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PubMed1996

Clinical usefulness of desmopressin for prevention of surgical bleeding in patients with symptomatic heterozygous factor XI deficiency.

Heterozygous factor XI (FXI) deficiency is sometimes associated with a significant bleeding tendency. Fresh frozen plasma of FXI concentrates are the mainstay of treatment in patients with a clear bleeding history, especially prior to surgery. However, these treatments are not completely free of risk. Furthermore, thrombosis has been reported in patients with FXI deficiency infused with FXI concentrate. No data are available on the possible efficacy of desmopressin in these patients. Two patients with a clear bleeding history associated with FXI deficiency and no additional haemostatic defects agreed to be treated with desmopressin before carpal tunnel surgery and dental extraction. The reduced basal FXI activity and antigen levels slightly increased after infusion, reaching borderline values. No bleeding was observed after surgical procedures. Desmopressin treatment seems a reasonable and useful choice in symptomatic, heterozygous FXI-deficient patients, thus reducing the cost of treatment, the risk of transmission of blood-borne viruses, and of thrombosis.

Blood Loss, Surgical↗
PubMed1994

Contact factors in plasma from women on oral contraception--significance of factor XI for the measured activity of factor XII.

The plasma levels of contact activation factors were measured in women using a low estrogen dose oral contraceptive (OC). Basic values for factor XII (FXII), factor XI (FXI), prekallikrein (PK), and high molecular weight kininogen (HK) were obtained in immunoassays by comparing with control plasma. The plasma levels of FXII and PK were significantly increased in OC plasma, to 147% and 146% respectively, whereas no significant increase could be registered for FXI (106%) or for HK (107%). Functional assays carried out with different peptide substrates (S-2222 for FXIIa, and S-2222, S-2302 and Bz-Pro-Phe-Arg-pNA for kallikrein) showed increases in OC plasma to about 150% for both proteases, in accordance with results obtained in radial immunodiffusion (RID). However, when FXIIa was measured with the high molecular weight substrate PK, no significant increase could be registered. Further experiments suggested this result to be due to the low level of FXI present in OC plasma, as compared to the levels of FXII and PK. Assays were carried out in mixtures of test plasma (OC or control plasma) and plasma deficient in FXI or FXII. The results obtained suggested that FXIa was present in some kind of association with part of FXIIa and part of kallikrein present. At low concentrations of FXI the functional activity of FXIIa was reduced, and the assay data indicated that an appropriate level of FXI was required to obtain maximum rate of hydrolysis of prekallikrein by FXIIa.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1997

In vivo coagulation activation following infusion of highly purified factor XI concentrate.

The use of factor XI concentrates has been associated with thrombosis. Plasma markers of coagulation activation were measured before and 30, 60, 120 and 240 min after six infusions of the BPL factor XI concentrate. Five studies were completed before surgical intervention, one was undertaken in a patient with an intracerebral haemorrhage. Significant elevation of levels of fibrinopeptide A (FpA) (P < 0.05) and thrombin-antithrombin (TAT) were demonstrated following six infusions and prothrombin fragment F1.2 following four. Levels of all three markers had risen 60 min following concentrate administration and FpA levels remained elevated throughout the study period. Levels of D-dimer rose in four patients at 240 min. These results indicate significant thrombin generation by 60 min and subsequent plasmin generation consistent with coagulation activation by the factor XI concentrate. The greatest elevation of activation markers was seen in those subjects with pre-existing coagulation activation. We advise caution in the use of these products and awareness of the risks in patients who may already have activated coagulation states.

Adult↗
PubMed2005

An insertion mutation of the bovine Fii gene is responsible for factor XI deficiency in Japanese black cattle.

