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Biomedical subjects

B S Coller

Publications and source records attributed to B S Coller.

At least 109 records · Page 6Linked to original sources
PubMed1987

Blood elements at surfaces: platelets.

This brief review is designed to highlight the limitations of our knowledge given the difficulties in simulating the in vivo condition in models established in vitro and ex vivo. Despite this uncertainty, mounting evidence indicates that the GPIIb-IIIa receptor mediates crucial platelet functions and that control over its interactions may offer the potential for altering platelet behavior in vivo. Since this receptor appears to be part of a generalized family of adhesive protein receptors that utilize the tripeptide RGD as a recognition signal, insights derived from platelet function may have broad biological implications.

Animals↗
PubMed1987

Diagnostic and therapeutic applications of antiplatelet monoclonal antibodies.

The interaction of platelets with natural and artificial surfaces is briefly reviewed, emphasizing the role of the platelet glycoprotein Ib and IIb/IIIa receptors. Studies utilizing monoclonal antibodies to these receptors for the diagnosis and therapy of hemorrhagic and thrombotic disorders are described, indicating the potential of such agents as platelet inhibitors.

Animals↗
PubMed1987

Type I Glanzmann thrombasthenia patients from the Iraqi-Jewish and Arab populations in Israel can be differentiated by platelet glycoprotein IIIa immunoblot analysis.

A sensitive immunoblot technique for platelet glycoprotein IIIa (GPIIIa) was used to analyze the platelets of patients living in Israel who meet the diagnostic criteria for type I Glanzmann thrombasthenia. When reacted with solubilized normal platelets, a rabbit antiserum to GPIIIa identified a major band at molecular weight (mol wt) 90,000 and three additional minor bands at Mr 110,000, 81,000, and 64,000. The major band could not be detected, and the minor bands were either markedly reduced or absent in the platelet samples from 14 of the 15 patients from the Iraqi-Jewish population. In contrast, in all four Arab patients tested, the major band was detectable, although at markedly reduced levels, and the minor bands were either markedly reduced or absent; an additional minor band at mol wt 47,000 was also present in the platelets from these patients. One Iraqi-Jewish patient had a unique pattern in which two of the bands were present but reduced and two were undetectable. We conclude that the protein defect, and thus presumably the genetic defect, causing Glanzmann thrombasthenia in the majority of patients in the Iraqi-Jewish population differs from that in the Arab population, and we confirm that there is considerable biochemical heterogeneity among the patients who meet the criteria for type I Glanzmann thrombasthenia.

Animals↗
PubMed1986

Potential application of labeled antibodies for thrombus detection.

Labeling platelets with monoclonal antibodies in whole blood for imaging thrombi is less cumbersome than the established 111In-oxine method.. 7E3, a murine monoclonal antibody directed against glycoprotein IIb and/or IIIa on both human and dog platelets was used to label canine platelets. Thrombi were induced by transcatheter placement of a copper coil followed by electrocoagulation. 7E3 was iodinated with 131I and labelled with 111In using 7E3-DTPA conjugate. Whole blood was incubated with 0.5-1.0 micrograms labeled 7E3/mL blood. In 4/4 dogs, experimental deep vein thrombi were identified using both 131I- and In 1/3 dogs, experimental coronary thrombus could be identified ex vivo at 4 h. Clot to blood ratios ranged between 7 to 13:1. Using the 111In-oxine method, 0/3 coronary thrombi were seen. Thus, 131I- and 111In-labeled 7E3 may be used to readily identify peripheral venous thrombi. For reliable and prompt identification of coronary thrombi, more rapid clearance of the labeled platelets is required.

Antibodies, Monoclonal↗
PubMed1986

Activation affects access to the platelet receptor for adhesive glycoproteins.

Blood platelets have a receptor for macromolecular adhesive glycoproteins, located on a heteroduplex membrane glycoprotein complex (GPIIb/IIIa) that only becomes "exposed" when platelets are activated. Binding of the adhesive glycoproteins, in particular fibrinogen, to the receptor is required for platelet aggregation, which in turn is required to arrest bleeding. A murine monoclonal antibody whose rate of binding to the receptor is affected by platelet activation was both cross-linked and fragmented to assess the effects of changes in molecular size on its rate of binding to unactivated and activated platelets. The results indicate that small molecules can bind more rapidly to the receptors on unactivated platelets than can large molecules and that activation involves a conformational and/or microenvironmental change that permits the large molecules to bind more rapidly.

