scholarly journals Hageman-factor-dependent fibrinolysis: generation of fibrinolytic activity by the interaction of human activated factor XI and plasminogen

Blood ◽  
1979 ◽  
Vol 54 (4) ◽  
pp. 850-862 ◽  
Author(s):  
RJ Jr Mandle ◽  
AP Kaplan
Keyword(s):  
Active Site ◽  
Fibrinolytic Activity ◽  
Gamma Globulin ◽  
Coagulation Factor ◽  
Globulin Fraction ◽  
Normal Human Plasma ◽  
Factor Xi ◽  
Hageman Factor ◽  
Factor Xia ◽  
Normal Human

Human coagulation factor XI has been purified, and upon activation with Hageman factor fragments, was found to convert the fibrinolytic proenzyme plasminogen to plasmin. This proactivator activity was shown to be functionally and antigenically distinct from prekallikrein. When the gamma-globulin fractions of plasma deficient in Hageman factor, prekallikrein and factor XI were isolated, factor-XI-deficient plasma possessed two-thirds of the plasminogen proactivator activity of the Hageman-factor-deficient plasma, while prekallikrein deficient plasma had only one-third of the plasminogen proactivator activity. Thus, the Hageman-factor-dependent plasminogen proactivator previously reported to be present in the gamma-globulin fraction of normal human plasma is a function of prekallikrein and factor XI, while the activity observed in prekallikrein-deficient plasma is attributable to factor XI. When compared utilizing digestion of iodinated fibrin, prekallikrein and factor XIa had similar potency per active site; they were, however, far less active than urokinase.

scholarly journals Hageman-factor-dependent fibrinolysis: generation of fibrinolytic activity by the interaction of human activated factor XI and plasminogen

Blood ◽  
1979 ◽  
Vol 54 (4) ◽  
pp. 850-862 ◽  
Author(s):  
RJ Jr Mandle ◽  
AP Kaplan
Keyword(s):  
Active Site ◽  
Fibrinolytic Activity ◽  
Gamma Globulin ◽  
Coagulation Factor ◽  
Globulin Fraction ◽  
Normal Human Plasma ◽  
Factor Xi ◽  
Hageman Factor ◽  
Factor Xia ◽  
Normal Human

Abstract Human coagulation factor XI has been purified, and upon activation with Hageman factor fragments, was found to convert the fibrinolytic proenzyme plasminogen to plasmin. This proactivator activity was shown to be functionally and antigenically distinct from prekallikrein. When the gamma-globulin fractions of plasma deficient in Hageman factor, prekallikrein and factor XI were isolated, factor-XI-deficient plasma possessed two-thirds of the plasminogen proactivator activity of the Hageman-factor-deficient plasma, while prekallikrein deficient plasma had only one-third of the plasminogen proactivator activity. Thus, the Hageman-factor-dependent plasminogen proactivator previously reported to be present in the gamma-globulin fraction of normal human plasma is a function of prekallikrein and factor XI, while the activity observed in prekallikrein-deficient plasma is attributable to factor XI. When compared utilizing digestion of iodinated fibrin, prekallikrein and factor XIa had similar potency per active site; they were, however, far less active than urokinase.

scholarly journals Inhibition of Factor XI by Myeloma Protein M.

1977 ◽  
Author(s):  
A. Rimon ◽  
I. Raz ◽  
M. Lahav
Keyword(s):  
Coagulation Factor ◽  
Coagulation Factors ◽  
Normal Human Plasma ◽  
Clotting Factors ◽  
Factor Xi ◽  
Myeloma Protein ◽  
Myeloma Proteins ◽  
Normal Human ◽  
Time Test ◽  
Hemostatic Disorders

Waldenstrom’s macroglobulinemia sometimes involves hemostatic disorders. It has been assumed that this may be due to interaction of the myeloma protein with soom blood coagulation factor(s). In the present investigation the sera of seven myeloma patients were studied for a possible interaction between the myeloma protein and clotting factors II, VIM, IX and XI.Normal human plasma was incubated for 30 mi η at 37°C with different dilutions of patients’ serum or of purified myeloma proteins. The ability of this mixture to restore the clotting times of various deficient plasmas was tested by the partial thromboplastin time test.Factor XI activity of normal plasma was substantially inhibited upon incubation with patient’s serum or with purified myeloma protein M. This effect seems to be specific for myeloma protein M since it was neither observed with myeloma proteins G or A, nor with normal IgM. Other coagulation factors investigated so far were not inhibited by myeloma protein M. It is concluded that this protein is specifically affine to factor XI resulting in hindering the latter’s activity.

scholarly journals Hageman Factor (HF) Dependent Fibrinolysis

1977 ◽  
Author(s):  
Allen P. Kaplan ◽  
Robert Mandle ◽  
Lewis D. Yecies ◽  
Henry L. Meier
Keyword(s):  
Molecular Weight ◽  
Heavy Chain ◽  
Light Chain ◽  
Active Site ◽  
Molecular Form ◽  
Enzymatic Reaction ◽  
Factor Xi ◽  
Hageman Factor ◽  
Charged Surfaces ◽  
Factor Xia

