scholarly journals Pharmacokinetics and Pharmacodynamics of Abelacimab (MAA868), a Novel Dual Inhibitor of Factor XI and Factor XIa

2021 ◽  
Author(s):  
B. Alexander Yi ◽  
Debra Freedholm ◽  
Nancy Widener ◽  
Xiaohui Wang ◽  
Emilie Simard ◽  
...  
Keyword(s):  
Pharmacokinetics And Pharmacodynamics ◽  
Factor Xi ◽  
Dual Inhibitor ◽  
Factor Xia

Acquired Factor XI Inhibitors in Two Patients with Hereditary Factor XI Deficiency

1984 ◽  
Vol 51 (03) ◽  
pp. 371-375 ◽  
Author(s):  
Kangathevy Morgan ◽  
Sandra Schiffman ◽  
Donald Feinstein
Keyword(s):  
Protein A ◽  
Lambda Light Chain ◽  
Factor Xi ◽  
Spontaneous Bleeding ◽  
Factor Xi Deficiency ◽  
Hereditary Factor ◽  
Coagulation Mechanism ◽  
Factor Xia ◽  
Polyclonal Igg ◽  
Glass Surfaces

SummaryTwo patients with hereditary factor XI deficiency developed inhibitors following plasma transfusions. Neither had severe spontaneous bleeding. The patients’ plasmas neutralized both factor XI in plasma, purified factor XI, and purified factor XIa. The inhibitor in both patients’ plasmas adsorbed to Protein A- Sepharose. The inhibitors eluted from Protein A-Sepharose were partially neutralized by kappa and lambda light chain antisera indicating that they were polyclonal IgG antibodies. Both inhibitors markedly decreased adsorption of factor XI to glass surfaces. The cleavage of factor XI by trypsin was unaffected by the inhibitors. The lack of severe spontaneous bleeding in both of these patients strongly suggests that an alternate coagulation mechanism bypassing factor XI must compensate for this severe defect.

Chemical Footprinting Reveals Conformational Changes Following Activation of Factor XI

2018 ◽  
Vol 118 (02) ◽  
pp. 340-350 ◽  
Author(s):  
Ingrid Stroo ◽  
J. Marquart ◽  
Kamran Bakhtiari ◽  
Tom Plug ◽  
Alexander Meijer ◽  
...  
Keyword(s):  
Conformational Change ◽  
Conformational Changes ◽  
Catalytic Domain ◽  
Active Form ◽  
Coagulation Factor ◽  
Lysine Residue ◽  
Factor Ix ◽  
Factor Xi ◽  
Lysine Residues ◽  
Factor Xia

AbstractCoagulation factor XI is activated by thrombin or factor XIIa resulting in a conformational change that converts the catalytic domain into its active form and exposing exosites for factor IX on the apple domains. Although crystal structures of the zymogen factor XI and the catalytic domain of the protease are available, the structure of the apple domains and hence the interactions with the catalytic domain in factor XIa are unknown. We now used chemical footprinting to identify lysine residue containing regions that undergo a conformational change following activation of factor XI. To this end, we employed tandem mass tag in conjunction with mass spectrometry. Fifty-two unique peptides were identified, covering 37 of the 41 lysine residues present in factor XI. Two identified lysine residues that showed altered flexibility upon activation were mutated to study their contribution in factor XI stability or enzymatic activity. Lys357, part of the connecting loop between A4 and the catalytic domain, was more reactive in factor XIa but mutation of this lysine residue did not impact on factor XIa activity. Lys516 and its possible interactor Glu380 are located in the catalytic domain and are covered by the activation loop of factor XIa. Mutating Glu380 enhanced Arg369 cleavage and thrombin generation in plasma. In conclusion, we have identified novel regions that undergo a conformational change following activation. This information improves knowledge about factor XI and will contribute to development of novel inhibitors or activators for this coagulation protein.

