[Factor XI deficiency: actuality and review of the literature]. / Déficit en facteur XI : actualités et revue de littérature.

Although two clusters have been identified in France, constitutional factor XI deficiency is a rare disorder. Acquired factor XI deficiency is extremely rare. The management of factor XI deficiency is not staightforward because of the unpredictable bleeding tendency that does not clearly relate to the factor XI level. Other haemostastis parameters have to be taken into account to evaluate the bleeding tendency. We report the cases of a congenital factor XI deficiency, an acquired factor XI deficiency and a von Willebrand disease associated to a factor XI deficiency. On the other hand, some interferences can lead to underestimation of factor XI and we report the case of an interference by lupus anticoagulant. The objective of this review is to better understand how to manage a reduced factor XI level.

Factor XI deficiency: phenotypic age-related considerations and clinical approach towards bleeding risk assessment.

ABSTRACT: Factor XI (FXI) deficiency is a rare bleeding disorder that presents complex challenges in patient assessment and bleeding risk management. Despite generally causing mild to moderate bleeding symptoms, clinical manifestations can vary, and bleeding tendency does not always correlate with FXI plasma levels or genotype. Our manuscript delves into the age-related nuances of FXI deficiency across an individual's lifespan. We emphasize issues faced by specific groups, including neonates and females of reproductive age experiencing abnormal uterine bleeding and postpartum hemorrhage. Older patients present unique challenges and concerns related to the management of bleeding as well as thrombotic complications. The current assortment of diagnostic laboratory assays shows limited success in predicting bleeding risk in the perisurgical setting of patients with FXI deficiency. This review explores the intricate interplay between individual bleeding profiles, surgical sites, and FXI activity levels. We also evaluate the accuracy of existing laboratory assays in predicting bleeding and discuss the potential role of investigational global assays in perioperative assessment. Furthermore, we outline our suggested diagnostic approach to refine treatment strategies and decision making. Available treatment options are presented, including antifibrinolytics, replacement products, and recombinant activated FVII. Finally, we discuss promising nonreplacement therapies for the treatment of rare bleeding disorders that can potentially address the challenges faced when managing FXI deficiency-related bleeding complications.

"Familial Multiple Coagulation Factor Deficiencies of FXI and FXII in an Asymptomatic Saudi Woman".

Factor XI deficiency (FXI) is the third most common coagulation factor deficiency after hemophilia A and B, ie, in the hierarchy after factors VIII and IX, taking into account von Willebrand's factor deficiency, as bleeding disorders are higher than in hemophilia C. Factor XII deficiency (FXII) is a congenital condition, inherited in the vast majority of cases in an autosomal recessive manner, more often associated with thromboembolic complications. A combination of both factor deficiencies has been found very rarely, and it can be familial multiple coagulation factor deficiency (FMCFD). This study reports the case of a 39-year-old woman from Saudi Arabia who had the combination of FXI and FXII deficiencies, known to be on treatment for hypothyroidism and was referred to a hematology clinic with an incidental finding of prolonged activated partial thromboplastin time (aPTT). Although there was no history of bleeding tendency, her siblings had a family history of an unknown type of bleeding disorder. On physical examination, the patient did not show any bruising, petechiae, or ecchymosis. The aPTT was 69 seconds (27-38) with normal use of other hemostatic agents and was corrected after a 50:50 mixing study. Intrinsic coagulation factors were evaluated, and they revealed severe FXI and moderate FXII deficiencies. Due to a strong family history, the patient was diagnosed with FMCFD. In conclusion, familial combined multiple clotting factor deficiency (FCMFD) is a rare condition that requires attention and reporting. The management strategy in such cases has not been well studied, especially in the long-term symptomatic patient with severe but asymptomatic combined FXI and FXII deficiencies, which is an area for review and further study.

Impact of genetic structural variants in factor XI deficiency: identification, accurate characterization, and inferred mechanism by long-read sequencing.

