Clinical and laboratory characteristics of patients with congenital factor XII deficiency in the Russian population

Introduction. The blood coagulation factor XII (FXII) is involved in opposing processes of hemostasis: contact activation of the intrinsic pathway of blood coagulation and fibrinolysis. What might the clinical picture of FXII deficiency present with: bleeding, thromboses or be asymptomatic? The issue remains debatable.

Aim: To present the clinical and laboratory characteristics of patients with congenital FXII deficiency in the Russian population.

Materials and methods. A retrospective study included 29 of 212 patients with FXII deficiency who underwent genetic analysis, confirming the hereditary nature of the disease.

Results. The mean APTT in the study group was 187 seconds (control 29–38 sec.). The mean FXII activity was 20%. The most common mutation of F12 in the Russian population was the nucleotide substitution c.1681 –1 G>A. The reasons for contacting a hematologist and conducting diagnostics of the disease were: preoperative examination in 9 (31%) patients; abnormalities in the coagulogram during examination prior to pregnancy planning or during examination for a chronic disease in 8 (28%) patients; bleeding — in 7 (24%) patients; abnormalities in the coagulogram during screening in pregnancy in 2 (7%); family examination in 2 (7%) patients. In 21 (72%) of 29 patients, the clinical picture was represented by hemorrhagic manifestations. Thrombotic events were noted in 2 (7%) of 29 patients. Among 16 (80%) women with a history of pregnancy, miscarriages occurred in 6 (38%).

Conclusion. The diagnosis of hereditary FXII deficiency is most often established during preoperative examination. However, 24% of patients consulted a hematologist with complaints of hemorrhagic manifestations, mostly mild or moderate. Surgical bleeding was noted in 21% of patients. The obstetric history of more than a third of women was complicated by miscarriages. In patients with hereditary FXII deficiency, it is necessary to be wary of mild spontaneous bleeding, surgical bleeding, miscarriage and, to a lesser extent, thromboses.

1. Yakovleva E.V., Zozulya N.I., Pshenichnikova O.S., et al. Hereditary combined deficiency of factors V and VIII: observations in the Russian population. Gematologiya I Transfusiologiya. 2024;69(3):344–55 (In Russian). DOI: 10.35754/0234-5730-2024-69-3-344-355

2. Schmaier A.H., Stavrou E.X. Factor XII — What’s important but not commonly thought about. Res Pract Thromb Haemost. 2019;3(4):599–606. DOI: 10.1002/rth2.12235.

3. Richards S., Aziz N, Bale S., 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. DOI: 10.1038/gim.2015.30.

4. Sim N.L., Kumar P., Hu J., Henikoff S., et al. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res. 2012;40(Web Server issue):W452–7. DOI: 10.1093/nar/gks539.

5. Demidova E., Salomashkina V., Pshenichnikova O., et al. Factor XII deficiency: a clinical and molecular genetic study. Int J Hematol. 2023;117(5):678–83. DOI: 10.1007/s12185-023-03535-9.

6. Lombardi A.M., Bortoletto E., Scarparo P., et al. Genetic study in patients with factor XII deficiency: a report of three new mutations exon 13 (Q501STOP), exon 14 (P547L) and -13C>T promoter region in three compound heterozygotes. Blood Coagul Fibrinolysis. 2008;19(7):639–43. DOI: 10.1097/MBC.0b013e32830d8629.

7. Hofferbert S., Müller J., Köstering H., et al. A novel 5’-upstream mutation in the factor XII gene is associated with a TaqI restriction site in an Alu repeat in factor XII-deficient patients. Hum Genet. 1996;97(6):838–41. DOI: 10.1007/BF02346200.

8. Schloesser M., Hofferbert S., Bartz U., Lutze G, at al. The novel acceptor splice site mutation 11396(G-->A) in the factor XII gene causes a truncated transcript in cross-reacting material negative patients. Hum Mol Genet. 1995;4(7):1235–7. DOI: 10.1093/hmg/4.7.1235.

