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PubMed2002

[Familial study of factor XI deficiency. Presurgical prophylactic treatment with desmopressin plus antifibrinolytics].

Factor XI deficiency is a rare inherited coagulation disorder. It rarely produces spontaneous bleeding although patients with this disorder are at risk for hemorrhagic complications after trauma or surgery. Because there is no clear correlation between the tendency to bleed and the severity of the disease itself, predicting hemorrhagic complications after surgery in patients with mild disease is difficult. This hereditary deficiency is characterized by prolongation of activated partial thromboplastin time with normal prothrombin time, and the demonstration of selective plasma factor XI deficit. Currently available products in the therapeutic arsenal are transfusion of fresh-frozen plasma, virus-inactivated factor XI concentrates, desmopressin (DDAVP) and antifibrinolytic drugs, whether alone or in combination. We describe a family with two affected children, in which the deficiency was identified as an autosomal recessive trait. Of the two patients, one required prophylactic treatment with desmopressin and tranexamic acid before surgery; the treatment was successful and no related complications were observed. The long-term outcome of individuals with this disease seems to be good with continuous follow up and early control of hemorrhagic episodes. Prophylactic therapy is not required, except when surgery is anticipated.

Antifibrinolytic Agents↗
PubMed1999

Factor XI deficiency in the French Basque Country.

Thirty-nine patients with factor XI deficiency were diagnosed in our general hospital, which serves all the French Basque Country (about 290 000 inhabitants), between 1985 and 1995. Biological and clinical data of these cases are reported herein. Factor XI deficiency seems significantly more frequent in Basques than in the other non-Ashkenazi populations. Molecular studies should be performed for typing these cases in the view of population genetics.

Adolescent↗
PubMed1981

The clinical importance of factor XI deficiency in an Ashkenazi Jewish patient.

Factor XI (PTA) deficiency, a coagulopathy, has been found to be relatively common in Ashkenazi Jews. Clinically it may manifest itself by varying forms of hemorrhage including postoperative bleeding. It is recommended that all Ashkenazi Jews have a partial thromboplastin time (PTT) coagulation test before surgery in order to rule out this coagulopathy, and if the PTT is abnormal a Factor XI assay should be done to confirm the diagnosis and ensure that proper therapy can be provided. A surgical case is presented with its ensuing complications resulting form lack of such information.

Adult↗
PubMed2005

A classification system for cross-reactive material-negative factor XI deficiency.

The bleeding disorder associated with factor XI (fXI) deficiency is typically inherited as an autosomal recessive trait. However, some fXI mutations may be associated with dominant disease transmission. FXI is a homodimer, a feature that could allow certain mutations to exert a dominant-negative effect on wild-type fXI secretion through heterodimer formation. We describe 2 novel fXI mutations (Ser225Phe and Cys398Tyr) that form intracellular dimers, are secreted poorly, and exhibit dominant-negative effects on wild-type fXI secretion in cotransfection experiments. Available data now suggest that mutations associated with crossreactive material-negative fXI deficiency fall into 1 of 3 mechanistic categories: (1) mutations that reduce or prevent polypeptide synthesis, (2) polypeptides that fail to form intracellular dimers and are retained in cells as monomers, and (3) polypeptides that form dimers that are not secreted. The latter category likely accounts for many cases of dominant disease transmission.

Adult↗
PubMed1991

Myocardial infarction in a patient with factor XI deficiency and a lupus anticoagulant.

A 64-year-old man with both Factor XI deficiency and a lupus anticoagulant who suffered two myocardial infarctions within a 3-month period is described. Although thromboembolic disorders, including myocardial infarction, have been associated with the antiphospholipid syndrome, myocardial infarction in patients with Factor XI deficiency is rare. The potential role of Factor XIa in fibrinolysis is discussed.

Antiphospholipid Syndrome↗
PubMed1999

Identification of a novel mutation in a non-Jewish factor XI deficient kindred.

