Mansour Aljabry
Factor XIII deficiency in the Saudi population, an underestimated bleeding risk. Review article and an illustrative case report with dental complications
FXIII,RBD,Bleeding
Introduction Congenital Factor (F) XIII deficiency is an autosomal recessive disorder caused by genetic variations in either F13A or F13B genes leading to a bleeding diathesis with variable severity. Patients with severe FXIII deficiency usually present with umbilical cord bleeding during the neonatal period. Ecchymosis, epistaxis, and post-trauma bleeding are the most frequently reported features in FXIII deficiency. Poor wound healing and recurrent delayed bleeding episodes are typical features of factor XIII deficiency as well. Diagnosis of FXIII deficiency can be made only with a high index of clinical suspicion and sets of FXIII-directed assays, as all primary coagulation tests are typically normal. Objectives and methodology This focused review sheds light on the key points related to FXIII deficiency in the Saudi population, focusing on the clinicopathological and therapeutic aspects highlighted with an illustrative case report incidentally diagnosed during a dental procedure. Results and conclusion The disorder is apparently underdiagnosed and underreported in the Saudi population, as only 49 cases of congenital FXIII deficiency have been reported. Moreover, no single case report of acquired FXIII deficiency has been reported in the population.
Factor XIII deficiency in the Saudi population, an underestimated bleeding risk. Review article and an illustrative case report with dental complications

Congenital Factor (F) XIII deficiency is an autosomal recessive disorder caused by genetic variations in either F13A or F13B genes leading to a bleeding diathesis with variable severity. Patients with severe FXIII deficiency usually present with umbilical cord bleeding during the neonatal period. Ecchymosis, epistaxis, and post-trauma bleeding are the most frequently reported features in FXIII deficiency. Poor wound healing and recurrent delayed bleeding episodes are typical features of factor XIII deficiency as well. Diagnosis of FXIII deficiency can be made only with a high index of clinical suspicion and sets of FXIII-directed assays, as all primary coagulation tests are typically normal.

This focused review sheds light on the key points related to FXIII deficiency in the Saudi population, focusing on the clinicopathological and therapeutic aspects highlighted with an illustrative case report incidentally diagnosed during a dental procedure.

The disorder is apparently underdiagnosed and underreported in the Saudi population, as only 49 cases of congenital FXIII deficiency have been reported. Moreover, no single case report of acquired FXIII deficiency has been reported in the population.

Factor XIII is a heterotetramer transglutaminase enzyme that plays a critical role in the last step of the coagulation pathway by forming covalent bonds between the fibrin chains and stabilizing the newly formed clots (Muszbek et al., 2011). Upon activation by thrombin, the catalytic A subunits of FXIII are cleaved to expose their active site, followed by dissociation of the carrier B subunits through a calcium-dependent mechanism (Fig. 1). FXIII is a pro-transglutaminase that circulates in the plasma as a tetrameric protein (F13A2B2). In plasma, this clotting factor consists of two carrier/inhibitory B subunits (F13B) and two potentially active catalytic subunits (F13A). The F13B occurs in excess in plasma and about 50% of this protein exists as free, non-complexed form. F13A2 dimer, but not F13B, has also been found in the cytoplasm of cells including monocytes/macrophages and platelets (Alshehri et al., 2021, Muszbek et al., 2011). Platelet-bound FXIII helps stabilize and retract clots, promoting wound healing via interaction with extracellular matrix proteins such as collagen, fibronectin, and thrombospondin (Muszbek et al., 2011, Schroeder and Kohler, 2016). Furthermore, the role of FXIII is not limited to hemostasis, as its role in osteoblastic differentiation, regulation of innate immunity, and migration of monocytes has been elucidated (Dorgalaleh & Rashidpanah, 2016).

