Antiplatelet therapy in pulmonary embolism: Mechanisms and evidence

Abstract

Pulmonary embolism (PE) is a common and potentially fatal manifestation of venous thromboembolism, typically resulting from thrombus formation in the venous circulation and subsequent embolization to the pulmonary arterial tree. Its pathobiology reflects the convergence of venous stasis, hypercoagulability, and endothelial dysfunction, which together initiate a thrombo-inflammatory cascade involving coagulation factors, vascular cells, and innate immune pathways. Although PE thrombi have classically been characterized as fibrin- and erythrocyte-rich structures, accumulating evidence supports an active and regulatory role for platelets across key stages relevant to PE, including thrombus formation, embolization potential, clot stabilization, resolution, and recurrence. Anticoagulation remains the foundation of PE prevention and treatment, with low-molecular-weight heparins, vitamin K antagonists, and direct oral anticoagulants representing the main therapeutic options in contemporary practice. In contrast, the role of antiplatelet therapy in PE remains to be further investigated. While antiplatelet agents may provide modest benefit in selected clinical settings—such as specific prophylactic scenarios and secondary prevention after discontinuation of anticoagulation—their efficacy is generally inferior to anticoagulants, and they are not recommended as first-line therapy for acute PE management. Mechanistically, platelets can contribute to PE-related thrombogenesis by providing procoagulant surfaces, amplifying thrombin generation, and mediating crosstalk with endothelial and innate immune cells, particularly neutrophils and monocytes. These interactions promote immunothrombosis, neutrophil extracellular trap formation, and thrombus stabilization, reinforcing the link between inflammation and coagulation within the venous-to-pulmonary thromboembolic continuum. The primary objective of this review is to critically interpret the role of antiplatelet therapy specifically in PE by integrating recent preclinical insights with contemporary clinical evidence. By synthesizing advances in platelet biology, experimental models, and clinical studies, this article evaluates the therapeutic potential, limitations, and future directions of platelet-targeted strategies in PE. A deeper understanding of platelet-driven mechanisms may inform the development of safer, more precise antithrombotic approaches that complement established anticoagulant therapies and improve outcomes in patients with PE.

Key Words: Pulmonary embolism; Platelets; Platelet aggregation inhibitors; Anticoagulation; Endothelial dysfunction

Core Tip: Although pulmonary embolism (PE) is classically considered a fibrin-rich, anticoagulation-responsive disorder, platelets are increasingly recognized as active participants in venous thrombogenesis and thrombo-inflammatory signaling. This mini-review examines the mechanistic and clinical evidence linking platelets to PE and critically evaluates the current and potential role of antiplatelet therapy in its prevention and management.

INTRODUCTION

Pulmonary embolism (PE) is a major cardiovascular emergency and remains one of the leading causes of preventable in-hospital mortality worldwide. As the most clinically serious manifestation of venous thromboembolism (VTE), PE typically arises from thrombi formed in the deep venous circulation, most commonly in the lower extremities, which subsequently embolize to the pulmonary arterial bed. Despite substantial advances in diagnosis, risk stratification, and anticoagulant therapy, PE continues to impose a considerable burden through acute mortality, recurrent thromboembolic events, chronic thromboembolic complications, and long-term functional impairment. Its clinical significance is further amplified by the heterogeneous nature of its presentation and the complexity of the biological processes underlying venous thrombogenesis and embolic progression.

Traditionally, venous thrombi and PE-associated emboli have been viewed as “red thrombi”, characterized predominantly by fibrin and erythrocytes and formed under low-shear conditions, in contrast to the platelet-rich “white thrombi” typical of arterial thrombosis. This dichotomous framework has long shaped therapeutic thinking, reinforcing the concept that anticoagulants, rather than antiplatelet agents, represent the most rational and effective pharmacologic strategy for PE prevention and treatment. Indeed, anticoagulation remains the cornerstone of contemporary PE management, with low-molecular-weight heparins, vitamin K antagonists, and direct oral anticoagulants (DOACs) forming the basis of current therapeutic algorithms and guideline recommendations[1,2].

However, this classical separation between arterial platelet-driven thrombosis and venous coagulation-driven thrombosis has increasingly been challenged. Experimental, translational, and human pathological studies now support a more integrated model in which venous thrombus formation is not a passive coagulation event but rather a dynamic thrombo-inflammatory process involving close interplay among coagulation pathways, endothelial activation, leukocyte recruitment, and platelet signaling. Within this framework, platelets appear to exert functions extending well beyond simple hemostasis. They may participate in the initiation and propagation of venous thrombosis by providing procoagulant phospholipid surfaces, facilitating thrombin generation, promoting leukocyte adhesion, and amplifying inflammatory signaling within the venous microenvironment. These activities are particularly relevant in the context of immunothrombosis, where innate immune responses and coagulation are tightly interconnected[3,4].

One of the most important mechanistic developments in recent years has been the recognition of platelet-leukocyte crosstalk as a potentially important contributor to venous thromboembolism biology. Increasing evidence suggests that platelets participate in these thrombo-inflammatory processes through their interactions with leukocytes and endothelial cells, contributing to thrombus formation and stabilization. These observations have expanded current concepts of PE pathogenesis by linking venous thrombosis to broader inflammatory and innate immune pathways and by suggesting that platelet activity may influence thrombus initiation, clot organization, and potentially embolization and recurrence[5,6]. Figure 1 illustrates the interplay between platelet activation, immunothrombosis, and the coagulation cascade in the pathogenesis of PE, as well as the potential points of therapeutic intervention.

Figure 1 Platelet-mediated immunothrombosis and the role of antiplatelet therapy in pulmonary embolism. C3a: Complement component 3a; C5a: Complement component 5a; NET: Neutrophil extracellular trap; P2Y12: Platelet purinergic P2Y12 receptor; PE: Pulmonary embolism; PSGL-1: P-selectin glycoprotein ligand 1; RBCs: Red blood cells; Xa: Activated coagulation factor X.

These biological insights have prompted renewed interest in whether platelet-targeted therapies might hold a clinically meaningful role in PE. Nevertheless, experimental and translational evidence suggests that platelet activation may contribute to thrombus propagation, embolization potential, and inflammatory signaling within the venous thromboembolic continuum. In contrast to anticoagulants, which directly target thrombin generation or factor Xa-dependent coagulation and have well-established efficacy in both acute treatment and secondary prevention, antiplatelet agents have shown more context-dependent benefit in VTE and they are not currently recommended as a substitute for standard anticoagulation in routine clinical care[2].

This disconnect between mechanistic plausibility and clinical uncertainty underscores an important gap in the current PE literature. While platelet activation is increasingly recognized as biologically relevant to PE, its precise contribution to PE-specific pathophysiology, and, critically, its therapeutic exploitability, remain incompletely defined. Much of the available evidence has been extrapolated from broader VTE populations, arterial thrombosis paradigms, or preclinical venous thrombosis models, with relatively limited direct focus on PE as a distinct clinical and biological entity. Consequently, there is a need for a focused synthesis that critically appraises platelet involvement specifically within the venous-to-pulmonary thromboembolic continuum and evaluates whether antiplatelet strategies can be rationally integrated into PE prevention or management.

In this mini-review, we examine the evolving role of platelets in PE by integrating current understanding of venous thrombo-inflammatory mechanisms with available clinical evidence on antiplatelet therapy. We discuss how platelet-mediated interactions with coagulation pathways, endothelial cells, and innate immune effectors may influence PE development and progression, and we assess the therapeutic implications of these insights in the context of established anticoagulant-based care. By bridging mechanistic and clinical perspectives, this review aims to clarify the potential, limitations, and future direction of platelet-targeted approaches in PE.

