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PubMed1991

Effect of fibrinogen concentration on the velocity of platelet aggregation.

The relationship between fibrinogen binding to its receptor and platelet aggregation has been investigated by comparing 125I-fibrinogen binding and aggregation velocities of gel-filtered platelets in the presence of adenosine diphosphate (ADP). Aggregometric responses at various fibrinogen concentrations are found to be bell-shaped and show a maximum at fibrinogen concentrations (Fmax) similar to the 125I-fibrinogen hemisaturating doses. At higher and lower fibrinogen concentrations, platelet aggregation velocities decrease in a parallel manner. Lowering ADP concentration increases Fmax, in agreement with the modulatory effect of ADP on fibrinogen binding to platelets. Variations of fibrinogen in the range of physiopathologic plasma concentrations affect platelet aggregation induced by any ADP dose. These results clarify the relationship between the fibrinogen binding process and aggregation and demonstrate that plasma fibrinogen concentration has a major influence on the velocity of platelet aggregation.

Adenosine Diphosphate↗
PubMed1990

In vivo defibrination results in markedly decreased amounts of fibrinogen in rat megakaryocytes and platelets.

Recently evidence was provided for a pathway whereby circulating fibrinogen enters megakaryocyte granules by an endocytic mechanism. Synthesis of fibrinogen by megakaryocytes has been reported. To determine the relationship between plasma fibrinogen and alpha-granule fibrinogen in megakaryocytes and platelets, the fibrinogen content of these cells was studied in rats defibrinated by use of Ancrod, a thrombinlike enzyme purified from the venom of Agkistrodon rhodostoma. Unlike thrombin, Ancrod does not induce platelet secretion. Rats were injected with Ancrod (50 units/kilogram body weight) at 8-hour intervals for 5 days. There were no significant changes in platelet counts. Blood from the treated rats failed to clot, and plasma fibrinogen levels were less than 15 mg/dl. Bone marrow from defibrinated rats and untreated control rats was stained immunohistochemically for fibrinogen and two other alpha-granule proteins, albumin and platelet factor 4 (PF4), in plastic-embedded sections. The presence of these three proteins in platelets was detected by Western blots. Only trace amounts of fibrinogen were detected in megakaryocytes and platelets from defibrinated rats, but fibrinogen in control megakaryocytes and platelets was readily demonstrated. However defibrinated and control rats did not differ in albumin and PF4 content in megakaryocytes and platelets. It is concluded that a major portion of rat platelet fibrinogen is derived from plasma by endocytosis by megakaryocytes.

Ancrod↗
PubMed1986

Defective platelet-fibrinogen interaction in hereditary canine thrombopathia.

A unique, intrinsic, hereditary canine platelet disorder attributable to abnormal fibrinogen receptor availability is described. Thrombopathic platelets from 13 severely affected basset hounds failed to aggregate in response to all agonists tested except thrombin. Normal platelet interaction with the various stimuli was inferred on the basis of their ability to elicit unimpaired shape change in thrombopathic platelets. No quantitative differences in major platelet membrane glycoproteins, intraplatelet fibrinogen, adenine nucleotides, or serotonin uptake were detected. Dense granule secretion was impaired. The ultrastructural appearance of thrombopathic platelets was normal. Fibrinogen-platelet interaction was evaluated by reacting platelet-rich plasma (PRP) with fibrinogen coupled to polymeric acrylonitrile beads and scoring the extent of stimulus-induced agglutination. The aggregatory responses of normal and thrombopathic platelets were closely correlated with fibrinogen receptor availability. In contrast to human platelets, epinephrine-stimulated canine platelets did not interact with immobilized fibrinogen, and arachidonate generally induced only weak agglutination. Thrombopathic platelets agglutinated fibrinogen beads at reduced rates when stimulated with physiologic doses of thrombin and high-dose calcium ionophore, A23187. Our data suggest that thrombin-mediated induction of canine platelet fibrinogen receptors may proceed by pathway(s) alternate to those shared by other platelet agonists, and/or that secreted granule constituents may act synergistically with thrombin to overcome inhibition of signal-response-coupled reactions mediating the interaction of fibrinogen with its receptor. This congenital platelet defect provides further evidence, in a species other than human, for the pivotal role of fibrinogen receptor induction in platelet aggregation.

