Article

Historical Observations on the Discovery of Platelets, Platelet Function Testing and the First Antiplatelet Agent

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Abstract

An understanding of the historical paths that have lead to our current state of knowledge in the field of platelet studies can be both illuminating and inspiring. Considering that the existence and function of platelets were initially described just barely over 100 years ago it is exciting to recognize how far our knowledge has advanced in such a relatively short period of time. Within 20 years of Giulio Bizzozero's definitive description of blood platelets investigators began to develop tests that could quantitate the relationship between platelets, hemostasis and bleeding, and these tests have continued to be refined ever since. At the same time, and well before the role of platelets and antiplatelet agents in cardiovascular disease was appreciated, several clinicians started using aspirin for the prevention of heart attacks. All three of these paths of research - platelet biology, platelet function testing and antiplatelet therapies - all converge on what is arguably one of the most important questions in clinical medicine today: how to best prevent arterial thrombosis. For the current and future pioneers of platelet research an understanding of how we got to where we are today will hopefully allow for a clearer and inspired vision of where we will go next.

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... Thus, today antiplatelets have become the cornerstone of platelet-dependent arterial thrombosis prevention and treatment [8]. Combined antiplatelet therapy is used to block different receptors involved in platelet activation and aggregation. ...
... Gradient elution was performed with the mobile phase consisting of 0.1% acetic acid water solution (solvent A) and acetonitrile/propan-2-ol 90 : 10 (solvent B; the flow rate set to 0.6 ml/min). A linear gradient profile was applied with the following proportions of solvent A: 0-1 min -75%, 8.0-8.5 min -5%, 8.51 min -75%. ...
Article
: The aim of the current study was to evaluate the impact of CYP2C192 (rs4244285), CYP4F23 (rs2108622), and nongenetic factors on platelet aggregation and to investigate the mechanism of CYP4F2's effect on platelet aggregation in the patients treated with dual antiplatelet therapy. A total of 146 patients were included in this study. Ticagrelor or clopidogrel were administered in a loading dose of 180 mg and 600 mg, respectively, in combination with aspirin (300 mg). Blood samples for analysis were taken the next morning after antiplatelet therapy induction. Clopidogrel users with the CYP2C1912 variant had higher platelet aggregation values (median 43, range 30-54%) compared with 11 wild-type carriers (median 33, range 15-77%; P = 0.009). Carriers of the CYP4F213 variant had higher platelet aggregation values than carriers of the 33 variant (median 34, range 8-70% vs. median 24.5, range 10-47%, P = 0.016, respectively). Higher CYP4F2 concentrations were detected in clopidogrel users than in ticagrelor users (median 3.6, range 1.6-22.0 ng/ml vs. median 2.3, range 1.6-27.2 ng/ml, P = 0.056, respectively) and in carriers of the CYP4F213 variant compared with carriers of the 11 variant (median 4.3, range 1.6-27.2 ng/ml vs. median 2.4, range 1.6-22.0 ng/ml, P = 0.009, respectively). No correlation between plasma 20-hydroxyeicosatetraenoic acid and CYP4F2 enzyme concentrations were detected (r = -0.045, P = 0.587). Our results proved that CYP2C192 might significantly affect antiplatelet function of clopidogrel. Plasma CYP4F2 concentrations were significantly lower in ticagrelor users than in clopidogrel users.
... Having the ability to measure whether and how much a drug is able to influence platelet function ex vivo has led to some remarkable contributions to cardiovascular medicine over the last several decades. For example, the nearly 40-year journey for aspirin to go from a hypothesized to a proven therapy for ischemic heart disease may have never occurred if not for a series of mechanistic investigations of its effects on platelet function (2). ...
... There are hundreds of variations and methods to test platelet function; all generate different results. The origins of platelet function testing date back over 100 years to the earliest description of bleeding times, and the first ex vivo platelet function test was described in 1929 (2). Since then, every manner of platelet disintegration, adhesion, stickiness, aggregation, agglutination, and activation has been quantitated in some form as a measure of platelet activity. ...
Article
Real knowledge is to know the extent of one's ignorance .—Confucius ([1][1]) Having the ability to measure whether and how much a drug is able to influence platelet function ex vivo has led to some remarkable contributions to cardiovascular medicine over the last several decades. For example,
... Even after the invention of the light microscope in 1590 by Dutch spectacle makers, Zaccharias and Hans Janssen descriptions of blood cells were not immediately forthcoming. It was not until 1658 that Dutch biologist Jan Swammerdam identified red blood cells [4,5]. Nevertheless, the key subcellular factors were not described until 1842. ...
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In many diseased conditions of the body, occasionally also in perfectly healthy individuals and in many of the lower animals, careful investi­gation of the blood proves that, in addition to the usual elements, there exist pale granular masses, which on closer inspection present a corpus­cular appearance (Plate V. fig. 1). There are probably few observers in the habit of examining blood who have not, at some time or other, met with these structures, and have been puzzled for an explanation of their presence and nature. In size they vary greatly, from half or quarter that of a white blood-corpuscle, to enormous masses occupying a large area of the field or even stretching completely across it. They usually assume a somewhat round or oval form, but may be elongated and narrow, or, from the existence of numerous projections, offer a very irregular outline. They have a compact solid look, and by focusing are seen to possess consider­able depth ; while in specimens examined without any reagents the filaments of fibrin adhere to them, and, entangled in their interior, white corpuscles are not unfrequently met with.