Factor XI deficiency in Japanese black cattle is an hereditary mild bleeding disorder with an autosomal recessive mode of inheritance. To characterize the molecular lesion causing factor XI deficiency in cattle, we isolated an entire coding region of the bovine F11 gene, which comprises 15 exons and 14 introns, and determined its nucleotide sequences. Comparison of the nucleotide sequences of the F11 gene between affected and unaffected animals revealed an insertion of 15 nucleotides in exon 9 of the affected animals. The insertion results in a substitution of one amino acid with six amino acids in a highly conserved amino acid sequence in the fourth apple domain of factor XI protein. Genotyping of the F11 gene in 109 Japanese black cattle revealed that the insertion clearly corresponded to the factor XI activities of the animals. We therefore concluded that the insertion of 15 nucleotides in the F11 gene is the causative mutation for factor XI deficiency in Japanese black cattle. Genotyping of the F11gene by detecting the insertion will be an effective DNA-based diagnostic system to prevent incidence of the disease.

Amino Acid Sequence↗
PubMed2006

Factor XI enhances fibrin generation and inhibits fibrinolysis in a coagulation model initiated by surface-coated tissue factor.

In-vitro studies have shown that thrombin-mediated factor XI activation enhances thrombin and fibrin formation, rendering the clot more thrombogenic and protecting it from lysis by activation of thrombin activatable fibrinolysis inhibitor. These effects of factor XI are only observed when coagulation is initiated by a low concentration of soluble tissue factor. At high concentrations of soluble tissue factor no effects of factor XI are seen on coagulation and fibrinolysis. In vivo, tissue factor is present in large amounts in the vascular wall. This makes it difficult to extrapolate these in-vitro findings on factor XI to the in-vivo situation. To address the question of whether factor XI could play a role in coagulation initiated on a tissue factor-containing surface we devised a static in-vitro coagulation model in which clotting is initiated in recalcified citrated plasma by tissue factor coated on the bottom of microtiter plates. The effect of factor XI was studied with an antibody that blocked the activation of factor IX by activated factor XI. The tissue factor coating strategy produced clotting times similar to those obtained with cultured tissue factor-expressing vessel wall cells (smooth muscle cells, fibroblasts and activated endothelial cells) grown to confluence in the same wells. A factor XI-dependent effect on clot formation and clot lysis was observed depending on the plasma volume used. In clots formed from small amounts of plasma (100 microl) no effect of factor XI was detected. In larger clots (200-300 microl) factor XI not only increased prothrombin activation and the fibrin formation rate but also inhibited fibrinolysis. Effects of factor XI were observed at short clotting times (3-4 min) similar to the clotting times found on cultured tissue factor-expressing vessel wall cells. This is in contrast with earlier studies using soluble tissue factor, in which effects of factor XI were only observed at much longer clotting times using low soluble tissue factor concentrations. We conclude that factor XI not only enhances coagulation initiated by surface bound tissue factor but also protects the clot against lysis once it is formed. On the basis of these results, we propose a coagulation model in which initial clot formation in the proximity of the tissue factor surface is not factor XI dependent. Clot formation becomes dependent on factor XI in the propagation phase when the clot is increasing in size. These findings support a role for factor XI in the propagation of clot growth after tissue factor-dependent initiation.

Blood Coagulation↗
PubMed1976

Combined deficiencies of Factor VIII (AHF) and Factor XI (PTA).

Combined deficiencies of Factor VIII and Factor XI associated with moderate degree of bleeding symptoms were found in 3 brothers. Examination of Factor VIII activity and Factor VIII-related antigen revealed that the Factor VIII activity/Factor VIII-related antigen ratio was significantly decreased in their mother and maternal grandmother consistent with the carrier state of hemophilia. Factor XI deficiency was found in 2 siblings, the father, and 2 of his sisters. The paternal grandmother was thought to carry the abnormal Factor X I gene, although her Factor XI level was normal, because of a significant bleeding history. It was concluded that the combined Factor VIII and XI deficiencies in the 3 brothers represent the coincidental inheritance of 2 separate and independent abnormal genes.

Adolescent↗
PubMed2006

Percutaneous coronary intervention in a patient with congenital factor XI deficiency and acquired inhibitor.

