Semin Thromb Hemost 2024; 50(02): 200-212
DOI: 10.1055/s-0043-1764471
Review Article

Novel Insights into Heterozygous Factor XIII Deficiency

Akbar Dorgalaleh
1   Hamin Tis Research Institute, Tehran, Iran
› Author Affiliations


The prevalence and clinical significance of heterozygous factor XIII (FXIII) deficiency has long been debated, with controversial reports emerging since 1988. In the absence of large epidemiologic studies, but based on a few studies, a prevalence of 1 per 1,000 to 5,000 is estimated. In southeastern Iran, a hotspot area for the disorder, a study of more than 3,500 individuals found an incidence of 3.5%. Between 1988 and 2023, a total of 308 individuals were found with heterozygous FXIII deficiency, of which molecular, laboratory, and clinical presentations were available for 207 individuals. A total of 49 variants were found in the F13A gene, most of which were missense (61.2%), followed by nonsense (12.2%) and small deletions (12.2%), most occurring in the catalytic domain (52.1%) of the FXIII-A protein and most frequently in exon 4 (17%) of the F13A gene. This pattern is relatively similar to homozygous (severe) FXIII deficiency. In general, heterozygous FXIII deficiency is an asymptomatic condition without spontaneous bleeding tendency, but it can lead to hemorrhagic complications in hemostatic challenges such as trauma, surgery, childbirth, and pregnancy. Postoperative bleeding, postpartum hemorrhage, and miscarriage are the most common clinical manifestations, while impaired wound healing has been rarely reported. Although some of these clinical manifestations can also be observed in the general population, they are more common in heterozygous FXIII deficiency. While studies of heterozygous FXIII deficiency conducted over the past 35 years have shed light on some of the ambiguities of this condition, further studies on a large number of heterozygotes are needed to answer the major questions related to heterozygous FXIII deficiency.

Publication History

Article published online:
20 March 2023

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  • References

  • 1 Dorgalaleh A, Rashidpanah J. Blood coagulation factor XIII and factor XIII deficiency. Blood Rev 2016; 30 (06) 461-475
  • 2 Dorgalaleh A, Naderi M, Hosseini MS. et al. Factor XIII deficiency in Iran: a comprehensive review of the literature. Semin Thromb Hemost 2015; 41 (03) 323-329
  • 3 Shetty S, Shelar T, Mirgal D. et al. Rare coagulation factor deficiencies: a countrywide screening data from India. Haemophilia 2014; 20 (04) 575-581
  • 4 Viswabandya A, Baidya S, Nair SC. et al. Correlating clinical manifestations with factor levels in rare bleeding disorders: a report from Southern India. Haemophilia 2012; 18 (03) e195-e200
  • 5 Shaikh AN, Khurshid M. Factor XIII deficiency in Pakistan. J Pak Med Assoc 1993; 43 (04) 67-69
  • 6 Dorgalaleh A, Tabibian S, Shams M. et al. A unique factor XIII mutation in southeastern Iran with an unexpectedly high prevalence: Khash factor XIII. Semin Thromb Hemost 2019; 45 (01) 43-49
  • 7 Naderi M, Dorgalaleh A, Alizadeh S. et al. Clinical manifestations and management of life-threatening bleeding in the largest group of patients with severe factor XIII deficiency. Int J Hematol 2014; 100 (05) 443-449
  • 8 Dorgalaleh A, Naderi M, Shamsizadeh M. Morbidity and mortality in a large number of Iranian patients with severe congenital factor XIII deficiency. Ann Hematol 2016; 95 (03) 451-455
  • 9 Muszbek L, Katona É. Diagnosis and management of congenital and acquired FXIII deficiencies. Semin Thromb Hemost 2016; 42 (04) 429-439
