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Excess of heme induces tissue factor-dependent activation of coagulation in mice.
Sparkenbaugh EM, Chantrathammachart P, Wang S, Jonas W, Kirchhofer D, Gailani D, Gruber A, Kasthuri R, Key NS, Mackman N, Pawlinski R
(2015) Haematologica 100: 308-14
MeSH Terms: Anemia, Hemolytic, Anemia, Sickle Cell, Animals, Antibodies, Blood Coagulation, Capillary Permeability, Cells, Cultured, Factor XI, Factor XIIa, Female, Gene Deletion, Gene Expression, Heme, Hemopexin, Humans, Injections, Intravenous, Leukocytes, Mononuclear, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, RNA, Small Interfering, Swine, Thromboplastin
Show Abstract · Added January 20, 2015
An excess of free heme is present in the blood during many types of hemolytic anemia. This has been linked to organ damage caused by heme-mediated oxidative stress and vascular inflammation. We investigated the mechanism of heme-induced coagulation activation in vivo. Heme caused coagulation activation in wild-type mice that was attenuated by an anti-tissue factor antibody and in mice expressing low levels of tissue factor. In contrast, neither factor XI deletion nor inhibition of factor XIIa-mediated factor XI activation reduced heme-induced coagulation activation, suggesting that the intrinsic coagulation pathway is not involved. We investigated the source of tissue factor in heme-induced coagulation activation. Heme increased the procoagulant activity of mouse macrophages and human PBMCs. Tissue factor-positive staining was observed on leukocytes isolated from the blood of heme-treated mice but not on endothelial cells in the lungs. Furthermore, heme increased vascular permeability in the mouse lungs, kidney and heart. Deletion of tissue factor from either myeloid cells, hematopoietic or endothelial cells, or inhibition of tissue factor expressed by non-hematopoietic cells did not reduce heme-induced coagulation activation. However, heme-induced activation of coagulation was abolished when both non-hematopoietic and hematopoietic cell tissue factor was inhibited. Finally, we demonstrated that coagulation activation was partially attenuated in sickle cell mice treated with recombinant hemopexin to neutralize free heme. Our results indicate that heme promotes tissue factor-dependent coagulation activation and induces tissue factor expression on leukocytes in vivo. We also demonstrated that free heme may contribute to thrombin generation in a mouse model of sickle cell disease.
Copyright© Ferrata Storti Foundation.
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25 MeSH Terms
Activated factor XI increases the procoagulant activity of the extrinsic pathway by inactivating tissue factor pathway inhibitor.
Puy C, Tucker EI, Matafonov A, Cheng Q, Zientek KD, Gailani D, Gruber A, McCarty OJ
(2015) Blood 125: 1488-96
MeSH Terms: Blood Coagulation, Blood Platelets, Blotting, Western, Cells, Cultured, Factor IX, Factor XIa, Factor Xa, Fibrin, Flow Cytometry, Human Umbilical Vein Endothelial Cells, Humans, Lipoproteins, Mutation, Recombinant Proteins
Show Abstract · Added January 20, 2015
Activation of coagulation factor XI (FXI) may play a role in hemostasis. The primary substrate of activated FXI (FXIa) is FIX, leading to FX activation (FXa) and thrombin generation. However, recent studies suggest the hemostatic role of FXI may not be restricted to the activation of FIX. We explored whether FXI could interact with and inhibit the activity of tissue factor pathway inhibitor (TFPI). TFPI is an essential reversible inhibitor of activated factor X (FXa) and also inhibits the FVIIa-TF complex. We found that FXIa neutralized both endothelium- and platelet-derived TFPI by cleaving the protein between the Kunitz (K) 1 and K2 domains (Lys86/Thr87) and at the active sites of the K2 (Arg107/Gly108) and K3 (Arg199/Ala200) domains. Addition of FXIa to plasma was able to reverse the ability of TFPI to prolong TF-initiated clotting times in FXI- or FIX-deficient plasma, as well as FXa-initiated clotting times in FX-deficient plasma. Treatment of cultured endothelial cells with FXIa increased the generation of FXa and promoted TF-dependent fibrin formation in recalcified plasma. Together, these results suggest that the hemostatic role of FXIa may be attributed not only to activation of FIX but also to promoting the extrinsic pathway of thrombin generation through inactivation of TFPI.
© 2015 by The American Society of Hematology.
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14 MeSH Terms
Factor XI antisense oligonucleotide for prevention of venous thrombosis.