scholarly journals Activation of Hageman Factor by Factor XIA-HMW Kininogen

1977 ◽  
Author(s):  
Henry L. Meier ◽  
Russell E. Thompson ◽  
Allen P. Kaplan
Keyword(s):  
Incubation Mixture ◽  
Factor Activity ◽  
Factor Xi ◽  
Feedback Mechanisms ◽  
Hageman Factor ◽  
Factor Xia ◽  
Time Periods ◽  
Kinetics Of ◽  
Additional Feedback ◽  
Coagulation And Fibrinolysis

Plasma deficient in prekallikrein possesses an abnormality in the kinetics of surface dependent initiation of coagulation and fibrinolysis. This defect appears to be secondary to a diminished rate of Hageman factor activation, however the abnormality is progressively diminished as the time of incubation of the plasma with appropriate surfaces is increased. Since factor XI and prekallikrein circulate bound to HMW kininogen and HMW kininogen is known to augment the activation of factor XI and prekallikrein by activated Hageman factor, the ability of factor XIA to activate Hageman factor was examined. One ug Hageman factor was bound to supercel alone, or in the presence of 1.5 ug HMW kininogen and 0.1 to 1.0 ug factor XIA for varying time periods (0–60 min). The pellet was washed X 3 and bound activated Hageman factor was assayed by its ability to convert prekallikrein to kallikrein. The kallikrein generated was quantified by release of p-nitroaniline from α-benzoyl phe-val-arg-p-nitroanilide. Factor XIA alone was a weak activator of Hageman factor and the quantity of kallikrein generated was augmented when HMW kininogen was included in the incubation mixture. With limited HMW kininogen the Hageman factor activity appeared proportional to the factor XIA added. The same result was obtained with factor XIA isolated from prekallikrein deficient plasma. The data suggest that factor XIA plus HMW kininogen may represent one of the additional feedback mechanisms by which Hageman factor may be activated and thereby contribute to the gradual activation observed in prekallikrein deficient plasma.

Pharmacokinetics and pharmacodynamics of BIBT 986, a novel small molecule dual inhibitor of thrombin and factor Xa

2006 ◽  
Vol 4 (7) ◽  
pp. 1502-1509 ◽  
Author(s):  
E. U. GRAEFE-MODY ◽  
U. SCHUHLY ◽  
K. RATHGEN ◽  
H. STAHLE ◽  
J. M. LEITNER ◽  
...  
Keyword(s):  
Small Molecule ◽  
Factor Xa ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Dual Inhibitor

scholarly journals Polyphosphate is a cofactor for the activation of factor XI by thrombin

Blood ◽  
2011 ◽  
Vol 118 (26) ◽  
pp. 6963-6970 ◽  
Author(s):  
Sharon H. Choi ◽  
Stephanie A. Smith ◽  
James H. Morrissey
Keyword(s):  
Human Platelets ◽  
Factor Xii ◽  
Factor Xi ◽  
Anionic Polymer ◽  
Factor Xi Deficiency ◽  
Anionic Polymers ◽  
Factor Xia ◽  
Normal Hemostasis

Abstract Factor XI deficiency is associated with a bleeding diathesis, but factor XII deficiency is not, indicating that, in normal hemostasis, factor XI must be activated in vivo by a protease other than factor XIIa. Several groups have identified thrombin as the most likely activator of factor XI, although this reaction is slow in solution. Although certain nonphysiologic anionic polymers and surfaces have been shown to enhance factor XI activation by thrombin, the physiologic cofactor for this reaction is uncertain. Activated platelets secrete the highly anionic polymer polyphosphate, and our previous studies have shown that polyphosphate has potent procoagulant activity. We now report that polyphosphate potently accelerates factor XI activation by α-thrombin, β-thrombin, and factor XIa and that these reactions are supported by polyphosphate polymers of the size secreted by activated human platelets. We therefore propose that polyphosphate is a natural cofactor for factor XI activation in plasma that may help explain the role of factor XI in hemostasis and thrombosis.