9. Sabater-Lleal M., Chillón M., Mordillo C., et al. Combined cis-regulator elements as important mechanism affecting FXII plasma levels. Thromb Res. 2010;125(2):e55–60. DOI: 10.1016/j.thromres.2009.08.019.

10. Ratnoff O.D., Colopy J.E. A familial hemorrhagic trait associated with a deficiency of a clot-promoting fraction of plasma. J Clin Invest. 1955;34(4):602–13. DOI: 10.1172/JCI103109.

11. Halbmayer W.M., Haushofer A., Schön R., et al. The prevalence of moderate and severe FXII (Hageman factor) deficiency among the normal population: evaluation of the incidence of FXII deficiency among 300 healthy blood donors. Thromb Haemost. 1994;71(1):68–72.

12. Didisheim P. Hageman factor deficiency (Hageman trait). Case report and review of the literature. Arch Intern Med. 1962;110:170–7. DOI: 10.1001/archinte.1962.03620200030007.

13. Nicholls J., Chan L.C., Koo Y.M., et al. Subdural haematoma and factor XII deficiency in a Chinese infant. Injury. 1993;24(3):202–3. DOI: 10.1016/0020-1383(93)90300-u.

14. Kovalainen S, Myllylä VV, Tolonen U, Hokkanen E. Recurrent subarachnoid haemorrhages in patient with Hageman factor deficiency. Lancet. 1979;12;1(8124):1035–6. DOI: 10.1016/s0140-6736(79)92792-2.

15. Moiz B., Sadiq M.W., Javed M.A., et al. Prolonged activated partial thromboplastin time secondary to factor XII deficiency in two surgical patients. Oxf Med Case Reports. 2021(3):omaa146. DOI: 10.1093/omcr/omaa146.

16. Vera C., Milana S., Radmila B., et al. Deficit F XII (Factor XII deficiency). Bilt Hematol Transfuz. 1984;12(2):59–63.

17. Lessiani G., Falco A., Nicolucci E., et al. Deep venous thrombosis and previous myocardial infarction in mild factor XII deficiency: a risk factor for both venous and arterial thrombosis. J Thromb Thrombolysis. 2009;27(3):348–51. DOI: 10.1007/s11239-008-0222-1.

18. Chaudhry L.A., El-Sadek W.Y.M., Chaudhry G.A., Al-Atawi F.E. Factor XII (Hageman Factor) Deficiency: a rare harbinger of life threatening complications. Pan Afr Med J. 2019;21;33:39. DOI: 10.11604/pamj.

19. Halbmayer W.M., Mannhalter C., Feichtinger C., et al. The prevalence of factor XII deficiency in 103 orally anticoagulated outpatients suffering from recurrent venous and/or arterial thromboembolism. Thromb Haemost. 1992;68(3):285– 90.

20. Girolami A., Ferrari S., Cosi E., et al. Thrombotic events in severe FXII deficiency in comparison with unaffected family members during a long observation period. J Thromb Thrombolysis. 2019;47(3):481–5. DOI: 10.1007/s11239-019-01819-8.

21. Läm B., Wuillemin W.A., Huber I., et al. Thromboembolism and bleeding tendency in congenital factor XII deficiency--a study on 74 subjects from 14 Swiss families. Thromb Haemost. 1991;12;65(2):117–21.

22. Ozgu-Erdinc AS., Togrul C., Aktulay A., et all. Factor XII (Hageman) levels in women with recurrent pregnancy loss. J Pregnancy. 2014;2014:459192. DOI: 10.1155/2014/459192.

23. Girolami A., Zocca N., Girolami B., et al. Pregnancies and oral contraceptive therapy in severe (homozygons) FXII deficiency: a study in 12 patients and review of the literature. J Thromb Thrombolysis. 2004;18(3):209–12. DOI: 10.1007/s11239-005-0348-3.

24. Pauer H.U., Burfeind P., Köstering H., et al. Factor XII deficiency is strongly associated with primary recurrent abortions. Fertil Steril. 2003;80(3):590–4. DOI: 10.1016/s0015-0282(03)00788-x.