Adenine Nucleotides↗
PubMed1986

Kinetics of platelet-activating factor 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine-induced fibrinogen binding to human platelets.

Platelet-activating factor 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF-acether) triggers exposure of fibrinogen binding sites on platelets via binding to specific receptors. Comparison of [3H]PAF-acether binding with 125I-fibrinogen binding shows that the rate with which PAF-acether binds to a number of receptors and not the degree of receptor occupancy determines how much fibrinogen binds. At low concentrations of PAF-acether (0.1-1.0 nM) binding site exposure is incomplete and parallels the rate of formation of the PAF-acether-receptor complex. Fibrinogen binding then primarily depends on the concentration of PAF-acether. At a high concentration of PAF-acether (500 nM) binding site exposure is complete within 2-5 min. Fibrinogen binding then depends on the concentration of fibrinogen. Exposure of binding sites in the absence of fibrinogen leads to disappearance of accessible binding sites. At 500 nM PAF-acether, this disappearance is exponential in nature and shows the same characteristics after 5-15 min incubation with fibrinogen as after 60 min. Exposure of binding sites is then complete within 5 min and their disappearance is not disturbed by other processes. At 0.5 nM PAF-acether, the same characteristics are found after 60 min incubation with fibrinogen, but shorter incubation times reveal an ongoing binding site exposure that interferes with the disappearance process. These results demonstrate close coupling between the PAF-acether receptors and fibrinogen binding sites and indicate that the rate of formation of the PAF-acether-receptor complex is a major factor in the regulation of binding site exposure.

Binding Sites↗
PubMed1987

Endogenous production of cytotoxic factor in mice induced by a combination of interferon-gamma and heterologous fibrinogen.

The ability of heterologous fibrinogen in combination with interferon (IFN)-gamma to induce endogenous production of cytotoxic factor was examined. Heterologous but not homologous fibrinogen induced high production of cytotoxic factor in IFN-gamma-primed mice. The cytotoxic activity was maximal 1 h after this triggering. The LD50 value of heterologous fibrinogen in mice was greater than 250 mg/kg i.v. But heterologous fibrinogen induced antibody, causing anaphylaxis. Therefore, the effect of successive injections of fibrinogens from a different species was tested. Cytotoxic factor could be produced repeatedly by successive treatments with a combination of IFN-gamma and heterologous fibrinogen from one species for 1 week, although the cytotoxic activity induced by successive injections gradually decreased. After the decrease of the triggering effect of heterologous fibrinogen of one species, heterologous fibrinogen from a different species could induce cytotoxic activity at the same level as that after the first triggering. Thus, a combination of IFN-gamma and heterologous fibrinogen is effective for cytotoxic factor production, provided different heterologous fibrinogens are used successively. This combination should be useful for endogenous cytotoxic factor production in clinical trials.

Animals↗
PubMed1988

Evidence of increased association of fibrinogen with platelets caused by sodium citrate.

