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PubMed1986

Failure of Routine Coagulation Screening Tests to Detect Heterozygous State of Bovine Factor XI Deficiency.

In a survey of coagulation, biochemical and hematological parameters in cattle homozygous (deficient), heterozygous (carrier) and non-affected (normal) for Factor XI deficiency, only the Activated Partial Thromboplastin Time (APTT) results correlated with plasma Factor XI activity levels. The APTT results and the thrombokinetics for the deficient animals were markedly different from the results of either the carrier or normal animals. However, the APTT assay was shown not to be sufficiently sensitive to differentiate between the normal and carrier state for the coagulation disorder. Not only was there no statistical difference between the mean APTT results for the normal and carrier animals, but the thrombokinetics for fibrin clot formation for the two groups were also similar.

Journal Article↗
PubMed1996

A binding site for thrombin in the apple 1 domain of factor XI.

Previously we defined a binding site for high molecular weight kininogen (HK) in the A1 domain of factor XI (FXI). Since thrombin can activate FXI and HK inhibits the activation of FXI by thrombin, we have identified a thrombin binding site in FXI. Both the recombinant A1 domain (Glu1-Ser90) and a synthetic peptide (Phe56-Ser86) containing the HK binding site inhibited FXI activation by thrombin. Both a monoclonal antibody, 5F7, recognizing the A1 domain, and the rA1 domain were shown to be competitive inhibitors of thrombin-catalyzed FXI activation. The peptides Ala45-Arg54 and Val59-Arg70 acted synergistically to inhibit FXI activation by thrombin. Mutant rA1 domain constructs (Val64 --> Ala and Ile77 --> Ala), which do not inhibit FXI binding to HK, retain full capacity to inhibit FXI activation by thrombin. The peptide Ala45-Arg54 inhibited thrombin-catalyzed FXI activation, whereas it had no effect on FXI binding to HK. In contrast, the peptide Asn72-Leu83 (which inhibited FXI binding to HK) did not inhibit FXI activation by thrombin. Thus, a thrombin binding site exists in the A1 domain of FXI spanning residues Ala45-Arg70 that is contiguous with but separate and distinct from the HK binding site. These sites may regulate which ligand is bound to FXI and through which pathway FXI is activated.

Amino Acid Sequence↗
PubMed1975

Hereditary giant platelet syndrome. Absence of collagen-induced coagulant activity and deficiency of factor-XI binding to platelets.

The platelets from two related patients with the hereditary giant platelet syndrome were examined. They were larger than normal but otherwise ultrastructurally normal; they contained increased storage pools of adenine nucleotides and heparin-neutralizing activity and took up serotonin at an increased rate. They aggregated normally with ADP and collagen but failed to aggregate with bovine factor VIII and Ristocetin. Some change in shape occurred with ADP, and the reduction in adenylate energy change after addition of ADP to platelet-rich plasma was smaller than normal. Platelet coagulant activities including contact product forming activity, intrinsic factor-Xa forming activity and platelet factor 3 activity were normal or increased, but collagen-induced coagulant activity was absent whether tested in washed platelet suspensions or platelet-rich plasma. Platelet washing experiments showed decreased binding of factors V and VIII to hereditary giant platelets and no detectable factor XI in washed platelet suspensions. It is concluded that (1) the hereditary giant platelets studied lacked a binding mechanism for factors, V, VIII and XI; (2) the normal development of collagen-induced coagulant activity apparently depends upon the binding of factor XI to the platelet membrane; and (3) the defective prothrombin consumption observed in these patients may have resulted from the failure of their platelets to bind factor XI.

Adenine Nucleotides↗
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↗
PubMed2001

Severe factor XI deficiency caused by compound heterozygosity for the type III mutation and a novel insertion in exon 9 (codons 324/325 +G).

We investigated a 42-year-old Caucasian woman with severe factor XI deficiency and her family members. Restriction enzyme analysis and DNA sequencing revealed compound heterozygosity in the patient for the known type III mutation, which is a Phe283Leu amino acid substitution in the fourth apple domain causing impaired dimerization and secretion, and for a novel frameshift mutation in exon 9 (codons 324/325 +G), leading to premature termination with lack of parts of the fourth apple domain and the downstream serine protease domain.

Adult↗
PubMed1984

Spontaneous factor XI inhibitors. Seven additional cases and a review of the literature.

