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PubMed1997

Colocalization of gold-labeled LDL and fibrinogen on platelets: enhanced fibrinogen binding induced by LDL.

Low-density lipoproteins (LDL) specifically bind to the human platelet integrin-alpha IIb and -beta 3 (Koller et al., J. Biol. Chem. 264: 12412-12418, 1989). We show by electron microscopy (EM) that gold (Au)-labeled LDL bind to sites randomly distributed on the surface of platelets in suspension. Within a few minutes, mobile ligand-receptor complexes are translocated from the surface to the open canalicular system (OCS), which finally centralizes as a broad belt. Binding and translocation of Au-LDL are independent of stimulation of platelets by ADP and are completely reversible. Au-fibrinogen shows a strikingly similar, though agonist-dependent, redistribution behavior. Platelets are markedly activated by LDL. This activation is initiated by the binding of LDL to the plasma membrane receptor, and receptor internalization is probably not required for the activation but may instead be one of its consequences. Coincubation with Au-LDL and Au-fibrinogen results in more pronounced activation. The amount of OCS-localized ligands is significantly increased, most likely reflecting enhanced receptor recycling. The two ligands show a tendency to segregate in separate clusters, indicating differences in their postbinding pathways.

Adenosine Diphosphate↗
PubMedDate not supplied

[Anticlotting activity of fragment D from fibrinogen and fibrin and its dependence on calcium presence when fragments are obtained from fibrinogen].

The CaCl2 concentration of about 10(-4) M slightly reduces the proteolytic fibrinogen degradation and greatly increases the anticlotting activity in the arising fragments D. With a rise in the CaCl2 concentration to 10(-2) M a subsequent limitation of proteolysis occurs, but less active fragments D are formed. These facts suggest that a moderate restriction of peptide bond cleavage enhances the fragment D activity, whereas excessive restriction exhibits an adverse effect. Fragment D originating from noncross-linked fibrin inhibits clotting stronger than its counterpart--the fibrinogen derivative. The following explanation seems plausible. Certain sites of the intact molecules, essential for the inhibitory activity of the prospective fragment D, become somewhat "enzyme-proof" (due to intermolecular links characteristic of polymeric fibrin), thus, avoiding proteolytic damage. Calcium ions presented at the optimum concentration may act similarly.

Binding Sites↗
PubMedDate not supplied

[Role of exogenous fibrinogen in the processes of degranulation of thrombocytes stimulated with thrombin. Ultrastructural study using fibrinogen labeled with colloidal gold].

Using colloidal gold-conjugated fibrinogen (F-Au) it is shown that exogenous fibrinogen can participate in the platelet release reaction. In the absence of F-Au, internal secretory vacuoles readily formed in human platelets stimulated with thrombin, but extrusion of their content was delayed. Upon incubation with F-Au, endocytic channels induced by F-Au-receptor interactions, fused with internal vacuoles, thus establishing spatial communications of the latter with the outer medium.

Blood Platelets↗
PubMed1984

Structure of the human gamma-fibrinogen gene. Alternate mRNA splicing near the 3' end of the gene produces gamma A and gamma B forms of gamma-fibrinogen.

The gamma chain of human fibrinogen exists in 2 nonallelic forms, gamma A and gamma B, which differ only in their carboxyl termini. We have found that only one genomic locus exists for gamma-fibrinogen and that the gamma A and gamma B chains arise by alternate mRNA splicing near the 3' end of this gene. In contrast to the rat gamma B mRNA which is produced by alternate splicing with identical polyadenylation sites, human gamma B is produced when the eighth intervening sequence remains unspliced and a polyadenylation signal within this intron is used. The new carboxyl terminus is 16 amino acids longer than the gamma A protein, and although there is only minimal homology between the rat and human carboxyl termini they share a very high proportion of acidic amino acids.

Amino Acid Sequence↗
PubMed1995

Non-peptide fibrinogen receptor antagonists. 7. Design and synthesis of a potent, orally active fibrinogen receptor antagonist.