Adenosine Diphosphate↗
PubMed1986

Intravenous gammaglobulin therapy in the management of a patient with idiopathic thrombocytopenic purpura and a warm autoimmune erythrocyte panagglutinin during pregnancy.

Intravenous gammaglobulin (IVIgG) was recently introduced for the treatment of idiopathic thrombocytopenic purpura (ITP). Reported is a previously splenectomized patient who had a severe exacerbation of her ITP during pregnancy and was managed with large doses of IVIgG throughout the second half of her pregnancy. She also had an autoimmune IgG erythrocyte panagglutinin on her red blood cells and in her serum, but only minimal evidence of hemolysis. There was little or no transplacental passage of her autoimmune antibodies since she delivered a normal fetus after 34 weeks of gestation who had a normal platelet count and no evidence of an antierythrocyte antibody. Interestingly, at the time of delivery the mother's serum IgG was dramatically elevated, but the cord serum IgG was normal for the length of gestation, indicating the presence of a dramatic and abnormal difference in IgG between maternal and fetal blood. This raises the possibility that the IVIgG therapy may have actually prevented transplacental passage of the pathological antibodies.

Adult↗
PubMed1986

Immunologic and biochemical characterization of homozygous and heterozygous Glanzmann thrombasthenia in the Iraqi-Jewish and Arab populations of Israel: comparison of techniques for carrier detection.

To define biochemically and immunologically the platelet defect in Iraqi-Jews and Arabs with Glanzmann thrombasthenia in Israel, we tested the platelets of 32 thrombasthenics and 37 obligate carriers from 19 families with affected members. Thrombasthenic platelets were devoid of glycoprotein IIb (GPIIb) as judged by polyacrylamide gel electrophoresis and devoid of the GPIIb/IIIa complex as judged by radio-electroimmunoassay. Binding of a murine monoclonal antibody directed at GPIIb and/or GPIIIa to intact thrombasthenic platelets averaged less than 2% of the control value. Evaluation of the number of molecules of antibody bound per platelet permitted discrimination between controls and obligate carriers with a high degree of accuracy (sensitivity = 91.9%, specificity = 92.3%). Obligate carriers could also be discriminated from controls by determining the ratio of GPIIb to GPIb by polyacrylamide gel electrophoresis and by quantifying the GPIIb/IIIa complex by radio-electroimmunoassay. These studies indicate that the thrombasthenics in Israel have the severe form of the disease (type I) and that the platelets of heterozygotes have significantly reduced amounts of both total and surface-exposed GPIIb and/or GPIIIa.

Adolescent↗
PubMed1986

The role of platelet membrane glycoproteins Ib and IIb-IIIa in platelet adherence to human artery subendothelium.

Platelet adherence to human artery subendothelium in blood from eight normal subjects, four patients with Glanzmann's thrombasthenia (deficiency of platelet membrane glycoproteins IIb and IIIa: GPIIb-IIIa), two patients with Bernard-Soulier syndrome (deficiency of platelet membrane glycoprotein Ib: GPIb) and one patient with von Willebrand's disease (VWD subtype III. deficient in factor VIII-von Willebrand factor: FVIII-VWF) was compared at various wall shear rates (300, 500, 1000, 1800 and 2500 s-1). Platelet adherence in blood from the patients with Glanzmann's thrombasthenia was within the normal range at shear rates below 1000 s-1. There was some decrease in adhesion at higher shear rates and platelets were less spread out on the subendothelium than normally at all shear rates. Platelet aggregate formation was almost totally absent. Platelet adherence in blood from patients with the Bernard-Soulier syndrome was strongly impaired at all shear rates. Platelet adherence in blood from the patient with VWD subtype III was normal at shear rates of 300 and 500 s-1, but impaired at shear rates above 1000 s-1. Aggregate formation was also decreased at these shear rates. Platelet adhesion was strongly inhibited by a monoclonal antibody against glycoprotein Ib, which had previously been shown to inhibit ristocetin-induced aggregation, at shear rates of 500 and 1800 s-1 but not at 300 s-1. Platelet adhesion at 1800 s-1 was also inhibited, though to a lesser extent, by two antibodies against GPIIb-IIIa. These antibodies also inhibited platelet aggregate formation. The data indicates that GPIb is involved in adhesion at the same shear rates as von Willebrand factor. Absence or inhibition of GPIIb-IIIa primarily causes a defect of aggregate formation but GPIIb-IIIa may also play a role in adhesion, particularly at high shear rates. The defect of adhesion in the Bernard-Soulier syndrome may be dependent on factors other than a deficiency of GPIb alone.