PE is a thrombotic vascular disease characterised by the presence of thrombus in the pulmonary arteries. Together with deep vein thrombosis fall under the category of VTE. It is a major cause of morbidity and mortality worldwide, affecting diverse patient populations across age groups and clinical settings[7]. Epidemiological assessments estimate that PE occurs in approximately 10 million individuals annually[8] with an incidence of approximately 60 to 70 per 100000[9] and, following stroke and heart attack, it represents the third commonest cause of cardiovascular mortality[10]. Mortality rates for acute PE are heterogeneous, influenced by severity at presentation, comorbidities, and timely access to diagnosis and treatment. In massive PE cases characterized by hemodynamic instability, mortality can reach 65%. By contrast, submassive PE, defined by right ventricular (RV) strain without overt hypotension, still carries elevated short-term risk but lower fatality rates. Epidemiological data reveal that PE risk is amplified in individuals with malignancy, recent surgery, prolonged immobilization, obesity, advanced age, or known thrombophilia[9]. PE develops because of multiple interacting risk factors that promote venous thrombosis and subsequent embolization to the pulmonary circulation. These risk factors can be broadly categorized into inherited (genetic) and acquired conditions.

Inherited thrombophilia represents an important group of permanent risk factors that predispose individuals to thromboembolic events. These include deficiencies of natural anticoagulant proteins such as protein C, protein S, and antithrombin, as well as genetic mutations affecting coagulation pathways, including factor V Leiden and the prothrombin gene mutation. Such abnormalities impair the physiological balance between procoagulant and anticoagulant mechanisms, thereby increasing the likelihood of thrombus formation. In addition, certain chronic clinical conditions, such as advanced age, malignancy, and a history of cardiovascular disease, including myocardial infarction and heart failure, are recognized as persistent patient-related risk factors for PE.

Acquired risk factors are often temporary and typically relate to clinical situations that promote venous stasis, endothelial injury, or hypercoagulability. Major surgical procedures, particularly orthopedic surgery, trauma, prolonged immobilization (for example during hospitalization or long-distance travel), and spinal cord injury are well-established transient contributors to VTE. These conditions may lead to reduced venous blood flow or vascular damage, thereby facilitating thrombus development.

Hormonal and physiological states that alter the coagulation system also contribute to an elevated risk of PE. Pregnancy is characterized by a physiological hypercoagulable state intended to prevent hemorrhage during childbirth, but it simultaneously increases the risk of thromboembolic complications. Similarly, the use of hormonal therapies, including estrogen-containing contraceptives or hormone replacement therapy, has been associated with increased coagulation activity and a higher incidence of VTE.

In addition to these factors, several cardiometabolic conditions and lifestyle behaviors have been linked to an increased likelihood of thrombus formation. Obesity, hypertension, cigarette smoking, hypercholesterolemia, and diabetes mellitus are associated with endothelial dysfunction, systemic inflammation, and prothrombotic changes that may contribute to the development of PE.

More recently, infectious diseases such as coronavirus disease 2019 (COVID-19) have been recognized as significant contributors to thromboembolic risk. Patients with COVID-19, particularly those with severe disease, frequently exhibit a hypercoagulable state characterized by increased inflammatory responses, endothelial injury, and activation of the coagulation cascade. These pathophysiological mechanisms create a prothrombotic environment that predisposes affected individuals to VTE, including PE[9].

PE is commonly classified according to the patient’s hemodynamic status at presentation, as this parameter is strongly associated with prognosis and guides therapeutic decision-making. Broadly, PE can be divided into two principal categories: Hemodynamically unstable PE and hemodynamically stable PE. Hemodynamically unstable PE, also referred to as high-risk PE in contemporary clinical guidelines, is defined by the presence of significant circulatory compromise. This condition is typically identified by a systolic blood pressure below 90 mmHg, a sustained reduction in SBP of at least 40 mmHg from baseline, or the requirement for vasopressor or inotropic support to maintain adequate perfusion. The designation “massive” PE, previously used in clinical practice, does not refer to the anatomical size of the embolus but rather to the severity of its hemodynamic consequences. Patients in this category are at substantial risk of early mortality, primarily due to obstructive shock resulting from acute RV failure caused by a sudden increase in pulmonary vascular resistance. Hemodynamically stable PE includes patients who maintain adequate systemic blood pressure and do not exhibit signs of shock. This group encompasses a broad clinical spectrum, ranging from asymptomatic or low-risk cases to patients who may experience mild hypotension that responds to supportive measures such as fluid administration. Despite preserved systemic blood pressure, some individuals demonstrate evidence of RV dysfunction, which indicates a higher risk of adverse outcomes. For this reason, current clinical guidelines further subdivide hemodynamically stable PE into intermediate-risk and low-risk categories[11,12]. Within the intermediate-risk group, the European Society of Cardiology classification distinguishes between intermediate-high risk and intermediate-low risk PE. Patients categorized as intermediate-high risk exhibit both imaging evidence of RV dysfunction and elevated cardiac biomarkers, such as serum troponin, indicating myocardial injury. In contrast, the intermediate-low risk group presents with only one of these findings—either RV dysfunction or elevated troponin levels. Patients without hemodynamic instability, RV dysfunction, or biomarker elevation are generally considered to have low-risk PE, and they typically have a more favorable prognosis[13].

The diagnosis of PE relies on a structured clinical approach combining patient evaluation, risk stratification, laboratory biomarkers, and imaging studies. Because symptoms of PE are often nonspecific, including dyspnea, chest pain, tachycardia, or syncope, clinicians must initially assess the probability of the disease using validated clinical prediction models. Tools such as the Wells score or the revised Geneva score allow clinicians to categorize patients into low, intermediate, or high probability groups based on risk factors including previous VTE, recent surgery or immobilization, malignancy, tachycardia, and clinical signs of deep vein thrombosis. In patients with a low pretest probability, the PE Rule-out Criteria may be applied to exclude PE without further testing when all criteria are negative. These clinical algorithms reduce unnecessary imaging while maintaining diagnostic safety[14]. Additionally, the YEARS algorithm is a simplified diagnostic approach designed to improve the evaluation of patients with suspected PE while reducing unnecessary imaging studies. It combines three clinical criteria—clinical signs of deep vein thrombosis (DVT), hemoptysis, and PE being considered the most likely diagnosis—with variable D-dimer thresholds. In patients with none of the YEARS criteria, PE can be safely excluded when the D-dimer level is < 1000 ng/mL, whereas in patients with one or more criteria, a lower threshold of < 500 ng/mL is applied. This strategy has been shown to safely decrease the use of computed tomography pulmonary angiography (CTPA) and has subsequently been adapted for use in pregnant women with suspected PE[15].

Laboratory testing, particularly measurement of D-dimers levels, plays an important role in the diagnostic process. D-dimer is a fibrin degradation product released during the breakdown of cross-linked fibrin and therefore reflects ongoing activation of coagulation and fibrinolysis. The test is highly sensitive but not specific for PE, meaning that normal D-dimers levels can effectively exclude PE in patients with low or intermediate clinical probability, whereas elevated values require confirmatory imaging studies[14]. As D-dimers levels naturally increase with age, age-adjusted thresholds have been introduced to improve diagnostic specificity in older patients without compromising sensitivity. Although D-dimer testing is useful for excluding PE, it cannot independently confirm the diagnosis due to the numerous conditions that may elevate its levels, including infection, inflammation, malignancy, trauma, or pregnancy[16-18]. Although D-dimer remains the cornerstone biomarker for the exclusion of PE, additional biomarkers may provide complementary information regarding the underlying pathophysiological processes. The thrombin-antithrombin complex is a sensitive marker of thrombin generation and coagulation activation, reflecting a hypercoagulable state. Thrombomodulin, an endothelial cell membrane glycoprotein, is released into the circulation following endothelial injury and serves as a marker of vascular endothelial dysfunction. In contrast, the plasmin-α₂-antiplasmin complex reflects activation of the fibrinolytic system and ongoing thrombus degradation. The combined assessment of these biomarkers alongside D-dimer may improve the evaluation of coagulation, endothelial damage, and fibrinolysis in patients with suspected PE and could enhance diagnostic accuracy and risk stratification[19].

