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PubMed2004

B beta Glu397 and B beta Asp398 but not B beta Asp432 are required for "B:b" interactions.

We synthesized three fibrinogen variants, BbetaE397A, BbetaD398A, and BbetaD432A, with substitutions at positions identified in crystallographic studies as critical for binding the "B" peptide, Gly-His-Arg-Pro-amide (GHRPam), to the "b" polymerization site. We examined thrombin- and batroxobin-catalyzed polymerization by turbidity measurements and found that BbetaE397A and BbetaD398A were impaired while BbetaD432A was normal. Changes in polymerization as a function of calcium were similar for variant and normal fibrinogens. We determined crystal structures of fragment D from the variant BbetaD398A in the absence and presence of GHRPam. In the absence of peptide, the structure showed that the alanine substitution altered only specific local interactions, as alignment of the variant structure with the analogous normal structure resulted in an RMSD of 0.53 A over all atoms. The structure also showed reduced occupancy of the beta2 calcium-binding site that includes the side chain carbonyl of BbetaD398, suggesting that calcium was not bound at this site in our polymerization studies. In the presence of peptide, the structure showed that GHRPam was not bound in the "b" site and the conformational changes associated with peptide binding to normal fragment D did not occur. This structure also showed GHRPam bound in the "a" polymerization site, although in two different conformations. Calcium binding was associated with only one of these conformations, suggesting that calcium binding to the gamma2-site and an alternative peptide conformation were induced by crystal packing. We conclude that BbetaE397 and BbetaD398 are essential for the "B:b" interaction, while BbetaD432 is not.

Alanine↗

PubMed2006

Binding of synthetic B knobs to fibrinogen changes the character of fibrin and inhibits its ability to activate tissue plasminogen activator and its destruction by plasmin.

Synthetic peptides corresponding to the amino-terminal sequence of the beta chain of fibrin increase the turbidity of fibrin clots, whether they are generated by the direct interaction of thrombin and fibrinogen or by the reassociation of fibrin monomers. The turbidity of batroxobin-induced clots, which are characteristically "fine," is increased even more dramatically. Pentapeptides are more effective than tetrapeptides. Surprisingly, the same peptides also delay fibrinolysis, whether activated by exogenously added plasmin or from the fibrin-enhanced stimulation of tissue plasminogen activator (tPA) activation of plasminogen. The peptides have only a very slight effect on the plasmic hydrolysis of a chromogenic peptide, either by the direct addition of plasmin or by plasmin generated from plasminogen by tPA. The synthetic peptides mimicking the B knobs appear to exert their action in two ways. First, they render fibrin less vulnerable to attack by plasmin. Second, they delay the fibrin activation of tPA. The latter is attributed to their ability to prevent the binding of the authentic B knob, which itself is located at the end of a flexible 50-residue tether and which needs time to find its elusive "hole". We propose that, when after a while the tethered knob does become inserted, it locks the betaC domain in a conformation that allows access to tPA-plasminogen-binding sites, whereas the untethered synthetic knobs restrict the fibrin to a conformation in which those sites remain inaccessible. Thus, although the interaction involving the A knob and gammaC hole is the basis for the polymerization of fibrin, the comparable but delayed interaction involving the B knob and the betaC hole is ultimately directed at preparing the clot for its eventual destruction.

Batroxobin↗

PubMed2005

Demonstration of enhanced endogenous fibrinolysis in thrombin activatable fibrinolysis inhibitor-deficient mice.

To investigate the importance of thrombin activatable fibrinolysis inhibitor (TAFI) in the stabilization of plasma clots, we have compared fibrinolysis in TAFI-deficient (KO) and wild-type (WT) littermate mice. TAFI-deficient mice were previously generated by targeted gene disruption. The level of TAFI activity generated in plasma from WT mice in the presence of added thrombin and thrombomodulin (activatable TAFI) is twice that of plasma from TAFI heterozygous mice (HET); no activatable TAFI is detected in TAFI KO plasma. In vitro, TAFI KO plasma clots lysed faster than WT plasma clots, and HET plasma clots lysed at an intermediate rate. The rate of clot lysis for KO mice is not changed in the presence of potato carboxypeptidase inhibitor, a specific inhibitor of TAFIa, whereas the WT and HET clot lysis rates are increased in the presence of potato carboxypeptidase inhibitor. C-terminal lysine residues are preserved on partially degraded clots from KO mice, but are absent from partially degraded WT clots. In vivo, in a batroxobin-induced pulmonary embolism model, KO mice displayed a lower retention of fibrin in the lungs than did WT mice. These results are the first demonstration of enhanced endogenous fibrinolysis in an in vivo model without the addition of exogenous thrombolytic.