scholarly journals Identification of a Binding Site for Glycoprotein Ibα in the Apple 3 Domain of Factor XI

2004 ◽  
Vol 279 (44) ◽  
pp. 45470-45476 ◽  
Author(s):  
Frank A. Baglia ◽  
David Gailani ◽  
José A. López ◽  
Peter N. Walsh
Keyword(s):  
Amino Acids ◽  
Binding Site ◽  
Thrombus Formation ◽  
Platelet Glycoprotein ◽  
Heparin Binding ◽  
Factor Xi ◽  
Platelet Binding ◽  
Factor Xia ◽  
Consolidation Phase ◽  
Platelet Thrombus

Factor XI (FXI) is a homodimeric plasma zymogen that is cleaved at two internal Arg369–Ile370bonds by thrombin, factor XIIa, or factor XIa. FXI circulates as a complex with the glycoprotein high molecular weight kininogen (HK). FXI binds to specific sites (Kd= ∼10 nm,Bmax= ∼1,500/platelet) on the surface of stimulated platelets, where it is efficiently activated by thrombin. The FXI Apple 3 (A3) domain mediates binding to platelets in the presence of HK and zinc ions (Zn2+) or prothrombin and calcium ions. The platelet glycoprotein (GP) Ib-IX-V complex is the receptor for FXI (Baglia, F. A., Badellino, K. O., Li, C. Q., Lopez, J. A., and Walsh, P. N. (2002)J. Biol. Chem.277, 1662–1668). Using surface plasmon resonance, we determined that FXI binds specifically to glycocalicin, the extracellular domain of GPIbα, in a Zn2+-dependent fashion (Kd= ∼52 nm). We now show that recombinant FXI A3 domain inhibits FXI inbinding to glycocalicin in the presence of Zn2+, whereas the recombinant FXI A1, A2, or A4 domains have no effect. Experiments with full-length recombinant FXI mutants show that, in the presence of Zn2+, glycocalicin binds FXI at a heparin-binding site in A3 (Lys252and Lys253) and not by amino acids previously shown to be required for platelet binding (Ser248, Arg250, Lys255, Phe260, and Gln263). However, binding in the presence of HK and Zn2+requires Ser248, Arg250, Lys255, Phe260, and GLn263and not Lys252and Lys253. Thus, binding of FXI to GPIbα is mediated by amino acids in the A3 domain in the presence or absence of HK. This interaction is important for the initiation of the consolidation phase of blood coagulation and the generation of thrombin at sites of platelet thrombus formation.

Factor XIa–specific IgG and a reversal agent to probe factor XI function in thrombosis and hemostasis

2016 ◽  
Vol 8 (353) ◽  
pp. 353ra112-353ra112 ◽  
Author(s):  
Tovo David ◽  
Yun Cheol Kim ◽  
Lauren K. Ely ◽  
Isaac Rondon ◽  
Huilan Gao ◽  
...  
Keyword(s):  
Factor Xi ◽  
Reversal Agent ◽  
Factor Xia ◽  
Specific Igg

scholarly journals Functional characterization of platelet-bound factor XIa: retention of factor XIa activity on the platelet surface

Blood ◽  
1986 ◽  
Vol 68 (1) ◽  
pp. 225-230 ◽  
Author(s):  
PN Walsh ◽  
D Sinha ◽  
A Koshy ◽  
FS Seaman ◽  
H Bradford
Keyword(s):  
Structural Integrity ◽  
Functional Characterization ◽  
Factor Ix ◽  
Scatchard Analysis ◽  
Factor Xi ◽  
Platelet Surface ◽  
Proteolytic Activation ◽  
Binding Data ◽  
Factor Xia ◽  
Activation Peptide

