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PubMed1993

The effect of antithrombin III-independent thrombin inhibitors and heparin on fibrin accretion onto fibrin-coated polyethylene.

Prosthetic vascular grafts become coated with a layer of fibrin that contributes to graft thrombosis and occlusion. We compared the effect of antithrombin III-independent inhibitors of thrombin with heparin for their ability to prevent fibrin accretion onto a model of a vascular graft formed in vitro by coating polyethylene tubing with thrombin bound to a layer of polymerized fibrin. Equivalent antithrombin concentrations of heparin, D-Phe-Pro-Arg CH2Cl (PPACK), recombinant hirudin (r-hirudin), and Hirulog-1 were added to barium chloride-absorbed plasma containing radiolabelled fibrinogen. Whereas, PPACK and r-hirudin persistently inhibited fibrin accretion, the inhibition by heparin was transient. Hirulog-1 had no effect on early fibrin accretion and was actually associated with enhanced accretion at 30 min (control 11.7 +/- 2.0 micrograms fibrin/cm2; Hirulog-1, 18.4 +/- 3.5 micrograms fibrin/cm2, p < 0.001). Both Hirulog-1 and r-hirudin displaced radiolabelled thrombin from the fibrin surface. Whereas hirudin-thrombin complexes are stable, Hirulog-1 produces only transient inhibition of the displaced thrombin thereby accounting for the enhanced fibrin accretion with this anticoagulant. These studies show that the antithrombin III-independent inhibitors, r-hirudin and PPACK, are more effective inhibitors of fibrin accretion onto fibrin-coated polyethylene than heparin or Hirulog-1. In addition, they emphasize the importance of determining the ability of anticoagulants to displace thrombin from fibrin and to form stable thrombin-inhibitor complexes; lack of stability of thrombin-inhibitor complexes must be countered by levels of anticoagulant that are adequate to maintain its effectiveness.

Amino Acid Chloromethyl Ketones↗
PubMed1989

[Diagnosis of disseminated intravascular coagulation: the value of soluble fibrin, D-dimers and fibrin(ogen) split products].

The validity of the fibrin(ogen) derivatives 'soluble fibrin, D-dimers and fibrin(ogen) degradation products' was compared with other parameters in early and sensitive diagnosing of disseminated intravascular coagulation (DIC). In a clinical study 900 patients' samples from separate, defined groups were examined, including course observations of intensive care patients (n = 38) and patients with acute pancreatitis. The fibrin(ogen) derivatives correlated very well with the degree of blood coagulation disturbances: in particular, D-dimers and soluble fibrin proved to be more sensitive in early diagnosis of DIC than other parameters. The SF-PS-turbidimetry demonstrated a good validity and practicality in the quantitative determination of soluble fibrin, but a suitable analyzer is essential. Determination of D-dimers is preferable to that of fibrin(ogen) degradation products (both in the latex-agglutination test) because of the better sensitivity and practicality; even more sensitive results were provided by the D-dimer-ELISA, which is, however, not practical in acute diagnostics. The decrease in protein C was at least equally sensitive as the antithrombin III-levels in indicating the consumption of the hemostatic potential. The decrease of thrombocyte counts and fibrinogen levels could first be detected in a later stage of DIC. In conclusion, D-dimers and soluble fibrin can improve the DIC diagnostics, making them more reliable; additionally, antithrombin III and possibly protein C deserve further consideration, although the fibrin(ogen) derivatives are apparently of greater importance.

Acute Disease↗
PubMed1998

Effects of fibrin micromorphology on neurite growth from dorsal root ganglia cultured in three-dimensional fibrin gels.

The effect of fibrin matrix micromorphology on neurite growth was investigated by measuring the length of neurites growing in three-dimensional fibrin gels with well characterized micromorphologies. Dorsal root ganglia (DRGs) from 7-day chick embryos were entrapped and cultured in gels made from varying concentrations of fibrinogen (5-15 mg/mL) or calcium (2-10 mM). The length of growing neurites was measured with light videomicroscopy, and the number and diameter of fibrin fiber bundles were measured from scanning electron micrographs. An increase in fibrinogen concentration caused a decrease in the average fiber bundle thickness, an increase in the number of fiber bundles, and a marked decrease in neurite length. Gels made with different calcium concentrations had a similar range of variation in fibrin fiber bundle number or diameter, but these variations had little effect on neurite and associated nonneuronal cell outgrowth. These results provide insights into the process of neurite advance within fibrin and may be useful in the design of fibrin-based materials used for peripheral nerve regeneration. Furthermore, this study provides the first detailed experimental data on the micromorphology of fibrin matrices made from more than 5 mg/mL of fibrinogen and indicates that existing kinetic models of fibrin polymerization do not accurately predict fibrin structure at these higher concentrations.

