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PubMedDate not supplied

The role of blood platelets in nucleoside metabolism: regulation of megakaryocyte development and platelet production.

In higher vertebrates, different types of blood cells develop from common precursors. Mammals are unique in possessing two types of blood cells--erythrocytes and platelets--which lack nuclei. Although platelets display consistent and easily-recognisable morphological and ultrastructural characteristics and show extreme metabolic and functional versatility, they are not true cells, being produced by fragmentation of giant polyploid precursors called megakaryocytes. At present, the physiological mechanisms which regulate megakaryocyte development and platelet production are not well understood. Platelets are actively involved in metabolism of purine derivatives and a significant platelet role in pyrimidine metabolism has also been demonstrated (see previous papers). Here an attempt is made to integrate information about platelet involvement in nucleic acid precursor metabolism with current concepts of haematopoiesis, particularly megakaryocyte development and platelet production. It is concluded (i) that megakaryocytic cells are immediate descendents of haematopoietic stem cells which have become polyploid as a result of genetic damage or metabolic imbalances, (ii) megakaryocytes and platelets are the ultimate regulators of stem cell development because they control the availability of thymidine and (iii) that the production of megakaryocytes and platelets is a physiological safety mechanism which prevents fixation of genetic damage and protects other cells from potentially cytotoxic and genotoxic stimuli.

Animals↗
PubMed1982

Human platelet basic protein. Its relation to low affinity platelet factor 4 and beta-thromboglobulin.

Human beta-thromboglobulin, low affinity platelet factor 4 and platelet basic protein have been purified to homogeneity from the material released by thrombin-stimulated platelets. Purification steps included isoelectric focusing and heparin-agarose chromatography. Antibodies against each of these proteins have been raised in rabbits. Antigenic identity of the proteins has been demonstrated in radioimmunoassay using 125I-labelled platelet basic protein or 125I-labelled low affinity platelet factor 4 and a variety of antibodies. The molecular weight of platelet basic protein estimated by gel filtration in 6 M guanidine hydrochloride using Sepharose 6B corresponded to approx. 10 000 daltons, slightly higher than that of beta-thromboglobulin (8851 daltons) and low affinity platelet factor 4 (9278 daltons). These findings raise the possibility that the formation of low affinity platelet factor 4 beta-thromboglobulin may be a consequence of the action of proteolytic enzymes on platelet basic protein.

Amino Acid Sequence↗
PubMed1989

The role of platelets in progressive glomerulosclerosis: mechanisms for intraglomerular platelet activation and pathogenetic consequences.

Purkerson et al. have hypothesized that platelet aggregation and release reactions contribute to the progressive sclerosis of remnant nephrons. The suggested mechanism for platelet activation is disruption of endothelium by the high hydraulic pressures characteristic of remnant nephrons, with platelet exposure to basement membrane collagen. We herein postulate additional mechanisms whereby platelets might be activated in the microcirculation of remnant nephrons: (i) kinetic activation due to high plasma flow rates; (ii) close cell contact due to concentration of blood cells and platelets in the glomerulus; (iii) concentration of protein macromolecules that act as agonists for platelet release; (iv) glomerular release of saturated and monenoic fatty acids that stimulate platelet synthesis of thromboxane A2; (v) glomerular release of membrane-bound pro-coagulant factor, triggering a chain reaction that activates both platelets and the intraglomerular coagulation cascade. Platelet activation could play a pathogenetic role in many of the known derangements of structure and function in remnant nephrons. This paradigm may also be partially applicable to the glomerulosclerosis of diabetes mellitus.

Animals↗
PubMed1995

Platelet membrane fluidity and platelet membrane lipid pattern in essential hypertension.

