Platelets and diseases: signal transduction and advances in targeted therapy

Abstract

Platelets are essential anucleate blood cells that play pivotal roles in hemostasis, tissue repair, and immune modulation. Originating from megakaryocytes in the bone marrow, platelets are small in size but possess a highly specialized structure that enables them to execute a wide range of physiological functions. The platelet cytoplasm is enriched with functional proteins, organelles, and granules that facilitate their activation and participation in tissue repair processes. Platelet membranes are densely populated with a variety of receptors, which, upon activation, initiate complex intracellular signaling cascades. These signaling pathways govern platelet activation, aggregation, and the release of bioactive molecules, including growth factors, cytokines, and chemokines. Through these mechanisms, platelets are integral to critical physiological processes such as thrombosis, wound healing, and immune surveillance. However, dysregulated platelet function can contribute to pathological conditions, including cancer metastasis, atherosclerosis, and chronic inflammation. Due to their central involvement in both normal physiology and disease, platelets have become prominent targets for therapeutic intervention. Current treatments primarily aim to modulate platelet signaling to prevent thrombosis in cardiovascular diseases or to reduce excessive platelet aggregation in other pathological conditions. Antiplatelet therapies are widely employed in clinical practice to mitigate clot formation in high-risk patients. As platelet biology continues to evolve, emerging therapeutic strategies focus on refining platelet modulation to enhance clinical outcomes and prevent complications associated with platelet dysfunction. This review explores the structure, signaling pathways, biological functions, and therapeutic potential of platelets, highlighting their roles in both physiological and pathological contexts.

Fig. 1

Number of growing published articles or studies from 1980 to Jun 2024, based on platelet medicine (pink), therapies (blue), and clinical trials (green). With the continuous discoveries of the structure and origin of platelets, as well as their involvement in many physiological and pathological precessions, the publication of using platelets for treatments has been increasing rapidly. The clinical trials studying platelet transfusion, PRP, and engineered platelets have also been increasing year by year. Data for this figure was extracted from PubMed by searching the term “platelet*” in combination with either “medicine,” “transfusion,” “PRP,” “therap*,” or “treatment.” Data of active clinical trials (recruiting, not yet recruiting, active, not recruiting, completed, enrolling by invitation, unknown status) were acquired from ClinicalTrials.gov

Fig. 2

The origin of platelets. Platelets are mainly derived from MKs in the bone marrow. HSCs gradually differentiate into primitive MKs through continuous proliferation and differentiation into multipotent progenitors and downstream progenitors. Primitive MKs gradually mature, mediated by TPO, forming complex membrane systems and storage granules. Mature MKs form proplatelets, extend into the surrounding sinusoids, and separate platelets through membrane invagination and fusion

Fig. 3

The structure and contents of platelets. Platelets participate in physiological and pathological processes through their complex structure and contents. There are multiple functional receptors expressed outside the platelet membrane and their glycan chain portions form surface glycocalyx. Platelets have no nuclei, and except for conventional organelles such as mitochondria and lysosomes, they also have unique tubular systems and storage granules. In addition, the platelet cytoskeleton provides support for platelet migration, adhesion and aggregation. Platelets also secrete vesicles that carry various signal factors, receptors, mitochondria, and nucleic acid

Fig. 4

Signal transduction and targeted drugs of a P2Y₁/P2Y₁₂, b PARs, and c GPIV/CLEC-2. P2Y₁/P2Y₁₂ and PARs are important GPCRs for platelets, which recognize ADP and thrombin, respectively, and trigger downstream signal transduction through coupled different G proteins, including PLCβ, Rho-GEF, PI3K, etc. GPVI and CLEC-2 are platelet surface immunoglobulin family receptors that participate in platelet activation and immune response through ITAM. These receptors and signal transduction collectively promote activation reactions mediated by platelet calcium influx, including secretion of granules, aggregation, thrombosis, etc. Targeted drugs targeting different receptors can effectively inhibit platelet activation, thereby reducing thrombus formation

Fig. 5

Biological functions of platelet mitochondria. In addition to providing energy to platelets through OXPHOS, platelet mitochondria are involved in regulating platelet activation and apoptosis. External stimuli can mediate intracellular calcium influx, leading to subsequent changes in mitochondrial membrane potential and increased OXPHOS. Under different intensities of stimulation, ROS and ATP produced by mitochondria promote platelet activation on one hand, and regulate platelet apoptosis through the CypD-mPTP pathway and apoptotic protein cascade pathway on the other hand. In addition, activated platelets can regulate immune response and various physiological functions by releasing mitochondria and mtDNA, which are captured by immune cells or tissue cells

Fig. 6

Roles of platelets in the biological processes of hemostasis and thrombosis. Under physiological conditions, platelets are regulated by the release of NO and PGI₂ from endothelial cells to maintain resting state and flow in circulation. When blood vessels are damaged, agonists and adhesion proteins quickly accumulate and promote platelet adhesion to the subendothelial extracellular matrix through surface receptors. After adhesion, platelets are activated by agonists and undergo morphological changes and degranulation. The released cytokines bind to platelet surface-specific receptors and further activate platelets through downstream signaling, recruiting free platelets in the circulation to aggregate. Ultimately, the fibrin network and platelets jointly form the thrombus

Fig. 7

Role of platelets in pathological conditions. This figure depicts the intercellular communication and signaling pathways through which platelets are widely involved in various pathological processes and disease development. Regulating immune response and inflammation is an important mechanism for platelets to participate in diseases, including recognizing antigens through TLRs, secreting pro-inflammatory factors, recruiting and activating immune cells, and secreting vesicles and mitochondria. Inflammatory reaction is the key pathological process of thrombotic diseases, complications of diabetes and autoimmune diseases. In addition, platelets promote tumor progression by promoting tumor cell growth and metastasis, EMT, endothelial cell angiogenesis, and forming TCIPA to suppress immune surveillance