Increased Platelet Activation Research Articles

Anti-high-mobility group box-1 treatment strategies improve trauma-induced coagulopathy in a mouse model of trauma and shock

BackgroundTrauma-induced coagulopathy is associated with platelet dysfunction and contributes to early mortality after traumatic injury. Plasma concentrations of the damage molecule high-mobility group box-1 (HMGB-1) increase after trauma, which may contribute to platelet dysfunction. We hypothesised that inhibition of HMGB-1 with a monoclonal antibody (mAb) or with recombinant thrombomodulin (rTM) improves trauma-induced coagulopathy in a murine model of trauma and shock. MethodsMale 129S2/SvPasOrlRJ mice were anaesthetised, mechanically ventilated, and randomised into five groups: (i) ventilation control (VENT), (ii) trauma/shock (TS), (iii) TS+anti-HMGB-1 mAb (TS+AB), (iv) TS+rTM (TS+TM), and (v) TS+anti-HMGB-1 mAb+rTM (TS+COMBI). Primary outcome was rotational thromboelastometry EXTEM. Secondary outcomes included tail bleeding time, platelet count, plasma HMGB-1 concentration, and platelet activation. ResultsTrauma and shock resulted in a hypocoagulable thromboelastometry profile, increased plasma HMGB-1, and increased platelet activation markers. TS+AB was associated with improved clot firmness after 5 min compared with TS (34 [33–37] vs 32 [29–34] mm; P=0.043). TS+COMBI was associated with decreased clot formation time (98 [92–125] vs 122 [111–148] s; P=0.018) and increased alpha angle (77 [72–78] vs 69 [64–71] degrees; P=0.003) compared with TS. TS+COMBI also reduced tail bleeding time compared with TS (P=0.007). The TS+TM and TS+COMBI groups had higher platelet counts compared with TS (P=0.044 and P=0.041, respectively). ConclusionsInhibition of HMGB-1 early after trauma in a mouse model improves clot formation and strength, preserves platelet count, and decreases bleeding time.

Platelet indices and blood pressure: a multivariable mendelian randomization study

BackgroundPlatelet indices are blood-based parameters reflecting the activation of platelets. Previous studies have identified an association between platelet indices and blood pressure (BP). However, causal inferences are prone to bias by confounding effects and reverse causation. We performed a Mendelian randomization (MR) study to compare the causal roles between genetically determined platelet indices and BP levels.MethodsSingle-nucleotide polymorphisms (SNPs) associated with platelet count (PLT), plateletcrit (PCT), mean platelet volume (MPV), platelet distribution width (PDW), and BP at the level of genome-wide significance (p < 5 × 10− 8) in the UK Biobank were used as instrumental variables. In bidirectional univariable MR analyses, inverse variance-weighted (IVW), MR‒Egger, and weighted median methods were used to obtain estimates for individual causal power. In addition, heterogeneity and sensitivity analyses were performed to examine the pleiotropy of effect estimates. Finally, multivariable MR analyses were undertaken to disentangle the comparative effects of four platelet indices on BP.ResultsIn the univariable MR analyses, increased levels of PLT and PCT were associated with higher BP, and PDW was associated with higher DBP alone. In the reverse direction, SBP had a minor influence on PLT and PCT. In multivariable MR analysis, PDW and PLT revealed an independent effect, whereas the association for PCT and MPV was insignificant after colinear correction.ConclusionThese findings suggest that platelets and BP may affect each other. PDW and PLT are independent platelet indices influencing BP. Increased platelet activation and aggregation may be involved in the pathogenesis of hypertension, which may provide insights into evaluating thromboembolic events in people with high BP. The necessity of initiating antiplatelet therapy among hypertension groups needs further investigation.

Increased platelet activation and lower platelet-monocyte aggregates in COVID-19 patients with severe pneumonia.

