Platelet Physiology and Biochemistry: A Topic as Relevant as Ever

As a part of the 50th anniversary celebrations of Seminars in Thrombosis and Hemostasis, each 2024 issue includes one “historical” paper that somehow stands out among the many excellent contributions to Seminars in Thrombosis and Hemostasis through the years. This issue's historical paper by Jurk and Kehrel, “Platelets: Physiology and Biochemistry” from 2005[1] [2] turns the spotlight on platelets. These small cells continue to fascinate us with their intricate pathways of function and their multiple interactions with other cells and physiological systems—and sometimes also to frustrate us when we try to measure different aspects of platelet function and translate these measurements into clinically useful biomarkers.

Platelets were described in the 19th century by several scientists as small, colorless particles in blood, often clumping together when studied under the light microscope; but for decades, the “small globules” or “corpuscles” were thought to be leukocyte fragments or erythrocyte precursors and were not considered as contributors to blood clotting.[3] Giulio Bizzozero was the first to postulate that platelets were a distinct type of blood cell, separate from erythrocytes and leukocytes; and in his seminal work published in 1882, he described platelet adhesion, aggregation, and thrombus formation in vivo upon experimental endothelial damage, establishing platelets as key components in hemostasis and thrombosis.[4] [5] The logical next step was the development of new methods to further investigate the mechanisms behind the observed platelet activation. The Duke bleeding time (although not specific for platelet function) was published in 1910,[6] whereas the first platelet adhesion tests measuring retention on glass surfaces were developed in the 1930s to 1940s.[7] A few years later, the first electron microscopy studies of platelets were published,[8] laying the foundation for our understanding of platelet physiology and biochemistry at the subcellular level. A major breakthrough for functional platelet analysis was development of light transmission aggregometry by Born in 1962 to 1963,[9] which enabled measurement of platelet responsiveness to distinct stimuli or “agonists.” Since then, new or refined techniques for assessing dynamic platelet function have been introduced; e.g., the Platelet Function Analyzer-100 and -200,[10] whole-blood impedance aggregometry available on semiautomated platforms with short turnaround times,[11] the serotonin release test,[12] and platelet flow cytometry, which allows for detailed assessment of platelet surface marker expression in both quiescent and stimulated platelets.[13] However, Born's method, with few modifications, continues to be the gold standard of platelet function testing.

The historical paper by Jurk and Kehrel, published 125 years after Bizzozero's observations, summarized state-of-the-art knowledge at the time on the different steps of platelet function: adhesion to damaged vessel wall through von Willebrand factor (VWF) and collagen binding; secretion of granule content with resulting autocrine activation and shape change; platelet aggregation through α_IIbβ₃ integrin-VWF/fibrinogen interactions; release of procoagulant microvesicles; and clot retraction. An important focus of the paper was the “new view” that activated platelets not only form the primary thrombus but also support thrombin generation through anionic phospholipid exposure on the outer cell membrane, with this facilitating stable fibrin clot formation—in other words, the coupling between primary and secondary hemostasis or the “cell-based model” of hemostasis, which emerged during these informative years.[14] Now, nearly 20 years later, this concept is widely integrated into our understanding of hemostasis and thrombosis. The paper by Jurk and Kehrel has become the second-most downloaded Seminars in Thrombosis and Hemostasis paper of all time (i.e., since the journal began in 1974) and continues to be placed high on the list of the journal's recent “Most read” papers. This is no doubt due to its clear and comprehensive overview of the topic, and no doubt also because the paper's description of the discrete processes of platelet activation: adhesion, secretion, aggregation, phospholipid flip-flopping, and clot retraction still fundamentally reflects how we understand and assess platelet function in the context of thrombosis and hemostasis.

What's new since 2005, then? An important development is that during the past 20 years, the relevance of platelets beyond thrombosis and hemostasis has really become evident. The role of platelets as immune effectors, both in the physiological inflammatory response and in pathological immune-mediated conditions is now widely accepted. Platelets interact with and activate leukocytes through direct cell–cell interactions and through release of cytokines, serotonin, and damage-associated pattern molecules[15]; they bind immune complexes through their Fcγ receptor[16]; and they activate the complement system.[17] We have also realized that platelets are intricately involved in tumor promotion and metastasis through interactions with the tumor microenvironment and priming of the “premetastatic niche.”[18] It is still an unresolved question for future research, how we can translate this knowledge into prevention of harmful inflammation or tumor progression for our patients by targeting platelets. Furthermore, the evolving “-omics” technologies have opened new ways for investigating platelet physiology. These technologies introduce not only new “wet laboratory” methods but also—and more importantly—a new approach to data analysis and information integration as compared with traditional single- (or few-) biomarker approaches for platelet function investigation. Platelet transcriptomics,[19] proteomics,[20] and lipidomics[21] are novel research fields, which have the potential to provide us with a new level of detailed knowledge of platelet biology—if we take care to interpret the data correctly.

Thus, platelet physiology continues to be a hot topic. Since 2005, Seminars in Thrombosis and Hemostasis has published innumerable papers and more than 10 special issues with platelets as the main topic, with issue titles ranging from inherited platelet disorders, over essential thrombocytosis and platelets in inflammation, to diagnostic evaluation of platelet function. Due to the continued popularity of the 2005 paper by Jurk and Kehrel, an “update paper” on platelet physiology was commissioned in 2016. This paper, written by Gremmel, Frelinger, and Michelson and simply titled “Platelet Physiology,”[22] went on to become the third most downloaded paper from Seminars in Thrombosis and Hemostasis, underscoring the continuous relevance of the subject. Perhaps a 2025 update is now warranted?

Publication History

Article published online:
08 April 2024

• References

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