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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↗
PubMed1986

Partial characterization of a binding site for von Willebrand factor on glycocalicin.

The binding of von Willebrand factor (vWF) to platelet membrane glycoprotein Ib (GpIb) facilitates platelet adhesion to vascular subendothelium. In this study, we provide evidence that the vWF binding site is on glycocalicin (GC), a proteolytic fragment of GpIb, and we examine the role of the carbohydrate portion of GC on that binding. The binding to platelets of 6D1, a monoclonal antibody that recognizes an epitope on GpIb and blocks ristocetin-induced vWF binding to platelets, was inhibited by purified GC. In addition, purified GC inhibited ristocetin-dependent binding of 125I-labeled vWF to platelets. Since GC contains 60% carbohydrate by weight, we assessed the role of carbohydrate sequences on its interaction with antibody 6D1 and vWF. Based on the known sequence of the major oligosaccharide chain of GC--N-acetyl neuraminic acid, galactose, N-acetyl glucosamine, N-acetyl galactosamine--we treated GC sequentially with neuraminidase, beta-galactosidase, and beta-N-acetylglucosaminidase. Removal of sialic acid and galactose residues did not affect GC binding. Removal of N-acetyl glucosamine residues did not affect GC binding to 6D1 but did decrease the ability of GC to inhibit vWF binding to platelets, increasing the concentration needed to inhibit binding by 50% (IC50) 40-fold. This suggests that a portion of the oligosaccharide chains on GC contributes to the vWF binding activity of this molecule.

Antibodies, Monoclonal↗
PubMed1985

Plasmin effect on platelet glycoprotein Ib-von Willebrand factor interactions.

We have studied the effect of streptokinase on platelets in platelet-rich plasma (PRP) and of plasmin on washed platelets. By three and one-half minutes after the addition of 50,000 IU/mL streptokinase to PRP, the maximum rate of ristocetin-induced platelet agglutination declined 40%, and by 60 minutes, it declined 70%. During the same time interval, the thrombin time increased from 20 seconds to over 120 seconds. At a concentration as low as 50 IU/mL, streptokinase reduced the maximum rate of ristocetin-induced platelet agglutination by 50% and prolonged the thrombin time to 1.5 times control value. Streptokinase added to PRP also caused inhibition of platelet aggregation following stimulation by 2.9 mumol/L adenosine diphosphate, 0.25 U/mL thrombin, and 0.025 mg/mL collagen. Plasmin, 0.05 to 1.0 CU/mL, reduced ristocetin-mediated agglutination of washed platelets in the presence of von Willebrand factor (vWF) from 66% of control to 2% of control, following a one-hour incubation. Autoradiograms produced following sodium dodecyl-polyacrylamide gel electrophoresis (SDS-PAGE) of plasmin-treated 125I-surface-labeled platelets demonstrated progressive loss of a protein with a molecular weight (mol wt) of 180,000; simultaneously, a protein with mol wt 135,000 appeared on autoradiograms produced following SDS-PAGE of the surrounding platelet medium. These proteins are similar in molecular weight to glycoprotein (gp) Ib, a platelet surface receptor for vWF, and glycocalicin, a proteolytic fragment of gpIb. By use of an enzyme-linked immunosorbent assay (ELISA) based immunoinhibition assay for glycocalicin, we were able to demonstrate that plasmin treatment of washed platelets released a glycocalicin-related antigen into the surrounding medium and that appearance of this material corresponding to loss of vWF-dependent, ristocetin-induced agglutination.

Blood Coagulation Factors↗
PubMed1988

Endocytosis of N-acetylglucosamine-containing glycoproteins by rat fibroblasts expressing a single species of chicken liver glycoprotein receptor.

A cDNA clone for the chicken liver receptor which mediates endocytosis of glycoproteins containing terminal N-acetylglucosamine has been isolated and sequenced, confirming the previously obtained amino acid sequence of this protein (which is also known as the chicken hepatic lectin). This cDNA was introduced into Rat-1 fibroblasts and expressed using the promotor in the long terminal repeat of Moloney murine leukemia virus. Cells expressing chicken receptor were identified by screening with antireceptor antibodies followed by fluorescein-conjugated second antibodies. Receptor expressed in these cells was indistinguishable on gel electrophoresis from receptor isolated from liver. Three clonally isolated lines were examined for their ability to bind agalacto-alpha 1-acid glycoproteins at 0 degrees C and to take up and degrade this ligand at 37 degrees C. The receptor number (50,000/cell), affinity for ligand (35 nM), and uptake rate (5 molecules ligand/surface receptor/h) are similar to those previously observed for chicken hepatocytes, and for the uptake of asialoglycoproteins by rat hepatocytes and hepatoma cells. These findings indicate that the chicken receptor correctly traverses the endocytic pathway in a rat cell even though the cytoplasmic domain of this protein shows no primary structural homology with the corresponding portion of the rat liver receptor or with receptors found in fibroblasts.

Acetylglucosamine↗