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At least 19 recordsLinked to original sources
PubMed1989

Inhibition of human megakaryocytopoiesis in vitro by platelet factor 4 (PF4) and a synthetic COOH-terminal PF4 peptide.

We report that highly purified human platelet factor 4 (PF4) inhibits human megakaryocytopoiesis in vitro. At greater than or equal to 25 micrograms/ml, PF4 inhibited megakaryocyte colony formation approximately 80% in unstimulated cultures, and approximately 58% in cultures containing recombinant human IL 3 and granulocyte-macrophage colony-stimulating factor. Because PF4 (25 micrograms/ml) had no effect on either myeloid or erythroid colony formation lineage specificity of this effect was suggested. A synthetic COOH-terminal PF4 peptide of 24, but not 13 residues, also inhibited megakaryocyte colony formation, whereas a synthetic 18-residue beta-thromboglobulin (beta-TG) peptide and native beta-TG had no such effect when assayed at similar concentrations. The mechanism of PF4-mediated inhibition was investigated. First, we enumerated total cell number, and examined cell maturation in control colonies (n = 200) and colonies (n = 100) that arose in PF4-containing cultures. Total cells per colony did not differ dramatically in the two groups (6.1 +/- 3.0 vs. 4.2 +/- 1.6, respectively), but the numbers of mature large cells per colony was significantly decreased in the presence of PF4 when compared with controls (1.6 +/- 1.5 vs. 3.9 +/- 2.3; P less than 0.001). Second, by using the human leukemia cell line HEL as a model for primitive megakaryocytic cells, we studied the effect of PF4 on cell doubling time, on the expression of both growth-regulated (H3, p53, c-myc,and c-myb), and non-growth-regulated (beta 2-microglobulin) genes. At high concentrations of native PF4 (50 micrograms/ml), no effect on cell doubling time, or H3 or p53 expression was discerned. In contrast, c-myc and c-myb were both upregulated. These results suggested the PF4 inhibited colony formation by impeding cell maturation, as opposed to cell proliferation, perhaps by inducing expression of c-myc and c-myb. The ability of PF4 to inhibit a normal cell maturation function was then tested. Megakaryocytes were incubated in synthetic PF4, or beta-TG peptides for 18 h and effect on Factor V steady-state mRNA levels was determined in 600 individual cells by in situ hybridization. beta-TG peptide had no effect on FV mRNA levels, whereas a approximately 60% decrease in expression of Factor V mRNA was found in megakaryocytes exposed to greater than or equal 100 ng/ml synthetic COOH-terminal PF4 peptide. Accordingly, PF4 modulates megakaryocyte maturation in vitro, and may function as a negative autocrine regulator of human megakaryocytopoiesis.

Amino Acid Sequence↗
PubMed1992

Inhibitory effect of platelet factor 4 (PF4) on the growth of human erythroleukemia cells: proposed mechanism of action of PF4.

The effect of platelet factor 4 (PF4) on the growth of human erythroleukemia cell line (HEL) and the binding characteristics of iodine 125-labeled PF4 to cells were studied to determine the mechanism of action of PF4. HEL cells were cocultured with various doses of PF4 in either a plasma clot system for colony assay or a liquid system for tritiated thymidine incorporation. A significant inhibition of HEL colony growth and tritiated thymidine incorporation was seen at PF4 doses of 1 microgram/ml and 0.5 microgram/ml, respectively. The inhibitory effect of PF4 could be abrogated by the addition of heparin (5 to 10 micrograms/ml). Enzyme-linked immunosorbent assay showed that PF4 had no obvious effect on the expression of platelet glycoprotein IIb/IIIa of HEL cells. Binding of 125I-PF4 to HEL cells reached equilibrium within 20 to 30 minutes with dissociation constant of 1.3 x 10(-10)M and Bmax of 6.3 pmol/10(5) cells and was inhibited by an excess of unlabeled PF4, beta TG, and heparin but was not affected by PMA, IL-3, IL-6, GM-CSF, and interferon-alpha. PF4 did not affect the binding of 125I-IL-3 and 125I-IL-6 to HEL cells. These data demonstrate that PF4 inhibits the growth of HEL cells by specific binding to HEL cells and suggest that the action of PF4 may be associated with the heparin-binding sites of the molecule.

