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At least 73 records · Page 4Linked to original sources
PubMed1991

HIV-seropositive thrombocytopenia: the action of zidovudine.

The action of zidovudine when administered to individuals with severe HIV thrombocytopenia was investigated. Four individuals with platelets less than 50 x 10(9)/l and CD4 cells greater than 200 x 10(6)/l were treated with 600 mg zidovudine per day for 6 weeks, no drug for 6 weeks, 1200 mg zidovudine per day for 6 weeks, then no drug for 6 weeks. Glycocalicin, a platelet protein which correlates inversely with platelet survival, was assayed before and after treatment. Glycocalicin indices were also measured in four additional individuals with HIV thrombocytopenia. Platelet counts rose 2.5-fold [95% confidence interval (Cl), 2.0-3.0)] for four subjects who received 600 mg zidovudine per day and 4.9-fold (95% Cl, 4.0-5.8) for three subjects receiving 1200 mg zidovudine per day. Platelet counts declined during drug-free intervals. Plasma glycocalicin indices were elevated in all with untreated HIV thrombocytopenia. Indices fell after zidovudine treatment in six of seven individuals, suggesting that zidovudine prolonged platelet survival. Analysis of 170 HIV-seropositive asymptomatic individuals [mean CD4 count 474 x x 10(6)/l, standard deviation (s.d.) 245 x 10(6)/l] revealed that 14 (8%) had less than 125 x 10(9)/l platelets but only 2 (1%) had less than 50 x 10(9)/l platelets. Platelet counts increased spontaneously in eight individuals with mild HIV thrombocytopenia among the 10 for whom repeat counts were available.

Adult↗
PubMed1991

Differential redistribution of platelet glycoproteins Ib and IIb-IIIa after plasmin stimulation.

The subcellular localization of the platelet membrane receptors glycoproteins (GP) Ib and IIb/IIIa [corrected] has been studied within resting platelets by a combination of biochemical and cytochemical techniques. While both GPIb and GPIIb/IIIa are localized within the plasma membrane and surface-connected canalicular system (SCCS) membranes, only GPIIb/IIIa is present within the internal face of alpha-granular membranes. Previous studies demonstrated that plasmin can induce platelet stimulation and also decrease ristocetin-induced platelet aggregation; it was suggested that this was because of GPIb degradation by plasmin. In this study, the respective localizations of both GPIb and GPIIb/IIIa were visualized during in vitro plasmin stimulation of platelets. Generally, plasmin induced shape change, pseudopod formation, organelle centralization either with or without alpha-granule release depending on the conditions of stimulation. Plasmin treatment of platelets at 37 degrees C resulted in the disappearance of GPIb from the cell surface and its subsequent redistribution into the channels and vesicles of the SCCS with no significant modification of GPIIb/IIIa remaining on the plasma membrane. Within degranulated platelets, GPIIb/IIIa was expressed on the plasma membrane and within membranes of large vacuoles containing the alpha-granule proteins. GPIb was virtually absent from these structures and mainly restricted to the SCCS. Addition of cytochalasin D inhibited the migration of GPIb to the SCCS. Biochemical measurements confirmed that no important hydrolysis of GPIb had occurred because only very little amounts of glycocalicin were generated during the reaction. In conclusion, in plasmin-treated platelets GPIIb/IIIa is externalized to the plasma membrane while GPIb is internalized into the SCCS. Although previous studies have suggested that plasmin degrades GPIb, the reduction in ristocetin-induced aggregation may be explained by its apparent redistribution within the membranes of the SCCS.

Blood Platelets↗
PubMed1991

New enzyme-linked immunosorbent assay for glycocalicin in plasma.

A new sandwich-type enzyme-linked immunosorbent assay for quantifying glycocalicin, a proteolytic fragment of platelet membrane glycoprotein Ib, is described. The assay is based on the use of two monoclonal antibodies raised against glycoprotein Ib and involves the avidin-biotin technique. The detection limit is 7 micrograms/L and the range of glycocalicin determined in plasma is 0.01 to 1 mg/L. Assay time is 2 h. The intra-assay CV ranged from 3.6% to 5.2%, the interassay CV from 5.4% to 8.0%. Analytical recovery of purified glycocalicin added to a plasma pool averaged 96%. In 36 healthy subjects, the mean glycocalicin concentration in plasma was 0.36 (SD 0.07) mg/L (2.7 nmol/L). We conclude that this assay is suitable for measuring glycocalicin in plasma and is also more sensitive and precise than the previously published immunoassays based on competitive binding assay.

