RÉSUMÉ
BACKGROUND: Factor XI (FXI) deficiency is an autosomal hemorrhagic disorder characterized by reduced plasma FXI levels. Multiple ancestral variants in the F11 gene have been identified in Ashkenazi Jews and other selected European populations. However, there are few reports of predominant variants in Chinese and/or East Asian populations. The aim of this study is to characterize the genotypes and phenotypes of FXI deficiency and identify the predominant variants. RESULTS: Of the 41 FXI-deficient patients, 39 exhibited severe FXI defects, considerably more than those with partial defects. The APTT levels showed a negative correlation with FXI activity levels (coefficient=-0.584, P < .001). Only nine patients experienced mild bleeding, including one partially defective patient and eight severely defective patients. The majority of patients were referred for preoperative screenings (n = 22) and checkups (n = 14). Genetic analysis revealed that 90% of the patients had genetic defects, with 2, 16, and 19 cases of heterozygous, homozygous, and compound heterozygous patients, respectively. Seventeen variants were detected in the F11 gene (6 novel), including eleven missense variants, four nonsense variants, and two small deletions scattered throughout the F11. Of the 11 missense variants, six have not yet been studied for in vitro expression. Protein modeling analyses indicated that all of these variants disrupted local structural stability by altering side-chain orientation and hydrogen bonds. Nine variants, consisting of three missense and six null variants, were detected with a frequency of two or more. The highest allele frequency was observed in p.Q281* (21.25%), p.W246* (17.50%), p.Y369* (12.50%), and p.L442Cfs*8 (12.50%). The former two were variants specific to East Asia, while the remaining two were southeast China-specific variants. CONCLUSION: Our population-based cohort demonstrated that no correlation between the level of FXI activity and the bleeding severity in FXI deficiency. Additionally, the prevalence of FXI deficiency may have been underestimated. The nonsense p.Q281* was the most common variant in southeast China, suggesting a possible founder effect.
Sujet(s)
Déficit en facteur XI , Facteur XI , Humains , Déficit en facteur XI/génétique , Femelle , Chine/épidémiologie , Mâle , Facteur XI/génétique , Adulte , Adulte d'âge moyen , Adolescent , Jeune adulte , Enfant , Génotype , Sujet âgéRÉSUMÉ
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.
Sujet(s)
Déficit en facteur XI , Humains , Déficit en facteur XI/diagnostic , Déficit en facteur XI/complications , Déficit en facteur XI/sang , Femelle , Mâle , Facteur XI/analyse , Maladies de von Willebrand/diagnostic , Maladies de von Willebrand/complications , France/épidémiologie , Adulte d'âge moyen , AdulteRÉSUMÉ
BACKGROUND Bariatric surgery (BS) has a lower percentage of complications than other abdominal surgeries. Hemorrhage in one of the most common complications and can be life-threatening. Hereditary factor XI (FXI) deficiency is a coagulation disorder that can result in excessive bleeding requiring intervention to restore hemostasis. Risks over benefits in patients with morbid obesity with BS indication, as well as those with FXI deficiency, should be carefully evaluated. This article reports the case of an obese woman with FXI deficiency -undergoing SG. CASE REPORT A 49-year-old woman with a BMI of 51 kg/m² was diagnosed as having severe FXI deficiency during preoperative exams prior to bariatric surgery. Virus-inactivated homo-group plasma 10 ml/kg infusion was administrated 1 h before surgery, during the entire procedure, and continuing until postoperative day (POD) 4. A very low-calorie ketogenic diet (VLCKD) was proposed to the patient 4 weeks before surgery. Laparoscopic sleeve gastrectomy was performed with staple-line reinforcement by oversewing the seromuscular layer using continuous suture. Subcutaneous enoxaparin 4000 U.I. was administered from POD 1 until POD 25 to prevent any thromboembolic event. The patient was discharged on POD 5 in good clinical condition. CONCLUSIONS Risks of bleeding andor thromboembolic events before or after BS are increased in patient with FXI deficiency. Bariatric surgery in these patients is safe in experienced BS centers, and the risks associated with the obesity seem to exceed those of the coagulopathy and surgery. Careful preoperative counseling, extensive hematological checks, and meticulous surgery are essential to reduce BS risks. Sleeve gastrectomy oversewing the stapler line seems a reasonable choice.
