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PubMed1979

Platelet receptors for human Factor VIII/von Willebrand protein: functional correlation of receptor occupancy and ristocetin-induced platelet aggregation.

Previous studies of von Willebrand disease indicate that a deficiency of blood clotting Factor VIII/von Willebrand factor (FVIII/vWF) activity is responsible for the failure of platelets to participate fully in the initial stages of hemostasis. We have recently identified specific FVIII/vWF binding sites on platelets, suggesting that the interaction of these sites with FVIII/vWF may be functionally important in the development of platelet clumps. We have now studied how different ristocetin concentrations, various known platelet aggregation inhibitors, and the exposure of platelets to proteases affect the ability of platelets to bind FVIII/vWF and to form aggregates. Our results demonstrate a highly significant linear correlation between the degree of FVIII/vWF receptor binding and the extent of ristocetin-induced platelet aggregation. Because neither FVIII/vWF binding nor platelet aggregation occurs after platelets are exposed to low concentrations of proteases, the FVIII/vWF receptors must be in the platelet membrane. We conclude that the interaction between FVIII/vWF protein and its receptors on the platelet membrane is an important mechanism by which platelet aggregation occurs during primary phase hemostasis.

Binding, Competitive↗
PubMed1976

Platelet membrane glycoproteins implicated in ristocetin-induced aggregation. Studies of the proteins on platelets from patients with Bernard-Soulier syndrome and von Willebrand's disease.

The antibiotic ristocetin only aggregates platelets in the presence of plasma von Willebrand factor. Platelets from patients with Bernard-Soulier syndrome do not aggregate upon addition of ristocetin although, in contrast to von Willebrand's disease, plasma levels of factor VIII complex (factor VIII clotting activity, von Willebrand factor activity, and von Willebrand antigen) are normal. The membrane surface of normal platelets was modified and compared to the surface of platelets from a patient with Bernard-Soulier syndrome in an attempt to identify the receptor involved in von Willebrand factor-ristocetin-induced aggregation. After the incubation of washed normal platelets with a preparation of ristocetin previously shown to contain a proteolytic contaminant, the aggregation response is significantly decreased on addition or normal plasma. Analaysis by gel electrophoresis of such platelets when stained for carbohydrate revealed a decrease in the relative amounts of membrane glycopro-eins. Chymotrypsin-treated normal platelets had less membrane glycoproteins in addition to giving a reduced aggregation response in ristocetin-induced aggregation. Staining of gels for protein and carbohydrate indicated that there was an extensive change in the surface of Bernard-Soulier platelets, whereas those from patients with von Willebrand's disease appeared the same as normal. Platelets from patients were labeled by the lactoperoxidase iodination technique. Not only was the relative intensity of staining of platelet-specific proteins and glycoproteins changed in Bernard-Soulier platelets, but the iodination of the glycoproteins on the membrane surface relative to other membrane constituents was lower. In contrast, platelets from patients with von Willebrand's disease showed a normal exposure of membrane components. These data suggest therefore that membrane glycoproteins may play a functional role in ristocetin-induced aggregation.

Binding Sites↗
PubMedDate not supplied

Oxygen consumption, platelet aggregation and release reactions in platelets freeze-preserved with dimethylsulfoxide.

Platelets were frozen with 4% or 5% DMSO at an overall rate of 2 to 3 C per minute and were stored at -80 C for as long as 10 months. They were washed with DMSO-plasma and acid-citrate-dextrose (ACD) solutions and were stored in 30 ml of autologous plasma at room temperature for about three hours before transfusion. Measurements were made of oxygen consumption, platelet aggregation and release reaction, platelet factor-3 and-4 activities, and platelet response to hypotonic stress. Platelet basal and latex stimulated oxygen consumption were found to be significantly impaired; platelet aggregation response to ADP, epinephrine, and collagen were decreased; platelet ATP and ADP content and release reactions were decreased; platelet antiheparin activity (platelet factor-4 level) was decreased; and the platelet response to hypotonic stress was impaired. What the results of these in vitro tests mean in relation to in vivo survival and hemostatic function of preserved platelets was not established.

Adenosine Diphosphate↗
PubMed1977

Factor XI and platelets: Evidence that platelets contain only minimal factor XI activity and antigen.

