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!