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.

[PERIOPERATIVE MANAGEMENT OF AN ADOLESCENT GIRL WITH SEVERE FACTOR XI DEFICIENCY AND INHIBITORS].

INTRODUCTION: Factor XI (FXI) deficiency is an autosomal bleeding disorder characterized by injury-related hemorrhage, mostly associated with surgical procedures at sites noted for high fibrinolytic activity. Severe FXI deficiency is defined when the FXI level is lower than 15-20 IU/dL. Perioperative prophylactic treatment for high-bleeding-risk surgery in patients with severe FXI deficiency is based on fresh frozen plasma (FFP) transfusions or FXI concentrate (where available). Exposure to FFP and to FXI concentrate may lead to the development of inhibitory antibodies against FXI. This phenomenon occurs mostly in patients with very severe FXI deficiency (baseline FXI <1IU/dL) and is associated with an increased risk of substantial perioperative bleeding, unresponsive to FXI replacement. Thus, in individuals with severe FXI deficiency, routine testing for the presence of inhibitory antibodies against FXI is recommended. We present a 17-year-old adolescent patient with very severe FXI deficiency, who developed an inhibitor to FXI following FFP exposure associated with neurosurgery for medulloblastoma. Prophylactic treatment for subsequent invasive procedures consisted of single low dose (10 mcg/kg) recombinant activated factor VII (rFVIIa) and tranexamic acid (Hexakapron). The procedures were performed uneventfully, with no hemorrhagic or thrombotic complications. In patients with very severe FXI deficiency, the development of inhibitory antibodies following plasma replacement therapy comprises a rare and challenging occurrence. The formulation of a safe and effective evidence-based protocol for hemostatic support in these patients requires multi-center collaboration.

Report of surgeries, their outcome and the thrombin generation assay in patients with Factor XI deficiency: A retrospective single-centre study.

BACKGROUND: In patients with FXI deficiency, the risk of surgery-related bleeding is poorly correlated with plasma FXI activity (FXI:C); the latter can therefore not be used as a reliable predictor of bleeding in surgeries. OBJECTIVES: The aim of this retrospective study was to determine whether thrombin generation assay (TGA) could be used to evaluate the risk of surgery-related bleeding in FXI-deficient patients. TGA parameters were compared to FXI:C values, haemostatic treatments and surgical outcomes. PATIENTS: All patients followed at the haemophilia treatment care centre (Lyon, France) with a FXI:C < 50IU/dL, and for whom a baseline TGA was performed between January 2014 and December 2019, were included. RESULTS: Among the 175 surgeries reported herein in 49 patients, FXI concentrates were used for 11 (6%) surgeries and fresh frozen plasma was used for five (3%) surgeries; these surgeries were performed in patients with two or three impaired TGA parameters. No haemostatic treatment was prescribed for 119 (68%) surgeries. A surgery-related bleeding occurred in 12 patients during 21 (12%) surgeries. Thrombin generation was significantly reduced or delayed in patients who reported surgery related-bleeding. Among the 34 (68%) surgeries performed without haemostatic treatment in patients with three impaired TGA parameters, a surgery-related bleeding was reported in 44% of cases (15 surgeries out of 34). CONCLUSION: The present study confirmed that TGA is an interesting laboratory test in FXI deficiency, for determining the bleeding risk and guiding the haemostatic management of surgeries, while taking into account the surgical bleeding risk and the history of bleeding.

Pediatric severe factor XI deficiency: A multicenter study.

BACKGROUND: Factor XI (FXI) deficiency is a rare autosomal recessive bleeding disorder. Only scarce publications address its clinical features in children. The increased prevalence of FXI deficiency in Israel enabled data collection for this large multicenter cohort study. OBJECTIVE: Some hemostatic challenges may be unique or more common in children, such as bleeding in the neonatal period or trauma-related injury. The current study was designed to explore the potential impact of these differences in children with severe FXI deficiency. METHODS: Medical files of all children with FXI level under 15% followed at five tertiary centers were evaluated. The retrieved data comprised demographic and clinical characteristics, including bleeding episodes, surgical interventions, treatment strategies, as well as laboratory features. RESULTS: Sixty children, whose median age at diagnosis was 4.2 years and their median FXI level was 4%, were included. Three children experienced triggered intracranial hemorrhage (ICH) and two children had major bleeds. No bleeding complications occurred in surgeries in which hemostatic treatment consisting mostly of tranexamic acid or fresh frozen plasma was applied (n = 45). In contrast, excessive bleeding was noted in 25% of surgical procedures performed without hemostatic preparation (p = .002). CONCLUSION: This study's findings confirm the generally favorable outcome of this rare bleeding disorder, with no spontaneous bleeds or cases of perinatal ICH. Nonetheless, proper diagnosis and adequate hemostasis in the surgical setting are imperative. Unlike previous studies in adults, our pediatric study suggests an association between the severity of FXI deficiency and bleeding tendency.