Washed platelet suspensions are almost always prepared from blood anticoagulated with sodium citrate. Because citrate has been reported to affect platelet function, we examined the involvement of citrate on the platelet-fibrinogen interactions. More iodine 125-labeled fibrinogen was bound on washed platelets from citrate-anticoagulated blood (CP) than on washed platelets from non-anticoagulated blood (PNB) obtained by the rapid gel filtration of native blood from the same donor. Scatchard analyses of the equilibrium binding data gave linear plots for PNB indicating a single class of binding sites with 16,480 +/- 2,800 fibrinogen molecules bound per platelet (Kd 5.6 x 10(-7) mol/L); CP gave curvilinear plots that, when resolved into two components assuming two classes of binding sites, gave a high-affinity site (4,950 +/- 970 molecules per platelet; Kd 1.29 x 10(-7) mol/L) and a low-affinity site (25,660 +/- 4,600 molecules per platelet; Kd 1.02 x 10(-6) mol/L). When blood from one donor was collected into 10 mmol/L and 20 mmol/L citrate, increased binding of 125I-fibrinogen was observed on platelets exposed to 20 mmol/L citrate. Exposure of PNB to varying citrate concentrations showed enhanced fibrinogen binding with increasing citrate concentrations; differences in the Kd values between non-citrate-treated PNB and citrate-treated PNB were apparent at about 7.5 mmol/L of citrate. The effects of citrate in increasing the association of fibrinogen with platelets were not caused by variations in the pH; although fibrinogen binding was diminished at low pH of the citrate used, more binding was observed in the presence of citrate than with buffer of the same pH. The effects of citrate appear to be on the platelet fibrinogen receptor because nonspecific binding was not affected by the citrate. Inasmuch as no carbon 14-labeled citric acid binding to platelets was observed, citrate may affect the platelet-fibrinogen interactions without binding to the platelets. We conclude that platelet exposure to citrate increases the fibrinogen binding and may lead to the appearance of curved Scatchard plots.

Blood Platelets↗
PubMed1979

Plasma fibrinogen in diabetes mellitus.

Plasma fibrinogen was measured in 285 diabetics (age range 15-85 years) and 209 controls (age range 23-74 years). Plasma fibrinogen concentration showed a positive skew distribution and an approximate normal distribution was obtained by log transformation. The mean log plasma fibrinogen in the diabetics was significantly increased (p less than 0.0001). Patients treated with a sulphonylurea (n = 81) had the highest mean log plasma fibrinogen concentration and this was significantly higher than in patients treated with insulin (n = 76; p less than 0.01), biguanides (n = 28; p less than 0.01) or sulphonyluera plus biguanides (n = 38; p less than 0.05). The biganide treated group had the lowest mean log plasma fibrinogen concentrations. No correlation was found between plasma fibrinogen and blood glucose, duration of diabetes or the presence of complications. Subjects with proliferative retinopathy (n = 38) had a similar mean plasma fibrinogen to those with background retinopathy (n = 55). Twenty-two maturity onset diabetics treated with a sulphonylurea and followed prospectively showed a significant increase in plasma fibrinogen after five months (p less than 0.0001), while a control diet treated group showed no alteration in plasma fibrinogen. It is concluded that plasma fibrinogen is significantly increased in diabetics and apart from age, the main factor related to the increase is treatment with sulphonylureas. It remains speculative whether this association has any correlation with long term cardiovascular morbidity.

Adolescent↗
PubMed1977

A study of the catabolism of fibrinogen after myocardial infarction.

The catabolism of fibrinogen was studied during the first week of acute myocardial infarction in twenty-three patients and in ten control patients. A trial was carried out using 125I-labelled fibrinogen. After myocardial infarction, the mean biological half-life of fibrinogen was 62.5 +/- 10.0 h and the mean plasma loss of fibrinogen per 24 hours was 34.1 +/- 6.9% of the intravascular fibrinogen pool. In the control group, respective values of 89.6 +/- 9.9 and 23.4 +/- 3.9% were obtained, which were in close agreement with published values for the normal catabolism of fibrinogen. The fractional catabolic rate of the intravascular fibrinogen pool was significantly increased in patients with myocardial infarction in contrast to the absolute plasma loss of fibrinogen which appeared to be the same as in subjects with normal plasma fibrinogen concentration. Possible explanations of the accelerated catabolism of fibrinogen after myocardial infarction are discussed.

Acute Disease↗
PubMed1981

Affinity labeling of a human platelet membrane protein with 5'-p-fluorosulfonylbenzoyl adenosine. Concomitant inhibition of ADP-induced platelet aggregation and fibrinogen receptor exposure.