Moreover, other biomarkers may assist in assessing the severity and prognosis of PE rather than establishing the diagnosis itself. Cardiac troponins are released when myocardial injury occurs and may be elevated in patients with PE who develop RV strain due to increased pulmonary artery pressure. Similarly, B-type natriuretic peptide or its precursor N-terminal proBNP can indicate RV dysfunction resulting from increased pressure overload in the pulmonary circulation[17]. Elevated levels of these biomarkers are associated with worse clinical outcomes and may help identify patients at higher risk of complications. Other laboratory parameters reflecting systemic inflammation, such as neutrophil-to-lymphocyte ratio, platelet count < 100 × 10⁹/L or a mean platelet volume > 12 fL at admission, platelet-to-lymphocyte ratio [platelet-to-lymphocyte ratio (PLR) > 200], have also been explored in research settings as potential indicators and prognostic factors of thromboinflammatory processes, although their diagnostic and prognostic value remains inconsistent across patient populations and is a matter of ongoing research[14,17].

Definitive diagnosis of PE generally requires imaging studies capable of visualizing thrombi within the pulmonary vasculature. CTPA is currently the most widely used and preferred imaging modality due to its high sensitivity and specificity[14,16-18]. This technique allows direct visualization of emboli within pulmonary arteries and can also provide information about the size and location of the clot, as well as secondary signs such as RV enlargement. In addition to confirming the diagnosis, CTPA helps guide risk stratification by identifying signs of right heart strain, which may indicate more severe disease. Despite its diagnostic advantages, CTPA may not be suitable for all patients, particularly those with severe renal impairment or contraindications to iodinated contrast agents[14,16].

In such situations, ventilation-perfusion (V/Q) scanning may be used as an alternative imaging modality. V/Q scanning evaluates the distribution of ventilation and blood flow within the lungs, and the presence of perfusion defects in areas with preserved ventilation suggests PE. Although V/Q scanning is less frequently used today compared with CTPA, it remains valuable in specific patient populations, including pregnant women or individuals who cannot tolerate contrast-enhanced imaging[19]. A normal V/Q scan effectively excludes PE, whereas high-probability scans strongly support the diagnosis[20,21].

Ultrasound-based diagnostic techniques can also contribute to the evaluation of suspected PE. Compression ultrasonography of the lower extremities is used to detect deep vein thrombosis, the most common source of emboli. Identification of DVT in a patient with symptoms suggestive of PE may support the diagnosis and guide treatment decisions even when direct imaging of the pulmonary arteries is unavailable. In addition, echocardiography may be used to assess RV function in patients with suspected PE, particularly in emergency situations where rapid evaluation is required. Findings such as RV dilation, impaired contractility, or increased pulmonary artery pressure may suggest the presence of significant pulmonary vascular obstruction, although echocardiography alone cannot definitively diagnose PE[22,23].

Once PE is confirmed, patients are stratified according to their risk of mortality and complications. Risk classification typically categorizes PE into high-risk (massive), intermediate-risk (submassive), and low-risk groups. High-risk PE is characterized by hemodynamic instability, including sustained hypotension or cardiogenic shock, and carries the highest mortality rate. Intermediate-risk PE involves RV dysfunction or elevated cardiac biomarkers in the absence of systemic hypotension. Low-risk PE refers to patients who remain hemodynamically stable without evidence of significant cardiac strain. Risk stratification is essential because it guides therapeutic decision-making and determines the intensity of treatment required[24].

Anticoagulation therapy represents the cornerstone of PE treatment and is initiated as soon as PE is suspected, provided there are no major contraindications[14]. Anticoagulants prevent further thrombus formation and allow the body’s endogenous fibrinolytic mechanisms to gradually dissolve existing clots. Initial therapy often involves parenteral anticoagulants such as unfractionated heparin or low-molecular-weight heparin. These agents act rapidly by inhibiting key components of the coagulation cascade, particularly thrombin and factor Xa. Low-molecular-weight heparins are frequently preferred because they offer more predictable pharmacokinetics, lower risk of heparin-induced thrombocytopenia, and do not require routine laboratory monitoring in most patients[25].

In recent years, DOACs have become increasingly favored for the treatment and long-term management of PE. Agents such as rivaroxaban, apixaban, dabigatran, and edoxaban directly inhibit specific coagulation factors and provide effective anticoagulation with fixed dosing and minimal monitoring requirements[25]. Compared with traditional vitamin K antagonists such as warfarin, DOACs generally have fewer dietary interactions, faster onset of action, and a lower risk of certain bleeding complications. However, warfarin remains an option in specific clinical situations, particularly when DOACs are contraindicated or unavailable[26].

The duration of anticoagulation therapy depends on the underlying cause of the embolic event and the patient’s risk of recurrence[27]. In cases of PE provoked by transient risk factors such as surgery, trauma, or immobilization, anticoagulation is typically continued for approximately three months. In contrast, patients with unprovoked PE or persistent risk factors such as malignancy or inherited thrombophilia may require extended or lifelong anticoagulation to prevent recurrence.

In patients with high-risk PE characterized by hemodynamic instability or shock, thrombolytic therapy may be necessary to rapidly dissolve the obstructing clot. Thrombolytic agents such as alteplase activate plasminogen to form plasmin, an enzyme that degrades fibrin within thrombi. By accelerating clot dissolution, thrombolytic therapy can quickly restore pulmonary blood flow and reduce RV strain. However, this treatment carries a significant risk of major bleeding, including intracranial hemorrhage, and is therefore reserved for life-threatening situations where the benefits outweigh the risks[27].

When systemic thrombolysis is contraindicated or unsuccessful, alternative interventional strategies may be considered. Catheter-directed therapies allow targeted delivery of thrombolytic agents directly into the pulmonary arteries or mechanical fragmentation and removal of the clot using specialized devices. These procedures can reduce clot burden while potentially lowering systemic bleeding risk compared with full-dose thrombolysis. In rare cases where both thrombolysis and catheter-based interventions are unsuitable or ineffective, surgical pulmonary embolectomy may be performed. This procedure involves direct surgical removal of emboli from the pulmonary arteries and is typically reserved for patients with severe, life-threatening PE[28].

Beyond conventional anticoagulation and thrombolytic therapy, recent research has begun to explore the role of thromboinflammatory mechanisms in PE pathogenesis. The interaction between platelets and immune cells, particularly neutrophils, contributes to the formation of neutrophil extracellular trap (NET) and the stabilization of thrombi within the pulmonary circulation. These findings suggest that future therapeutic strategies might target platelet-mediated inflammatory pathways or NET formation in addition to the coagulation cascade. Potential approaches under investigation include inhibitors of P-selectin-mediated platelet-leukocyte interactions, agents that prevent NET formation, and therapies that modulate complement activation. However, these strategies remain largely experimental and have not yet been validated in large clinical trials for the treatment of PE[29].

Overall, PE is a complex disorder involving both coagulation abnormalities and immune-mediated processes. Accurate diagnosis requires careful integration of clinical assessment, laboratory testing, and imaging techniques, while effective treatment focuses primarily on anticoagulation to prevent clot propagation and recurrence. In severe cases, thrombolytic therapy, catheter-based interventions, or surgical embolectomy may be required to rapidly restore pulmonary circulation. As understanding of thromboinflammation and platelet involvement continues to expand, future research may provide new therapeutic options that more precisely target the cellular and molecular mechanisms underlying PE formation and progression.

PLATELET BIOLOGY

Platelets are small, anucleate cellular fragments derived from megakaryocytes, typically measuring between 2 µm and 4 µm in diameter[30]. Despite lacking a nucleus, they contain a complex intracellular architecture that includes α-granules, dense granules, lysosomes and an organized cytoskeletal network enabling rapid morphological and functional responses to activation stimuli. Their plasma membrane is enriched with multiple adhesion receptors and glycoproteins, including the glycoprotein Ib-IX-V complex, integrins αIIbβ3 and α2β1, and adhesion molecules[31], such as P-selectin[32]. These receptors mediate platelet adhesion and aggregation by binding extracellular matrix components exposed after endothelial injury, including von Willebrand factor (vWF), collagen, laminin, and fibrinogen[31].

