• aspirin;
  • history;
  • platelets;
  • thrombosis;
  • thrombocytopenia;
  • Willebrand


  1. Top of page
  2. Abstract
  3. Introduction
  4. The Descriptive Period
  5. The Mechanistic Period
  6. The future
  7. Conclusion
  8. Acknowledgement
  9. Disclosure of Conflict of Interest
  10. References

Summary.  Platelets are a remarkable mammalian adaptation that are required for human survival by virtue of their ability to prevent and arrest bleeding. Ironically, however, in the past century, the platelets’ hemostatic activity became maladaptive for the increasingly large percentage of individuals who develop age-dependent progressive atherosclerosis. As a result, platelets also make a major contribution to ischemic thrombotic vascular disease, the leading cause of death worldwide. In this brief review, I provide historical descriptions of a highly selected group of topics to provide a framework for understanding our current knowledge and the trends that are likely to continue into the future of platelet research. For convenience, I separate the eras of platelet research into the “Descriptive Period” extending from ∼1880–1960 and the “Mechanistic Period” encompassing the past ∼50 years since 1960. We currently are reaching yet another inflection point, as there is a major shift from a focus on traditional biochemistry and cell and molecular biology to an era of single molecule biophysics, single cell biology, single cell molecular biology, structural biology, computational simulations, and the high-throughput, data-dense techniques collectively named with the “omics postfix”. Given the progress made in understanding, diagnosing, and treating many rare and common platelet disorders during the past 50 years, I think it appropriate to consider it a Golden Age of Platelet Research and to recognize all of the investigators who have made important contributions to this remarkable achievement..


  1. Top of page
  2. Abstract
  3. Introduction
  4. The Descriptive Period
  5. The Mechanistic Period
  6. The future
  7. Conclusion
  8. Acknowledgement
  9. Disclosure of Conflict of Interest
  10. References

Platelets are a remarkable mammalian adaptation that are required for human survival by virtue of their ability to prevent and arrest bleeding. Ironically, however, in the past century, the platelets’ haemostatic activity became maladaptive for the increasingly large percentage of individuals who develop age-dependent progressive atherosclerosis. As a result, platelets also make a major contribution to ischaemic thrombotic vascular disease, the leading cause of death worldwide [1]. Thus was born the need to develop anti-platelet therapies to attenuate platelet function in individuals at risk of arterial thrombosis. The wide range of platelet contributions to health and disease has stimulated intense study of platelet function. In this brief review, I provide historical descriptions of a highly selected group of topics to provide a framework for understanding our current knowledge and the trends that are likely to continue into the future of platelet research. For convenience, I will separate the eras of platelet research into an initial ‘Descriptive Period’ extending from approximately 1880 to 1960, during which many of the classic clinical features of platelet disorders were detailed (Fig. 1) and a subsequent ‘Mechanistic Period’ encompassing the past approximately 50 years, made possible by the introduction of biochemical, cell biologic, molecular biologic, and most recently, structural biologic, genomic, and computational techniques. Unfortunately, the limitations of space make it impossible to include the names in the text of the large number of distinguished investigators who made many of the important contributions. Several excellent histories of platelet discoveries are referenced throughout for those interested in additional details.


Figure 1.  Timeline of first clinical reports of important platelet disorders.

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The Descriptive Period

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Descriptive Period
  5. The Mechanistic Period
  6. The future
  7. Conclusion
  8. Acknowledgement
  9. Disclosure of Conflict of Interest
  10. References

Discovery of platelets and megakaryocytes

The Descriptive Period began with the elegant and comprehensive intravascular microscopy and ingenious in vitro flow chamber studies reported by Bizzozero in 1881–1882 [2,3]. Although others probably observed platelets earlier [4,5], he correctly identified the platelet’s role in both haemostasis and thrombosis. He was also the first to describe bone marrow megakaryocytes [6], but Wright was the first to identify the megakaryocyte as the precursor cell to the platelet, aided by the new staining techniques he developed [7,8]. Osler in 1886 [9] established that platelets contribute to human thrombotic disorders, discovering them in white thrombi in atheromatous aortic lesions and on diseased heart valves.

Descriptions of clinical syndromes and early studies of platelet physiology

Many important clinical disorders were described during the Descriptive Period, providing compelling evidence of the importance of platelets in haemostasis and spurring interest in platelet physiology [10–13]. These include what would later be renamed immune thrombocytopenia (1735/1883) [14], May–Hegglin anomaly (1909/1945) [15], thrombocytopenic haemorrhage (1910) [16], Glanzmann thrombasthenia (1918) [17], thrombotic thrombocytopenic purpura (Moschcowitz syndrome, 1924) [18,19], von Willebrand disease (1926) [20–22], and Bernard–Soulier syndrome (1948) [23]. Similarly, assays for platelet function were developed, including clot retraction (1878/1951) [24] and the Duke bleeding time (1910) [16]. Histologic examination of sites of vascular injury in experimental animals using light microscopy and later electron microscopy established the sequence of events, including platelet adhesion and aggregation, followed by degranulation, the loss of distinct borders between platelets, and platelet thrombus contraction, which were collectively termed ‘viscous metamorphosis’ [5,25]. Studies of serum led to the discoveries that thrombin is a strong platelet activator and that platelets are secretory cells that store and release the vasoactive compound serotonin, a derivative of tryptophan [26]. The observation that platelets adhere to connective tissue led to the discovery that collagen is also a potent platelet activator [25,27]. Clot retraction was studied in detail [24] leading to the discovery that platelets contain the contractile proteins actin and myosin, initially termed thrombosthenin [28], the first non-muscle cell shown to have these elements [29].

The different mechanisms of thrombocytopenia were studied intensely during the Descriptive Period. In particular, the pioneering and courageous studies of Harrington et al., [30] in which blood components from patients with immune thrombocytopenia were infused into volunteers, including Harrington himself, demonstrated that the agent causing immune thrombocytopenia could be passively transferred with plasma. His group went on to define many important aspects of immune thrombocytopenia, including the crucial role of antibodies, and the beneficial effects of splenectomy and glucocorticoid therapy on platelet clearance [31].