Circulating anticoagulants are endogenous blood components that inhibit the action of clotting factors. In some inhibitor conditions this inactivation in the function of the hemostatic system may lead to life-threatening hemorrhagic diathesis. Inhibitors directed against factor XI are generally associated with little or no impairment of the hemostatic system. We analyzed all reported cases of spontaneous factor XI inhibitor in the international literature, as well as cases identified at the Yale--New Haven (Conn) Hospital between 1970 and 1980, considering clinical spectrum, diagnosis, and therapy.

Adolescent↗
PubMed2004

[Factor XI].

Explore the source record for details and available documents.

Biomarkers↗
PubMed1976

Heterozygous and homozygous factor XI defect in consanguineous family.

A woman with symptoms of prolonged post-traumatic bleeding was found to have a severe defect of factor XI, and was thought to be homozygously affected. Both her parents, who were first cousins, and all her three children, though asymptomatic, showed a moderate defect and appeared to be heterozygous. Both her parents' factor XI levels were about twice those in her children, and this was thought to be an age effect.

Age Factors↗
PubMed2003

Factor XI deficiency--from molecular genetics to clinical management.

Factor XI (FXI) deficiency is a rare bleeding disorder, but is known to occur more frequently in a number of well-defined populations. FXI deficiency is most notable for its variable clinical phenotype. The FXI gene is located at the distal end of the long arm of chromosome 4 and encodes a 607 amino acid mature protein, which is a zymogen for a serine protease. Although the serine protease domain is similar to that of many other coagulation factors, the heavy chain differs in that it contains four tandem Apple domains. FXI is also unique in that it exists as a homodimer, with this dimerization appearing essential for normal function. A total of 39 different FXI mutations have been identified to date, affecting both the catalytic and Apple domains. This article will review the molecular genetics of FXI deficiency with particular focus on the implications of these findings for the clinical management of this condition. The potential utility of alternatives to plasma-derived FXI concentrate, such as recombinant factor VIIa (rFVIIa, NovoSeven) will also be explored.

Amino Acid Sequence↗
PubMed2003

Inherited factor XI deficiency confers no protection against acute myocardial infarction.

BACKGROUND AND PURPOSE: Factor XI (FXI) contributes to thrombin generation thereby affecting fibrin formation and to down regulation of fibrinolysis by activation of thrombin-activatable fibrinolysis inhibitor (TAFI). The purpose of this study was to evaluate whether patients with severe FXI deficiency are protected against acute myocardial infarction (AMI). METHODS: The incidence of AMI in patients with severe FXI deficiency (FXI activity less than 15 U dL(-1)) whose age was 35 years or more was compared to the incidence of AMI in age and gender matched persons of the general population. Atherosclerotic risk factors were assessed in FXI deficient patients and blood was tested for prothrombotic parameters such as FV Leiden, prothrombin G20210A, lupus anticoagulant, and platelet membrane polymorphisms. The common mutations causing FXI deficiency in Jews were also examined. RESULTS: Of 96 patients with severe FXI deficiency (55 women and 41 men) 16 had a history of AMI (6 women and 10 men). The median age at the time of AMI was 64.5 for women and 58 for men. The calculated annual rate of AMI in men was similar to the expected in the general Israeli population, whereas in women it was almost 2-fold higher, but this difference did not reach statistical significance. One or more atherosclerotic risk factors were observed in 13 of 16 patients (81.3%) with AMI compared to 44 of 79 patients (55.7%) without AMI (P < 0.001). The frequency distributions of platelet polymorphisms and of prothrombotic polymorphisms were not different between patients with severe FXI deficiency who experienced or not an AMI. None of the patients had lupus anticoagulant. The common genotypes which cause FXI deficiency in Jews were similarly distributed in patients with and without AMI. CONCLUSIONS: Severe FXI deficiency does not confer protection against AMI.

Adult↗
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

Factor XI deficiency in an Ashkenazi Jewish child, causing severe postoperative hemorrhage.

Although inherited coagulation factor deficiencies with negative bleeding histories are rare, cases such as the one presented herein may not be diagnosed at the time of surgery and may experience severe hemostatic problems postoperatively. It may be prudent to obtain an activated partial thromboplastin time preoperatively for all Ashkenazi Jews, including those with a negative history for a hemostatic disorder, because of the high incidence of factor XI deficiency in their population. Surgeons and anesthesiologists should be aware of the existence of this and other uncommon hemostatic disorders and their treatment when faced with serious, apparently unexplained postoperative hemorrhage.

Adenoidectomy↗