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PubMed1987

Platelet activation in muscle contraction headache and migraine.

In migraine, the role of platelets is regarded as an important factor. We investigated plasma beta-thromboglobulin (BTG), platelet factor 4 (PF4), and 5-hydroxytryptamine (5-HT) in migraine patients and muscle contraction headache (MCH) patients during headache-free periods. The mean values of the plasma BTG, PF4, and 5-HT concentrations in the migraine group and the MCH group were significantly higher than those in healthy controls. The mean value of the plasma BTG concentration was significantly higher in the migraine group than in the MCH group, but the differences in the mean plasma PF4 and 5-HT concentrations between the two groups were not significant. Continuous platelet activation exists in both MCH patients and migraine patients. From the biochemical point of view, we have provided evidence for a similarity between migraine and MCH.

Adolescent↗
PubMed2000

Cytokines in WBC-reduced apheresis PCs during storage: a comparison of two WBC-reduction methods.

BACKGROUND: Several studies have suggested that cytokine accumulation during storage of platelet concentrates (PCs) may mediate nonhemolytic febrile transfusion reactions and that a reduction in WBC numbers prevents the generation of cytokines. Despite efforts to minimize WBC contamination in apheresis PCs, high numbers of WBCs and increased cytokine levels may still occur, depending on the quality of the apheresis device employed. STUDY DESIGN AND METHODS: This study was undertaken to investigate whether PCs collected with WBC-reduction devices (Spectra LRS, COBE;or MCS+ LDP, Haemonetics) were sufficiently depleted of WBCs to limit cytokine accumulation during storage. The study evaluated 1) the levels of cytokines of WBC and platelet origin in two types of apheresis PCs during storage and 2) the effects of prestorage filtration on cytokine levels in the Spectra LRS PCs. RESULTS: In the Spectra LRS PCs, low levels of IL-6, IL-8, and monotype chemoattractant protein 1 (MCP-1) were detected in Day 1 PCs, and they remained consistent during the shelf life. RANTES, platelet factor 4 (PF4), beta-thromboglobulin (beta-TG), and transforming growth factor (TGF)-beta1 were also detected in these PCs, and their levels increased significantly on storage. Prestorage filtration of Spectra LRS PCs did not further reduce the levels of IL-6, IL-8, MCP-1, PF4, beta-TG, and TGF-beta1 in the filtered component. In the MCS+ LDP PCs, IL-6 was detected on Day 1, and its level increased significantly on storage, whereas the levels in the Spectra PCs remained steady. IL-8 levels were lower in MCS+ LDP PCs than in Spectra LRS PCs of the same age. MCP-1 levels were similar in both products on Day 1 and marginally increased in stored MCS+ LDP PCs. Substantial amounts of RANTES, PF4, beta-TG, and TGF-beta1 occurred in Day 1 MCS+ LDP PCs, and, on storage, these levels rose significantly. CONCLUSION: Despite a significant reduction in levels of WBC-derived cytokines, platelet-derived cytokines were present in different amounts in the two products.

Blood Platelets↗
PubMed2001

Peripheral blood progenitor cell grafts contain high levels of platelet-secreted mediators.

BACKGROUND: The cytokine network in peripheral blood progenitor cell (PBPC) grafts may affect hematopoietic reconstitution or the risk of postransplant relapse of malignant disorders through effects on normal progenitor cells or contaminating malignant cells. Whether thrombopoietin (TPO), SCF, and platelet-secreted mediators are parts of this network was investigated. STUDY DESIGN AND METHODS: Peripheral blood and PBPC plasma samples were collected consecutively from patients with malignant disorders who underwent PBPC harvest. Blood samples were collected immediately before and after apheresis. Patients underwent mobilization by chemotherapy plus G-CSF, except for one patient who received only G-CSF. Plasma levels were also determined for healthy controls. RESULTS: PBPC grafts had greater levels of platelet-secreted platelet factor 4 (PF4), beta-thromboglobulin, and platelet-derived growth factor isoform AB, as compared with venous levels in patients and controls. Although platelet and PF4 levels in autografts were significantly correlated, the graft:blood ratio was higher for PF4 than for platelets. In both the patients' blood and the autografts, TPO levels were increased from the levels in normal controls. Blood and graft levels of SCF were within the normal range. CONCLUSION: The cytokine network of PBPC autografts includes increased levels of TPO and several platelet-derived mediators.