BACKGROUND: Factor XI deficiency has been associated with bleeding diathesis mostly secondary to trauma and post-operatively depending on the severity of deficiency. Cases with factor XI deficiency having undergone cardiac surgery and coronary intervention after appropriate replacement therapy have been reported in the past. The presence of inhibitor in factor XI deficiency poses a hematological challenge and literature regarding coronary intervention in such patients is limited. Immunosuppressive therapy, plasma exchange and factor VII product transfusions have been used prior to cardiac interventions in few such reported cases. METHOD: We report our approach in such a case of Percutaneous Transluminal Coronary Angioplasty in a 72-year-old male of Jewish origin who has congenital factor XI deficiency complicated with acquired inhibitor. RESULTS: In some cases, the acuity of the coronary syndrome may mandate immediate coronary intervention. However, patient's history of factor XI deficiency and acquired inhibitor pose a major dilemma of further course of action. We performed percutaneous balloon angioplasty in this case with no anti-coagulant and with favorable outcome. CONCLUSION: Under these circumstances of significant coagulation disorder and based on the case report, we recommend that balloon angioplasty be undertaken with no additional anti-coagulation other than Aspirin.

Aged↗
PubMed1991

Factor XI activation in a revised model of blood coagulation.

Coagulation factor XI is activated in vitro by factor XIIa in the presence of high molecular weight kininogen (HMWK) and a negatively charged surface. Factor XII deficiency is not associated with bleeding, which suggests that another mechanism for factor XI activation exists in vivo. A revised model of coagulation is proposed in which factor XI is activated by thrombin. In the absence of cofactors, thrombin is more effective (kcat/Km = 1.6 x 10(5)) than factor XIIa (1.7 x 10(4)) in activating factor XI. Dextran sulfate enhances activation of factor XI by thrombin 2000-fold; part of this effect is due to autoactivation of factor XI by activated factor XI.

Blood Coagulation↗
PubMed1992

Fibrinogen blocks the autoactivation and thrombin-mediated activation of factor XI on dextran sulfate.

The intrinsic pathway of blood coagulation is activated when factor XIa, one of the three contact-system enzymes, is generated and then activates factor IX. Factor XI has been shown to be efficiently activated in vitro by surface-bound factor XIIa after factor XI is transported to the surface by its cofactor, high molecular weight kininogen (HK). However, individuals lacking any of the three contact-system proteins--namely, factor XII, prekallikrein, and HK--do not suffer from bleeding abnormalities. This mystery has led several investigators to search for an "alternate" activation pathway for factor XI. Recently, factor XI has been reported to be autoactivated on the soluble "surface" dextran sulfate, and thrombin was shown to accelerate the autoactivation. However, it was also reported that HK, the cofactor for factor XIIa-mediated activation of factor XI, actually diminishes the thrombin-catalyzed activation rate of factor XI. Nonetheless, it was suggested that thrombin was a more efficient activator than factor XIIa. In this report we investigated the effect of fibrinogen, the major coagulation protein in plasma, on the activation rate of factor XI. Fibrinogen, the preferred substrate for thrombin in plasma, virtually prevented autoactivation of factor XI as well as the thrombin-mediated activation of factor XI, while having no effect on factor XIIa-catalyzed activation. HK dramatically curtailed the autoactivation of factor XI in addition to the thrombin-mediated activation. These data indicate that factor XI would not be autoactivated in a plasma environment, and thrombin would, therefore, be unlikely to potentiate the activation. We believe that the "missing pathway" for factor XI activation remains an enigma that warrants further investigation.

Dextran Sulfate↗
PubMed1989

Functional domains in the heavy-chain region of factor XI: a high molecular weight kininogen-binding site and a substrate-binding site for factor IX.

