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PubMed1996

Platelet internalization in early thrombogenesis.

Activated platelets rapidly internalize ligand-alpha(IIb)beta 3 complexes and particulates. The platelets sequester these primarily to the surface-connected canalicular system (SCCS), alpha-granules or evaginated surfaces. This occurs swiftly as activation initiates shape change, internal transformation, and secretion out of the platelet SCCS. The transmembrane signaling mechanism for internalization is through the platelet submembranous, detergent-resistant, cytochalasin B-resistant cytoskeletal filaments, not cytoplasmic actin filaments. This work proposes the model that platelet internalization responses contribute in the retraction of clots and participate in vivo in thrombus development at sites of coronary artery injury. In isometric clot retraction, the retracting platelets show internalization of fibrinogen-gold and fibrin while spreading on the polymerizing fibrin strands. The combination of platelet internalization (retracting) with evagination (spreading) on fibrin strands appear to approximate and organize nearby platelets into the developing thrombi. Ex vivo findings are similar under flowing conditions on denuded rabbit aortic endothelium with fibrinogen-gold markers. Early thrombi developing in vivo at sites of congenital coronary artery lesions in perinatal piglets show fibrin strands internalized into the SCCS of platelets. A thrombogenesis model is proposed that shows that platelet internalization responses anchor fibrin and approximate platelets, thus enhancing thrombus development and retraction.

Animals↗
PubMed1992

[Effect of different vascular prosthesis materials on blood platelets, blood clotting and fibrinolysis].

Studies were performed on Dacron vascular prostheses (USA), Gore-Tex (Germany), polyester prostheses (Czechoslovakia), Lawsan (Russia), as well as on DALLON-standard and DALLON-double velour prostheses (Poland), non-impregnated or impregnated with collagen, with heparin and albumin, with antithrombotic and antibacterial preparation, and with antibacterial preparation. In vitro, all the materials of vascular prostheses cause an adhesion of platelets in different degree, increase the availability of platelet factor 3, release platelet factor 4, reduce the blood clot retraction, shorten clotting time of the whole blood as well as recalcination time of intact plasma and increase the prothrombin consumption. None of the materials induced platelet aggregation nor influenced the activity of fibrinolytic system. Prostheses impregnated with collagen or with heparin and albumin were the most thrombogenic. Those impregnated with antibacterial preparation or with antibacterial and antithrombotic preparations, and Gore-Tex prostheses showed the lowest thrombogenicity. Thrombogenicity of vascular prostheses not only depends on chemical structure of the material, but on the method of fibre manufacturing by individual producers as well.

Animals↗
PubMed1975

Investigations on some coagulability tests in atherosclerosis.

Coagulation and fibrinolysis were investigated in a group of atherosclerosis patients, a group of neonates and a control group, determining the clot retraction time, the amount and quality of the blood platelets, and euglobulin lysis time. The results showed that fibrinolytic activity values are about equal in the two experimental groups, whereas clot retraction time, number of thrombocytes, thrombocyte adhesiveness, and agglutination sharply differed. Hyperadhesiveness and hyperagglutination were found in 75% of the atherosclerosis patients, with a clot retraction time of 79% and 290,000 thrombocytes/mm3 as compared to the hypoadhesiveness and hypoagglutination found in all the neonates, in which clot retraction was 43% and the number of thrombocytes 115,000. All values differed from those of the control lot.

Adult↗
PubMed1997

Calpain cleavage of focal adhesion proteins regulates the cytoskeletal attachment of integrin alphaIIbbeta3 (platelet glycoprotein IIb/IIIa) and the cellular retraction of fibrin clots.