The role of factor XI (FXI) in blood coagulation has been clarified in recent years by descriptions of FXI-deficient patients who are prone to excessive bleeding after haemostatic challenge. We have studied a large kindred of an Italian FXI-deficient patient with a previously undescribed mutation. The propositus, a 68-year-old woman, presented with a cerebral thromboembolic event but had no history of bleeding (FXI activity 1.6 U/dl). A sensitive ELISA failed to detect FXI antigen in the propositus. Sequence analysis of the entire FXI gene revealed a TGG to TGC transversion in codon 228 of exon 7 (FXI-W228C). This missense mutation results in a Trp to Cys substitution within the third apple domain of FXI. We conclude that this novel mutation occurred in a structurally conserved region and may therefore have interfered with either chain folding and secretion or stability of FXI and was responsible for the inherited abnormality seen in this kindred. It is unclear why this kindred does not exhibit a bleeding tendency but it may correlate with a FXI-like antigen and factor IX binding activity expressed on platelets.

Aged↗
PubMed1983

Pulmonary valvulotomy in Factor XI deficiency.

This is the first reported case in the English literature of Factor XI deficiency in a child from India. He underwent open-heart surgery and pulmonary valvulotomy without excessive or delayed hemorrhage using plasma infusion to sustain Factor XI levels at about 40% of normal before, and for 10 days after surgery. The management of this child is presented as an approach to patients with Factor XI deficiency who require major surgery.

Child, Preschool↗
PubMed2006

Simulation of normal, carrier and affected controls for large-scale genotyping of cattle for factor XI deficiency.

An insertion mutation within exon 12 of the factor XI gene has been described in Holstein cattle. This has opened the prospect for large-scale screening of cattle using the polymerase chain reaction (PCR) technique for the rapid identification of heterozygous animals. To facilitate such a screening process, the mutant and normal alleles of factor XI gene, represented by 244- and 320-bp PCR amplified fragments, were individually cloned in Escherichia coli using a multicopy plasmid cloning vehicle to generate pFXI-N and pFXI-M, respectively. The authenticity of the inserts was confirmed by nucleotide sequencing. A nested PCR method was developed, by which PCR amplicons generated from primers with annealing sites on the recombinant plasmids and by flanking the insert were used as templates for amplification of the diagnostic products using factor XI gene-specific primers. An equimolar mixture of both PCR amplicons, originating from pFXI-N and pFXI-M, constituted the carrier control while the individual amplicons were the affected and normal controls. The controls were used as references for in-gel comparison to screen a population of 307 cattle and 259 water buffaloes; the frequency of the mutant allele was found to be 0. No DNA size standards were required in this study. The simulated control DNA samples representing normal, carrier and affected cattle have the potential to help in large-scale screening of a cattle population for individuals that are carriers or affected by factor XI deficiency.

Alleles↗
PubMed2000

A novel type of factor XI deficiency showing compound genetic abnormalities: a nonsense mutation and an impaired transcription.

We studied a 29-year-old Japanese male patient with factor XI deficiency; we also studied his parents and one sibling. Factor XI coagulation activity and antigen levels were extremely low (less than 1% of normal level) in both the patient and his brother, and they were half the normal levels in both parents. Sequence analysis of all 15 exons and the exon-intron boundaries of the factor XI gene amplified by polymerase chain reaction revealed a nonsense mutation in exon 8 (Gln263-->Stop). Although the parents are first cousins, the mutation was unexpectedly heterozygous in all the family members except the father, who showed the homozygous wild type, indicating that this mutation alone was not sufficient to account for the factor XI deficiency. To explore the genetic abnormality in the father, we analyzed allele-specific expression of the platelet factor XI gene using reverse transcription-polymerase chain reaction and subsequent restriction enzyme digestion. As a result, gene expression from only one allele was severely impaired in the father. This result implies an additional mutation in some regulatory element of the factor XI gene from paternal inheritance. We concluded that the factor XI deficiency of the patient was caused by compound heterozygous genetic abnormalities.

