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Mitral valve prolapse (MVP) is a predisposing factor for cerebral ischemia, especially in young adults. Cerebral embolization of intracardiac thrombi is the probable mechanism in many cases. Platelets play a key role in the development of thrombi. We found that platelet factor 4, a marker protein of platelet activation, was elevated in 12 of 33 MVP patients (36%) without a history of stroke. This finding indicates that platelets are frequently activated in asymptomatic MVP patients and may allow identification of a subgroup of MVP patients with activated platelets who are at increased risk for emboli.

It is now generally accepted by neurologists that most transient ischaemic attacks, particularly in the carotid artery territory, have a thromboembolic basis. These emboli are, for the most part, fibrin-platelet aggregates. Others which contain atheromatous debris are more likely to produce longer lasting neurological deficits. If one assumes this hypothesis then it is reasonable to employ drugs which interfere with platelet aggregation in order to prevent cerebrovascular symptoms and signs. Acetylsalicylic acid (aspirin) prevents aggregation by inhibiting the 'release reaction' initiated by thromboxane A2. This inhibition lasts for the life of the affected platelets. Recent trials in the United States and Canada have demonstrated a positive clinical benefit from the employment of aspirin in patients suffering from transient cerebral ischaemic attacks and amaurosis fugax. There was a reduction or cessation of the attacks in both males and females and a 50% reduction of stroke morbidity and mortality in males.

Platelet factor 4-like activity, circulating platelet-aggregate ratios, ristocetin cofactor, Willebrand antigen, ADP-induced platelet aggregation-enhancing factor, and quantitative platelet aggregation response to ADP, epinephrine, and collagen in platelet-rich plasma were measured in four groups of subjects with similar age and sex distribution. Neither platelet factor 4-like activity nor circulating platelet-aggregate ratios differentiated these four groups. Platelet aggregation studies with ADP a subthreshold concentration support the concept of hypersensitivity of diabetic platelets in males. Male and female subjects differ significantly in their quantitative response to aggregating agents when such studies are done under similar conditions. Willebrand factor activity and Willebrand antigen normally increase with age. Elevation in these activities above that accounted for by age characterizes the presence of vascular disease but not diabetes mellitus in the absence of vascular disease. A plasma factor enhancing platelet aggregation could not be demonstrated in most diabetic patients in this study.

An experimental preparation was developed to assess changes in surface-induced arterial thrombosis in nine dogs with woven Dacron aortic prostheses. The preparation consisted in measuring the occlusion time of an A-V shunt with controlled flow rate (200 mg/min). This measurement depended on formation of an occlusive, platelet-rich thrombus on a diaphragm of polyester mesh. Two to 6 months after placement of thoracoabdominal aortic prostheses, all animals demonstrated striking prolongation of A-V shung occlusion time. This occurred in the presence and absence of heparin anticoagulation. No change in A-V shunt occlusion time was noted in dogs who had sham operations. These findings complement out studies showing biochemical and functional changes in circulating platelets in dogs with aortic prostheses, and together they are consistent with mild platelet damage sufficient to impair surface-induced thrombosis. They also support our contention than, in dogs, platelets interact reversibly with prosthetic surfaces.

In 23 patients with untreated idiopathic thrombocytopenic purpura (TP), the relation of thrombokinetics to quantitative determinations of megakaryocytes in bone marrow sections was studied. The megakaryocytes were classified into maturation stages, and platelet sizes were determined. Megarkaryocyte number and volume per microliter of bone marrow were significantly higher in ITP as compared to controls. The megakaryocyte number and volume were inversely related to the peripheral platelet count. Platelet production rate was significantly increased in ITP and related to the megakaryocyte number and volume. The megakaryocytes were shifted towards more immature forms in ITP, suggesting an increased turnover rate of the expanded recognizable metakaryocyte compartment. Platelet size was significantly increased in ITP, and the mean platelet diameter was 1.6 times normal. There was a significant relationship between platelet size and platelet production rate, as well as an inverse relationship between platelet size and platelet mean life-span (MLS). There was also a significant correlation between platelet size and the proportion of young megakaryocytes.

