We used IVs of the four platelet indices and BP in the current study to explore their association. In the univariable MR, we found that the levels of PLT and PCT predicted by host genetics were causally associated with an increase in BP (SBP, DBP). PDW was associated with DBP, and the magnitude of its association with SBP was similar but nonsignificant. Univariable MR rules out external interference, but it still fails to disentangle and compare the effects of correlated platelet indices on BP. In MVMR, the relationship between PWD and SBP was again significant, which could be the effect of PDW was concealed by other indices in the univariable MR model. The effect of PLT and PDW on BP remained robust after correcting for collinearity in MVMR (Model 2), whereas PLT and PCT associations with BP became non-significant. These findings suggest that PLT and PDW are the critical traits underlying the positive associations of platelet activation with elevated BP. In the reverse MR, we observed a negligible effect of SBP on PLT and PCT. It means that even a considerable increase in SBP may result in only subtle changes in PCT and PLT. It is worth noting that the findings should not be extrapolated to the extremes, as no amount of BP in humans can increase both PCT and PLT to a significant degree. However, small (beta value) does not imply zero, the p-values were statistically significant suggesting a causal relationship.

Several studies have reported that platelet activation is related to cardiovascular morbidity and mortality [23, 32]. Platelet indices are blood-based parameters related to platelet morphology and proliferation kinetics, and they can be used to reflect the activation of platelets. Increased platelet indices were observed in multiple diseases, such as ischaemic heart disease and ischaemic strokes [19, 24] [33, 34]. So the pathway from platelet activation to changes in platelet indices have been established. In this context, we can theorize that BP level changes when platelets are activated to cause changes in platelet indices. Our findings of the univariable MR study align with earlier studies on PLT concerning the elevation of BP [14, 22]. To the best of our knowledge, no MR study has evaluated the effect of the other platelet indices on BP, whereas the association of hypertension with those indices has been reported in observational studies [14,15,16]. Some studies have also shown that MPV is associated with the incidence of hypertension. Nevertheless, it is worth noting that the conclusions from observational studies are prone to be biased by confounding effects and reverse causation. Our study found no association between MPV and BP, except for PCT.

Studies on the comparative effects of platelet indices on BP are limited. Given the coassociation among platelet indices, it is necessary to explore which trait or traits predominate the influence of platelets on BP. We then performed MVMR to disentangle the comparative effects of platelet indices. The present MR study expanded the preexisting evidence to show that PLT alone with PDW exhibited independent effects. PLT, as is commonly known, measures platelet counts per unit volume of blood, while PCT is the volume occupied by platelets in blood expressed as a percentage and MPV is a marker of the average size of platelets. Therefore, PCT is analogous to the total platelet volume in some way and is correlated to the product of MPV and PLT. The results of MVMR excluding PCT after the colinear test provide evidence that heterogeneity of platelet size, i.e., PDW, is a marker of more significant importance among PCT and MPV. Therefore, high PLT and PDW might be an indication to recognize the role of platelet activation in interpreting the process of hypertension.

In in vitro studies, the increased shear force that platelets are exposed to due to high BP could lead to platelet activation, and the giant platelets are more aggregated and reactive than the smaller platelets [35, 36]. In the reverse direction, the present study found that SBP influences PLT and PCT. However, a previous MR study based on a smaller sample size revealed that hypertension has no effect on PLT [22]. The discrepancy might be caused by inadequate power due to limited phenotypic variance explained by the genetic variants used and/or small sample size for outcomes. Nevertheless, whether BP has effects on platelet activation needs more study.

The benefit obtained from a reduction in BP is undisputed [37, 38]. So the findings of our study are relevant in both clinical and public health terms. We revealed that platelet activation is one of the causes of elevated BP and that it is mirrored by platelet indices, which are potentially valuable markers for evaluating hypertension progression and the early diagnosis of thromboembolic disease. Among the four platelet indices, PLT and PDW played independent and dominant roles, which should be emphasized in clinical practice. As previous studies have shown that platelet activation plays a significant role in embolic disease; the use of antiplatelet management therapies in individuals with high BP should be considered [12, 39]. However, there is a tendency to ignore this primary prevention, and a great deal of attention has been paied to the re-prevention after cardiovascular events. In this study, we give the evidence that antiplatelet therapy in people with high BP is reasonable, so the primary prevention of CVDs in hypertension group should be emphasized. The latest review showed no evidence that antiplatelet therapy modifies mortality in patients with elevated BP for primary prevention [13]. The reason for this result is that bleeding events outweighed the potential benefits. However, this does not mean that antiplatelet therapy is worthless for people with hypertension. In contrast, small doses of antiplatelet therapy may benefit a specific population if BP is controlled smoothly and the risk of bleeding and embolism is accurately assessed. Overall, further randomized controlled trials (RCTs) assessing antithrombotic therapy with complete documentation of all benefits and harms are required in patients with elevated BP.

A consistent limitation of all the discussed observational studies is that platelet indices are influenced by various conditions, which can confound the analysis. Therefore, the strengths of our study are that this potential source of bias was overcome through the use of genetic variants as instruments for platelet indices and the possibility of reverse causation was explored [28, 29, 40]. Furthermore, the multivariable MR method was the major strength, which compared the roles of different correlated platelet traits in BP elevation. We also implemented a rigorous methodological approach, incorporating a range of sensitivity analyses to explore potential bias due to genetic pleiotropy.

This study also has limitations. First, the GWAS of traits associated with platelets was performed in the UK Biobank population, and BP data were available from meta-analyses published by the International Consortium of Blood Pressure (ICBP) and UK Biobank studies. Therefore, there is the potential for overlap in samples and bias related to this fact [31]. Second, we added a more significant number of SNPs as IVs with no horizontal pleiotropy to increase the R2. As a result, the improvement of SNPs in the instrument came increasingly due to heterogeneity. Third, we only included four platelet indices in the study; there may be other hematological markers related to platelets, which means that the dominant role of PLT and PDW could need adjustment when including other traits, such as platelet-large cell ratio (P-LCR).

MR assumes a linear relationship between the exposure and outcome [41], which, in our case, included genetically determined platelet indices and BP level. For this reason, the results of our MR analysis should not be extrapolated to extremes of platelet indices and BP. Of particular note is the possibility that platelets may be a causal risk factor for the progression rather than the onset of hypertension; there could be distinct causes for the initiation and progression of a disease, which means that the causal exposures for disease onset may not necessarily be causal for disease progression (and vice versa) [42].