Factor-XI activity of platelets has been studied in platelet-rich plasmas and isolated platelet suspensions. Fresh platelets in both environments had little or no measurable factor-XI activity. Frozen and thawed platelet-rich normal plasma had markedly elevated apparent factor-XI activity and factor-XI activity as compared to platelet-poor plasma. Frozen and thawed platelet-rich and platelet-poor normal plasmas had equivalent factor-XI antigen. Platelets isolated from normal blood and from factor-XI deficient blood had the same small amounts of apparent factor-XI activity, which increased slightly on freezing and thawing. The data indicates that minimal factor XI is associated with the platelet. The markedly elevated apparent factor-XI activity of frozen and thawed platelet-rich plasma is shown to reflect the interaction of a platelet activator with plasma clotting factors to produce a later activated-clotting-intermediate.

Antigens↗
PubMed1976

Adhesion of human blood platelets to glass polymer surfaces. II. Demonstration of the presence of a natural platelet adhesion inhibitor in plasma and serum.

Adhesiveness of washed platelets resuspended in citrated plasma, serum, or several different media has been investigated. A method specific for quanititation of adhesion was used. Platelets suspended in saline of Tyrode's solution were found to be highly adhesive to glass, polyethylene, polyvinyl chloride, or Cuprophane. This adhesiveness of platelets to test surfaces decreased by nearly 50% when plasma was the suspension medium. When the suspension medium was serum, the decrease in adhesion was nearly 75%. Cohn fraction V also decreased the adhesiveness of platelets significantly, but highly purfied albumin had only a small effect. Several pharmacologic agents decreased platelet adhesiveness when added to platelets suspended in plasma or serum, but had negligible effect on the adhesiveness of platelets suspended in artificial media devoid of proteins. Normal washed platelets, when suspended in citrated plasma obtained from an afibrinogenemic donor or in normal serum, showed a significant decrease in adhesion compared to the same platelets suspended in normal citrated plasma. Addition of fibrinogen to afibrinogenemic plasma or normal serum restored the adhesiveness of platelets to normal levels. Normal platelets resuspended in plasma obtained from a thrombasthenic donor exhibited normal adhesiveness. These observations suggested that while fibrinogen promotes platelet adhesion, plasma or serum possess also an adhesion-inhibiting activity.

Afibrinogenemia↗
PubMed1977

Mechanism of complement-mediated activation of human blood platelets in vitro: comparison of normal and paroxysmal nocturnal hemoglobinuria platelets.

The paroxysmal nocturnal hemoglobinuria (PNH) platelet differs from the normal human platelet in its interaction with activated complement components: (a) when complement is activated by the alternative pathway, greater amounts of C3 are fixed to the PNH platelet than to the normal platelet; (b) the platelet-release reaction, as measured by serotonin release, occurs after C3 fixation to the PNH platelet. This reaction does not occur with normal platelets; (c) although serotonin release mediated by antibody alone was the same for normal and PNH platelets, antibody-initiated complement activation resulted in the fixation of greater amounts of C3 to PNH platelets and greater consequent serotonin release; and (d) nearly maximal serotonin release; and (d) nearly maximal serotonin release from PNH platelets occurs after the fixation of C3 (or perhaps C5) to the membrane without completion of the terminal sequence. In contrast, completion of the terminal complement sequence beyond C5 is required for maximal serotonin release from normal platelets. These abnormalities of interaction of complement components and PNH platelets may explain the occurrence of thromboses in this disease.

Antibodies↗
PubMed1979

Platelet heterogeneity. Relationship between buoyant density, size, lipid peroxidation and platelet age.

Human platelets were separated into 2 density populations by repeated centrifugations of platelet-rich plasma at increasing gravitational force. The heaviest platelet fraction was rich in larger platelets. The lightest platelet fraction was rich in smaller platelets. In both fractions and in the platelet button, lipid peroxidation (malonaldehyde-MDA-production after addition of thrombin) was measured at basal condition, on the 1st, 3rd, 5th, 7th and 9th day after aspirin ingestion. At basal conditions and after ingestion of aspirin, MDA production was higher in the heavy-large platelets than in light-small ones, but a parallel increase of MDA production was observed in the light and in the heavy population and in the platelet button. The data are not compatible with the hypothesis that platelet density and size are age-related. Aspirin inhibits platelet lipid peroxidation by permanently acetylating their cyclooxygenase and if the heaviest platelets were the young ones, lipid peroxidation should reappear sooner in them.

