Immunobiology of Fibrinogen. EMERGENCE OF NEOANTIGENIC EXPRESSIONS DURING PHYSIOLOGIC CLEAVAGE IN VITRO AND IN VIVO

Plow, Edward F.; Edgington, Thomas S.

doi:10.1172/jci107183

Cited by 83 publications

(41 citation statements)

References 37 publications

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“…Isolation of the proteins of the coagulation pathways has made possible not only biochemical characterization but also immunochemical analyses of concentration, molecular heterogeneity, and specific functional activity of these proteins in plasma (33)(34)(35)(36)(37)(38)(39) as well as specific assays of the activated enzyme (40) and proteolytic degradation products (41,42). The molecular biology of Factor X is inordinately complex as evidenced by its multiple interactions; and precise analyses of molecular mass are required for studies of the functional biology ofthis molecule in thrombotic and hemostatic diseases.…”

Section: Discussionmentioning

confidence: 99%

Combined Functional and Immunochemical Analysis of Normal and Abnormal Human Factor X

Fair¹,

Plow²,

Edgington³

1979

J. Clin. Invest.

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A B S T R A C T Human Factor X was isolated from Cohn fraction III and characterized by polyacrylamide gel electrophoresis, amino acid composition, and isoelectric focusing. Two molecular forms with biological activity were observed at isoelectric points of 4.8 and 5.0. Antisera generated to Factor X was monospecific and used to establish an equilibrium competitive inhibition radioimmunoassay. This assay was specific for human Factor X and did not cross-react with human prothrombin or bovine Factor X within the sensitivity range of 6-300 ng Factor X antigen/ml. The mean concentration of Factor X based on the antigen was 11.9 ,ug0ml, whereas concentration values based on coagulant activity was 7.8 ,ug/ml. This 30% difference in measurement appears to result from the presence of a subpopulation of Factor X molecules devoid of coagulant activity. The radioimmunoassay was used to qualitatively and quantitatively compare purified Factor X to plasmic Factor X obtained from normal, warfarintreated, acquired Factor X-deficient, and congenitaldeficient patients. In all but one case, the Factor X present in these plasmas was immunochemically identical to the purified Factor X and permitted precise quantitation of these abnormal Factor X molecules. Factor X procoagulant activity was analyzed relative to Factor X antigen and the specific activities were used to characterize normal and abnormal Factor X molecules. Reduced Factor X activity in plasmas from warfarin-treated and acquired Factor Xdeficient patients was attributed to both decreases in Factor X antigen and decreased function of the Factor X molecules. Congenitally deficient patients, in general, showed a reduction in Factor X antigen in parallel with Factor X procoagulant activities This is publication

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Section: Discussionmentioning

confidence: 99%

Combined Functional and Immunochemical Analysis of Normal and Abnormal Human Factor X

Fair¹,

Plow²,

Edgington³

1979

J. Clin. Invest.

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“…Fibrinogen and fibrin cleavage fragments, produced by plasmin, were isolated by molecular exclusion chromatography on 6%o beaded agarose (A-1.5, 200-400 mesh, Bio-Rad Laboratories, Richmond, Calif.) followed by anion exchange chromatography on DEAE-cellulose for fibrinogen fragment D (fg-D) 1 and fg-E. The characteristics of fragments as prepared in this laboratory have been previously described (15)(16)(17), and each isolated fragment appeared to be homogeneous based on sedimentation velocity, molecular exclusion chromatography, immunoelectrophoresis, and polyacrylamide gel ellectrophoresis. Radioiodination with "2JI was performed according to the modified chloramine T method of McConahey and Dixon (25) 20 min at 1,800 g, and 0.5 ml of the supernate was removed and counted for -y emission at 22.5-55 keV.…”

Section: Methodsmentioning

confidence: 99%

“…Fibrinogenrelated antigens in serum were quantitated by radial diffusion techniques (15). Sera containing fibrinogen-related antigens utilized in this study were collected from patients with diseases commonly associated with circulating fibrinogen/fibrin degradation products including: meningococcemia, metastatic carcinoma, gram-negative septacemia, and obstetrical complications.…”

Section: Methodsmentioning

confidence: 99%

“…The cleavage of fibrinogen or fibrin by plasmin leads to a series of defined fragments (11)(12)(13), which exhibit structural and conformational modifications as well as the expression of specific cleavage-associated neoantigens not associated with the parent molecules (14)(15)(16). Twro independent cryptic neoantigens have been demonstrated in this system utilizing heterologous immune responses; one is present in the C-terminal aspects (D region) (14,15) and the second in the N-terminal region (E region) (16). Cleavage fragments expressing these neoantigens are not present in the plasma of healthy adults at concentrations greater than 20 nM (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