  • 10 Ivaskevicius V, Biswas A, Loreth R. et al. Mutations affecting disulphide bonds contribute to a fairly common prevalence of F13B gene defects: results of a genetic study in 14 families with factor XIII B deficiency. Haemophilia 2010; 16 (04) 675-682
  • 11 Ivaskevicius V, Biswas A, Bevans C. et al. Identification of eight novel coagulation factor XIII subunit A mutations: implied consequences for structure and function. Haematologica 2010; 95 (06) 956-962
  • 12 Seitz R, Duckert F, Lopaciuk S, Muszbek L, Rodeghiero F, Seligsohn U. Study Group. ETRO Working Party on Factor XIII questionnaire on congenital factor XIII deficiency in Europe: status and perspectives. Semin Thromb Hemost 1996; 22 (05) 415-418
  • 13 Mannucci PM. Bleeding symptoms in heterozygous factor XIII [corrected] deficiency. Haematologica 2010; 95 (09) e6
  • 14 Schroeder V, Kohler HP. Factor XIII deficiency: an update. Semin Thromb Hemost 2013; 39 (06) 632-641
  • 15 Biswas A, Ivaskevicius V, Thomas A, Oldenburg J. Coagulation factor XIII deficiency. Diagnosis, prevalence and management of inherited and acquired forms. Hamostaseologie 2014; 34 (02) 160-166
  • 16 Duckert F, Jung E, Shmerling DH. A hitherto undescribed congenital haemorrhagic diathesis probably due to fibrin stabilizing factor deficiency. Thromb Diath Haemorrh 1960; 5 (02) 179-186
  • 17 Egbring R, Seitz R, Gürten GV. et al. Bleeding complications in heterozygotes with congenital factor XIII deficiency. In: Mosesson MW, Amrani DL, Siebenlist KR, DiOrio JP, eds. Fibrinogen 3: Biochemistry, Biological Functions, Gene Regulation and Expression. Amsterdam: Elsevier 1988;341–346
  • 18 Egbring R, Rohner I, Lerch L, Fuchs G, Kröniger A, Seitz R. Bleeding complications in patients with heterozygous FXIII subunit A deficiency?. Blood Coagul Fibrinolysis 1995; 6: 340
  • 19 Egbring R, Kröniger A, Seitz R. Factor XIII deficiency: pathogenic mechanisms and clinical significance. Semin Thromb Hemost 1996; 22 (05) 419-425
  • 20 Mahmoodi M, Peyvandi F, Afrasiabi A, Ghaffarpasand F, Karimi M. Bleeding symptoms in heterozygous carriers of inherited coagulation disorders in southern Iran. Blood Coagul Fibrinolysis 2011; 22 (05) 396-401
  • 21 Fisher S, Rikover M, Naor S. Factor 13 deficiency with severe hemorrhagic diathesis. Blood 1966; 28 (01) 34-39
  • 22 Ikkala E, Myllylae G, Nevanlinna HR. Transfusion therapy in factor XIII (FSF) deficiency. Scand J Haematol 1964; 1 (04) 308-312
  • 23 Ivaskevicius V, Seitz R, Kohler HP. et al; Study Group. International registry on factor XIII deficiency: a basis formed mostly on European data. Thromb Haemost 2007; 97 (06) 914-921
  • 24 Weiss A, Lee KC, Brumund KT, Chang DC, Bouvet M. Risk factors for hematoma after thyroidectomy: results from the nationwide inpatient sample. Surgery 2014; 156 (02) 399-404
  • 25 Ivaskevicius V, Windyga J, Baran B. et al. Phenotype-genotype correlation in eight Polish patients with inherited Factor XIII deficiency: identification of three novel mutations. Haemophilia 2007; 13 (05) 649-657
  • 26 Jia S, He Y, Lu M. et al. Identification of novel pathogenic F13A1 mutation and novel NBEAL2 gene missense mutation in a pedigree with hereditary congenital factor XIII deficiency. Gene 2019; 702 (02) 143-147
  • 27 Moret A, Zúñiga Á, Ayala JM. et al. Factor XIII deficiency in two Spanish families with a novel variant in gene F13A1 detected by next-generation sequencing; symptoms and clinical management. J Thromb Thrombolysis 2020; 50 (03) 686-688
  • 28 Deng J, Li D, Mei H, Tang L, Wang HF, Hu Y. Novel deep intronic mutation in the coagulation factor XIII a chain gene leading to unexpected RNA splicing in a patient with factor XIII deficiency. BMC Med Genet 2020; 21 (01) 9
