A G>A Transition in the Non-Coding Exon 1 of the Factor XI Gene as the Cause of Factor XI Deficiency in Three Afro-Caribbean Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1788-1788
Author(s):  
Michael J. Mitchell ◽  
Letian Dai ◽  
Anwar Alhaq ◽  
Geoffrey F. Savidge
Keyword(s):  
Base Change ◽  
Clinical Severity ◽  
Molecular Defect ◽  
Polymorphism Analysis ◽  
Bleeding Tendency ◽  
Translation Efficiency ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Plasma Factor ◽  
Exon 1

Abstract Factor XI deficiency (MIM 264900) is an autosomal bleeding disorder of variable clinical severity. In contrast to haemophilia A or B the clinical symptoms do not correlate well with plasma levels of factor XI; it is therefore difficult to predict the bleeding tendency from either the factor level or the molecular defect. FXI deficiency is particularly common in the Ashkenazi Jews with a heterozygous frequency of 9%, associated with two common founder mutations E117X (Type II) and F283L (Type III). However, factor XI deficiency is found in all ethnic groups, with causative mutations being highly heterogeneous - mutations having been described in all exons with the exception of the non-coding exon 1. In a study of >120 ethnically diverse factor XI deficient patients, three patients of Afro-Caribbean origin were found to be heterozygous for a G>A transition at nucleotide −53 within exon 1 of the factor XI gene. All three patients showed a low FXI:C on at least 3 different occasions (SM[female] 44.3–57.1, AB[female] 42.3–51.2 and GA[male] 70.3–72.9, Range 76–136u/dl). The 2 female patients were both reported to have a lupus anticoagulant which may explain the lower levels seen, although a lupus screen was negative. No variation within the coding sequence of the factor XI gene was detected. Two of the patients were heterozygous for the −403 G>T promoter polymorphism, whilst the remaining patient was homozygous for the −403 T allele and heterozygous for the −273 C>G polymorphism. Analysis of >50 factor XI alleles in patients of Afro-Caribbean origin failed to detect this base change in individuals with normal factor XI levels. Purine-rich sequences, such as that in exon 1 affected by the −53 G>A substitution, are known to form extremely stable minihairpin loops. These sequences /structures have been shown to be important as splicing enhancers and in mRNA stability, particularly in making them more resistant to nucleases. Within the 5′ untranslated region (5′-UTR) of genes they have been demonstrated to be important in modulating translation efficiency. The -53 G>A substitution is located just 10 bases prior to the start of the factor XI mRNA and any of these mechanism could potentially explain the causative nature of this change. The -53 G>A substitution is predicted to cause ‘slippage’ within the postulated minihairpin loop, potentially making it unstable. Further work is on-going to try and prove and explain the causality of this mutation. We speculate that the -53 G>A base change affects the normal processing of factor XI mRNA and, possibly in combination with the promoter polymorphisms, results in a mildly reduced plasma factor XI level.

Activation of Factor IX by Polymorphonuclear Leukocytes from a Patient with Chronic Granulocytic Leukemia, and from a Patient with Factor XI Deficiency

1979 ◽  
Author(s):  
H.S. Kingdon ◽  
J.C. Herion
Keyword(s):  
Polymorphonuclear Leukocytes ◽  
Cell Suspensions ◽  
Factor Ix ◽  
Prolonged Storage ◽  
Bleeding Tendency ◽  
Factor Xi ◽  
Chronic Granulocytic Leukemia ◽  
Factor Xi Deficiency ◽  
Plasma Factor ◽  
Granulocytic Leukemia

We have previously reported that preparations of polymorphonuclear leukocytes (PMNs) from normal human blood are capable of activating Factor IX in the presence of calcium ion (Thrombosis Research, 13, 501-507, 1978). In the outrent studies, we demonstrated that cell suspensions subjected to freezing and thawing wete as active or more active than the suspensions subjected to ultrasonic disruption which were used previously. Furthermore, the Factor IX activating activity survived prolonged storage of the frozen cell suspensions. PMNs from a patient with chronic granulocytic leukemia contained potent Factor IX activator, as did PMNs from a patient with severe factor XI deficiency (plasma Factor XI < 1%). Preliminary experiments suggest that the Factor IX activator may reside in the granule fraction of the cells, since Factor IX activation was not observed when strontium was substituted for calcium, we conclude that Factor XIa> is not involved in this cellular activation phenomenon. Furthermore, the presence of an alternate mechanism for activating Factor IX in the blood of the Factor XI deficient patient may explain why the bleeding tendency in this deficiency state is so much milder than in Factor IX or Factor VIII deficiencies.(Supported in part by USPHS grants HL-16633, and DE-0 2668).