The intracellular thiol protease calpain catalyzes the limited proteolysis of various focal adhesion structural proteins and signaling enzymes in adherent cells. In human platelets, calpain activation is dependent on fibrinogen binding to integrin alphaIIbbeta3 and subsequent platelet aggregation, suggesting a potential role for this protease in the regulation of postaggregation responses. In this study, we have examined the effects of calpain activation on several postaggregation events in human platelets, including the cytoskeletal attachment of integrin alphaIIbbeta3, the tyrosine phosphorylation of cytoskeletal proteins, and the cellular retraction of fibrin clots. We demonstrate that calpain activation in either washed platelets or platelet-rich plasma is associated with a marked reduction in platelet-mediated fibrin clot retraction. This relaxation of clot retraction was observed in both thrombin and ionophore A23187-stimulated platelets. Calcium dose-response studies (extracellular calcium concentrations between 0.1 microM and 1 M) revealed a strong correlation between calpain activation and relaxed clot retraction. Furthermore, pretreating platelets with the calpain inhibitors calpeptin and calpain inhibitor I prevented the calpain-mediated reduction in clot retraction. Relaxed fibrin clot retraction was associated with the cleavage of several platelet focal adhesion structural proteins and signaling enzymes, resulting in the dissociation of talin, pp60(c-)src, and integrin alphaIIbbeta3 from the contractile cytoskeleton and the tyrosine dephosphorylation of multiple cytoskeletal proteins. These studies suggest an important role for calpain in the regulation of multiple postaggregation events in human platelets. The ability of calpain to inhibit clot retraction is likely to be due to the cleavage of both structural and signaling proteins involved in modulating integrin-cytoskeletal interactions.

Blood Platelets↗
PubMed1982

Plasminogen, plasminogen activator, and platelets in the regulation of clot lysis. Reconstitution and patient studies.

Dilute clot lysis was assayed by release of soluble 125I fibrin degradation products from dPPP clots containing varying amounts of plasminogen activator and platelets. Plasminogen activator in the absence of platelets gave an approximately linear rate of lysis, with a rate proportional to its concentration. Addition of platelets to achieve normal clot retraction had little effect on the lysis rate in the absence of plasminogen activator or in the presence of very high plasminogen activator levels. However, with intermediate plasminogen activator levels, platelet-mediated clot retraction was associated with an accelerated rate of clot lysis when retraction reached 75% to 90%. The length of the lag phase before the start of the accelerated phase varied with the number of platelets and rate of clot retraction. The interaction of clot retraction and lysis was further explored in selected patients to determine (1) whether the contributions of platelet and plasma factors in these cases was similar to those seen in our studies of reconstituted plasma and (2) whether our experience with reconstituted systems could be used in the study of disorders of fibrinolysis involving platelets and fibrinolytic enzymes.

Blood Coagulation↗
PubMed1995

Reductions in platelet force development by cardiopulmonary bypass are associated with hemorrhage.

Quantitative assessment of platelet dysfunction after cardiopulmonary bypass (CPB) and prediction of excessive microvascular bleeding remain elusive goals. We used a sensitive instrument capable of simultaneously measuring the force generated by platelets during plasma clot retraction and global clot strength. We hypothesized that CPB would significantly reduce these two variables. Platelet-rich plasma was obtained from eight patients undergoing aortocoronary revascularization prior to induction, after 90 min of CPB, and after protamine administration. Platelet force development was measured using a standardized technique that controlled for platelet number and permitted clot formation in the presence of heparin. Despite the presence of a measurable elastic modulus, platelet force development during bypass was abolished. Peak platelet force development after CPB was significantly lower than before CPB (5255 +/- 955 dynes vs 11,600 +/- 780 dynes, P = 0.01). The percent recovery (after/before bypass) of peak platelet force development inversely correlated with tube thoracostomy drainage during the first 24 h after placement (rs = -0.71, P = 0.048). This study demonstrates that CPB has dramatic effects on platelet force development. The correlation between the percent recovery of peak platelet force development and blood loss supports the clinical relevance of this measurement.

Aged↗
PubMed2005

A cluster of basic amino acid residues in the gamma370-381 sequence of fibrinogen comprises a binding site for platelet integrin alpha(IIb)beta3 (glycoprotein IIb/IIIa).