Adult↗
PubMed2004

Recombinant platelet factor 4 for heparin neutralization.

Protamine sulfate has been used for many years to reverse the effects of unfractionated heparin, but it can cause hemodynamic changes and other serious side effects. Platelet factor 4 (PF4) is a naturally occurring protein synthesized in megakaryocytes and eventually stored in the alpha granules of platelets for later release. Although the complete physiologic role of PF4 is unknown, it is highly effective for the neutralization of heparin anticoagulation. Several preliminary animal studies and trials using blood obtained from cardiopulmonary bypass circuits suggested recombinant PF4 (rPF4) would be an effective alternative to protamine. In the first open-label, phase 1 human study, patients received rPF4 in doses of 0.5, 1.0, 2.5, or 5.0 mg/kg over 3 minutes to reverse heparin anticoagulation after diagnostic cardiac catheterization. There were no important hemodynamic changes and the rPF4 was highly effective in neutralizing heparin. Serial measurements of rPF4 levels showed a monophasic elimination pattern with a serum half-life of 25.5 +/- 13.5 minutes that was independent of dose administered. A randomized and blinded trial comparing rPF4 to protamine confirmed the safety and effectiveness of rPF4. Although rPF4 was initially being evaluated as a clinical alternative to protamine, it is not currently being developed for general clinical use.

Aged↗
PubMed1997

Recognition and management of heparin-induced thrombocytopenia (HIT) and thrombosis.

An immune response to heparin, which is clinically manifested by the development of thrombocytopenia with or without thrombosis, is stimulated by a complex of heparin with platelet factor 4 (PF4). The primary thrombotic events in patients with heparin-induced thrombocytopenia (HIT) are more frequently venous than arterial. The development of antibodies, however, does not always result in thrombocytopenia or in catastrophic events. The antibodies, which are of the IgG, IgM, and IgA isotypes, can be easily measured by an ELISA that contains a complex of heparin-platelet factor 4 (PF4). Initial antibody formation can be greatly reduced by limiting the exposure to unfractionated heparin or by the use of low-molecular-weight heparin. For those patients who require anticoagulation and who have antibodies to heparin-PF4, danaparoid (Orgaran), a low-molecular weight heparinoid that does not react with the antibodies, is now commercially available; argatroban, a thrombin-specific inhibitor, can also be obtained for compassionate use. The use of these agents during anticoagulation with warfarin is preferable to the simple discontinuation of heparin and intitiation of warfarin, because the latter treatment can result in ongoing thrombosis.

Anticoagulants↗
PubMed2005

Decreased levels of CXC-chemokines in serum of benzene-exposed workers identified by array-based proteomics.

Benzene is an important industrial chemical and environmental contaminant that causes leukemia. To obtain mechanistic insight into benzene's mechanism of action, we examined the impact of benzene on the human serum proteome in a study of exposed healthy shoe-factory workers and unexposed controls. Two sequential studies were performed, each using sera from 10 workers exposed to benzene (overall mean benzene air level >30 ppm) and 10 controls. Serum samples were subjected to anion-exchange fractionation and bound to three types of ProteinChip arrays (Ciphergen Biosystems, Fremont, CA) [hydrophobic (H50), metal affinity (IMAC3-Cu), and cation exchange (WCX2)]. Protein-expression patterns were detected by surface-enhanced laser desorption/ionization (SELDI)-TOF MS. Three proteins (4.1, 7.7, and 9.3 kDa) were consistently down-regulated in exposed compared with control subjects in both studies. All proteins were highly inversely correlated with individual estimates of benzene exposure (r > 0.75). The 7.7- and 9.3-kDa proteins were subsequently identified as platelet factor (PF)4 and connective tissue activating peptide (CTAP)-III. Initial proteomic results for PF4 and CTAP-III were subsequently confirmed in a single experiment using a ProteinChip-array-based immunoassay(Ciphergen Biosystems). The altered expression of the platelet-derived CXC-chemokines (40% and 63% for PF4 and CTAP-III, respectively) could not be explained by changes in absolute platelet counts. Thus, SELDI-TOF analysis of a limited number of exposed and unexposed subjects revealed that lowered expression of PF4 and CTAP-III proteins is a potential biomarker of benzene's early biologic effects and may play a role in the immunosuppressive effects of benzene.