Cell Division↗
PubMed1986

Platelet factor 4 (PF4) and heparin released platelet factor 4 (HR-PF4) in diabetes mellitus. Effect of the duration of the disease.

Several investigators have reported an altered platelet function in diabetes mellitus as measured by elevated levels of platelet specific proteins platelet factor 4 (PF4) and B-thromboglobulin (BTG). We studied 20 insulin dependent (IDD), 20 non insulin dependent (NIDD) diabetic males without overt clinical symptoms of cardiovascular disorders and 30 normal controls. We evaluated PF4, BTG and heparin released platelet factor 4 (HR-PF4) as measured 2.5 minutes after a bolus injection of 5,000 I.U. of a commercial mucous heparin. The patients showed normal levels of both PF4 and BTG. Furthermore HR-PF4 failed to show statistically significant variation between patients and controls. However when the diabetics were divided on the basis of the duration of the disease, the IDD had an increased HR-PF4 mean level and the trend became statistically significant when diabetes existed more than 17 years (patients HR-PF4 149.1 ng/ml, range 17.3-194; controls HR-PF4 110.9 ng/ml range 50-160, less than p less than 0.05). NIDD failed to reveal the same pattern. Although the significance of HR-PF4 is unknown, insulin dependent diabetes mellitus after many years could cause a potentially dangerous, silent vascular damage with enhanced platelet vessel wall interaction as measured by an elevated HR-PF4.

Adolescent↗
PubMed1985

Standardization of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4): a collaborative study to establish international standards for beta-TG and PF4.

An international collaborative study was carried out to determine the suitability of freeze-dried preparations of beta-TG and PF4 to serve as international standards, and to compare these materials with other purified preparations and with plasma samples. Although problems remain with the accurate measurement of these proteins, it has been demonstrated that common standards improve the precision of measurement by RIA and provide an essential foundation for future work into the effects of assay system differences. The World Health Organization established in 1984 the purified preparation of beta-TG (83/501) and the purified preparation of PF4 (83/505) as International Standards, with assigned potencies of 500 International Units per ampoule and 400 International Units per ampoule, respectively.

Beta-Globulins↗
PubMed1976

Immunoassay of human platelet factor 4(PF4, antiheparin factor) by radial immunodiffusion.

Human platelet factor 4 antigen (PF4 antigen) was measured in platelets and in plasma by means of single radial immunodiffusion. Anti-PF4 antibody obtained in rabbits by injecting highly purified human PF4 was monospecific in double immunodiffusion and in quantitative "rocket" immunoelectrophoresis. A high degree of correlation was observed between the precipitation zones in the radial immunodiffusion method and the amount of purified PF4 (in the range of 0.6 to 50.0 mug per milliliter) or the number of platelets in plasma (in the range of 5 x 10(6) to 1.6 x 10(8) platelets per milliliter applied. The sensitivity of the method was 30 to 125 times higher as compared with clotting assay (antiheparin activity) and the standard error of the method was 2.3 per cent. The method was specific for the antigen present in platelets since human leukocytes and erythrocytes gave negative results. Release of PF4 antigen from washed platelets challenged with thrombin, collagen, ADP, and antigen-antibody complexes was measured by the radial immunodiffusion assay. It usually paralleled the release of 3H-serotonin but PF4 antigen was a more sensitive marker for platelet release reaction. Release of PF4 antigen was usually 2 to 4 times higher than release of the antiheparin activity as measured by clotting assay when both were compared as percentage of total content in platelets. The level of PF4 antigen was determined in platelet-rich plasma (PRP) and platelet-free plasma (PFP) obtained from 12 healthy volunteers. While the mean level of extraplatelet pool of PF4 antigen in PFP was 0.72 +/- 0.92 mug per milliliter, PRP contained 80 +/- 22 mug of PF4 antigen per 10(9) platelets. Addition of thrombin (1 U. per milliliter) liberated all of the PF4 antigen (78 +/- 24 mug) present in PRP but ADP (50 muM) released only 31 +/- 22 mug of PF4 antigen per 10(9) platelets. The presence of heparin did not interfere with the assay of intraplatelet or extraplatelet PF4 by single radial immunodiffusion. The method described represents a simple, sensitive, quantitative, and specific assay for human PF4 antigen possessing antiheparin activity.

Adenosine Diphosphate↗
PubMed1985

Disappearance of human platelet factor 4 (PF4) in rabbits: does an immediate component exist?