Erich von Willebrand described the bleeding disorder that bears his name based on studying a 5 year old girl in the Åland Islands and 65 other members of her family [20–22]. The disorder clearly differed from haemophilia in its cardinal manifestations since it was inherited as an autosomal dominant trait rather than as an X-linked trait, bleeding was primarily mucocutaneous, the bleeding time was prolonged, and the clotting time was normal. Thus, the disorder had many of the characteristics of a platelet abnormality, but it was unclear whether the defect was intrinsic to the platelet or resided in a plasma cofactor needed for platelet function. Studies conducted in the 1950s by several groups demonstrated a partial deficiency in factor VIII, but when compared to the levels in patients with haemophilia A, the reduction was not able to account for the bleeding symptoms [32–36]. They also demonstrated that the plasma fraction termed Cohn fraction 1 from normal individuals could correct the bleeding time when infused into patients with von Willebrand disease and produce a paradoxically exaggerated increase in factor VIII [32,33].

Early treatments

A number of important therapies were developed during the Descriptive Period. Platelet transfusion therapy for thrombocytopenia was inaugurated with Duke’s [16] compelling demonstration in 1910 of the immediate haemostatic efficacy of direct donation of whole blood to correct severe thrombocytopenia. It would take another 35 years, however, before there was a systematic effort to improve the techniques of platelet transfusion, spurred by the recognition that thrombocytopenic haemorrhage was a major cause of death after radiation exposure to atomic weapons [37,38]. Further impetus for improving platelet transfusion therapy near the end of the Descriptive Period came from the evidence that thrombocytopenic haemorrhage was also a major cause of death from radiation therapy and the then-new chemotherapeutic agents [39]. Thus, platelet transfusion therapy became crucial for the success of modern chemotherapy.

Splenectomy for what would later be termed immune thrombocytopenia was introduced in 1916 based on the recommendation of Kaznelson, who was a medical student in Prague [14,40] (Fig. 2). The first surgery was performed by Professor Schloffer and the first patient’s platelet count increased from < 1000 μL-2 to approximately 500 000 μL−1. Corticosteroid therapy was also introduced for immune thrombocytopenia during the Descriptive Period [41].


Figure 2.  Dates of introduction or US FDA approval of selected therapies for platelet disorders.

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The Mechanistic Period

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Descriptive Period
  5. The Mechanistic Period
  6. The future
  7. Conclusion
  8. Acknowledgement
  9. Disclosure of Conflict of Interest
  10. References

Megakaryopoiesis and thrombopoiesis

Although the existence of a humoral factor that stimulates megakaryocyte production was postulated by Kelemen [42] near the end of the Descriptive Period based on rodent studies of thrombocytopenia, attempts to purify thrombopoietin (Tpo) during the next 30 years achieved only limited progress [43,44], in part because they relied on complex in vivo, radiolabeled methionine incorporation assays [45]. In vitro culture methods on semisolid media developed in the 1970s made it possible to define the colony- and burst-forming megakaryocyte units (CFU-MK and BFU-MK), along with their precursors, as well as variably-specific transcription factors (e.g. SCL, GATA1, GATA2, NF-E2, and ets family members) and cytokine receptors involved in megakaryopoiesis [45]. The breakthrough, however, came when several groups recognised that the cellular proto-oncogene of the murine myeloproliferative leukaemia virus (c-Mpl) was a member of the cytokine receptor family, and that because it was expressed in megakaryocyte precursors, it was a strong candidate to be the receptor for Tpo. In 1994, studies by multiple groups using c-MPL for affinity purification or direct biochemical purification techniques resulted in the purification and cloning of Tpo [46–49]. Tpo was shown to increase platelet counts in animals and humans by enhancing both megakaryocyte proliferation and survival. Loss of either Tpo or its receptor was shown to result in severe thrombocytopenia, demonstrating Tpo’s important physiologic role. In fact, a number of patients with inherited amegakaryocytic thrombocytopenia were found to have mutations in c-MPL [50].

Studies of Tpo also provided insights into the regulation of the platelet count, which is normally maintained at a level that is ten-fold higher than that required to prevent spontaneous bleeding. Much can be explained by a model in which Tpo catabolism is controlled by the total mass of platelets and megakaryocytes via their binding and degradation of Tpo [51], with potential additional roles for regulated Tpo expression and/or cytokine (e.g. IL-6)-induced upregulation of Tpo expression [45].

Studies of megakaryopoiesis have also provided insights into the endomitotic process that allows megakaryocytes to increase their ploidy and mass without undergoing division [52–55]. They also shed light on how organelles and granules move along microtubule tracks to the tips of proplatelets [56,57] before they extend into the vascular sinuses in the bone marrow, bend and fragment, giving rise to thousands of platelets [58–61]. Studies of the myeloproliferative and megakaryocytic disorders associated with Down’s syndrome trisomy 21 have provided valuable insights into transcription factors that control megakaryopoiesis [62,63].

Platelet biochemistry

The early phase of the Mechanistic Period was marked by bringing the new tools of biochemistry to bear on the platelet phenomena that had already been described and by developing more quantitative techniques to evaluate and dissect the phenomena. The platelet’s protein and lipid composition, inorganic constituents, enzymatic activities, and energy metabolism were defined and quantified [10,64]. Hellem et al. [65] developed a method for measuring platelet ‘adhesiveness’ using columns of glass beads, and found an association between ‘adhesiveness’ and the blood hematocrit. Based on that finding, they postulated that red cells must have a powerful platelet activating agent and this led them to discover the platelet aggregating activity of ADP [66]. Modifications of the platelet ‘adhesiveness’ assay (later termed the platelet retention test since it reflects both adhesion to glass and platelet aggregation) helped to define the abnormalities in platelet function in uraemia, afibrinogenaemia, Glanzmann thrombasthenia, Bernard–Soulier syndrome, and von Willebrand disease, including the accentuation of the platelet function defect in von Willebrand disease under high shear conditions [67–69]. It also furnished the first assay to support the purification of von Willebrand factor (VWF) [70]. Biochemical analysis of platelet granule contents demonstrated the presence of adhesive glycoproteins such as fibrinogen, VWF, and thrombospondin-1 in α granules, along with cytokines and platelet-specific proteins such as platelet factor 4 and the β-thromboglobulin family of proteins [71–73]. The presence of a ‘storage pool’ of ADP, ATP, and serotonin in the calcium-rich dense bodies was also discovered and characterised [74].