Upon activation, the platelet membrane undergoes lipid rearrangement with externalization of phosphatidylserine, creating a negatively charged surface that supports assembly of coagulation factor complexes and accelerates thrombin generation. This biochemical transformation illustrates the central role of platelets in linking primary hemostasis with the coagulation cascade. Platelets, therefore, serve not only as structural components of thrombi, but also as catalytic platforms facilitating coagulation reactions[33].

Granule secretion is another key element of platelet function. Dense granules release adenosine diphosphate (ADP), serotonin, and calcium ions, which amplify platelet recruitment and activation through autocrine and paracrine signaling. α-granules release fibrinogen, vWF, and coagulation factors V and VIII together with inflammatory mediators such as interleukin-1β, linking hemostatic responses with inflammatory signaling pathways. Lysosomal enzymes further modify the extracellular microenvironment and contribute to thrombus remodeling[31].

Beyond their hemostatic role, platelets participate actively in immune regulation. Activated platelets express P-selectin on their surface, enabling binding to P-selectin glycoprotein ligand-1 (PSGL-1) on neutrophils and other leukocytes. These platelet-leukocyte interactions promote formation of heterotypic aggregates that integrate inflammatory signaling with thrombus formation[32]. Engagement of Toll-like receptors, particularly TLR4, allows platelets to recognize pathogen-associated molecular patterns and initiate intracellular signaling cascades involving nuclear factor-κB, leading to expression of inflammatory mediators and tissue factor[33,34].

One important consequence of platelet-immune cell interaction is the induction of NET formation[32]. Platelet activation can stimulate neutrophils through TLR4 signaling or through release of high-mobility group box-1 (HMGB1) from platelet-derived microparticles. NET formation involves chromatin decondensation mediated by peptidylarginine deiminase-4 (PAD4), generating extracellular DNA-protein structures that trap platelets, erythrocytes, and coagulation factors. These structures stabilize thrombi and reinforce the link between inflammation and coagulation[35].

Experimental studies support the pathological significance of platelet-driven NET formation. For example, inhibition of NETs through DNase administration or genetic deletion of PAD4 reduces hypercoagulability and tissue injury in models of ischemia-reperfusion injury, highlighting the contribution of NET-mediated thrombosis to systemic thrombo-inflammatory conditions[36]. Similar mechanisms have been observed in septic shock, where platelet-neutrophil interactions promote production of procoagulant microvesicles and NETs that enhance intravascular thrombosis[37].

Despite their immunological versatility, platelets are less abundant within venous thrombi than in arterial clots, which are typically platelet-rich. Venous thrombi, as the ones associated with PE, contain larger proportions of fibrin and erythrocytes, explaining why therapies targeting coagulation factors may exhibit a greater effectiveness than isolated inhibition of platelet aggregation. Nevertheless, platelet activation contributes to thrombus propagation, embolization potential, and inflammatory signaling within the venous thromboembolic continuum[38].

Clinical investigations have explored hematological markers reflecting platelet-associated inflammation in PE. For instance, the PLR has been evaluated as a prognostic marker; although elevated levels may correlate with disease severity in some cohorts, it does not consistently predict outcomes after adjustment for comorbid conditions, a variability which highlights the heterogeneous contribution of platelet-mediated inflammation across different patient populations[39].

Mechanisms of platelet activation

Platelet activation in PE arises from the integration of mechanical injury signals, coagulation-related stimuli, and inflammatory mediators. One of the primary activation pathways involves exposure of subendothelial collagen following endothelial disruption. Platelet glycoprotein VI (GPVI), an immunoreceptor tyrosine-based activation motif -containing receptor, binds collagen and initiates intracellular signaling through Syk kinase. This pathway activates phospholipase Cγ2, triggering intracellular calcium mobilization and diacylglycerol generation that drive cytoskeletal rearrangement, granule secretion, and platelet shape change.

GPVI signaling may also be triggered by polymerized fibrin within established thrombi. Binding of fibrin to the GPVI-Fc receptor γ-chain complex promotes additional thrombin generation and platelet recruitment, sustaining platelet activation even in the absence of exposed collagen. This mechanism allows platelets to remain active within mature thrombi and contributes to thrombus stabilization.

In parallel, several G-protein-coupled receptors regulate platelet activation through soluble agonists. Thrombin activates protease-activated receptors PAR1 and PAR4, while ADP released from platelet dense granules activates P2Y1 and P2Y12 receptors. These pathways converge on phospholipase C activation and intracellular calcium signaling, resulting in integrin activation and platelet aggregation. The P2Y1 receptor primarily initiates platelet activation, whereas P2Y12 signaling sustains the aggregation response. Downstream signaling includes activation of the small GTPase RAP1 through the guanine nucleotide exchange factor CalDAG-GEFI. RAP1 maintains integrin αIIbβ3 in a high-affinity state, enabling fibrinogen bridging between adjacent platelets and stabilizing platelet aggregates under flow conditions[31].

Inflammatory mediators also modulate platelet activation in PE. The damage-associated molecular pattern HMGB1 can interact with the receptor for advanced glycation end products on neutrophils and indirectly promote platelet activation through leukocyte-derived mediators. This inflammatory signaling contributes to NET formation, further amplifying platelet recruitment and thrombus stabilization[35].

Complement activation provides an additional mechanism linking inflammation and platelet activation. Complement fragments C3a and C5a bind to receptors expressed on various cell types, including platelets, promoting integrin activation and inflammatory signaling[40]. Deposition of complement component C3b on platelet surfaces following P-selectin expression enhances platelet adhesion to leukocytes, facilitating thrombus stabilization in inflammatory environments such as sepsis or viral infections[41].

Reactive oxygen species (ROS) generated within platelet mitochondria represent another important activation mechanism. Opening of mitochondrial permeability transition pores increases mitochondrial ROS production, which promotes assembly of NADPH oxidase complexes and amplifies oxidative signaling pathways. ROS function as secondary messengers that enhance granule release and integrin activation, thereby reinforcing platelet aggregation[42].

Interactions with immune cells further contribute to platelet activation during thrombo-inflammatory conditions. For example, inflammatory cytokines such as interleukin-1β and monocyte chemoattractant protein-1 produced by activated leukocytes create a pro-adhesive endothelial environment that promotes platelet tethering and aggregation. This environment facilitates sustained platelet activity even in the absence of strong hemostatic stimuli[43].

Although these molecular mechanisms illustrate the extensive involvement of platelets in thrombus formation, their therapeutic targeting in PE remains limited. Anticoagulants inhibit thrombin generation and factor Xa activity, thereby suppressing both fibrin formation and platelet activation mediated by thrombin signaling. Consequently, anticoagulation therapy remains more effective than antiplatelet drugs for preventing thrombus propagation in VTE.

IMMUNOTHROMBOSIS IN PULMONARY EMBOLISM

PE is increasingly recognized not only as a consequence of classical coagulation abnormalities but also as a manifestation of immunothrombosis, a biological process in which innate immune mechanisms interact with the coagulation system to generate intravascular thrombi. This concept expands the traditional view of thrombosis by emphasizing the role of immune cells, inflammatory mediators, and endothelial activation in the formation and stabilization of thrombi within the venous circulation and pulmonary vasculature. Under physiological conditions, immunothrombosis contributes to host defense by trapping pathogens and limiting their dissemination. However, when dysregulated, this protective mechanism can promote pathological clot formation and embolization[44].

Platelets are increasingly recognized as important coordinators linking coagulation and immune signaling pathways within the process of immunothrombosis. In PE, interactions among activated platelets, leukocytes, endothelial cells, and complement pathways contribute to a prothrombotic and proinflammatory microenvironment that may promote thrombus stabilization and persistence.

A crucial component of immunothrombosis is the formation of NETs. NETs consist of decondensed chromatin fibers decorated with antimicrobial proteins including neutrophil elastase, myeloperoxidase, and histones. These structures serve as physical scaffolds that capture platelets, erythrocytes, and coagulation factors within the developing thrombus. NET-associated histones possess procoagulant properties and may further stimulate platelet activation, potentially creating a feedback loop that promotes thrombus growth and stability. Within pulmonary emboli formed under inflammatory conditions, NET-rich architectures may contribute to resistance to endogenous fibrinolysis due to the dense cellular and molecular networks embedded within the clot[45].