Animals↗

PubMed1981

Pseudointima in expanded polytetrafluoroethylene graft implanted in the inferior vena cava of normal and defibrinogenated dogs.

The pseudointimal formation in an expanded polytetrafluoroethylene graft implanted in the canine inferior vena cava was studied by light and transmission electron microscopy. Five of 6 grafts in the control group and all of the 10 grafts in the batroxobin-defibrinogenated group were patent, and provided for the investigation. The thickness of the mural thrombus formed within 3 days was significantly decreased in the severely defibrinogenated dogs, in which the fibrinogen concentration was below 0.40 gm/L, as compared to the controls and the moderately defibrinogenated dogs, in which the fibrinogen concentration was at highest 0.72-0.87 gm/L. In spite of reducing the fibrinogen concentration to unmeasurable levels after 3 days, there was no obvious difference in the process of pseudointimal formation between the moderately defibrinogenated dogs and the controls. In the severely defibrinogenated dogs, loose and spongoid mural thrombus required a longer time to be reorganized.

Animals↗

PubMed2000

Prevention of rat cerebral aneurysm formation by inhibition of nitric oxide synthase.

BACKGROUND: Cerebral saccular aneurysm is a major cause of subarachnoid hemorrhage, one of the cerebrovascular diseases with the highest mortality. The mechanisms underlying the development of aneurysms, however, still remain unclear. We have made a series of reports on an animal model of experimentally induced cerebral aneurysms that resemble human cerebral aneurysms in their location and morphology, suggesting that the arterial wall degeneration associated with aneurysm formation develops near the apex of arterial bifurcation as a result of an increase in wall shear stress. Using the animal model and human specimens, we examined the role of nitric oxide (NO) in the degenerative changes and cerebral aneurysm formation. METHODS AND RESULTS: Inducible NO synthase (iNOS) was immunohistochemically located at the orifice of human and rat aneurysms. Nitrotyrosine distribution was also seen in the human aneurysm. Although no iNOS immunostaining was found in normal arteries, iNOS immunoreactivity was observed in parallel with the development of early aneurysmal changes in rats. In contrast, during the early development of aneurysm, endothelial NOS immunostaining in the endothelium was weakened compared with that in the control arteries. An NOS inhibitor, aminoguanidine, attenuated both early aneurysmal changes and the incidence of induced aneurysms. A defibrinogenic agent, batroxobin, which may diminish shear stress by reduction of blood viscosity, prevented iNOS induction as well as early aneurysmal changes. CONCLUSIONS: The evidence suggests that NO, particularly that derived from iNOS, is a key requirement for the development of cerebral aneurysm. The iNOS induction may be caused by an increase in shear stress near the apex.

Animals↗

PubMed2000

Thromboelastograph assay for measuring the mechanical strength of fibrin sealant clots.

In order to provide sustained hemostasis or tissue sealing, fibrin sealants must generate adhesive clots with mechanical properties capable of resisting forces, such as shear, that might break or tear the clot. Commercial preparations of fibrin sealants should generate clots of adequate and consistent mechanical strength. The mechanical strength of fibrin sealants is often measured as bonding strength in in vivo or ex vivo animal wound models. These tests can be useful predictors of clinical efficacy. However, these, as well as many in vitro tensile strength tests for fibrin sealant, tend to be laboratory specific and require extensive reagent preparation time and analyst training. The thromboelastograph has historically been used to screen for plasma protein and platelet disorders that lead to defective clot formation. The authors have developed a simple in vitro test, using a standard thromboelastograph that can provide reliable, reproducible information on the rheology of clots generated by fibrin sealant preparations. Using this method, the shear strength of fibrin sealant clots was measured and shown to correlate with the fibrinogen, but not the thrombin, concentration in the sealant. Shear strength was also shown to correlate with the sealant concentration of the fibrin cross-linking proenzyme, factor XIII. Sealants containing lysine, which can act as an alternate substrate for factor XIII enzyme and prevent efficient fibrin chain cross-linking, were shown by this method to generate clots of substantially reduced shear strength. The method distinguished between thrombin-catalyzed clot formation and other fibrinogen clotting mechanisms as evidenced by the significantly lower shear strength associated with batroxobin-generated fibrin clots.

Batroxobin↗

PubMed2003

Recombinant BbetaArg14His fibrinogen implies participation of N-terminus of Bbeta chain in desA fibrin polymerization.