BACKGROUND: Congenital factor XI (FXI) deficiency is a probably underestimated coagulopathy that confers antithrombotic protection. Characterization of genetic defects in F11 is mainly focused on the identification of single-nucleotide variants and small insertion/deletions because they represent up to 99% of the alterations accounting for factor deficiency, with only 3 gross gene defects of structural variants (SVs) having been described. OBJECTIVES: To identify and characterize the SVs affecting F11. METHODS: The study was performed in 93 unrelated subjects with FXI deficiency recruited in Spanish hospitals over a period of 25 years (1997-2022). F11 was analyzed by next-generation sequencing, multiplex ligand probe amplification, and long-read sequencing. RESULTS: Our study identified 30 different genetic variants. Interestingly, we found 3 SVs, all heterozygous: a complex duplication affecting exons 8 and 9, a tandem duplication of exon 14, and a large deletion affecting the whole gene. Nucleotide resolution obtained by long-read sequencing revealed Alu repetitive elements involved in all breakpoints. The large deletion was probably generated de novo in the paternal allele during gametogenesis, and despite affecting 30 additional genes, no syndromic features were described. CONCLUSION: SVs may account for a high proportion of F11 genetic defects implicated in the molecular pathology of congenital FXI deficiency. These SVs, likely caused by a nonallelic homologous recombination involving repetitive elements, are heterogeneous in both type and length and may be de novo. These data support the inclusion of methods to detect SVs in this disorder, with long-read-based methods being the most appropriate because they detect all SVs and achieve adequate nucleotide resolution.

Detection and Gene Mutation Analysis of Three Variations in Two Unrelated Chinese Hereditary Coagulation Factor XI Deficiency Families.

INTRODUCTION: Three variations including a novel F11 gene variation were detected in two unrelated Chinese families with coagulation factor XI deficiency, and their possible pathogenesis was elucidated. METHODS: The genomic DNA of the probands' pedigrees was extracted, and all exons and flanking sequences of F11 gene were subjected to PCR amplification and Sanger sequencing. ClustalX-2.1-win, Mutation Taster, and Swiss-Pdb Viewer software were used to analyze the conservation and impact of the variations on protein function and structure. RESULTS: DNA sequencing showed that the proband one had p.Gly350Glu and p.Trp501stop complex heterozygous variations, while the proband two took p.Pro338Leu and p.Trp501stop compound heterozygous variations. Conservation, structural, and functional analysis of variant amino acids indicated that these three variations were harmful and probably affected the structure and function of the variable protein. CONCLUSIONS: Three variations including p.Pro338Leu, p.Gly350Glu, and p.Trp501stop responsible for the reduction of the FXI activities were herein detected. Notably, the p.Pro338Leu variation was discovered for the first time in the world. Furthermore, the p.Gly350Glu was first reported in China.

Factor XI deficiency: About 20 cases and literature review.

INTRODUCTION: Factor XI deficiency is a rare coagulation disorder with variable bleeding manifestations. AIM: To evaluate the correlation between the degree of factorXI deficiency and the clinical expression of the disease. METHODS: Retrospective study, spanning 10 years from January 1, 2010 to December 31, 2019, concerning patients followed at the Hemophilia Center at Aziza Othmana Hospital in Tunis. The data were collected from the medical records. The determination of PT, APTT, fibrinogen level and coagulation factors are performed by coagulometric technique on STA® compact / ACL TOP®. FactorXI deficiency was confirmed on two different samples. Statistical analysis of the clinical-biological correlation was performed using the chi-square test. The significance level was 0.05. RESULTS: Twenty patients were collected. The mean age of discovery was 25 years with a sex ratio (M/F) =0.33. The circumstances of discovery were incidental in 14 patients. A family history of bleeding was reported in 30% of cases. Eight patients underwent surgery, six of whom had a simple postoperative course. The APTT was prolonged and isolated in 75% of cases. The hemostasis test was normal in 5 cases. The average FactorXI level was 24%. The tendency to bleed did not seem to be correlated with FactorXI levels. CONCLUSION: Prospective multicenter studies including molecular study would be necessary to better elucidate this rare disorder.

Evaluation of thrombin generation assay in factor XI deficiency.

INTRODUCTION: Factor XI (FXI) deficiency is characterized by a lack of correlation between FXI plasma levels and the occurrence of hemorrhagic events. The main objective of our study was to determine whether thrombin generation assay (TGA) could be used to assess the hemorrhagic phenotype of patients with FXI deficiency. MATERIAL AND METHODS: All patients had confirmed laboratory measurement of FXI < 50% in two plasma samples. Relevant bleeding history was evaluated by a senior physician. TGA was performed with Calibrated Automated Thrombography, in platelet poor plasma, from patients and healthy controls. The assay was performed with PPP low reagent (1 pM of human tissue factor). RESULTS: Seventy-six patients with FXI deficiency were included between 2011 and 2020. Among them, eight patients had severe deficiency (FXI < 15%). Mean age was 34 years [range: 9-77]. Endogenous thrombin potential (ETP) was significantly lower in patients with FXI deficiency and bleeding (573 nM·min [225-1214]) or no bleeding (732 nM·min [222-1435]), compared to healthy controls (1184 nM·min [933-1518]). No difference was observed for ETP and peak between patients with FXI deficiency and bleeding and patients with FXI deficiency and no bleeding. No difference was observed for ETP (923 nM·min [377-1497] vs 1063 nM·min [252-2529]), peak (82 nM [28-154] vs 131 nM [20-330]) or velocity (13.7 nM/min [3.6-29.6] vs 26.5 nM/min [2.5-90]) in women with (n = 4) and without history (n = 17) of post-partum bleeding. No difference of thrombin generation was observed in pregnant women with FXI deficiency (ETP: 1395 nM·min [351-2529]; peak: 154 nM [26-330]; velocity: 29.6 nM/min [4.1-90.0]), compared to healthy controls and a control group of healthy pregnant women. CONCLUSION: In conclusion, under our experimental condition, a non-significant decrease of thrombin generation was observed in plasma samples of patients with FXI deficiency and bleeding. Our results suggest an increase of coagulation parameters during pregnancy in women with FXI deficiency. A larger sample size or other experimental conditions are required to evaluate the use of TGA in FXI deficiency.