Adolescent↗
PubMed1991

Fetal platelet consumption: a feature of placental insufficiency.

The involvement of fetal platelets in placental insufficiency was investigated. Platelet life span and the rate of platelet turnover were measured by a novel technique in fetuses with moderate and severe placental insufficiency and in controls. This procedure involves the measurement of platelet count and concentration of free glycocalicin in plasma. Placental insufficiency was defined by antenatal Doppler ultrasound analysis of the umbilical artery waveform, which was used to categorize the subjects according to whether their systolic-diastolic ratios were normal, moderately raised, or severely raised. Mean platelet life span in fetuses affected by placental insufficiency was only 60% of the normal fetal platelet life span (P less than .001). In addition, affected fetuses had a higher rate of platelet turnover, reflected in an elevated plasma glycocalicin concentration (4.06 +/- 0.19 versus 3.28 +/- 0.15 microgram/mL for severe placental insufficiency and control fetuses, respectively; P less than .01). Platelet life span did not differ between the moderate and severe placental insufficiency groups. We hypothesize that the observed changes in platelet life span and turnover result from increased platelet activation, which plays a role in the development of placental insufficiency.

Female↗
PubMed1991

Measurement of receptor concentration and forward-binding rate constant via radiopharmacokinetic modeling of technetium-99m-galactosyl-neoglycoalbumin.

Technetium-99m-galactosyl-neoglycoalbumin (99mTc-NGA) is a synthetic ligand to the hepatocyte receptor, hepatic binding protein (HBP). A five-state mathematical model containing a bimolecular chemical reaction was utilized for quantitative estimation of the following physiologic and biochemical parameters: extrahepatic plasma volume Ve; hepatic plasma flow F and volume Vh; receptor-ligand forward-binding rate constant kb and reaction volume Vr; and receptor concentration [R]o. Nine normal subjects were studied. Given (a) liver and heart time-activity data, (b) the patient's weight, height, and hematocrit, (c) the fraction of injected dose in a 3-min blood sample, and (d) the amount and galactose density of the NGA dose, a computer program executed a curve-fit to the kinetic model. Systematic error, as measured by reduced chi-square, ranged from 1.43 to 2.56. Based on the nine imaging studies, the mean and relative error of each parameter were: [R]o, 0.813 +/- (0.11) microM; kb, 2.25 +/- (0.15) microM-1 min-1; F, 0.896 +/- (0.20) liter/min; Ve, 1.67 +/- (0.27) liter; and Vh, 0.228 +/- (0.22) liter. Two unique features of 99mTc-NGA radiopharmacokinetic systems permit the simultaneous estimates of receptor quantity, ligand affinity, and hepatic plasma flow. The first is the ability to administer a quantity of ligand capable of occupying a significant fraction of receptor; and the second is a simple model structure that conserves mass.

Adult↗
PubMed1991

Validation of in vivo receptor measurements via in vitro radioassay: technetium-99m-galactosyl-neoglycoalbumin as prototype model.

Hepatic binding protein (HBP) is a hepatocyte-specific receptor for serum asialoglycoproteins. The receptor also recognizes a synthetic glycoprotein that has been developed as a radiopharmaceutical, technetium-99m-galactosyl-neoglycoalbumin (99mTc-NGA). This report describes the correlation between receptor parameters measured in vivo via kinetic modeling of 99mTc-NGA and those measured by in vitro radioassay of biopsied liver tissue. Eleven patients with diffuse hepatic disease underwent percutaneous liver biopsy followed by a 99mTc-NGA functional imaging study. In vivo measurements of HBP quantity Ro and forward binding rate constant kb obtained from the kinetic analysis of 99mTc-NGA liver and blood time-activity data were compared to total receptor quantity and the HBP-99mTc-NGA association constant KA as measured by Scatchard binding assay of the biopsied tissue. The correlation coefficients between in vivo and in vitro measurements were 0.73 (df = 8, p = 0.015) and 0.98 (df = 8, p less than 0.01) for Ro and kb, respectively. The in vivo measurements of HBP biochemistry via kinetic analysis of the radiopharmaceutical time-activity data reflect the average concentration and affinity of the receptor. This study further substantiates the validity of 99mTc-NGA as a quantitative probe for the HBP receptor.