We synthesized BbetaArg14His fibrinogen with histidine substituted for arginine at the Bbeta thrombin-cleavage site. This substitution led to a 300-fold decrease in the rate of thrombin-catalyzed fibrinopeptide B (FpB, Bbeta 1-14) release, whereas the rate of FpA release was normal with either thrombin or the FpA-specific enzyme, batroxobin. Both thrombin- and batroxobincatalyzed polymerization of BbetaArg14His fibrinogen were significantly impaired, with a longer lag time, slower rate of lateral aggregation, and decreased final turbidity. Moreover, desA monomer polymerization was similarly impaired, demonstrating that the histidine substitution itself, and not the lack of FpB cleavage, caused the abnormal polymerization of BbetaArg14His fibrin. Scanning electron microscopy showed BbetaArg14His fibrin fibers were thinner than normal (BbetaArg14His, approximately 70 nm; normal, approximately 100 nm; P <.0001), as expected from the decreased final turbidity. We conclude that the N-terminus of the Bbeta chain is involved in the lateral aggregation of normal desAprotofibrils and that the Arg-->His substitution disrupts these interactions in BbetaArg14His fibrinogen.

Amino Acid Substitution↗

PubMed2000

The cleavage and inactivation of plasminogen activator inhibitor type 1 and alpha2-antiplasmin by reptilase, a thrombin-like venom enzyme.

Reptilase, defibrase and ancrod are thrombin-like venom enzymes that cleave fibrinogen to release fibrinopeptide-A and generate fibrin monomers. Although these enzymes decrease fibrinogen levels in vivo, presumably by enhancing fibrinolytic activity, the mechanism has not been identified. In the present study, we analyzed their effects on the inhibitors of fibrinolysis. Plasminogen activator inhibitor-1 (PAI-1) was cleaved at its C-terminus by reptilase and lost its specific activity. Alpha2-antiplasmin (alpha2-AP) was cleaved both at the Pro19-Leu20 peptide bond and at its C-terminus by reptilase, and also lost its specific activity. The apparent second-order rate constants (mol/l per min per Batroxobin unit) were 0.22 for the cleavage of PAI-1 (3.2 micromol/l) and 0.19 for that of alpha2AP (6.4 micromol/l), which were approximately 200-fold lower than that (47.0) for the cleavage of fibrinogen (1.1 micromol/l). Neither defibrase nor ancrod cleaved and inactivated these inhibitors. Only reptilase enhanced euglobulin clot lysis in vitro at high concentration, due probably to PAI-1 inactivation. Since all these three enzymes enhance fibrinolysis similarly during defibrination therapy, the neutralization or inactivation of the inhibitors of fibrinolysis appeared not to represent the main mechanism for the enhancement.

Ancrod↗

PubMed1990

Fibrinogen Stony Brook II: partial characterization of a heterozygously transmitted peptide A anomaly.

We describe preliminary studies of a new familial dysfibrinogen, fibrinogen Stony Brook II, present in a propositus and his mother. Both presented with a history of unexplained and chronic joint swelling following trauma, and the propositus suffered recurrent knee haemarthroses following arthroscopic surgery. Prolonged plasma thrombin times required a 3-5 fold excess of normal plasma for correction. Isolated fibrinogen displayed prolonged clotting times and delayed onset of clot turbidity. Also, an abnormal peptide could be released by thrombin but not by batroxobin along with approximately half the expected amounts of normal A peptide. Assessed by its thrombin release and by its early HPLC retention position, the abnormal peptide suggests a possible A alpha-16-Arg----His substitution. The data suggests an association in these probands between this heterozygously transmitted anomaly and the apparently impaired healing in hypovascular sites.

Afibrinogenemia↗

PubMed1985

[Hemodilution, defibrinogenation and plasmapheresis in hemorheology].

Blood and plasma viscosity can be influenced by various therapeutic procedures: among these, that of hemodilution stands out. This can be hypovolemic, normovolemic or hypervolemic; it is hypovolemic if blood subtraction is not followed by a liquid reintroduction, it is normovolemic or hypervolemic if there is a liquid reintroduction of the same or higher quantity than the subtracted blood mass. This method has been considered very favorably by surgery in order to save blood for transfusions. Hypervolemic hemodilution can also be carried out without blood subtraction; a report on this method shows good clinical results and positive hematochemical and hemodynamic effects obtained on 93 peripheral vasculopathic patients at stages III and IV of the Fontaine classification. Plasmapheresis, which would be best called plasma-exchange, consists in the removal of that part of the patient's plasma containing abnormal proteins, immune complexes or toxins, and in its substitution by other colloids or crystalloids. Defibrinogenation is not much employed in Italy, as the most effective drugs, such as ancrod and batroxobin are not available in this country. The good results reported were transitory, due to the rapid appearance of antibodies which can inhibit the effects of these drugs. Nevertheless, there also exist minor fibrinogenolytic drugs.