Animals↗
PubMed1994

Fibrin structures during tissue-type plasminogen activator-mediated fibrinolysis studied by laser light scattering: relation to fibrin enhancement of plasminogen activation.

The aim was to relate fibrin structure and the stimulatory effect of fibrin on plasminogen activation during t-PA-mediated fibrinolysis using Lys78-plasminogen as activator substrate. Structural studies were undertaken by static and dynamic laser light scattering, cryo transmission electron microscopy and by the measurement of conversion of fibrin to X-, Y- and D-fragments. The kinetics of plasmin formation were monitored by measurement of the rate of pNA-release from Val-Leu-Lys-pNA. The process of fibrin formation and degradation comprised three phases. In the first phase, protofibrils with an average length of about 10 times that of fibrinogen were formed. The duration of this phase decreased with increasing t-PA concentration. The second phase was characterized by a sudden elongation and lateral aggregation of fibrin fibers, most pronounced at low levels of t-PA, and by formation of fragment X-polymer. The third phase was dominated by fragmentation of fibers and by formation of Y- and D-fragments. Plasmin degraded the fibers from within, resulting in the formation of long loose bundles, which subsequently disintegrated into thin filaments with a length of less than 10 and a mass per length close to one relative to fibrinogen. Plasmin generation at high t-PA concentrations sets in just prior to (and at low t-PA concentrations shortly after) the onset of the rapid second phase of elongation and lateral aggregation of fibrin fibers. The maximal rate of plasmin formation per mol t-PA was the same at all concentrations of activator and was achieved close to the time of the peak level of fragment X-polymer. Plasmin formation ceased after formation of substantial amounts of Y- and D-fragments. At this stage the length was between 300 and 3 and the mass per length close to 1, both relative to fibrinogen. In conclusion our results indicate that (1) formation of short fibrin protofibrils is the minimal requirement for the onset of the stimulatory effect of fibrin on plasminogen activation by t-PA, (2) formation of fragment X protofibrils is sufficient to induce optimal stimulation of plasminogen activation, and (3) plasmin degrades laterally aggregated fibrin fibers from within, resulting in the conversion of the fibers into long loose bundles, which later disintegrate into thin filaments.

Amino Acid Sequence↗
PubMed1985

Quantitative characterization of the binding of plasminogen to intact fibrin clots, lysine-sepharose, and fibrin cleaved by plasmin.

The binding of human Glu- and Lys-plasminogens to intact fibrin clots, to lysine-Sepharose, and to fibrin cleaved by plasmin was quantitatively characterized. On intact fibrin clots, there was one strong binding site for Glu-plasminogen with a dissociation constant, Kd, of 25 microM and one strong binding site for Lys-plasminogen with a Kd of 7.9 microM. In both cases, the number of plasminogen binding sites per fibrin monomer was 1. Also, a much weaker binding site for Glu-plasminogen was observed with a Kd of about 350 microM. Limited digestion of fibrin by plasmin created additional binding sites for plasminogen with Kd values similar to the binding of plasminogen to lysine-Sepharose. This was predictable given the observations that plasminogen binds to lysine-Sepharose and can be eluted with epsilon-aminocaproic acid [Deutsch, D.G., & Mertz, E.T. (1970) Science (Washington, D.C.) 170, 1095-1096] and that plasmin preferentially cleaves fibrin at the carboxy side of lysyl residues [Weinstein, M.J., & Doolittle, R.F. (1972) Biochim. Biophys. Acta 258, 577-590], because the structures of the lysyl moiety in lysine-Sepharose and of epsilon-aminocaproic acid are identical with the structure of a COOH-terminal lysyl residue created by plasmin cleavage of fibrin. The Kd for the binding of Glu-plasminogen to lysine-Sepharose was 43 microM and for fibrin partially cleaved by plasmin 48 microM. The Kd for the binding of Lys-plasminogen to lysine-Sepharose was 30 microM. With fibrin partially cleaved by plasmin, there were two types of binding sites for Lys-plasminogen, one with a Kd of 7.6 microM and the other with a Kd of 44 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

Affinity Labels↗
PubMed2000

Thrombogenic effects of a nonthrombin-based fibrin sealant compared with thrombin-based fibrin sealant on microvenous anastomoses in a rat model.