Incubation of washed human blood platelets with 5'-p-fluorosulfonylbenzoyl [3H]adenosine (FSBA) covalently labels a single polypeptide of Mr = 100,000. Protection by ADP has suggested that an ADP receptor on the platelet surface membrane was modified. The modified cells, unlike native platelets, failed to aggregate in response to ADP (100 microM) and fibrinogen (1 mg/ml). The extent of binding of 125I-fibrinogen and aggregation was inhibited to a degree related to the incorporation of 5'-p-sulfonylbenzoyl adenosine (SBA) into platelets, indicating FSBA could inhibit the exposure of fibrinogen receptors by ADP necessary for aggregation. Incubation of SBA platelets with alpha-chymotrypsin cleaved the covalently labeled polypeptide and concomitantly reversed the inhibition of aggregation and fibrinogen binding. Platelets proteolytically digested by chymotrypsin prior to exposure to FSBA did not require ADP for aggregation and fibrinogen binding. Moreover, subsequent exposure to FSBA did not inhibit aggregation or fibrinogen binding. The affinity reagent FSBA can displace fibrinogen bound to platelets in the presence of ADP, as well as promote the rapid disaggregation of the platelets. The apparent initial pseudo-first order rate constant of dissociation of fibrinogen was linearly proportional to FSBA concentrations. These studies suggest that a single polypeptide can be altered either by ADP-induced conformational changes or proteolysis by chymotrypsin to reveal latent fibrinogen receptors and promote aggregation of platelets after fibrinogen binding.

Adenosine↗
PubMed1983

Fibrinogen binding to human platelet plasma membranes. Identification of two steps requiring divalent cations.

Fibrinogen binding to platelet plasma membranes, which is a prerequisite for platelet aggregation, was determined by incubating 125I-labeled fibrinogen with isolated membranes and measuring the amount of radioactivity sedimenting with the membranes through 15% sucrose. Fibrinogen binding was optimal at 10(-3) M Ca2+. Scatchard analyses of the fibrinogen binding showed that the membrane capacity for fibrinogen was 1.6 X 10(-12) mol/mg of membrane protein, with a dissociation constant (Kd) = 1.2 X 10(-8) M. When Ca2+ levels were manipulated by the addition of varying amounts of EGTA at a fixed Mg2+ concentration of 3 X 10(-3) M, specific binding of fibrinogen to platelet membranes occurred only at Ca2+ concentrations greater than or equal to 10(-6) M. Membranes isolated from platelets of an individual with Glanzmann's thrombasthenia bound only 12% as much fibrinogen as control platelets. The data in the present study suggest that there are two divalent cation binding sites that must be occupied for fibrinogen to bind: one site is specific for calcium and is saturated at 10(-6) M Ca2+; the other site is less specific and is saturated at a 10(-3) M concentration of either Ca2+ or Mg2+. Fibrinogen binding to intact platelets and, consequently, platelet aggregation only required 10(-3) M extracellular divalent cation and was not specific for Ca2+. These data indicate that the cytoplasm is a potential source for the requirement of 10(-6) M Ca2+, and that changes in the intracellular concentration of Ca2+ may cause the expression of fibrinogen receptors during ADP-induced platelet activation.

Blood Platelet Disorders↗
PubMed1983

Steady state kinetic parameters for the thrombin-catalyzed conversion of human fibrinogen to fibrin.