Sujet(s)
Déficit en facteur XI , Gastrectomie , Laparoscopie , Obésité morbide , Humains , Femelle , Adulte d'âge moyen , Gastrectomie/méthodes , Déficit en facteur XI/complications , Obésité morbide/chirurgie , Agrafage chirurgicalRÉSUMÉ
INTRODUCTION: Due to their low prevalence, rare bleeding disorders (RBDs) remain poorly characterized. AIM: To gain insight of RBDs through our clinical practice. METHODS: Retrospective study of the medical records of RBD patients followed up at the Central University Hospital of Asturias between January 2019 and December 2022. RESULTS: A total of 149 patients were included. Factor (F) VII (44 %) and FXI (40 %) deficiencies were the most common diagnosed coagulopathies. Most of the patients were asymptomatic (60.4 %) and the most frequent type of bleeding were mucocutaneous and after surgery. All replacement treatments were administered on demand and no patient was on a prophylaxis regimen. Currently available products were safe; allergic reactions after administration of plasma were the most frequent complication. Genetic analysis, carried out on 55 patients (37 %), showed that the most frequent mutations in RBDs are of missense type (71.9 %). We identified 11 different novel genetic alterations in affected genes. The c.802C > T (p.Arg268Cys) variant, previously described, was identified in 71 % (15 of 21) of the patients with FXI deficiency genotyped and none were related (probable founder effect). CONCLUSION: Our study on an unusual large single center cohort of RBD patients portrays location-dependent distinct genetic drives and clinical practice particularities.
Sujet(s)
Troubles de l'hémostase et de la coagulation , Déficit en facteur XI , Humains , Études rétrospectives , Centres de soins tertiaires , Troubles de l'hémostase et de la coagulation/épidémiologie , Hémorragie/diagnostic , Génotype , Maladies rares/diagnosticRÉSUMÉ
BACKGROUND: Coagulation factor XI deficiency is an autosomal recessive hereditary disease with a low incidence. It usually occurs after surgery or trauma; Esophageal cancer is a common malignant tumor of the digestive tract in China. But so far, surgery-based comprehensive treatment of esophageal cancer still dominates. CASE PRESENTATION: We report a case of an Asian patient with XI factor deficiency and lower esophageal squamous cell carcinoma who was admitted to our hospital recently. After active preoperative preparation, the operation was successfully performed, and there was no obvious abnormal bleeding during and after the operation. CONCLUSIONS: Coagulation factor XI deficiency is a relatively rare disease, and patients with the disease will face a greater risk of bleeding during the perioperative period. The encouraging perioperative outcome enables us to have a deeper understanding of surgical treatment strategies for patients with Coagulation factor XI deficiency.
Sujet(s)
Tumeurs de l'oesophage , Carcinome épidermoïde de l'oesophage , Déficit en facteur XI , Humains , Tumeurs de l'oesophage/complications , Tumeurs de l'oesophage/chirurgie , Carcinome épidermoïde de l'oesophage/complications , Carcinome épidermoïde de l'oesophage/chirurgie , Facteur XI , Déficit en facteur XI/complications , Hémorragie/étiologie , Mâle , Sujet âgéRÉSUMÉ
Acquired factor XI deficiencies due to factor-specific inhibitors are rare and may be associated with lupus anticoagulant. We report a 63-year-old male with suspected postsurgical bleeding, prior surgical site infection, an isolated prolonged activated partial thromboplastin time, and a positive lupus anticoagulant. Although the factor II assay was normal, factor VIII and IX assays initially demonstrated nonparallelism with factor activity that consistently increased to normal reference ranges with serial dilutions. A discrepancy in factor XI activity results was discovered when the in-house method demonstrated undetectable activity (<3%); send-out testing using different instrument/reagent combinations revealed the presence of factor XI activity between 70% and 76%. The patient received surgical follow-up and was subsequently discharged home. Given the differential in vitro inhibition of factor XI activity on our initial in-house testing, this case highlights the importance of recognizing factor assay interference in the presence of a known lupus anticoagulant inhibitor, with strategies to mitigate potentially erroneous results.