scholarly journals A molecular genetic study of factor XI deficiency

Blood ◽  
1991 ◽  
Vol 77 (9) ◽  
pp. 1942-1948
Author(s):  
JF Hancock ◽  
K Wieland ◽  
RE Pugh ◽  
U Martinowitz ◽  
S Schulman ◽  
...  
Keyword(s):  
Molecular Genetic ◽  
Severe Bleeding ◽  
Compound Heterozygous ◽  
Type I ◽  
Bleeding Tendency ◽  
Factor Xi ◽  
Molecular Genetic Study ◽  
Factor Xi Deficiency ◽  
Increased Risk ◽  
Plasma Factor

Factor XI deficiency is a rare bleeding diathesis found predominantly in Ashkenazi Jewish kindreds. A recent study of six Jewish patients identified three distinct mutations (Types I, II, and III) in the factor XI gene that were sufficient to fully define the genotypes of the patients. We have investigated 63 patients with factor XI deficiency and find overall allele frequencies of 44% for the type II mutation, 31% for the type III mutation, and 0% for the type I mutation. Therefore, 25% of the mutant factor XI alleles in our sample remain undefined. However, the distribution of mutant alleles is significantly different between Jewish and non-Jewish populations with hitherto undefined mutations accounting for 84% of the disease alleles in non-Jewish patients. Plasma factor XI:C levels were found to differ significantly between different homozygous and compound heterozygous genotypes and the inheritance of the II/III genotype was found to carry an increased risk of the most severe bleeding tendency.

A molecular genetic study of factor XI deficiency

Blood ◽  
1991 ◽  
Vol 77 (9) ◽  
pp. 1942-1948 ◽  
Author(s):  
JF Hancock ◽  
K Wieland ◽  
RE Pugh ◽  
U Martinowitz ◽  
S Schulman ◽  
...  
Keyword(s):  
Molecular Genetic ◽  
Severe Bleeding ◽  
Compound Heterozygous ◽  
Type I ◽  
Bleeding Tendency ◽  
Factor Xi ◽  
Molecular Genetic Study ◽  
Factor Xi Deficiency ◽  
Increased Risk ◽  
Plasma Factor

Abstract Factor XI deficiency is a rare bleeding diathesis found predominantly in Ashkenazi Jewish kindreds. A recent study of six Jewish patients identified three distinct mutations (Types I, II, and III) in the factor XI gene that were sufficient to fully define the genotypes of the patients. We have investigated 63 patients with factor XI deficiency and find overall allele frequencies of 44% for the type II mutation, 31% for the type III mutation, and 0% for the type I mutation. Therefore, 25% of the mutant factor XI alleles in our sample remain undefined. However, the distribution of mutant alleles is significantly different between Jewish and non-Jewish populations with hitherto undefined mutations accounting for 84% of the disease alleles in non-Jewish patients. Plasma factor XI:C levels were found to differ significantly between different homozygous and compound heterozygous genotypes and the inheritance of the II/III genotype was found to carry an increased risk of the most severe bleeding tendency.

An Alu-mediated 31.5-kb deletion as the cause of factor XI deficiency in 2 unrelated patients

Blood ◽  
2004 ◽  
Vol 104 (8) ◽  
pp. 2394-2396 ◽  
Author(s):  
Michael Mitchell ◽  
Letian Dai ◽  
Geoffrey Savidge ◽  
Anwar Alhaq
Keyword(s):  
Mutation Screening ◽  
Chromosome Complement ◽  
Large Deletion ◽  
Causative Mutation ◽  
Molecular Defect ◽  
Bleeding Tendency ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Barr Virus ◽  
Epstein Barr

Abstract Factor XI deficiency (MIM 264900) is an autosomal bleeding disorder of variable severity. Inheritance is not completely recessive as heterozygotes may display a distinct, if mild, bleeding tendency. Recent studies have shown the causative mutations of factor XI deficiency, outside the Ashkenazi Jewish population, to be highly heterogeneous. We studied 39 consecutively referred patients with factor XI deficiency to identify the molecular defect. Conventional mutation screening failed to identify a causative mutation in 4 of the 39 patients. Epstein-Barr virus (EBV)–transformed cells from these 4 patients were converted from a diploid to haploid chromosome complement. Subsequent analysis showed that 2 of the patients had a large deletion, which was masked in the heterozygous state by the presence of a normal allele. We report here the first confirmed whole gene deletion as the causative mutation of factor XI deficiency, the result of unequal homologous recombination between flanking Alu repeat sequences.