A group of 53 healthy donors has been compared with another group of patients suffering from lipid metabolic disorders of Fredrickson type IIa (n = 14), IIb (n = 11) and IV (n = 21). In the course of three weeks the determinations have been carried out of lipid mechanism parameters, of Apoprotein B, of aggregation response upon ADP and adrenaline++ induction, of beta thromboglobulin, of heparin neutralizing activity, of malonyldialdehyde production upon N-ethylmaleimide stimulation and of the amount of circulating aggregates. In patients with HLP of IIa and IIb type a significant increase of plasmic beta thromboglobulin level was noted as well as shifts of other thrombocytic parameters towards higher platelet reactivity. The correlation between individual platelet parameters and parameters of lipid metabolism was statistically significant only in the case of cholesterol and malonyldialdehyde. A positive correlation of Apo B with BTG and with the aggregation response together with the observation of an increased Apo B concentration in normolipemic subjects with changed platelet reactivity, are indicative of an important role of Apo B during platelet activation in vivo.

Aspirin plus dipyridamole reduces platelet accumulation on short-term Dacron vascular grafts in man. To determine whether drug inhibition of platelet deposition is sustained on older grafts, we studied 18 men aged 41 to 87 years who had Dacron aortic bifurcation grafts in place a mean of 43.4 months (range 9.8 to 121.0) before and during short-term therapy with aspirin (325 mg tid) plus dipyridamole (75 mg tid). During both the baseline and drug studies, indium-111 (111In) platelet deposition was quantitated by two techniques, standard planar imaging performed at 24, 48, and 72 hr after injection of platelets and single photon emission computed tomographic imaging performed at 24 and 72 hr after injection. All analyses were performed in a blinded fashion. On both the planar and tomographic images, platelet accumulation on the graft was quantitated by a graft/blood ratio that compared activity in the graft to simultaneously collected whole blood 111In platelet activity. Aspirin plus dipyridamole reduced the tomographic graft/blood ratio at 24 hr (20.6 +/- 3.5 vs 17.3 +/- 2.5) (+/-SEM) and at 72 hr (29.0 +/- 4.8 vs 25.0 +/- 4.1) after injection of platelets (p = .02). Dacron vascular grafts. Similarly, the planar graft/blood ratio was reduced at 24 hr (2.7 +/- 0.5 vs 2.4 +/- 0.5), 48 hr (3.7 +/- 0.9 vs 3.1 +/- 0.7), and 72 hr (4.0 +/- 0.9 vs 3.6 +/- 0.8) (p = .04). We conclude that aspirin (325 mg tid) plus dipyridamole (75 mg tid) reduces platelet accumulation on long-term Dacron vascular grafts.

Platelets play an important role in the development of atherosclerosis. The arachidonic acid, whose oxygenated metabolites are potent regulators of the platelet-vessel wall interactions, is released from membrane phospholipids by the phospholipase (s) system (s). These membrane-linked phenomena are strongly modulated by the membrane physical properties. The present study was carried out to investigate the relationship between membrane fluidity and arachidonic acid metabolism in platelets from atherosclerotic patients. Twenty-one patients with peripheral vascular disease and twelve controls were studied. Platelets from patients showed an increase in membrane fluidity and enhanced thrombin-stimulated thromboxane synthesis. No alterations were found, however, in total phospholipid fatty acid composition. A significant decrease in the cholesterol/phospholipid ratio could account for the alterations in the membrane physical properties described in the platelets from patients.