Neutrophils represent one of the principal cellular participants in this process. Recruitment of neutrophils to sites of vascular injury is facilitated by chemokines released from activated platelets, including platelet factor 4 and interleukin-1β. Platelet surface P-selectin interacts with PSGL-1 expressed on neutrophils, promoting the formation of platelet-neutrophil aggregates that enhance inflammatory signaling and thrombus propagation[46,47]. Following activation, neutrophils undergo NETosis through mechanisms involving ROS production and activation of PAD4, which catalyzes histone citrullination and chromatin decondensation. Conditions associated with metabolic stress, such as hyperglycemia, may intensify this process by increasing oxidative signaling pathways that stimulate both NET release and platelet activation[48].

Monocytes also contribute significantly to immunothrombotic processes through expression of tissue factor, the primary initiator of the extrinsic coagulation pathway. Platelet-derived microparticles and inflammatory cytokines stimulate monocytes to express tissue factor on phosphatidylserine-rich membranes, providing a catalytic surface for thrombin generation. In certain inflammatory disorders, including autoimmune or atherosclerotic conditions, circulating monocyte-derived microparticles carrying tissue factor may become incorporated into venous thrombi and further enhance fibrin deposition[49].

The vascular endothelium plays a permissive and regulatory role in this cellular network. Under inflammatory stress, endothelial cells upregulate adhesion molecules such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, facilitating attachment of leukocytes and platelets to the vessel wall[50]. Endothelial activation also promotes the release of vWF from Weibel-Palade bodies, enabling platelet adhesion even before significant fibrin deposition occurs. During systemic inflammatory conditions such as infection or ischemia-reperfusion injury, endothelial dysfunction increases vascular permeability and exposes subendothelial matrix components, thereby amplifying thrombus formation within the venous circulation[51].

Although neutrophils and monocytes are the predominant immune contributors, other immune cells may participate in specific pathological contexts. Eosinophils, for example, are capable of forming eosinophil extracellular traps (EETs) under proinflammatory stimulation. These DNA-based structures resemble NETs but contain distinct granule proteins such as eosinophil peroxidase and major basic protein[52]. While their role in PE remains less clearly defined, EET formation has been observed in inflammatory disorders associated with increased thrombotic risk, suggesting a possible contribution to thrombo-inflammatory clot architecture in selected patient populations[53].

The complement system represents another important mediator linking immunity and coagulation. Complement activation products, particularly C3a and C5a, recruit neutrophils and monocytes while also enhancing platelet activation and endothelial inflammation. Deposition of complement components on NETs prolongs their structural stability and increases their capacity to bind coagulation factors. Complement proteins may also attach to platelet surfaces following P-selectin expression, strengthening platelet-leukocyte interactions within developing thrombi. These mechanisms contribute to the formation of cellular microenvironments characterized by intense inflammatory signaling and resistance to fibrinolysis[54].

Clinical observations are consistent with a role for immunothrombosis in the pathophysiology of PE, although its precise clinical significance remains incompletely defined. Elevated markers of neutrophil activation, NET formation, and systemic inflammation have been detected in patients with severe thromboembolic disease[55]. Similar mechanisms have been described in sepsis-associated microvascular thrombosis, where coordinated activation of neutrophils, complement pathways, and coagulation factors leads to widespread intravascular clot formation and organ dysfunction[56]. Infection-related thrombotic syndromes, including COVID-19-associated coagulopathy, further illustrate how intense systemic inflammation can promote PE through immunothrombotic pathways[57].

Despite the growing recognition of immunothrombosis, translating these mechanistic insights into targeted therapies remains challenging. Anticoagulants continue to represent the cornerstone of PE treatment because they inhibit the enzymatic reactions of the coagulation cascade that underpin both traditional thrombosis and immunothrombotic processes. In contrast, antiplatelet agents primarily inhibit platelet aggregation and therefore do not directly disrupt the fibrin-rich core of venous thrombi or the complex immune cell networks embedded within them. As a result, the clinical efficacy of antiplatelet therapy alone in PE remains debated[58].

PRECLINICAL MODELS OF PULMONARY EMBOLISM

Preclinical modeling of PE relies primarily on murine venous thrombosis platforms, reflecting the clinical observation that most PE events originate from DVT rather than primary pulmonary vascular thrombosis. Murine models allow controlled induction of thrombi in upstream veins, most commonly the infrarenal inferior vena cava (IVC) or femoral vein, providing mechanistic insight into thrombus formation, propagation, and resolution. Because spontaneous PE is rare in laboratory species, thrombosis is typically triggered through physical interventions, including IVC ligation, stenosis, or endothelial injury, or via chemical agents such as ferric chloride. These approaches generate reproducible thrombi that can subsequently embolize to the pulmonary circulation, enabling controlled studies of embolic dynamics and therapeutic interventions[59,60].

A range of murine DVT models is available, each differing in thrombus induction method and hemodynamic conditions. Stasis (ligation) and low-flow stenosis models simulate complete or partial flow cessation, whereas electrolytic and ferric chloride models activate the endothelium via free radicals. Low-flow IVC stenosis models are particularly useful for investigating early thrombus formation under conditions resembling Virchow’s triad, while the electrolytic IVC model generates highly reproducible non-occlusive thrombi along the direction of blood flow, suitable for testing antithrombotic or thrombolytic therapies. The femoral vein electrolytic model adds clinical relevance through the presence of venous valves, key sites of human thrombogenesis. These models are primarily designed to study the upstream venous events that precede embolization, as most murine models do not spontaneously produce pulmonary emboli, yet they remain indispensable for evaluating interventions aimed at limiting thrombus extension, recurrence, and embolic complications[61].

Assessment of embolic burden and thrombus fate in the pulmonary vasculature has traditionally relied on ex vivo measurements such as thrombus weight and histological reconstruction, which provide quantitative and compositional insights but are inherently terminal. Recent advances in in vivo imaging, including magnetic resonance imaging, contrast-enhanced micro-computed tomography, high-frequency ultrasonography, and radionuclide-based techniques, now permit longitudinal, noninvasive visualization of thrombus formation, embolization, and pulmonary vascular obstruction. Intravital microscopy and targeted molecular imaging further enable real-time characterization of cellular and molecular processes within thrombi, including fibrin deposition, platelet accumulation, leukocyte recruitment, and endothelial activation, thus enhancing mechanistic understanding and facilitating evaluation of novel thrombolytic or antithrombotic strategies[60].

PE can lead to acute or chronic pulmonary hypertension (PH) due to elevated pulmonary vascular resistance, vascular remodeling, and RV stress. Preclinical PE models, by enabling controlled embolization and quantification of thrombotic burden, also permit investigation of pulmonary hemodynamic changes and right heart adaptations. Rodent models of PH, including pulmonary artery banding, monocrotaline, SU5416 + hypoxia, or multi-hit approaches combining metabolic syndrome with pulmonary endothelial injury, replicate aspects of pulmonary vascular remodeling, RV hypertrophy, and hemodynamic stress. While ischemic or pressure-overload models induce left ventricular dysfunction and secondary PH, metabolic and multi-hit models better reproduce HFpEF-associated diastolic dysfunction with mild PH. These platforms allow study of the progression from acute thromboembolic events to PH, providing a framework to evaluate interventions targeting both thrombotic and hypertensive sequelae[61].