Sujet(s)
Facteur XI , Inhibiteur lupique de la coagulation , Humains , Inhibiteur lupique de la coagulation/sang , Mâle , Adulte d'âge moyen , Facteur XI/antagonistes et inhibiteurs , Tests de coagulation sanguine/méthodes , Déficit en facteur XI/sang , Temps partiel de thromboplastine/méthodesRÉSUMÉ
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.
Sujet(s)
Troubles de l'hémostase et de la coagulation , Déficit en facteur XI , Thrombose , Grossesse , Femelle , Nouveau-né , Humains , Déficit en facteur XI/complications , Déficit en facteur XI/diagnostic , Déficit en facteur XI/thérapie , Hémorragie/étiologie , Hémorragie/complications , Troubles de l'hémostase et de la coagulation/complications , Thrombose/complications , Appréciation des risques , Facteur XIRÉSUMÉ
ABSTRACT: Unique among coagulation factors, the coagulation factor XI (FXI) arose through a duplication of the gene KLKB1, which encodes plasma prekallikrein. This evolutionary origin sets FXI apart structurally because it is a homodimer with 2 identical subunits composed of 4 apple and 1 catalytic domain. Each domain exhibits unique affinities for binding partners within the coagulation cascade, regulating the conversion of FXI to a serine protease as well as the selectivity of substrates cleaved by the active form of FXI. Beyond serving as the molecular nexus for the extrinsic and contact pathways to propagate thrombin generation by way of activating FIX, the function of FXI extends to contribute to barrier function, platelet activation, inflammation, and the immune response. Herein, we critically review the current understanding of the molecular biology of FXI, touching on some functional consequences at the cell, tissue, and organ level. We conclude each section by highlighting the DNA mutations within each domain that present as FXI deficiency. Together, a narrative review of the structure-function of the domains of FXI is imperative to understand the etiology of hemophilia C as well as to identify regions of FXI to safely inhibit the pathological function of activation or activity of FXI without compromising the physiologic role of FXI.
Sujet(s)
Déficit en facteur XI , Facteur XI , Humains , Facteur XI/génétique , Déficit en facteur XI/génétique , Coagulation sanguine/génétique , Domaine catalytique , Thrombine/métabolisme , BiologieRÉSUMÉ
To examine real-life clinical data regarding hereditary factor XI (FXI) deficiency from a secondary care centre. Retrospective review of clinical records for every FXI:C 0.7âIU/ml or less reported from 2012 to 2020. Seventy-nine patients were included. Six (7.6%) had a severe deficiency (FXI:C <0.2âIU/ml). Only 55 (69.6%) patients were referred to the Haemostasis Centre. Among them, six (15%) were subsequently not identified at increased haemorrhagic risk before a surgical/obstetrical procedure. Thirty-three (41.8%) experienced at least one bleeding event, minor (25 patients) and/or major (16 patients). Minor bleedings were predominantly spontaneous and more frequent in women, major events were mainly provoked. No correlation was found between FXI:C and risk of bleeding ( P â=â0.9153). Lower FXI:C, but not a positive bleeding history, was related with higher likelihood of being referred to the Haemostasis Centre ( P â=â0.0333). Hereditary FXI deficiency prevalence is likely underestimated, real-life clinical practices outside reference centres could be suboptimal.