The design, synthesis, and pharmacological evaluation of L-734,217, a potent, low-molecular weight, orally active fibrinogen receptor antagonist, is reported. A strategy for producing low-molecular weight inhibitors from the peptide c-[(Ac)CRGDC] A, previously reported from these laboratories, is outlined. This strategy combines a retrodesign analysis of the conformationally defined cyclic peptide A with stereochemical information present in the arginine-glycine-aspartic acid (RGD) tripeptide sequence, culminating with the discovery of L-734,217. L-734,217 inhibited the aggregation of human, dog, and chimpanzee platelets at concentrations below 100 nM and was found to be > 15000-fold less effective at inhibiting the attachment of human umbilical vein endothelial cells to fibrinogen, fibronectin, and vitronectin than it was at inhibiting the aggregation of platelets. L-734,217 showed significant ex vivo antiplatelet activity following oral administration in dogs and chimpanzees at doses of 1.0 and 2.0 mg/kg, respectively, and has been selected as a clinical candidate for development as an antithrombotic agent.

Administration, Oral↗
PubMed1985

Fibrinogen Irvine: a qualitatively abnormal fibrinogen associated with the predisposition to recurrent visceral and peripheral venous thrombosis.

A slow clotting dysfibrinogen with delayed anodal immunoelectrophoretic mobility and impaired fibrinopeptide A release has been identified in a patient with recurrent portal vein and deep venous thrombosis. Affected family members tested in the initial screening were asymptomatic. The proband's father died of pulmonary embolism at age 44 years and had mesenteric thrombosis at necropsy. The association of a plasma protein abnormality with visceral thrombosis is unusual and has never been observed previously with a dysfibrinogen. The qualitative abnormality is transmitted as an autosomal codominant and is tentatively designated, fibrinogen Irvine.

Adult↗
PubMed1982

Inhibition of thrombin cleavage of fibrinogen by polyestradiol phosphate; interaction with the crucial arginine residues in fibrinogen required for enzymic cleavage.

1. Polyestradiol phosphate (PEP) has been demonstrated to have inhibitory activity against hyaluronidase, acid phosphatase and alkaline phosphatase (Fernö et al., 1958). 2. PEP has a marked inhibitory action against thrombin in the blood clotting reaction in which thrombin cleaves four fibrinopeptides from fibrinogen resulting first in the formation of monomeric fibrin and then polymeric fibrin fibrils (Baughman, 1970; Magnusson, 1970).

Arginine↗
PubMed1993

Fibrinogen internalization by ADP-stimulated blood platelets. Ultrastructural studies with fibrinogen-colloidal gold probes.

Interaction of gel filtered, ADP-stimulated human platelets with low (0.05 mg/ml) and high (1 mg/ml) fibrinogen (Fg) was examined by transmission electron microscopy. To visualize exogenous Fg in a course of its interaction with stimulated platelets, Fg coupled to 18-nm colloidal gold (Fg-Au) was employed. In the presence of either Fg or Fg-Au, rapid changes of platelets morphology indicative of resting to activated state transition, were observed. Without external ligands, stimulated platelet suspensions resemble rather control (untreated) samples. Using Fg-Au, it has been found that initial binding of gold labels to platelet surfaces is immediately followed by gold accumulation in plasmalemma pits subjected to further internalization. Serial sections proved that at 1 min, some of the labeled endocytic structures are already isolated in the platelet cytoplasm. After prolonged (20 min) incubations, different platelet subfractions have been found. Many single or loosely aggregated platelets with little or no surface labeling contained abundant stores of internal labels. In these cells, Fg-Au is localized in vacuole-like and/or granule-like structures. Some post-stimulated (discoidal) platelets are likely to release Fg-Au previously internalized. In the centers of platelet aggregates concentrated labels filled intercellular spaces and voluminous intraplatelet cavities, either open or occluded. These results indicate on different ultimate fates of exogenous Fg processed by the ADP-stimulated platelets. The data obtained suggest also that after initial binding, exogenous Fg may be implicated not only in aggregation, but in activation-related cellular responses as well.