Aspirin↗
PubMed1978

Inhibition of platelet aggregation by protease inhibitors. Possible involvement of proteases in platelet aggregation.

The possible participation of proteases in human platelet aggregation was explored using various protease inhibitors and substrates. Protease inhibitors used included naturally occurring inhibitors of serine proteases and synthetic inhibitors that modify the active site of protease. Substrates used were synthetic substrates for the trypsin type as well as for the chymotrypsin type of protease. All these inhibitors and substrates inhibited platelet aggregation and serotonin release induced by ADP, collagen, epinephrine, or thrombin. In ADP- and epinephrine-induced platelet aggregation the second phase of aggregation was most efficiently inhibited. The inhibitors suppressed the formation of malondialdehyde during platelet aggregation. Release by aggregating agents of arachidonate and its metabolites from indomethacin-treated platelets as well as nontreated platelets was also inhibited. The inhibitors apperar to interact with stimulated platelets but not with unstimulated platelets. These observations suggest that the interaction of an aggregating agent with its platelet receptor activates a unique precursor serine protease that in turn activates platelet phospholipase to liberate arachidonic acid (the precursor of the potent platelet aggregating agent thromboxane A2) from platelet phospholipids.

Arachidonic Acids↗
PubMed1976

Effect of platelet age on adhesiveness to collagen and platelet surface charge.

Adhesion to collagen was investigated as a function of platelet age in rat platelets. Platelet adherence was measured using EDTA-containing platelet- rich plasma which was added to preparations of collagen fibers clamped between magnetic stirrers by recording changes in light transmission. The plot of light transmission versus logarithm of time was linear and allowed calculation of a slope factor which related to the rate of adherence. Neither the amount of collagen nor the platelet count were limiting in the test. Young platelet populations (less than or equal to 1 day old) were obtained during the recovery phase from immune induced thrombocytopenia. Old platelet populations were prepared by blocking thrombopoiesis with cyclophosphamide. Young platelets showed a moderate but statistically significant increase in adhesivity to collagen but old platelets did not differ significantly from randomly aged platelets in this function. The electrophoretic mobility of platelets was not affected by their age.

Animals↗
PubMed1979

In vivo platelet retention in human bleeding-time wounds. I. Normal subjects and patients with platelet dysfunction.

PRB was measured in standardized skin puncture wounds. Platelets in wound blood samples collected in EDTA-heparin-containing micropipettes were counted electronically following gravity separation of plasma. The relationship between the wound platelet count (expressed as percent of the venous blood platelet count) and time was found to be linear during the first 3 min of bleeding. The slope of the linear regression line for percent of venous blood platelet count vs. time was 20.8 +/- 8.9 (mean +/- S.D.) in 31 normal subjects. Nine of 10 patients with significant, nonpharmacologic platelet dysfunction were found to have markedly decreased PRB. The determination of PRB was found to be reproducible, and control studies excluded platelet clumping and sedimentation of platelets as factors which significantly influenced the results. In contrast to previous observations, the results of this study indicate that platelets are removed from circulating blood at an increasing rate during the first 3 min of bleeding in normal subjects. Furthermore, a significant degree of EDTA-reversible clumping of platelets normally occurs during bleeding. The method described permits an accurate assessment of the quantitative and dynamic aspects of platelet participation in the arrest of bleeding. The determination of PRB holds promise in the evaluation of the biological significance of in vitro evidence of platelet dysfunction, and it may be useful in the evaluation of patients with hemorrhagic and thromboembolic disorders.

Blood Coagulation↗
PubMed1978

A platelet procoagulant activity associated with platelet shape change.

