Reactive oxygen species: Orchestrating the delicate dance of platelet life and death

Figures

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  Fig. 1. The PRISMA flowchart illustrates the literature screening process, detailing the strategy and number of articles screened, the number of articles excluded, and the number of articles included in the final analysis. "Age-old studies" refer to studies that were published or completed a long time ago, especially those before the 1960s, which are widely considered old. "Limited relevance" refers to those that are not fully consistent with the research background or content of this review or have little relevance to the issues discussed in this review.

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  Fig. 2. Summary diagram of ROS generation and removal in platelets. NOX1 and NOX2 are the main ROS-generating enzymes in platelets, mediating the generation of intracellular ROS through the stimulation of collagen and thrombin. As the main organelles for ROS production, mitochondria produce ROS through their electron transport chain, and the endoplasmic reticulum produces ROS through CYP450. Enzymes such as COX1 in platelets produce peroxides and release ROS during the catalysis of arachidonic acid metabolism. Some antioxidant enzymes in cells inhibit the production of excessive ROS to maintain redox balance in the body. Different distributions of SOD1-3 can convert ROS to hydrogen peroxide, which is subsequently decomposed by CAT. NAC can be converted to GSH in vivo to play an antioxidant role. ROS generation and scavenging work together to maintain the dynamic balance of ROS in platelets. NOX, NADPH oxidase; SOD, superoxide dismutase; GSH, glutathione; CAT, catalase.

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  Fig. 3. Platelet production summary chart. These cells initially differentiate from hematopoietic stem cells into pluripotent progenitors, common myeloid progenitors, megakaryotic erythroid progenitors and megakaryotic progenitors, respectively, and then into MKs. MKs undergo intranuclear mitosis, polyploidization and the formation of an invaginated membrane system (IMS) to become mature MKs. The cytoplasm of mature MKs then undergoes reorganization to form extensions known as proplatelets, which migrate to vascular ecological niches in the bone marrow and eventually release platelets into the circulation in response to blood shear forces. TPO is a key regulator of platelet production. Other regulators include the interleukin family. In addition, many transcription factors, such as GATA-1, NF-E2, RUNX1, and TAL1, are involved in regulating various stages of this process. HSCs, hematopoietic stem cells; MPPs, multipotent progenitor cells; CMPs, common myeloid progenitor cells; MEPs, megakaryocytic erythroid progenitor cells; MKPs, megakaryocytic progenitor cells.

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  Fig. 4. Regulation of ROS during MK differentiation and platelet production. ROS play a crucial role in the process of thrombopoiesis. A carefully titrated level of ROS acts as a choreographer, guiding each step of the process. 1. Progressive differentiation of HSCs into mature MKs, accompanied by a gradual increase in ROS levels in the hematopoietic microenvironment; 2. ROS in the microenvironment accelerate mitotic G1 to S phase and polyploid formation in the MK nucleus and promote MK development to ensure that platelets have sufficient genetic material. 3. ROS induce MK migration from the bone marrow niche to the vascular niche and release platelets into the circulation in response to vascular shear. 4. Elevated ROS levels in the bone marrow microenvironment induce cytoskeletal changes in MKs, leading to the formation of proplatelets and promoting their migration toward the vascular endothelium, where they ultimately form platelet buds under vascular shear forces. The rise in ROS at this stage supports proplatelet formation, as well as MK apoptosis, ultimately facilitating platelet release. Notably, the physiological process of MK differentiation and platelet release is accompanied by…

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  Fig. 5. Diagram of the mechanism of ROS-regulated thrombopoiesis. As crucial second messengers in a dynamic feedback loop, ROS not only activate key signaling pathways involved in megakaryocyte maturation and platelet production but are also regulated by multiple proteins and transcription factors. This interplay between ROS and signaling pathways orchestrates megakaryocyte function and ultimately governs platelet formation. However, the mechanism of platelet regulation by ROS is still far from perfect and will be an interesting area for future research. MMP, Mitochondrial membrane potential, ΔΨm.

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  Fig. 6. ROS modulate platelet function. NOX1 and NOX2 are important sources of ROS in platelets and are considered to be responsible for platelet activation. Collagen and thrombin lead to the generation of platelet ROS through platelet NOX1 and NOX2, respectively. ROS produced by NOX1 not only enhance the binding of GPVI to collagen but also induce the generation of TXA2 and further augment platelet function by activating the PI3K/AKT pathway. Similarly, ROS generated by NOX2 activate platelet integrin αIIbβ3, strengthen its interaction with fibrinogen, induce the release of platelet granules, and upregulate P-selectin expression, thereby promoting platelet adhesion and aggregation. Additionally, NOX2-derived ROS activate the JAK/STAT pathway, further enhancing platelet functionality. ROS are important regulators of thrombus formation in vivo and can stimulate platelet activation. Reasonable ROS levels can promote various physiological processes of coagulation, such as mediating the binding of GPVI to collagen, promoting the release of platelet granules, activating integrin αIIbβ3, and increasing the expression of platelet P-selectin. Therefore, platelet activation and coagulation are…

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  Fig. 7. Excessive levels of ROS impair platelet lifespan. Excess ROS disrupt the redox balance of platelets, increase the expression of the apoptotic proteins Bax and Bak, decrease the mitochondrial membrane potential, lead to the phosphorylation of p38MAPK, ERK and JNK, and facilitate the liberation of cytochrome c and its binding to Apaf-1, thereby activating mitochondrial caspase pathway-induced apoptosis. Excess ROS also cause lipid peroxidation in platelets. All of these factors lead to apoptosis, increase platelet clearance, and shorten the platelet lifespan, thus severely reducing the number of platelets. ROS-induced mitochondrial apoptosis in platelets can generate additional ROS through the activation of caspase-3, leading to a sustained loss of ΔΨm thereby creating a vicious cycle. Notably, antioxidants such as NAC can significantly attenuate platelet apoptosis. Cyto c, Cytochrome c; ΔΨm, mitochondrial membrane potential.