Adenosine Diphosphate↗
PubMed1988

Fibrinogen association with human monocytes: evidence for constitutive expression of fibrinogen receptors and for involvement of Mac-1 (CD18, CR3) in the binding.

Radiolabeled fibrinogen (Fg) specifically binds to mononuclear leukocytes (MNL) and to purified monocytes, but not to nylon-nonadherent lymphocytes. The association is rapid, Ca++-dependent and reversible. MNL containing Fg-binding monocytes had not been exposed to endotoxin (less than 4 pg/mL) during the isolation and the binding test, and Fg binding was not altered by preincubation of MNL with lipopolysaccharide. The binding of Fg was inhibited by anti-Mac-1 antibodies (OKM1). Antibodies to surface-bound Fg were able to induce luminol-dependent chemiluminescence, indicating that Fg binding sites have receptor function. Emission of a signal depended on MNL exposure to Fg, on specific, divalent antibodies, but not on the antibody Fc portion. These data show that human monocytes constitutively express specific Fg receptors and suggest that Mac-1, a member of the integrin superfamily, is involved in Fg recognition.

Adenosine Diphosphate↗
PubMed1998

Role of the gamma chain Ala-Gly-Asp-Val and Aalpha chain Arg-Gly-Asp-Ser sites of fibrinogen in coaggregation of platelets and fibrinogen-coated beads.

Fibrinogen (Fg) mediates platelet aggregation and adhesion to artificial surfaces. The carboxyl terminus of the gamma chain of Fg (residues AGDV at gamma408-411) is known to play an exclusive role in platelet aggregation, while there is no known role for the consensus RGD sites in the Aalpha chain. In this study, we used flow cytometry to measure the coaggregation (CA) of platelets with Fg-coated beads, and investigated which domains in surface-immobilized Fg support platelet adhesion. CA of platelets with Fg-beads was nearly abolished in the presence of 4A5, a monoclonal antibody (mAb) whose epitope includes AGDV, while Z69/8, a mAb that also binds to the gamma chain carboxyl terminus but does not cover AGDV, had little effect. When beads were coated with recombinant Fg (rFg) lacking AGDV, CA was similarly abolished. In contrast, beads coated with Fg that lacked the RGDS site, supported platelet CA as did intact Fg. These results were confirmed in experiments that measured the binding of activated soluble glycoprotein IIb and IIIa (GPIIbIIIa), the platelet membrane glycoprotein complex known to be the Fg receptor, to immobilized Fg. This binding was inhibited by mAb 4A5, but not by mAb Z69/8. Binding was totally retained when beads were coated with Fg lacking RGDS, but was completely lost when beads were coated with Fg lacking AGDV. These results demonstrated that the AGDV sequence on the carboxyl terminus of the gamma chain of Fg plays an exclusive role in platelet adhesion to surface-immobilized Fg, while the carboxyl terminus of the Aalpha chain, including a consensus RGD site, is not required.

Antibodies, Monoclonal↗
PubMed1998

The fibrinogen RIBS-I epitope (gamma373-385) appears proximate to the gamma408-411 adhesive domain but is not involved in interaction between receptor-bound or surface-adsorbed fibrinogen and platelet GPIIbIIIa.

