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Semin Thromb Hemost 2025; 51(08): 841-843
DOI: 10.1055/s-0045-1811582
Preface

Platelets in Personalized Medicine

Authors

  • Julie Brogaard Larsen

    1   Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
    2   Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

  • Joseph E. Aslan

    3   Division of Cardiovascular Medicine, School of Medicine, Oregon Health and Science University, Portland, Oregon
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Welcome to the last issue of Seminars in Thrombosis and Hemostasis for 2025, where we close the year around the theme of “Platelets in Personalized Medicine.” This issue centers on the continually emerging roles for platelets as executives of hemostasis, thrombosis, and inflammation, and how details on platelet mechanisms might inform therapeutic and diagnostic efforts in cardiovascular, inflammatory, autoimmune, and other conditions. We also build new platelet function tests as biomarkers in disseminated intravascular coagulation (DIC) and cardiovascular disease—and get a closer look into more recent additions to the platelet biomarker panel, platelet microRNAs.

In the first article of the issue, Bendas et al. thoroughly review roles of the platelet-derived CD40 ligand (CD40L) in immunity and hemostasis.[1] Originally discovered as an effector molecule in the adaptive immune system, CD40L is also expressed on platelets and is shed from platelets upon activation to circulate as soluble (s)CD40L. As reviewed by Bendas et al., both membrane-bound and sCD40L bridge immunity and hemostasis, as sCD40L enhances platelet activation and endothelial procoagulant properties, while platelet–CD40L induces immune cell maturation, cytokine production, and antibody secretion. However—like many components of the immune and hemostatic systems—the prohemostatic and proinflammatory effects of CD40L likely have multiple roles in physiology and disease. Here, the authors discuss the developing roles of CD40L in HIV-associated cognitive impairment and tumor progression, and roles for both CD40L activators and blockers as therapies in clinical trials for different conditions.

Continuing on this path, Zhang et al. review platelet activation and platelet–immune interactions in venous thromboembolism (VTE).[2] While classification of “white thrombi” and “red thrombi” remains anatomically accurate, it is now widely accepted that platelets contribute to thrombus formation both in the arterial and the venous vasculature. As reviewed by Zhang et al., multiple preclinical thrombosis models show that platelet activation contributes to venous thrombus formation, highlighting roles for protease-activated receptors (e.g., PAR4), Toll-like receptors, platelet-derived extracellular vesicles (EVs), and platelet-induced neutrophil extracellular trap formation in VTE and as potential therapeutic targets. A challenge remains in how to translate knowledge of platelet mechanisms into strategies for VTE prevention and treatment. Acetylsalicylic acid (ASA) has been investigated extensively as VTE prophylaxis since it is low-cost, widely available, and can be taken orally. It has been shown to be non-inferior to traditional (anticoagulant) VTE prophylaxis in selected populations, most notably after fractures[3]; however, high-risk patients have not been consistently included in these studies, and the efficacy of ASA as thromboprophylaxis in general is still disputed, while it is not considered for VTE treatment. More potent antiplatelet agents could have higher efficacy, but probably at the cost of a higher bleeding risk. For instance, the recent discovery of platelet heat shock protein 47 (HSP47) regulation during hibernation in brown bears and immobilization in humans may have relevance here.[4] Though clinical studies are still underway, targets such as HSP47 may offer new targets for modulating platelet function in the context of VTE, seemingly without increased bleeding risk.

Platelets not only contribute to venous thrombosis, but also to DIC. Platelet consumption is a hallmark of DIC, and low platelet count is included in all currently used DIC scoring systems. However, thrombocytopenia is present in a multitude of conditions, including bleeding and hematological disorders, as well as viral infection, autoimmunity, and liver cirrhosis and as medication side effects. These are all common in critically ill patients and may confound the biochemical diagnosis of DIC. Accordingly, additional diagnostic biomarkers for DIC have been much sought after. Here, Petersen et al. review the potential of platelet function parameters to improve DIC diagnosis.[5] Platelet aggregation and sP-selectin are promising markers, especially when adjusting for platelet count. However, platelet aggregation assays are labor-heavy and prone to preanalytical issues; sP-selectin would be easier to implement in the routine laboratory.

Next, we move on to the roles of platelets in cardiovascular disease, with two reviews by Momi and Gresele[6] and by He et al.[7] Momi and Gresele give a historic overview of how our understanding of platelets in atherosclerosis has developed over the past several decades and in more recent years.[6] As the authors note, inflammation was proposed as a crucial part of atherogenesis already by Rudolf Virchow, and the concept of atherosclerosis as an inflammatory disorder is now well-established. Our understanding of platelets as both hemostatic and immune effector cells has developed in parallel, and platelets emerge as not only critical drivers of plaque thrombosis but also as active players in atherogenesis through interactions with the endothelium and immune cells. He et al. dive deeper into these mechanisms, highlighting that platelets induce intimal and medial vascular calcification, a process closely related to but not synonymous with atherosclerosis, and which is itself associated with increased cardiovascular morbidity and mortality.[7] These mechanisms include EV signaling; direct interactions with vascular smooth muscle cells; platelet secretion of platelet factor 4, platelet-derived growth factor and bone matrix-regulating proteins; and (again) CD40L signaling. Thus, these two reviews highlight the prophylactic potential of targeting platelets early in atherosclerotic disease. However, as reviewed by Momi and Gresele, traditional antiplatelet agents such as ASA and P2Y12 receptors have not been convincingly demonstrated to prevent atherosclerosis development.[6] Other agents, for example, vorapaxar, tirofiban, and newer NO-releasing COX inhibitors, show more promise. However, as Momi and Gresele point out,[6] “the observation that the drug combination producing the most striking inhibition of platelet aggregation gave the most effective inhibition of intimal proliferation, suggests that a very profound suppression of platelet activation may be required to prevent atherosclerosis.” Again, the risk of bleeding with potent antiplatelet agents should be in balance with the benefits of inhibiting atherosclerosis. Interestingly, platelet indices (mean platelet volume [MPV], platelet distribution width) have been independently associated with vascular calcification and major adverse cardiovascular events, as reviewed by He et al.; thus, these biomarkers could potentially have value in risk stratification.