Benzene↗
PubMed1989

Immunoregulatory activity of peptides related to platelet factor 4.

Platelet factor 4 (PF4), a secreted platelet protein, alleviates concanavalin A-induced immunosuppression in mice. We now find that activity also resides in (i) the C-terminal tridecapeptide of PF4 (P13S), (ii) an analog of this in which arginine replaces the lysine residues and in which the last two amino acids are absent, (iii) the C-terminal 18 amino acids of low-affinity platelet factor 4, which is very similar to P13S, and (iv) peptide fragments of P13S that contain only 5-9 amino acids. P13S treated with fluorescamine to derivatize the free amino groups retained immunoregulatory activity but did not bind to heparin-agarose. The N-terminal and middle portions of PF4, polylysine, protamine, and three unrelated peptides were inactive in this assay.

Amino Acid Sequence↗
PubMed2003

Role of salicylic acid in systemic resistance induced by Pseudomonas fluorescens against Fusarium oxysporum f. sp. ciceri in chickpea.

Selected isolates of Pseudomonas fluorescens (Pf1-94, Pf4-92, Pf12-94, Pf151-94 and Pf179-94) and chemical resistance inducers (salicylic acid, acetylsalicylic acid, DL-norvaline, indole-3-carbinol and lichenan) were examined for growth promotion and induced systemic resistance against Fusarium wilt of chickpea. A marked increase in shoot and root length was observed in P. fluorescens treated plants. The isolates of P. fluorescens systemically induced resistance against Fusarium wilt of chickpea caused by Fusarium. oxysporum f.sp. ciceri (FocRs1), and significantly (P = 0.05) reduced the wilt disease by 26-50% as compared to control. Varied degree of protection against Fusarium wilt was recorded with chemical inducers. The reduction in disease was more pronounced when chemical inducers were applied with P. fluorescens. Among chemical inducers, SA showed the highest protection of chickpea seedlings against wilting. Fifty two- to 64% reduction of wilting was observed in soil treated with isolate Pf4-92 along with chemical inducers. A significant (P = 0.05; r = -0.946) negative correlation was observed in concentration of salicylic acid and mycelial growth of FocRs1 and at a concentration of 2000 microg ml(-1) mycelial growth was completely arrested. Exogenously supplied SA also stimulated systemic resistance against wilt and reduced the disease severity by 23% and 43% in the plants treated with 40 and 80 microg ml(-1) of SA through root application. All the isolates of P. fluorescens produced SA in synthetic medium and in root tissues. HPLC analysis indicated that Pf4-92 produced comparatively more SA than the other isolates. 1700 to 2000 nanog SA g(-1) fresh root was detected from the application site of root after one day of bacterization whereas, the amount of SA at distant site ranged between 400-500 nanog. After three days of bacterization the SA level decreased and was found more or less equal at both the detection sites.

Antifungal Agents↗
PubMed2004

Thrombopoietin-induced Dami cells as a model for alpha-granule biogenesis.