PCA was measured for human PRP by determining recalcification times assayed in a minimal-dilution, controlled PH/PCO2 system in a siliconized cuvette, with the use of light transmission measurements (aggregometry). Platelet shape, aggregation, and plasma clotting end points were assayed photometrically, with platelet morphology and aggregation studied in parallel by light microscopy. With varying concentrations of ADP preincubated with PRP initially containing essentially disc-shaped platelets, it was found that induced shape change in the absence of an aggregation is necessary and sufficient for the development of PCA. This was consistently measurable as a shortening of recalcification times by approximately 50% for suspensions of shape-changed platelets vs. disc-shaped platelets. The pharmacologic inhibition of the endoperoxide pathway-mediated platelet secondary aggregation and release by aspirin administered in vivo does not impair the ability of human platelets to develop this PCA. Inhibition of shape change with amounts of 5'-adenosine monophosphate insufficient to affect coagulation tests in the absence of platelets leads to 80% to 90% inhibition of the ADP-induced PCA. This PCA is shown to be fully reversible, with morphologic reversion of shape-changed platelets to the discoid form, and is shown to be distinct from other PCAs previously described for platelets activated in different ways, such as PF3 activity. It is suggested that the binding of coagulation factors to the platelet membrane may be regulated concomitantly with shape change.

Adenosine Diphosphate↗
PubMed1979

Content and subcellular localization of catecholamines and 5-hydroxytryptamine in human and animal blood platelets: monoamine distribution between platelets and plasma.

1 The content of adrenaline (Ad), noradrenaline (NA) and dopamine was measured in human, guinea-pig, cat, rabbit and rat blood platelets by a highly sensitive and specific radioenzymatic method.2 In all platelet specimens analyzed, the content of the three catecholamines (CA) was several thousand times lower than that of 5-hydroxytryptamine (5-HT).3 In basal conditions, the NA concentration in platelets and plasma always exceeded that of Ad and dopamine.4 In rat and rabbit platelets, Ad, NA and dopamine were present only in the free (unconjugated) form.5 Platelets of rats with storage pool deficiency (Fawn-hooded) contained much less 5-HT and CA than normal rat platelets.6 Following restraint stress, platelets of Fawn-hooded rats, in contrast to normal rat platelets, did not accumulate CA in spite of a dramatic rise in plasma CA.7 Reserpine, a monoamine depletor, released CA as well as 5-HT from rabbit platelets in vivo.8 Subcellular fractionation experiments with rabbit platelets indicate that both CA and 5-HT are most concentrated in the fraction consisting of pure 5-HT organelles.9 Both in humans and rabbits the concentration gradient between platelets and plasma was much lower for CA than for 5-HT, indicating that a high affinity transport mechanism operates in vivo for 5-HT but not for CA.10 In conclusion, the present data show that both human and animal platelets contain Ad, NA and dopamine. The bulk of the CA seems to be stored as unconjugated amines together with 5-HT, histamine and p-octopamine in a multitransmitter storage site, namely the 5-HT organelle.

Adult↗
PubMed1976

Studies on platelet plasma membranes. I. Characterization of surface proteins of human platelets labeled with diazotized (125i)-diiodosulfanilic acid.

A polar, nonpenetrating compound of high specific activity, diazotized (125I)-diiodosulfanilic acid (DD125ISA), has been developed as a label for exposed proteins of the human platelet plasma membrane, and platelet proteins and the pattern of labeling have been studied with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). That DD125ISA binds specifically to membrane proteins was demonstrated by: (1) the specific activity of isolated membrane protein was five to seven times that of whole platelet protein and (2) no proteins of intact platelets were labeled which were not represented in the isolated plasma membrane. That the DD125ISA-labeled membrane proteins were exposed on the cell surface was demonstrated by: (1) DD125ISA-labeled proteins were altered by trypsin treatment of intact, labeled platelets and (2) the pattern of labeling produced by reaction of isolated membranes with DD125ISA was quite different from that produced by the labeling of intact platelets. Analysis of platelet membrane proteins by SDS-PAGE demonstrated the glycoproteins previously described at 150,000 daltons (termed glycoprotein I) and 92,000 daltons (glycoprotein III) but we could discriminate two apparently distinct glycoproteins in the intermediate region (IIa: 125,000 daltons, and II: 118,000 daltons). Glycoproteins I and III were constant whereas IIa was clearly visible only in unreduced samples and II was predominant in reduced samples. Reaction of DD125ISA with intact platelets resulted in equal labeling of three of these four membrane glycoproteins (IIa, II, and III). The pattern of exposed proteins on the platelet surface labeled by DD125ISA was different from lactoperoxidase-131I, which labeled predominantly the 92,000 dalton glycoprotein, as demonstrated by simultaneous SDS-PAGE analysis. Therefore three glycoproteins of the human platelet plasma membrane are exposed to a radioisotope probe on the platelet surface and are accessible for contact interactions.

Azo Compounds↗