Congenital FXIII deficiency is an autosomal recessive disorder caused by genetic variations in either F13A or F13B genes, located on chromosomes 6p24-p25 and 1q31-32.1, respectively (Hsieh & Nugent, 2008). The vast majority of reported genetic defects are missense variations involving F13A genes leading to severe bleeding phenotype, whereas F13B variations account only for 5% and usually give rise to less severe bleeding manifestations with FXIII activity lowered to 5% to 10%. (Ivaskevicius et al., 2007). It is worth mentioning that a deficiency of B subunits renders A subunits unstable, leading to a relative deficiency of F13A. To date, 172 variations involving the F13A gene have been reported in the literature, of which missense variations account for 51.3%, followed by deletions and insertions in 23.7% of the cases, splice site alterations (13.5%) and nonsense variations (11.5%). Similarly, 25 variations were observed within the B subunit gene of FXIII, with missense variations being the most common type (Dorgalaleh et al., 2022). Acquired FXIII decency is a rare disorder caused by autoimmune conditions, hyper-consumption, or hypo synthesis (Biswas et al., 2014, Chuliber et al., 2021, Yan et al., 2018).

The severity of clinical features of FXIII deficiency correlates strongly with the level of factor XIII deficiency (Peyvandi et al., 2012a, Peyvandi et al., 2012b). Patients with severe FXIII deficiency usually present with umbilical cord bleeding in up to 80% of neonates during the neonatal period, while post-traumatic bleeding events are commonly reported in older children. Life-threatening bleeding complications such as intracranial hematoma (ICH) was documented in up to 30% of patients with FXIII deficiency compared with around 22% and 7.8% in severe hemophilia A and hemophilia B, respectively (Bertamino et al., 2015, Zanon and Pasca, 2019). Menorrhagia and recurrent abortion in the first trimester of pregnancy are commonly noticed. Ecchymosis, epistaxis, and post-trauma bleeding are the most frequently reported features in FXIII deficiency. Poor wound healing and recurrent delayed bleeding episodes are typical features of factor XIII deficiency as well (Peyvandi, Di Michele, et al., 2012).

The initial coagulation tests, including prothrombin time/ international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT), are typically normal in FXIII deficiency. The diagnosis can be made by more specific tests, like FXIII activity assay, antigen assay, inhibitor assay, and molecular studies. The clot solubility test is neither specific nor sensitive and can yield false positive results or might underestimate the severity of FXIII deficiency. Accurate estimation of FXIII antigenic level can be performed via immunological assays utilizing immunoturbidimetric and enzyme-linked immunoassays (ELISA). The molecular causes can be investigated through genetic analysis for chromosomes 6p24-p25 and 1q31-32.1 to determine the implicated gene variations in either F13A or F13B subunits, respectively. FXIII inhibitor assays for neutralizing and non-neutralizing autoantibodies are tested whenever acquired FXIII deficiency is suspected (Dorgalaleh et al., 2016).

The long half-life of FXIII (∼9 days) and the debatable point that 5% of FXIII can maintain normal hemostasis have made FXIII deficiency a suitable target for prophylaxis. The availability of recombinant F13A2. (rF13A2) the drug has revolutionized the management of FXIII deficiency. rF13A2 is a safe and effective drug in preventing all kinds of bleeding episodes and can be administered once monthly, in which a single dose of 35 U/kg is sufficient to maintain a trough level of FXIII more than 5% for up to 4 weeks (Carcao et al., 2018). The old available options include fresh frozen plasma (FFP), cryoprecipitate (CRYO), and viral inactivated FXIII concentrate. Cryoprecipitate is the most commonly available product, which contains around 30% of plasma FXIII. The peri-operative bleeding is a common complication in patients with FXIII deficiency. The FXIII activity of at least 50% needs to be maintained in patients undergoing major surgical procedures (Mangla et al., 2022). The assessment of each patient should be individualized, considering the kind of procedure, the severity of bleeding risks, and each patient's need (Gupta et al., 2007, Strauss et al., 2017). Patients should be prepared 3–5 days prior to dental procedures via administration of 1-unit CRYO per 5 kg body weight, 25 mg/kg tranexamic acid, and antibiotics for 3–5 days (Pai et al., 2020).

A comprehensive literature search was conducted in different scientific publishing websites including PubMed, Web of science, google scholar, peer-reviewed online local and international journals. The aim of the current review is to shed light on the key points related to FXIII deficiency in the Saudi population, focusing on the clinicopathological and therapeutic aspects. A total of 28 relevant scientific resources were initially collected. After assessment for their suitability, only 9 articles were included in the current study as they addressed related aspects of FXIII deficiency in the Saudi population.