Adult↗
PubMed1988

Noonan syndrome: partial factor XI deficiency.

Among the multiple extracardiac abnormalities seen in the Noonan syndrome, several authors have mentioned an unexplained bleeding tendency. In 1983 Kitchens and Alexander reported on a partial deficiency of coagulation factor XI in four patients with Noonan syndrome. We examined 9 patients with Noonan syndrome and 9 of their 18 parents (3 of them also had Noonan syndrome). Four Noonan patients were found to have a partial deficiency of factor XI (30-65%). The Noonan patients had a mean factor XI level of 67%, significantly lower than the normal parents (mean level of 109%). Our study suggests a relationship between Noonan syndrome and a partial deficiency of factor XI.

Blood Coagulation Disorders↗
PubMed1984

The relationship between factor XI coagulant and factor XI antigenic activity in cattle.

Factor XI protein, isolated from normal bovine plasma, was used to raise antiserum in rabbits. The antisera was partially purified and used in a neutralization-inhibition assay to investigate the relationship between factor XI coagulant activity and antigenic material in the plasma of normal cattle and cattle homozygous and heterozygous for factor XI deficiency. Factor XI antigen was reduced in both the homozygous and heterozygous animals to levels comparable to the factor XI coagulant activity. The reduction of immunologically cross-reactive material to normal factor XI suggests that the factor XI coagulation defect is associated with the absence of a normal protein.

Animals↗
PubMed1999

Factor XI deficiency: implications for management of patients undergoing aesthetic surgery.

We report our experience in patients with an abnormal partial thromboplastin time elevation due to factor XI deficiency (Rosenthal syndrome) who presented for aesthetic surgery consideration. Preoperative evaluation included a thorough history, physical examination, coagulation profile, and hematological consultation. Nine of 10 patients underwent 12 elective aesthetic procedures without undue intraoperative or postoperative bleeding. Based on these findings, we stratified patients as low risk or high risk. Low-risk patients were those with greater than 15 percent factor XI levels, or those with 5 to 14 percent factor XI levels but a history of multiple major surgical procedures without bleeding complications. High-risk patients were those with factor XI levels less than 15 percent, history of bleeding either spontaneously or with surgery, and a family history of bleeding diathesis from factor XI deficiency. Low-risk patients had fresh frozen plasma available for the procedure, whereas high-risk patients received fresh frozen plasma 2 hours before surgery. We conclude that (1) in these patients with abnormally high partial thromboplastin time values and no prior known bleeding disorder, we have identified factor XI deficiency as the prevalent coagulopathy; (2) partial thromboplastin time does not necessarily correlate with factor XI levels; (3) patients can be classified as high or low risk for elective surgery based on factor XI levels and prior surgical or family history; (4) recommendations for perioperative management can be made based on this risk profile; and (5) aesthetic surgery can be performed successfully and safely on patients with factor XI deficiency on a case-by-case basis when appropriate guidelines are enforced.

Adolescent↗
PubMed2005

Structural interpretation of 42 mutations causing factor XI deficiency using homology modeling.

BACKGROUND: Factor (F)XI is important in the consolidation phase of blood coagulation. The structural effects of mutations causing FXI deficiency have not been well described due to the lack of a structure for FXI. OBJECTIVES: To develop molecular models of the four apple (Ap) and serine protease (SP) domains in FXI in order to assess the structural effects of published FXI mutations in the light of their phenotypes. METHODS: The Ap domains were modeled using the NMR structure of an adhesin from Eimeria tenella. The SP domain was modeled using the crystal structure of beta-tryptase. RESULTS: The effect of 42 mutations causing FXI deficiency was analyzed using homology models for the Ap and SP domains in FXI. Protein misfolding was implicated as the likely structural mechanism of disease in six of 14 mutations in the four Ap domains with Type I phenotypes. Likewise, misfolding was implicated in eight of 14 mutations in the SP domain with Type I phenotypes. Unlike other coagulation factor deficiencies, Type II phenotypes based on a catalytically dysfunctional FXI are uncommon. The structural models indicated that two known Type II mutations in the Ap domains could be correlated with functional defects in substrate or cofactor binding, and likewise four Type II mutations in the SP domain would disrupt the active site. CONCLUSIONS: New FXI disease-causing mutations can now be structurally characterized to complement phenotypic data, and expression studies can be designed to verify the molecular basis of each deficiency.