Adolescent↗
PubMed1986

Studies on the binding of an alloimmune and two murine monoclonal antibodies to the platelet glycoprotein IIb-IIIa complex receptor.

The platelet-binding characteristics of three different antibodies that completely block adenosine diphosphate (ADP)-induced platelet fibrinogen binding and react with glycoproteins IIb, IIIa, or both, were studied. Two of the antibodies are murine monoclonal antibodies (10E5 and 7E3), and the third is an alloimmune antibody produced by a patient with Glanzmann's thrombasthenia who has received multiple transfusions (E.S.). The two monoclonals differ in that 7E3, but not 10E5, binds to dog platelets as well as to human platelets. In mutual competition studies, 7E3 did not interfere with 10E5 binding, indicating that both antibodies could bind to the complex simultaneously. E.S. IgG produced only minor inhibition of 10E5 binding, but nearly complete inhibition of 7E3 binding, suggesting that its epitope lies closer to the 7E3 epitope than the 10E5 epitope. Ethylenediaminetetraacetic acid (EDTA) pretreatment of intact platelets at 22 degrees C and pH 7.75 did not affect 10E5 binding, but significantly inhibited 7E3 binding. Similar treatment of intact or solubilized platelets at high pH and temperature produced splitting of the glycoprotein IIb-IIIa (GPIIb-IIIa) complex and loss of both 10E5 and 7E3 binding. The 10E5 bound equally well to unactivated and activated platelets, and even rapid fixation of whole blood produced only a modest decrease in 10E5 binding. Preincubation of platelets with either E.S. IgG or 10E5 partially prevented EDTA from splitting the complex, and both monoclonal antibodies were able to bind to such complexes despite the EDTA treatment. These studies indicate that the binding of antibodies to several different epitopes on the GPIIb-IIIa complex can result in similar functional properties in blocking fibrinogen binding and platelet aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1986

Antithrombotic effect of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor in an experimental animal model.

A murine monoclonal antibody directed at the platelet glycoprotein IIb/IIIa complex, which blocks platelet aggregation ex vivo, was tested for its antithrombotic effects in an established animal model of acute platelet thrombus formation in partially stenosed arteries. Infusion of 0.7 to 0.8 mg/kg of the F(ab')2 fragment of the antibody completely blocked new thrombus formation despite multiple provocations, making it the most potent antithrombotic agent tested in this model.

Animals↗
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↗
PubMed1986

Management of factor XI deficiency in gynecologic and obstetric patients.

Deficiency of factor XI (plasma thromboplastin antecedent) can result in severe bleeding in women undergoing obstetric or gynecologic procedures, with the highest risk in women of Ashkenazi Jewish background. Most patients do not bleed if treated with sufficient fresh frozen plasma to maintain a factor XI level of 30% or more but occasionally patients may require higher levels. Plasma infusion should be continued for several days, even if bleeding does not seem excessive, since delayed bleeding is not uncommon. The use of hepatitis B vaccine and of plasma from a single donor, may reduce the risk of hepatitis.

Adult↗
PubMed1985

Thiol-specific probes indicate that the beta-chain of platelet glycoprotein Ib is a transmembrane protein with a reactive endofacial sulfhydryl group.