  • 29 Shen MC, Chen M, Chang SP, Lin PT, Hsieh HN, Lin KH. Segmental uniparental disomy as a rare cause of congenital severe factor XIII deficiency in a girl with only one heterozygous carrier parent. Pediatr Hematol Oncol 2018; 35 7-8 442-446
  • 30 Sun L, Yan Q, Wang Y. et al. Pathogenicity analysis of variations and prenatal diagnosis in a hereditary coagulation factor XIII deficiency family. Hematology 2018; 23 (08) 501-509
  • 31 Handrkova H, Borhany M, Schroeder V. et al. Identification of two novel missense mutations causing severe factor XIII deficiency. Haemophilia 2015; 21 (03) e253 –e256
  • 32 Borhany M, Handrková H, Cairo A. et al. Congenital factor XIII deficiency in Pakistan: characterization of seven families and identification of four novel mutations. Haemophilia 2014; 20 (04) 568-574
  • 33 Farah RA, Al Danaf JZ, Chahinian RA. et al. Spontaneous epidural hematoma in a child with inherited factor XIII deficiency. J Pediatr Hematol Oncol 2014; 36 (01) 62-65
  • 34 Souri M, Biswas A, Misawa M, Omura H, Ichinose A. Severe congenital factor XIII deficiency caused by novel W187X and G273V mutations in the F13A gene; diagnosis and classification according to the ISTH/SSC guidelines. Haemophilia 2014; 20 (02) 255-262
  • 35 Castaman G, Giacomelli SH, Schroeder V. et al. Further evidence of heterogeneity of gene defects in Italian families with factor XIII deficiency. Haemophilia 2012; 18 (01) e6 –e8
  • 36 Castaman G, Giacomelli SH, Ivaskevicius V. et al. Molecular characterization of five Italian families with inherited severe factor XIII deficiency. Haemophilia 2008; 14 (01) 96-102
  • 37 Halverstadt A, Walsh S, Roth SM, Ferrell RE, Hagberg JM. Identification of a novel mutation combination in factor XIII deficiency: genetic update to the first reported case in the United States. Int J Hematol 2006; 83 (02) 144-146
  • 38 Bamberg C, Mickley L, Henkelmann A. et al. The impact of antenatal factor XIII levels on postpartum haemorrhage: a prospective observational study. Arch Gynecol Obstet 2019; 299 (02) 421-430
  • 39 Naderi M, Mirzaei I, Yaghoubi S, Milani I, Cohan N. Postpartum hemorrhage in heterozygote factor XIII deficient women compared with healthy women. A cross-sectional experience from Iran. Clin Appl Thromb Hemost 2021; 27: 107 60296211051714
  • 40 Karlsson O, Jeppsson A, Hellgren M. A longitudinal study of factor XIII activity, fibrinogen concentration, platelet count and clot strength during normal pregnancy. Thromb Res 2014; 134 (03) 750-752
  • 41 Haslinger C, Korte W, Hothorn T, Brun R, Greenberg C, Zimmermann R. The impact of prepartum factor XIII activity on postpartum blood loss. J Thromb Haemost 2020; 18 (06) 1310-1319
  • 42 Karlsson O, Jeppsson A, Hellgren M. Factor XIII activity at onset of labour and association with postpartum haemorrhage: an exploratory post-hoc study. Int J Obstet Anesth 2021; 47: 103174
  • 43 Xiang H, Wang C, Pan H. et al. Exome-sequencing identifies novel genes associated with recurrent pregnancy loss in a Chinese cohort. Front Genet 2021; 12 (12) 746082
  • 44 de Moerloose P, Casini A, Neerman-Arbez M. Congenital fibrinogen disorders: an update. Semin Thromb Hemost 2013; 39 (06) 585-595
  • 45 Inbal A, Muszbek L. Coagulation factor deficiencies and pregnancy loss. Semin Thromb Hemost 2003; 29 (02) 171-174
  • 46 Sharief LA, Kadir RA. Congenital factor XIII deficiency in women: a systematic review of literature. Haemophilia 2013; 19 (06) e349-e357
  • 47 Cerenzia G, Serrao L, Carillo C, Manna MR, Niccoli VS. Congenital factor XIII deficiency in pregnancy. A case report [Italian]. Minerva Ginecol 1999; 51 (10) 409-412