Plasma Kallikrein Contributes to Coagulation in the Absence of Factor XI by Activating Factor IX.

OBJECTIVES: FXIa (factor XIa) induces clot formation, and human congenital FXI deficiency protects against venous thromboembolism and stroke. In contrast, the role of FXI in hemostasis is rather small, especially compared with FIX deficiency. Little is known about the cause of the difference in phenotypes associated with FIX deficiency and FXI deficiency. We speculated that activation of FIX via the intrinsic coagulation is not solely dependent on FXI(a; activated FXI) and aimed at identifying an FXI-independent FIX activation pathway. Approach and Results: We observed that ellagic acid and long-chain polyphosphates activated the coagulation system in FXI-deficient plasma, as could be demonstrated by measurement of thrombin generation, FIXa-AT (antithrombin), and FXa-AT complex levels, suggesting an FXI bypass route of FIX activation. Addition of a specific PKa (plasma kallikrein) inhibitor to FXI-deficient plasma decreased thrombin generation, prolonged activated partial thromboplastin time, and diminished FIXa-AT and FXa-AT complex formation, indicating that PKa plays a role in the FXI bypass route of FIX activation. In addition, FIXa-AT complex formation was significantly increased in F11-/- mice treated with ellagic acid or long-chain polyphosphates compared with controls and this increase was significantly reduced by inhibition of PKa. CONCLUSIONS: We demonstrated that activation of FXII leads to thrombin generation via FIX activation by PKa in the absence of FXI. These findings may, in part, explain the different phenotypes associated with FIX and FXI deficiencies.

Management of factor XI deficiency in oncological liver and colorectal surgery by therapeutic plasma exchange: A case report.

INTRODUCTION: Factor XI (FXI) deficiency is a rare congenital hemostatic disorder associated with increased bleeding tendency in trauma, surgery or when other hemostatic defects are present. Perioperative hemostatic management of a patient with a severe FXI deficiency undergoing major oncological liver and colorectal surgery with therapeutic plasma exchange (TPE) with fresh frozen plasma (FFP) is reported. CASE DESCRIPTION: A 54-year-old male with severe FXI deficiency was scheduled for resection of synchronous rectal cancer and multiple liver metastases. Baseline prothrombin time (PT) was 97 %, activated partial thromboplastin time (aPTT) 89 s(s) and FXI levels <1 IU/dL. The rotational thromboelastometry (ROTEM™) presented a prolonged INTEM clotting time (CT) = 443 s (RV 100-240 s) and a clot formation time (CFT) = 110 s (RV 30-100 s). TPE with FFP was carried out achieving FXI levels up to 46 IU/dL and an aPTT of 33 s, normalizing thromboelastometry parameters to an INTEM CT = 152 s and a CFT = 86 s before the procedure. After surgery, the patient received daily FFP to maintain FXI levels above 30 IU/dL until discharge on the eighth day. A total of 30 FFP units were transfused during hospital stay. No significant bleeding events neither transfusion related complications were observed during the perioperative period. CONCLUSION: Given the lack of correlation between FXI levels and bleeding risk, a multidisciplinary approach based on daily FXI levels monitoring, close clinical assessment and factor supplementation is mandatory. In conclusion, TPE with FFP is an efficacious alternative strategy to correct severe FXI deficiency in patients undergoing major surgery.

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.

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.

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.

Perioperative anesthetic management in a patient with factor XI deficiency undergoing coronary artery bypass graft surgery.

Spontaneous bleeding is rare in patients with factor XI deficiency and significant bleeding usually occurs after a trauma or a surgical procedure. It is difficult to maintain hemostatic balance in these patients. In the present case report, a 68-year-old male patient with no chronic disease was scheduled for elective cardiopulmonary bypass surgery. Eight units of fresh-frozen plasma (FFP) were slowly infused and the operation was initiated with the activated partial thromboplastin time (aPTT) of 34.5, which was 108.7 in the preoperative period. Tranexamic acid bolus was administered before the skin incision and continued throughout the operation. Intraoperative aPTT was measured intermittently and a total of six units of FFP were administered. After 76 minutes of cross-clamp time, the patient was separated from cardiopulmonary bypass without any problem. There is no consensus regarding the management of bleeding during cardiac surgery in patients with factor XI deficiency. The common approach includes normalizing the factor levels via FFP infusion or factor concentrates in the preoperative period, proceeding with surgery following the replacement, and close monitoring of perioperative factor levels and aPTT values.