The bleeding time, using the Simplate method, horizontal incision, and venostasis, was measured in a study of 51 patients admitted to a coronary care unit within 12 hours of the onset of chest pain. The bleeding time was significantly shorter in the 28 patients who were found to have definite myocardial infarction compared with the 23 others with chest pain but no definite infarction (p less than 0.0005). A bleeding time of less than 212 seconds correctly classified 84% of patients (sensitivity for definite myocardial infarction 89%) presenting to the coronary care unit with chest pain. Multiple regression analysis showed the bleeding time in all patients to be determined independently (and with high significance) by the following variables in order of importance: diagnostic group, platelet mass (platelet count X mean volume), and age. Packed cell volume was not a significant determinant. In the group with definite myocardial infarction considered alone the same order of variables was observed in predicting bleeding time, but none of them was significant. A major variable reducing bleeding time in acute myocardial infarction remains to be determined. There was no association between bleeding time and creatine phosphokinase activity or infarct size in the group with definite myocardial infarction.

It is suggested that an occlusive thrombus in a coronary artery develops at the site of an intimal tear but that in the interval between initiation of the thrombus and occlusion of the artery emboli are likely to be shed continually, causing multiple occlusions of myocardial vessels in the area of supply. Multiple and confluent areas of ischaemia can progress to complete occlusion of the coronary artery, or the intimal tear can regress and heal. Such a pathogenesis could account for the very variable clinical and pathological findings in myocardial infarction and for the apparently paradoxical time-relationship between coronary artery thrombosis and myocardial infarction.

Seventeen consecutive patients under evaluation for Sjögren's syndrome (SS) had a lower lip salivary gland biopsy performed. Using a monoclonal mouse immunoglobulin against human platelet glycoprotein Ib in an indirect immunoperoxidase technique, it was found that platelets accumulate intravascularly in the inflamed salivary glandular areas. Platelets were demonstrated in the interstitial tissue of inflamed salivary glands from two patients. Saliva from 17 consecutive patients with previously well-established primary SS and 11 healthy controls, and blood from 11 of the patients and all controls were then examined for platelets and the platelet-specific release product beta-thromboglobulin (beta-TG). Platelets were not demonstrated in saliva from patients or controls. beta-TG was detected in saliva from five patients (11-150 ng/ml), but in none of the controls. There were no correlations between saliva beta-TG levels and saliva secretion rates or plasma beta-TG levels. We conclude that platelet release of beta-TG into saliva in patients with primary SS most likely is a result of immunoinflammatory reactions in salivary glands. Measurement of beta-TG in saliva may be of value in the estimation of disease activity.

Bernard-Soulier syndrome (BSS) is a rare autosomal bleeding disorder characterized clinically by prolonged skin bleeding time, normal clot retraction and thrombocytopenia with large and morphologically abnormal platelets, and biochemically by the absence of platelet membrane glycoproteins (GP) Ib, V and IX. GP Ib and GP IX exist in the platelet membrane as a heterodimer complex which acts as the major receptor mediating platelet adhesion to blood vessel subendothelium. Studies with BSS platelets have proved particularly rewarding in the investigation of the GP Ib-IX complex as a multifunctional receptor protein. The transmembrane complex contains binding domains for von Willebrand factor, thrombin, fibrin and quinine/quinidine drug-dependent antibodies as well as an attachment site on the cytoplasmic side of the membrane for a platelet cytoskeleton. In addition, the internal segment of the beta-chain of GP Ib contains a cyclic AMP-dependent protein kinase-associated phosphorylation site which appears to regulate platelet reactivity. Limited proteolytic cleavage of the complex, in particular the GP Ib alpha-chain, has allowed immunological and functional characterization of three distinct domains; a 45 kDa segment at the N-terminal end of the alpha-chain of GP Ib, which contains binding sites for von Willebrand factor and thrombin, a 90 kDa highly glycosylated region of GP Ib alpha and a membrane-associated region consisting of the remnant of GP Ib alpha disulphide-linked to GP Ib beta and non-covalently-complexed with GP IX. This membrane-associated region contains the antigenic epitope(s) for quinine/quinidine drug-dependent antibodies. It is highly probable that the future study of platelets from patients with the Bernard-Soulier syndrome will further clarify the role of the GP Ib-IX complex in platelet physiology.