Adhesive interactions of platelet integrin alpha(IIb)beta3 with fibrinogen and fibrin are central events in hemostasis and thrombosis. However, the mechanisms by which alpha(IIb)beta3 binds these ligands remain incompletely understood. We have recently demonstrated that alpha(IIb)beta3 binds the gamma365-383 sequence in the gammaC-domain of fibrin(ogen). This sequence contains neither the AGDV nor the RGD recognition motifs, known to bind alpha(IIb)beta3, suggesting the different specificity of the integrin. Here, using peptide arrays, mutant fibrinogens, and recombinant mutant gammaC-domains, we have examined the mechanism whereby alpha(IIb)beta3 binds gamma365-383. The alpha(IIb)beta3-binding activity was localized within gamma370-381, with two short sequences, gamma370ATWKTR375 and gamma376WYSMKK381, being able to independently bind the integrin. Furthermore, recognition of alpha(IIb)beta3 by gamma370-381 depended on four basic residues, Lys373, Arg375, Lys380, and Lys381. Simultaneous replacement of these amino acids and deletion of the gamma408AGDV411 sequence in the recombinant gammaC-domain resulted in the loss of alpha(IIb)beta3-mediated platelet adhesion. Confirming the critical roles of the identified residues, abnormal fibrinogen Kaiserslautern, in which gammaLys380 is replaced by Asn, demonstrated delayed clot retraction and impaired alpha(IIb)beta3 binding. Also, a mutant recombinant fibrinogen modeled after the naturally occurring variant Osaka V (gammaArg375 --> Gly) showed delayed clot retraction and reduced binding to purified alpha(IIb)beta3. These results identify the gamma370-381 sequence of fibrin(ogen) as the binding site for alpha(IIb)beta3 involved in platelet adhesion and clot retraction and define the new recognition specificity of this integrin.

Amino Acid Sequence↗
PubMed1995

Fibrin structure and concentration alter clot elastic modulus but do not alter platelet mediated force development.

During clot retraction, platelets interact with fibrin resulting in marked reduction of clot volume. Altered fibrin structure has been reported to affect clot retraction as measured by serum expression. This study was performed to test whether such altered retraction was the result of increased resistance to network collapse or due to decreased force development by platelets. Altered fibrin structure was documented as variation of fibre mass/length ratios (mu) and shifts in clot elastic modulus. The force developed by platelets during clotting was measured directly. Increasing the fibrinogen concentration led to thinner fibre formation (decreased mu), and a linear increase in gel elastic modulus. Over a fibrinogen concentration range of 100 to 400 mg/dl, force development was minimally affected. Force development and clot elastic modulus increased in a linear fashion with increasing platelet concentration. Increasing the calcium concentration from 5 to 20 mM caused a 160% increase in fibrin fibre size (mu), and a 52% decline in clot modulus. Force developed at 1200 s declined by 17%. At 15 mg/ml, dextran and hydroxyethyl starch (HES) also increased mu, and decreased clot modulus; however, both agents markedly reduced force development. Increasing ionic strength or the addition of IgG decreased mu and increased gel elastic modulus. Force development increased modestly with increased ionic strength, did not change with addition of IgG in saline and declined with addition of IgG in maltose. This study indicates that force development is primarily dependent on platelet function while clot modulus depends on both fibrin structure and platelet function.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Coagulation↗
PubMed1984

[Criteria for hemostasis in kidney transplant patients. Comparison of patients undergoing immunosuppression with cyclosporin and azathioprine steroids].

Studies on one-year function conducted by the European Multicenter Trial showed that, after renal allograft transplantation, bleeding complications were only found in patients treated with cyclosporin as compared with those treated with azathioprin/steroids. To investigate a possible relationship between the bleeding tendency and the cyclosporin treatment, 18 parameters of hemostasis were studied in 11 patients, 6 of whom received cyclosporin A and the other 5 conventional treatment with azathioprin/steroids. Bleeding tendency could not be related to any specific coagulation parameter. Of interest is that clot retraction was significantly lower in the cyclosporin group (88 +/- 9% vs. 125 +/- 10%). Considering the fact that the skin bleeding time according to Ivy was normal in all patients, the clinical significance of the lower levels of the clot retraction appears to be minor. Discriminant analysis showed that these significantly lower clot retraction values could not be related to the lower platelet count levels in platelet rich plasma (205 000 +/- 85 000/mm3 vs. 280 000 +/- 67 000/mm3) but were associated with cyclosporin A treatment. All factor-VIII related activities were elevated in both groups. The main difference between the cyclosporin group and the conventionally treated group was significantly elevated levels of factor VIII procoagulant antigen (VIII: CAg) (cyclosporin A treated group: VIII: CAg 435 +/- 145%, conventionally treated group: VIII: CAg 215 +/- 99%). These results suggest hypercoagulability rather than bleeding tendency under cyclosporin treatment.

