in carriers of hemophilia. Blood, 2006, 108(1): 52-56

[4] ShinozawaK, AmanoK, HagiwaraT, et al.. Genetic analysis of carrier status in female members of Japanese hemophilia families. J Thromb Haemost, 2021, 19(6): 1493-1505

[5] GaragiolaI, MortarinoM, SiboniSM, et al.. X Chromosome inactivation: a modifier of factor VIII and IX plasma levels and bleeding phenotype in Haemophilia carriers. Eur J Hum Genet, 2021, 29(2): 241-249

[6] WhitakerS, AistonH, HungWT, et al.. Haemophilia Carriers Experience Study (CARES): A mixed method exploration into the experience of womenwho are carriers of Haemophilia. Haemophilia, 2021, 27(5): 848-853

[7] PuntMC, AaldersTH, BloemenkampK, et al.. The experiences and attitudes of hemophilia carriers around pregnancy: A qualitative systematic review. J Thromb Haemost, 2020, 18(7): 1626-1636

[8] BlanchetteVS, KeyNS, LjungLR, et al.. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost, 2014, 12(11): 1935-1939

[9] YangJ, TangS, ZhouW. Effect of Mindfulness-Based Stress Reduction Therapy on Work Stress and Mental Health of Psychiatric Nurses. Psychiatria Danubina, 2018, 30(2): 189-196

[10] ChenW, HeW, ZengL, et al.. Mental health status of Chinese physicians working in intensive care unit. J Crit Care, 2021, 61: 227-232

[11] ChoS, PerryAM, ChengAM, et al.. Advances in Hemophilia A Management. Adv Pediatr, 2022, 69(1): 133-147

[12] GoodeveAC. Hemophilia B: molecular pathogenesis and mutation analysis. J Thromb Haemost, 2015, 13(7): 1184-1195

[13] ChaigneauM, BotrosM, GrabellJ, et al.. Challenges and knowledge gaps facing hemophilia carriers today: Perspectives from patients and health care providers. Res Pract Thromb Haemost, 2022, 6(6): e12783

[14] Torres-OrtunoA. Hemophilia carriers: quality of life and management at different life stages. Blood Coagul Fibrinolysis, 2020, 31(1S): S12-S14

[15] LiT, MillerCH, DriggersJ, et al.. Mutation analysis of a cohort of US patients with hemophilia B. Am J Hematol, 2014, 89(4): 375-379

[16] KhanM, NazA, AhmedJ, et al.. Mutation Spectrum and Genotype-Phenotype Analyses in a Pakistani Cohort With Hemophilia B. Clin Appl Thromb Hemost, 2018, 24(5): 741-748

[17] FengY, LiQ, ShiP, et al.. Mutation analysis in the F8 gene in 485 families with haemophilia A and prenatal diagnosis in China. Haemophilia, 2021, 27(1): e88-e92

[18] LabarqueV, PerinparajahV, BouskillV, et al.. Utility of factor V and factor V to von Willebrand factor ratio in identifying 277 unselected carriers of hemophilia A. Am J Hematol, 2017, 92(6): E94-E96

[19] GilbertL, ParoskieA, GailaniD, et al.. Haemophilia A carriers experience reduced health-related quality of life. Haemophilia, 2015, 21(6): 761-765

[20] LambertC, MeiteN D, SanogoI, et al.. Hemophilia carrier’s awareness, diagnosis, and management in emerging countries: a cross-sectional study in Cote d’Ivoire (Ivory Coast). Orphanet J Rare Dis, 2019, 14(1): 26

[21] StaberJ, CroteauS E, DavisJ, et al.. The spectrum of bleeding in women and girls with haemophilia B. Haemophilia, 2018, 24(2): 180-185

[22] LimpergP F, HavermanL, PetersM, et al.. Psychosocial functioning of mothers of boys with haemophilia. Haemophilia, 2016, 22(1): e57-e60

[23] PerezL. Hemophilia carriers and women with coagulopathies: challenges in the occupational arena. Blood Coagul Fibrinolysis, 2020, 31(1S): S15-S16

[24] MingotC M. General concepts on hemophilia A and on women carrying the disease. Blood Coagul Fibrinolysis, 2020, 31(1S): S1-S3

[25] WeiY, LiH, WangH, et al.. Psychological Status of Volunteers in a Phase I Clinical Trial Assessed by Symptom Checklist 90 (SCL-90) and Eysenck Personality Questionnaire (EPQ). Med Sci Monit, 2018, 24: 4968-4973

[26] Myrin-WestessonL, BaghaeiF, FribergF. The experience of being a female carrier of haemophilia and the mother of a haemophilic child. Haemophilia, 2013, 19(2): 219-224