Megakaryocytic alpha-granules contain secretory proteins relevant to megakaryocyte and platelet functions. Understanding alpha-granule biogenesis is hampered because human primary megakaryocytes are difficult to manipulate. Existing promegakaryocytic cell lines do not spontaneously exhibit mature alpha-granules. Dami cells, transfected with the megakaryocytic platelet factor 4, fused to GFP (PF4-GFP), were induced in the presence of thrombopoietin (TPO), a megakaryocyte cytokine and PMA. Using confocal microscopy, PF4-GFP colocalized with von Willebrand Factor (vWF) in newly formed storage granules. Immunoelectron microscopy demonstrated alpha-granule-like features, including a dense core or parallel tubules and colocalization of PF4-GFP and vWF. Hence, TPO-treated Dami cells are a suitable model to study alpha-granules and their biogenesis.

Cell Compartmentation↗
PubMed1984

Redistribution of alpha-granules and their contents in thrombin-stimulated platelets.

The redistribution of beta-thromboglobulin (beta TG), platelet Factor 4 (PF4), and fibrinogen from the alpha granules of the platelet after stimulation with thrombin was studied by morphologic and immunocytochemical techniques. The use of tannic acid stain and quick-freeze techniques revealed several thrombin-induced morphologic changes. First, the normally discoid platelet became rounder in form, with filopodia, and the granules clustered in its center. The granules then fused with one another and with elements of the surface-connected canalicular system (SCCS) to form large vacuoles in the center of the cell and near the periphery. Neither these vacuoles nor the alpha granules appeared to fuse with the plasma membrane, but the vacuoles were connected to the extracellular space by wide necks, presumably formed by enlargement of the narrow necks connecting the SCCS to the surface of the unstimulated cell. The presence of fibrinogen, beta TG, and PF4 in corresponding large intracellular vacuoles and along the platelet plasma membrane after thrombin stimulation was demonstrated by immunocytochemical techniques in saponin-permeabilized and nonpermeabilized platelets. Immunocytochemical labeling of the three proteins on frozen thin sections of thrombin-stimulated platelets confirmed these findings and showed that all three proteins reached the plasma membrane by the same pathway. We conclude that thrombin stimulation of platelets causes at least some of the fibrinogen, beta TG, and PF4 stored in their alpha granules to be redistributed to their plasma membranes by way of surface-connected vacuoles formed by fusion of the alpha granules with elements of the SCCS.

Blood Platelets↗
PubMed1995

The IP-10 chemokine binds to a specific cell surface heparan sulfate site shared with platelet factor 4 and inhibits endothelial cell proliferation.

IP-10 is a member of the chemokine family of cytokines and is induced in a variety of cells in response to interferon gamma and lipopolysaccharide. The self-aggregation common to many chemokines, including IP-10, has hindered the identification of a specific IP-10 receptor. Using an IP-10 alkaline phosphatase fusion protein that fortuitously blocks this self-aggregation, we have identified an IP-10 binding site on a variety of cells including endothelial, epithelial, and hematopoietic cells. This binding site has a Kd of 25 nM, is inhibited by recombinant murine or human IP-10, and is dependent on the presence of cell surface heparan sulfate proteoglycans (HSPG). This conclusion is based on the findings that IP-10 binding to cells is: (a) inhibited by heparin and heparan sulfate; (b) sensitive to a 1 M NaCl wash; (c) eliminated by treatment with heparinase and trypsin; and (d) absent on mutant CHO cells that do not express cell surface HSPG. Platelet factor 4 (PF4), but not IL-8, monocyte chemoattractant protein-1, RANTES, monocyte inflammatory protein (MIP)-1 alpha, or MIP-1 beta, can compete effectively with IP-10 for binding to the cell surface. Furthermore, IP-10 shares with PF4 the ability to inhibit endothelial cell proliferation (IC50 = 150 nM). These studies demonstrate specificity in the interaction of chemokines and HSPG, and they define IP-10 and PF4 as a distinct subset of chemokines sharing an HSPG-binding site and angiostatic properties.

Animals↗
PubMed1990

Platelet responses to intravenous infusion of Intralipid in healthy volunteers.