Twelve male New Zealand rabbits were injected with 21 micrograms/kg of human platelet factor 4 antigen (PF4). The decay of the protein followed a monoexponential curve for the first 5 mins, with a half-life (t 1/2) of 1.94 mins and a calculated concentration at 0 time (CO) of 79.4 ng/ml. Five rabbits were pre-treated with heparin (2.500 I.U. i.v.) and 3 mins later were injected with the same amount of PF4. PF4 decay followed a monoexponential curve with a t 1/2 of 25.3 mins, and with CO of 380.8 ng/ml. This value is not greatly different from the one calculated assuming an immediate and uniform distribution in plasma (482.7 ng/ml for a plasma volume of 43.5 ml/kg). The 12 rabbits injected with PF4 were divided in 3 groups, in which heparin was given at 10', 30' or 60' after PF4, respectively. After heparin the peak levels of PF4 were 139.9 ng/ml, 65.3 ng/ml and 52.7 ng/ml, respectively. The following monoexponential PF4 decay had t 1/2 of 20.7, 25.6 and 26.0 mins, respectively. In a separate group of 4 animals, we studied heparin decay after an intravenous bolus of 2.500 I.U. Heparin decay could not be described by a monoexponential equation and was different from the decay of PF4 injected after heparin. On the basis of the present data we suggest the presence of an immediate component of PF4 decay, most likely due to uptake by the tissues. Heparin pretreatment may avoid this uptake process.

Animals↗
PubMed1975

Antigenic and antiheparin properties of human platelet factor 4 (PF4).

Platelet factor 4 (PF4, a heparin-neutralizing protein) was isolated from washed human platelets. It was found to be homogenous by SDS-polyacrylamide gel electrophoresis, immunodiffusion, and immunoelectrophoresis, when tested with monospecific antibody produced in rabbits. PF4 is a heat-stable protein, but its antiheparin activity and antigenicity are destroyed by trypsin. The molecular weight of PF4 as calculated by amino acid analysis is approximately 8000 and by SDS-polyacrylamide gel electrophoresis with beta-mercaptoethanol, 7100 daltons. PF4 migrated to the cathode at pH 8.6. The interaction of PF4 with heparin resulted in the formation of a complex which migrated to the anode, as tested by immunoelectrophoresis. Incubation of purified PF4 with its antibody at 37 degrees C resulted in a loss of antiheparin activity. The presence of antiheparin activity and of PG4 antigen in material released during platelet aggregation by various agents and at various stages of the preparative procedure closely correlated. It has been concluded that PF4 antigen and antiheparin activity are two properties of the same protein. Comparison of human and pig PF4 revealed significant biochemical and antigenic differences.

Amino Acids↗
PubMed1992

Urinary platelet factor four (Pf4) levels in mesangial IgA glomerulonephritis and thin basement membrane disease.

The aim of this study was to assess the significance of platelet factor four (Pf4) excretion in the urine of patients with mesangial IgA glomerulonephritis (IgAGN) and thin basement membrane disease (TBMD), and ascertain if Pf4 is a useful parameter to distinguish these diseases. The concentration of Pf4 in urine (Pf4) was determined by an enzyme linked immunoabsorbent assay (ELISA) in patients with IgAGN (n = 80), TBMD (n = 37), membranous nephropathy (MN) (n = 12), minimal change nephrotic syndrome (MCNS) (n = 3), crescentic glomerulonephritis (CGN) (n = 6) and in healthy controls (n = 20), and then compared with urinalysis and renal function. An immunoperoxidase method was used to examine urine sediments for the presence of platelets. Urinary Pf4 was detected in 35 out of 80 patients with IgAGN (median 0.15, range 0.07-2.5 ng/ml, n = 35), in only 2 out of 37 patients with TBMD (p less than 0.005), in all patients with CGN and in no patients from MN, MCNS or control groups. A positive correlation between urinary Pf4 levels and red blood cell counts was observed in patients with IgAGN (r = 0.876, p less than 0.001), but not in TBMD. Pf4 did not correlate with proteinuria or plasma creatinine in either group. Platelets were detected in urine in 10 out of 15 patients with IgAGN but in only 1 out of 9 patients with TBMD. Urinary red blood cell counts in all of these 24 patients were over 100,000/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1987

Relevance of platelet factor four (PF4) plasma levels in multiple sclerosis.