Büller HR, Bethune C, Bhanot S, Gailani D, Monia BP, Raskob GE, Segers A, Verhamme P, Weitz JI, FXI-ASO TKA Investigators
(2015) N Engl J Med 372: 232-40
MeSH Terms: Adult, Aged, Anticoagulants, Arthroplasty, Replacement, Knee, Blood Coagulation, Clinical Protocols, Enoxaparin, Factor XI, Female, Hemorrhage, Humans, Length of Stay, Male, Middle Aged, Oligonucleotides, Oligonucleotides, Antisense, Partial Thromboplastin Time, Postoperative Complications, Venous Thrombosis
Show Abstract · Added January 20, 2015
BACKGROUND - Experimental data indicate that reducing factor XI levels attenuates thrombosis without causing bleeding, but the role of factor XI in the prevention of postoperative venous thrombosis in humans is unknown. FXI-ASO (ISIS 416858) is a second-generation antisense oligonucleotide that specifically reduces factor XI levels. We compared the efficacy and safety of FXI-ASO with those of enoxaparin in patients undergoing total knee arthroplasty.
METHODS - In this open-label, parallel-group study, we randomly assigned 300 patients who were undergoing elective primary unilateral total knee arthroplasty to receive one of two doses of FXI-ASO (200 mg or 300 mg) or 40 mg of enoxaparin once daily. The primary efficacy outcome was the incidence of venous thromboembolism (assessed by mandatory bilateral venography or report of symptomatic events). The principal safety outcome was major or clinically relevant nonmajor bleeding.
RESULTS - Around the time of surgery, the mean (±SE) factor XI levels were 0.38±0.01 units per milliliter in the 200-mg FXI-ASO group, 0.20±0.01 units per milliliter in the 300-mg FXI-ASO group, and 0.93±0.02 units per milliliter in the enoxaparin group. The primary efficacy outcome occurred in 36 of 134 patients (27%) who received the 200-mg dose of FXI-ASO and in 3 of 71 patients (4%) who received the 300-mg dose of FXI-ASO, as compared with 21 of 69 patients (30%) who received enoxaparin. The 200-mg regimen was noninferior, and the 300-mg regimen was superior, to enoxaparin (P<0.001). Bleeding occurred in 3%, 3%, and 8% of the patients in the three study groups, respectively.
CONCLUSIONS - This study showed that factor XI contributes to postoperative venous thromboembolism; reducing factor XI levels in patients undergoing elective primary unilateral total knee arthroplasty was an effective method for its prevention and appeared to be safe with respect to the risk of bleeding. (Funded by Isis Pharmaceuticals; FXI-ASO TKA ClinicalTrials.gov number, NCT01713361.).
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19 MeSH Terms
Transglutaminase factor XIII promotes arthritis through mechanisms linked to inflammation and bone erosion.
Raghu H, Cruz C, Rewerts CL, Frederick MD, Thornton S, Mullins ES, Schoenecker JG, Degen JL, Flick MJ
(2015) Blood 125: 427-37
MeSH Terms: Animals, Arthritis, Experimental, Blotting, Western, Bone Diseases, Cell Differentiation, Cells, Cultured, Collagen, Factor XIII, Female, Inflammation, Male, Mice, Mice, Inbred DBA, Mice, Knockout, Osteoclasts, RANK Ligand, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added February 22, 2016
Rheumatoid arthritis is a chronic inflammatory disease characterized by synovial hyperplasia, inflammatory cell infiltration, irreversible cartilage and bone destruction, and exuberant coagulation system activity within joint tissue. Here, we demonstrate that the coagulation transglutaminase, factor XIII (fXIII), drives arthritis pathogenesis by promoting local inflammatory and tissue degradative and remodeling events. All pathological features of collagen-induced arthritis (CIA) were significantly reduced in fXIII-deficient mice. However, the most striking difference in outcome was the preservation of cartilage and bone in fXIIIA(-/-) mice concurrent with reduced osteoclast numbers and activity. The local expression of osteoclast effectors receptor activator of nuclear factor-κB ligand (RANKL) and tartrate resistant acid phosphatase were significantly diminished in CIA-challenged and even unchallenged fXIIIA(-/-) mice relative to wild-type animals, but were similar in wild-type and fibrinogen-deficient mice. Impaired osteoclast formation in fXIIIA(-/-) mice was not due to an inherent deficiency of monocyte precursors, but it was linked to reduced RANKL-driven osteoclast formation. Furthermore, treatment of mice with the pan-transglutaminase inhibitor cystamine resulted in significantly diminished CIA pathology and local markers of osteoclastogenesis. Thus, eliminating fXIIIA limits inflammatory arthritis and protects from cartilage and bone destruction in part through mechanisms linked to reduced RANKL-mediated osteoclastogenesis. In summary, therapeutic strategies targeting fXIII activity may prove beneficial in limiting arthropathies and other degenerative bone diseases.
© 2015 by The American Society of Hematology.
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19 MeSH Terms
Development of anti-factor XIII antibodies in a patient with hereditary factor XIII deficiency receiving therapy for chronic hepatitis C.