The increased procoagulant platelets and platelet activation are associated with thrombosis in COVID-19. In this study, we investigated platelet activation in COVID-19 patients and their association with other disease markers. COVID-19 patients were classified into three severity groups: no pneumonia, mild-to-moderate pneumonia, and severe pneumonia. The expression of P-selectin and activated glycoprotein (aGP) IIb/IIIa on the platelet surface and platelet-leukocyte aggregates were measured prospectively on admission days 1, 7, and 10 by flow cytometry. P-selectin expression, platelet-neutrophil, platelet-lymphocyte, and platelet-monocyte aggregates were higher in COVID-19 patients than in uninfected control individuals. In contrast, aGPIIb/IIIa expression was not different between patients and controls. Severe pneumonia patients had lower platelet-monocyte aggregates than patients without pneumonia and patients with mild-to-moderate pneumonia. Platelet-neutrophil and platelet-lymphocyte aggregates were not different among groups. There was no change in platelet-leukocyte aggregates and P-selectin expression on days 1, 7, and 10. aGPIIb/IIIa expression was not different among patient groups. Still, adenosine diphosphate (ADP)-induced aGPIIb/IIIa expression was lower in severe pneumonia than in patients without and with mild-to-moderate pneumonia. Platelet-monocyte aggregates exhibited a weak positive correlation with lymphocyte count and weak negative correlations with interleukin-6, D-dimer, lactate dehydrogenase, and nitrite. COVID-19 patients have higher platelet-leukocyte aggregates and P-selectin expression than controls, indicating increased platelet activation. Compared within patient groups, platelet-monocyte aggregates were lower in severe pneumonia patients.

Increased Platelet Activation demonstrated by Elevated CD36 and P-Selectin Expression in 1-Year Post-Recovered COVID-19 Patients.

Coronavirus disease 2019 (COVID-19)-associated hypercoagulability and platelet hyperactivity are characteristic of COVID-19 infection and contribute to an increased thrombotic burden. This clinical phenomenon is observed during acute illness and the immediate post-recovery period. In addition to findings of hypercoagulability, endotheliopathy, and inflammation from our previous study of 39 COVID-19 survivors at a time point approximating 1 year after their recovery from COVID-19,[1] we evaluated the platelet activation profile of a subset of 36 patients, demonstrating increased platelet activation with elevated CD36 and P-selectin expression compared with healthy individuals without COVID-19 infection.

Elevated mean platelet volume may predict vaso-occlusive complications in type diabetes mellitus

Diabetes is an international metabolic pandemic condition. In this metabolic issue, increased platelet activity may play the role of mean platelet volume (MPV) as a risk factor for the development of vascular disease.

A Phytoprostane from Gracilaria longissima Increases Platelet Activation, Platelet Adhesion to Leukocytes and Endothelial Cell Migration by Potential Binding to EP3 Prostaglandin Receptor.

Plant phytoprostanes (PhytoPs) are lipid oxidative stress mediators that share structural similarities with mammal prostaglandins (PGs). They have been demonstrated to modulate inflammatory processes mediated by prostaglandins. The present study aims to test the effects of the most abundant oxylipin from Gracilaria longissima, ent-9-D1t-Phytoprostane (9-D1t-PhytoP), on platelet activation and vascular cells as well as clarify possible interactions with platelets and the endothelial EP3 receptor Platelet and monocyte activation was assessed by flow cytometry in the presence of purified 9-D1t-PhytoP. Cell migration was studied using the human Ea.hy926 cell line by performing a scratch wound healing assay. The RNA expression of inflammatory markers was evaluated by RT-PCR under inflammatory conditions. Blind docking consensus was applied to the study of the interactions of selected ligands against the EP3 receptor protein. The 9D1t-PhytoP exerts several pharmacological effects; these include prothrombotic and wound-healing properties. In endothelial cells, 9D1t-PhytP mimics the migration stimulus of PGE2. Computational analysis revealed that 9D1t-PhytP forms a stable complex with the hydrophobic pocket of the EP3 receptor by interaction with the same residues as misoprostol and prostaglandin E2 (PGE2), thus supporting its potential as an EP3 agonist. The potential to form procoagulant platelets and the higher endothelial migration rate of the 9-D1t-PhytoP, together with its capability to interact with PGE2 main target receptor in platelets suggest herein that this oxylipin could be a strong candidate for pharmaceutical research from a multitarget perspective.

Platelet functions in tethered heifers in the process of growing them

In the course of growing heifers on tethered content, there is a tendency to some decrease in the severity of platelet lipid peroxidation due to an increase in their antioxidant protection. In platelets, this is accompanied by activation of the actin-myosin system, a high level of adenosine phosphates, and their intense secretion in the case of platelet participation in hemostasis. The observed heifers showed a tendency to increase the hemostatic functions of platelets, manifested in the blood and in vitro. The revealed slight increase in platelet activity in tethered heifers is caused by maturation during rearing of surface and intracellular mechanisms of platelet participation in hemostasis and microcirculation processes.

Fibrinogen, Coagulation, and Ageing.