The efficacy and safety of tissue adhesives needs to be clearly defined. A thrombin-based preparation of fibrin sealant has recently been shown to have deleterious effects on microvascular anastomoses in an animal model. The authors found that fibrin sealant constructed with a high concentration of bovine thrombin (1,000 IU per milliliter) was detrimental to microvascular patency when applied to the anastomosis in a rat free flap model. The microvenous anastomosis had the highest rate of thrombosis and failure in this model. A nonthrombin-based fibrin sealant has recently become available for experimental investigation. This study examined the thrombogenic effect of this nonthrombin-based fibrin sealant on microvenous anastomoses in a rat free flap model compared with the effect of traditionally prepared fibrin sealant with varying concentrations of thrombin. The conclusions reveal that flap survival with application of the nonthrombin-based fibrin sealant to the anastomosis was comparable with flap survival of the control animals. Flap survival with application of the traditionally prepared thrombin-based fibrin sealant was also comparable with flap survival of the control animals when a concentration of 500 IU per milliliter of thrombin was used. However, flap survival decreased significantly (p <0.005) when a concentration of 1,000 IU per milliliter of thrombin was used in the construct of the fibrin adhesive. These results support the previous findings of the harmful effects of thrombin when used in high concentrations and applied to the microvenous anastomosis of this free flap model. Moreover, this initial investigation with a nonthrombin-based fibrin sealant did not show any deleterious effects on the microvenous anastomosis compared with control animals.

Anastomosis, Surgical↗
PubMed1986

Fibrin in peritonitis. V. Fibrin inhibits phagocytic killing of Escherichia coli by human polymorphonuclear leukocytes.

Fibrin deposition initiated by peritonitis is thought to be an important local defense mechanism because it sequesters and walls off bacterial spillage. However, fibrin has been shown to predispose to residual abscess formation in rat peritonitis model. To examine the potential mechanisms of this effect, fibrin was tested in vitro for its inhibitory effect on neutrophil function. At all concentrations tested (50-1000 mg/dl), fibrin significantly impaired the ability of neutrophils to kill Escherichia coli. This inhibition occurred in a dose dependent fashion with almost complete prevention of killing at the highest concentration tested. Further studies showed that pre-exposure to fibrin did not reduce the neutrophil's ability to degranulate, undergo a respiratory burst, or kill E. coli, indicating that fibrin did not cause irreversible damage to the normal microbicidal functions of the neutrophil. However, fibrin, at physiologic concentrations, significantly impaired phagocytosis of radiolabeled E. coli. The data support the concept that phagocytosis of bacteria is impaired by neutrophils enmeshed in fibrin. Thus, contaminated fibrin could act as a nidus for residual abscesses formation following peritonitis even if an adequate number of normal leukocytes were present.

Escherichia coli↗
PubMedDate not supplied

Bioactivity of the vascular endothelial growth factor trapped in fibrin clots: production of IL-6 and IL-8 in monocytes by fibrin clots.

The blood coagulation cascade is activated following vascular-wall injury. The serine protease thrombin is the final protease in this cascade that causes the formation of fibrin from fibrinogen. Thrombin also causes the activation of platelets, which are trapped in a fibrin net followed by hemostasis. Platelets gathered into fibrin clots release several growth factors such as platelet-derived growth factor and transforming growth factor beta. In the present study, we demonstrated that the vascular endothelial growth factor (VEGF) could be bound to fibrin clots in the plasma, and that incubation of the endothelial cells with these VEGF-bound fibrin clots induced proliferation of endothelial cells. Thus, it suggests that clot-bound VEGF may play a role in wound healing through the proliferation of endothelial cells and vascular smooth-muscle cells. On the other hand, a noticeable migration of monocytes was observed when they were cultured on dishes in the presence of VEGF-bound fibrin clots. Moreover, peripheral blood monocytes incubated in the presence of VEGF-bound fibrin clots strikingly increased the production of IL-6 and IL-8, demonstrating that VEGF trapped in fibrin clots not only induces proliferation of human umbilical vein endothelial cells and migration of monocytes but also enhances secretion of IL-6 and IL-8. Thus, our data suggest that fibrin clots that contain several growth factors act as a bioactive reservoir and may play an important role in hemostasis as well as wound healing.

Blood Coagulation↗
PubMed2004

Salmon fibrin supports an increased number of sprouts and decreased degradation while maintaining sprout length relative to human fibrin in an in vitro angiogenesis model.