In order to study the role of platelets in Multiple Sclerosis (MS) we assessed, in a group of patients during a quiescent phase of the disease, the plasma levels of beta-thromboglobulin (beta-TG) and platelet factor four (PF4) both in absence of treatment and during administration of aspirin (ASA) at the dose of 50 mg/daily. In the MS patients studied, the basal plasma levels of beta-TG and PF4 were significantly higher than in control subjects. The increase in the beta-TG plasma levels occurred independently of the age, sex and severity of the disease, whereas the modification in the PF4 plasma levels was significantly correlated with the severity of the disease. Administration to the patients of ASA, at the dose that does not affect prostacyclin production, determined a decrease of beta-TG in 77% of the patients. Mean PF4 plasma levels remained unchanged. These results suggest that PF4 in the plasma of MS patients may originate not only from the platelets but also from the mast cells following platelet aggregating factor (PAF) stimulation and immunocomplex formation.

Adult↗
PubMed1987

Raised plasma concentrations of platelet factor 4 (PF4) in Crohn's disease.

Plasma platelet factor 4 (PF4), secreted by the platelets, is an index of platelet aggregation and thromboembolic risk. The authors assessed PF4 in 20 patients with Crohn's disease (ileitis in 13 patients, ileocolitis in seven) and in 20 healthy volunteers. Disease activity was low (Crohn's Disease Activity Index less than 150) in 11 patients and high in nine. Radioimmunoassay of PF4 using Abbott's Kit was performed on one sample of plasma from each subject (nv less than or equal to 0.324 nmol/ml), (nv less than or equal to 10 ng/ml). A significantly higher concentration of PF4 was found in Crohn's disease patients: 4.625 +/- 1.1 nmol/ml (142.5 +/- 36 ng/ml) than in the control group: 0.189 +/- 0.07 nmol/ml (5.6 +/- 4.8 ng/ml) (Z = 5.396, p less than 0.0001). No correlation was present between PF4 levels and activity, the site of disease, or medical treatment with or without prednisone.

Adult↗
PubMed1988

Serial determinations of PF4 and beta TG: comparisons between multiple venipunctures vs a catheter infusion system.

Platelet factor 4 (PF4) and beta thromboglobulin (beta TG) are platelet-specific proteins which are released upon platelet aggregation and which can be accurately measured by radioimmunoassay. We devised a catheter-infusion system that enables serial determinations of these proteins. In 20 subjects (10 healthy volunteers and 10 patients with stable coronary artery disease), we compared samples collected by individual venipunctures with those simultaneously obtained by means of a simple catheter-infusion system. At least 5 samples were obtained over a period of time which was as long as 60 min, and at least 30 min. Subjects with stable coronary artery disease were selected so that they would be expected to have stable and normal PF4 and beta TG levels. Thus, elevations of either PF4 or beta TG would represent artifacts secondary to sampling technique. Analysis of the results demonstrated that the catheter-infusion system was equivalent to individual venipunctures for determination of PF4 and beta TG. 16.8% of samples obtained via the catheter and 17.2% of those obtained by individual venipunctures were spuriously elevated. A second series of studies were performed to refine the technique further by examining the impact of infusion rate and the addition of citrate phosphate dextrose (CPD) to the infusate. Ten additional subjects had catheter systems utilized in both arms simultaneously. The addition of CPD resulted in significantly less abnormal values at slower infusion rates (1 and 2.5 cc/min). At 5 cc/min D5/w or saline alone are suitable. These investigations confirm that this simple catheter system is equivalent to individual venipunctures for determination of PF4 and beta TG while avoiding patient discomfort.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Inhibition of thrombin generation by heparin and low molecular weight (LMW) heparins in the absence and presence of platelet factor 4 (PF4).