The aggregometer and flow chamber studies

The need for more quantitative and robust methods of assessing platelet function led both Born and O’Brien to develop turbidometric platelet aggregometry in 1962 [75,76]. This allowed for the characterisation of the unique platelet effects of the different agonists that had been, and were being, discovered, including ADP, epinephrine, thrombin, collagen, vasopressin, and serotonin. The discovery that with citrated platelet-rich plasma ADP and epinephrine produce aggregometer tracings that could be divided into two separate phases, or waves, led to the definition of the role of the platelet release reaction, including the release of ADP from dense bodies and the release of arachidonic acid and its subsequent conversion into thromboxane A2, in amplifying the platelet aggregation response [77–80]. The subsequent development of the lumi-aggregometer allowed for simultaneous measurement of both platelet aggregate formation and release of ATP from dense bodies [81]. Aggregometer studies were also crucial in more precisely defining the roles of phospholipids, phosphoinositol hydrolysis, diacylglycerol, and Ca2+ mobilisation in platelet activation [82–86], as well as the functional defects in many of the previously described inherited platelet disorders [87–90], and the newly described Storage Pool disorders [91], the Gray platelet syndrome [92], and disorders of platelet secretion [93,94]. The roles of fibrinogen and VWF in mediating platelet–platelet interactions via binding to αIIbβ3 [95–98] and GPIb [99], respectively were also facilitated by aggregometer studies. Similarly, studies using newly designed flow chambers defined platelet-ligand and platelet–platelet interactions as a function of shear rate, introducing and partially simulating an important aspect of the in vivo milieu [100–103].

Platelet coagulant activity

Platelets were shown to greatly accelerate blood coagulation and this property was initially termed platelet factor 3 (PF-3) [10,104]. This factor was only ‘made available’ when platelets were activated under certain conditions, or when they were subjected to physical trauma, as with freezing and thawing. Extensive studies of the platelet lipids and proteins responsible for the nearly 100 000-fold increase in the rate of thrombin generation identified exteriorisation of the negatively charged phospholipid phosphatidylserine as a primary contributor to recruitment of coagulation factors and enhancement of catalytic efficiency [105,106]. A series of platelet protein receptors for coagulation factors were also identified and their contributions continue to be the subject of study [107–109]. The role of fibrin in enhancing platelet-mediated thrombin generation was also identified [110]. Platelet microparticles, small fragments of platelets that circulate in health and in disease, were found to have coagulant activity and to be biologically active [111,112]. Studies of a single patient, Mrs Scott, first described by Weiss et al. in 1979 [113] provided important insights. Her bleeding symptoms differed from patients with qualitative or quantitative defects in platelets in that she did not have easy bruising; she did, however, have menorrhagia and post-partum haemorrhage. Her platelets failed to expose negatively-charged phospholipids upon activation, apparently as part of generalised defect in cell vesiculation [114–116]. Information from advanced biophysical tools and structural biology insights have been combined to provide a detailed image of the underlying mechanisms by which platelets contribute to thrombin generation [111,112,117–120].

The endothelial lining, inhibitors of platelet function, and platelet–leukocyte interactions

The endothelial lining of blood vessels prevents platelet interactions with the vessel wall by both synthesising platelet inhibitors and ‘hiding’ the subendothelial platelet-adhesive proteins from the platelet’s view. Studies by the groups led by Moncada and Weksler demonstrated that endothelial cells synthesise prostaglandin I2 (PGI2, prostacyclin) from arachidonic acid [121,122]. Subsequently, endothelial cells were found to synthesise the platelet inhibitor nitric oxide (NO), which acts synergistically with prostacyclin [123–125]. Finally, Marcus et al. [126,127] also identified an endothelial ecto-ADPase [CD39; ecto-nucleotide pyrophosphatase/phosphodiesterase (E-NPP)] capable of rapidly metabolising the platelet activator ADP (as well as ATP) to the inactive compound AMP. The subsequent conversion of AMP to adenosine by the ecto-5′-nucleotidase CD73 on the endothelial cells of some vessels and on some leukocytes yields adenosine, an inhibitor of platelet activation [128–130]. Marcus [131,132] also identified the extraordinary high content of arachidonic acid in platelets and the complex transcellular eicosanoid metabolism that occurs between platelets, endothelial cells, and leukocytes.

Platelets can also interact with, and roll on, intact endothelium via multiple receptors when the endothelium is activated to secrete large VWF multimers and expose P-selectin [133]. Complex mechanisms involving similar interactions underly platelet–leukocyte interactions [134–136].

When the endothelial cell lining is disrupted, platelets adhere to the denuded surface via receptors for the adhesive proteins that are exposed and/or deposited from plasma, in particular, the interactions of platelet GPIbα with VWF [137–139] and both GPVI and α2β1 with collagen [140,141]. GPIbα has a carbohydrate-rich region that allows it to extend far from the platelet surface and so it attaches first. Engagement of these receptors initiates platelet activation, resulting in activation of αIIbβ3 and recruitment of additional platelets.

Platelet receptors and ligands

The concept of cell receptors controlling cell physiology also emerged in the early part of the Mechanistic Period. Initially receptors were characterised functionally and pharmacologically based on biochemical responses and later they were characterised by their ability to release intracellular Ca++, monitored by cation-sensitive dyes [142,143]. The introduction of radionucleotides in biomedical research made it possible to perform direct ligand binding studies in select cases [95,96]. The introduction of sodium-dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) allowed for detailed biochemical assessment and was a great aid to receptor purification and characterisation [99,144]. It also provided the initial glycoprotein (GP) nomenclature for many of the receptors [145]. The sensitivity and specificity of SDS-PAGE was greatly enhanced by combining it with platelet surface labelling techniques and immunoblotting [145,146]. Other immunologic techniques, including cross-immunoelectrophoresis allowed for assessing protein–protein interactions under non-denaturing conditions, helping to define ligand–receptor interactions [99,144,145,147]. Monoclonal antibody development was an additional major advance, providing essentially unlimited amounts of standardised reagents that could unequivocally identify specific receptors by immunoblotting and other techniques [147,148]. In addition, the development of monoclonal antibodies that could inhibit platelet function provided tools that could dissect the contribution of each receptor [147,149–152]. This was particularly important in understanding the roles of receptors that could bind more than one ligand, such as αIIbβ3 and αVβ3, and of ligands like VWF and fibrinogen that could bind to more than one receptor. Monoclonal antibodies that reacted selectively with activated αIIbβ3, most notably PAC1 [153], or with P-selectin [154,155], which is confined to α-granule membranes, made it possible to monitor the activation state of αIIbβ3 and the release reaction, respectively. Similarly, monoclonal antibodies were developed that reported on the conformational changes in receptors after ligand binding [156]. Many of the initial monoclonal antibody studies were performed with radiolabeled antibodies, which required special care and handling. The development of flow cytometry made it possible to substitute more generally available fluorescently-labelled antibodies and permitted analysis of the binding of antibodies to individual platelets [157–159] and even to small platelet microparticles, which are biologically active and support blood coagulation [160,161].