Factor XI Deficiency.

Factor XI (FXI) deficiency (hemophilia C or Rosenthal disease) was first described in the 1950s in a multigenerational family experiencing bleeding related to surgery and dental procedures. Managing patients with FXI deficiency presents several challenges, including a lack of correlation of bleeding symptoms with FXI activity levels, the large volume of fresh frozen plasma required to achieve hemostatic FXI levels, lack of availability of FXI concentrate in certain regions of the world, and the inherent thrombotic risk associated with replacement therapy. This article summarizes presentation, diagnosis, and management of patients with FXI deficiency in a variety of clinical settings.

Tissue Factor-Independent Coagulation Correlates with Clinical Phenotype in Factor XI Deficiency and Replacement Therapy.

BACKGROUND: In factor XI (FXI) deficiency, bleeding cannot be predicted by routine analyses. Since FXI is involved in tissue factor (TF)-independent propagation loop of coagulation, we hypothesized that investigating the spatiotemporal separated phases of coagulation (TF-dependent and -independent) could improve diagnostics. OBJECTIVES: This article investigates the correlation of parameters describing TF-dependent and -independent coagulation with the clinical phenotype of FXI deficiency and their ability to assess hemostasis after FXI replacement. METHODS: We analyzed: (1) plasma from healthy controls (n = 53); (2) normal plasma (n = 4) spiked with increasing concentrations of a specific FXI inhibitor (C7P); (3) plasma from FXI-deficient patients (n = 24) with different clinical phenotypes (13 bleeders, 8 non-bleeders, 3 prothrombotics); (4) FXI-deficient plasma spiked with FXI concentrate (n = 6); and (5) plasma from FXI-deficient patients after FXI replacement (n = 7). Thrombin generation was measured with the reference method calibrated automated thrombogram and with Thrombodynamics (TD), a novel global assay differentiating TF-dependent and -independent coagulation. RESULTS: C7P dose-dependently decreased FXI activity, prolonged activated partial thromboplastin time, and hampered TF-independent coagulation. In FXI-deficient bleeders, TD parameters describing TF-independent propagation of coagulation and fibrin clot formation were reduced compared with controls and FXI-deficient nonbleeders and increased in FXI-deficient patients with prothrombotic phenotype. Receiver operating characteristic analysis indicated that TF-independent parameters were useful for discriminating FXI-deficient bleeders from non-bleeders. In FXI-deficient plasma spiked with FXI concentrate and in patients receiving FXI replacement, TD parameters were shifted toward hypercoagulation already at plasma FXI levels around 20%. CONCLUSION: TF-independent coagulation parameters assessed by TD have the potential to identify the clinical phenotype in FXI-deficient patients and to monitor FXI replacement therapy.

First case of delayed traumatic intracerebral hemorrhage in a patient with undiagnosed factor XI deficiency: diagnosis and management review.

Factor XI (FXI) deficiency, also known as hemophilia C, is included in the rare bleeding disorders (RBDs). It is distinct from other coagulation factor deficiencies because it rarely presents as spontaneous hemorrhage, but rather as bleeding after trauma or surgery; in addition, the severity of bleeding does not correlate with FXI levels. Most delayed traumatic intracerebral hemorrhage (DTICH) occurs during the first 72 hours of the trauma. Factors that contribute to its formation include local or systemic coagulopathy, among others. Hemorrhagic cases of FXI deficiency related to the central nervous system (CNS) are very rare, with only 13 reported cases. To the best of our knowledge, this is the first reported case of a DTICH in a patient with undiagnosed FXI deficiency.

Postpartum haemorrhage in women with mild factor XI deficiency.