Other emerging biomarkers for cardiovascular disease include platelet microRNAs, which are small, non-coding RNA molecules important for posttranscriptational gene regulation. A review by Nissen and Pedersen overviews four microRNAs which are expressed in platelets or megakaryocytes, including miR-223, miR-126, miR-21, and miR-150.[8] Expression of these microRNAs are associated with altered platelet maturation and enhanced platelet reactivity, where miR-223 has shown particular promise in improving prediction of major adverse cardiovascular events in comparison to traditional risk factors. Interestingly, platelet microRNA expression levels change in response to antiplatelet therapy. While the extent to which platelet microRNAs are directly involved in cardiovascular pathophysiology, they may add value as biomarkers for cardiovascular risk and treatment response. With this biomarker angle in mind, the authors advocate for standardization and enhancing consistency in microRNA research methods.

Shifting away from the prothrombotic roles of platelets, we next turn to Urbański et al., who provide insights on platelet dysfunction in one of the most common microdeletion syndromes worldwide, the 22q11.2 deletion syndrome.[9] Thrombocytopenia, increased MPV, and platelet dysfunction are common features in these patients. This may partly be explained by GP1BB hemizygosity, and thus reduced platelet GPIb-VI-IX expression, as the GP1BB gene is located in the 22q11.2 region. However, bleeding phenotypes vary widely in these patients and do not appear to be fully explained by GPIb-VI-IX expression. This has prompted research into other areas in the 22q11.2 region with a possible effect on megakaryopoiesis and platelet function, with the identification of, for example, copy number variants in the LCR22A-B area; the SEPTIN5 gene, which is involved in granula migration and secretion; and DGCR8 which is involved in microRNA formation. Other features of 22q11.2 deletion syndrome, including autoimmunity and reduced thyroid function, may also contribute to thrombocytopenia and bleeding. The paper by Urbański et al. gives a comprehensive overview of currently known mechanisms behind platelet dysfunction in a group of patients with a complex disorder who truly require a personalized and multidisciplinary approach; the paper also demonstrates that findings in patients with genetic disorders often provide valuable general pathophysiological knowledge and turn out to be of interest for many other patients.

In persons who already suffered a cardiovascular event, the risk of a recurrent major cardiovascular event is substantial, despite relevant antiplatelet therapy. A major goal of the our field remains to classify patients with aspirin or clopidogrel resistance, or “high on-treatment platelet reactivity,” with a view to individual risk assessment: Can we easily tell who will benefit from antiplatelet medicine and who will not? However, this has not proved to be a simple task. In an original paper, Zhou et al. investigate the ability of four different platelet function tests to detect high on-treatment platelet reactivity and to predict the recurrence of major cardiovascular events in ST-elevation myocardial infarction (STEMI) patients treated with clopidogrel and with a 7-year follow-up.[10] The tests include VerifyNow, thromboelastography (TEG) with platelet mapping, ADP-induced vasodilator-stimulated phosphorylation measured by flow cytometry, and the PL-11 platelet analyzer. The authors find significant discrepancies between these methods, with 13% of patients classified as having high on-treatment platelet reactivity with PL-11 and 58% with TEG. VerifyNow had the best predictive value for long-term major cardiovascular events, and, though the study included a relatively small number of patients (n = 98), VerifyNow significantly improved prediction when added to traditional cardiovascular risk factors. Similar results have been found by other authors. The study supports the use of testing for high on-treatment platelet reactivity in clopidogrel-treated patients, at least in select, high-risk patients where the absolute risk reduction may be most favorable—and, not least, it highlights the importance of selecting the proper platelet function tests for the purpose.

The last paper in the present issue, a case report by Wang et al., perfectly describes an example of personalized medicine, namely current uses (and limitations) of known biomarkers of platelet function to determine bleeding tendency in the individual patient.[11] In a young patient with epistaxis and a family history of bleeding tendency, a panel of platelet-related tests are applied, assessing various aspects of platelet physiology: Platelet count, platelet size and morphology, platelet aggregation after stimulation with various agonists, platelet genetics, and platelet surface marker expression using flow cytometry. Through this panel of methodologies, the authors identify the likely culprit, a pathogenic variant in the ITGA2B gene, only described once before, which is present in the proband and affected family members and associated with abnormal αIIbβ3 clustering on the platelet surface and reduced aggregation potential. Nonetheless, piecing the puzzle together in platelet dysfunction is not always easy, as this case illustrates. Furthermore, many state-of-the-art tests may not be available for all patients; while some are common (e.g., platelet count and indices), more dynamic platelet function and genetics tests demand technical and interpretational skill. Thus, there is still a need to identify new platelet biomarkers to improve diagnostic precision—and also for technologies and platelet diagnostics that can be made readily available to patients worldwide.

We hope that you enjoy this issue as we move toward 2026!



Publikationsverlauf

Artikel online veröffentlicht:
15. Oktober 2025

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