Factor XI deficiency is associated with lower risk for cardiovascular and venous thromboembolism events.

Factor XI deficiency is one of the rare inherited coagulation factor deficiencies. However, its incidence is high within the Ashkenazi Jewish community. Because factor XI displays both procoagulant and antifibrinolytic activities, it has been postulated that an underlying cardiovascular benefit may exist with factor XI deficiency. This historical cohort study was performed using the electronic database of Clalit Health Services, the largest health care provider in Israel. All adults tested for factor XI activity between 2002 and 2014 were included in the study. Factor XI activity was classified into 3 categories: normal (activity >50%), mild deficiency (activity = 30%-50%), and moderate-severe deficiency (activity ≤30%). The cohort was followed until 31 December 2015 for incidence of cardiovascular events (composite of myocardial infarction, stroke, and transient ischemic attack) and venous thromboembolism (VTE). Of the 10 193 included patients, 8958 (88.9%) had normal factor XI activity, 690 (6.8%) had mild deficiency, and 542 (5.3%) had moderate-severe deficiency. Compared with individuals with normal activity, the adjusted hazard ratio (HR) for cardiovascular events was 0.52 (95% confidence interval [CI], 0.31-0.87) in those with mild deficiency, and 0.57 (95% CI, 0.35-0.93) in those with moderate-severe factor XI deficiency. The incidence of VTE was lower in those with factor XI deficiency (activity <50%) compared with those with normal activity; adjusted HR = 0.26 (95% CI, 0.08-0.84). In summary, factor XI deficiency is associated with decreased incidence of cardiovascular events and VTE.

Factor XI deficiency is not associated with an increased risk of pneumonia and pneumonia-related mortality.

INTRODUCTION: Drugs targeting factor XI (FXI) shows promising results in reducing postoperative VTE. Recently, researchers have shown that FXI knockout mice had a worse outcome when infected with pathogens for pneumonia, raising concerns about the safety of these drugs. AIM: To investigate the effect of FXI deficiency on the incidence of pneumonia and outcomes of pneumonia in humans. METHODS: Using the computerized database of the largest healthcare provider in Israel, we identified adults who were tested for FXI activity between January of 2002 and December of 2014 (n = 10 193). Patients were followed up until December of 2016 for the occurrence of pneumonia and pneumonia requiring hospitalization as a proxy of severe pneumonia. RESULTS: A total of 8958 (87.9%) had normal FXI activity, 804 (7.9%) had partial deficiency and 431 (4.2%) had severe deficiency; 722 individuals had pneumonia during 70 881 person-years of follow-up (incidence rate: 10.2 per 1000 person-years). Compared to those with normal FXI activity, the adjusted HR for pneumonia was 0.87 (95% CI, 0.67-1.14), and 0.95 (0.69-1.30) for those with partial and severe FXI deficiency, respectively. Overall, 256 individuals were hospitalized for pneumonia during 72 209 person-years of follow-up (incidence rate: 3.5 per 1000 person-years). The corresponding HR for severe pneumonia was 1.0 (0.70-1.48) and 0.86 (0.53-1.40) in those with partial and severe FXI deficiency, respectively. FXI deficiency was not significantly associated with 30-day and 90-day mortality among patients with pneumonia. CONCLUSION: FXI deficiency was not associated with an increased risk of pneumonia, pneumonia severity or short-term mortality among patients with pneumonia.

Perioperative management of a redo aortic root replacement in a patient with severe factor XI deficiency.

Factor XI deficiency is associated with significant bleeding in the setting of trauma and surgery. We present a patient with FXI deficiency and multiple red blood cell allo-antibodies requiring repeat aortic root replacement and discuss the perioperative management of patients with FXI deficiency undergoing cardiac surgery.

Severe Ankle Arthritis After Multiple Hemarthrosis Secondary to Factor XI Deficiency: A Case Report.

Hemophilic arthropathy of the ankle is an extremely unique condition that affects a small subset of the population in the United States. We present the case of a 66-year-old male with factor XI deficiency, which, over years of repetitive microtrauma as a professional soccer player, led to multiple hemarthrosis and severe arthropathy of his right ankle. The patient successfully underwent total ankle replacement arthroplasty and was able to return to recreational sports and competitive road cycling.

Factor XI deficiency enhances the pulmonary allergic response to house dust mite in mice independent of factor XII.