The HF dependent fibrinolytic pathway is initiated by binding of HF (M. W. 80,000) and a complex of prekallikrein and high molecular weight (HMW) kininogen (M. W. 280,000) to negatively charged surfaces. A reciprocal reaction proceeds in which HFA converts prekallikrein to kallikrein and kallikrein activates HF. The rate of each enzymatic reaction is augmented by HMW kininogen. The active site of HF, as assessed by incorporation of 3H-DFP, in the surface bound enzyme does not form upon binding in the presence or absence of HMW kininogen, but is generated upon activation by kallikrein. The product, HFA (M. W. 80,000), is subsequently cleaved to liberate the active Hageman factor fragments (M. W. 28,000). Two forms of prekallikrein (M. W. 88,000 and 85,000) are cleaved by HFA to yield kallikreins in which a heavy chain (M. W. 52,000) is disulfide linked to a light chain (36,000 or 33,000) and, for each molecular form, the active site is in the light chain. Kallikrein activates plasminogen (M. W. 94,000) to yield a plasmin consisting of a heavy chain (M. W. 58,000) disulfide linked to a light chain (M. W. 27,000) and again, the active site is in the light chain. Digestion of prekallikrein by kallikrein yields proenzymes of molecular weight 78,000 and 75,000 that appear to represent the previously described plasminogen proactivator. Factor XI circulates bound to HMW kininogen, is activated by HFA in the presence of HMW kininogen, and factor XIA-HMW kininogen activates HF. Thus factor XI may contribute to the gradual activation of HF and evolution of fibrinolytic activity in prekallikrein deficient plasma. A further role for factor XIA as a plasminogen activator will be discussed.

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.

scholarly journals Effect of Chylomicrons on the Fibrinolytic Activity of Normal Human Plasma in Vitro

1959 ◽  
Vol 7 (2) ◽  
pp. 205-209 ◽  
Author(s):  
THOMAS C. MERIGAN ◽  
JOHN W. FARQUHAR ◽  
JAMES H. WILLIAMS ◽  
MAURICE SOKOLOW
Keyword(s):  
Human Plasma ◽  
Fibrinolytic Activity ◽  
Normal Human Plasma ◽  
Normal Human

Detection and Quantitation of Cleaved and Uncleaved High Molecular Weight Kininogen in Plasma by Ligand Blotting with Radiolabeled Plasma Prekallikrein or Factor XI

1988 ◽  
Vol 59 (02) ◽  
pp. 151-161 ◽  
Author(s):  
Bernhard Lämmle ◽  
Bruce L Zuraw ◽  
Mary Jo Heeb ◽  
Hans Peter Schwarz ◽  
Mauro Berrettini ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Human Plasma ◽  
High Molecular Weight ◽  
Sodium Dodecyl ◽  
Normal Human Plasma ◽  
Single Chain ◽  
Factor Xi ◽  
Sds Page ◽  
Normal Human

SummaryA method for the quantitative assay of native single chain and kallikrein cleaved two-chain high molecular weight (HMW)-kininogen in plasma is described. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of whole plasma is followed by electrotransfer of the electropherogram to nitrocellulose membranes and detection of the blotted HMW-kininogen with its physiologic ligands, radiolabeled plasma prekallikrein or radiolabeled factor XI. Using unreduced SDS-PAGE cleaved two-chain HMW-kininogen (Mr ∼107,000 and 95,000), is elec-trophoretically separated from uncleaved single chain HMW-kininogen (Mr ∼150,000). Counting the radioactivity of the nitrocellulose pieces corresponding to cleaved HMW-kininogen permits its quantitative measurement by comparison with standards consisting of decreasing amounts of fully dextran sulfate activated normal human plasma. Single chain HMW-kininogen is similarly assayed using reduced SDS-PAGE and unactivated normal human plasma standards.This technique is highly specific and sensitive to about 50 ng of either cleaved or uncleaved HMW-kininogen. Varying amounts of cleaved HMW-kininogen were found in a small series of plasmas from patients suffering from various inflammatory conditions. Higher levels of in vivo cleaved HMW-kininogen were observed during acute attacks of hereditary angioedema due to Cl-inhibitor deficiency. This technique may be useful for the assessment of the degree of in vitro or in vivo activation of the contact system.

