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PubMed1997

Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis.

Recently, it has been shown that Factor XI can be activated by thrombin, and that Factor XIa significantly contributes to the generation of thrombin via the intrinsic pathway after the clot has been formed. This additional thrombin, generated inside the clot, was found to protect the clot from fibrinolysis. A plausible mechanism for this inhibitory effect of thrombin involves TAFI (thrombin-activatable fibrinolysis inhibitor, procarboxypeptidase B) which, upon activation, may inhibit fibrinolysis by removing carboxy-terminal lysines from fibrin. We studied the role of Factor XI and TAFI in fibrinolysis using a clot lysis assay. The lysis time was decreased twofold when TAFI was absent, when TAFI activation was inhibited by anti-TAFI antibodies, or when activated TAFI was inhibited by the competitive inhibitor (2-guanidinoethylmercapto)succinic acid. Inhibition of either TAFI activation or Factor XIa exhibited equivalent profibrinolytic effects. In the absence of TAFI, no additional effect of anti-Factor XI was observed on the rate of clot lysis. We conclude that the mechanism of Factor XI-dependent inhibition of fibrinolysis is through the generation of thrombin via the intrinsic pathway, and is dependent upon TAFI. This pathway may play a role in determining the fate of in vivo formed clots.

Antibodies, Monoclonal↗
PubMed1998

The second exon-encoded factor XII region is involved in the interaction of factor XII with factor XI and does not contribute to the binding site for negatively charged surfaces.

Contact system activation, in vitro, is triggered by activation of factor XII (FXII) on binding to an activator, such as negatively charged surfaces. A putative surface-binding site of FXII has been located within the amino acid residues 1-28 by identifying the epitope recognized by a monoclonal antibody (MoAb), B7C9, which inhibits kaolin-induced clotting activity. To further elucidate the role of the amino terminal binding site in the regulation of FXII activation, we have characterized a FXII recombinant protein (rFXII-triangle up19) deleted of the amino acid residues 3-19, which are encoded by the second exon of FXII gene. A plasmid encoding for rFXII-triangle up19 was constructed and expressed in HepG2 cells by using vaccinia virus. Purified rFXII-triangle up19 migrated as a single band of Mr 77,000 on sodium dodecyl sulfate (SDS)-polyacrylamide gel, did not bind to MoAb B7C9 immobilized on Protein A-Sepharose, thus confirming that it lacked the epitope for this MoAb, and had no amidolytic activity towards the chromogenic substrate S-2302 in the absence of activator. rFXII-triangle up19 specific clotting activity was lower (44%) than that of native FXII. The activation rate of rFXII-triangle up19 by kallikrein in the absence of dextran sulfate was about four times higher than that of full-length FXII and was increased in the presence of dextran sulfate. However, rFXII-triangle up19 underwent autoactivation in the presence of dextran sulfate. Labeled rFXII-triangle up19 bound to kaolin, which binding was equally well inhibited by either, rFXII-triangle up19 or full-length FXII (IC50 = 7.2 +/- 2.2 nmol/L for both proteins). Accordingly, a synthetic peptide corresponding to FXII amino acid residues 3-19 did not inhibit the binding of labeled full-length FXII to kaolin. rFXII-triangle up19 generated a similar amount of FXIIa- and kallikrein-C1-inhibitor complexes in FXII-deficient plasma in the presence of kaolin, as did full-length FXII; but generated less factor XIa-C1-inhibitor complexes (50%) than full-length FXII. This impaired factor XI activation by rFXII-triangle up19a was also observed in a purified system and was independent of the presence of high molecular weight kininogen. Furthermore, the synthetic peptide 3-19, preincubated with factor XI, inhibited up to 30% activation of factor XI both in the purified system as well as in plasma. These results together indicate that amino acid residues 3-19 of FXII are involved in the activation of factor XI and do not contribute to the binding of FXII to negatively charged surfaces.