In a group of subjects with essential hypertension platelets were studied in resting conditions: platelet membrane fluidity was measured with the fluorescent probe 1.4-(trimethylamino)-phenyl-4-phenylhexatriene (TMA-DPH), platelet membrane cholesterol/phospholipid ratio was evaluated separating the membrane lipids with column chromatography, and platelet membrane individual phospholipids were determined using two-dimensional thin-layer chromatography. From the obtained results, it is evident that platelet membrane fluidity does not differentiate normals from hypertensives; platelet membrane cholesterol/phospholipid ratio is increased in hypertensives, while of the platelet membrane individual phospholipids, only the phosphatidylcholine is increased. In normals and hypertensives, no relation is evident between platelet membrane fluidity, platelet membrane lipid pattern, and systolic and diastolic blood pressure values.

Adult↗
PubMed1999

Annexin V and platelet antigen expression is not altered during storage of platelet concentrates obtained with the AMICUS cell separator.

During storage of platelet concentrate the so-called "storage lesion" occurs. During this time, platelets loose their morphological and functional capacities that are necessary for proper in vivo efficacy following transfusion. Annexin V represents a marker for apoptosis. In this study, Annexin V and additional antigens were analyzed by flow cytometry. Platelet concentrates were obtained with a new cell separator (AMICUS Separator, Fenwal). Following apheresis, platelet units were stored for an experimentally prolonged time of seven days. Daily aliquots of the platelet-rich plasma were obtained to measure Annexin V and platelet antigens CD62p, CD63, CD41a, CD42b, and the binding of fibrinogen. All analyses were performed using flow cytometry. During storage, no significant changes in mean channel fluorescence intensity (MCFI) of CD41a (P = 0.99) and CD42b (P = 0.29), percentage of CD62p+ and CD63+ platelets (P = 0.23 for CD62p; P = 0.52 for CD63), and the binding of fibrinogen to platelets occurred (P = 0.85). Also, the expression of Annexin V remained constant with no significant change (P = 0.36). This study shows that antigens of platelets, obtained with the AMICUS cell separator are well preserved during storage. Regarding Annexin V, no obvious signs of apoptosis can be detected by flow cytometry. These findings demonstrate the high degree of biocompatibility of the apheresis device and storage container.

Annexin A5↗
PubMed1995

Biosynthesis of platelet-activating factor in normal and inflamed human colon mucosa: evidence for the involvement of the pathway of platelet-activating factor synthesis de novo in inflammatory bowel disease.

1. Platelet-activating factor can be synthesized by two distinct biochemical pathways and is degraded by a number of enzymes, the first step of which is deacetylation by a specific acetyl hydrolase. 2. The biochemical pathway of platelet-activating factor synthesis de novo and the first step in platelet-activating factor degradation have been investigated for the first time in incubates of normal human colon mucosa and in inflamed mucosa from patients with inflammatory bowel disease. 3. In the presence of 100 mumol/l CDP-choline and 100 mumol/l hexadecyl acetyl glycerol, homogenates from inflamed mucosa synthesized significantly greater platelet-activating factor [851 +/- 574 pmol/mg of protein (mean +/- SEM) in 90 min incubation] than normal mucosa [105 +/- 61 pmol/mg of protein in 90 min incubation] (P < 0.05). 4. Under the same conditions of assay, the percentage turnover to inactive lyso-platelet-activating factor was similar in inflamed mucosa (35.5 +/- 9.4%) and normal mucosa (42.7 +/- 8.5%) in 90 min (P > 0.05). 5. The identity of platelet-activating factor was confirmed by HPLC, by its mobility on TLC and by the ability of WEB 2170, a selective platelet-activating factor receptor antagonist, to block its platelet-aggregatory action. 6. These findings confirm the presence of the pathway for the synthesis de novo of the potently proinflammatory platelet-activating factor in human colon mucosa in inflammatory bowel disease.

Aged↗
PubMed1997

Endogenously elicited antibodies to platelet derived growth factor-BB and platelet cytosolic protein inhibit aortic lesion development in the cholesterol-fed rabbit.