  • 48 Padmanabhan LD, Mhaskar R, Mhaskar A, Ross CR. Factor XIII deficiency: a rare cause of repeated abortions. Singapore Med J 2004; 45 (04) 186-187
  • 49 Bick RL. Recurrent miscarriage syndrome and infertility caused by blood coagulation protein or platelet defects. Hematol Oncol Clin North Am 2000; 14 (05) 1117-1131
  • 50 Fu M, Liu J, Xing J. et al. Reference intervals for coagulation parameters in non-pregnant and pregnant women. Sci Rep 2022; 12 (01) 1519
  • 51 Coopland A, Alkjaersig N, Fletcher AP. Reduction in plasma factor 13 (fibrin stabilizing factor) concentration during pregnancy. J Lab Clin Med 1969; 73 (01) 144-153
  • 52 Sharief LT, Lawrie AS, Mackie IJ, Smith C, Peyvandi F, Kadir RA. Changes in factor XIII level during pregnancy. Haemophilia 2014; 20 (02) e144-e148
  • 53 van Wersch JW, Vooijs ME, Ubachs JM. Coagulation factor XIII in pregnant smokers and non-smokers. Int J Clin Lab Res 1997; 27 (01) 68-71
  • 54 Sharief LA. Reproduction and Coagulation Factor XIII in Women. Doctoral Dissertation. University College London, London; 2013
  • 55 Kobayashi T, Terao T, Kojima T, Takamatsu J, Kamiya T, Saito H. Congenital factor XIII deficiency with treatment of factor XIII concentrate and normal vaginal delivery. Gynecol Obstet Invest 1990; 29 (03) 235-238
  • 56 Burrows RF, Ray JG, Burrows EA. Bleeding risk and reproductive capacity among patients with factor XIII deficiency: a case presentation and review of the literature. Obstet Gynecol Surv 2000; 55 (02) 103-108
  • 57 Zhang X, Du W, Fang Q. Risk factors for postoperative haemorrhage after total thyroidectomy: clinical results based on 2,678 patients. Sci Rep 2017; 7 (01) 7075
  • 58 Lak M, Peyvandi F, Ali Sharifian A, Karimi K, Mannucci PM. Pattern of symptoms in 93 Iranian patients with severe factor XIII deficiency. J Thromb Haemost 2003; 1 (08) 1852-1853
  • 59 Korte W, Hinnen C, Degiacomi P. et al. XIII deficiency in the surgical intensive care unit is more frequent than a relevant fibrinogen deficiency. Haemostaseologie 2007; 27: A61
  • 60 Korte W. F. XIII in perioperative coagulation management. Baillieres Best Pract Res Clin Anaesthesiol 2010; 24 (01) 85-93
  • 61 Johansson PI, Sørensen AM, Perner A. et al. Disseminated intravascular coagulation or acute coagulopathy of trauma shock early after trauma? An observational study. Crit Care 2011; 15 (06) R272
  • 62 Sorensen B, Fries D. Emerging treatment strategies for trauma-induced coagulopathy. Br J Surg 2012; 99 (1, Suppl 1): 40-50
  • 63 Fries D, Streif W, Margreiter J. et al. The effects of perioperatively administered crystalloids and colloids on concentrations of molecular markers of activated coagulation and fibrinolysis. Blood Coagul Fibrinolysis 2004; 15 (03) 213-219
  • 64 Gerlach R, Raabe A, Zimmermann M, Siegemund A, Seifert V. Factor XIII deficiency and postoperative hemorrhage after neurosurgical procedures. Surg Neurol 2000; 54 (03) 260-264 , discussion 264–265
  • 65 Gerlach R, Tölle F, Raabe A, Zimmermann M, Siegemund A, Seifert V. Increased risk for postoperative hemorrhage after intracranial surgery in patients with decreased factor XIII activity: implications of a prospective study. Stroke 2002; 33 (06) 1618-1623
  • 66 Korte WC, Szadkowski C, Gähler A. et al. Factor XIII substitution in surgical cancer patients at high risk for intraoperative bleeding. Anesthesiology 2009; 110 (02) 239-245
  • 67 Gödje O, Gallmeier U, Schelian M, Grünewald M, Mair H. Coagulation factor XIII reduces postoperative bleeding after coronary surgery with extracorporeal circulation. Thorac Cardiovasc Surg 2006; 54 (01) 26-33