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Acetylsalicylic acid (ASA, aspirin) and sodium salicylate inhibit platelet aggregation induced by collagen, antigen-antibody complexes, gamma globulin-coated particles or thrombin. These compounds suppress the release of platelet constituents, such as adenosine diphosphate (ADP) and serotonin, induced by such stimuli. Since ASA and sodium salicylate do not inhibit ADP-induced platelet aggregation, it appears that their effect on the action of the other stimuli is due to a decrease in the amount of ADP released. The administration of ASA to rabbits (in doses which inhibited collagen-induced platelet aggregation) impaired hemostasis, prolonged platelet survival, and diminished the amount of deposit formed in an extracorporeal shunt.
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Secondary aggregation of platelets was produced in 8 of 10 normal subjects by a critical concentration of adenosine diphosphate (ADP) ranging from 1.0-2.0 μM. Shortening of the Russell Viper Venom clotting time and release of serotonin-14C were also observed with the critical concentration of ADP or with higher levels, but did not occur in the two subjects who showed only primary aggregation in response to ADP. Ingestion of 1.3 gm of acetylsalicylic acid in a divided dose 1 and 2 hours prior to testing abolished secondary aggregation, serotonin release, and platelet factor-3 activation induced by ADP, as well as aggregation and serotonin release induced by connective tissue particles, but did not affect primary ADP-induced aggregation.
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We conducted a multicenter, double-blind, placebo-controlled randomized trial of aspirin treatment (324 mg in buffered solution daily) for 12 weeks in 1266 men with unstable angina (625 taking aspirin and 641 placebo). The principal end points were death and acute myocardial infarction diagnosed by the presence of creatine kinase MB or pathologic Q-wave changes on electrocardiograms. The incidence of death or acute myocardial infarction was 51 per cent lower in the aspirin group than in the placebo group: 31 patients (5.0 per cent) as compared with 65 (10.1 per cent); P = 0.0005. Nonfatal acute myocardial infarction was 51 per cent lower in the aspirin group: 21 patients (3.4 per cent) as compared with 44 (6.9 per cent); P = 0.005. The reduction in mortality in the aspirin group was also 51 per cent--10 patients (1.6 per cent) as compared with 21 (3.3 per cent)--although it was not statistically significant; P = 0.054. There was no difference in gastrointestinal symptoms or evidence of blood loss between the treatment and control groups. Our data show that aspirin has a protective effect against acute myocardial infarction in men with unstable angina, and they suggest a similar effect on mortality.
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Bizzozero was born in 1846 and graduated in medicine at the age of 20 years. After working in Pavia for some years he was appointed Professor of General Pathology in Turin. Here he collaborated with many famous scientists in Italy and abroad. His interest in hematopoietic cells culminated in a description of platelets and their essential involvement in the blood clotting mechanism in vivo. Before Bizzozero's work, the description of platelets had been unclear, and both red and white cells were thought to be required for formation of blood clots. Although Bizzozero's discovery was disputed vigorously for several years, he was finally vindicated in 1892, unfortunately 1 year after his death. Apart from his extensive work, he bequeathed to science the benefit of his logical descriptions and rigorous experimental approach.
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The major conclusions of this position article are as follows: (1) In the absence of a history of a bleeding disorder, the bleeding time is not a useful predictor of the risk of hemorrhage associated with surgical procedures. (2) A normal bleeding time does not exclude the possibility of excessive hemorrhage associated with invasive procedures. (3) The bleeding time cannot be used to reliably identify patients who may have recently ingested aspirin or nonsteroidal anti-inflammatory agents or those who have a platelet defect attributable to these drugs. The best preoperative screen to predict bleeding continues to be a carefully conducted clinical history that includes family and previous dental, obstetric, surgical, traumatic injury, transfusion, and drug histories. A history suggesting a possible bleeding disorder may require further evaluation; such an evaluation may include performance of the bleeding time test, as well as a determination of the platelet count, the prothrombin time, and the activated partial thromboplastin time. In the absence of a history of excessive bleeding, the bleeding time fails as a screening test and is, therefore, not indicated as a routine preoperative test.