Accumulation of arterial platelets was calculated from 51Cr radioactivity in the intima-inner media of flushed, perfuse-fixed aortas and branch vessels of cynomolgus monkeys 48 hours after labeling of the blood platelets. In normo-cholesterolemic controls the radioactivity per square centimeter of tissue was consistently higher in aortic branching sites (circumostial aorta) than in the remainder of the aorta. In monkeys given 10 and 100 days of hypercholesterolemic diet radioactivity rose in circumostial aorta in proportion to increases in streaks and in areas of Evans blue uptake. In branch artery inner wall, where intimal changes were minimal and usually absent, counts were significantly greater in animals given 100 days of hypercholesterolemic diet than in controls. After 10 days of hypercholesterolemic diet the mean radioactivity in aortic branch artery inner wall uniformly exceeded control values, but usually nonsignificantly, permitting the speculation that changes in platelet-intima interactions may occur in widespread fashion throughout the arterial tree very early in hypercholesterolemia when lesion formation is incipient or absent.

Recently, conflicting results have been published about a possible relationship between platelet activity and exercise-induced myocardial ischemia. The present study was performed to investigate platelet behavior during a graded symptom-limited bicycle ergometer test both in relation to the intensity of exercise and to exercise-induced myocardial ischemia. Plasma concentrations of platelet factor 4 (PF4) and beta-thromboglobulin (beta-TG) were measured by radioimmunoassays in 53 patients who had had acute myocardial infarction 10 weeks before the study and, for comparison, in 9 healthy individuals. In the whole group of the 53 patients there was no significant alteration in platelet-specific proteins during exercise, whereas physical activity induced a 2- to 3-fold increase in beta-TG and PF4 levels in the controls. However, on differentiation of the patients as to their individual exercise performance, significant exercise-associated platelet activation was demonstrable in those who reached more than 75% of their calculated maximal working capacity, whereas no correlation was found between platelet activity and exercise-induced myocardial ischemia. Thus, the results from this study indicate that in vivo platelet activation is a physiological phenomenon which occurs when a certain degree of physical intensity is exceeded, independent of the precipitation of myocardial ischemia.

Human platelets were labelled with aqueous 111In-tropolonate in comparison with 111In-oxinate. In normals the labelling efficiency with 111In-tropolonate was higher (93% +/- 2%) than with 111In-oxinate (67% +/- 8%) (P less than 0.05). In cases of severe thrombocytopenia, lower labelling efficiencies were obtained. In six normals a mean platelet life of 9 days +/- 3 days and an initial recovery of 59% +/- 15% were obtained. In twelve patients with thrombocytopenia the mean platelet life was 4 days +/- 4 days and the initial recovery was 58% +/- 20%. The absolute uptake of radioactivity in spleen and in liver in both groups are reported.

The coronary microcirculation was examined for platelet and fibrin thrombi in hearts from 21 normal subjects and 244 cardiac patients, including 168 with ischemic heart disease (IHD) and 76 with other types of heart disease. Seventy-seven cases were sudden cardiac death (SCD). No microthrombi were present in any of the normal hearts, whereas platelet and fibrin thrombin were present in the coronary microcirculation in 32 of 244 cardiac cases (13.1%), including 19 with IHD and 13 with other types of heart disease and after cardiac surgery. The microthrombi were either embolic or represented in situ thrombosis, depending upon the underlying pathologic process. There was no significant difference in the incidence of microthrombi in SCD patients, with IHD (10 of 50, 20%) compared with patients who survived longer (nine of 93, 10%). In SCD patients, however, platelet microthrombin were more frequent in patients less than 45 years of age compared with those older than 45 years of age (p = 0.0002). We concluded that coronary microcirculatory thrombi are not uncommon in heart disease. A subgroup of SCD in young patients with IHD has been identified in whom microcirculatory platelet thrombosis is the main cardiac pathologic process. The significance of this process is emphasized by the associated myocardial damage.