Asthma is associated with activation of coagulation in the airways. The coagulation system can be initiated via the extrinsic tissue factor-dependent pathway or via the intrinsic pathway, in which the central player factor XI (FXI) can be either activated via active factor XII (FXIIa) or via thrombin. We aimed to determine the role of the intrinsic coagulation system and its possible route of activation in allergic lung inflammation induced by the clinically relevant human allergen house dust mite (HDM). Wild-type (WT), FXI knockout (KO), and FXII KO mice were subjected to repeated exposure to HDM via the airways, and inflammatory responses were compared. FXI KO mice showed increased influx of eosinophils into lung tissue, accompanied by elevated local levels of the main eosinophil chemoattractant eotaxin. Although gross lung pathology and airway mucus production did not differ between groups, FXI KO mice displayed an impaired endothelial/epithelial barrier function, as reflected by elevated levels of total protein and IgM in bronchoalveolar lavage fluid. FXI KO mice had a stronger systemic IgE response with an almost completely absent HDM-specific IgG1 response. The phenotype of FXII KO mice was, except for a higher HDM-specific IgG1 response, similar to that of WT mice. In conclusion, FXI attenuates part of the allergic response to repeated administration of HDM in the airways by a mechanism that is independent of activation via FXII.

Sample conditions determine the ability of thrombin generation parameters to identify bleeding phenotype in FXI deficiency.

Individuals with Factor XI (FXI) deficiency have a variable bleeding tendency that does not correlate with FXI:C levels or genotype. Comparing a range of sample conditions, we tested whether the thrombin generation assay (TGA) could discriminate between control subjects (n = 50) and FXI-deficient individuals (n = 97), and between those with bleeding tendency (n = 50) and without (n = 24). The comparison used platelet-rich plasma (PRP) and platelet-poor plasma (PPP), either with or without corn trypsin inhibitor (CTI) to prevent contact activation, over a range of tissue factor (TF) concentrations. When contact activation was inhibited and platelets were absent, FXI:C levels did not correlate with thrombin generation parameters, and control and FXI-deficient individuals were not distinguished. In all other sample types, the best discrimination was obtained using TF 0.5 pM and assay measures: endogenous thrombin potential (ETP) and peak height. We showed that although a number of conditions could distinguish differences between the groups tested, TGA measured in PRP with CTI best differentiated between bleeders and nonbleeders. These measures provided high sensitivity and specificity (peak height receiver operating characteristic [ROC] area under the curve [AUC] = 0.9362; P < .0001) (ETP ROC AUC = 0.9362; P < .0001). We conclude that by using sample conditions directed to test specific pathways of FXI activation, the TGA can identify bleeding phenotype in FXI deficiency.

Evaluation of the use of rotational thromboelastometry in the assessment of FXI deficency.

INTRODUCTION: The absence of a reliable clinical test to predict bleeding tendency leaves factor XI (FXI)-deficient individuals at risk of overtreatment or under treatment. AIM: To assess whether rotational thromboelastometry has value in detection of FXI deficiency and identification of bleeding tendency. METHODS: Thromboelastometry was measured in whole blood and platelet-rich plasma (PRP) samples containing corn trypsin inhibitor (CTI) from controls (n = 50) and FXI-deficient individuals (n = 93) at tissue factor (TF) 0.12 pm. The effect of tissue plasminogen activator was also assessed. For analysis, FXI-deficient individuals were divided into bleeders (n = 24) and non-bleeders (n = 44) based on experience of tonsillectomy and/or dental extraction prior to diagnosis. RESULTS: In whole blood, thromboelastometry distinguished those with major FXI deficiency (FXI:C ≤ 15 IU dL-1 ) but not partial deficiency from control populations, but did not identify bleeding phenotype. In PRP, bleeders had significantly longer clot formation time [CFT; 434 ± 179 s vs. 277 ± 70 s (mean ± SD); P < 0.05] and smaller α angle [43.8 ± 9.5° vs. 52.4 ± 5.8° (mean ± SD); P < 0.05] compared to non-bleeders. However, these parameters were found to depend on multiple additional variables and on an individual basis, ROC analysis showed test specificity for bleeding phenotype identification to be only 38.5% at 100% sensitivity: CFT (area under first derivative curve: AUC = 0.8091, P = 0.0014), α angle (AUC = 0.7804, P = 0.006). CONCLUSION: Thromboelastometry in PRP with CTI samples triggered with TF 0.12 pm was able to distinguish between bleeders and non-bleeders in FXI deficiency, but poor specificity restricts its clinical application as a test to identify bleeding phenotype. Further technical advances to the assay may allow better discrimination.