CLINICAL EVIDENCE ON ANTIPLATELET AGENTS IN PULMONARY EMBOLISM

The ASPIRE trial by Timothy A. Brighton et al[62] evaluated the effect of low-dose aspirin (100 mg daily) in patients who had completed anticoagulation after a first unprovoked VTE, including PE. Over a median follow-up of 37.2 months, aspirin was associated with a non-significant reduction in recurrent VTE, including PE [4.8% vs 6.5% per year; hazard ratio (HR) 0.74, P = 0.09]. However, when considering patients who were actively receiving treatment, aspirin significantly reduced recurrence risk. Importantly, aspirin led to a significant reduction in major vascular events (including PE, myocardial infarction, stroke, and cardiovascular death) by approximately 34%, and improved overall net clinical benefit by 33%. The incidence of major or clinically relevant bleeding was low and did not differ significantly from placebo. These findings suggest that although aspirin is less effective than full anticoagulation, it represents a safe and modestly effective antiplatelet strategy for secondary prevention of thromboembolic events, including PE, particularly in patients who discontinue anticoagulant therapy.

The EINSTEIN CHOICE trial by Weitz et al[63] investigated extended antithrombotic therapy in patients with prior VTE, including PE, who had completed 6-12 months of anticoagulation. The study demonstrated that both therapeutic-dose rivaroxaban (20 mg) and lower-dose rivaroxaban (10 mg) were significantly more effective than aspirin in preventing recurrent events, including PE. Specifically, recurrent VTE occurred in only 1.5% and 1.2% of patients receiving rivaroxaban (20 mg and 10 mg, respectively), compared with 4.4% in those receiving aspirin, corresponding to a relative risk reduction of approximately 70%. Importantly, this substantial reduction in recurrence—including clinically relevant PE—was achieved without a significant increase in major bleeding, as bleeding rates remained low and comparable across all groups. These findings highlight that, in the context of secondary prevention after PE, continued anticoagulation with rivaroxaban is markedly more effective than antiplatelet therapy with aspirin, even at a reduced dose, and provides a favorable balance between efficacy and safety.

The study by Steele et al[64] investigated the pathophysiology and treatment of recurrent venous thrombosis, including patients with a history of PE. The results demonstrated that abnormalities in platelet survival, fibrinogen turnover, and fibrinolytic activity were highly prevalent, with shortened platelet survival observed in 80% of patients, highlighting the central role of platelet activation in thromboembolic disease. Importantly, platelet-suppressant therapy with sulfinpyrazone significantly improved platelet survival and was associated with complete prevention of recurrent thrombotic events, including those that could lead to PE, during the treatment period (0/14 patients). In contrast, lytic therapy improved fibrinolytic parameters but did not reduce recurrence rates (3/7 patients), while placebo was associated with a high rate of recurrent thrombosis (4/11 patients). Discontinuation of anticoagulation (warfarin) was linked to worsening fibrinogen dynamics and recurrence in some patients. Overall, these findings suggest that platelet dysfunction plays a key role in recurrent PE, and that antiplatelet therapy may offer clinically meaningful protection, particularly in patients who continue to have events despite anticoagulation.

The pulmonary embolism prevention (PEP) Trial was a large randomized, double-blind, placebo-controlled study of 17444 high-risk surgical patients (hip fracture and elective hip/knee arthroplasty) that tested 160 mg enteric-coated aspirin daily for 35 days vs placebo (intention-to-treat). Patients with hip fracture were older (mean 79 years) than elective arthroplasty patients (mean 67). Concomitant prophylaxis (heparin, mechanical methods) was allowed. Aspirin significantly lowered VTE overall by approximately 34%: DVT fell from 1.5% to 1.0% (29% relative reduction), PE from 1.2% to 0.7% (43% reduction), and the composite VTE from 2.5% to 1.6% (36% relative, approximately 9 fewer events per 1000 treated). Fatal PE decreased from 0.6% to 0.3% (58% reduction). Benefits were clearest in hip-fracture patients; reductions in the elective group were smaller and not statistically significant alone but consistent in pooled analyses. Effects were seen regardless of other prophylaxis use. Aspirin did not significantly change myocardial infarction, stroke, or overall mortality at 35 days (a small, nondefinitive rise in MI in hip-fracture patients was noted). Bleeding increased modestly, mainly nonfatal and transfusion-requiring events (approximately 6 excess per 1000), without more fatal bleeding or intracranial hemorrhage. So, according to this study, low-dose aspirin after major orthopedic surgery—especially hip fracture—substantially reduces VTE and fatal PE with a modest rise in nonfatal bleeding, making it a low-cost, practical thromboprophylaxis option alone or alongside other measures[65].

The WARFASA trial randomized 403 patients with a first, unprovoked VTE who had completed 6-18 months of vitamin K antagonist therapy to receive aspirin 100 mg daily (n = 205) or placebo (n = 197) and followed them for a median of approximately 24 months. The primary outcome was symptomatic, objectively confirmed recurrent VTE (DVT or nonfatal/fatal PE); recurrent PE accounted for 27 of 71 recurrences (two fatal). Recurrent VTE occurred in 28 patients on aspirin vs 43 on placebo (6.6% vs 11.2% per year; hazard ratio 0.58, 95%CI: 0.36-0.93, P = 0.02). On-treatment analysis showed similar benefit (5.9% vs 11.0% per year; HR 0.55). Major bleeding was uncommon and similar between groups (one episode each). Subgroup analysis suggested a larger relative benefit in patients whose index event was PE. In short, aspirin 100 mg daily reduced recurrent VTE including PE by about 40% without a clear increase in major bleeding[66].

The CRISTAL randomized trial evaluated the efficacy of aspirin compared with enoxaparin for thromboprophylaxis after total hip or knee arthroplasty in patients with osteoarthritis, with PE included among the main symptomatic thromboembolic outcomes. A total of 9711 patients were enrolled across 31 hospitals in Australia, receiving either aspirin 100 mg daily or enoxaparin 40 mg daily postoperatively. Within 90 days after surgery, 79 cases of PE were recorded overall. Specifically, 58 PE events (1.1%) occurred in the aspirin group, compared with 21 events (0.6%) in the enoxaparin group. Although this difference did not reach statistical significance (estimated difference 0.44%, 95%CI: -0.19 to 1.08; P = 0.17), the numerically higher rate of PE in the aspirin group suggests a less effective protective effect compared with enoxaparin. Overall, the study supports the view that enoxaparin may offer superior postoperative protection against clinically important thromboembolic complications such as PE following major lower-limb arthroplasty[67].

In the EPCAT II randomized controlled trial, Anderson et al[68] investigated the efficacy and safety of aspirin compared with rivaroxaban for extended thromboprophylaxis following total hip or total knee arthroplasty (TKA). Unlike studies evaluating aspirin as sole prophylaxis from the immediate postoperative period, all participants in this trial initially received rivaroxaban 10 mg once daily for the first 5 postoperative days. Subsequently, patients were randomized either to continue rivaroxaban or to switch to aspirin 81 mg daily. Extended prophylaxis was administered for an additional 9 days after TKA and 30 days after total hip arthroplasty (THA), with clinical follow-up extending to 90 days.

With respect to PE, the incidence of clinically significant thromboembolic complications was very low in both treatment groups. The primary efficacy outcome, defined as symptomatic proximal deep-vein thrombosis or PE, occurred in 0.64% of patients receiving aspirin and 0.70% of those continuing rivaroxaban, demonstrating that aspirin was noninferior to rivaroxaban for extended prophylaxis in this setting. Importantly, only one fatal PE was reported during the study, and this occurred in the aspirin group, in a patient who had undergone TKA. This event was documented 31 days after randomization and 17 days after completion of aspirin prophylaxis.

Overall, the findings of this trial indicate that, when preceded by an initial 5-day postoperative course of rivaroxaban, aspirin offers comparable protection against PE and other clinically important thromboembolic events following hip or knee arthroplasty. Nevertheless, the study design is particularly important for interpretation, as these results support aspirin as part of a sequential prophylactic strategy rather than as immediate monotherapy from the first postoperative day[68].