The introduction of molecular biologic techniques allowed for the detailed analysis of the subunit structures and homology of different receptors, defining the major families of receptors as integrins (αIIbβ3, αVβ3, α2β1, α5β1, and α6β1), leucine-rich repeat receptors (GPIbα, GPIbβ, GPV, GPIX), immunoglobulin repeat receptors (PECAM-1, GPVI, FcγRIIA, CLEC-2), selectins (P-selectin), tetraspanins (CD9, CD151, TSSC6, CD63, and Tspan9) [162,163], and G protein-coupled 7 transmembrane receptors (including, among others, PAR-1, PAR-4, P2Y1, P2Y12, vasopressin V1a, serotonin 5-HT2A, and adenosine receptors A2a and A2b) [128,164,165]. Of particular importance in integrin receptor biology was the extrapolation from studies of α5β1 [166] that both αIIbβ3 and αVβ3 could be inhibited by peptides containing the Arg-Gly-Asp (RGD) sequence [167]. Structural biology studies using nuclear magnetic resonance, x-ray crystallography, electron microscopy, and molecular dynamics simulations now permit atomic level resolution of the receptors and receptor–ligand interactions [168–173]. Transgenic mice with targeted deletions of receptors or mutant receptors have confirmed and extended our understanding of the roles of the different receptors [174,175], although extrapolation from mouse to human platelets needs to be tempered because of the unique aspects of human vs. mouse platelets, such as the repertoire of functional thrombin receptors [176], and the differences in physiology, most notably the mouse’s approximately 600 beats per minute heart rate!

Insights into the signal transduction pathways triggered by ligand binding also derived from studies of the receptors. Our understanding of collagen signalling through GPVI had its origin in the 1989 description of a patient with an isolated defect in collagen-induced platelet aggregation whose platelets also had a defect in GPVI [177,178]. Subsequent functional studies and the cloning of the GPVI led to the recognition that it is coexpressed with the FcR γ-chain and requires a dimeric structure to achieve high affinity for collagen [179]. GPVI cross-linked by polymerised collagen (or collagen-related peptides or the snake venom convulxin) was elegantly shown to initiate Srk kinase-dependent tyrosine phosphorylation of the FcR γ-chain ITAM, leading to recruitment and activation of Syk. Downstream from Syk is a cascade of intermediates similar to those in immune cell signalling, including LAT, SLP-76, PI3-kinase and PLCγ2, ultimately leading to the conversion of PIP2 into 1,2-diacylglycerol and inositol 1,4,5-trisphosphate IP3, resulting in an increase in cytoplasmic calcium and granule exocytosis [180]. Signalling through the GPIb/X/V complex leading to inside-out signalling could be inferred from the contribution of αIIbβ3 to ristocetin-induced platelet aggregation and from studies identifying the roles of VWF and fibrinogen in shear-induced platelet aggregation [181]. The signal transduction details, including the roles of tyrosine kinases, were then worked out in several laboratories [182–185]. Signalling through αIIbβ3 (‘outside-in’) was shown to include roles for Src, Syk, Gα13 and the phosphorylation of two tyrosine residues in the β3 integrin subunit cytoplasmic tail [186–190]. ‘Inside-out’ signalling to activate αIIbβ3 via changes in its conformation so that it adopts a high affinity ligand binding state was elucidated by elegant functional studies of the roles of talin and kindlin in binding to the β3 cytoplasmic tail and the separation of the transmembrane domains [191–199]. The physiologic role of kindlin-3 was supported by the identification in 2009 of patients with a profound defect in platelet function as part of leukocyte adhesion deficiency-III (LAD-III) resulting in a serious bleeding diathesis in association with mutations in kindlin-3 [197,198,200–202]. CLEC-2, a C-type lectin receptor, has multiple ligands including the snake venom rhodocytin, tumor-associated podoplanin and HIV-1, and has been implicated in haemostasis, thrombosis, tumor metastases, and lymphangiogenesis; it also signals through tyrosine phosphorylation of its cytoplasmic tail followed by the binding of Syk [203–208]. Signalling through the G protein-coupled 7 transmembrane domain receptors was investigated in great detail including the pairings with specific Gα subunits, the downstream effects on second messengers, and the feedback control mechanisms [164,165]. Balancing the platelet receptors involved in initiating signalling are inhibitory receptors containing the immune receptor tyrosine-based inhibitory motif (ITIM), most notably PECAM-1 and G6b-B [209–214]. A third platelet ITIM containing receptor, TREM-like Transcript-1, however, may not serve an inhibitory function; in fact, it may enhance platelet function and contribution to platelet–leukocyte interactions [215].

Clinical diagnosis, carrier detection, and prenatal diagnosis

Biochemical and molecular biological advances, most notably the application of the reverse polymerase chain reaction (PCR) to study the small amount of platelet mRNA [216], revolutionised the diagnosis and characterisation of patients with disorders affecting platelet receptors. In particular, Glanzmann thrombasthenia was defined as a defect in either αIIb or β3 [217,218], Bernard–Soulier syndrome was defined as due to an abnormality in GPIbα, GPIbβ, or GPIX [219], platelet-type von Willebrand disease was defined as a defect in GPIb [220], and other defects were identified in P2Y12, GPVI, and many other receptors [221]. Monoclonal antibodies were rapidly applied to the diagnosis of the disorders and in select cases, carrier detection; they also made possible prenatal diagnosis based on fetal blood sampling at approximately 18–20 weeks of gestation [222,223]. Since megakaryocytes also synthesise VWF, platelet mRNA-based PCR was also used to define the molecular biologic defects in VWF and correlate them with the current subtyping of the disorder [224,225]. Practical benefits to patients accrued rapidly from the advances in molecular biology, including the ability to perform unequivocal carrier detection and prenatal diagnosis using chorionic villus sampling at just approximately 11 weeks of gestation [226].