To probe the molecular interactions of factor XI we have prepared two monoclonal antibodies (MoAbs; 5F7 and 3C1), each of which binds the heavy chain of reduced and alkylated factor XIa. Competitive solid phase radioimmunoassay (RIA) binding studies revealed that 5F7 and 3C1 are directed against different epitopes within factor XI. One antibody (5F7) blocked the surface-mediated proteolytic activation of factor XI and its binding to HMW kininogen, but had no effect on factor-XIa-catalyzed factor IX activation. The other antibody (3C1) is a competitive inhibitor of factor-IX activation by factor XIa, but blocked factor-XI binding to HMW kininogen only at 1,000-fold higher concentration than 5F7. Moreover, HMW kininogen had no effect on the kinetics of factor-XIa-catalyzed factor-IX activation. Furthermore, factor XI CNBr peptide fragments that bind to the 5F7 and 3C1 antibodies were isolated. The peptides that bound to the 5F7 antibody blocked the binding of HMW kininogen to factor XI but did not inhibit factor-XIa-catalyzed factor-IX activation. However, the peptides isolated by the 3C1 antibody inhibited factor-XIa-catalyzed factor-IX activation and had no effect on factor-XI binding to HMW kininogen. Our results indicate that distinct functional domains within the heavy chain region of factor XI are important for the binding of factor XI to HMW kininogen and for activation of factor IX by factor XIa.

Antibodies, Monoclonal↗
PubMed1983

Isolation and functional characterization of the active light chain of activated human blood coagulation factor XI.

Human blood coagulation Factor XIa was reduced and alkylated under mild conditions. The mixture containing alkylated heavy and light chains was subjected to affinity chromatography on high Mr kininogen-Sepharose. Alkylation experiments using [14C]iodoacetamide showed that a single disulfide bridge between the light and heavy chains was broken to release the light chain. The alkylated light chain (Mr = 35,000) did not bind to high Mr kininogen-Sepharose while the heavy chain (Mr = 48,000), like Factors XI and XIa, bound with high affinity. The isolated light chain retained the specific amidolytic activity of native Factor XIa against the oligopeptide substrate, pyroGlu-Pro-Arg-p-nitroanilide. Km and kcat values for this substrate were 0.56 mM and 350 s-1 for both Factor XIa and its light chain, and the amidolytic assay was not affected by CaCl2. However, in clotting assays using Factor XI-deficient plasma in the presence of kaolin, the light chain was only 1% as active as native Factor XIa. Human coagulation Factor IX was purified and labeled with sodium [3H]borohydride on its carbohydrate moieties. When this radiolabeled Factor IX was mixed with Factor XIa, an excellent correlation was observed between the appearance of Factor IXa clotting activity and tritiated activation peptide that was soluble in cold trichloroacetic acid. Factor XIa in the presence of 5 mM CaCl2 activated 3H-Factor IX 600 times faster than Factor XIa in the presence of EDTA. In the absence of calcium, Factor XIa and its light chain were equally active in activating 3H-Factor IX. In contrast to Factor XIa, the light chain in this reaction was inhibited by calcium ions such that, in the presence of 5 mM CaCl2, Factor XIa was 2000 times more effective than its light chain. Neither phospholipid nor high Mr kininogen and kaolin affected the activity of Factor XIa or its light chain in the activation of 3H-Factor IX. These observations show that the light chain region of Factor XIa contains the entire enzymatic active site. The heavy chain region contains the high affinity binding site for high Mr kininogen. Furthermore the heavy chain region of Factor XIa plays a major role in the calcium-dependent mechanisms that contribute to the activation of Factor IX.

Acetamides↗
PubMed1982

Factor XI antigen and activity in human platelets.