We used two membrane-permeable fluorescent reagents, monobromobimane and N-[[5-(dimethylamino)-1-naphthalenyl]sulfonyl]aziridine (N-dansylaziridine), and one membrane-impermeable fluorescent probe, monobromo(trimethylammonio)bimane, all three of which react selectively with protein thiols, to assess the presence of reactive sulfhydryls in the platelet glycoprotein Ib (GPIb) molecule and establish the topology of any GPIb-reactive thiols in the platelet membrane. Intact platelets were reacted with 1-10 mM monobromobimane or monobromo(trimethylammonio)bimane or 50-100 microM N-dansylaziridine for 30-60 min at 37 degree C. The platelets were then washed, solubilized in 1% Triton X-100, and analyzed by nonreduced-reduced polyacrylamide gel electrophoresis either directly or indirectly after immunopurification of GPIb. Monobromobimane and N-dansylaziridine labeled GPIb beta but not GPIb alpha in intact platelets. This labeling could be inhibited by pretreating the platelets with either N-ethylmalemide or p-(chloromercuri)benzenesulfonic acid, confirming the specificity of these probes for thiol groups. Monobromo(trimethylammonio)bimane, the membrane-impermeable reagent, did not label GPIb beta in intact platelets. However, it did label GPIb beta in sonicated platelets, indicating that the thiol group of GPIb beta occupies an intracellular location. Since the carbohydrate moiety of GPIb beta can be labeled from the outside of intact platelets with membrane-impermeable reagents, we conclude that GPIb beta has a transmembrane orientation.

Aziridines↗
PubMed1985

Thrombus radioimmunoscintigraphy: an approach using monoclonal antiplatelet antibody.

Thrombus detection and localization is of cardinal importance in clinical medicine. The currently available method using autologous 111In-labeled platelets is too lengthy and complex for everyday use. It requires careful separation of the platelets prior to labeling and visualization of the thrombus becomes possible only 24 hr after injection. An approach to thrombus imaging using a monoclonal antiplatelet antibody labeled with 111In or 123I is described. The antibody (7E3) prepared against human platelets inhibits the interaction between fibrinogen-coated beads and both human and dog platelets. 7E3 is an IgG1 that binds to the complexed glycoprotein IIb/IIIa. Ninety percent of a tracer dose of radiolabeled 7E3 binds to human platelets and 50% binds to dog platelets. In vitro studies showed that virtually all of the platelet-bound radioactivity becomes incorporated into clots formed by adding thrombin to whole blood. 7E3 was labeled with 111In by the cyclic anhydride diethylenetriaminepentaacetic acid method or by radioiodination with 123I. At a ratio of 1:50 (anhydride:7E3) the specific activity ranged between 10 and 40 muCi/micrograms (1 Ci = 37 GBq) without change in the antibody characteristics. In vivo studies in dogs were performed by preincubating for 1 hr the radiolabeled 7E3 with citrated blood or by directly injecting the radiolabeled 7E3 intravenously. Experimental thrombi were induced by transcatheter placement of copper coils into peripheral arteries and veins as well as in the superior vena cava and pulmonary artery. With gamma camera, visualization of venous and arterial thrombi as well as sites of intimal injury without visible thrombi, could be observed 1-1.5 hr after injection. There was no need for delayed imaging because of the fast clearance of radioactivity from the circulation nor was there need for blood pool subtraction. Two to 10-hr thrombi could be imaged but 48-hr thrombi were not detectable with this method. No change in platelet counts before and after the injection of labeled 7E3 nor increased bleeding tendency occurred. The advantages of this method are a shorter preimaging preparation time, faster visualization after injection, and no need for delayed imaging or subtraction techniques. For these reasons human investigations seem to be warranted.

Animals↗
PubMed1985

IgA inhibitor to factor VIII/von Willebrand factor.

A 60-year-old Black female presented with a haemorrhagic diathesis and an acquired factor VIII/von Willebrand factor (VIII/vWf) inhibitor. This inhibitor was classified as an IgA immunoglobulin and was active not only against factor VIII coagulant (VIII:C) activity but also against plasma von Willebrand factor (vWf). The purified IgA also interacted with normal platelets to inhibit ristocetin-induced platelet aggregation (RIPA). In contrast, studies with haemophilia A plasma and platelets revealed that the inhibitor did not react significantly with these plasmas or platelets. The significant differences in the inhibition of vWf assay both of the plasma and the platelets of the haemophilia A patients suggests that part of the haemorrhagic diathesis may be related not only to the inhibition of VIII:C but also to interference with platelet function. In addition, these studies suggest that there may be significant differences in the factor VIII-related antigen (VIII R:Ag) on platelets in haemophilia A patients compared to normal.