In an interesting recent retrospective case-control study, Suresh et al[69] investigated whether prehospital aspirin use was associated with improved outcomes in patients hospitalized with acute PE. The study included 323 adults with computed tomography-confirmed PE, of whom 90 patients (27.9%) had been taking aspirin daily for at least 7 days before admission. The findings suggested that prior aspirin exposure was associated with a less severe clinical presentation of PE. More specifically, patients using aspirin before hospitalization had significantly lower rates of RV strain on computed tomography (22.2% vs 34.8%), intensive care unit admission (16.7% vs 28.8%), shock (2.2% vs 9.9%), and in-hospital mortality (3.3% vs 11.6%). In addition, aspirin users required catheter-directed thrombolysis less frequently, while no significant differences were observed in mechanical ventilation or cardiac arrest. Overall, the study suggests that prehospital aspirin use may be associated with reduced severity and improved in-hospital outcomes in acute PE, possibly through attenuation of thromboinflammatory mechanisms and RV stress. However, because this was a single-center retrospective observational study, the findings should be interpreted cautiously and considered hypothesis-generating rather than definitive evidence of benefit.

Mosher et al[70] conducted a large retrospective analysis of the ACS-NSQIP database to evaluate contemporary trends in VTE after THA and TKA between 2009 and 2022, with particular relevance to PE. The study included 975575 patients overall (382515 THA and 593060 TKA) and identified 3807 PE events within 30 days postoperatively. PE occurred more frequently after TKA (0.5%) than after THA (0.3%), confirming that PE remains an important early postoperative complication after major lower-limb arthroplasty. Importantly, the study demonstrated a significant decline in PE rates over time, especially in the TKA population, where the 30-day incidence decreased from 0.8% in 2009 to 0.4% in 2022. After multivariable adjustment, patients undergoing TKA in 2022 had significantly lower odds of postoperative PE compared with those in 2009 (odds ratio 0.59, P < 0.01), whereas no significant temporal change was observed for THA. Additional risk factors for PE included advanced age (≥ 80 years), higher body mass index, chronic obstructive pulmonary disease, higher American Society of Anesthesiologists physical status classification class, and inpatient surgical setting, while outpatient procedures were associated with lower PE risk. These findings suggest that modern thromboprophylaxis strategies, early mobilization, and enhanced recovery pathways have likely contributed to the reduction in postoperative PE, particularly after TKA.

In summary, evidence from the WARFASA and ASPIRE trials suggests that low-dose aspirin can modestly reduce the risk of recurrent PE after discontinuation of anticoagulant therapy, with little increase in major bleeding. In the orthopedic setting, the PEP trial further demonstrated that aspirin reduces postoperative PE and fatal PE, supporting its role in thromboprophylaxis among selected surgical patients. These findings indicate that platelet inhibition may contribute to PE prevention, particularly when long-term anticoagulation is not continued.

Despite these benefits, antiplatelet therapy remains inferior to anticoagulation for preventing recurrent PE. The EINSTEIN-CHOICE trial showed that both standard- and low-dose rivaroxaban reduced recurrent VTE, including PE, by approximately 70% compared with aspirin, without a significant increase in major bleeding. Similarly, the CRISTAL trial suggested superior protection against postoperative PE with enoxaparin compared with aspirin, whereas EPCAT II demonstrated non-inferiority of aspirin only when preceded by an initial course of rivaroxaban. Therefore, while aspirin may be considered in selected low-risk patients or when anticoagulation is contraindicated, current evidence supports anticoagulants as the primary strategy for PE prevention and secondary prophylaxis.

NOVEL APPROACHES IN THE TREATMENT OF PULMONARY EMBOLISM

Targeting platelet activation has emerged as a promising area of investigation in the development of novel antithrombotic therapies, with multiple pathways offering promising avenues for intervention. The GPVI signaling pathway has emerged as a key target due to its critical role in platelet adhesion and activation, and both pharmacological inhibition and genetic knockout studies have demonstrated potent antithrombotic effects without increased bleeding risk[71-73]. Similarly, targeting platelet integrins, including α6 and αIIbβ3, may reduce arterial thrombosis while preserving essential hemostatic function[74-76]. Soluble CD39 and ANTP266 have demonstrated antithrombotic activity in preclinical studies through mechanisms that limit platelet activation and thrombus formation[77-80]. In addition, RUC4 and novel inhibitors of αIIbβ3 outside-in signaling have shown encouraging experimental results as potential strategies for achieving effective thrombosis prevention with a reduced risk of bleeding[81-83]. Other strategies focus on modulating intracellular signaling and granule release, exemplified by the PI3Kβ inhibitor AZD6482 and peptides such as C-ST5, which reduce platelet activation and NET formation, thereby mitigating thrombotic complications[77,78]. Advances in precision medicine highlight the importance of individualized platelet profiling, as genetic variations in receptors like P2Y12 and GPVI can alter platelet reactivity and therapeutic response, underscoring the potential for genotype-guided interventions[84,85]. Furthermore, immunotherapy approaches, including monoclonal antibodies targeting platelet receptors or platelet-leukocyte interactions, have demonstrated the ability to reduce thrombosis while maintaining normal hemostasis, with early clinical trials confirming safety and efficacy in healthy volunteers[86-88]. Despite these promising developments, translating preclinical findings into clinical practice remains challenging, requiring careful evaluation of safety, tolerability, and long-term efficacy. Future research integrating molecular insights, biomarker-driven patient stratification, and immunomodulatory strategies is poised to advance antiplatelet therapy, offering more selective, effective, and personalized management options for patients at risk of PE while minimizing bleeding complications.

Emerging antiplatelet agents provide additional innovative mechanisms. Tyrphostin AG538, a TREM2 receptor agonist, inhibits platelet activation and thrombosis, demonstrating potential for PE prevention. In vitro and in vivo experiments showed that AG538 binds TREM2, suppresses platelet aggregation, granule release, spreading, and clot retraction, and reduces arterial thrombus formation. Importantly, in mouse models, oral AG538 alleviated PE without increasing bleeding risk. Mechanistically, AG538 inhibits the SHIP1-Akt signaling pathway downstream of TREM2, highlighting its potential as a novel antiplatelet agent with a favorable safety profile[89].

The naphthalimide derivative compound 5 inhibits platelet activation and thrombus formation via suppression of collagen receptor GPVI signaling. In vitro, compound 5 blocked collagen- and convulxin-induced platelet aggregation, reduced granule release, calcium mobilization, and GPIIb/IIIa activation, and suppressed extracellular signal-regulated kinase and c-Jun N-terminal kinase phosphorylation. In vivo, compound 5 prevented PE in mice and delayed thrombus formation in mesenteric microvessels, though high doses tended to increase bleeding risk. These results suggest compound 5 as a potential antiplatelet and antithrombotic agent with relevance for PE prevention, pending optimization to minimize bleeding[90].

Kv1.3 potassium channels are highly expressed in platelets and play a key role in regulating intracellular calcium ([Ca²⁺]ᵢ), which is essential for platelet activation and thrombus formation. This study developed a specific monoclonal antibody, 6E12#15, that selectively blocks human and mouse Kv1.3 channels. In vitro, 6E12#15 inhibited platelet aggregation, adhesion, integrin αIIbβ3 activation, P-selectin exposure, and ATP release, while reducing agonist-induced [Ca²⁺]ᵢ elevation. In vivo, treatment with 6E12#15 significantly decreased thrombus formation in a mesenteric arteriole injury model and protected against collagen/epinephrine-induced PE without affecting normal hemostasis. Kv1.3-/- mice showed impaired platelet aggregation but normal thrombus formation due to compensatory increases in platelet production. These findings indicate that Kv1.3 channels are critical modulators of platelet function and represent a promising target for antiplatelet therapy[91].

Despite these promising developments, several important challenges must be acknowledged. Most of the agents discussed remain in preclinical or early-phase clinical development, and their efficacy in patients with PE has yet to be established. Furthermore, although many of these approaches aim to dissociate antithrombotic effects from impairment of physiological hemostasis, bleeding risk remains a critical concern for any therapy targeting platelet function. Results from experimental models may not fully translate to the complex clinical setting of PE, where patient heterogeneity, comorbidities, and concomitant anticoagulant use can substantially influence both efficacy and safety. Consequently, rigorous clinical trials will be required to determine whether these novel platelet-targeted strategies can provide meaningful therapeutic benefit while maintaining an acceptable safety profile.