“…Twro independent cryptic neoantigens have been demonstrated in this system utilizing heterologous immune responses; one is present in the C-terminal aspects (D region) (14,15) and the second in the N-terminal region (E region) (16). Cleavage fragments expressing these neoantigens are not present in the plasma of healthy adults at concentrations greater than 20 nM (15)(16)(17). In a number of pathological conditions leading to the activation of plasminogen, cleavage fragments are generated (18)(19)(20)(21)(22), and physical exercise (23) as well as forms of stress (24) mav also lead to increased levels of cleavage fragments.…”

Section: Introductionmentioning

confidence: 99%

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Immune responses to the cleavage-associated neoantigens of fibrinogen in man. Identification and characterization of humoral antibodies specific for cleavage fragments.

Plow

Edgington

1975

J. Clin. Invest.

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A B S T R A C T Cleavage of human fibrinogen and fibrin by plasmin is associated with modification of native antigenic expression and the exposure of cleavage-associated neoantigenic sites on the derivative molecular fragments.In this study, the presence of humoral antibodies in man to cleavage-associated neoantigens has been demonstrated by primary antigen binding radioimmunochemical assays. Specific binding of radioiodinated human fibrinogen D fragment by serum immunoglobulins was demonstrated in 52 of 59 random normal human sera and was independent of immunoglobulin concentration. Binding was mediated by F(ab')2 fragments of IgG, and specificity for neoantigens was indicated by the capacity of the D fragment but not native fibrinogen to competitively inhibit the antibody. The population distribution of antibody to these cleavage-associated neoantigens indicated the presence of a major group of individuals (77%) with a mean antigen binding capacity of 11.8 pmol/ml serum. Two minor populations with: (a) low or undetectable binding capacities (<6.0 pmol/ml serum) and (b) exhibiting markedly elevated binding capacities (> 18.0 pmol/ml serum) were delineated. Independent of these features, sera could also be readily separated into two groups that differed with respect to relative antibody affinity. The antibodies in most sera exhibited marked heterogeneity of binding affinity, whereas a small group of sera contained antibodies exlhibiting relative homoThis is Scripps Clinic and Research Foundation publication EP-964.

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Fibrinogen houston: A dysfibrinogen exhibiting defective fibrin monomer aggregation and α‐chain cross‐linkages

Weinger¹,

Rudy²,

Moake³

et al. 1980

American J Hematol

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A 38-year-old male patient with a life-long history of easy bruising and mild bleeding had a prolonged activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). Reptilase (Bathrops atrox) clotting time was normal. His undiluted and diluted plasma prolonged the APTT, PT, and TT of normal plasma. Fibrin produced from patient plasma was insoluble in 5 M urea. Plasma fibrinogen level was increased when measured as clottable protein and by Laurell electroimmunoassay. Specific assays of plasma factors II, V, VII, X, VIII, IX, XI, and XII were normal. A circulating antithrombin in patient plasma was excluded by demonstrating normal thrombin-induced platelet aggregation of gel-separated platelets in the presence of patient plasma. Purified patient fibrinogen reproduced the anticoagulant effect of patient plasma. Patient fibrinogen antigen was similar to normal fibrinogen antigen by immunodiffusion, immunoelectrophoresis (pH 5.2 and 8.6), and crossed immunoelectrophoresis. His unreduced purified fibrinogen had normal migration on polyacrylamide slab gels. Also, the migration in gel slabs of A alpha, B beta and gamma-polypeptide chains, produced by mercaptoethanol reduction of purified patient fibrinogen, was similar to reduced normal fibrinogen. Thrombin-induced total fibrinopeptide release was normal. However, fibrin monomers produced from patient fibrinogen by thrombin (devoid of fibrinopeptides A and B) reaggregated abnormally; fibrin monomers produced by reptilase (devoid of only fibrinopeptides A) reaggregated normally. Fibrin generated from patient plasma in the presence of factor XIII and calcium, was defective in the formation of covalently bonded alpha-alpha polymers and demonstrated an increased susceptibility to the lytic effects of plasmin (generated in vitro by the addition of streptokinase).

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Immunobiology of Fibrinogen. EMERGENCE OF NEOANTIGENIC EXPRESSIONS DURING PHYSIOLOGIC CLEAVAGE IN VITRO AND IN VIVO

Cited by 83 publications

References 37 publications

Combined Functional and Immunochemical Analysis of Normal and Abnormal Human Factor X

Combined Functional and Immunochemical Analysis of Normal and Abnormal Human Factor X

Immune responses to the cleavage-associated neoantigens of fibrinogen in man. Identification and characterization of humoral antibodies specific for cleavage fragments.

Fibrinogen houston: A dysfibrinogen exhibiting defective fibrin monomer aggregation and α‐chain cross‐linkages

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