Previously we have shown that both factor XI and factor XIa are bound specifically to distinct, high-affinity sites on the surface of activated platelets in the presence of high Mr kininogen. To determine the functional significance of factor XIa binding to platelets, bound factor XIa has now been compared with the unbound enzyme. Platelets incubated with thrombin, high Mr kininogen, and 125I-labeled factor XIa bound 130 to 500 molecules of factor XIa per platelet. Scatchard analysis of binding data give a dissociation constant (Kd) of 822 pmol/L +/- 140 (SEM). Rates of factor IX activation, assayed by release of trichloroacetic acid-soluble 3H-labeled activation peptide from purified [3H]-factor IX, were similar when factor XIa was bound to platelets and when it was free in solution. The platelet-bound factor XIa was isolated by centrifugation through 20% sucrose and was functionally characterized both in a factor XIa coagulation assay and in the factor IX activation peptide release assay in comparison with unbound factor XIa in the presence of treated platelets. The functional activity of platelet-bound factor XIa as a factor IX activator as well as its structural integrity were shown to be fully retained on the platelet surface. Since platelets bind factor XI and promote its proteolytic activation to factor XIa, factor XIa binding to platelets may serve to localize factor IX activation to the hemostatic plug, where factor XIa is protected from inactivation by plasma protease inhibitors and where acceleration of subsequent coagulation reactions can occur.

Surface Independent Factor XI Activation by Thrombin in the Presence of High Molecular Weight Kininogen

1994 ◽  
Vol 72 (03) ◽  
pp. 397-402 ◽  
Author(s):  
Peter A Kr von dem Borne ◽  
Stefan J Koppelman ◽  
Bonno N Bouma ◽  
Joost C M Meijers
Keyword(s):  
Molecular Weight ◽  
Blood Coagulation ◽  
High Molecular Weight ◽  
Dextran Sulfate ◽  
Factor Xa ◽  
Factor X ◽  
High Molecular Weight Kininogen ◽  
Factor Xi ◽  
Factor Xia

SummaryA deficiency of one of the proteins of the contact system of blood coagulation does not result in a bleeding disorder. For this reason activation of blood coagulation via this system is believed to be an in vitro artefact. However, patients deficient in factor XI do suffer from variable bleeding abnormalities. Recently, an alternative pathway for factor XI activation has been described. Factor XI was found to be activated by thrombin in the presence of dextran sulfate as a surface. However, high molecular weight kininogen (HK), to which factor XI is bound in plasma, and fibrinogen were shown to block this activation suggesting it to be an in vitro phenomenon. We investigated the thrombin-mediated factor XI activation using an amplified detection system consisting of factors IX, VIII and X, which was shown to be very sensitive for factor XIa activity. This assay is approximately 4 to 5 orders of magnitude more sensitive than the normal factor XIa activity assay using a chromogenic substrate. With this assay we found that factor XI activation by thrombin could take place in the absence of dextran sulfate. The initial activation rate was approximately 0.3 pM/min (using 25 nM factor XI and 10 nM thrombin). The presence of dextran sulfate enhanced this rate about 8500-fold. A very rapid and complete factor X activation was observed in the presence of dextran sulfate. Although only minute amounts of factor XIa were formed in the absence of dextran sulfate, significant activation of factor X was detected in the amplification assay within a few minutes. HK inhibited the activation of factor XI by thrombin strongly in the presence, yet only slightly in the absence of dextran sulfate (26 and 1.2 times, respectively). Despite the strong inhibition of HK on the activation of factor XI by thrombin in the presence of dextran sulfate, HK had only a minor effect on the factor Xa generation.We conclude that activation of factor XI by thrombin can take place regardless of the presence of a surface or HK. This activation might therefore be physiologically relevant. The inhibitory effect of HK on the thrombin-mediated factor XI activation is largely dextran sulfate dependent. Due to the amplification in the intrinsic system, trace amounts of factor XIa might generate physiological sufficient amounts of factor Xa for an adequate haemostatic response.

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