Blood Coagulation↗
PubMed1981

Definition of the population at risk of bleeding due to factor XI deficiency in Ashkenazic Jews and the value of activated partial thromboplastin time in its detection.

The previously found high gene frequency of hereditary Factor XI deficiency among Ashkenazic Jews, and the risk of bleeding following trauma in this disorder, prompted us to define the population at risk of bleeding and to evaluate the activated partial thromboplastin time (APTT) as a screening test for its detection. The APTT values of 30 patients with severe Factor XI deficiency (0 to 0.14 unit/ml) overlapped only minimally with the APTT of 56 healthy subjects with Factor XI levels greater than 0.5 unit/ml. In contrast, APTT values of partially deficient patients (Factor XI: 0.15 to 0.49 unit/ml) overlapped substantially with the APTT values of the healthy subjects. However, when only subjects at risk of bleeding were considered (Factor XI less than 0.3 unit/ml), the overlap of APTT values was much smaller. The apparent frequency of this population at risk in the general Ashkenazic population was found to be 3.05%. If a cutoff point of an APTT value at the 80th percentile of the normal range is taken for detection of subjects belonging to this group, one will miss only 4.4% of these cases, with confidence limits of 0.1 to 21%.

Blood Coagulation Tests↗
PubMed2001

A case of chronic myelomonocytic leukaemia and factor XI deficiency with a circulating anticoagulant.

Inhibitors against factor XI (FXI) have been frequently described in patients who acquired inhibitors (due to auto-immune disorders, malignancies or infections), but less often in those with a congenital deficiency of this factor, who had received plasma infusions. The present report concerns one such inhibitor found in the plasma of a patient with chronic myelomonocytic leukaemia and infected by B19 parvovirus, who was neither a heterozygote nor a homozygote for FXI deficiency, and who had no bleeding tendency despite a very low FXI level. Taking this case into account, we discuss and present the clinical and biological features of acquired FXI deficiency caused by an inhibitor.

Aged↗
PubMed1979

Evidence against collagen activation of platelet-associated factor XI as a mechanism for initiating intrinsic clotting.

Collagen activation of platelet-associated Factor XI has been proposed as a mechanism for initiating intrinsic clotting independent of Factor XII. Since this could explain the lack of bleeding in patients with hereditary Factor XII deficiency, prekallikrein deficiency and high molecular weight kininogen deficiency, we subjected the hypothesis to rigorous testing. Incubation of isolated platelets with collagen and calcium ions failed to generate activity shortening the clotting time of an activated Factor XI (XIa) assay that had been modified to eliminate effects due to platelet-associated activated Factor V. Nor could generation of traces of Factor XIa in such mixtures be detected by incubation with purified Factor IX and testing for the generation of activated Factor IX (IXa) in clotting and amidolytic assays. Moreover, when blood or platelet-rich plasma containing added 125I-Factor IX was incubated with calcium ions and collagen and then subjected to reduced sodium dodecyl sulfate polyacrylamide gel electrophoresis, the radioactivity profiles revealed only native 125I-Factor IX without evidence of the polypeptide chains of Factor IXa. The negative results of this study mitigate against the hypothesis that collagen activation of platelet-associated Factor XI represents a physiologically significant mechanism for initiating clotting independent of Factor XII.

Animals↗
PubMed2000

Activation of clotting factors XI and IX in patients with acute myocardial infarction.