The World Health Organization estimates that the world's population over 60years of age will nearly double in the next 30years. This change imposes increasing demands on health and social services with increased disease burden in older people, hereafter defined as people aged 60years or more. An older population will have a greater incidence of cardiovascular disease partly due to higher levels of blood fibrinogen, increased levels of some coagulation factors, and increased platelet activity. These factors lead to a hypercoagulable state which can alter haemostasis, causing an imbalance in appropriate coagulation, which plays a crucial role in the development of cardiovascular diseases. These changes in haemostasis are not only affected by age but also by gender and the effects of hormones, or lack thereof in menopause for older females, ethnicity, other comorbidities, medication interactions, and overall health as we age. Another confounding factor is how we measure fibrinogen and coagulation through laboratory and point-of-care testing and how our decision-making on disease and treatment (including anticoagulation) is managed. It is known throughout life that in normal healthy individuals the levels of fibrinogen and coagulation factors change, however, reference intervals to guide diagnosis and management are based on only two life stages, paediatric, and adult ranges. There are no specific diagnostic guidelines based on reference intervals for an older population. How ageing relates to alterations in haemostasis and the impact of the disease will be discussed in this chapter. Along with the effect of anticoagulation, laboratory testing of fibrinogen and coagulation, future directions, and implications will be presented.

Do Mean Platelet Volume and Platelet Distribution Width Have An Association with White Matter Hyperintensities in Migraine Patients?

Abstract Objective: Increased prevalence of white matter hyperintensities (WMH) is reported in migraine patients; however, the pathophysiology and the progression of these lesions are not definitely clear. Mean platelet volume (MPV) and platelet distribution width (PDW) are easily obtained markers for platelet activity. The aim of this study is to evaluate the relationship between the presence of WMH and MPV and PDW in patients with migraine in order to determine the role of platelet activity in the pathophysiology of WMH. Methods: Patients who were admitted to the neurology outpatient clinics of Baskent University Hospital from January 2011 to December 2015 with migraine and between 18 and 55 years of age were evaluated retrospectively. The blood samples were taken and total blood count parameters including MPV and PDW were analyzed. Brain magnetic resonance images were evaluated. Results: Totally, 218 patients were evaluated in this study. Forty-eight (22.0%) patients had WMH in the brain magnetic resonance imaging. In patients with WMH, the median of age was higher than the patients without WMH and the difference was statistically significant (P &lt; 0.05). There was no statistically significant difference between MPV, PDW values, and the presence of WMH. Conclusions: There are multiple theories suggested for the mechanism of WMH, but the major cause and pathophysiology are still undetermined. Our data suggested that increased platelet activity is insufficient by itself to explain the pathophysiology of WMH in migraine patients and to improve the knowledge on this issue further large longitudinal studies should be performed.

Impact of obstructive sleep apnea on platelet activation and development of silent brain infarctions

BackgroundObstructive sleep apnea (OSA) is a unique potent predictor for stroke compared to other predictors. By aiding in the adherence of leukocytes and platelets, soluble P-selectin (sP-selectin) contributes to the development of ischemic stroke. The objective of this study was to investigate the independent impact of OSA on platelet activation and development of silent brain infarction. Twenty-four OSA patients and 24 controls were studied in a case–control study, who underwent one-night polysomnography, magnetic resonance imaging for evaluation of silent brain infarctions (SBI), measurement of serum (sP-selectin) levels for assessment of increased platelet activation and C-reactive protein (CRP) serum levels.ResultsOut of 24 patients, 5 (20.8%) had mild OSA and 8 (33.3%) had moderate and 11 (45.8%) had severe OSA. Serum levels of sP-selectin were statistically significantly higher in moderate and severe groups (p < 0.001). Eleven (57.9%) patients in moderate and severe OSA had SBI. Fifty percent of patients with moderate OSA had elevated serum sP-selectin and 25.0% of them had SBI and 81.8% of severe OSA patients had elevated serum sP-selectin and 81.8% of them had SBI. Patients with mild OSA and controls had no SBI and normal serum sP-selectin level. CRP was statistically significantly higher in moderate and severe OSA groups (16.6% and 45.8%) than the mild and control groups (4.1% and 0%) (p < 0.001).ConclusionModerate and severe obstructive sleep apnea were associated independently with elevated serum sP-selectin reflecting increased platelet function, elevated inflammatory marker CRP and an increased risk of silent brain infarctions.

Role of platelet indices as diagnostic and predictive biomarkers for comorbidity of diabetes and metabolic syndrome in southern Ethiopia: A comparative cross-sectional study.