The carboxyl terminus of the fibrinogen (Fg) gamma chain (gamma400-411) is necessary and sufficient to support platelet aggregation and adhesion. However, a monoclonal antibody (mAb) to the Fg RIBS-I epitope (gamma373-385), the anti-Fg-RIBS-I, which binds only to platelet-bound or surface-adsorbed Fg but not soluble Fg, inhibits platelet aggregation. In this study, we showed that this same antibody also inhibits the adhesion of platelets to Fg-coated polystyrene beads. We then investigated the mechanisms by which the anti-Fg-RIBS-I antibody inhibits platelet aggregation and adhesion. The Fg RIBS-I epitope does not interact with platelet GPIIbIIIa, since recombinant Fg missing the last four amino acids, the Ala-Gly-Asp-Val, on the carboxyl terminus of its gamma chains supports neither platelet aggregation nor adhesion to surfaces, nor GPIIbIIIa binding, while it binds anti-Fg-RIBS-I normally. Purified, soluble GPIIbIIIa (265 kDa) inhibits the binding of both the anti-Fg-RIBS-I and 4A5 (a mAb specific to gamma408-411 of Fg), however, peptide G13 (1.5 kDa), corresponding to the Fg gamma chain binding domain on GPIIba (GPIIb300-312), only inhibits the binding of 4A5, and does not affect the binding of the anti-Fg-RIBS-I to Fg. The anti-Fg-RIBS-I reduces the on-rate of the 4A5 binding to Fg with no measurable changes in the dissociation of the Fg-bound 4A5. These data indicate that the inhibition of platelet aggregation and adhesion by the anti-Fg-RIBS-I antibody is due to the steric hindrance of the Fg gamma400-411 to platelet GPIIbIIIa. Thus the Fg RIBS-I epitope (gamma373-385) does not appear to be involved in direct interaction with platelet GPIIbIIIa, leaving the gamma408-411 of Fg as the sole domain mediating platelet aggregation and adhesion.

Antibodies, Monoclonal↗
PubMed1985

Mechanism of action of thrombin on fibrinogen: NMR evidence for a beta-bend at or near fibrinogen A alpha Gly(P5)-Gly(P4).

The following synthetic linear A alpha fibrinogen-like peptides were studied by NMR spectroscopy in aqueous solution: Ac-Asp(P10)-Phe(P9)-Leu-Ala-Glu-Gly(P5)-Gly(P4)-Gly(P3)-Val- Arg(P1)-Gly-(P1)-Pro-Arg(P3')-Val-NHCH3 (F-8), Ac-Phe-Leu-Ala-Glu-Gly-Gly(P4)-Gly(P3)-Val-Arg-Gly-Pro-NHCH3 (F-6), Ac-Leu-Ala-Glu-Gly-Gly(P4)-Gly(P3)-Val-Arg-Gly-Pro-NHCH3 (F-7), and Ac-Gly-Gly(P4)-Gly-(P3)-Val-Arg-Gly-Pro-NHCH3 (F-9). The temperature dependence of the amide proton chemical shift is smaller by approximately 22% for the Gly(P3) amide proton in F-9, F-6, and F-8 and is similarly smaller for the Gly(P4) amide proton in F-6 and F-8, but not F-9, relative to the other amide protons in these peptides. The exchange rates with solvent water for the Gly(P3) amide proton in each of these four peptides were determined by solvent spin saturation transfer experiments. The exchange rate constant for the Gly(P3) amide proton of F-8 was half that of the rate constant determined for this proton in F-9, F-7, and F-6. In conjunction with previously reported data for the rate of hydrolysis of the Arg(P1)-Gly(P1') bond by thrombin, these results suggest that there is a beta-bend at Gly(P5)-Gly(P4), possibly stabilized by salt links between Asp(P10) and Arg(P3') and between phosphorylated Ser(P14) and Arg(P7'), which brings Phe(P9) close to the hydrolyzable Arg-Gly bonds.(ABSTRACT TRUNCATED AT 250 WORDS)

Amides↗
PubMed1995

Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp sequence of fibrinogen. (Aminobenzamidino)succinyl (ABAS) series of orally active fibrinogen receptor antagonists.