Several studies have indicated that growth factors, such as platelet derived growth factor (PDGF), may be important in atherogenesis. These factors are released from platelets, or expressed by cells of the arterial wall. In order to study their role in atherogenesis more directly, rabbits were immunized with PDGF-BB, platelet cytosolic protein, or human serum albumin (HSA), until high titres of antibody were attained. Atherosclerotic lesions were subsequently induced by feeding the animals with a 2% cholesterol enriched diet. At the end of approximately 3 months, the extent of aortic lesion development was assessed by image analysis of en face preparations of aortae stained with Oil Red-O, and histological segments of aortae taken at the level of the first intercostal artery branch point. The endogenous antibodies were characterized with respect to their cross-reactivity, and ability to neutralize PDGF and platelet cytosol-induced cell proliferation and migration in vitro. The endogenous, anti-PDGF-BB antibody was isoform specific, and neutralized the mitogenic and chemotactic properties of PDGF-BB and rabbit platelet cytosolic protein in vitro. The anti-platelet cytosol antibody partially inhibited the chemotactic and mitogenic properties of rabbit platelet cytosolic protein. Compared to non-immune rabbits (n = 5), animals immunized with HSA (n = 4) had a significantly larger area of aortic lesion involvement (P < 0.01), whereas aortic lesions in rabbits immunized with PDGF-BB (n = 5), or platelet cytosolic protein (n = 7) were significantly smaller than either non-immune animals, or animals immunized with HSA (P < 0.05). The same pattern was observed for other measures of aortic lesion involvement including aortic intima:media ratio at the level of the first intercostal artery. These data suggest that PDGF-BB, and possibly other platelet-associated growth factors, are involved in cholesterol-induced atherosclerosis.

Animals↗
PubMed2000

Platelet function in patients with familial hypertriglyceridemia: evidence that platelet reactivity is modulated by apolipoprotein E content of very-low-density lipoprotein particles.

We evaluated platelet function in patients with familial hypertriglyceridemia (FHTG). Compared with healthy gender-matched controls, platelets from patients showed lower aggregation (P < .01) and thromboxane formation (P < .01) in response to collagen. Very-low-density lipoprotein (VLDL) particles obtained from the patients inhibited collagen-induced aggregation, whereas VLDL particles from controls had opposite effects. The VLDL-induced effect was regulated by its apolipoprotein E (apoE) content. Indeed, apoE-VLDL-rich fractions caused antiaggregative effects, whereas apoE-VLDL-poor fractions produced a strong proaggregative response. Since we have recently demonstrated that VLDL particles may regulate the activity of platelet low-density lipoprotein (LDL) receptor by a phenomenon of downregulation and desensitization, in this study, we have investigated the effect of prolonged exposure to circulating VLDL levels on the activity of platelet LDL receptor by a double-blind controlled study with gemfibrozil (600 mg twice daily) in 18 subjects with FHTG. Platelets from patients exhibited fewer platelet LDL receptors and 125I-LDL binding was saturable at a lower protein concentration. After 6 months, gemfibrozil therapy versus placebo had a marked lipid-lowering effect, significantly decreased triglycerides (61%), VLDL cholesterol (72%), apoB (28%), and apoE (55%), and increased high-density lipoprotein (44%) and apoA-I (18%). Furthermore, gemfibrozil affected the apoprotein composition of VLDL: total protein increased by 28%, the molar ratio of apoE to apoB decreased 64%, and apoE content decreased 55%. However, no differences in phospholipid, triglyceride, or total cholesterol were detected. Moreover, platelet function was markedly altered by gemfibrozil therapy. Collagen-induced aggregation and thromboxane formation were significantly enhanced (P < .01). The initial antiaggregative pattern of VLDL particles was changed to a significant proaggregative effect (P < .01), and the number of LDL binding sites was markedly upregulated (P < .001). Both receptor upregulation and the change in the aggregative effect of VLDL particles were associated with the reduction of apoE content in VLDL particles (P < .05). The overall results indicate that in the regulation of platelet reactivity in hypertriglyceridemic patients, apoE content of VLDL particles and their interaction with the platelet LDL receptor are involved.