Steady state kinetic parameters were evaluated for the hydrolytic release of fibrinopeptides A and B (FPA and FPB) from human fibrinogen by human thrombin at pH 7.4, 37 degrees C, and gamma/2 0.15. At low concentrations of fibrinogen (less than 0.4 microM), the release of FPA from A alpha-chains was first order with respect to both the concentration of fibrinogen A alpha-chains and thrombin. The second order rate constant yielded a value of 11.6 (+/- 0.3) X 10(6) M-1 S-1 for the specificity constant (kcat/Km) for this process. Values of 84 (+/- 4) S-1 and 7.2 (+/- 0.9) microM were evaluated for kcat and Km for the thrombin-catalyzed release of FPA from normal human fibrinogen. The amino acid replacement ArgA alpha 16 leads to His present in fibrinogen Petoskey was shown to result in a 160-fold decrease in the specificity constant for hydrolysis at A alpha 16 and concomitant release of FPA. A kinetic analysis for determination of the sequentiality of release of fibrinopeptides was presented. It indicated that at least 97% of FPB was released after FPA. The specificity constant for release of FPB from intact fibrinogen (if it occurs) was less than 3% of that for release of FPA and less than 10% of that for release of FPB from des-A fibrinogen. The specificity constant for the release of FPB from des-A fibrinogen was 4.2 (+/- 0.2) X 10(6) M-1 S-1. The polymerization inhibitors EDTA and Gly-Pro-Arg-Pro inhibited release of FPB but not FPA. These observations are consistent with the generally accepted view that the predominant pathway for the conversion of normal human fibrinogen to fibrin is one wherein FPA is released, des-A fibrinogen polymerizes, and then FPB is released.

Edetic Acid↗
PubMed1983

Factors influencing the deaggregation of chymotrypsin-treated human platelets aggregated by fibrinogen.

Washed human platelets aggregated by ADP can be deaggregated by EDTA or PGE1, provided the release reaction does not occur; when the release reaction occurs platelets deaggregate less readily. Platelets treated with chymotrypsin are aggregated by fibrinogen indicating that fibrinogen receptors may be permanently exposed by this treatment. Fibrinogen-induced aggregation of chymotrypsin-treated platelets provides another method of bringing platelets into close contact with each other. Although EDTA deaggregated chymotrypsin-treated platelets aggregated by fibrinogen in a medium containing a physiological concentration of Ca2+, EDTA did not deaggregate these platelets if they were in a medium without calcium in which the release reaction occurs. In this medium, when ASA was added to prevent the release reaction, EDTA caused deaggregation. More fibrinogen associated with platelets in the medium without calcium than in the calcium-containing medium. In both media, EDTA displaced approximately half of the fibrinogen indicating that deaggregation is not solely dependent on dissociation of fibrinogen from its receptors. Thus when platelets undergo the release reaction, a form of platelet-to-platelet adhesion occurs that is not disrupted by chelation of divalent cations and is therefore not likely to involve only fibrinogen or thrombospondin and fibrinogen since the association of fibrinogen with its receptor requires Ca2+ and the binding of thrombospondin to platelets that have undergone the release reaction is also dependent on Ca2+.

Alprostadil↗
PubMed1983

The action of thrombin on modified fibrinogen.

The modification of canine fibrinogen with citraconic anhydride modified the epsilon-amino groups of the fibrinogen and at the same time generated additional negative charges into the protein. The addition of thrombin to the modified fibrinogen did not induce polymerization; however, the fibrinopeptide was released at a faster rate than from the unmodified fibrinogen. The physical properties of the citraconylated fibrinogen were markedly altered by the modification of 50-60 lysine residues in one hour. A modified fibrinopeptide-A was released by thrombin from the modified fibrinogen and was electrophoretically more anionic than the unmodified fibrinopeptide-A. Edman analysis confirmed the modification of the lysine residue present in the peptide. The rate of removal of citraconylated fibrinopeptide-A from modified fibrinogen by thrombin was 30 to 40 percent greater than the cleavage of unmodified fibrinopeptide-A from unmodified fibrinogen. However, the modification of 60 or more lysine residues in the fibrinogen produced a decrease in the rate of cleavage of citraconylated fibrinopeptide-A. The results suggest that additional negative charge in the vicinity of the attachment of fibrinopeptide-A to canine fibrinogen aids in the removal of the peptide by thrombin.