Ancrod↗

PubMed1979

[The use of reptilase for electrophoresis of heparinized plasma (author's transl)].

Fibrinogen can be precipitated from Heparin-plasma by Reptilase (Batroxobin). The electrophoretic pattern of the supernatant on cellulose acetate is nearly identical with that of the corresponding serum. This technique is also useful in differentiating a gradient of fibrinogen (caused by effects of anticoagulants) from a myeloma peak.

Batroxobin↗

PubMed1981

[Fibrinogen and plantar edema induced by lambda carrageenan].

1. Batroxobine which induces fibrinogen consumption, accelerates the development of 48/80 and lambda carrageenan oedema: in the rat the various products released from fibrinogen and fibrin increase these inflammatory reactions. 2. Heparin and epsilon-aminocaproic acid have no influence on carrageenan oedema: the derivatives of fibrinogen do not take part in the constitution of the inflammatory reaction induced by carrageenan. 3. The anti-inflammatory action of this sulfated polygalactose does not depend on its anti-coagulant activity.

Animals↗

PubMed1982

Effects of various antiplatelet drugs and defibrinating agent on experimental glomerulonephritis in rats.

Two types of experimental GN induced by immunological procedures. Heymann-type AIC-GN and NTN, were treated with anticoagulant agents. Dipyridamole, aspirin, ticlopidine or batroxobin was administered either to rats with AIC-GN for 14 to 28 days or to NTN rats 2 days prior to injection with NTS and 14 to 21 days thereafter. A significant decrease in the amount of urinary protein was observed only in rats treated with 12.5 to 50.0 mg/kg dipyridamole daily, whereas no significant decrease in proteinuria was observed in either AIC-GN or NTN rats treated with the other agents. Histopathologically, no improvement in the light and electron microscopic findings was noted in AIC-GN rats treated with these agents, even with dipyridamole. On the other hand, in NTN rats, light and electron microscopic study of the kidneys from rats sacrificed 30 to 60 min after NTS injection revealed that platelet aggregation and inflammatory changes in the glomeruli were remarkable reduced in rats pretreated with 56.4 mg/kg aspirin or 50.0 mg/tg triclopidine daily, but no difference in the renal lesions between rats treated with aspirin or triclopidine and control animals were observed 2 weeks after NTS injection. No histological improvement was observed in rats pretreated with dipyridamole. It would be reasonable to conclude from these results that the favorable effect of dipyridamole on proteinuria is not related to its antiplatelet activity and that platelet aggregation is not essential to the development of renal lesions in rat AIC-GN and NTN. (J Lab Clin Med 99:428, 1982.)

Animals↗

PubMed1983

Chemical control of hyperfibrinolytic states by synthetic inhibitors of fibrinolytic enzymes.

The effects of two types of synthetic inhibitor of fibrinolytic enzymes (omega-aminocarboxylic acids, benzamidine derivatives) on intravascular fibrinolysis and fibrinogenolysis were studied in rats. Generalised primary fibrinogenolysis was produced by infusion of human plasminogen-streptokinase complex, secondary fibrinolysis was induced by infusion of the thrombin-like enzyme batroxobin. The inhibitors exerted different effects on the hyperfibrinolytic states. The omega-aminocarboxylic acids (PAMBA, AMCA) inhibited fibrinolysis more effective than fibrinogenolysis. In contrast, the benzamidines (APPA, NANP) were more potent inhibitors of fibrinogenolysis. Aprotinin examined for comparison behaved like the benzamidine derivatives.

4-Aminobenzoic Acid↗

PubMed1983

[Fibrinolytic and defibrinogenation therapy].

Plasma fibrinogen is one of the main determinants of blood viscosity and is known to play an important role in the pathogenesis of venous and arterial thromboembolism. The pharmacological intervention on these factors can be achieved by lowering fibrinogen. Plasma fibrinogen concentrations can be lowered by fast-acting and slow-acting drugs. Among fast-acting drugs, fibrinolytic agents (such as streptokinase, urokinase, brinase and plasmin) act by cleaving FGN directly or indirectly through the formation of the proteolytic enzyme plasmin. Defibrinogenating agents (ancrod and batroxobin) are thrombin-like enzymes which induce the in vivo formation of fibrin microclots characterized by a peculiar physicochemical structure rendering them more easily cleared by the reticuloendothelial system. There is a clear-cut evidence for the clinical efficacy of fast-acting FGN-lowering drugs in the prevention and treatment of a number of clinical conditions associated with thromboembolic manifestations. However, it is not well established to which extent the effectiveness is due to their action on blood viscosity rather than to their fibrinolytic and anticoagulant properties. Slow-acting drugs (such as anabolic steroids, clofibrate, ticlopidine and pentoxifylline) decrease plasma FGN less rapidly and to a smaller extent than fast-acting drugs. Unlike these, they can be employed in long-term treatments. Clinical trials have clearly shown their clinical efficacy in a number of conditions associated with an altered microcirculation (Raynaud's syndrome, liposclerosis and postphlebitic syndrome). Their effect on blood viscosity is likely to be an important determinant of the clinical efficacy of these drugs.