Adult↗
PubMed1988

Platelet crossmatching. A direct approach to the selection of platelet transfusions for the alloimmunized thrombocytopenic patient.

Selection of platelets for alloimmunized, thrombocytopenic patients has traditionally been based on HLA matching. This approach is indirect and may not adequately recognize incompatibility between the recipient and the platelet donor. The authors evaluated the usefulness of directly showing donor-recipient compatibility by crossmatching the patient's serum with prospective platelet donors who were not preselected on the basis of their HLA type. Eleven alloimmunized patients were chosen for study, and crossmatching was done by a radiolabeled antiglobulin test. These patients had high levels of HLA alloantibody, and their unusual HLA types made the provision of HLA-matched platelets difficult. When the crossmatch was compatible, the mean one-hour corrected count increment was 18,379 +/- 4,670 (1 standard deviation), n = 22, and at 18-24 hours, 7,318 +/- 3,317. If the crossmatch was positive, the mean one-hour corrected increment was 2,536 +/- 3,057, and at 18-24 hours, 227 +/- 657, n = 16. There were two false negative crossmatches and one false positive crossmatch. One hundred forty-eight crossmatches were done to find 48 potential donors, who, by conventional selection using HLA matching, would not have been considered appropriate donors. These results show that successful platelet transfusions for alloimmunized thrombocytopenic patients can be prospectively selected by platelet crossmatching without the need of doing expensive HLA typing of a large population of platelet donors. Although it may be difficult to find compatible platelets for some patients with broadly reactive HLA antibodies, platelet crossmatching may detect compatible donors who are ordinarily excluded on the basis of their HLA phenotype.

Blood Grouping and Crossmatching↗
PubMed1990

Measurement of platelet von Willebrand factor is dependent on method of platelet isolation.

The authors have compared platelet von Willebrand factor antigen and ristocetin cofactor activity measurements in a normal population, using two different previously published platelet isolation techniques. Preparation of a platelet lysate by platelet washes using Tyrode's albumin solution and inhibitors yielded a threefold higher vWF antigen and a twofold higher ristocetin cofactor activity measurement as compared to platelets isolated by tris buffered saline washes containing 0.1% (weight/volume) Na2EDTA. Contamination by plasma von Willebrand factor to account for the higher values found by the first method was excluded by monitoring the presence of added purified I125 von Willebrand factor to platelet rich plasma. vWF multimer analysis showed the same distribution of multimers in both preparations but suggested a relative decrease in lower molecular weight multimers with the second method. Platelet isolation can result in significant loss of platelet von Willebrand factor, with a preferential loss of lower molecular weight multimers, likely resulting from unintentional platelet release.

Antigens↗
PubMed1993

Sodium nitroprusside, an endothelium-derived relaxing factor congener, increases platelet cyclic GMP levels and inhibits epinephrine-exacerbated in vivo platelet thrombus formation in stenosed canine coronary arteries.