Synthetic stable analogues of thromboxane A2 (TXA2), cyclic endoperoxides (PGH2) and prostacyclin (PGI2) opened up new opportunities for investigating the mechanisms of action of these compounds. They proved to be useful pharmacological probes for characterizing PGI2 and TXA2/PGH2 receptors. Over the past few years, new synthetic antagonists with high specificity allowed the modulation of biological responses to endogenous eicosanoids. These compounds will, therefore, considerably promote our understanding of the biological function and significance of arachidonate metabolites. The present review summarizes current concepts that have arisen concerning platelet and vascular PGI2 and TXA2/PGH2 receptors, their transmembrane signal transduction, as well as their possible implications in the pathophysiology of cardiovascular disease.

The hypothesis that abnormalities of platelet function may relate to the occurrence or recurrence of subarachnoid hemorrhage (SAH) has been examined. Seventy patients with SAH and 65 control individuals were studied. The adenosine diphosphate (ADP) threshold for secondary platelet aggregation was significantly higher in the SAH group than in the controls. In tests using 4.0 micrograms/ml ADP, the percent platelet aggregation (at 2 minutes) and the maximum rate of platelet aggregation (over 20 seconds) were significantly lower in the SAH patients. There was no difference in total platelet count between the two groups. Platelet adhesiveness was lower in the SAH patients when compared to controls. Circulating microaggregates did not differ between the two groups. The results indicate that reduced platelet function does relate to SAH and may either contribute to aneurysmal rupture in cases of SAH or be a consequence of it.

Satellitism of platelets to monocytes was observed in 3 patients suffering from polycythaemia vera, a myeloproliferative disorder and chronic lymphocytic leukaemia. This phenomenon occurred on cells in the buffy coat obtained from venous blood anticoagulated with heparin. The existence of platelet satellitism was reported to occur mainly to polymorphonuclears, but the present observation, as well as a previous report from our department, indicated that it may also exist to monocytes. Satellitism was achieved either by adherence of the platelets to monocytes, giving the impression of rosette formation, or by fusion of platelet pseudopodia with the monocyte membrane. The importance of this phenomenon in the evaluation of the platelet count using automatic instruments is discussed.

The ability of tumor cells to initiate coagulation and subsequent platelet aggregation is believed to facilitate the metastatic process. The mechanism by which tumor cells initiate thrombotic alterations is unclear. We have purified a plasma membrane protein platelet aggregating activity/procoagulant activity (PAA/PCA) from several rodent tumors which initiates the coagulation of homologous plasma and aggregation of homologous platelets by a mechanism independent of factor VII. This protein does not possess any proteinase activity; however, its activity is dependent upon the presence of factor X. In addition, PAA/PCA requires reconstitution with phospholipid for expression of activity. These results suggest that tumor cells express a unique protein which possesses procoagulant activity resulting in thrombin generation. Thrombin is responsible for subsequent tumor-cell-induced platelet aggregation.

Previous ultrastructural investigation have not identified abnormal lysosomes in platelets obtained from humans or animals with the Chediak-Higashi Syndrome. We report here a patient whose megakaryocytes and platelets were found to contain giant granules when viewed by light and electron microscopy. The granules measured up to 1.5 micrometer in diameter, contained either homogeneous or heterogeneous material, were acid phosphatase positive, and were present in approximately 30% of bone marrow megakaryocytes and 5% of circulating platelets. A decrease was observed in serotonin containing dense granules, serotonin uptake and serotonin release as reported previously. Microtubules in platelets and megakaryocytes were intact and no other morphologic abnormalities were identified. No clinical evidence of bleeding was observed in this patient and platelet counts have been normal. The lack of giant platelet lysosomes in other reported cases of Chediak-Higashi Syndrome attests to significant heterogeneity in this disease with a spectrum of clinical and laboratory findings.