Salmon-derived fibrin has been proposed as a preferred alternative to human or bovine fibrin because of its reduced potential for disease transmission. Here we evaluate salmon fibrin as an alternative ECM support for therapeutic angiogenesis applications, such as vascularizing engineered tissues. Human umbilical vein endothelial cells (HUVEC) seeded on gelatin beads and suspended in either salmon or human fibrin sprouted and formed capillary-like structures. Sprout length was generally increased with the addition of bFGF and VEGF and further increased with the addition of phorbol myristate acetate (PMA). The number of sprouts per bead was increased 61-188% in salmon fibrin relative to human fibrin (alpha < 0.0005) in cultures receiving growth factors and PMA, while average sprout lengths were similar for HUVEC within human or salmon fibrin. Additionally, under these conditions in the absence of a protease inhibitor, HUVEC appeared to degrade human, but not salmon, fibrin. These results support the idea that salmon fibrin may be an attractive alternative ECM able to support microvascular network formation.

Animals↗
PubMed1976

Fibrin formation: the role of the fibrinogen-fibrin monomer complex.

The process of fibrin formation using highly purified fibrinogen and thrombin was studied using laser fluctuation spectroscopy, a method that rapidly determines particle size in a solution. Two periods in fibrin clot formation were noted: an induction period during which no fibrin polymerization occurred and a period of rapid increase in particle size. Direct measurement of fibrin monomer polymerization and fibrinopeptide release showed no evidence of an induction period. These observations were best explained by a kinetic model for fibrin clot formation incorporating a reversible fibrinogen-fibrin monomer complex. In this model, the complex serves as a buffer system during the earliest phase of fibrin formation. This prevents the accumulation of free polymerizable fibrin monomer until an appreciable amount of fibrinogen has reacted with thrombin, at which point the fibrin monomer level rises rapidly and polymerization proceeds. Clinically, the complex may be a homeostatic mechanism preventing pathological clotting during periods of elevated fibrinogen.

Animals↗
PubMed1976

The effect of the fibrinogen concentration and the leukocyte count on intravascular fibrin deposition from soluble fibrin monomer complexes.

Fibrin formation from fibrin monomer (FM) complexes was studied in experimental animals utilizing a previously described technique for quantitating fibrin deposition. A uniform thrombin infusion was used to produce FM, fibrinolysis being inhibited by EACA. In vivo complex formation between FM and 125I-fibrinogen was demonstrated chromatographically. A direct correlation was found between blood fibrinogen concentration and fibrin deposition in organs. By contrast, an inverse correlation between fibrinogen concentration and both enzymatic or non-enzymatic fibrin formation was found in vitro. The mechanism by which fibrinogen potentiates FM precipitation in vivo could not be explained by coprecipitation of fibrinogen in the complex which could not be demonstrated. The inhibitory effect of HN2 on fibrin deposition despite the associated hyperfibrinogemia induced by this drug is believed to underscore the importance of leukocytes in certain types of fibrin deposition. A correlation between the leukocyte count and fibrin formation from FM was also found. It was concluded that the risk of intravascular fibrin deposition is increased by a raised fibrinogen level especially when accompanied by leukocytosis.

Animals↗
PubMed1975

Cross-linking of fibrinogen and fibrin by fibrin-stablizing factor (factor XIIIa).

Factor XIIIa catalyzed intermolecular cross-linking of fibrinogen at initial rates that varied in direct (first order) proportion to the fibrinogen concentration, which differed from the well known zero order relationship in fibrin cross-linking. Preferential cross-linking of gamma-chains occurred with both substrates. The differences in rates and order of reaction were attributed mainly to effect of self-alignment of the gamma-chains in fibrin which enabled the cross-linking enzyme to interact with paired chains as a single rather than two independent entities. Studies on mixtures of fibrinogen and fibrin indicated factor XIIIa had near equal affinities for the two substrates. At low concentrations with which cross-linking of fibrinogen proceeded sluggishly compared to fibrin, fibrinogen inhibited stabilization of fibrin clots by competitively partitioning factor XIIIa away from the fribin. Additional inhibition arose from cross-linking of fibrin in soluble combination with fibrinogen in mixtures containing fibrinogen in large excess over fibrin. The observations demonstrate ways in which fibrinogen normally helps to suppress both polymerization and cross-linking of small amounts of fibrin produced within the circulation. At very high concentrations above 30 mg. per milliliter, fibrinogen underwent cross-linking at faster initial rates than the cross-linking of fibrin. Rapid cross-linking of concentrated fibrogen raises the possibility that filtration enrichment may be a factor contributing to abnormal formation of the highly insoluble fibrinogen deposits occurring in atheromatous tissue.

Animals↗
PubMed1993

Fibrin affinity of urokinase-type plasminogen activator. Evidence that Zn2+ mediates strong and specific interaction of single-chain urokinase with fibrin.