Sodium nitroprusside (SNP), a nitrosovasodilator, increases platelet cyclic GMP levels and inhibits platelet activity in vitro. The antiplatelet properties of SNP are not well established in vivo, however, and consequently are not appreciated by clinicians. In our established model of mechanically stenosed canine coronary arteries (MSCA) with intimal damage, periodic acute platelet thrombus formation (APTF) occurs, followed by embolization distally, which then causes cyclic flow reductions (CFRs) in coronary blood flow. Aspirin (ASA) abolished platelet-mediated CFRs in our model, but they recur when epinephrine (EPI) is infused (0.2 microgram/kg/min). SNP was given continuously intravenously (i.v.) to 17 dogs with MSCA; CFRs were abolished in all dogs by SNP at 4.4 +/- 2.7 micrograms/kg/min (mean +/- SD). Mean arterial blood pressure (MAP) decreased by 19 +/- 9 mm Hg (p < 0.001) from control, while heart rate (HR) increased 35 +/- 20 beats/min (p < 0.001). Platelet cyclic GMP levels were 2.9 +/- 1.1 pmol/10(8) platelets before SNP infusion, and increased to 4.3 +/- 1.6 pmol/10(8) platelets (p < 0.05) when CFRs were abolished. CFRs were not renewed during the continued SNP infusion when EPI was infused at 0.2 microgram/kg/min for 20 min in 11 dogs, but CFRs returned within 5-25 min after the SNP infusion was terminated. The return of CFRs occurred together with a decrease in platelet cyclic GMP levels to 3.3 +/- 1.4 pmol/10(8) platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Studies on quinine- and quinidine-dependent antibodies against platelets and their reaction with platelets in the Bernard-Soulier syndrome.

The sera of 14 patients with quinine/quinidine-dependent thrombocytopenia were studied in the platelet suspension immunofluorescence test (PSIFT), the 51Cr-lysis assay and the complement fixation test (CFT). When anti-Ig or anti-IgG reagents were used, the PSIFT proved to be a little more sensitive than the 51Cr-lysis assay and far more sensitive than the CFT. With the PSIFT, it was possible to determine the immunoglobulin class of the antibodies, which in all sera was IgG of the subclass IgG1. In two sera there were also IgG3 antibodies, and in the sera of three patients additional IgM drug-dependent platelet antibodies were detected. With the anti-C3 reagent, however, lower titres were observed in the PSIFT than in the 51Cr-lysis assay, in contrast to the results with other complement-binding IgG platelet antibodies. The F(ab')2 fragments of the antibodies did not react in the PSIFT. This indicates that the Fc part of the antibody is essential for the fixation on the platelet membrane. These findings support the theory that in this syndrome drug-antibody complexes area formed in he absence of platelets that selectively adhere to the Fc receptor on platelets. The platelets of patients with the Bernard-Soulier syndrome (BSS) reacted normally with the quinine/quinidine-dependent antibodies in some of the sera, but not with those in other sera in the PSIFT. However, lysis of BSS platelets was never observed. The results of absorption studies showed a reflection of the results in the PSIFT, indicating that the receptor for the quinine/quinidine-dependent antibodies is not absent in this disease but altered. Whether a reaction with BSS platelets will take place depends on characteristics of the antibodies.

Antibodies↗
PubMed1985

The kinetics of unmatched and HLA-matched 111in-labelled homologous platelets in recipients with chronic marrow hypoplasia and anti-platelet immunity.

The kinetics of homologous platelets, labelled in plasma with 111In-tropolonate, have been studied in five recipients with chronic marrow hypoplasia and severe thrombocytopenia, who were refractory to platelet transfusions as a result of alloimmunization. Mean platelet life span (MPLS), recovery, plasma 111In level and splenic and hepatic uptake kinetics were studied on two occasions, one using HLA-matched platelets and the other unmatched platelets. In each case, recovery of labelled platelets at 1 h post-injection and MPLS improved with HLA matching, although this improvement was highly variable. Only two of the five subjects would have derived any significant benefit from HLA-matched as compared with unmatched platelet transfusions. It was concluded that the need exists for additional cross-matching procedures, possibly related to platelet specific antigens, in patients who remain refractory to platelet transfusion.

Adolescent↗
PubMed1993

Concurrent label method with 111In and 51Cr allows accurate evaluation of platelet viability of stored platelet concentrates.