Thromboembolism remains a frequent and serious problem in cardiac patients. Methods to identify the thrombosis-prone patient and the identification of safe and effective forms of treatment would be of great value. The accumulating evidence which indicates that abnormalities in platelet tests are often present in cardiac patients and may help identify those at greatest risk of thrombosis is encouraging. It suggests that patients with cardiac disease are desirable groups for investigation. It also indicates that the platelet survival test may be useful as a reference against which new and more practical tests can be compared, as well as a means to identify useful platelet suppressant drugs or to monitor the effects of these drugs.

A 70 percent reduction in the rate of blood flow through the common carotid artery in rabbits caused a 21 percent decrease in the diameter of this artery within 2 weeks. The smooth muscle relaxant papaverine did not attenuate the response; therefore, such reductions in diameter probably reflect a structural modification of the arterial wall rather than sustained contraction of smooth muscle. This arterial response to reduced blood flow was abolished when the endothelium was removed from the vessels. It appears that the endothelium is essential for the compensatory arterial response to long-term changes in luminal blood flow rates.

Platelet aggregation and serotonin-release in vitro and some coagulation and fibrinolysis parameters were studied closely in 12 patients with non-complicated acute transmural myocardial infarction from the very beginning, for 3 weeks. The aggregability with ADP, epinephrine and collagen and the serotonin-release was significantly reduced the first days. Significantly increased aggregability and serotonin-release developed after a week, with peak activity on days 14-16. Most patients still exhibited increased activity at the discharge on days 21-22. Positive ethanol gelation tests developed after day 1 in most patients with a peak at day 5, contemporary with peak activities of factor VIII and negatively correlated to factor XIII activity, quantitated biologically. These values were normalized on discharge. Antithrombin III (Xa) remained unchanged, normal to slightly elevated. The fibrinolytic activity decreased after day 1 with lowest activity on day 5, contemporary with peak activity of antiplasmin. Around 50% of the patients showed decreased activity on discharge.

The grey platelet syndrome is a rare inherited disorder characterized by a marked decrease or absence of alpha-granules and of platelet-specific alpha-granule proteins. By utilizing platelets from two patients with this syndrome, we here demonstrate that the initial response of human platelets to alpha-thrombin does not require the presence of alpha-granules nor the effective release of their constituents. Furthermore, these platelets respond to thrombin with a normal, dose-dependent membrane potential change, and a normal secondary release of diS-C3-(5) thought to be released in parallel with beta-glucuronidase from the lysosomal granules. These results give new insight into the initial steps in the thrombin response of normal platelets.

A factor derived from platelets stimulates the proliferation of smooth muscle cells in culture, and is likely important in stimulating smooth muscle proliferative lesions of atherogenesis in vivo. The platelet factor is produced during platelet aggregation when serum is made from whole blood. In vitro, smooth muscle cells are potent aggregating agents for platelets, while endothelial cells can inhibit this aggregating effect. Better understanding of the interactions of platelets, smooth muscle cells, and endothelium would facilitate developing effective means of intervening in or preventing the smooth muscle proliferative lesions of atherosclerosis.

The importance of granulocytes and/or platelets in endotoxin-induced generalized intravascular coagulation was studied as well as thrombocytopenic rabbits. Neutropenia and thrombocytopenia were induced by oral administration of busulphan. Generalized intravascular coagulation, as indicated by renal glomerular microclot formation, was initiated by two intravenous injections of endotoxin. Granulocyte counts before the second injection of endotoxin were most significantly related to activation of intravascular coagulation whereas platelet counts either before the first or second injection of endotoxin were not definitely related to the activation process. Renal glomerular microclots occurred in rabbits after two injections of endotoxin even when the platelet counts were between 500 and 5000/mul. These experiments indicated that granulocytes but not platelets are essential to the activation of endotoxin-induced intravascular coagulation.