Adult↗
PubMed1983

[Variant of Paris-I Lariboisière thrombasthenia, a molecular anomaly of the IIb-IIIa platelet glycoprotein complex].

Platelet GP IIb-IIIa complex is missing or strongly reduced in thrombasthenia type I or II; in parallel the binding of fibrinogen is either nil or strongly reduced after platelet activation and these platelets do not aggregate. In the platelets of the described variant, GP IIb-IIIa level and PLA1 antigen are around 50% of the normal but the fibrinogen sites are either missing or unavailable. The hypothesis is that the patient's platelets lack the specific receptor site for fibrinogen at the GP IIb-IIIa level. However, platelet fibrinogen is normal as is the clot retraction. The study of this variant allows new concepts on platelet aggregation and clot retraction.

Blood Platelet Disorders↗
PubMed1992

Platelet function in chronic leukemias.

Bleeding time, clot retraction, platelet factor 3 availability and platelet aggregation in response to ADP, epinephrine, collagen and ristocetin were studied in 12 cases of chronic leukemia which included eight of chronic myeloid leukemia, two of chronic lymphatic leukemia and two of CLL related disorders. One or more abnormalities in platelet function were detected in all the cases. Among the cases of CML, bleeding time was prolonged in one, clot retraction was impaired in one and PF3 availability was decreased in one case. Defects in platelet aggregation were variable. Among the cases of CLL and CLL related disorders, bleeding time was prolonged in two, clot retraction was impaired in one and PF3 availability was decreased in three cases. Platelet aggregation responses were significantly impaired in all the cases.

Blood Platelets↗
PubMed1998

[Vascular pathology. A study of some blood parameters indicative of leukocyte activation and platelet dysfunction].

BACKGROUND: In vascular pathology the endothelial lesions easily reflect on blood cells, inducing a reactive state. In the present study the eventual presence of activation signals in leukocytes and platelets was tested. METHODS: Fifty-eight subjects with major vascular pathology and 14 with lower limbs venous insufficiency were studied, together with a control group of 25 normal subjects. Elastase PMN, superoxide ion, leukocytes and subpopulation count, platelet factor 3, clot retraction, heparin in neutralizing activity (HNA plasmatic and intraplatelet), platelet count and volume were tested. RESULTS: As regards leukocytes, it was observed a significative increase of elastase PMN and monocytes number for both the studied pathologies, of superoxide ion and leukocyte number only for major vascular pathology; for platelets, an inhibition of functionality, revealed by clot retraction test for arterious and venous pathologies and by HNA test only for the venous one. CONCLUSIONS: As regards the leukocyte activation, elastase PMN is particularly responsive to the endothelial lesion both in arterious and in venous districts, while superoxide ion appears to increase in presence of a marked alteration. The level of monocytes is indicative of an inflammatory condition and of leukocytes of an atherosclerotic inflammatory process. As for platelets, the test clot retraction is specifically sensible to the endothelial abnormality in both the arterious and venous pathologies with addition of an abnormal HNA test only in venous insufficiency. This platelet dysfunction is probably due to endothelial release of vasoactive and heparin amplifying substances.

Aged↗
PubMed2005

The likelihood ratio of sonographic findings for the diagnosis of hemorrhagic ovarian cysts.