Metabolic syndromes (MetS) and diabetes mellitus (DM) comorbidity is a growing major global public health problem with huge morbidity and mortality. It is a pro-inflammatory and prothrombotic disorder characterized by alteration of platelet indices and increased platelet activation, however, the tendency to use them in diagnosis is not yet fully evaluated in our context and there is limited evidence on the role of platelet indices in predicting and differentiating DM+MetS comorbidity in Ethiopia. Thus, this study aimed to evaluate platelet indices in HC, DM, and DM+MetS, and to determine their role in the prediction of DM+MetS comorbidity risk and the distinction between DM+MetS and DM or healthy persons in southwest Ethiopia. A comparative cross-sectional study was conducted in Wolkite University specialized hospital from March to August 2021. A total of 336 study participants (112 healthy controls (HC), 112 DM, 112 DM+MetS) was included in this study. Anthropmetric data were measured and the venous blood sample was collected to determine platelet indices, lipid profiles, and blood glucose levels. The SPSS version 21 statistical software was used to perform receiver operating curve (ROC), one-way ANOVA, and independent T-test analysis. The p-value for statistical significance was set at &lt;0.05. In the present study, we found a significant difference in the mean value of PLT, MPV, and PDW between DM+MetS, DM, and HC. A statistically significant difference in the mean value of MPV and PDW was observed between HC and DM+MetS as well as DM and DM+MetS (p-value&lt;0.001). At the cutoff value of 9.65fl with a sensitivity of 81.3% and a specificity of 67.9%, MPV differentiates DM+MetS from HC with an AUC of 0.859. MPV can differentiate DM+MetS from DM at a cutoff value of 10.05fl with sensitivity, specificity, and an AUC of 67.9%, 65.2%, and 0.675, respectively. At the cutoff value of 9.65fl with a sensitivity of 69.6% and a specificity of 67.9%, MPV differentiates DM from HC with an AUC of 0.747. The best platelet parameter identified in this study for predicting the presence of DM+MetS comorbidity was MPV (AUC=0.859; 95%CI=0.81-0.90). In this study, a significant difference in the mean value of PLT, MPV, and PDW was found between DM+MetS, DM, and HC. The mean value of platelet indices showed significant increases in DM+MetS patients in comparison to HC and DM. MPV has been identified as a good potential marker to predict DM+MetS comorbidity and to differentiate DM+MetS comorbidity from the HC or DM. Our results show that MPV could be a good hematological marker to differentiate DM+MetS comorbidity from the HC or DM, and may offer supportive information for early diagnosis, prevention, and control. Thus, the findings of this study should be taken into account for the prevention and control of DM+MetS comorbidity.

Abstract 10178: Concurrent Left Ventricular and Left Anterior Coronary Artery Thrombus; Is Covid-19 an Innocent Bystander?

Case presentation: A 36-year-old male was admitted to a local hospital with respiratory failure secondary to COVID-19 pneumonia. Initial management included oxygen, dexamethasone and baricitinib. On day 14 of illness the patient developed severe chest pain associated with widespread dynamic ST segment elevation and an elevated high sensitivity troponin I (17516 ng/L). He was transferred to a tertiary center for cardiac evaluation. Cardiovascular risk factors included treated hypertension and obesity (BMI 34). Physical exam revealed a blood pressure of 145/95 mmHg, regular heart rate at 90 bpm and coarse crepitations in bilateral lower lungs with a 3L oxygen requirement. Differentials included myopericarditis however, clinical suspicion for an acute coronary syndrome remained high. Urgent coronary angiogram revealed a large filling defect (figure 1A) at the mid-vessel of the LAD at the 1st diagonal bifurcation, likely a thrombus. Dual antiplatelet therapy, heparin and tirofiban infusion were commenced. Furthermore, echocardiography performed the same day revealed a reduced LVEF secondary to LAD territory hypokinesis and an associated apical left ventricular thrombus measuring 2.2x1.3 cm (figure 1B). Once established on anticoagulation the patient experienced no further chest pain and was discharged home on warfarin.The left ventricular thrombus was monitored for resolution in the community with serial transthoracic echocardiograms. Discussion: Raised highly sensitive troponin in the vicinity of severe COVID-19 infection is common, however, when associated with chest pain and or dynamic ECG changes myocarditis must be considered. The cytokine storm triggered by a SARS-CoV-2 infection can be thrombogenic, resulting from increased platelet activation and decreased fibrinolysis. This process may further complicate the evaluation and acute coronary syndrome does need consideration, even in those patients at a younger age with minimal risk factors.