Amino Acid Sequence↗
PubMed1995

One of the two common mutations causing factor XI deficiency in Ashkenazi Jews (type II) is also prevalent in Iraqi Jews, who represent the ancient gene pool of Jews.

In recent years four mutations causing factor XI deficiency have been identified in Jews of Ashkenazi (European) origin. Two of them, type II (a nonsense mutation) and type III (a missense mutation), were found to prevail among 125 unrelated Ashkenazi Jews with severe factor XI deficiency. A finding of type II mutation in four unrelated Iraqi-Jewish families raised the possibility that this mutation is also common in Iraqi Jews, who represent the ancient gene pool of the Jews. A molecular-based analysis performed in 1,040 consecutively hospitalized patients disclosed the following results: Among 531 Ashkenazi-Jewish patients, the type II allele frequency was 0.0217 and among 509 Iraqi-Jewish patients, 0.0167 (P = .50). The type III allele frequency in the Ashkenazi-Jewish patients was 0.0254, whereas none of 502 Iraqi-Jewish patients examined had this mutation. These data suggest that the type II mutation was present in Jews already 2.5 millenia ago. The data also indicate that the estimated risk for severe factor XI deficiency in Ashkenazi Jews (due to either genotype) is 0.22% and in Iraqi Jews, 0.03%, and that the estimated risk of heterozygosity in Ashkenazi Jews is 9.0% and in Iraqi Jews, 3.3%. As patients with severe factor XI deficiency are prone to bleeding after injury and patients with partial deficiency may have similar bleeding complications when an additional hemostatic derangement is present, the observed high frequencies should be borne in mind when surgery is planned for individuals belonging to these populations.

Aged↗
PubMed2004

[FXI gene mutations in two pedigrees of congenital clotting factor XI deficiency].

OBJECTIVES: To identify the FXI gene mutations in two Chinese pedigrees of congenital factor XI deficiency. METHODS: The peripheral blood samples were collected from the probands and their family members and the plasma FXI:C and FXI:Ag were determined. All the exons and exon-intron boundries of FXI gene were amplified with PCR and sequenced thereafter. RESULTS: A nonsense mutation Trp228stop and two missense mutations Glu323Lys and Leu172Pro were disclosed in the two pedigrees. All mutations existed in a heterozygous state. CONCLUSION: The FXI gene mutations Trp228stop, Glu323Lys and Leu172Pro attribute to the pathogenesis of the congenital factor XI deficiency in Chinese. The Leu172Pro is identified for the first time.

Adult↗
PubMed1988

Transfusion-induced specific anti-factor XI inhibitor in a patient with previously unrecognized factor XI deficiency.

This article reports the rare occurrence and investigation of a specific anti-factor XI inhibitor that arose after fresh-frozen plasma infusion into a patient with previously unrecognized Factor XI deficiency. The IgG fraction of the patient's plasma that contained anti-Factor XI antibody was isolated by chromatography on DEAE-Affigel and concentrated. It was shown to exert inhibitory effect on purified Factor XI and XIa both in the activated and nonactivated partial thromboplastin time assay.

Aged↗
PubMed1985

Spontaneous hematomyelia secondary to factor XI deficiency. Case report.

A 34-year-old woman with Factor XI deficiency presented with rapidly progressive quadriplegia following a 1-week prodrome of cervical pain. At operation, a spontaneous hematomyelia was evacuated from the C4-6 vertebral level. The pathophysiology of spontaneous hematomyelia is discussed.

Adult↗