Our initial orally active fibrinogen receptor antagonist benzamidinopentanoyl (BAP) series which was discovered through truncation of our i.v. antiplatelet agent (SC-52012) demonstrated modest oral activity in canine studies (ethyl [5-(4-amindinophenyl)pentanoyl]-3-amino-3-(3-pyridyl)propionate, 1e). Introduction of an amide bond adjacent to the benzamidine led to a novel series with an (aminobenzamidino)succinyl (ABAS) Arg-Gly surrogate that had improved in vitro potency (5-17 times) relative to the BAP series. Four ester prodrug/acid active metabolite pairs (2a/2e, 60a/60e, 62a/62e, 63a/63e) from the ABAS series which varied in their 3-substituent on the beta-amino ester "aspartate mimetic" were prepared in enantiomerically enriched form (> 95:5), and they were evaluated in canine studies for their ability to block collagen-induced aggregation in platelet-rich plasma, the elimination profile (t1/2 beta-phase), repeated oral dosing studies, and oral systemic availability. Of the four ester prodrug/acid active metabolite pairs, 2e/2a (SC-54684A/SC-54701A) has the most favorable properties in the above studies with an IC50 = 67 +/- 5 nM (dog platelet-rich plasma, collagen), t1/2 beta = 1.6 h (ester) and 6.5 h (acid), no adverse effects upon repeated dosing, and a drug oral systemic availability of 62% (area under curve (AUC) of acid 2a (drug) following ig administration of ester 2e (prodrug, 2.5 mg/kg) divided by AUC of acid 2a (drug) following i.v. administration of ester 2e (prodrug, 2.5 mg/kg) as determined by HPLRC). In further pharmacokinetic studies using nonlabeled 2e/2a, the oral systemic availability (ester 2e ig/ester 2e i.v.) of 2e was measured to be in the range of 44.7-53.0%. The more biologically relevant oral systemic availability (ester 2e ig/acid 2a i.v.) of 2e was found to be in the range of 22.0-26.4%. A pharmacophore model based on inhibitors from several different benzamidine classes including 2a (ABAS class) was developed using a combination of molecular modeling (MM2) and pharmacophore identification (APOLLO) methods.

Administration, Oral↗
PubMed1977

Fibrinogen Seattle: a qualitatively abnormal fibrinogen in a patient with tetralogy of Fallot.

A dysfibrinogen was detected in the plasma of a 14-year-old asymptomatic Caucasian boy who had tetralogy of Fallot. The mutant molecular species could be traced through four generations in an autosomal dominant type of inheritance pattern. Nine of 14 family members were found to have the coagulopathy. Following laboratory and clinical evaluation, the proband underwent radical repair of the cardiac defect without incident. This variant is tentatively designated fibrinogen Seattle pending further characterization.

Adolescent↗
PubMed2000

Neither the A- nor B-repeat regions of the fibrinogen-binding protein of Streptococcus equi subsp. equi are essential for fibrinogen binding.

The major cell wall-associated protein (FgBP) of Streptococcus equi subsp. equi possesses two internal blocks of repeated sequence (A and B) and binds horse fibrinogen (Fg) avidly through residues located in the N-terminal half of the molecule. In the present study, we investigated the roles of the two repeats blocks in Fg binding through construction of recombinant FgBP proteins containing defined internal deletions of sequence. Ligand binding experiments clearly showed that neither repeat is essential for Fg binding. However, residues within the B repeats seem to play a major role in the aberrant mobility observed for FgBP following sodium dodecyl sulfate polyacrylamide gel electrophoresis.

Animals↗
PubMed1989

Fibrinogen-mediated epidermal cell migration: structural correlates for fibrinogen function.

Previously we showed that epidermal cells are able to use fibrinogen (FGN) as a migration substratum during wound closure. The goal of the present study was to determine the structural features of FGN that allow this migration. Pieces of glass coated with native, fragmented, or other modified forms of FGN were implanted into full-thickness skin wounds of adult newts such that migrating epidermal cells would encounter the implant. In this system, a coating of FGN allowed considerably more migration than a coating of BSA. At high concentrations, heat-denatured FGN supported as much migration as the same amount of intact FGN. Fraction I-9, a circulating form of FGN missing a 20-30K (K = 10(3) Mr) carboxy-terminal segment of the A alpha chain, was no less effective than intact FGN. Comparison of the isolated D1 and E fragments of FGN showed migration only on D1, but never to the extent seen on intact FGN containing the same amount of D1. Plasmin digestion of D1 in the presence of EDTA, a process which produces D3, a fragment differing from D1 by the loss of the carboxy-terminal 109 amino acids of the gamma chain, caused a significant loss of activity in the D fragment. Migration was good on implants coated with relatively high concentrations of purified A alpha chains but gamma chains were inactive. Migration over intact FGN was almost totally blocked by 230 microM-Arg-Gly-Asp-Ser (RGDS), a peptide known to interact with integrin-type receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