INTRODUCTION: With the advent of direct-to-consumer genetic testing, mild factor XI deficiency is increasingly recognized. There are limited data regarding the risk of postpartum haemorrhage (PPH) among women with mild FXI deficiency following obstetrical delivery. AIM: To assess the risk of PPH among women with mild FXI deficiency undergoing vaginal or caesarean delivery. METHODS: We conducted a retrospective, case-control study, in women with FXI levels between 20% and 70% of normal. For a control population, delivery outcomes were analysed in 200 women (between 2016 and 2018) without known bleeding disorders. RESULTS: There was no PPH among 45 vaginal deliveries in women with mild FXI deficiency compared with one PPH among 125 vaginal deliveries in the control cohort. The rate of PPH was significantly higher among the 26 caesarean deliveries in women with mild FXI deficiency relative to 75 control caesarean deliveries (odds ratio 2.73, 95% CI 1.02-7.26, P = .04). Prior history of haemorrhage was a strong predictor of PPH following caesarean delivery. All women who developed PPH following caesarean delivery had either a history of haemorrhage or independent risk factor for PPH. CONCLUSION: Due to the low rates of postpartum haemorrhage following vaginal delivery, routine prophylaxis to prevent postpartum haemorrhage in the setting of mild FXI deficiency does not appear warranted, especially in the absence of a bleeding history. Mild FXI deficiency is associated with an increased risk of PPH following caesarean delivery.

The clinical management of factor XI deficiency in pregnant women.

INTRODUCTION: Factor XI (FXI) deficiency is associated with highly variable bleeding, including excessive gynecologic and obstetrical bleeding. Since approximately 20% of FXI-deficient women will experience pregnancy-related bleeding, careful planning and knowledge of appropriate hemostatic management is pivotal for their care. AREAS COVERED: In this manuscript, authors present our current understanding of the role of FXI in hemostasis, the nature of the bleeding phenotype caused by its deficiency, and the impact of deficiency on obstetrical care. The authors searched PubMed with the terms, 'factor XI', 'factor XI deficiency', 'women', 'pregnancy', and 'obstetrics' to identify literature on these topics. Expectations of pregnancy-related complications in women with FXI deficiency, including antepartum, abortion-related, and postpartum bleeding, as well as bleeding associated with regional anesthesia are discussed. Recommendations for the care of these women are considered, including guidance for management of prophylactic care and acute bleeding. EXPERT COMMENTARY: FXI deficiency results in a bleeding diathesis in some, but not all, patients, making treatment decisions and clinical management challenging. Currently available laboratory assays are not particularly useful for distinguishing patients with FXI deficiency who are prone to bleeding from those who are not. There is a need for alternative testing strategies to address this limitation.

Combined Congenital Hypodysfibrinogemia and Factor XI Deficiency in a Chinese Family.

Both congenital hypodysfibrinogenemia and factor XI deficiency are rare coagulopathies caused by mutations within the fibrinogen and F11 genes, respectively. To investigate the pathogenesis of combined congenital hypodysfibrinogenemia with factor XI (FXI) deficiency in a Chinese family, coagulation assays, FXI activity (the 1-stage method), fibrinogen activity (the Clauss method), and antigen (prothrombin time [PT]-derived method) were performed. The sequences of fibrinogen genes and F11 were amplified by PCR and analyzed by direct sequencing. The proband as well as his grandmother, father, aunt, and sister showed a low plasma concentration of fibrinogen measured by the Clauss method and a slightly decreased result by the PT-derived method; finally, c.1097A>G in exon 8 of FGG was detected in the pedigree, which caused His340Arg mutation. His grandfather had a slightly prolonged activated partial thromboplastin time (APTT) due to low FXI activity. FXI deficiency was a compound heterozygote inherited with missense mutations of c.434A>G in exon 5 as well as c.1253G>T in exon 11 which caused HGV p.His145Arg and Gly400Val mutations, respectively. The grandfather had no qualitative or quantitative defect in fibrinogen. The proband and his father and aunt had c.434A>G at the exon 5 mutation site and no decrease in FXI activity. His mother had no fibrinogen or F11 gene mutations. Plasma fibrin polymerization was delayed. The proband in our study showed typical changes of congenital hypodysfibrinogemia in the clotting analyses with delayed fibrin polymerization, but although he was a heterozygous carrier of the c.434A>G variant in the F11 gene, he had no decrease in FXI activity and no bleeding tendency, thus questioning the pathogenicity of the identified variant in the F11 gene. To our knowledge, this is the first report of a case of combined hypodysfibrinogenemia and FXI deficiency confirmed by molecular genetic tests.