Sujet(s)
Déficit en facteur XI , Facteur XI , Femelle , Humains , Facteur XI/génétique , Déficit en facteur XI/épidémiologie , Déficit en facteur XI/génétique , Hémorragie/complications , Italie/épidémiologie , Maladies négligées/complications , Études rétrospectives , MâleRÉSUMÉ
Factor XI is a zymogen with an important role in the coagulation cascade. It is activated by FXII, thrombin and or it can be autoactivated. It has a prothrombotic effect after being activated by thrombin, but also through its antifibrinolytic action, stabilizing the formed clot. Hereditary deficiency of FXI causes haemophilia C - a disease manifested by an usually provoked, small to moderate mucosal bleeding. People with severe FXI deficiency have a low risk of thrombotic events. Conversely, increased FXI values have been found to be associated with increased risk of venous thromboembolism and ischemic stroke. Lowering serum FXI levels has become a treatment target for the prevention of thrombotic events. New pharmacological agents - FXI inhibitors - have been investigated in phase II clinical trials, with promising results in terms of efficacy and safety in the prevention of thrombotic events. FXI inhibitors are emerging as new anticoagulant agents with broad indication prospects beyond direct oral anticoagulants and vitamin K antagonists.
Sujet(s)
Facteur XI , Humains , Facteur XI/antagonistes et inhibiteurs , Facteur XI/métabolisme , Anticoagulants/usage thérapeutique , Coagulation sanguine/effets des médicaments et des substances chimiques , Thrombose/prévention et contrôle , Thrombose/étiologie , Déficit en facteur XI/complications , Déficit en facteur XI/traitement médicamenteux , Fibrinolytiques/usage thérapeutique , Arginine/analogues et dérivés , Arginine/usage thérapeutiqueRÉSUMÉ
Japanese Brown cattle are the second most popular Wagyu breed, and the Kumamoto sub-breed shows better daily gain and carcass weight. One of the breeding objectives for this sub-breed is to reduce genetic defects. Chondrodysplastic dwarfism and factor VIII deficiency have been identified as genetic diseases in the Kumamoto sub-breed. Previously, we detected individuals in the Kumamoto sub-breed with causative alleles of genetic diseases identified in Japanese Black cattle. In the current study, 11 mutations responsible for genetic diseases in the Wagyu breeds were analyzed to evaluate the risk of genetic diseases in the Kumamoto sub-breed. Genotyping revealed the causative mutations of chondrodysplastic dwarfism, factor XI deficiency, and factor XIII deficiency and suggested the appearance of affected animals in this sub-breed. DNA testing for these diseases is needed to prevent economic loses in beef production using the Kumamoto sub-breed.
Sujet(s)
Maladies des bovins , Nanisme , Déficit en facteur XI , Déficit en facteur XIII , Humains , Bovins/génétique , Animaux , Déficit en facteur XI/génétique , Déficit en facteur XI/médecine vétérinaire , Allèles , Déficit en facteur XIII/génétique , Déficit en facteur XIII/médecine vétérinaire , Sélection , Nanisme/génétique , Nanisme/médecine vétérinaire , Maladies des bovins/génétiqueRÉSUMÉ
OBJECTIVE: To explore the molecular pathogenesis of a Chinese pedigree affected with Hereditary coagulation factor â ª (Fâ ª) deficiency due to variants of the F11 gene. METHODS: A male proband with Hereditary coagulation factor â ª deficiency who was admitted to the First Affiliated Hospital of Wenzhou Medical University due to urinary calculi on November 30, 2020 and his family members (7 individuals from 3 generations in total) were selected as the study subjects. Clinical data of the proband were collected, and relevant coagulation indices of the proband and his family members were determined. Genomic DNA of peripheral blood samples was extracted for PCR amplification. All exons, flanking sequences, and 5' and 3' untranslated regions of the F11 gene of the proband were analyzed by direct sequencing. And the corresponding sites were subjected to sequencing in other family members. The conservation of amino acid variation sites was analyzed by bioinformatic software, and the effect of the variant on the protein function was analyzed. Variants were graded based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). RESULTS: The proband was a 36-year-old male. His activated partial thromboplastin time (APTT) was 89.2s, which was significantly prolonged. The Fâ ª activity (Fâ ª:C) and Fâ ª antigen (Fâ ª:Ag) were 2.0% and 3.5%, respectively, which were extremely reduced. Both the proband and his sister were found to harbor compound heterozygous variants of the F11 gene, including a c.689G>T (p.Cys230Phe) missense variant in exon 7 from their father and a c.1556G>A (p.Trp519*) nonsense variant in exon 13 from their mother. Conservation analysis indicated the Cys230 site to be highly conserved. The c.1556G>A (p.Trp519*) variant was known to be pathogenic, whilst the c.689G>T variant was classified as likely pathogenic (PM2+PM5+PP1+PP3+PP4) based on the ACMG guidelines. CONCLUSION: The c.689G>T and c.1556G>A compound heterozygous variants of the F11 gene probably underlay the pathogenesis of Fâ ª deficiency in this pedigree.
