Platelets are small anucleate discoid cells derived from megakaryocytes in bone marrow. Each megakaryocyte produces up to 1,000–5,000 platelets and approximately 1×10¹¹ platelets/day are generated under physiologic conditions [1]. They play an essential role in hemostasis, thrombosis, inflammation, and vascular injury, and contribute to the pathogenesis of atherogenesis and thrombosis. Platelet indices are automatically derived from a routine complete blood count by automated hematology equipment without additional cost [1].

Among these platelet indices, mean platelet volume (MPV) is potentially an important parameter of platelet reactivity and size, and a readily available marker for platelet function [2]. Larger platelets are more active and have higher thrombotic potential because they are younger, have more expression of adhesion receptors, contain more intracytoplasmic granules, are more metabolically and enzymatically reactive, and aggregate more strongly with collagen in such as exposed endothelial cells, hence possessing increased thrombogenic and inflammatory characteristics [2]. Platelets represent a time-dependent swelling when blood samples are anticoagulated with Ethylenediaminetetraacetic acid (EDTA), however, this phenomenon was not observed in the citrate tube [3]. Therefore, it is recommended that MPV be measured in venous blood collected in ethylenediamine tetraacetic acid within 2 hours.

MPV has also been proposed as a marker of platelet consumption and resulting compensatory bone marrow response during the disease process [4]. Thrombopoietin and interleukine-6 (IL-6) are important cytokines in the production of platelets from megakaryocytes in the bone marrow. In particular, IL-6 stimulates the growth of megakaryocytes through surface receptors, which increases nuclear ploidy and the size of megakaryocytes and the shedding of larger cytoplasmic fragments [5]. MPV is inversely proportional to the platelet count in both physiological and some pathological conditions due to the tendency to maintain a constant platelet mass [6].

The relationship between MPV and thrombotic events such as cardiovascular and cerebrovascular diseases is not surprising, because platelets with increased MPV are abundant in aggregatory molecules and adhesive substances [7]. Besides hemostasis and thrombosis, platelet count and MPV have been researched as inflammatory markers. MPV is one of the most widely evaluated blood parameters associated with platelet function, especially in inflammatory conditions. Increased MPV has been observed in autoimmune intestinal diseases, rheumatoid diseases, diabetes, coronavirus disease 2019 (COVID-19) and various cancers [8]. In this study, we review recent perspectives on the various clinical implications of MPV (Fig. 1) through literature review.

Coronary artery disease (CAD) is one of the most common causes of death worldwide, showing the highest age-standardized rate 108.8 deaths per 100,000 [9-11]. Many risk factors for CAD have been found, including hypertension, diabetes, hyperlipidemia, obesity, smoking, and metabolic syndrome [10]. However, some individuals do not develop CAD despite having these risk factors, and conversely, CAD can develop in individuals who do not have any risk factors [9]. High-sensitivity C-reactive protein, carotid intimal media thickness and coronary calcium score have been proposed as effective biological markers for predicting CAD, however, because they are difficult and expensive to measure and unavailable in routine practice, there is a need to identify biological markers that are more clinically accessible [10].

MPV is significantly larger in patients with CAD and slow coronary blood flow than in controls [7,10]. In addition, MPV tends to be larger in acute coronary events than in stable CAD [10]. Moreover, patients with high MPV are more than twice as likely to develop CAD than patients with low MPV [7,11] Homocysteine, a well-known risk factor for cardiovascular disease, has been associated with an increase in platelet activation, which is very frequent in patients with cardiovascular disease [11]. The relationship between homocysteine and cardiovascular disease events is significantly stronger in patients with a large MPV [11].