Sosa R, Gailani D, Neff AT
(2014) Haemophilia 20: e429-32
MeSH Terms: Adult, Antibodies, Antiviral Agents, Blood Coagulation Factor Inhibitors, Factor XIII, Factor XIII Deficiency, Female, Hepatitis C, Chronic, Humans, Immunosuppressive Agents, Treatment Outcome
Added January 20, 2015
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11 MeSH Terms
Factor XI as a target for antithrombotic therapy.
Bane CE, Gailani D
(2014) Drug Discov Today 19: 1454-8
MeSH Terms: Animals, Anticoagulants, Blood Coagulation, Drug Design, Factor XI, Factor XIa, Fibrinolytic Agents, Hemorrhage, Humans, Thromboembolism
Show Abstract · Added January 20, 2015
Anticoagulants currently used in clinical practice to treat thromboembolic disorders are effective but increase the risk of severe bleeding because they target proteins that are essential for normal coagulation (hemostasis). Drugs with better safety profiles are required for prevention and treatment of thromboembolic disease. Coagulation factor XIa has emerged as a novel target for safer anticoagulant therapy because of its role in thrombosis and its relatively small contribution to hemostasis.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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10 MeSH Terms
The mechanism underlying activation of factor IX by factor XIa.
Gailani D, Geng Y, Verhamme I, Sun MF, Bajaj SP, Messer A, Emsley J
(2014) Thromb Res 133 Suppl 1: S48-51
MeSH Terms: Amino Acid Sequence, Animals, Factor IX, Factor XIa, Humans, Models, Molecular, Molecular Sequence Data, Protein Conformation, Protein Multimerization
Show Abstract · Added May 19, 2014
Factor XI (fXI) is the zymogen of a plasma protease, factor XIa (fXIa), that contributes to thrombin generation during blood coagulation by proteolytic conversion of factor IX (fIX) to factor IXaβ (fIXaβ). There is considerable interest in fXIa as a therapeutic target because it contributes to thrombosis, while serving a relatively minor role in hemostasis. FXI/XIa has a distinctly different structure than other plasma coagulation proteases. Specifically, the protein lacks a phospholipid-binding Gla-domain, and is a homodimer. Each subunit of a fXIa dimer contains four apple domains (A1 to A4) and one trypsin-like catalytic domain. The A3 domain contains a binding site (exosite) that largely determines affinity and specificity for the substrate fIX. After binding to fXIa, fIX undergoes a single cleavage to form the intermediate fIXα. FIXα then rebinds to the A3 domain to undergo a second cleavage, generating fIXaβ. The catalytic efficiency for the second cleavage is ~7-fold greater than that of the first cleavage, limiting fIXα accumulation. Residues at the N-terminus and C-terminus of the fXIa A3 domain likely form the fIX binding site. The dimeric conformation of fXIa is not required for normal fIX activation in solution. However, monomeric forms of fXI do not reconstitute fXI-deficient mice in arterial thrombosis models, indicating the dimer is required for normal function in vivo. FXI must be a dimer to be activated normal by the protease fXIIa. It is also possible that the dimeric structure is an adaptation that allows fXI/XIa to bind to a surface through one subunit, while binding to its substrate fIX through the other.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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9 MeSH Terms
Factor XII inhibition reduces thrombus formation in a primate thrombosis model.
Matafonov A, Leung PY, Gailani AE, Grach SL, Puy C, Cheng Q, Sun MF, McCarty OJ, Tucker EI, Kataoka H, Renné T, Morrissey JH, Gruber A, Gailani D
(2014) Blood 123: 1739-46
MeSH Terms: Animals, Antibodies, Monoclonal, Blood Coagulation, Disease Models, Animal, Factor XI, Factor XII, Factor XII Deficiency, Factor XIIa, Fibrin, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Papio, Recombinant Proteins, Thrombin, Thromboplastin, Thrombosis
Show Abstract · Added May 19, 2014
The plasma zymogens factor XII (fXII) and factor XI (fXI) contribute to thrombosis in a variety of mouse models. These proteins serve a limited role in hemostasis, suggesting that antithrombotic therapies targeting them may be associated with low bleeding risks. Although there is substantial epidemiologic evidence supporting a role for fXI in human thrombosis, the situation is not as clear for fXII. We generated monoclonal antibodies (9A2 and 15H8) against the human fXII heavy chain that interfere with fXII conversion to the protease factor XIIa (fXIIa). The anti-fXII antibodies were tested in models in which anti-fXI antibodies are known to have antithrombotic effects. Both anti-fXII antibodies reduced fibrin formation in human blood perfused through collagen-coated tubes. fXII-deficient mice are resistant to ferric chloride-induced arterial thrombosis, and this resistance can be reversed by infusion of human fXII. 9A2 partially blocks, and 15H8 completely blocks, the prothrombotic effect of fXII in this model. 15H8 prolonged the activated partial thromboplastin time of baboon and human plasmas. 15H8 reduced fibrin formation in collagen-coated vascular grafts inserted into arteriovenous shunts in baboons, and reduced fibrin and platelet accumulation downstream of the graft. These findings support a role for fXII in thrombus formation in primates.