Phosphorylation of Coagulation Factor XI by a Casein Kinase Released by Activated Human Platelets Increases Its Susceptibility to Activation by Factor XIIa and Thrombin

1999 ◽  
Vol 82 (10) ◽  
pp. 1283-1288 ◽  
Author(s):  
Graciela Elgue ◽  
Bo Nilsson ◽  
Kristina Nilsson Ekdahl
Keyword(s):  
Plasma Proteins ◽  
Regulatory Mechanism ◽  
Coagulation Factor ◽  
Human Platelets ◽  
Casein Kinase ◽  
Coagulation Cascade ◽  
Factor Xi ◽  
Activated Platelets ◽  
Factor Xiia ◽  
Factor Xia

SummaryPrevious studies suggest that activated platelets facilitate the cleavage of factor XI by both factor XIIa and thrombin. Extracellular phosphorylation is a mechanism by which the function of plasma proteins can be regulated. Phosphorylation is mediated by a casein kinase which is released by activated platelets concomitant with large amounts of ATP and Ca2+. The purpose of this study was to investigate if factor XI is phosphorylated by a platelet casein kinase and whether phosphorylation may affect its activation properties. It was shown that supernatants from platelets which contain platelet casein kinase phosphorylated factor XI. By Western blot analysis it was shown that phosphorylation of factor XI substantially increased its susceptibility to cleavage by factor XIIa, and, to a lesser extent, by thrombin. The generated factor XIa was functionally active in that it cleaved the chromogenic substrate S2366, and in that factor XIa-antithrombin and thrombin-antithrombin complexes were generated when phosphorylated factor XI was added to blood plasma. The present study indicates that platelet-mediated phosphorylation of factor XI enhances the cleavage of factor XI into XIa and that the generated XIa possesses functional activity. Phosphorylation of factor XI might be an essential regulatory mechanism by which platelets mediate amplification of the coagulation cascade.

Factor XIa Induced Activation of the Intrinsic Cascade In Vivo

1996 ◽  
Vol 75 (03) ◽  
pp. 445-449 ◽  
Author(s):  
Hugo ten Cate ◽  
Bart J Biemond ◽  
Marcel Levi ◽  
Walter A Wuillemin ◽  
Kenneth Bauer ◽  
...  
Keyword(s):  
Human Factor ◽  
Coagulation Factor ◽  
Thrombin Inhibitor ◽  
Bleeding Tendency ◽  
Loading Dose ◽  
Factor Xi ◽  
Factor Xia ◽  
Initial Activation ◽  
Baseline Values

SummaryCoagulation factor XI is a glycoprotein of the contact factor system. Its deficiency is associated with a highly variable bleeding tendency, thus a role in relation to hemostasis appears to exist. However, the importance of factor XI for stimulating intrinsic coagulation in vivo has not yet been determined. To study the procoagulant effects of human factor Xla in vivo, we infused the purified enzyme into normal chimpanzees (100 Μg) in the absence or presence of the thrombin inhibitor rec-hirudin (1.0 mg/kg loading dose plus 0.3 mg/kg body wt continuous infusion). Factor Xla elicited an immediate activation of factors IX, X, and prothrombin, as measured by their respective activation fragments. However, whereas the activation of factors IX and X was immediate and shortlasting, (peak increments of 6- and 1.4-fold of baseline at 5 minutes after injection), the conversion of prothrombin gradually increased, reaching a summit of 6-fold baseline values after 60 min, and remaining elevated during the course of the experiments. Thrombin-antithrombin complexes also remained elevated during the study period. In the presence of hirudin, the initial activation of factors IX, X, and prothrombin was unchanged, however the further increment in prothrombin fragment FI+2 was markedly inhibited. These results demonstrate that factor Xla is a potential agonist of the intrinsic cascade in vivo, which activity is enhanced in the presence of thrombin.

Studies on the Adsorption and Activation of the Hageman Factor (Factor XII) by Collagen and Elastin

1965 ◽  
Vol 14 (03/04) ◽  
pp. 387-400 ◽  
Author(s):  
St Niewiarowski ◽  
E Bańkowski ◽  
Irena Rogowicka
Keyword(s):  
Experimental Evidence ◽  
Whole Blood ◽  
Factor Xii ◽  
Normal Amount ◽  
Normal Human Plasma ◽  
Clotting Time ◽  
Adsorption Time ◽  
Hageman Factor ◽  
Normal Human

SummaryIt has been found that Hageman factor is adsorbed from normal human plasma by collagen and elastin. The adsorption is dependent upon the concentration of both substances and upon the adsorption time. The adsorption by collagen is almost selective. By the procedure of the repeated adsorption it is possible to obtain plasma containing 3-5% of Hageman factor normal value and normal amount of PTA (factor XI). At pH 9.5-10.0 the Hageman factor can be eluted in part from collagen shaken previously with human or pig plasma, its recovery in the eluates from elastin is poor.Experimental evidence is presented that the Hageman factor is activated following adsorption on collagen. The eluates from collagen have been compared with those prepared in a similar manner from kaolin and celite. All eluates possess clot promoting, TAMe arginine esterase and fibrinolytic activities. They shorten considerably the clotting time of the whole blood in siliconized tubes.It has been suggested that collagen may act as an intrinsic trigger of the blood coagulation in vivo by adsorbing and activating the Hageman factor.

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