The molecular biologic tools also revolutionised our understanding of the alloimmune thrombocytopenias, including neonatal alloimmune thrombocytopenia and post-transfusion purpura, which had been characterised serologically in the 1960s [227–229]. Thus, the amino acid substitutions in the glycoproteins responsible for antibody production were defined, tools were developed to test for potential incompatibilities, and effective therapies introduced [230–235].

von Willebrand disease

Building on the observation that the clinical platelet function abnormality in von Willebrand disease could be dramatically improved by a plasma factor [32,33,236], Ted Zimmerman in Oscar Ratnoff’s [237] laboratory established that most patients with von Willebrand disease have reduced levels of a protein present in normal plasma and the plasma of patients with haemophilia A. A series of biochemical studies ultimately showed that VWF and factor VIII are separate molecules, but as was suspected from the transfusion studies, they circulate as a complex in plasma [22,238]. The unfortunate choice of the term ‘factor VIII-related antigen’ for VWF created considerable confusion, some of which remains for those new to the field to this day. Studies of VWF immunology, biochemistry, and molecular biology defined its subunit structure, its remarkable multimeric structure, its association with factor VIII, its ability to bind to collagen, GPIbα, and αIIbβ3, and its cleavage by ADAMTS13 [139,239–242]. Studies of VWF carbohydrate defined functional variants [243] and the role of blood group carbohydrates in its in vivo survival, leading to close correlations between blood type and VWF plasma levels that also translate into haemorrhagic and thrombotic risk [244–247]. The important roles of endothelial cells and megakaryocytes in VWF synthesis were also defined, and the importance of platelet vs. plasma VWF debated [248,249]. The remarkable discovery in 1971 by Howard and Firkin, who systematically studied drugs that produced thrombocytopenia in humans, that the antibiotic ristocetin could agglutinate/aggregate platelets only in the presence of VWF provided more robust functional assays than the platelet retention test for diagnosing von Willebrand disease, purifying VWF, and demonstrating that the higher molecular weight multimers are functionally more effective in agglutinating/aggregating platelets [22,250–252]. Subsequent studies showed that the snake venom protein botrocetin could also agglutinate platelets in the presence of VWF, providing another tool for assaying VWF [253]. The important role of ADAMTS13 in controlling the size of VWF multimers through proteolysis was later defined, spurred by research on thrombotic thrombocytopenic purpura [19]. Collectively, these advances allowed for the classification of von Willebrand disease into a large number of different subtypes, including the rare platelet-type associated with abnormalities in GPIbα, with both diagnostic and therapeutic importance [240].

Studies of fibrinogen defined the importance of the γ chain C-terminal peptides and other regions in interacting with αIIbβ3 and the role of other regions in binding to αVβ3 and other receptors such as αMβ2 and αXβ2 [254–259]. The differences between platelet interactions with fibrinogen vs. fibrin were also characterised [260–265].

Thrombotic thrombocytopenic purpura (TTP)

For more than a half-century after Moschcowitz’s description of TTP, haematologists were powerless to prevent the usually rapid progression to death of the uncontrolled thrombotic microangiopathic process manifested by haemolytic anaemia, thrombocytopenia, and ischaemic organ damage, especially to the brain and kidney [19]. Thus, the 1976–1977 reports by several groups of striking benefit from exchange transfusion, plasma or cryoprecipitate-poor plasma infusion, and/or plasmapheresis were met with enormous interest [19]. Plasma exchange rapidly became the treatment of choice and dramatically improved the prognosis [19]. Despite employing sophisticated machinery, however, plasma exchange is intellectually very unsophisticated since it is based on the premise of removing whole plasma to presumably remove a single toxic substance and replace whole plasma to presumably replace another single substance. Moake and colleagues provided a vital clue in 1982 when they observed unusually large VWF multimers in the plasma of patients with TTP and postulated that these contributed to the development of platelet thrombi and resulted from a defect in multimer processing [19,266]. They were prescient on both accounts as subsequent groups in 1987–1988 identified the VWF processing activity as a metalloproteinase, later identified as ADAMTS13, and confirmed a defect in VWF multimer cleaving activity in patients with TTP, identifying the cause as autoantibody formation [267–269]. This led to the introduction of rituximab treatment to diminish autoantibody production, another therapeutic advance [270]. Shortly thereafter, investigators identified long strings of VWF extending out from the surface of endothelial cells to which platelets could attach in the absence of ADAMTS13, providing an explanation for the source of the unusually large VWF multimers [19,133]. Cytokines or hormonal changes presumably trigger TTP in the absence of ADAMTS13 activity by enhancing endothelial cell production of VWF. Subsequently, patients with inherited forms of the disease (Upshaw–Schulman syndrome) were shown to have mutations in the ADAMTS13 gene [271–275]. The success of plasma exchange could then be explained by its ability to both remove the autoantibodies to ADAMTS13 and replace the missing ADAMTS13. Most recently, preliminary data with an oligonucleotide aptamer that inhibits the binding of VWF to GPIb (ARC1779) appear promising in treating the acute thrombotic phase of the disorder [276]. Looking to the future it is possible that recombinant ADAMTS13 therapy could reverse the acute thrombotic process in TTP and perhaps serve as an antiplatelet therapy more broadly. Since complement activation has also been implicated in the pathophysiology of the disorder in some patients, it may provide an additional target for intervention [277].

Platelet transfusion therapy

Major advances in platelet transfusion therapy since the 1960s included improved anticoagulants; development of the differential centrifugation technique to produce platelet concentrates; recognition of the benefits of room temperature preparation and storage; improved plastics and conditions of bag storage to facilitate gas exchange and maintenance of pH; cryopreservation; human leukocyte (HLA) matching or purposeful partial mismatching to improve responses in patients refractory to random donor platelets as well as to reduce the risk of alloimmunisation in patients needing life-long platelet transfusions; platelet ‘cross-matching;’ single donor platelet collection via continuous-flow centrifugation; blood screening assays to prevent transmission of infectious agents; hepatitis B vaccination; prestorage leukoreduction to decrease febrile transfusion reactions; ultraviolet irradiation and leukoreduction to decrease platelet immunogenicity; development of synthetic storage solutions; new methods to eliminate viable pathogens by damaging their DNA; sensitive techniques to detect the growth of pathogens in stored platelets; and controlled clinical trials to define the most appropriate platelet count at which to prophylactically transfuse platelets [278–289]. Ironically, one of the most important advances in platelet transfusion was not based on improving the platelet product, but rather recognising that aspirin, which was commonly prescribed to patients for fever or pain in the Descriptive Period, inhibited platelet function and thus should be avoided in thrombocytopenic patients [290]. Multiple attempts have been made to develop artificial or semi-artificial platelet substitutes over more than 50 years, but this goal still remains elusive [10,291,292].

Drug-induced thrombocytopenia

Drug-induced thrombocytopenia was recognised to be associated with a broad array of agents, some of which produced direct or indirect effects on megakaryocytes, others of which operated through immune clearance, and others, such as quinine and quinidine, that could actually cause platelet lysis [293]. Heparin-induced thrombocytopenia (HIT), and its association with the thrombotic ‘white clot’ syndrome, was identified as being of major clinical importance, with a broad spectrum of manifestations including both arterial and venous thrombosis [294]. The important role of PF4 in HIT was elucidated and a variety of diagnostic assays were developed, but none of these are ideal for real-time clinical decision making [295].