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20 MeSH Terms
Evidence for factor IX-independent roles for factor XIa in blood coagulation.
Matafonov A, Cheng Q, Geng Y, Verhamme IM, Umunakwe O, Tucker EI, Sun MF, Serebrov V, Gruber A, Gailani D
(2013) J Thromb Haemost 11: 2118-27
MeSH Terms: Animals, Blood Coagulation, Electrophoresis, Polyacrylamide Gel, Factor IX, Factor XIa, Humans, Mice, Mice, Inbred C57BL, Proteolysis
Show Abstract · Added May 19, 2014
BACKGROUND - Factor XIa is traditionally assigned a role in FIX activation during coagulation. However, recent evidence suggests this protease may have additional plasma substrates.
OBJECTIVE - To determine whether FXIa promotes thrombin generation and coagulation in plasma in the absence of FIX, and to determine whether FXI-deficiency produces an antithrombotic effect in mice independently of FIX.
METHODS - FXIa, FXIa variants and anti-FXIa antibodies were tested for their effects on plasma coagulation and thrombin generation in the absence of FIX, and for their effects on the activation of purified coagulation factors. Mice with combined FIX and FXI deficiency were compared with mice lacking either FIX or FXI in an arterial thrombosis model.
RESULTS - In FIX-deficient plasma, FXIa induced thrombin generation, and anti-FXIa antibodies prolonged clotting times. This process involved FXIa-mediated conversion of FX and FV to their active forms. Activation of FV by FXIa required the A3 domain on the FXIa heavy chain, whereas activation of FX did not. FX activation by FXIa, unlike FIX activation, was not a calcium-dependent process. Mice lacking both FIX and FXI were more resistant to ferric chloride-induced carotid artery occlusion than FXI-deficient or FIX-deficient mice.
CONCLUSION - In addition to its predominant role as an activator of FIX, FXIa may contribute to coagulation by activating FX and FV. As the latter reactions do not require calcium, they may make important contributions to in vitro clotting triggered by contact activation. The reactions may be relevant to FXIa's roles in hemostasis and in promoting thrombosis.
© 2013 International Society on Thrombosis and Haemostasis.
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9 MeSH Terms
Factor XI anion-binding sites are required for productive interactions with polyphosphate.
Geng Y, Verhamme IM, Smith SA, Cheng Q, Sun M, Sheehan JP, Morrissey JH, Gailani D
(2013) J Thromb Haemost 11: 2020-8
MeSH Terms: Animals, Anions, Antithrombins, Binding Sites, Blood Coagulation, Cattle, Factor IX, Factor XI, Factor XIa, Heparin, Humans, Mice, Mice, Inbred C57BL, Polymers, Polyphosphates, Recombinant Proteins, Thrombin, Thrombosis
Show Abstract · Added May 19, 2014
BACKGROUND - Conversion of factor XI (FXI) to FXIa is enhanced by polymers of inorganic phosphate (polyP). This process requires FXI to bind to polyP. Each FXIa subunit contains anion-binding sites (ABSs) on the apple 3 (A3) and catalytic domains that are required for normal heparin-mediated enhancement of FXIa inhibition by antithrombin.
AIMS - To determine the importance of FXI ABSs to polyP enhancement of FXI activation.
METHODS - Recombinant FXI variants lacking one or both ABSs were tested in polyP-dependent purified protein systems, plasma clotting assays, and a murine thrombosis model.
RESULTS - In the presence of polyP, activation rates for FXI lacking either ABS were reduced compared with wild-type FXI, and FXI lacking both sites had an even greater defect. In contrast to heparin, polyP binding to FXIa did not enhance inhibition by antithrombin and did not interfere with FXIa activation of FIX. FXI lacking one or both ABSs does not reconstitute FXI-deficient plasma as well as wild-type FXI when polyP was used to initiate coagulation. In FXI-deficient mice, FXI lacking one or more ABSs was inferior to wild-type FXI in supporting arterial thrombus formation.
CONCLUSIONS - The ABSs on FXIa that are required for expression of heparin's cofactor activity during protease inhibition by antithrombin are also required for expression of polyP cofactor activity during FXI activation. These sites may contribute to FXI-dependent thrombotic processes.
© 2013 International Society on Thrombosis and Haemostasis.
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18 MeSH Terms