Platelet function and morphology were studied in eight healthy male volunteers before, immediately after, and 1 d after the infusion of 250 mL of 10% Intralipid. The plasma concentrations of the platelet-release products beta-thromboglobulin (beta-TG), serotonin (5-HT), and platelet factor 4 (PF4) and the threshold to ADP- and adrenaline-induced aggregation were determined ex vivo. In addition the platelets were examined by electron microscopy. Although platelets released beta-TG, PF4, and 5-HT after the infusion, there was no significant change in ex vivo aggregability. About 3% of the platelets had internalized small-sized lipid particles (0.1-0.2 micron) whereas no other morphological changes were detected. The release products may negatively affect the hemorheological properties of the microcirculation in critically ill patients. The release of PF4 may explain the antiheparin effect of parenteral lipid therapy.

Adult↗
PubMed1999

Decision analysis for use of platelet aggregation test, carbon 14-serotonin release assay, and heparin-platelet factor 4 enzyme-linked immunosorbent assay for diagnosis of heparin-induced thrombocytopenia.

The value of the platelet aggregation test, carbon 14-labeled serotonin release assay (SRA), and heparin-platelet factor 4 enzyme-linked immunosorbent assay (H-PF4 ELISA) for the diagnosis of heparin-induced thrombocytopenia was evaluated by studying blood samples from 100 patients with suspected heparin-induced thrombocytopenia, and categorized into 4 clinical groups: unlikely (n = 22), possible (34), probable (36), and definite (8) thrombocytopenia. Results of the platelet aggregation test were positive in 40 of 44 patients with probable or definite heparin-induced thrombocytopenia (sensitivity 91%) and in 5 of 22 unlikely to have heparin-induced thrombocytopenia (specificity 77%). The SRA exhibited sensitivity of 88% and negative predictive value of 81%, close to those values for the platelet aggregation test; specificity and positive predictive value were 100%. The sensitivity of the heparin-PF4 ELISA was 97%, with specificity 86%, and a positive correlation was recorded between the level of antibodies to H-PF4 and clinical score (P = 0.66). When ELISA was used with the platelet aggregation test or SRA, positive predictive value and specificity were 100% when both tests yielded positive results, and negative predictive value was 100% when both tests yielded negative results. A biologic flow chart was designed that presented a choice based on the results of the platelet aggregation test or SRA in association with ELISA, and enabled more accurate and specific identification of heparin-induced thrombocytopenia.

Carbon Radioisotopes↗
PubMed1990

Filtration of platelet-poor plasma specimens yields platelet-free plasma. Application for batch analysis of beta-thromboglobulin and platelet factor 4.

The authors investigated filtration of platelet-poor plasma through a 0.2-micron filter for the analysis of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) in frozen specimens. Platelets were detected by electron micrograph in the platelet-poor plasma preparation without filtration. No platelets or platelet fragments were seen after filtration. Freezing the unfiltered specimens resulted in a significant increase in the beta-TG and PF4 concentrations, presumably because of release of these proteins from the platelet alpha-granules during freezing and thawing. There was no change in the PF4 levels and only a slight decrease in beta-TG levels after freezing of the filtered specimens. The filtered samples could be frozen for later batch analysis, resulting in considerable cost savings to the laboratory.

Blood Platelets↗
PubMed1983

Plasma concentrations of platelet-specific proteins in young female acute myocardial infarction survivors and their age-matched female controls.

The steady state plasma concentrations of the two platelet-specific proteins beta-thromboglobulin (BTG) and platelet factor 4 (PF4) were determined in two groups of females: 36 acute myocardial infarction (AMI) survivors, and 38 age-matched control subjects. For the AMI patients the mean BTG and PF4 values were 57 +/- 4 and 14.1 +/- 1.7 ng/ml, respectively. These two means significantly exceeded the corresponding means for the controls, 40 +/- 2 and 10.3 +/- 0.6 ng/ml, respectively. Similar results have recently been reported by other workers who investigated patients with coronary artery disease; however, in no previous study were the values for BTG and PF4 related to those obtained for control subjects matched with respect to sex and age. The present results therefore further support the concept that increased platelet activation and secretion is taking place in steady state patients who previously have sustained an AMI.