Amino Acids↗
PubMed1984

The role of the carbohydrate moiety in the biologic properties of fibrinogen.

The carbohydrate moiety of some glycoproteins influences their secretion and functional properties. We have examined the importance of the oligosaccharide chains of fibrinogen in this regard. Fibrinogen was labeled de novo by the addition to rabbit hepatocyte monolayer cultures of either 3H-amino-acids or [2-3H] mannose, in the presence or absence of tunicamycin, a potent inhibitor of glycosylation. Inhibition of glycosylation, which ranged from 75 to 80%, was determined by incorporation of [2-3H]mannose as quantitated by gel filtration. Synthesis and secretion of fibrinogen were quantitated by 3H-amino-acid incorporation, using anti-fibrinogen immunoaffinity column chromatography of medium and cell homogenates. Tunicamycin did not appreciably inhibit fibrinogen synthesis, as compared to a 30-40% inhibition of overall protein synthesis, determined by incorporation of 3H-amino-acids into trichloroacetic acid-precipitable material. There was no evidence that secretion of fibrinogen was impaired. Fibrinogen from medium was copurified by adding cold plasma fibrinogen as carrier. Nonglycosylated fibrinogen was found to be functional as demonstrated by incorporation of radioactivity into clots of the copurified material at a rate identical to that of glycosylated fibrinogen. When clotted in the presence of Ca2+ and Factor XIII, cross-linking of glycosylated and nonglycosylated fibrin was demonstrable on fluorography of sodium dodecyl sulfate-polyacrylamide gels, showing disappearance of gamma-chain and appearance of gamma-gamma-dimers.

Animals↗
PubMed1983

Xenopus fibrinogen. Characterization of subunits and hormonal regulation of biosynthesis.

In this paper we describe the purification and characterization of Xenopus plasma fibrinogen and the hormonal factors which regulate synthesis and secretion of fibrinogen in liver parenchymal cells in primary culture. As in other vertebrate species, Xenopus fibrinogen is composed of three nonidentical polypeptide chains, A alpha, B beta, and gamma. In contrast to mammalian fibrinogens, the B beta chain of Xenopus fibrinogen has a higher apparent molecular weight than the A alpha chain. The gamma chain has the lowest molecular weight in the frog protein, as in that of other species. The relatively large size of the frog B beta chain results from the unusually large size of the NH2-terminal B fibrinopeptide, which is released by thrombin cleavage of fibrinogen. Hormonal regulation of fibrinogen biosynthesis was examined using a primary cell culture system. Purified Xenopus liver parenchymal cells, maintained for several weeks in a defined culture medium, gradually decrease the synthesis and secretion of fibrinogen. Sustained production of this protein is dependent upon the addition of a glucocorticoid, dexamethasone, to the culture medium. Fibrinogen production is suppressed if an estrogen, estradiol-17 beta, is added to the culture medium together with dexamethasone and triiodothyronine. The Xenopus system provides new insight into the structure of fibrinogen, the evolution of this protein, and the hormonal factors which regulate its synthesis.

Animals↗
PubMed1982

The zymogen forms of blood coagulation factor XIII bind specifically to fibrinogen.