Interactions of components of the fibrinolytic system with fibrin play a key role in localization and regulation of plasminogen activation at the clot surface. Although interaction of tissue plasminogen activator (tPA) with fibrin is well established, the prevailing view is that urokinase-type plasminogen activator (uPA) does not bind to fibrin. In this report, I show that although there is little or no interaction of single-chain urokinase (Sc-uPA), two-chain urokinase (Tc-uPA), or low molecular weight urokinase (LMW-uPA) with fibrin in the absence of divalent metal cations, Sc-uPA is effectively bound to fibrin in the presence of Zn2+. By comparison, Tc-uPA is poorly bound and LMW-uPA is not bound to fibrin in the presence of the metal ion. The Zn(2+)-mediated fibrin binding of Sc-uPA is reversible, specific, and saturable. The interaction involves a single class of binding site with dissociation constant of 0.3 microM and stoichiometry of 2.7. Lacking apparent affinity for fibrin, uPA has not been considered to play a role in physiological fibrinolysis. The present study conclusively shows that Sc-uPA possesses a latent affinity for fibrin that is expressed in the presence of Zn2+. These findings raise the possibility that Zn2+ plays a regulatory role in uPA-mediated fibrinolysis by promoting effective localization of Sc-uPA at the clot surface.

Cations↗
PubMed2001

Fibrinogen and fibrin are anti-adhesive for keratinocytes: a mechanism for fibrin eschar slough during wound repair.

During cutaneous wound repair the epidermis avoids the fibrin-rich clot; rather it migrates down the collagen-rich dermal wound margin and over fibronectin-rich granulation tissue. The mechanism(s) underlying keratinocyte movement in this precise pathway has not been previously addressed. Here we demonstrate that cultured human keratinocytes do not express functional fibrinogen/fibrin receptors, specifically alpha v beta 3. Biologic modifiers known to induce integrin expression or activation did not induce adhesion to fibrin, fibrinogen, or its fragments. Epidermal explant outgrowth and single epidermal cell migration failed to occur on either fibrin or fibrinogen. Surprisingly, fibrin and fibrinogen mixed at physiologic molar ratios with fibronectin abrogated keratinocyte attachment to fibronectin. Keratinocytes transduced with the beta 3 integrin subunit cDNA, expressed alpha v beta 3 on their surface and attached to and spread on fibrinogen and fibrin. beta-gal cDNA-transduced keratinocytes did not demonstrate this activity. Furthermore, beta 3 cDNA-transduced keratinocyte adhesion to fibrin was inhibited by LM609 monoclonal antibody to alpha v beta 3 in a concentration-dependent fashion. From these data, we conclude that normal human keratinocytes cannot interact with fibrinogen and its derivatives due to the lack of alpha v beta 3. Thus, fibrinogen and fibrin are authentic anti-adhesive for keratinocytes. This may be a fundamental reason why the migrating epidermis dissects the fibrin eschar from wounds.

Animals↗
PubMed2001

Like fibrin, (DD)E, the major degradation product of crosslinked fibrin, protects plasmin from inhibition by alpha2-antiplasmin.

Plasmin generation is localized to the fibrin surface because tissue-type plasminogen activator (t-PA) and plasminogen bind to fibrin, an interaction that stimulates plasminogen activation over a hundred-fold. To ensure efficient fibrinolysis, plasmin bound to fibrin is protected from inhibition by alpha2-antiplasmin. (DD)E, a major soluble degradation product of cross-linked fibrin that is a potent stimulator of t-PA, compromises the fibrin-specificity of t-PA by promoting systemic activation of plasminogen. In this study we investigated whether (DD)E also protects plasmin from inhibition by alpha2-antiplasmin, facilitating degradation of this soluble t-PA effector. (DD)E and fibrin reduce the rate of plasmin inhibition by alpha2-antiplasmin by 5- and 10-fold, respectively. Kringle-dependent binding of plasmin to (DD)E and fibrin, with Kd values of 52 and 410 nM, respectively, contributes to the protective effect. When (DD)E is extensively degraded by plasmin, yielding uncomplexed fragment E and (DD), protection of plasmin from inhibition by alpha2-antiplasmin is attenuated. These studies indicate that (DD)E-bound plasmin, whose generation reflects the ability of (DD)E to stimulate plasminogen activation by t-PA, has the capacity to degrade (DD)E by virtue of its resistance to inhibition. This provides a mechanism to limit the concentration of (DD)E and maintain the fibrin-specificity of t-PA.

Antifibrinolytic Agents↗