  • 68 Kanda A, Kaneko K, Obayashi O, Mogami A. The massive bleeding after the operation of hip joint surgery with the acquired haemorrhagic coagulation factor XIII(13) deficiency: two case reports. Case Rep Orthop 2013; 2013: 473014-473017
  • 69 Watanabe N, Yokoyama Y, Ebata T. et al. Clinical influence of preoperative factor XIII activity in patients undergoing pancreatoduodenectomy. HPB (Oxford) 2017; 19 (11) 972-977
  • 70 Gemmati D, Zeri G, Orioli E. et al. Factor XIII-A dynamics in acute myocardial infarction: a novel prognostic biomarker?. Thromb Haemost 2015; 114 (01) 123-132
  • 71 von Meijenfeldt FA, Havervall S, Adelmeijer J. et al. COVID-19 is associated with an acquired factor XIII deficiency. Thromb Haemost 2021; 121 (12) 1668-1669
  • 72 Dragu A, Bach AD, Leffler M, Unglaub F, Horch RE. Acute and diffuse postoperative bleeding after free latissimus dorsi flap--Factor XIII deficiency: a case report and review of the literature. Med Sci Monit 2009; 15 (01) CS1 –CS4
  • 73 Bagoly Z, Koncz Z, Hársfalvi J, Muszbek L. Factor XIII, clot structure, thrombosis. Thromb Res 2012; 129 (03) 382-387
  • 74 Duval C, Ali M, Chaudhry WW, Ridger VC, Ariëns RA, Philippou H. Factor XIII A-subunit V34L variant affects thrombus cross-linking in a murine model of thrombosis. Arterioscler Thromb Vasc Biol 2016; 36 (02) 308-316
  • 75 Muszbek L, Bagoly Z, Cairo A, Peyvandi F. Novel aspects of factor XIII deficiency. Curr Opin Hematol 2011; 18 (05) 366-372
  • 76 Supsrisunjai C, Hsu CK, Michael M. et al. Coagulation factor XIII-A subunit missense mutation in the pathobiology of autosomal dominant multiple dermatofibromas. J Invest Dermatol 2020; 140 (03) 624-635.e7
  • 77 Medeiros AD, Silva AV, Lima FP, Vasconcelos CV, Macedo LM, Melo NM. Effect of factor XIII on the healing of rat skin in use of corticosteroid. Revis Colé Bras Cirurg 2002; 29: 324-329
  • 78 Dorgalaleh A, Bahraini M, Shams M. et al. Molecular basis of rare congenital bleeding disorders. Blood Rev 2022; 9: 101029
  • 79 Ma S, Chen C, Liang Q. et al. Phenotype and genotype of FXIII deficiency in two unrelated probands: identification of a novel F13A1 large deletion mediated by complex rearrangement. Orphanet J Rare Dis 2019; 14 (01) 182
  • 80 Anwar R, Miloszewski KJ, Markham AF. Identification of a large deletion, spanning exons 4 to 11 of the human factor XIIIA gene, in a factor XIII-deficient family. Blood 1998; 91 (01) 149-153
  • 81 Thomas A, Ivaškevičius V, Zawadzki C, Goudemand J, Biswas A, Oldenburg J. Characterization of a novel large deletion caused by double-stranded breaks in 6-bp microhomologous sequences of intron 11 and 12 of the F13A1 gene. Hum Genome Var 2016; 3 (01) 15059
  • 82 Ivaškevičius V, Biswas A, Garly ML, Oldenburg J. Comparison of F13A1 gene mutations in 73 patients treated with recombinant FXIII-A2 . Haemophilia 2017; 23 (03) e194-e203
  • 83 Souri M, Yee VC, Fujii N, Ichinose A. Molecular modeling predicts structural changes in the A subunit of factor XIII caused by two novel mutations identified in a neonate with severe congenital factor XIII deficiency. Thromb Res 2012; 130 (03) 506-510
  • 84 Biswas A, Ivaskevicius V, Thomas A. et al. Eight novel F13A1 gene missense mutations in patients with mild FXIII deficiency: in silico analysis suggests changes in FXIII-A subunit structure/function. Ann Hematol 2014; 93 (10) 1665-1676
  • 85 Thomas A, Biswas A, Dodt J. et al. Coagulation factor XIIIA subunit missense mutations affect structure and function at the various steps of factor XIII action. Hum Mutat 2016; 37 (10) 1030-1041
  • 86 Li B, Billur R, Maurer MC. et al. Proline 36 of the factor XIII activation peptide plays a crucial role in substrate recognition and zymogen activation. Thromb Haemost 2018; 118 (12) 2037-2045