MPV was found to be an independent predictor of long-term mortality in CAD patients. It has been reported that a 1 femtoliter increase in MPV levels is significantly related to a rise of 29% in the risk of follow-up mortality [9]. In the background pathophysiology, activated platelets can also intensify the inflammatory process, resulting in plaque formation, progression and instability [9]. Simultaneously, endothelial dysfunction shows a close association with higher MPV values. The damaged endothelium enhances platelet reactivity and aggregation, thereby increasing the risk of coronary thrombosis [9,12]. Because larger platelets are more active than smaller ones, they have greater prothrombotic behavior, secreting more pro-thrombotic substances and adhering more strongly to vascular surfaces. MPV is a valuable, easily measurable marker for assessing risk and prognosis in CAD patients, potentially guiding therapeutic decisions and risk stratification strategies [9,12].

Antiplatelet treatment decreases the incidence of both complications and ischemic cardiovascular events after percutaneous coronary intervention [13]. It has been suggested that high MPV levels are associated with low responses to aspirin and clopidogrel [14]. Some studies have reported that an increase in MPV over time after percutaneous coronary intervention is associated with high platelet reactivity during anti-platelet therapy [15]. Moreover, MPV was suggested to be superior to platelet function testing in terms of predicting cardiac death or cardiovascular events in patients who had undergone percutaneous coronary intervention, particularly in an acute coronary syndrome group [16]. Although there has been some debate, MPV should not be overlooked as a marker for impaired prognosis in patients with vascular disorders [7].

In addition, previous studies have suggested a potential relationship between MPV and poor clinical outcomes for acute ischemic stroke, however, the conclusions have remained controversial. One meta-analysis suggested that elevated MPV may be a predictor of adverse clinical outcomes in acute ischemic stroke, especially in non-thrombolytic patients [17]. Further studies are also needed to investigate MPV changes in thrombophilic conditions such as venous thrombosis.

In autoimmune diseases, immune complexes activate platelets. In rheumatoid arthritis, the platelet is a source of prostaglandins within the inflamed synovium [18]. Platelet-derived vesicles, which are abundant in synovial fluid, stimulate synovial fibroblasts to release inflammatory mediators [18]. Moreover, serotonin released by platelets enhances endothelial permeability of the inflamed synovium [19]. High-grade inflammation accompanies a low MPV in rheumatoid arthritis, possibly due to the preferential consumption of larger platelets at the sites of inflammation [19]. Inverse correlations of MPV with erythrocyte sedimentation rate, C-reactive protein, and disease activity score in 28 joints were found in rheumatoid arthritis patients [20]. MPV is negatively correlated with both the Bath Ankylosing Spondylitis Disease Activity Index in ankylosing spondylitis and with C-reactive protein in psoriatic patients. An inverse correlation of MPV with erythrocyte sedimentation rate is also seen in lupus patients [20]. Overall, a low MPV level indicated an inflammatory state in a large number of rheumatic patients [20]. Some investigators have suggested that MPV can be used as a negative marker in these patients [21].

Inflammatory bowel disease (IBD) is a complex disorder in which environmental and genetic factors such as an altered immune microbiome axis and increased intestinal permeability lead to a dysregulated immune system, inducing gastrointestinal damage [22]. Ulcerative colitis and Crohn’s disease fall into this category. One meta-analysis found that inflammatory bowel disease patients had 0.83fL lower MPV as compared to the healthy control group. This could also be due to consumption or sequestration of larger platelets in the damaged vascular segments associated with high-grade inflammation in the disease [19,22,23].

Autoimmune thyroid disease is the most common autoimmune disease, mainly including Graves’ disease and Hashimoto’s thyroiditis. It has been found that platelets and MPV were significantly higher in the autoimmune thyroid disease population [24]. The conventional perception that abnormal thyroid hormone levels lead to elevated MPV could explain this phenomenon [24].

However, MPV has been reported to be elevated in autoimmune inflammatory diseases such as Behcet’s disease and psoriasis [25-27]. In particular extracutaneous comorbidities, patients with psoriasis are more likely to exhibit comorbid atherosclerotic vascular diseases such as cardiovascular, cerebrovascular, and peripheral vascular diseases [25]. In Behcet’s disease, several mechanisms such as infection, immune complexes and environmental factors have been suggested as causative factors [26]. These pathogenic factors are thought to activate platelets and increase MPV in these two diseases. As such, the determinant of whether MPV increases or decreases appears to be how many large and young platelets are formed and how quickly they are consumed at the site. MPV was significantly lower in highgrade inflammatory diseases such as rheumatoid arthritis or inflammatory bowel disease compared to a healthy control group [27]. On the other hand, low-grade inflammatory diseases such as Behcet’s disease or psoriasis show higher MPV compared to a healthy control group [27].