Adult↗
PubMed1990

Pharmacological studies on the mechanism of pressure inhibition of human platelet aggregation.

Platelet shape change and aggregation in response to adenosine diphosphate (ADP), epinephrine, collagen, thrombin, ristocetin, and phorbol myristate acetate (PMA) were studied photometrically at 1 ATA air and 35 ATA helium (He). Pressure inhibited aggregation in response to all agents except PMA. Dose response curves were constructed for ADP and epinephrine at 1 ATA and 35 ATA in the presence of acetylsalicyclic acid (ASA) 2.5 . 10(-4) M, which prevents aggregation due to released ADP and other granular constituents thus allowing study of the effect of the added stimulus alone. Pressure inhibited aggregation and yielded a shallower dose response curve. Pharmacologically, this would be interpreted as non-competitive blockade or reduced availability of receptors. All of the agonist agents inhibited by pressure are dependent upon extracellular Ca2+ for their function. All unmask other receptors (integrins) for adhesive proteins, principally fibrinogen. These integrins incorporate Ca2+ to become active. In contrast, PMA-induced aggregation, and shape change, are independent of extracellular Ca2+ and were unaffected by pressure. It is proposed that pressure may distort Ca2(+)-dependent surface glycoprotein receptors in a manner that reduces ligand affinity and hence inhibits platelet aggregation. The possibility that other calcium-mediated cell processes are affected by pressure cannot be discounted.

Adenosine Triphosphate↗
PubMed1986

Receptor patching and capping of platelet membranes induced by monoclonal antibodies.

Redistribution of glycoproteins (GP) Ib, glycocalicin, IIb, and IIIa on the surface of human platelets in response to stimulation with corresponding monoclonal antibodies (MoAb) and a polyclonal antiglycocalicin antibody was studied by immunofluorescence, immunoelectron microscopy, and a quantitative radioimmune assay. Immobilization of the antigens by prefixation with formaldehyde showed a uniform distribution over the surface of the platelet. Incubation of unfixed platelets with specific MoAb against various epitopes on GPIIb and/or IIIa resulted in a time-dependent patching, subsequent capping, and after prolonged exposure to the antibody/label complex, internalization of the complex, possibly by endocytosis. In contrast, GPIb could not be shown to cap. From these results we conclude that platelet GPIIb and/or IIIa undergo spatial rearrangement in a manner analogous to that observed in lymphocytes, whereas GPIb does not. Since both GPIb and GPIIb and/or IIIa seem to be transmembraneous GP associated with the cytoskeleton, a special, though unidentified, role of GPIIb/IIIa in the induction of lateral membrane mobility is postulated.

Antibodies, Monoclonal↗
PubMed1986

Proteolysis of platelet glycoprotein Ib by plasmin is facilitated by plasmin lysine-binding regions.

We have characterized the effects of plasmin on glycoprotein Ib (GpIb), a platelet membrane receptor for von Willebrand factor (vWF), and on glycocalicin, a fragment of the alpha chain of GpIb that contains the vWF-binding region. The addition of 4.5 X 10(-7) mol/L plasmin to washed platelets caused a time-dependent decrease in ristocetin-induced, vWF-dependent platelet agglutination. epsilon-Aminocaproic acid (EACA) inhibited plasmin release of glycocalicin-related antigen from washed platelets and preserved vWF-dependent platelet agglutination, thus indicating that the lysine-binding sites on plasmin facilitated its degradation of GpIb. To demonstrate a direct interaction between plasmin and the vWF-binding region of GpIb we incubated purified glycocalicin with plasmin. Plasmin degraded the glycocalicin into two small carbohydrate-poor peptides and into a larger carbohydrate-rich fragment. EACA was able to inhibit plasmin-mediated degradation of glycocalicin in a concentration-dependent fashion. These studies indicated that plasmin degradation of GpIb was due to a direct interaction between plasmin and GpIb and that this effect was mediated by the lysine-binding region of the plasmin molecule.

Aminocaproates↗