Spectrum of Factor XI Mutations in a Large Cohort - 116 Index Cases, 141 Mutations.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1027-1027
Author(s):  
Michael J. Mitchell ◽  
Roger Mountfield ◽  
Rachel Butler ◽  
Anwar Alhaq ◽  
Letian Dai ◽  
...  
Keyword(s):  
Jewish Population ◽  
Molecular Defect ◽  
Type Ii ◽  
Ashkenazi Jewish ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Type Iii ◽  
Jewish Ancestry ◽  
Ashkenazi Jewish Population ◽  
Index Cases

Abstract Factor XI deficiency (MIM 264900) is an autosomal bleeding disorder of variable clinical severity. In contrast to haemophilia A or B the clinical symptoms do not correlate well with plasma levels of factor XI; it is therefore difficult to predict the bleeding tendency from either the factor level or the molecular defect. FXI deficiency is particularly common in the Ashkenazi Jews with a heterozygous frequency of ~9%, associated with two common founder mutations - E117X (Type II) and F283L (Type III). Recent studies have shown that mutations causing Factor XI deficiency are heterogeneous outside the Ashkenazi Jewish population. We have studied 116 index cases from an ethnically diverse U.K. population in order to better understand the spectrum of mutations responsible for factor XI deficiency. Of the index cases, 25 were of Ashkenazi Jewish ancestry, 2 were of Afro-Caribbean origin, 9 Asian, 3 Arabic, 1 New Zealand Maori and 73 white Caucasian; ancestry was unknown in three patients. We have identified a total of 141 causative mutations in 107 patients. Of the nine patients in whom a mutation remained unidentified, six were reproducibly factor XI deficient with no evidence of inhibitors, but in three the diagnosis was inconclusive. The 141 mutations included 54 different sequence variants and 5 whole gene deletions of which there are at least two forms. Of the variants, forty-one are missense mutations, eight nonsense mutations, four splice site mutations and one small deletion. Twenty-seven of these varients are novel and reported here for the first time. Three common mutations were identified, with similar frequencies. The Type II mutation (E117X) accounted for 14.9% of the total mutations, the Type III mutation (F283L) 12.1% and the C128X “UK mutation” 11.3%. Together these three mutations account for more than a third (38.3%) of the total. Outside of these three ‘common’ mutations, no other mutation was identified in more than 3 individuals. Despite the heterogeneous nature of factor XI mutations, with mutations being identified in all 15 exons of the factor XI gene, almost two thirds (65%) of the mutations could be covered in just 3 amplicons - exons 5, 15 and 8/9/10. All patients with Ashkenazi Jewish ancestry had Type II and/or Type III mutations. Three Jewish patients were compound heterozygous for the Type II mutation and another ‘non-Jewish’ mutation. One Arabic patient was homozygous for the Type II mutation. The C128X mutation was only identified in patients with a clear British ancestry. However, not all repeat mutations were restricted to a single ethnic group. Four mutations were identified in more than one ethnic group, three of which were located at CpG sites. This study confirms the ethnic and molecular heterogeneity of factor XI deficiency despite its historical association with the Ashkenazi Jewish population and the Type II & Type III mutations. Our study also reinforces the difficulty of predicting clinical phenotype from molecular defect in factor XI deficiency.