Washed platelets, contaminated with less than 0.20% plasma factor XI, were examined for the presence of factor XI antigen and activity. These platelets contained a factor-XI-like coagulant activity (0.67 +/- 0.11 U/10(11) platelets) that remained constant after successive washes. By means of indirect immunofluorescence, a monospecific antibody to factor XI showed specific staining of both normal platelets and platelets from patients deficient in plasma factor XI. Radiolabeled Triton extracts of washed platelets and labeled purified factor XI solutions were analyzed for factor XI antigen by Staph A immunoprecipitation analysis using antibody to purified plasma factor XI followed by SDS gel electrophoresis. On unreduced gels, the platelet material ran as a single band having an apparent molecular weight of 220,000 daltons, whereas purified plasma factor XI gave a single band at 160,000 daltons. On reduced gels, the platelet material analyzed as a single band at 52,000 daltons, whereas purified factor XI gave a single band of 80,000 daltons. Analysis of a partially purified factor XI preparation from platelets by immunoelectrophoresis revealed that the platelet preparation displayed a slightly lower cathodal electrophoretic mobility at pH 8.6 than did plasma factor XI and yet appeared to possess complete antigenic identity with plasma factor XI. These results indicate that platelets possess a form of factor XI that exists as a disulfide-linked 52,000-dalton tetramer in contrast to the plasma form that circulates as a 80,000-dalton disulfide-linked dimer.

Antigens↗
PubMed1975

Pulmonary embolism with factor XI deficiency.

A patient with factor XI deficiency had pulmonary embolism, although his factor XI assay was less than 1% of normal and his postoperative course was complicated by prolonged bleeding. Programs designed to prevent postoperative venous thrombosis should be carried out in factor XI-deficient patients, since the deficient state offers no protection from a pulmonary embolus. All surgical patients who are to receive low-dose heparin therapy as a part of such a program should be screened by means of preoperative determination of the partial thromboplastin time, to identify previously unsuspected bleeding disorders.

Aged↗
PubMed1991

Factor XI deficiency acquired by liver transplantation.

Factor XI deficiency (the Rosenthal syndrome), an autosomal recessive genetic defect, was transmitted to a patient after orthotopic liver transplantation. The deficiency was manifested by an isolated prolonged activated partial thromboplastin time (aPTT) after surgery. Hematologic evaluation using specific factor analysis revealed an absolute deficiency of factor XI. Stored serum obtained from the organ recipient before transplantation showed normal factor XI levels. When the liver donor's family was questioned, it was discovered that he was of Ashkenazi Jewish descent and that he had a history of bleeding after dental procedures. Before his death from intracerebral bleeding, he was documented to have an isolated prolonged aPTT value. This case shows that potentially morbid genetic defects can be transmitted by organ transplantation. It also provides evidence confirming that the liver is the only site of factor XI production.

Factor XI Deficiency↗
PubMed1992

Apple four in human blood coagulation factor XI mediates dimer formation.

Human blood coagulation factor XI is a dimer composed of two identical subunits. Each subunit contains four apple domains as tandem repeats followed by a serine protease region. A disulfide bridge between Cys321 of each fourth apple domain links the subunits together. The role of Cys321 in the dimerization of factor XI was examined by mutagenesis followed by expression of its cDNA in baby hamster kidney cells. The recombinant proteins were then purified from the tissue culture medium and shown to have full biological activity. Normal recombinant factor XI was secreted as a dimer as determined by SDS-PAGE, while recombinant factor XI-Cys321 Ser migrated as a monomer under these conditions. Gel filtration studies, however, revealed that each protein existed as a dimer under native conditions, indicating that the disulfide bond between Cys321 of each factor XI monomer was not necessary for dimer formation. The fourth apple domain (apple4) of factor XI was then introduced into tissue plasminogen activator (tPA) to investigate its role in the dimerization of other polypeptide chains. The fusion protein, containing apple4 (apple4-tPA), formed dimers as detected by SDS-PAGE and gel filtration. Furthermore, dimerization was specific to apple4, while apple3 had no effect on dimerization. These data further indicated that the apple4 domain of factor XI mediates dimerization of the two subunits and the interchain disulfide bond involving Cys321 was not essential for dimer formation.

Amino Acid Sequence↗
PubMed2004

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

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.

Alu Elements↗