The precision and reproducibility of 111In and 51Cr platelet radiolabel agents for in vivo kinetic studies of stored platelet concentrates (PC) were investigated. The objective was to develop a precise method with concurrent labelling of two platelet populations using different isotopes, which would allow identification of small differences in in vivo platelet quality. Identical labelling procedures were used to investigate the effects of PC storage age, different methods of red cell (RBC) and white cell (WBC) contamination correction, and label elution correction on the results of 111In and 51Cr kinetic studies. 111In and 51Cr platelet survival curves from the same PC, even when uncorrected for elution and RBC contamination, exhibited excellent correlation, irrespective of the age of the concentrate and its viability. However, slightly higher, but statistically significant, post-infusion per cent recoveries with 51Cr labelled platelets were found. Two factors were identified as the cause for this difference. There was a higher affinity of contaminating RBC/WBC in PC for 51Cr than for 111In. With determination of RBC/WBC activity by centrifugation/density separation, RBC/WBC fractions from the injectate were found to contain 12.6 +/- 3.8% v 7.1 +/- 3.6% of total 51Cr and 111In activity, respectively, in 20 studies. In addition, there was a significantly higher 111In activity in plasma immediately post-infusion than with 51Cr, 5.2 +/- 1.3% v 2.8 +/- 1.6%, respectively, suggesting more label elution or carryover. After correction for the activity of RBC/WBC and for elution or carryover, essentially identical 51Cr/111In platelet survival curves were found. In 31 stored PC studies, the absolute average difference between 51Cr and 111In per cent recoveries was only 4 +/- 3% in a group of donors whose platelet recoveries ranged from 10% to 80%. Similarly, the average difference between 51Cr and 111In survival was only 8 +/- 4 h within a range of survivals from 40 to 220 h. In conclusion, after correction for elution and contaminating RBC/WBC binding, these studies show that 51Cr and 111In may be used interchangeably for labelling of stored PC, and that small differences between test and control platelets could be reliably detected using concurrent labelling with simultaneous infusion.

Blood Component Transfusion↗
PubMed1979

Effect of normal human serum on the binding of specific antibodies and platelet-unrelated immune complexes to human platelets.

Radiolabelled staphylococcal protein A was used to quantitate the binding of IgG on stored human platelets from human sera containing specific antibodies reactive with platelets and rabbit serum containing immune complexes (IC). Normal human serum (NHS) inhibited the binding of IC onto platelets and to various extents also the binding of specific antibodies. The attachment of inhibitors to platelets seemed to be reversible. The considerable difference in the inhibitory capacities of IgG-deficient sera and monomeric IgG indicates that IgG is the major inhibitory component of NHS. The binding of IgG from NHS onto platelets evidently hampers the detection of weak platelet antibodies even with the most sensitive tests. Purified Clq, known to modify the reactions of IC with fresh platelets did not alter the binding of IC onto stored platelets. A monoclonal, antiglobulin-active rheumatoid factor of IgM class displayed only moderate inhibition. Therefore, the application of RF or Clq for the differentiation of the binding induced by IC or antibodies is not useful in this assay system. The heterogeneity of immunologic receptors of platelets provides an explanation of the inhibitory inefficiency of Clq.

Adult↗
PubMed1983

Monoclonal antibodies against platelet membrane glycoproteins. Characterization and effect on platelet function.

The specificity of five monoclonal antibodies (P1-P6) against platelet surface components was determined by immunoprecipitation of surface-labelled platelets from normal donors and patients with known platelet glycoprotein defects, followed by analysis by gel electrophoresis. Three (P2, P4 and P6) precipitated glycoproteins IIb and IIIa and, in addition, P2 precipitated glycoprotein Ia. P1 precipitated normally only glycoprotein Ib also Ia when the platelets were pretreated with neuraminidase. P3 precipitated principally glycoprotein Ia but glycoprotein Ib was also weakly precipitated. The effects of the monoclonals on platelet function were tested. P1 and P2 completely inhibited and P3 slightly inhibited thrombin-induced platelet aggregation. P2 also inhibited collagen-induced aggregation and partially inhibited ADP-induced platelet aggregation. P3, P4 and P6 partially inhibited ADP-induced platelet aggregation. None had any effect on ristocetin-induced aggregation despite P1 and P3 binding to glycoprotein Ib. These results confirm the role of glycoproteins IIb and IIIa in aggregation induced by various agents and suggest that the function of glycoprotein Ib in thrombin-induced aggregation is more important than previously suspected and that glycoprotein Ia may also be involved in platelet functions.