Thrombopoietin and related drugs

Soon after Tpo was cloned, two companies developed recombinant forms of Tpo for clinical use and demonstrated their ability to increase platelet counts in healthy humans. Platelet increments were also induced in patients receiving some forms of chemotherapy, but not the most myelosuppressive forms [296–299]. Clinical development of these agents was stopped, however, when healthy individuals who received one of the preparations developed thrombocytopenia in association with developing antibodies to Tpo [300]. After a multiyear lag, two agents that activate the thrombopoietin receptor demonstrated safety and efficacy in treating patients with immune thrombocytopenia. One agent (romiplostim), a success of phage library screening and ‘peptibody’ engineering, consists of a human immunoglobulin IgG1 Fc fragment framework onto which was grafted two dimeric copies of a Tpo receptor stimulating peptide distinct from the Tpo amino acid sequence [301–303]. The other (eltrombopag), a success of organic molecule library screening, is an orally active small molecule that binds to the receptor at a site near the transmembrane region [302,304]. Both drugs have proved efficacious in treating refractory immune thrombocytopenia, albeit perhaps with a minor risk of thrombosis in those at high risk [301,305]. Benefit has also been reported in treating patients with hepatitis C and thrombocytopenia [306], but thrombotic complications of the therapy have led to its reappraisal for this indication [307,308]. Future uses of these agents may include some of the inherited platelet abnormalities associated with abnormalities of nonmuscle myosin heavy chain IIA (MYH9; May–Hegglin anomaly, Epstein syndrome, Fechtner syndrome, and Sebastian platelet syndrome) and neonatal thrombocytopenia [309,310].

Antiplatelet therapy

Platelets in arterial thrombosis  The role of platelets in arterial thrombosis was the subject of considerable speculation for many years, but direct evidence to confirm their importance did not appear until the pioneering 1967 studies from Mustard’s group that showed that infusing ADP into the coronary arteries (or left ventricle) of pigs could initiate cardiac ischaemia and arrhythmias [311,312]. Subsequent flow chamber studies lent further support [313], as did Folt’s development of a dog model of unstable angina [314]. The antithrombotic effects of aspirin in many of these models [312,313] set the stage for systematically assessing aspirin’s antithrombotic effects in humans (Fig. 2).

Aspirin  The history of aspirin extends back to the use of the willow for joint pain and inflamed wounds in ancient Egypt and Greece, and goes through 18th century reports of willow extract being an effective therapy for arthritis and fever to the synthesis of salicylic acid in the 19th century [315,316]. In 1897 Felix Hoffmann of Bayer developed an industrial synthesis for acetylsalicylic acid and the compound gained rapid and broad acceptance as an antipyretic and anti-inflammatory drug under the name aspirin (‘a’ from acetyl and ‘spir’ from the plant Spriea ulmania, a source of salicylic acid). Aspirin was noted by astute clinicians to impair haemostasis as early as 1938 when gastrointestinal bleeding was linked to aspirin ingestion [317], and it was his observation of prolonged bleeding after tonsillectomy in patients given aspirin that led Craven [318] in the 1940s and 1950s to prescribe aspirin prophylaxis to thousands of men at high risk of cardiovascular disease, with remarkable results. Subsequently, in the 1950s and 1960s, aspirin was found to prolong the bleeding time, especially in patients with von Willebrand disease or telangiectasias [319]. In fact, Quick [319] proposed to use the excessive prolongation of the bleeding time after aspirin ingestion as a method to enhance the sensitivity of diagnosing von Willebrand disease (‘aspirin to tolerance test’).

Although doses of aspirin above 6 g were demonstrated in the 1940s to alter coagulation by effects on multiple clotting factors [320], the inhibitory effect of relatively low doses of aspirin on platelet function was first reported in 1967 by Weiss’s laboratory, building on his personal observation that aspirin increased his bleeding from razor nicks [313,321]. Others working at the very same time in parallel confirmed and extended these studies, demonstrating the inhibitory effects of aspirin on the second wave of platelet aggregation induced by ADP [322–326]. Subsequent studies in many related fields led the groups of Vane and Bergström, Samuelsson, and Smith and Willis to the discovery of aspirin’s mechanism of action via its effects on the cyclooxygenase enzymes required for the synthesis of prostaglandins and thromboxanes from arachidonic acid [327–333]. The crystal structure of the aspirin-cyclooxygenase complex provided the structural basis of the inhibitor [334].

After a number of painful false starts [335], in the 1980s aspirin became the first clinical antiplatelet therapy to achieve U.S. Food and Drug Administration (FDA) approval based on evidence of its beneficial effects in patients with previous arterial thrombotic events [336,337]. Its efficacy in treating myocardial infarctions was unequivocally established in 1988 in the large ISIS-2 trial [338] and in the previous year it was reported to be of benefit in patients undergoing what was then a new procedure, percutaneous transluminal coronary angioplasty [339]. Despite promising results in the primary prevention of myocardial infarction in the U.S. Physicians Study, and its common use for this indication, aspirin has never received FDA approval for primary prevention and its use remains controversial except in those at greatest risk [340,341]. Currently, there is considerable focus on, and controversy about, the issue of aspirin ‘resistance,’ a term that has been variably defined [342–345]. Despite intensive investigation over many decades, doubts about the optimal dose of aspirin, and whether there is any benefit in personalising the dose (or adding, or switching to another antiplatelet agent) based on monitoring one or more of its effects remain important and unresolved issues [346].

P2Y12 antagonists  In 1974 two groups reported on a series of thienopyridine and furopyridine derivatives that had anti-inflammatory effects and variably inhibited ADP-induced platelet aggregation when administered to rats [347]. The 2-chloro thienopyridine derivative, later named ticlopidine, was found to be a potent prodrug inhibitor of the initial wave of platelet aggregation. It subsequently was shown to selectively inhibit ADP-induced platelet aggregation and prevent fibrinogen binding to αIIbβ3. In human studies it was found to have greater antithrombotic efficacy than aspirin in a wide variety of indications, including secondary prevention of vascular events after stroke, transient ischaemic attacks, and unstable angina, leading to initial U.S. FDA approval in 1991. Most importantly, in 1996 the combination of aspirin and ticlopidine was shown to protect against thrombotic complications of coronary artery stenting [348]. Ticlopidine, however, had serious albeit uncommon complications, including bone marrow toxicity leading to clinically significant neutropenia in just under 1% of patients and the induction of TTP in an even smaller percentage of patients [349].

