Novel Insights into Heterozygous Factor XIII Deficiency

Abstract

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.

Post-renal Biopsy Retroperitoneal Haematoma Accompanied by Decreased Coagulation Factor XIII Levels in Immunoglobulin A Nephropathy

“…FXIIID may be congenital or acquired, and congenital FXIIID is a rare autosomal recessive bleeding disorder [ 9 ]. FXIII activity in patients with severe congenital FXIIID is undetectable [ 9 ], while in heterozygous FXIIID, FXIII activity is typically between 30% and 70% [ 10 ]. The FXIII activity level required to prevent spontaneous major bleeding is 15% [ 11 ], and the requirement for FXIII increases during surgery and bleeding because of hyperconsumption.…”

“…Postoperative/tooth extraction bleeding has been reported in patients with heterozygous FXIIID who had FXIII activity between 23% and 71% [ 10 ]. The bleeding risk after surgical procedures is higher in heterozygotes with FXIIID than in healthy individuals because the baseline levels of FXIII are lower [ 10 ]. By contrast, acquired FXIIID is caused by the generation of antibodies, hyperconsumption, or hyposynthesis due to an underlying comorbidity [ 9 ].…”

“…Postoperative/tooth extraction bleeding has been reported in patients with heterozygous FXIIID who had FXIII activity between 23% and 71% [10]. The bleeding risk after surgical procedures is higher in heterozygotes with FXIIID than in healthy individuals because the baseline levels of FXIII are lower [10].…”