In acute coronary events, plaque rupture and the subsequent formation of the catalytic tissue factor-factor VIIa complex is considered to initiate coagulation. It is unknown whether clotting factors XI and IX are activated in acute coronary events. Therefore, we prospectively investigated the activation of clotting factors XI and IX as well as activation of the contact system and the common pathway in 50 patients with acute myocardial infarction (AMI), in 50 patients with unstable angina pectoris (UAP), and in 50 patients with stable angina pectoris (SAP). Factor XIa-C1 inhibitor complexes, which reflect acute activation of factor XI, were detected in 24% of the patients with AMI, 8% of the patients with UAP, and 4% of the patients with SAP (P<0.05), whereas factor XIa-alpha(1)-antitrypsin complexes, which reflect chronic activation, were observed equally in all 3 study groups. Factor IX peptide levels were significantly higher in the patients with AMI and UAP compared with the patients with SAP (P<0.01). No differences regarding markers of the common pathway were demonstrated. Fibrinopeptide A levels were elevated in patients with AMI compared with patients with UAP and those with SAP (P<0.01). Factor XIIa- or kallikrein-C1 inhibitor complexes were not increased. In conclusion, this is the first demonstration of the activation of clotting factors XI and IX in patients with acute coronary syndromes. Because these clotting factors are considered to be important for continuous thrombin generation and clot stability, their activation might have clinical and therapeutic consequences.

Angina Pectoris↗
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↗
PubMed1994

Factor XI deficiency in Kerry Blue Terriers.

A 9-year-old female Kerry Blue Terrier with postoperative hemorrhage and prolonged activated partial thromboplastin and activated clotting times was determined to have factor XI deficiency. Transfusions of fresh-frozen plasma given on 4 consecutive days transiently returned the values for activated clotting time and plasma factor XI activity to within reference range limits and controlled the hemorrhage. Analysis of data from 10 other factor XI-deficient Kerry Blue Terriers with a tendency for mild posttraumatic or postoperative bleeding was suggestive of an autosomal mode of inheritance, with a mild tendency for posttraumatic or postoperative bleeding in homozygous and heterozygous dogs. Factor XI deficiency is the only contact phase protein defect that causes a bleeding disorder in animals, which can be explained by the fact that thrombin is more efficient than factor XIIa in activating factor XI. Factor XIa plays a key role in sustaining coagulation.

Animals↗
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↗
PubMedDate not supplied

Conformational analysis of synthetic peptides encompassing the factor XI and prekallikrein overlapping binding domains of high molecular weight kininogen.

High molecular weight kininogen, a plasma glycoprotein, circulates as a noncovalent complex with either prekallikrein or factor XI, two other plasma glycoproteins. The binding domain for factor XI within kininogen, Pro556-Met613 (58 residues), wholly contains the binding domain for prekallikrein, Ser565-Lys595 (31 residues), but Trp569-Lys595 (27 residues) retains some ability to bind prekallikrein. Complex formation between these proteins is mediated by recognition between complementary domains. The 58-residue factor XI peptide domain has now been prepared following a strategy of condensation of long-chain peptide fragments prepared using orthogonal chemistry protocols. The 58-, 31-, and 27-residue peptides assume very different structures in aqueous solution as revealed by differential scanning calorimetry, intrinsic fluorescence emission, and circular dichroism spectroscopies. Thus, the 31-residue peptide shows a broad endothermic transition in differential scanning calorimetry (DSC), but the 58-mer undergoes a well-defined, two-state transition (Tm 43 degrees C; transition enthalpy approximately 30 kcal/mol). The 58- and 27-residue peptides continuously lose structure with increasing temperature, but the 31-mer retains significant structure even at temperatures approaching 90 degrees C. Lys595 plays a critical role in maintaining structure through electrostatic contacts, probably with Asp572 in the N-terminal segment of the 31-residue sequence. Isothermal ligand titration calorimetry was used to directly assess the ability of the 31-, 27-, and 58-residue peptides to bind prekallikrein. The 31-residue peptide binds prekallikrein with 25-fold higher affinity (Kd = 1.0 x 10(-6) M) than the 58-residue peptide and with 5.4-fold higher affinity than the 27-residue peptide. Hence, the essential features of the 31-residue peptide domain required for binding prekallikrein are absent in the 58-residue peptide, which is optimized for binding factor XI. The results suggest that a conformational change may occur within kininogen that causes expression of one domain structure in preference to the other.

Amino Acid Sequence↗
PubMed2002

Factor XI deficiency in Iranians: its clinical manifestations in comparison with those of classic hemophilia.