The Use of Factor XI Concentrates (Hemoleven, LFB) in Patients with Congenital Factor XI Deficiency and a Known Bleeding Tendency.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1796-1796
Author(s):  
Vickie McDonald ◽  
Savidge F. Geoffrey ◽  
Savita Rangarajan ◽  
Mike Mitchell
Keyword(s):  
Fresh Frozen Plasma ◽  
Incidence Rates ◽  
Treatment Modalities ◽  
Bleeding Tendency ◽  
Normal Range ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Unit Dose ◽  
The Mean ◽  
Congenital Factor

Abstract Traditional treatment modalities for FXI deficiency (UK prevalence 400 cases) include antifibrinolytics, desmopressin, fresh frozen plasma (FFP) and FXI concentrates but there has been reluctance to use FXI concentrates because of reported incidence rates of thrombosis up to 10%. Concerns over the safety and efficacy of FFP, with additional viral inactivation steps possibly leading to reduced FXI recoveries, have led us to increase our use of FXI concentrates. We aimed to assess the indications, dosage, recovery, efficacy and safety of Hemoleven, a plasma derived, purified and virally inactivated FXI concentrate, which also contains heparin and antithrombin, in patients with congenital factor XI deficiency. A retrospective study was performed using hospital notes and laboratory records of all patients who had received Hemoleven over a 2-year period. Eleven patients (6 male, 5 female) had been treated with a median age of 38 years (range 7–74) and mean baseline FXI:C levels of 25.4U/dl (3–50). All patients received Hemoleven as prophylaxis for surgery or dental work and had all previously had excess bleeding when surgically challenged. One patient died of a condition unrelated to FXI treatment. Pre- and post-FXI:C levels were available for a total of 60 treatment episodes of which 25 were 1000-unit doses and 35 were 2000-unit doses. The mean increase in FXI:C per 1000-unit dose was 25.4 U/dl (12.4–43.9) while the mean increase in FXI:C per 2000-unit dose was 50.5 U/dl (11.8–106.5). This is consistent with the manufacturer’s data. Ten minute post infusion FXI:C levels were above the normal range (73–133 U/kg) in 8% of patients given 1000 units and 11% of patients given 2000 units but below the normal range in 24% of patients who received 1000 units and 20% of patients who received 2000 units. 90% of treatment episodes led to FXI:C levels above the usual treatment target of 65 U/dl. Genetic analysis of 9/11 patients showed that 2 were homozygous (one type II and one type III), 6 were heterozygous for other recognised mutations and one had no mutation identified but apparent absence of RNA from one allele demonstrated in a relative by qRT-PCR. No excess bleeding or inhibitor development was recorded even in one patient who had had a poor haemostatic response with FFP. There were no episodes of arterial or venous thrombotic complications within this group and no clinical or laboratory evidence of DIC following treatment. In summary, treatment with factor XI concentrates gave consistent increments in FXI:C at the doses given and achieved good haemostasis with no episodes of thrombosis in this study, even in patients over the age of 60y. While the risk of prion transmission is still unknown, use of FXI concentrates is not associated with the risks of fluid overload and TRALI that are seen with FFP. We acknowledge that the study includes small numbers of patients however the cohort of patients with a bleeding diathesis in this condition is small. We conclude that Hemoleven appears to be an effective and reliable treatment for patients with FXI:C deficiency but should be given in the context of FXI:C level monitoring in order to detect those patients who may develop high levels and possible thrombosis.

Correlation of a Condensed Bleeding Score with New Diagnosis of a Congenital Bleeding Disorder in Patients Referred to a Tertiary Centre

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1226-1226
Author(s):  
Deepa Ranjani Jayakody Arachchillage ◽  
Tina Biss ◽  
John Hanley ◽  
Kate Talks
Keyword(s):  
Laboratory Tests ◽  
Conflicts Of Interest ◽  
Bleeding Disorder ◽  
Bleeding Tendency ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Number Of Patients ◽  
Abnormal Bleeding ◽  
Bleeding Score