Article
The discovery of aspirin is customarily said to have resulted from Felix Hoffmann's rheumatic father encouraging his son to produce a medicine devoid of the unpleasant effects of sodium salicylate. Hoffmann, a chemist in the pharmaceutical laboratory of the German dye manufacturer Friedrich Bayer & Co in Elberfeld, consulted the chemical literature and came across the synthesis of acetylsalicylic acid and then prepared the first sample of pure acetylsalicylic acid on 10 August 1897. This was marketed in 1899 under the registered trademark of Aspirin. This account of the discovery first appeared in 1934 as a footnote in a history of chemical engineering written by Albrecht Schmidt, a chemist who had recently retired from IG Farbenindustrie—the organisation into which F Bayer & Co had been incorporated in 1925.1 #### Summary points Until now, it has been generally accepted that Felix Hoffmann developed aspirin to help his rheumatic father In 1949 Hoffman's former colleague Arthur Eichengrun claimed that the work had been done under his direction Analysis of relevant archival and published material now supports Eichengrun's claim and throws doubt on the reliability of the source crediting Hoffmann It is likely that acetylsalicylic acid was synthesised under Eichengrun's direction and that it would not have been introduced in 1899 without his intervention The footnote also stated that Hoffmann had arranged for several chemical derivatives of salicylic acid to be examined, not just its acetyl ester. No indication was given of what the others were, but in 1899 Heinrich Dreser, head of the experimental pharmacology laboratory at Elberfeld, named them in a paper as propionyl, butyryl, valeryl, and benzoyl salicylic acids.2 He further alluded to them in 1907,3 and again in 1918.4 No earlier reports of the preparation of any of these are to be found, but three of them appear …
Article
At the occasion of the first centennial anniversary of Giulio Bizzozero’s death (1901), an impossible interview is presented to honour this distinguished and creative investigator. The imaginary conversation between a reporter and Bizzozero – aged 36 years – takes place at the University of Turin in 1882, few months after Bizzozero’s announcement of the discovery of a new blood corpuscle with seemingly important function in thrombosis and blood coagulation. “An investigator who is not prepared in advance to look for other than the known elements – says Bizzozero – will be attracted only by the red and white corpuscles.” Having discovered blood platelets, Bizzozero, convinced that scientific and social progress should proceed hand in hand, will turn – as a scientist and a member of the Italian Kingdom’s Senate – to such social issues as the welfare of the poor. He will die in Turin, aged 55 years, shortly after Giuseppe Verdi, few months before the conferment of the first Nobel Prize for Medicine (to E. von Behring).
Article
A one-stage macroscopic test for platelet agglutination was used to study the effect of thrombin and thrombin-cation mixtures on washed platelets. Conclusions regarding platelet agglutination are as follows: (a) Canine, bovine, or human thrombin alone does not cause agglutination of canine or human platelets. (b) Thrombin with calcium or magnesium causes rapid platelet agglutination. Both calcium and magnesium are active at physiologic concentrations. Divalent manganese or cadmium ions can be substituted for calcium or magnesium. (c) The agglutination reaction is affected but little by the species of origin of thrombin or platelets, or by variations in ionic strength or pH over a broad range. (d) Temperature at which the reaction is carried out is critical; optimal temperature for the test is 28 degrees C. (e) Agglutination is inhibited by high ionic strength, by pH values outside the range 6.4-8.6, and by temperatures outside the range 25-28 degrees C. High concentrations of calcium have a specific inhibitory effect. (f) Platelet agglutination time is as sensitive an index of thrombin concentration as is the fibrinogen clotting time. A comparison is made between divalent cations which influence platelet agglutination induced by thrombin, TAg', and TAg. A similar comparison is made of cations influencing the action of thrombin on the "substrates," fibrinogen, TAMe, and platelets.
Article
Max Schultze published the first accurate and convincing description of platelets as part of a study devoted mainly to the white blood cells in 1865. He recognised them as a normal constituent of the blood and 'enthusiastically recommended' them as an object for further study by 'those concerned with the in-depth study of the blood of humans'. In 1882, Bizzozero demonstrated the value of this recommendation in his much more comprehensive study. He observed them microscopically in the circulating blood of living animals and in the blood removed from the blood vessels. In well-planned experiments, he showed that they were the first component of the blood to adhere to damaged blood vessel walls in vivo and, in vitro, that they were the first components of the blood to adhere to threads that subsequently became covered with fibrin.
Article
The variable response to antiplatelet therapy has led to the use of platelet function tests to monitor the effects of antiplatelet drugs in cardiovascular diseases. The goal is to guide antiplatelet therapy to the optimal dose for the prevention or treatment of thrombosis while minimizing hemorrhagic side effects. The bleeding time is no longer recommended for use because of its nonspecificity and lack of clinical correlations. The current de facto "gold standard" test of platelet function is turbidometric platelet aggregometry. Although this method has been successful in measuring the aggregation of platelets in a glycoprotein (GP) IIb/IIIa (integrin alpha(IIb)beta(3))-dependent manner, it has several limitations, including poor reproducibility, high sample volume, requirement for sample preparation, length of assay time, requirement for a skilled technician, and cost. Therefore, new options for platelet function testing have been developed to address these disadvantages and to meet the need for point-of-care testing that can be performed at or near a patient's bedside without requiring a high degree of technical expertise. The new tests include VerifyNow (Accumetrics, San Diego, CA); Plateletworks (Helena Laboratories, Beaumont, TX); Thrombelastograph PlateletMapping System (Haemoscope Corporation, Niles, IL); Impact cone and plate(let) analyzer (DiaMed, Cressier, Switzerland); and Platelet Function Analyzer 100 (PFA-100; Dade Behring, Newark, DE). In patients treated with antiplatelet drugs, the degree of platelet inhibition, as determined by several of these new platelet function assays, has been shown to predict major adverse cardiac events.