The ability of several low molecular weight (LMW) heparins and unfractionated heparin (UFH) to inhibit thrombin generation, and their anti-Xa and anti-IIa activities, were measured in the absence and presence of platelet factor 4 (PF4). The LMW heparins studied were 2-5 times less potent, on a weight basis, than UFH as inhibitors of thrombin generation in platelet-poor plasma; the inhibition of thrombin generation by LMW heparins correlated better with their anti-IIa activity (r = 0.98) than with their anti-Xa activity (r = 0.69). At low concentrations of PF4, the activity of LMW heparins in the thrombin generation test was neutralized less than that of UFH, but at higher PF4 concentrations all their activities could be neutralized except in anti-Xa assays. These observations support the hypothesis that anti-IIa activity is important for inhibition of thrombin generation by LMW heparins in vitro. However, when all the anti-IIa activity of LMW heparins was neutralized by PF4, considerable inhibitory activity remained in thrombin generation and anti-Xa assays, indicating that a portion of the anti-Xa activity of LMW heparins also contributes towards inhibition of thrombin generation.

Factor Xa Inhibitors↗
PubMed1990

Negative regulation of human megakaryocytopoiesis by human platelet factor 4 (PF4) and connective tissue-activating peptide (CTAP-III).

We have previously reported that human platelet factor 4 (PF4) and beta-thromboglobulin inhibit human megakaryocyte (meg) colony formation in vitro. Here, we report further findings concerning the effect of PF4 as well as another platelet-derived factor: connective tissue-activating peptide (CTAP-III). Addition of these factors (2.5-10 micrograms/ml) into normal marrow cultures resulted in a significant decrease of meg colonies, especially the mixed-meg colonies, BFU-meg and large CFU-meg, suggesting that they inhibit both proliferation and maturation of meg progenitor cells, with a predominant effect on earlier progenitor cells. Comparison of the effects of the two factors showed that their major effects were similar, with some difference in inhibitory degree. These results indicate that both PF4 and CTAP-III are potent inhibitors of meg colony formation and involved in negative autocrine regulation of megakaryocytopoiesis.

Bone Marrow Cells↗
PubMed1991

[The changes in plasma beta-thromboglobulin (beta-TG), platelet factor 4 (PF4) and thromboxane B2 (TXB2) after a bronchial provocation test (BPT) with house dust (HD) allergen].

In order to investigate the role of platelets in allergic asthma, the time related changes in plasma levels of beta-TG, PF4 and TXB2 were evaluated following BPT with HD in 19 patients with bronchial asthma who were positive in skin test and RAST to HD. The results obtained were as follows. 1) Plasma beta-TG and PF4 levels tended to increase following BPT with HD at the time of immediate asthmatic response (IAR) in patients showing IAR alone. 2) Plasma beta-TG and PF4 levels increased significantly (p less than 0.05) at IAR and tended to increase at the time of late asthmatic response (LAR) in patients showing a dual asthmatic response (DAR). 3) The levels of plasma TXB2 in patients showing IAR alone significantly increased at IAR (p less than 0.05) and gradually decreased and the levels of plasma TXB2 in patients showing a DAR increased in each period of IAR, 3 hr after BPT and LAR, and the peak of TXB2 was observed in 3 hours after BPT. 4) These results suggest that platelets are activated at IAR and there was also a possible activation in platelets at LAR.

Adult↗
PubMed1985

beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) in obstetrical cases.

The plasma levels of beta-Thromboglobulin (beta-TG) and Platelet Factor 4 (PF4) were measured in patients during the normal obstetrical period and in pre-eclampsia. A significant increase was observed in the two proteins with respect to the non-pregnant control group but no difference was seen between pregnancy and puerperium in either the normal or pre-eclamptic cases. The one significant variation in the concentration of the two proteins was a sharp rise during parturition. There was no correlation between beta-TG, PF4 and either the platelet count or creatinine but urea and uric acid did show a slight correlation with the two platelet proteins.

Adult↗
PubMedDate not supplied

Platelet factor 4 (PF4) in septicaemia.

The plasma concentrations of platelet factor 4 were measured in ten patients with septicaemia. In the acute phase the platelet factor 4 values were elevated (27.1 +/- 20.1 ng/ml; mean +/- SD; normal values 4.7 +/- 1.2 ng/ml), and declined significantly after treatment with antibiotics and surgical therapy, respectively (10.6 +/- 7.3 ng/ml; p less than 0.005). The determination of prothrombin time, fibrinopeptide A, AT III and platelet counts demonstrated a coagulation disorder in the acute phase of septicaemia in all patients; a thrombocytopenia (less than 100,000/mm3) was observed in three cases. We suggest that the measurement of platelet factor 4 concentration could be useful as an in vivo indicator and as a follow-up parameter of increased platelet activation.

Adult↗