Abstract Abstract 1226 The performance and utility of a condensed bleeding score (Bowman et al, J Thromb Haemost., 2008;6:2062) in relation to the diagnosis of a congenital bleeding disorder in new referrals to a regional haemostasis clinic over an 8 month period is presented. Between November 2010 and June 2011, 50 patients over the age of 16 (median age, 31 years; range, 16–79), including 32 females, were referred for investigation of a possible congenital bleeding disorder following detection of abnormal coagulation results and/or presentation with a bleeding history. A bleeding score was performed as part of their initial assessment. 12(24%) patients were from local referral and 38(76%) patients were referred from other hospitals in the region for further investigation of a suspected bleeding disorder. Basic coagulation tests (activated partial thromboplastin time (APTT), prothrombin time Clauss fibrinogen and platelet count) were normal in the referred patients from other centres. 50% (6/12) of the local referrals were for investigation of a prolonged APTT detected on routine coagulation screening prior to major surgery. The median bleeding score was 6 with a range of −1 to 14 (Table 1). The presence of a congenital bleeding disorder was confirmed in 31 of the 50 patients (62%), including 19/31 (61%) of the female patients and 12/31(39%) of the males. Correlation of an abnormal bleeding score (score ≥ 4) with diagnosis of a congenital bleeding disorder was only seen for diagnosis of type 1 Von Willebrand Disease (VWD) (Table 2). Analysis of the cases with low scores and abnormal results identified two groups of patients; firstly, those who had not yet had a significant haemostatic challenge, and secondly, those in whom the abnormal coagulation results were explained by a non-haemostatically significant reduction in a coagulation factor level (e.g. FVII, 15%; dysfibrinogenaemia; F XII deficiency). These clinically insignificant laboratory abnormalities explain the discrepancy between the number of patients with abnormal laboratory tests (35) and the number of patients diagnosed with a congenital bleeding disorder (31).Table 1Bleeding score (range)Number of patients with normal lab resultsNumber of patients with abnormal lab results−1 to +1382–44105–74128–102311–1422Total1535Table 2DiagnosisNumber of patientsMedian bleeding scoreAge rangeType 1 VWD116 (4–10)17–51Type 2 VWD48 (5–13)17–36Factor XI123 (1–8)17–76Platelet function defect46 (2–9)17–57 Compared to previous reports the range of scores found with this assessment tool was narrow and could not exclude patients from further laboratory assessment. However the condensed bleeding score has only been validated prospectively for the diagnosis of type 1 VWD and all patients in this cohort who were diagnosed with type 1 VWD had an abnormal bleeding score (≥ 4). This observation supports the role of this scoring system in the assessment of patients for type 1 VWD. The use of the condensed bleeding score in assessing patients with suspected factor XI deficiency is difficult due to the lack of a phenotypic relationship between residual factor XI activity and a bleeding tendency. Furthermore, although factor XI deficiency is a rare congenital bleeding disorder in our cohort of patients 12/31(39%) were diagnosed with factor XI deficiency. This may explain the overall lack of correlation between bleeding score and diagnosis of a congenital bleeding disorder. Patients who have an abnormal bleeding score but normal laboratory tests need consideration of further investigations before concluding they are normal. The possibility of an acquired bleeding disorder should be considered. A thorough drug history is also important as one of the patients with a bleeding score of 14 was taking a non-steroidal anti-inflammatory drug. The use of the condensed bleeding score in the detection of congenital bleeding disorders other than type 1 VWD requires further validation in a larger number of patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Tissue-Specific Expression of Functional Platelet Factor XI Is Independent of Plasma Factor XI Expression

Blood ◽  
1998 ◽  
Vol 91 (10) ◽  
pp. 3800-3807 ◽  
Author(s):  
Chang-jun Hu ◽  
Frank A. Baglia ◽  
David C.B. Mills ◽  
Barbara A. Konkle ◽  
Peter N. Walsh
Keyword(s):  
Binding Sites ◽  
Factor Xi ◽  
Specific Expression ◽  
Platelet Factor ◽  
Platelet Surface ◽  
Tissue Specific ◽  
Factor Xi Deficiency ◽  
Plasma Factor ◽  
Granule Membrane ◽  
Granule Secretion

Abstract Platelet factor XI is an alternatively spliced product of the factor XI gene expressed specifically within megakaryocytes and platelets as an approximately 1.9-kb mRNA transcript (compared with ∼2.1 kb in liver cells) lacking exon V. Flow cytometry with an affinity-purified factor XI antibody, with PAC1 antibody (to the GPIIb/IIIa complex on activated platelets), and with S12 antibody (to P-selectin, an α-granule membrane protein expressed on the platelet surface during secretion) on platelets activated with ADP, thrombin, thrombin receptor peptide (SFLLRN amide), or collagen at various concentrations exposed platelet factor XI and PAC1 antibody binding in parallel. Unactivated platelets expressed approximately 40% of total platelet factor XI but no PAC1 binding sites. Enhanced membrane exposure of platelet factor XI is independent of α-granule secretion, because ADP and collagen exposed platelet factor XI but no S12 binding sites. Platelets from four patients with plasma factor XI deficiency (<0.04 U/mL) had normal constitutive and activation-dependent expression of platelet factor XI. Well-washed platelets from normal and from factor XI-deficient donors incubated with low concentrations of thrombin (0.05 to 0.1 U/mL) corrected the clotting defect observed with factor XI-deficient plasma. Thus, functionally active platelet factor XI is differentially expressed on platelet membranes in a tissue-specific manner both constitutively and in a concentration-dependent fashion by various agonists in the absence of detectable plasma factor XI.