DISCUSSION

The integration of platelet biology, immunothrombosis, and clinical evidence presented in this review reveals a complex role for antiplatelet therapy in PE that extends beyond traditional views of VTE. While anticoagulation remains the foundation of PE management, mechanistic insights into platelet-mediated thromboinflammatory pathways provide a rationale for reconsidering when platelet-targeted strategies might complement existing therapies.

The classical distinction between platelet-rich arterial thrombi and fibrin-rich venous thrombi has historically diminished the perceived importance of platelets in PE. However, emerging experimental and translational evidence suggests that platelets contribute to venous thrombus formation through multiple mechanisms. Platelets provide procoagulant surfaces via phosphatidylserine externalization, supporting assembly of coagulation factor complexes and accelerating thrombin generation[33]. This catalytic function is particularly relevant in venous circulation, where low shear conditions favor coagulation factor assembly on activated platelet membranes.

In addition, platelets appear to function as immune-responsive cells that link innate immunity and thrombosis. Formation of platelet-neutrophil aggregates via P-selectin/PSGL-1 interactions and subsequent induction of NETosis have been proposed as important mechanisms linking platelet activation to thrombus stabilization[32,46]. NETs create physically stable matrices that resist fibrinolysis and perpetuate local inflammation[39]. Complement activation further potentiates this process, with fragments C3a and C5a enhancing platelet activation and promoting platelet-leukocyte adhesion[40]. Together, these pathways support the concept that platelet involvement in PE may be embedded within a broader network of immune and inflammatory interactions.Despite robust mechanistic rationale, clinical evidence reveals a more tempered picture. Secondary prevention trials consistently demonstrate that aspirin provides modest protection against recurrent VTE, with relative risk reductions of approximately 30%-40% compared with placebo[62,66]. However, these benefits are substantially inferior to those achieved with continued anticoagulation using DOACs, which reduce recurrence risk by approximately 70% relative to aspirin[63].

Several factors may explain this discrepancy. First, the structural composition of venous thrombi, characterized by high fibrin and erythrocyte content relative to platelets, means that inhibiting platelet aggregation alone may not sufficiently disrupt established venous thrombi. Anticoagulants directly undermine thrombus structural integrity by targeting fibrin generation[38].

Second, temporal dynamics influence the therapeutic window for antiplatelet interventions. Platelet activation appears most critical during early thrombus initiation, whereas established venous thrombi may become less dependent on continued platelet recruitment. This could explain why antiplatelet therapy provides greater benefit in prophylactic settings, such as after orthopedic surgery[65], compared with treatment of established disease.

Third, redundancy of platelet activation pathways presents a therapeutic challenge. Inhibiting a single pathway through cyclooxygenase-1 blockade may be insufficient to fully attenuate platelet contributions when alternative activation routes—including GPVI-mediated collagen signaling, thrombin-stimulated PAR activation, and ADP-dependent P2Y signaling—remain intact[31].

Surgical thromboprophylaxis trials further illustrate this complexity. While the PEP trial demonstrated that aspirin alone reduces PE risk following hip fracture surgery, the CRISTAL trial suggested enoxaparin provides numerically superior protection after elective arthroplasty[67]. The EPCAT II trial showed that aspirin following an initial anticoagulation course achieves comparable efficacy to continued rivaroxaban[68], highlighting that timing and context critically influence outcomes.

It is important to note that a key limitation of the current evidence base is that most randomized trials were designed to assess recurrent VTE rather than PE-specific outcomes. Consequently, many conclusions regarding the efficacy of antiplatelet therapy in PE are extrapolated from composite VTE endpoints. While this approach is biologically plausible given the shared pathogenesis of DVT and PE, dedicated studies focusing specifically on PE are needed to determine the true clinical value of platelet-targeted interventions in this population.

The disconnect between mechanistic understanding and clinical efficacy underscores several translational gaps. Patient selection remains critical, as the contribution of platelets to pathogenesis likely varies substantially across patient populations. Current prognostic markers such as platelet-to-lymphocyte ratio have shown inconsistent predictive value[39], suggesting that more sophisticated approaches—including flow cytometric assessment of platelet activation markers or quantification of platelet-leukocyte aggregates—may provide better stratification.

Development of novel antiplatelet agents targeting pathways more specific to thromboinflammatory venous thrombosis offers promise. GPVI inhibitors, such as Revacept and ACT017, target collagen receptors critical for platelet adhesion without disrupting hemostatic functions[73]. Kv1.3 channel inhibitors and TREM2 agonists have demonstrated antithrombotic efficacy in experimental PE models without increasing bleeding risk[91,89]. These approaches suggest that selective targeting of platelet activation pathways distinct from traditional hemostatic mechanisms may achieve a more favorable therapeutic index.

From a clinical perspective, several conclusions emerge. Firstly, antiplatelet therapy should not replace anticoagulation for acute PE treatment or secondary prevention in patients who remain candidates for anticoagulation. The superiority of DOACs over aspirin firmly establishes anticoagulation as the preferred approach[63]. Second, aspirin may represent a reasonable alternative for secondary prevention in selected patients who cannot or will not continue anticoagulation, reducing recurrence risk by approximately one-third compared with placebo[62,66]. Third, in surgical thromboprophylaxis, aspirin appears most effective when preceded by an initial course of anticoagulation, as demonstrated in EPCAT II[68].

The evidence reviewed highlights an important paradigm shift in the understanding of PE, moving beyond the traditional concept of venous thrombosis as a purely coagulation-driven process toward a more integrated model involving immunothrombosis and platelet-mediated inflammation. Experimental studies convincingly demonstrate that platelets actively participate in venous thrombus formation through interactions with neutrophils, complement activation, and NET formation, thereby contributing not only to thrombus initiation but also to thrombus stabilization and resistance to fibrinolysis. However, the translation of these mechanistic insights into clinical benefit remains incomplete. Although aspirin reduced recurrent VTE and PE in the WARFASA and ASPIRE trials, the magnitude of benefit was modest, and the EINSTEIN-CHOICE trial clearly established the superior efficacy of continued anticoagulation with rivaroxaban. This discrepancy suggests that while platelets are biologically relevant in PE pathogenesis, they may function primarily as amplifiers of thromboinflammatory processes rather than as the dominant drivers of thrombus propagation, which remains largely dependent on the coagulation cascade and fibrin generation.

A critical implication of these findings is that current antiplatelet strategies may not adequately target the platelet-dependent mechanisms most relevant to PE. Aspirin selectively inhibits thromboxane A₂-mediated activation, yet leaves multiple alternative pathways intact, including thrombin-, ADP-, and collagen-mediated platelet signaling. This may explain why clinical outcomes have fallen short of the promise suggested by experimental models. Furthermore, the apparent variability in efficacy across clinical settings—including the favorable results of the PEP and EPCAT II trials compared with the less convincing findings of CRISTAL—indicates that the contribution of platelets to PE is highly context-dependent and influenced by factors such as thrombus stage, surgical trauma, and concurrent anticoagulant use. Consequently, the future role of platelet-targeted therapy in PE is unlikely to lie in replacing anticoagulation but rather in developing more selective antithromboinflammatory approaches and identifying patient subgroups with heightened platelet-driven disease. Until such precision strategies become available, anticoagulation remains the cornerstone of PE prevention and treatment, while antiplatelet therapy should be viewed as a complementary or alternative option only in carefully selected clinical scenarios.

CONCLUSION

This review integrates mechanistic insights from platelet biology and immunothrombosis with clinical evidence to critically appraise antiplatelet therapy in PE. While platelets actively participate in venous thrombogenesis through procoagulant and immunothrombotic mechanisms, clinical evidence demonstrates that antiplatelet therapy provides only modest benefit compared with anticoagulation. This apparent paradox reflects venous thrombus structure, redundancy of platelet activation pathways, and temporal dynamics of thrombus formation. Future progress will depend on improved patient selection, development of agents targeting thromboinflammatory pathways with greater specificity, and exploration of combination strategies that address both coagulation and platelet-immune interactions