Factor 11 single-nucleotide variants in women with heavy menstrual bleeding.

In a previous study it was shown that lower factor XI (FXI) levels in women with heavy menstrual bleeding (HMB). Our aim was to determine the single-nucleotide variants (SNVs) in the F11 gene in women with HMB. In addition, an extensive literature search was performed to determine the clinical significance of each SNV. Patients referred for HMB (PBAC-score >100) were included. With direct sequencing analysis of all 15 exons and flanking introns of the F11 gene, 29 different non-structural SNVs were detected in 49 patients with HMB. Interestingly, most of these SNVs have previously been associated with venous thrombosis instead of bleeding. These findings have not helped to elucidate the molecular basis of HMB. They also question the specificity of previously reported F11 variations in patients with thrombosis. More studies are needed to explain the lower FXI levels seen in patients with HMB. IMPACT STATEMENT Women with mild deficiencies of factor XI (FXI) (< 70%) are prone to excessive bleeding during menstruation. Bleeding manifestations are not well correlated with plasma FXI levels and bleeding episodes can vary widely among patients with similar low FXI levels. In a previous study we showed that women with heavy menstrual bleeding (HMB) had normal, but on average, lower levels of FXI than controls. In light of these findings, we performed F11 gene analysis to determine the single-nucleotide variants (SNVs) in women with HMB and performed an extensive literature search to determine the clinical significance of each SNV. By direct sequencing analysis of the F11 gene we found 29 different non-structural SNVs in 49 women with heavy menstrual bleeding. Remarkably, a number of these SNVs have previously been implicated in thrombosis. These findings have not helped to elucidate the molecular basis of lower FXI levels in HMB. They also question the specificity of previously reported F11 variations in patients with thrombosis. More studies are needed to explain the lower FXI levels seen in patients with HMB.

Clinical manifestations and mutation spectrum of 57 subjects with congenital factor XI deficiency in China.

Congenital factor XI (FXI) deficiency is a rare bleeding disorder with unpredictable bleeding tendency. Few studies in a large cohort have been reported regarding associations between FXI activity (FXI:C) or genotypes and bleeding symptoms currently. This study characterized clinical manifestations and mutation spectrum of 57 subjects with FXI deficiency in China. Clinical data were collected and mutations were identified by direct sequencing and determined by mRNA analysis. The result revealed bleeding symptoms were only found in 12 patients (12/57, 21.1%) with severely reduced FXI:C, and prolonged bleeding post injury/surgery as well as easy bruising were the commonest bleeding manifestations presented in respective 5 cases (5/12, 41.7%). A total number of 37 mutations were identified including 19 missense mutations, 9 nonsense mutations, 6 splice site mutations and 3 small deletions. Among them, 4 missense mutations, 5 splice mutations, 3 small deletions and a nonsense mutation were newly detected. W228*, G400V, Q263* and c.1136-4delGTTG with a total frequency of 48.3% were the most four common mutations in Chinese patients. RT-PCR analysis was carried out and confirmed that both c.596-8T>A and c.1136-4delGTTG were pathogenic due to frameshift resulting in respective truncated proteins. Our findings suggested clinical manifestations had little to do with FXI:C or genotypes, which required further study. This study, the largest investigation of FXI deficiency in China revealed that the F11 mutation spectrum of Chinese population was distinct from those of other populations earlier established.

Perioperative management of factor XI deficiency in a patient undergoing hip arthroplasty.

Factor XI deficiency, or hemophilia C, is a rare autosomal recessive bleeding disorder often diagnosed by inappropriate bleeding associated with trauma or a surgical procedure, and reports of anesthetic management of this disorder are rare. We experienced an 85-year-old man with femoral neck fracture who was diagnosed preoperatively with factor XI deficiency based on abnormally long activated partial thromboplastin time (APTT). He was scheduled for bipolar hip arthroplasty and was prepared for surgery by transfusion of fresh frozen plasma (FFP), instead of factor XI concentrates, which are not commercially available in Japan. Five units of FFP were transfused 6 days before surgery, and 10 units of FFP with 2 units of red concentrated cells (RCC) were used on the day of surgery. Transfusion of FFP shortened the APTT to a level sufficient to allow hemostasis, although not to within the normal range. Although the patient required transfusion of 2 units of RCC postoperatively, no bleeding complications occurred. For bipolar hip arthroplasty, transfusion of FFP produced sufficient hemostasis without the use of tranexamic acid, factor VII preparations, or desmopressin.