Neonatal sepsis is a significant cause of newborn morbidity and mortality [28]. In the neonatal sepsis group, MPV was significantly higher compared to the control group [27]. An increased MPV during the first day of postpartum may be predictive of early-onset neonatal sepsis and mortality [28]. The MPV was also higher during a late-onset sepsis event which is a usual complication of preterm newborns in the neonatal intensive care unit [29]. Therefore, a simple routine hematologic blood test for MPV can help with both the diagnosis and prognosis of neonatal sepsis [27,28].

COVID-19 is one of the most prevalent infectious diseases in the world. Increased MPV is associated with severity and mortality in patients with COVID-19 [30]. The mechanisms of platelet alteration in COVID-19 infection seem to be complex and multifactorial [30]. Coronavirus directly involves the bone marrow, and IL-6 directly acts on megakaryocytes to produc more platelets [31].

More than 500,000 fetal and neonatal deaths and more than 70,000 maternal deaths per year occur worldwide due to pre-eclampsia [32]. Preeclampsia might affect maternal multiple organs and present as HELLP-syndrome including hemolysis, elevated liver enzymes, low platelet counts, cerebral symptoms in severe cases as eclampsia [33]. Pregnancy changes the maternal hemostatic equilibrium, shifting it toward a hypercoagulable state and exacerbating this equilibrium shift [34]. Even in normal pregnancy, an increase in platelet aggregation is compensated for by an increase in platelet synthesis and MPV [35]. In conditions complicated by hypertensive disorders, uncontrolled intravascular platelet activation, fibrin deposition, and platelet consumption have been described, resulting in increased MPV towards the end of gestation [33,37]. Endothelial cell dysfunction increases platelet activation, leading to increased total platelet consumption, which causes thrombocytopenia, a prevalent hematological abnormality in pre-eclampsia [2]. Therefore, MPV was significantly higher in the pre-eclampsia than in the healthy pregnant group [34,36].

Platelets could also be associated with tumor proliferation and angiogenesis by secretion of various growth factors and interleukins [37]. IL-6 may be related to tumor progression via proliferation and differentiation of megakaryocyte progenitor cells [38]. MPV can be affected under these circumstances. In malignant tumors in one recent systematic review, MPV was higher in pre-treatment states and subsequently decreased after treatment [39]. Tumor cells secrete cytokines that contribute to a prothrombotic microenvironment, like platelet activation [40]. By secreting proinflammatory cytokines and growth factors, platelets play a pivotal role in cancer progression and metastasis, because inflammation is a critical component of tumor progression [41]. An increase in MPV is found in many neoplastic diseases, although in some cancers a decrease has been reported. Many studies in gastric, breast, endometrium, thyroid, and lung cancer have found an increased MPV in cancer patients [41]. However, decreased MPV was observed in renal cell carcinoma and gallbladder cancer [41]. These results emphasize that specific organs and different types of tumors or stages of cancer may affect MPV in different manners [41]. In addition, chemotherapy can also decrease MPV, reflecting a reduction in inflammatory burdens [42].

MPV increases when platelets become activated and that large platelets are more likely to be reactive than small ones. MPV can be a potential easily measured in vivo marker for platelet activation. For example, MPV has been regarded as a predictive factor of long-term mortality in coronary artery disease patients. However, in many other disease conditions, changes in MPV have been reported to vary depending on the cause of the increase or decrease in platelet size, and there are even conditions in which there is no change in MPV. Therefore, we believe that increasing or decreasing MPV requires a disease-specific approach and will require further studies to validate its clinical utility.