To examine the possibility that Factor XIII zymogens bind to fibrinogen, we have studied the reaction between radiolabeled Factor XIII and fibrinogen coupled to beads. Platelet and plasma Factor XIII were iodinated with Na(125I)iodide using lactoperoxidase. Both forms of 125I-Factor XIII retained greater than 92% of the transglutaminase activity. 125I-platelet and plasma Factor XIII specifically bound to human fibrinogen covalently coupled to either carboxylated latex or acrylonitrile beads but not to fetuin- or albumin-coated beads. Unlabeled platelet Factor XIII inhibited 90% of the total binding of 125I-platelet and 125I-plasma Factor XIII to fibrinogen, whereas human IgG, fetuin, and serum albumin had no effect. These data suggest that 125I-platelet and plasma Factor XIII specifically bind to fibrinogen by the a2 subunit. 125I-Factor XIII which was bound to the fibrinogen beads migrated identically to unbound material on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Soluble fibrinogen inhibited binding of 125I-Factor XIII to fibrinogen beads, indicating that binding is not due to alteration of the fibrinogen coupled to the beads. Binding of 125I-Factor XIII was reversible and time- and temperature-dependent: maximal binding occurred by 1 min at 37 degrees C. Binding was independent of calcium; 10 mM EDTA had no effect. Binding was dependent on sodium chloride concentration; complete inhibition of binding occurred at concentrations above 300 mM NaCl. The Kd for binding, 1 X 10(-8) M, is approximately 7-fold higher than the concentration of Factor XIII in plasma. These data support the hypothesis that Factor XIII circulates in plasma bound to fibrinogen. This interaction may play a role in regulating the physiologic activation and function of Factor XIII.

Blood Platelets↗
PubMed1993

[Fibrinogen, a vascular risk factor].

Epidemiological studies have consistently correlated plasma fibrinogen level to the risk of coronary heart disease (CHD) and acute ischemic stroke. Several mechanisms have been proposed such as the role of fibrinogen in the viscosity of blood, the participation of fibrinogen in both fibrin clot formation and platelet aggregation. However, there is no evidence that the increase in fibrinogen is directly responsible for the vascular disease since the cytokines which participate to the synthesis of fibrinogen by the hepatocytes, such as interleukin 6, could also induce an endothelial cell damage by increasing tumor necrotic factor (TNF) production. In these conditions fibrinogen increase could therefore only represent a marker of cytokine production which in turn is responsible for vascular injury. In addition, for the pathogenesis of atherosclerosis, the influence of fibrinogen is not only mediated by way of increased fibrinogen concentration but could be due to a structurally variant fibrinogen. The recent epidemiological studies have shown that the variation at the beta locus of fibrinogen is associated with an increase risk of peripheral atherosclerosis. The finding concerning dysfibrinogenemia and thrombosis (Dusart and Tampere) create further opportunities to enrich knowledge of the link between the association of abnormal gel structure and thrombotic diseases such as myocardial infarction or stroke at young age. This abnormal clot structure could contribute to thrombogenicity by decreasing the capacity of these clots to be degraded by fibrinolytic enzymes or by decreasing thrombin binding since fibrin is considered as a "thrombin trap".(ABSTRACT TRUNCATED AT 250 WORDS)

Fibrinogen↗
PubMed1996

Internalization of bound fibrinogen modulates platelet aggregation.

In agonist-stimulated platelets, the integrin alpha IIb beta 3 (glycoprotein IIb-IIIa) is converted from an inactive to an active fibrinogen receptor, thereby mediating platelet aggregation. With time after agonist addition, at least two events occur: fibrinogen becomes irreversibly bound to the platelet and, when stirring is delayed, platelets lose the ability to aggregate despite the presence of maximally bound fibrinogen. Because we previously identified an actively internalized pool of alpha IIb, beta 3 in platelets, we explored the possibility that both of these events might result from the internalization of fibrinogen bound to active alpha IIb beta 3. Under conditions of irreversible fibrinogen binding, fluorescence microscopy showed that biotinylated fibrinogen is rapidly internalized by activated platelets to a surface-inaccessible, intracellular pool. Flow cytometric analysis showed that the observed loss in accessibility to extracellular probes immediately precedes a loss in ability to the platelets to aggregate. Moreover, prevention of irreversible fibrinogen binding results in a prevention of internalization and a retention of aggregation capacity. Thus, the internalization of fibrinogen from the activated platelet surface appears to contribute not only to the irreversible phase of fibrinogen binding, but also to the downregulation of platelet adhesiveness. Fibrinogen internalization is therefore likely to represent a fundamental regulatory mechanism that modulates platelet function.

Adenosine Diphosphate↗