Adult↗
PubMed1985

Plasma concentrations of platelet-specific proteins and serum thromboxane B2 production in response to treatment with dipyridamole. A pilot study of 27 post-myocardial infarction patients.

In the present study 27 post-myocardial infarction patients were treated with Persantin capsules (Depot-Kapseln, sustained release form), containing 200 mg dipyridamole, b.i.d. over a period of 3 weeks. Baseline levels for plasma beta-thromboglobulin (BTG), platelet factor 4 (PF4), and serum thromboxane B2 (TXB2) were obtained on day 0 and subsequently on days 1, 3, 5, 7, 14 and 21. The baseline levels for plasma BTG and PF4 as well as for serum TXB2 significantly exceeded those for a control group consisting of healthy subjects. The plasma values for BTG and PF4 remained unchanged during the whole study period. During the first week of study the levels for serum X TXB2 were unchanged; however, on days 14 and 21 the means for TXB2 dropped significantly. There is experimental work to suggest that dipyridamole may exert an inhibitory effect on platelet thromboxane biosynthesis. The present results support this concept.

Adult↗
PubMed2002

Heparanase and platelet factor-4 induce smooth muscle cell proliferation and migration via bFGF release from the ECM.

Basic fibroblast growth factor (bFGF) has been shown to play an instrumental role in the cascade of events leading to restenosis; however, the mechanisms of bFGF activation following vascular injury have remained elusive. We have demonstrated that heparanase and platelet factor-4 (PF4), released from activated platelets at the site of injury, liberate bFGF from the extracellular matrix (ECM) of vascular smooth muscle cells (SMC), resulting in the induction of SMC proliferation and migration. Increases in proliferation and migration were inhibited by treatment with a bFGF-neutralizing antibody, suggesting that proliferation and migration in response to heparanase or PF4 are mediated by bFGF activation. When platelets were seeded on top of SMCs, degranulation products were found to release bFGF from the ECM, increasing cell proliferation and cell migration. Again, these increases in SMC proliferation and migration were inhibited by treatment with an anti-bFGF antibody. Furthermore, these increases in proliferation were completely inhibited by treatment with an anti-heparanase antibody. Platelet degranulation products, such as heparanase and PF4, may liberate bFGF from extracellular sequestration, activating the growth factor and inducing the SMC proliferation and migration that contribute to the wound healing response following vascular injury.

Blood Platelets↗
PubMedDate not supplied

Tirofiban administration attenuates platelet and platelet-neutrophil conjugation but not neutrophil degranulation during in vitro VAD circulation.

Ventricular Assist Devices (VADs) have been used as bridges to heart transplantation. However, VAD circulation is complicated by the incidence of thromboembolism, prolonged bleeding, and activation of the inflammatory cascade. We hypothesize that platelet and neutrophil activation are interrelated and linked to the activation of the glycoprotein (GP) IIb/IIIa platelet receptor. The purpose of this study is to evaluate the effects of Tirofiban, a platelet GP IIb/IIIa receptor inhibitor, on platelet and neutrophil activation during simulated VAD circulation. Two groups of five in vitro VAD circuits were simulated with and without Tirofiban using 450 cc of human blood. Blood samples were drawn at specific time intervals up to 72 hours, measuring leukotriene C4 (LTC4), platelet factor four (PF4), and neutrophil elastase. Tirofiban decreased serum levels of PF4 and LTC4 during VAD circulation. Neutrophil elastase secretion was not affected by Tirofiban administration. Preconditioning of VAD circulation with Tirofiban attenuated platelet activation as demonstrated by a decrease in serum PF4 levels. Tirofiban administration ameliorates the inflammatory response by altering platelet-neutrophil interaction as demonstrated by a decrease in LTC4 production. Continued elastase secretion indicates that the inflammatory response is not completely inhibited by Tirofiban administration. These results suggest that neutrophils may be activated by alternative mechanisms. Early complement activation has been demonstrated during in vivo and in vitro VAD circulation and may play a role in mediating inflammatory and thromboembolic reactions during VAD use.

Blood Platelets↗