OBJECTIVE: The purpose of this study was to quantify the likelihood ratio (LR) of specific sonographic features and experienced sonologist assessment in diagnosing a hemorrhagic ovarian cyst and to better understand the diagnostic power of sonography in making this diagnosis. METHODS: Two sonologists, blinded to the patient's clinical history, independently reviewed the sonograms of 252 adnexal masses. For each mass, each sonologist recorded features using a standardized checklist, which included observations regarding the presence of fibrin strands, a retracting clot, septations, and wall irregularity. Each reviewer independently chose 1 specific conclusion from a list of possibilities that included the diagnosis of a hemorrhagic ovarian cyst. Sonographic observations and sonologist predictions were compared with pathologic findings (n = 214) or follow-up sonography (n = 38). RESULTS: Of the 252 masses, there were 30 hemorrhagic cysts. One sonologist correctly identified 25 hemorrhagic cysts, with 1 false-positive, 2 false-negative, and 3 indeterminate calls (LR 185). The other sonologist correctly identified 24 hemorrhagic cysts, with 1 false-positive, 0 false-negative, and 6 indeterminate calls (LR 178). The 2 cases incorrectly diagnosed as hemorrhagic cysts were endometriomas at pathologic diagnosis. Specific sonographic observations and combinations of observations performed as follows: retracting clot (LR >67); fibrin strands (LR 40); fibrin strands and no septations (LR 100); and fibrin strands, no septations, and smooth wall (LR 200). CONCLUSIONS: Fibrin strands and a retracting clot are paramount observations in allowing high confidence in the diagnosis of hemorrhagic ovarian cysts. Approximately 90% of hemorrhagic ovarian cysts will exhibit at least 1 of these 2 features.

Diagnosis, Differential↗
PubMed2000

A Leu262Pro mutation in the integrin beta(3) subunit results in an alpha(IIb)-beta(3) complex that binds fibrin but not fibrinogen.

Platelet retraction of a fibrin clot is mediated by the platelet fibrinogen receptor, alpha(IIb)beta(3). In certain forms of the inherited platelet disorder, Glanzmann thrombasthenia (GT), mutant alpha(IIb)beta(3) may interact normally with fibrin yet fail to support fibrinogen-dependent aggregation. We describe a patient (LD) with such a form of GT. Platelets from LD supported normal clot retraction but failed to bind fibrinogen. Platelet analysis using flow cytometry and immunoblotting showed reduced but clearly detectable alpha(IIb)beta(3), findings consistent with type II GT. Genotyping of LD revealed 2 novel beta(3) mutations: a deletion of nucleotides 867 to 868, resulting in a premature stop codon at amino acid residue 267, and a T883C missense mutation, resulting in a leucine (Leu) 262-to-proline (Pro) substitution. Leu262 is highly conserved among beta integrin subunits and lies within an intrachain loop implicated in subunit association. Leu262Probeta(3) cotransfected with wild-type alpha(IIb) into COS-7 cells showed delayed intracellular maturation and reduced surface expression of easily dissociable complexes. In human embryonic kidney 293 cells, Leu262Probeta(3) formed a complex with endogenous a(v) and retracted fibrin clots similarly to wild-type beta(3). The same cells, however, were unable to bind immobilized fibrinogen. The molecular requirements for alpha(IIb)beta(3) to interact with fibrin compared with fibrinogen, therefore, appear to differ. The region surrounding beta(3) Leu262 may maintain beta(3) in a fibrinogen-binding, competent form, but it appears not to be required for receptor interactions with fibrin.

Amino Acid Sequence↗
PubMed1988

Localization of the domains of fibrin involved in binding to platelets.

The molecular basis of platelet-fibrin interactions has been investigated by using synthetic peptides as potential inhibitors of fibrin protofibril and fibrinogen binding to ADP-stimulated platelets, adhesion of fibrin fibers to the platelet surface, and platelet-mediated clot retraction. Synthetic peptides of sequence RGDS and HHLGGAKQAGDV, corresponding to regions of the fibrinogen alpha- and gamma-chains previously identified as platelet recognition sites, inhibited the binding of radiolabelled soluble fibrin oligomers to ADP-stimulated platelets with IC50 values of 10 and 40 microM, respectively. Synthetic GPRP and GHRP, corresponding to the N-terminal tripeptide sequence of the fibrin alpha-chains and the tetrapeptide sequence of the beta-chains, respectively, were minimally effective in blocking soluble fibrin polymer binding to ADP-stimulated platelets. Platelet functions which are unique to the three-dimensional fibrin network were examined by measurements of the extent of adhesion of fluorophore-labelled fibrin to platelets with a microfluorimetric technique and by light scattering measurements of the time course of clot retraction. Inhibition of fibrin-platelet adhesion by RGDS, HHLGGAKQAGDV and GHRP exhibited a similar, linear dependence reaching 1/2 maximum at about 200 microM, suggesting nonspecific effects. GPRP inhibited fibrin assembly but did not appear to have specific effects on fibrin-platelet adhesion. Only RGDS effected clot retraction, causing a 4-6-fold decrease in rate at 230 microM. These results indicate that fibrinogen and fibrin protofibrils, which are obligatory intermediates on the fibrin assembly pathway, share a set of common platelet recognition sites located at specific regions of the alpha- and gamma-chains of the multinodular fibrin(ogen) molecules. The RGDS site is also involved in mediating interactions between the three-dimensional fibrin network and stimulated platelets.