Clopidogrel, another thienopyridine, was approved for clinical use in 1998 based on its superiority to aspirin in the secondary prevention of vascular events [350]. It subsequently showed efficacy in acute coronary syndromes and, in particular, in patients undergo percutaneous coronary interventions with stents [351]. In 2001, Hollopeter et al., building on studies by other groups [352,353], reported both the cloning of the elusive P2Y12 ADP receptor, the target of ticlopidine and clopidogrel, and a mutation in the P2Y12 gene in a patient with a mild bleeding disorder associated with a lack of platelet response to ADP [354]. The extracellular Cys groups identified in P2Y12 provided a logical target for the thiol-containing active metabolite of clopidogrel, as well as an explanation for the recognised prolonged effects of the drug being due to irreversible inactivation of P2Y12. Clopidogrel had a more favorable toxicity profile than ticlopidine, which led to its rapid clinical adoption [355].

In 2003 Gurbel et al. [356] reported that standard doses of clopidogrel produced very variable antiplatelet effects when administered to different patients and in 2004 Matetzky et al. [357] reported that the variability in response to clopidogrel correlated with clinical outcomes in patients undergoing coronary artery stenting. Subsequent studies by many groups confirmed these observations and identified interindividual variations in the clopidogrel cytochrome P450 activation process as the major source of variability. A genome-wide association study identified CYP2C19 variants as the major contributor to variable response, accounting for approximately 12% of the variability [358]. Clinical studies also identified CYP2C19 variants as correlates of clinical outcomes [359,360]. Collectively, these data raised the possibility of improving antiplatelet therapy using functional and/or genetic assays, and several small randomised studies have demonstrated that function test-guided therapy can improve outcomes in patients with poor antiplatelet responses to clopidogrel by either increasing the dose of clopidogrel or by adding an αIIbβ3 antagonist [361–363]. This approach, however, remains controversial [364]. The previously accepted clopidogrel activation scheme and the role of CYP2C19 was recently challenged, however, by a study identifying the importance of paraoxanase 1 and its variants in the antiplatelet and clinical responses to clopidogrel [365].

Prasugrel was the third thienopyridine approved by the FDA as an antiplatelet agent. It was cleverly designed so that the gastrointestinal esterases that ordinarily inactivate approximately 85% of the clopidogrel that is ingested actually catalyse the first step in prasugrel’s activation [366,367]. It consistently achieves greater platelet inhibition than clopidogrel and it is essentially unaffected by the CYP2C19 variants that seriously impair clopidogrel’s activation. In clinical studies it demonstrated both increased antithrombotic efficacy and increased risk of bleeding relative to clopidogrel, with the elderly and those with low body weight or a history of previous stroke or transient ischaemic attack at greatest risk of bleeding [366]. As a result, it is currently reserved for patients at high risk of thrombosis and/or who do not have an acceptable antiplatelet response to clopidogrel. Whether monitoring its antiplatelet effects would allow for selecting a dose that retains its greater efficacy while reducing its bleeding risk remains to be tested.

Several non-thienopyrdine P2Y12 inhibitors are in clinical development, including ticagrelor (formerly AZD6140), an oral direct acting inhibitor that has rapid onset and offset of action. It demonstrated antiplatelet effects in patients who did not respond to clopidogrel and greater overall antithrombotic efficacy than clopidogrel in a pivotal study [368,369]. There were, however, unexplained major regional differences in the efficacy endpoint, with North American patients receiving ticagrelor having a higher rate of thrombotic complications. Ticagrelor was also associated with an increase in bleeding events, cardiac ventricular pauses, and dyspnea. It remains under review by the U.S. FDA at the time of writing [370,371]. Cangrelor, an intravenous competitive inhibitor of the P2Y12 receptor did not achieve its prespecified efficacy endpoint in a pivotal study and so its future is uncertain [367,372]. Ellinogrel is an intravenously and orally active direct acting P2Y12 receptor antagonist with rapid onset and offset that is able to inhibit the platelets of patients who do not respond to clopidogrel [373,374]. Early phase studies appear promising, but no pivotal trials have yet been reported.

αIIbβ3 (GPIIb/IIIa) antagonists  Identification of the central role of αIIbβ3 (initially termed GPIIb/IIIa) in mediating platelet aggregation through studies of patients with Glanzmann thrombasthenia and studies of fibrinogen binding logically led to its candidacy as a target for antiplatelet therapy [375]. Two separate approaches were taken to developing a therapeutic agent that could block ligand binding to the receptor: (i) Modifying a murine monoclonal antibody that blocked ligand binding to αIIbβ3 (7E3) into a murine/human chimeric Fab fragment (abciximab) [376,377]; and (ii) Building on the observation that small peptides and snake venoms containing the Arg-Gly-Asp (RGD) or Lys-Gly-Asp (KGD) sequences could inhibit ligand binding to αIIbβ3 to produce a cyclic peptide inhibitor (eptifibatide) [378,379] and a nonpeptide RGD mimic inhibitor (tirofiban) [380,381]. All of these agents were able to inhibit platelet aggregation to a greater extent than aspirin, ticlopidine, or clopidogrel, virtually eliminating aggregation when more than 80% of the receptors were blocked. Their U.S. FDA approvals in 1994 (abciximab) and 1998 (eptifibatide, tirofiban) marked the first example of selecting an antiplatelet target based on knowledge of platelet physiology and creating an antagonist based on rational design. They demonstrated efficacy in reducing ischaemic complications of percutaneous coronary interventions (with or without stents) and the treatment of acute coronary syndromes [382–384]. They did, however, increase the risk of haemorrhage. As a result, with the introduction of bivalirudin and loading dose treatment with clopidogrel to speed its onset of antiplatelet effects, αIIbβ3 antagonist therapy has increasingly been limited to patients at the highest risk of thrombosis. Since most of the haemorrhage associated with these agents occurs at the site of instrumentation, the risk is much lower when procedures are performed transradially rather than through the femoral artery [385]. All three agents must be administered intravenously and each has been associated to variable degrees with the development of thrombocytopenia [386]. Current experimental uses of these agents include intracoronary administration [387], use in conjunction with thrombus extraction devices [388], and very early administration to abort the development of myocardial damage [389–391]. A number of oral αIIbβ3 antagonists were developed and tested in large scale clinical trials for secondary prophylaxis, but none proved efficacious and they increased the risk of bleeding and thrombocytopenia [392]. Several of the clinical studies found that they produced an increase in thrombotic events, perhaps due to their inducing the active conformation of αIIbβ3 [393]. New agents that block αIIbβ3 while having a reduced ability to induce conformational changes in the receptor are currently in preclinical development [394].