Blood Coagulation Factors↗
PubMed1985

Asialo von Willebrand factor interactions with platelets. Interdependence of glycoproteins Ib and IIb/IIIa for binding and aggregation.

Asialo von Willebrand factor (AS-vWf) binds to and aggregates normal human platelets in the absence of ristocetin. Maximal specific binding of AS-vWf is 1-2 micrograms vWf protein/10(8) platelets. Despite the specificity of the binding, only 60% of the bound AS-vWf can be dissociated after equilibrium has been reached. We investigated the site of binding and the mechanism of aggregation of platelets by AS-vWf by (a) pre-incubating platelets with either of two monoclonal antibodies, one against glycoprotein Ib (GPIb) or a second against the glycoprotein IIb/IIIa complex (GPIIb/IIIa), and (b) varying the concentration of fibrinogen in the medium. The results of our studies indicate that AS-vWf binds initially to GPIb. This binding then results in the exposure of receptors for AS-vWf on GPIIb/IIIa. In the presence of plasma fibrinogen, both AS-vWf and fibrinogen bind to GPIIb/IIIa. In the presence of plasma fibrinogen, 50% more AS-vWf binds to the platelet, and this additional AS-vWf binds almost exclusively to GPIIb/IIIa. Despite this enhanced binding of AS-vWf in the absence of fibrinogen, platelet aggregation is much less than that which occurs in the presence of plasma fibrinogen. Comparative studies of AS-vWf binding to normal platelets and the platelets of patients with Glanzmann's thrombasthenia reveal decreased binding to the thrombasthenic platelets and a marked decrease in the extent of platelet aggregation. These studies indicate that AS-vWf binding to, and ensuing aggregation of, platelets is different from that observed with intact vWf protein when platelets are stimulated with either ristocetin or thrombin. The AS-vWf binds to GPIb which, in turn, makes additional AS-vWf receptors available on GPIIb/IIIa. If plasma fibrinogen is present, it competes with the AS-vWf for binding to GPIIb/IIIa and causes aggregation of platelets. In the presence of plasma fibrinogen, more of the AS-vWf binds to GPIIb/IIIa, but this AS-vWf is much less effective than fibrinogen in supporting platelet aggregation.

Antibodies, Monoclonal↗
PubMed1985

A new murine monoclonal antibody reports an activation-dependent change in the conformation and/or microenvironment of the platelet glycoprotein IIb/IIIa complex.

Considerable evidence indicates that the glycoprotein (GP) IIb/IIIa complex on human platelets functions as a receptor for fibrinogen, but little is known about the mechanism of receptor "exposure." To investigate this mechanism, our previously described murine monoclonal antibody (10E5) and a new monoclonal antibody (7E3), both of which block the binding of fibrinogen to platelets and bind to GPIIb and/or GPIIIa, were radiolabeled and their rates of binding to native and ADP-activated platelets were studied. At low concentrations, 125I-10E5 bound nearly equally rapidly to both native and activated platelets, whereas 125I-7E3 bound slowly to native platelets and much more rapidly to activated platelets. This increased rate of 7E3 binding is unlikely to be due to an increase in the number of GPIIb/IIIa sites on the surface of activated platelets because: (a) the rate of 10E5 binding was unchanged; (b) the total number of surface GPIIb/IIIa sites increased by only 2-10% with activation as judged by equilibrium binding of near-saturating concentrations of 10E5 and 7E3, and (c) there was less than 1% release of platelet factor 4 with activation, indicating minimal fusion of alpha-granule membranes (a potential source of GPIIb/IIIa) with the plasma membrane. Other activators (epinephrine, thrombin, and ionophore A 23187) also increased the rate of 7E3 binding, as did digestion of platelets with chymotrypsin. Aspirin did not affect the rate of binding of 7E3, whereas apyrase, prostaglandin E1, and dibucaine all inhibited the enhancement of the 7E3-binding rate produced by ADP. These data provide evidence for an activation-dependent change in the conformation and/or microenvironment of the GPIIb/IIIa complex, and offer a method of studying the receptor exposure mechanism that does not rely on the binding of fibrinogen itself.

Adenosine Diphosphate↗