Platelets are anucleate cells whose dysregulation contributes to thrombocytopenia during sepsis. Thrombocytopenia is an early complication of Gram-negative infection, in which lipopolysaccharide (LPS) serves as a principal mediator; however, its precise contribution remains unclear. In this study, LPS, at concentration 10 µg/mL, did not induce human platelet aggregation but significantly potentiated low-dose collagen (0.5 μg/mL)-induced aggregation, ATP release, intracellular calcium levels ([Ca²⁺]i) and P-selectin expression. Scanning electron microscopy revealed that either collagen or LPS activated filopodia elongation in human platelets, whereas LPS combined with collagen further activated the phenotype of platelet activation (lamellipodia formation). Beyond these activation responses, LPS also increased TLR4 expression and triggered hallmark apoptotic events, including mitochondrial depolarization, Bax expression, caspase-8 and caspase-3 activation, and phosphatidylserine exposure, concomitant with downregulation of Bcl-2. Moreover, LPS-induced apoptotic platelets displayed ultrastructural changes, characterized by membrane blebbing and filopodia loss. Thus, these findings present the first evidence that LPS enhances platelet aggregation in association with apoptosis through the TLR4–Bax/Bcl-2–mitochondrial dysfunction–caspase-8/3 activation signaling pathway, providing mechanistic insight into sepsis-associated thrombocytopenia.

Post-cardiac arrest syndrome (PCAS) remains a major cause of mortality and neurological impairment following successful resuscitation, yet the mechanisms linking global ischemia–reperfusion injury to microvascular and systemic dysfunction are not yet completely understood. While prior work has focused on inflammation, endothelial injury, and circulatory collapse, the central role of platelets in coordinating these pathological processes has not been comprehensively examined. This review provides the first integrated framework positioning platelets as core modulators, rather than secondary participants, in PCAS pathophysiology. We synthesize emerging evidence demonstrating that ischemia and reperfusion transform platelets into potent thromboinflammatory effectors through oxidative stress, DAMP-mediated pattern recognition signaling, and mitochondrial dysfunction. Hyperactivated platelets drive cerebral microthrombus formation, coronary no-reflow, and peripheral organ hypoperfusion, while platelet–leukocyte aggregates, neutrophil extracellular traps, and platelet-derived microparticles amplify systemic inflammation and endothelial injury. We further highlight the clinical significance of dynamic platelet dysfunction in coagulopathy, prognostication, and responses to post-arrest therapies including targeted temperature management and ECMO. Finally, we outline a novel, platelet-centered therapeutic paradigm, emphasizing selective interventions, such as GPVI inhibition, P-selectin blockade, FXI/XIa inhibition, and NETosis modulation, that target pathological platelet activity while preserving essential hemostatic function. In this review, by reframing platelets as the central determinants of PCAS, we report new mechanistic insights and therapeutic opportunities that are complementary to the existing post-arrest strategies and have the potential to improve survival and neurological outcomes after cardiac arrest.

Background/Objectives: Platelets are anucleate cells that play a crucial role in primary hemostasis and arterial thrombosis, contributing to cardiovascular diseases. Eugenol, a bioactive phenolic compound, exhibits vasodilatory, antibacterial, and anticancer properties and inhibits platelet aggregation induced by collagen and arachidonic acid (AA). AA is a critical lipid component of the platelet membrane and a precursor for potent signaling molecules that mediate platelet activation. However, the precise mechanisms through which eugenol modulates AA-stimulated platelet activation remain unclear. Methods: Human platelets were pretreated with eugenol and subsequently stimulated with AA. Platelet aggregation, ATP release, intracellular calcium mobilization, and P-selectin expression were measured. JNK, p38 MAPK, ERK, and vasodilator-stimulated phosphoprotein (VASP) phosphorylation were analyzed by Western blotting. SP600125, SQ22536, and ODQ were used to examine the involvement of JNK and cyclic nucleotide signaling pathways. Antithrombotic effects were further evaluated in a mouse mesenteric thrombosis model. Results: Eugenol significantly suppressed AA-induced platelet aggregation, ATP release, calcium mobilization, and P-selectin expression, selectively reducing JNK phosphorylation without affecting p38 MAPK or ERK. SP600125 produced similar inhibitory effects. Neither SQ22536 nor ODQ reversed eugenol’s inhibitory effects on platelet aggregation. Furthermore, eugenol did not alter VASP phosphorylation at Ser157 or Ser239. In vivo, real-time intravital imaging showed that eugenol and SP600125 delayed thrombus formation and prolonged occlusion time. Conclusions: These findings suggest that eugenol exerts inhibitory effects that may involve modulation of JNK phosphorylation, independent of cyclic nucleotide/VASP pathways in AA-induced platelet activation, highlighting its potential as an antithrombotic agent.