An 11-year-old male patient was admitted to the rehabilitation hospital with a pediatric neurodegenerative disorder. A dental examination revealed poor oral hygiene, multiple carious teeth, and the urgent need to extract the first lower molar tooth. There was no evidence of periodontitis. No significant bleeding history was given by the patient's relatives in the patient or his family, and no bleeding manifestations were detected during the clinical examination. Complete blood count was normal apart from mild hypochromic microcytic anemia, while PT and aPTT were normal. However, the molar extraction was complicated with severe bleeding during the procedure; hence 1 unit of packed RBC was transfused. The patient continued to have mild oozing despite the pressure pack, which had been applied locally, and he bled excessively for 8 h after the procedure. Urgent consultation with the hematology team was made with suspicion of von Willebrand disease (vWD) or other rare bleeding disorder (RBD). Laboratory investigation for vWF:Ag, vWF:RCO, and platelet aggregation study were all within normal range while factor XIII level was severely low (0.09 U/mL, the normal range is 0.5–1.8 U/mL), indicating FXIII deficiency. Two units of cryoprecipitate were administered to cease the bleeding, followed by 40 IU/kg IV of plasma-derived FXIII as a prophylactic approach on a monthly basis. Regular follow-up by the dental team was done daily until complete healing. Two weeks later, caries were treated and excavated without any complications.

To date, 49 cases of congenital FXIII deficiency have been reported in the Saudi population (Table 1). The disorder is underdiagnosed and underreported in a society with a high prevalence of consanguinity, reaching up to 45% (Dorgalaleh et al., 2018, Middle et al., 2007, Palla et al., 2015).

In a retrospective analysis of 17 cases with FXIII deficiency followed for 20 years in a tertiary hospital, 71% of patients presented with recurrent hematoma, 55% with post-circumcision bleeding, and 41% presented at birth with umbilical stump bleeding. In addition, poor wound healing and keloid formation were documented in 18% of patients. The life-threatening manifestation, such as intracranial bleeding and cephalohematomas, occurred in 18% of patients (Al-Sharif et al., 2002). Islam et al. reported five patients with FXIII deficiency with serious bleeding manifestations, such as fatal post-circumcision bleeding in 2 infants and excessive post-dental extraction bleeding (Islam & Quadri, 1999).23 Post-tonsillectomy hemorrhage and abnormal keloid scar were the presenting features in 2 different case reports (Albahkaly et al., 2012, AlEssa et al., 2016). AlSaleh et al. found that FXIII deficiency was the most serious RBDs. All patients had very low factor levels and severe bleeding manifestations, including the umbilical stump and severe post-trauma bleeding. FXIII deficiency was found to be the most common RBD occurring, with a frequency of 38.59% (al Saleh et al., 2014).

To the best of the authors’ knowledge, no molecular analysis has been performed yet on any of the 49 reported cases from Saudi Arabia. In the middle east, the vast majority of molecularly analyzed FXIII deficiency cases were reported in Iran, as 366 patients were genetically assayed. According to Drogalaleh et al., all variations involved F13A subunits, of which 72.7% were missense, whereas only 27.3% were insertions or deletions. The most frequent point variations were c.562 T > C (Trp187Arg), c.233G > A (Arg77His), c.2111G > A (Arg703Gln), and c.1226G > A (Arg408Gln) (Dorgalaleh et al., 2018).

Almost all patients receive either or both FFP and cryoprecipitate on demand. Whole blood and antifibrinolytic agent have been used in some patients as well. According to AlSaleh et al., pediatric patients were managed with FXIII in a prophylactic manner with an excellent outcome (al Saleh et al., 2014). Plasma-derived FXIII and recombinant FXIII have been administered in a recent unpublished study by Aljabry et al., conducted in a large tertiary center.

FXIII deficiency is a serious bleeding disorder, as the majority of Saudi patients had very low factor levels and severe bleeding manifestations. However, the epidemiological data regarding the actual scale of FXIII deficiency in the Saudi population are insufficient and mainly obtained from case reports and small case series. High throughput technologies for advanced molecular analysis are highly needed to elucidate the nature of the implicated genetic variations in FXIII deficiency. Furthermore, increasing the awareness about clinicopathological features of the disorder among dentists and general practitioners is highly needed as most of the reported cases had been referred from the primary and dental units.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.