Amino Acid Sequence↗
PubMed2003

Thrombolytic potency of acid-stabilized plasmin: superiority over tissue-type plasminogen activator in an in vitro model of catheter-assisted thrombolysis.

Plasmin, the direct fibrinolytic enzyme, was compared with tissue plasminogen activator (t-PA) in an in vitro thrombolysis model. Plasmin has been prepared in a highly pure form from human plasma and has been stabilized against auto-degradation by low-pH formulation. This acidified formulation of plasmin has been designed to have a low buffering capacity so that it can be directly infused into clots in a stable and latently active form. This low-pH formulation has been shown to be equivalent to a neutral-pH formulation of plasmin in its extent of clot lysis. An in vitro model of catheter-assisted thrombolysis has been devised in which large (12 x 0.6 cm), retracted clots are treated with an intrathrombus thrombolytic agent via a multi-sideport catheter. Plasmin dissolves these plasminogen-deficient clots in a dose-dependent manner and is clearly superior to t-PA. In this model system, t-PA exhibits efficacy only when retracted clots are replenished with plasminogen.

Catheterization↗
PubMed1984

Identification of human platelet membrane fibrinogen receptors by immunochemical techniques.

The fibrinogen receptors of platelets were investigated with the use of three types of anti-platelet membrane antibodies and three types of platelets. We found that antisera raised in rabbits against membranes prepared from human intact, chymotrypsin- or pronase-treated platelets inhibited the fibrinogen-induced aggregations of ADP-stimulated intact platelets, chymotrypsin-treated platelets and pronase-treated platelets. These antisera also blocked the binding of 125I-fibrinogen to ADP-stimulated intact, chymotrypsin-treated, and pronase-treated platelets. These results suggest that all three antisera blocked the interaction of fibrinogen with its receptor on the surface of the three types of platelets studied. Fibrin clot retraction by intact platelets was also inhibited by these three antibodies indicating an important role of platelet membrane proteins in clot retraction. As demonstrated by techniques using 125I-surface labeling, Staphylococcus aureus immunoprecipitation, SDS-polyacrylamide gel electrophoresis and autoradiography, anti-intact platelet membrane antibody immunoprecipitated the membrane glycoproteins GPIIb, GPIII and a protein with an apparent molecular weight of 66 000 from detergent solubilized surface 125I-iodinated chymotrypsin-treated platelets. Anti-chymotrypsin and anti-pronase-treated platelet membrane antisera immunoprecipitated mostly GPIII and the 66 000 molecular weight protein from detergent solubilized, surface 125I-iodinated chymotrypsin-treated platelets. The 66 000 Mr protein was not found on the surface of intact (unstimulated) platelets which do not bind 125I-fibrinogen and are not aggregated by fibrinogen without the prior addition of ADP. The ability of anti-platelet membrane antibodies to block fibrinogen-induced platelet aggregation and fibrinogen binding to platelets correlated with their ability to immunoprecipitate a 66 000 Mr protein from the platelet surface. It is proposed that the 66 000 Mr protein may be the fibrinogen binding domain of GPIII which becomes permanently exposed on the surface of chymotrypsin and pronase-treated platelets following proteolysis and which becomes exposed upon stimulation of intact platelets by agents such as ADP.

Autoradiography↗