Ancrod↗

PubMed1981

Haemostatic clot formation at anastomosis of synthetic venous graft in defibrinogenated dogs: a scanning electron microscopic study.

A segment of the inferior vena cava was replaced by an expanded polytetrafluoroethylene graft in 13 dogs. Five of them served as a control group, while the other 8 were moderately or severely defibrinogenated with subcutaneous batroxobin. Plasma fibrinogen decreased to extremely low values throughout the experiment in the defibrinogenated dogs except in the moderately treated group in which it temporarily rose to 0.72-0.87 g/l on the first postoperative day. Scanning electron microscopic observations of the haemostatic clot formed at the anastomoses of the graft revealed no significant morphological differences in platelet adhesion and/or aggregation between the three groups. These findings confirmed that platelets play a key role in primary haemostasis during defibrinogenation. The fibrin network was slightly diminished and only short fibrin filaments could be seen in the moderately and severely defibrinogenated groups respectively. These differences in composition of the clots are discussed in relation to their haemostatic capacity.

Animals↗

PubMed1982

Effect of calcium and synthetic peptides on fibrin polymerization.

Human fibrinogen was subjected to limited proteolytic attack by thrombin, batroxobin or Agkistrodon contortrix thrombin-like enzyme, yielding desAB-, desA- or desB-fibrin monomers, respectively. Turbidity curves demonstrated that, with all three enzymes, the polymerization process was strongly accelerated by increasing the calcium concentration from 10(-5) M to 10(-4) M. Synthetic peptide Gly-His-Arg (5 mM), an analogue of the aminoterminal sequence of fibrin beta-chain, inhibited aggregation of desB-fibrin monomers at physiological calcium concentration whereas it enhanced aggregation of desA- and desAB-fibrin monomers at calcium concentrations below 10(-4) M. On the other hand, Gly-Pro-Arg (1 mM) corresponding to the amino-terminus of fibrin alpha-chain, dramatically inhibited aggregation of both desA- and desB-fibrins, but it only moderately affected the polymerization of thrombin-induced monomers. We conclude that the observed effects of Gly-Pro-Arg and Gly-His-Arg are not due solely to their competition with fibrin amino-termini for the respective binding sites in the D-domain, but rather reflect conformational changes in fibrin monomers which affect the polymerization process.

Batroxobin↗

PubMed1993

Unusual A alpha 16Arg-->Cys dysfibrinogenaemic family: absence of normal A alpha-chains in fibrinogen from two of four heterozygous siblings.

We describe studies of fibrinogen from an asymptomatic family, Fibrinogen Frankfurt XIII, with the substitution A alpha 16Arg-->Cys. The mother's fibrinogen was normal as assessed by plasma fibrinogen assays but the father and four children were affected. Two affected siblings and their father had thrombin times approximately 20 s longer than controls, fibrinogen of 35-52 mg/dl by clotting assay and normal levels by immunoassay. Measured by HPLC their fibrinogen had decreased amounts of releasable fibrinopeptide A (FpA) relative to normal controls. In addition, their fibrinogen was partly coagulable with batroxobin and fully coagulable with thrombin; consistent with its incomplete FpA release. In contrast, plasma from the other two siblings had thrombin times > 2 min longer than controls, and their fibrinogen was < 10 mg/dl by clotting assay and normal by immunoassay. Their isolated fibrinogen did not release FpA (n = 5) and formed thrombin clots only at cold temperatures indicating formation of desBB fibrin. Assessed by SDS-PAGE, only monomeric fibrinogen was seen in isolated fibrinogen, washed and unreduced plasma immunoprecipitates, non-crosslinked plasma clots or 56 degrees C precipitates. DNA sequencing of PCR products using oligonucleotide primers which flanked sequences coding for A alpha 7Asp to 35Phe, disclosed mutant (C-->T, coding for A alpha 16Cys) and wild type alleles present in both severely affected siblings. It is concluded that circulating fibrinogen contained only mutant FpA. A possible second mutation, not apparent from plasma assays on the mother, is believed to account for the absence of releasable normal FpA in circulating fibrinogen.

Alleles↗