Animals↗
PubMed1994

Fluconazole and platelet microbicidal protein inhibit Candida adherence to platelets in vitro.

Adherence to vascular endothelium is considered an essential step in the pathogenesis of hematogenously disseminated candidiasis. Platelets have been shown to promote Candida adherence to vascular endothelium in vitro. In contrast, recent studies indicate that platelets may also play a role in the primary host defense against endovascular infection by secretion of alpha granule-derived platelet microbicidal protein (PMP), which possesses both bactericidal and fungicidal activities as well as antiadherence properties. We examined the influences of PMP and the antifungal agent fluconazole on the adherence of Candida albicans to rabbit platelets, as measured by quantitative flow cytometry. In the absence of PMP and fluconazole, adherence of C. albicans to platelets was rapid (complete within 1 min), saturable, and reversible. Following 2 h of exposure to fluconazole at 10x the MIC, platelet binding of C. albicans was substantially reduced (mean reduction, 32.1%; P = 0.08). Similarly, exposure of C. albicans to PMP (range, 0.5 to 5 micrograms/ml) for 2 h (but not 30 min) significantly reduced candidal adherence to platelets 43.1 to 62.1%; (reduction range, P < 0.05). Moreover, exposure of C. albicans to PMP (5 micrograms/ml for 30 min) and then fluconazole (10x the MIC for 2 h) further decreased candidal adherence to platelets in comparison with the adherence after exposure to either agent alone (mean reduction, 57.2%; P = 0.02 and 0.05, respectively). These data demonstrate that PMP and fluconazole individually reduce the ability of C. albicans to bind to platelets in vitro and that the antiadherence activities of fluconazole are augmented by PMP.

Animals↗
PubMed2000

Influence of platelets and platelet microbicidal protein susceptibility on the fate of Staphylococcus aureus in an in vitro model of infective endocarditis.

Several lines of evidence indicate that platelets protect against endovascular infections such as infective endocarditis (IE). It is highly likely that a principal mechanism of this platelet host defense role is the release of platelet microbicidal proteins (PMPs) in response to agonists generated at sites of endovascular infection. We studied the ability of platelets to limit the colonization and proliferation of Staphylococcus aureus in an in vitro model of IE. Three isogenic S. aureus strains, differing in their in vitro susceptibility to thrombin-induced platelet microbicidal protein-1 (tPMP), were used: ISP479C (parental strain; highly susceptible to tPMP [tPMP(s)]); ISP479R (transposon mutant derived from ISP479; tPMP resistant [tPMP(r)]); or 757-5 (tPMP(r) transductant of the ISP479R genotype in the ISP479 parental background). Time-kill assays and in vitro IE models were used to examine the temporal relationship between thrombin-induced platelet activation and S. aureus killing. In time-kill studies, early platelet activation (30 min prior to bacterial exposure) correlated with a significant bactericidal effect against tPMP(s) ISP479C (r(2) > 0.90, P < 0.02) but not against tPMP(r) strains, ISP479R or 757-5. In the IE model, thrombin activation significantly inhibited proliferation of ISP479C within simulated vegetations compared to strains ISP479R or 757-5 (P < 0.05). The latter differences were observed despite there being no detectable differences among the three S. aureus strains in initial colonization of simulated vegetations. Collectively, these data indicate that platelets limit intravegetation proliferation of tPMP(s) but not tPMP(r) S. aureus. These findings underscore the likelihood that platelets play an important antimicrobial host defense role in preventing and/or limiting endovascular infections due to tPMP(s) pathogens.

Anti-Infective Agents↗