PAR-1 antagonists  The landmark discovery by Coughlin and colleagues in 1991 of the thrombin PAR-1 receptor and its novel mechanism of activation via a newly created ‘tethered ligand’ after thrombin cleavage not only provided an explanation for the complex data on thrombin as both ligand and enzyme, but also provided an exciting new rational target for antiplatelet therapy [395]. Two different agents are currently in late phase clinical testing, vorapaxar (formerly SCH 530348) [396,397] and atopaxar (formerly E5555) [398]. An unexpectedly high rate of cerebral haemorrhage in patients treated with vorapaxar led to its discontinuation in one study but a study of patients undergoing percutaneous coronary interventions remains ongoing at the time of writing. Atopaxar has been well tolerated in dose ranging studies in the Japanese population [398].

The future

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Descriptive Period
  5. The Mechanistic Period
  6. The future
  7. Conclusion
  8. Acknowledgement
  9. Disclosure of Conflict of Interest
  10. References

The role of platelets beyond haemostasis and thrombosis

Inflammation, the immune response, wound healing, angiogenesis, and antibacterial activity  Since haemostasis is the necessary first step in the response of tissue to injury, it would be beneficial if it also facilitated the transition to the next steps in the process, namely inflammation [136], the immune response [399], wound healing [136], angiogenesis [400,401], and the control of infectious agents [402,403]. In fact, there are abundant data supporting potentially important roles for platelets in each of these processes. As additional molecular and genetic details become available about the specific mechanisms, new opportunities are likely to emerge to intervene in these processes through modifying platelet function. Platelets have also been implicated in some other interesting processes of medical significance, in particular, closure of the ductus arteriosus [404] and liver regeneration [405], the latter through an effect of serotonin.

Platelets and malignancy  Studies by Gasic et al. [406] more than 50 years ago demonstrated that platelets played at least a permissive role in metastasis formation. Subsequent studies documented the complex interrelationships that exist between platelets and tumour cells and between platelets and tumour angiogenesis [407,408]. More recent studies are focusing on the ability of tumours to alter platelets such that they transmit information to both bone and bone marrow that may facilitate tumor growth and metastasis [409]. The future challenge is to develop interventions that build on our increasingly sophisticated knowledge of the molecular interactions and arrest or reverse both the primary malignancies and the metastases.

Platelet production, stem cell replacement therapy, megakaryopoiesis, and platelet transfusion

The advances in understanding stem cell biology, the basic mechanisms of megakaryocyte differentiation, and platelet production offer the potential to improve stem cell replacement therapy and platelet transfusion therapy. One of the limitations of cord blood bone marrow reconstitution is the delay in megakaryocyte engraftment and achieving haemostatic levels of circulating platelets. Application of ex vivo expansion of CD34+ precursors through Notch signalling in cord blood cells is showing promise in achieving more rapid increases in peripheral blood cell counts [410,411].

Megakaryocytes have been generated from both mouse and human embryonic stem cells when cultured in vitro under various conditions, but the final step to platelet production has been difficult to achieve with high efficiency or yield [412–417]. Most recently, the technology of induced pluripotent stem cell (iPS) has been applied to human dermal fibroblasts. Using a feeder layer of cells, and a combination of Tpo, cytokines, and growth factors under precise conditions, Takayama’s group was successful in obtaining platelets that both circulated in the blood of immunodeficient mice for more than 24 h and participated in thrombus formation [418]. Additional insights into the complex and variable roles of c-MYC during megakaryopoiesis and platelet production may offer additional opportunities to achieve patient-specific platelets produced in vitro for transfusion, thus eliminating the immunologic responses that make some patients refractory to platelet transfusions [416,418]. There is good reason for platelets to lead the way in the use of iPS-derived cells since the concerns about the teratogenicity of iPS cells can be eliminated by transfusing only the anucleate platelets and irradiating them. The search for an artificial platelet substitute will certainly continue and this quest may be significantly advanced if nanotechnology is able to develop biocompatible matrices since the platelet’s small size is an important feature of its biology, reducing the shear force it experiences relative to large cells at comparable shear rates.


  1. Top of page
  2. Abstract
  3. Introduction
  4. The Descriptive Period
  5. The Mechanistic Period
  6. The future
  7. Conclusion
  8. Acknowledgement
  9. Disclosure of Conflict of Interest
  10. References

In reflecting on the current state of platelet research, I have the impression that we are reaching yet another inflection point, as there is a major shift from a focus on traditional biochemistry and cell and molecular biology to an era of single molecule biophysics, single cell biology, single cell molecular biology, structural biology, computational simulations, and the high-throughput, data-dense techniques collectively named with the ‘omics’ postfix. Given the progress made in understanding, diagnosing, and treating many rare and common platelet disorders during the past 50 years, I think it appropriate to consider it a Golden Age of Platelet Research and to recognise all of the investigators who not only made important contributions to this remarkable achievement, but also created a mutually supportive community of colleagues dedicated to the common goal of understanding platelet biology so as to improve human health.


  1. Top of page
  2. Abstract
  3. Introduction
  4. The Descriptive Period
  5. The Mechanistic Period
  6. The future
  7. Conclusion
  8. Acknowledgement
  9. Disclosure of Conflict of Interest
  10. References

Supported, in part, by grant HL19278 from the National Heart, Lung, and Blood Institute, CTSA grant ULRR024143 from the National Center for Research Resources, NIH, and funds from Stony Brook University.

Disclosure of Conflict of Interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Descriptive Period
  5. The Mechanistic Period
  6. The future
  7. Conclusion
  8. Acknowledgement
  9. Disclosure of Conflict of Interest
  10. References

Dr Coller is an inventor of abciximab (Centocor) and in accord with Federal law and the policies of the Research Foundation of the State University of New York, receives royalties based on the sales of abciximab. Dr Coller is an inventor of the VerifyNow assays (Accumetrics), and in accord with Federal law and the policies of the Mount Sinai School of Medicine, receives royalties based on the sales of the VerifyNow assays. Dr Coller is an inventor of small molecule αIIbβ3 antagonists (RUC-1 and RUC-2) and Rockefeller University has applied for patents on these molecules.


  1. Top of page
  2. Abstract
  3. Introduction
  4. The Descriptive Period
  5. The Mechanistic Period
  6. The future
  7. Conclusion
  8. Acknowledgement
  9. Disclosure of Conflict of Interest
  10. References
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