Sujet(s)
Déficit en facteur XI , Facteur XI , Adulte , Humains , Mâle , Régions 3' non traduites , Peuples d'Asie de l'Est , Facteur XI/génétique , Déficit en facteur XI/génétique , Temps partiel de thromboplastine , PedigreeRÉSUMÉ
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.
Sujet(s)
Déficit en facteur XI , Hémophilie A , Femelle , Humains , Adulte , Arabie saoudite , Déficit en facteur XI/complications , Déficit en facteur XI/diagnostic , Facteurs de la coagulation sanguineRÉSUMÉ
Factor XI deficiency is associated with a bleeding tendency in some patients. Factor XI helps to reduce fibrinolysis. Bleeding risk is increased in factor XI-deficient patients during surgeries with high fibrinolytic activity, including nasopharyngeal/oropharyngeal and genitourinary surgeries. Treatment options for factor XI-deficient patients include fresh frozen plasma (FFP), antifibrinolytics, recombinant factor VIIa, and factor XI concentrates (available in Australia, Canada, and some European countries). 4-factor prothrombin complex concentrate (4-factor PCC) is an extract of FFP comprised of unactivated factors II, VII, IX, and X, proteins C and S, and heparin. It has been used for cardiac surgical bleeding. We report the first case of a patient with severe factor XI deficiency and cardiac surgical bleeding, which resolved with the combination of 4-factor PCC and FFP after lack of response to FFP alone.
Sujet(s)
Déficit en facteur XI , Humains , Déficit en facteur XI/complications , Facteur XI , Facteurs de la coagulation sanguine/usage thérapeutique , Perte sanguine peropératoire , Plasma sanguin , Facteur IXRÉSUMÉ
INTRODUCTION: Dominant-negative effects have been described for 10 F11 variants in the literature. AIM: The current study aimed at identifying putative dominant-negative F11 variants. MATERIAL AND METHODS: This research consisted in a retrospective analysis of routine laboratory data. RESULTS: In a series of 170 patients with moderate/mild factor XI (FXI) deficiencies, we identified heterozygous carriers of previously reported dominant-negative variants (p.Ser243Phe, p.Cys416Tyr, and p.Gly418Val) with FXI activities inconsistent with a dominant-negative effect. Our findings also do not support a dominant-negative effect of p.Gly418Ala. We also identified a set of patients carrying heterozygous variants, among which five out of 11 are novel, with FXI activities suggesting a dominant-negative effect (p.His53Tyr, p.Cys110Gly, p.Cys140Tyr, p.Glu245Lys, p.Trp246Cys, p.Glu315Lys, p.Ile421Thr, p.Trp425Cys, p.Glu565Lys, p.Thr593Met, and p.Trp617Ter). However, for all but two of these variants, individuals with close to half normal FXI coagulant activity (FXI:C) were identified, indicating an inconstant dominant effect. CONCLUSION: Our data show that for some F11 variants recognized has having dominant-negative effects, such effects actually do not occur in many individuals. The present data suggest that for these patients, the intracellular quality control mechanisms eliminate the variant monomeric polypeptide before homodimer assembly, thereby allowing only the wild-type homodimer to assemble and resulting in half normal activities. In contrast, in patients with markedly decreased activities, some mutant polypeptides might escape this first quality control. In turn, assembly of heterodimeric molecules as well as mutant homodimers would result in activities closer to 1:4 of FXI:C normal range.