BACKGROUND AND OBJECTIVES: In patients with factor XI(FXI) deficiency the bleeding tendency is poorly correlated with plasma factor levels. The purpose of this study was to evaluate whether or not this discrepancy is also present in a large series of patients from Iran, a previously unexplored ethnic group. DESIGN AND METHODS: In 28 FXI - deficient patients bleeding symptoms and their relation to FXI levels were compared with those of 100 patients with factor VIII (FVIII)deficiency (classic hemophilia), matched for severity of factor deficiency. RESULTS: Spontaneous bleeding was definitely less frequentin FXI deficiency than in hemophilia, whereas postoperative and post-traumatic bleeding occurred with comparable frequencies. Among FXI-deficient patients the severity of symptoms was poorly correlated with FXI levels, mildly deficient patients bleeding almost as frequently as those severely deficient. In contrast, in patients with classic hemophilia there was a close relation between the severity of bleeding and degree of FVIII deficiency. INTERPRETATION AND CONCLUSIONS: As in other ethnic groups, in Iranians factor XI deficiency is less severe than classic hemophilia and the bleeding tendency is poorly correlated to plasma factor levels.

Factor XI↗
PubMed1982

Factor XI assay results in the CAP survey (1981).

Data from the 1981 CAP Survey for factor XI assay is reviewed. Different instrument reagent combinations are ranked according to precision and sensitivity. Results of the survey questionnaire are analyzed. There is poor correlation between precision and sensitivity of most systems (i.e., instrument and reagent combinations). For any given system, precision appears to decrease with increasing severity of the factor XI deficiency of the specimen. Some comparisons are made to recent CAP surveys of factor VIII and IX activity. Considerable interlaboratory variation is noted with respect to technical aspects of factor assays (i.e., dilution of normal plasma used to construct the standard curve, etc.). Procedures used by some laboratories in handling patient specimens for factor assays, such as freezing the patient specimen, may decrease the chance of identifying a mild factor XI deficiency. The need for standardization of factor assays is evident from the survey data.

Factor XI↗
PubMed1986

Management of factor XI deficiency in gynecologic and obstetric patients.

Deficiency of factor XI (plasma thromboplastin antecedent) can result in severe bleeding in women undergoing obstetric or gynecologic procedures, with the highest risk in women of Ashkenazi Jewish background. Most patients do not bleed if treated with sufficient fresh frozen plasma to maintain a factor XI level of 30% or more but occasionally patients may require higher levels. Plasma infusion should be continued for several days, even if bleeding does not seem excessive, since delayed bleeding is not uncommon. The use of hepatitis B vaccine and of plasma from a single donor, may reduce the risk of hepatitis.

Adult↗
PubMed1996

[Factor XI deficiency, a new way of substitution: human purified concentrates].

Case report of a 26-year-old patient, admitted for severe craniofacial trauma, with facial injuries and intracranial haemorrhage. Preoperative tests showed an aPTT = 64 s (control = 29 s), rapidly recognized as being caused by a major constitutional factor XI deficiency (0.06 Ul.mL-1). Considering the neurological risk and the indication for surgery, concentrates of factor XI were administered at a dosage of 25 Ul.kg-1. This treatment was associated with a biological normalization and uneventful surgery. In patients experiencing a factor XI deficiency, the use of fresh frozen plasma will probably decrease and only administered in emergency cases when factor XI concentrates are not available.

Adult↗
PubMed1998

Characterization of a heparin binding site on the heavy chain of factor XI.

