Cardiovascular risk factors are similar in late premenopausal and early postmenopausal women, matched by age and body composition, with the exception that postmenopausal women have higher high- and low-density lipoprotein-cholesterol levels. A 3-month intervention of high-intensity aerobic training reduces risk factors for type 2 diabetes and cardiovascular disease to a similar extent in late premenopausal and early postmenopausal women.

Background The risk of atherothrombotic events increases after the menopause. Regular physical activity has been shown to reduce platelet reactivity in younger women, but it is unknown how regular exercise affects platelet function after the menopause. Objectives To examine the effects of regular aerobic exercise in late premenopausal and recent postmenopausal women by testing basal platelet reactivity and platelet sensitivity to prostacyclin and nitric oxide. Methods Twenty-five sedentary, but healthy, late premenopausal and 24 matched recently postmenopausal women, mean (95% confidence interval) 49.1 (48.2-49.9) and 53.7 (52.5-55.0) years old, participated in an intervention study: 3-month high-intensity supervised aerobic spinning-cycle training (1 h, × 3/week). Basal platelet reactivity was analyzed in platelet-rich plasma from venous blood as agonist-induced % aggregation. In a subgroup of 13 premenopausal and 14 postmenopausal women, platelet reactivity was tested ex vivo after femoral arterial infusion of prostacyclin, acetylcholine, a cyclooxygenase inhibitor, and after acute one-leg knee extensor exercise. Results Basal platelet reactivity (%aggregation) to TRAP-6 (1 μm) was higher in the postmenopausal, 59% (50-68), than the premenopausal women, 45% (35-55). Exercise training reduced basal platelet reactivity to collagen (1 μg mL ) in the premenopausal women only: from 63% (55-71%) to 51% (41-62%). After the training intervention, platelet aggregation was more inhibited by the arterial prostacyclin infusion and the acute exercise in both premenopausal and postmenopausal women. Conclusions These results highlight previously unknown cardioprotective aspects of regular aerobic exercise in premenopausal and postmenopausal women, improving their regulation of platelet reactivity through an increased platelet sensitivity to prostacyclin, which may counterbalance the increased atherothrombotic risk associated with the menopause.

Rationale: Data on the molecular mechanisms that regulate platelet-pulmonary endothelial adhesion under conditions of hypoxia are lacking, but may have important therapeutic implications.Conclusions: The NEDD9-P-selectin protein-protein interaction is a modifiable target with which to inhibit platelet-pulmonary endothelial adhesion and thromboembolic vascular remodeling, with potential therapeutic implications for patients with disorders of increased hypoxia signaling pathways, including CTEPH.

The current guidelines following an acute coronary syndrome recommend dual‐antiplatelet therapy (DAPT) (aspirin plus a P2Y12 antagonist) alongside lifestyle modifications, including more regular physical activity. It is currently unknown whether regular exercise affects the pharmacology of DAPT. Aim To explore how exercise‐induced improvements in vascular and platelet function affect the efficacy of DAPT, in a cross‐sectional study of men with different physical activity levels (training status). Methods A total of 42 healthy, normal‐weight, middle‐aged men were divided into 3 groups: untrained, moderately trained and well‐trained. Their platelet reactivity (agonist‐induced % aggregation) was investigated in platelet‐rich plasma at rest and after inhibition with aspirin and ticagrelor and/or prostacyclin and nitric oxide added to the blood in vitro, and after physiological tests of vascular function; passive movement of the leg, flow‐mediated dilation and one‐leg knee‐extensor exercise. Vascular function of the femoral artery (changes in arterial blood flow) was assessed by ultrasound Doppler. Results Platelets from the well‐trained subjects had lower basal reactivity, a higher sensitivity to the anti‐aggregatory effects of prostacyclin and were more potently inhibited by DAPT compared to the untrained subjects. The moderately trained and well‐trained subjects had a superior vascular function compared to untrained subjects, and their platelets were more inhibited by the passive movement, flow‐mediated dilation and one‐leg knee‐extensor exercise. Discussion A habitually active lifestyle leads to an increased platelet sensitivity to pharmacological and physiological platelet inhibitors. We suggest that physical activity habits (training status) should be considered when personalizing and optimizing antithrombotic treatment strategies.

Antisense oligonucleotides (ASOs) are DNA-based, disease-modifying drugs. Clinical trials with 2'-O-methoxyethyl (2’MOE) ASOs have reported dose- and sequencespecific lowering of platelet counts according to two phenotypes. Phenotype 1 is a moderate (but not clinically severe) drop in platelet count. Phenotype 2 is rare, severe thrombocytopenia. This paper will focus on the underlying cause of the more common Phenotype 1, investigating the effects of ASOs on platelet production and platelet function. Five phosphorothioate ASOs were included: three 2’MOE sequences; 487660 (no effects on platelet count), 104838 (associated with Phenotype 1), 501861 (effects unknown) and two CpG sequences; 120704 and ODN 2395 (known to activate platelets). Human cord blood-derived megakaryocytes were treated with these ASOs to study effects on proplatelet production. Platelet activation (surface P-selectin) and platelet-leukocyte aggregates (PLAs) were analyzed in ASO-treated blood from healthy human volunteers. None of the ASOs inhibited proplatelet production from human megakaryocytes. All the ASOs were shown to bind to the platelet receptor glycoprotein VI (GPVI, KD ~0.2-1.5μM). CpG ASOs had the highest affinity to GPVI and the most potent platelet activating effects and PLA formation. 2’MOE ASO 487660 had no detectable platelet effects, while 2’MOE ASOs 104838 and 501861 triggered moderate platelet activation and SYK-dependent formation of PLAs. Donors with higher platelet GPVI levels had larger ASO-induced platelet activation. Sequence-dependent ASO-induced platelet activation and PLAs may explain Phenotype 1- moderate drops in platelet count. Platelet GPVI levels could be useful as a screening tool to identify patients at higher risk of ASO-induced platelet side effects.