Definition of the Bleeding Tendency in Factor XI-Deficient Kindreds–A Clinical and Laboratory Study

1995 ◽  
Vol 73 (02) ◽  
pp. 194-202 ◽  
Author(s):  
P H B Bolton-Maggs ◽  
D A Patterson ◽  
R T Wensley ◽  
E G D Tuddenham
Keyword(s):  
Convincing Evidence ◽  
Factor Vii ◽  
Bleeding Tendency ◽  
Factor Xi ◽  
Excessive Bleeding ◽  
North West ◽  
Factor Xi Deficiency ◽  
History Analysis ◽  
Definition Of ◽  
Von Willebrand

SummaryIndividuals with severe factor XI deficiency are prone to excessive bleeding after injury or surgery, but the existence of a haemorrhagic tendency in partial factor XI deficiency is controversial. In this study, 172 members of 30 kindreds (20 non-Jewish) transmitting factor XI deficiency in North West England were interviewed and a bleeding history questionnaire completed. Blood was taken for coagulation assays. The questionnaires were categorised independently by two assessors to determine presence or absence of a bleeding tendency, in the absence of information about the factor XI level or family history. Analysis shows that 48% of heterozygotes have a bleeding tendency. Eighteen (60%) families came to attention because of bleeding problems in heterozygotes. Comparison of histories between partially deficient and non-deficient individuals demonstrated a higher incidence of menstrual problems, an increase in significant bruising, and an increased likelihood of excessive bleeding after tonsillectomy and dental extractions.The incidence of von Willebrand’s disease was not increased, but individuals with heterozygous factor XI deficiency who were bleeders tended to have lower levels of factor VIIIc and von Willebrand factor, and were more commonly of blood group 0. These features may contribute to the bleeding tendency. There was no evidence of alteration in factor VII activity (as defined by the ratio of activity to antigen) between the bleeders and non-bleeders.This is convincing evidence for abnormal bleeding in factor XI deficiency which is not confined to severely deficient patients.

A Sardinian Family with Factor XI Deficiency

2019 ◽  
Vol 39 (04) ◽  
pp. 398-403
Author(s):  
Doris Barcellona ◽  
Giovanni Favuzzi ◽  
Maria Luigia Vannini ◽  
Sebastiana Maria Piras ◽  
Maria Filomena Ruberto ◽  
...  
Keyword(s):  
Dna Analysis ◽  
Incidental Finding ◽  
Prognostic Significance ◽  
Family Members ◽  
The Other ◽  
Waveform Analysis ◽  
Bleeding Tendency ◽  
Factor Xi ◽  
Maximum Acceleration ◽  
Factor Xi Deficiency

Introduction Factor XI (FXI) deficiency is a bleeding disorder which causes a bleeding tendency after trauma or surgery. An inhibitor may be acquired secondary to replacement therapy. Aim To study on genetical and functional grounds a family admitted to our Haemostasis and Thrombosis Centre for an incidental finding of a prolonged activated partial thromboplastin time (aPTT) in three members. Methods aPTT mixing test, dosage of FXI activity and antigen, FXI inhibitor titration, DNA analysis and clot waveform analysis (CWA) were performed. Results Patients II.1, II.3 and II.4 showed a severe FXI deficiency (0.7, 0.7 and 1.8%, respectively) and low antigen level. Since the proposita was already treated with plasma, the dosage of the inhibitor was determined to be 6.4 Bethesda units. They were homozygous for the p.Glu117Stop mutation. The other family members were heterozygous. The velocity and the maximum acceleration of the clot formation were lower than those of the other family members and the normal subjects but higher than those of patients with acquired haemophilia A. Conclusion A mixing test of a prolonged aPTT should be performed because it will be present both in patients with or without the inhibitor. A molecular analysis in severe FXI deficiency is warranted as it may have prognostic significance. CWA may be helpful for better understanding the pathophysiology of this kind of defect.

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