The glycosaminoglycan heparin enhances several reactions involving coagulation factor XI (FXI) including activation of FXI by factor XIIa, thrombin, and autoactivation; and inactivation of activated FXI (FXIa) by serine protease inhibitors. We examined the effect of heparin on inhibition of FXIa by the inhibitors C1-inhibitor (C1-INH) and antithrombin III (ATIII). Second order rate constants for inhibition in the absence of heparin were 1.57 x 10(3) and 0.91 x 10(3) M-1 s-1 for C1-INH and ATIII, respectively. Therapeutic heparin concentrations (0.1-1.0 units/ml) enhanced inhibition by ATIII 20-55-fold compared with 0.1-7.0-fold for C1-INH. For both inhibitors, the effect of heparin over a wide range of concentrations (10(-1) to 10(5) units/ml) produced bell-shaped curves, demonstrating that inhibition occurs by a template mechanism requiring both inhibitor and protease to bind to heparin. This implies that FXI/XIa contains structural elements that interact with heparin. Human FXI contains a sequence of amino acids (R250-I-K-K-S-K) in the apple 3 domain of the heavy chain that binds heparin (Ho, D., Badellino, K., Baglia, F., and Walsh, P. (1998) J. Biol. Chem. 273, 16382-16390). To determine the importance of this sequence to heparin-mediated reactions, recombinant FXI molecules with alanine substitutions for basic amino acids were expressed in 293 fibroblasts, and tested in heparin-dependent assays. Inhibition of FXIa by ATIII in the presence of heparin was decreased 4-fold by alanine substitution at Lys253 (A253), with smaller effects noted for mutants A255 and A252. FXI undergoes autoactivation to FXIa in the presence of heparin. The rate of autoactivation was decreased substantially for A253 with modest decreases for A255 and A252. Substituting all four charged residues in the sequence resulted in a profound decrease in autoactivation, significantly greater than for any single substitution. Relative affinity for heparin was tested by determining the concentration of NaCl required to elute FXIa from heparin-Sepharose. Wild type FXIa eluted from the column at 320 mM NaCl, whereas FXIa with multiple substitutions (A252-254 or A250-255) eluted at 230 mM NaCl. All proteins with single substitutions in charged amino acids eluted at intermediate NaCl concentrations. The data indicate that FXI/XIa must bind to heparin for optimal inhibition by ATIII and for autoactivation. Lys253 is the most important amino acid involved in binding, and Lys255 and Lys252 also have roles in interactions with heparin.

Alanine↗
PubMed2005

DNA extraction from bovine mummified fetuses and detection of factor XI gene deficiency in the mummies.

Genomic DNA extracted from bovine mummified tissue is valuable material for detection of some genes that may contribute to fetal abnormalities. In this study bovine genomic DNA was extracted from the hardened tissue samples of ten bovine mummified fetuses. The amount of genomic DNA extracted from 2 g of the mummified tissues by the phenol/chloroform-ethanol method was low (less than 4 microg/ml) for all samples. The extracted DNA was then amplified by the GenomiPhi DNA amplification system. After amplification, the amount of DNA was increased to more than 100 microg/ml for all samples. This amplification system was shown to be a good tool for amplifying the genomic DNA of the mummified fetuses. The amplified genomic DNA was used for testing the mummies for Factor XI gene deficiency, an autosomal recessive deficiency involved in the early stages of the intrinsic blood coagulation pathway. Exon 12 of the Factor XI gene of the mummies was amplified by PCR. Two of the ten mummified fetuses were heterozygous for the Factor XI gene as indicated by the presence of two amplified DNA fragments of 320 bp and 244 bp. Factor XI deficiency has already been described in Holstein cattle. However, no report is available for bovine fetus. In this study, DNA was extracted and amplified from the bovine mummified fetuses, and the samples were successfully tested for Factor XI gene deficiency in the mummies.

Animals↗
PubMed1983

Hemorrhage in a cat caused by inhibition of factor XI (plasma thromboplastin antecedent).

A coagulation profile from a 5-year-old neutered male cat with severe epistaxis revealed an intrinsic coagulation defect characterized by prolonged activated partial thromboplastin time, with normal bleeding time, platelet count, and prothrombin time. Subsequent factor XI analyses, using bovine factor XI-deficient plasma, revealed factor XI deficiency. Hematologic and clinical studies on the cat failed to reveal an underlying disease process that might have resulted in acquired factor XI inhibition.

Animals↗