Thromboinflammation in oncogynecological patients

Studies of the pathogenesis of thrombosis and inflammation and their contribution to tumor progression and metastasis in cancer patients, initiated many decades ago, have been continued to this day. At the same time, thrombosis and inflammation are inextricably linked to each other. One of the central places in thromboinflammation is held by the loss of normal antithrombotic and anti-inflammatory function in endothelial cells, which leads to dysregulated coagulation, imbalanced the complement system, platelet activation and recruitment of leukocytes in the microvasculature. In turn, tumor cells affect the hemostasis by releasing procoagulant substances, activating fibrinolysis, proteolysis, increasing platelet activation and aggregation, releasing adhesion molecules, secreting pro-inflammatory and pro-angiogenic cytokines. Future research aims to advance an understanding of thromboinflammation in oncology, particularly focusing on the role of platelets beyond hemostasis and thrombosis, as well as some new players in the process. In the future, the main attention will be paid to investigating molecular mechanisms that regulate cancer-related thromboinflammation, providing insights into mechanisms underlying both inflammation and thrombosis as pathogenetic components in cancer patients. Altogether, it will provide an opportunity to create new, modern strategies to treat cancer patients.

Effect of stimulated platelets in COVID-19 thrombosis: Role of alpha7 nicotinic acetylcholine receptor.

Since early 2020, SARS-CoV-2-induced infection resulted in global pandemics with high morbidity, especially in the adult population. COVID-19 is a highly prothrombotic condition associated with subsequent multiorgan failure and lethal outcomes. The exact mechanism of the prothrombotic state is not well understood and might be multifactorial. Nevertheless, platelets are attributed to play a crucial role in COVID-19-associated thrombosis. To date, platelets' role was defined primarily in thrombosis and homeostasis. Currently, more focus has been set on their part in inflammation and immunity. Moreover, their ability to release various soluble factors under activation as well as internalize and degrade specific pathogens has been highly addressed in viral research. This review article will discuss platelet role in COVID-19-associated thrombosis and their role in the cholinergic anti-inflammatory pathway. Multiple studies confirmed that platelets display a hyperactivated phenotype in COVID-19 patients. Critically ill patients demonstrate increased platelet activation markers such as P-selectin, PF4, or serotonin. In addition, platelets contain acetylcholine and express α7 nicotinic acetylcholine receptors (α7nAchR). Thus, acetylcholine can be released under activation, and α7nAchR can be stimulated in an autocrine manner and support platelet function. α7 receptor is one of the most important mediators of the anti-inflammatory properties as it is associated with humoral and intrinsic immunity and was demonstrated to contribute to better outcomes in COVID-19 patients when under stimulation. Hematopoietic α7nAchR deficiency increases platelet activation and, in experimental studies, α7nAchR stimulation can diminish the pro-inflammatory state and modulate platelet reactiveness via increased levels of NO. NO has been described to inhibit platelet adhesion, activation, and aggregation. In addition, acetylcholine has been demonstrated to decrease platelet aggregation possibly by blocking the e p-38 pathway. SARS-CoV-2 proteins have been found to be similar to neurotoxins which can bind to nAChR and prevent the action of acetylcholine. Concluding, the platelet role in COVID-19 thrombotic events could be explained by their active function in the cholinergic anti-inflammatory pathway.

The LIPL study lipid panels and platelet activity in coronary heart disease

Abstract Introduction Measuring lipid panel in the fasting state can be inconvenient for patients and may aggravate their compliance. Moreover, people spend most of the day in the nonfasting state. Hence, it suggests that the changes in the process of atherosclerosis happen mainly under the influence of nonfasting lipids. Up to date, the studies in the postprandial state were primarily performed in healthy subjects. Aim This exploratory study investigates the change in lipid profile and platelet activity in patients with different cardiovascular risk profiles in the postprandial state. Methods The studied population consists of 66 patients with different cardiovascular risks: patients with coronary artery disease (CAD) and diabetes mellitus type 2 (DM2) (n=20), CAD without DM2 (n=25), and a healthy control group (n=21). Lipid variables and markers of platelet function were assessed during the fasting state and 3 and 5 hours after a standardized fat meal using a standardized oral fat tolerance test (OFTT), a milkshake with 90g of fat. The platelet activity was measured with a Multiplate test using ADP, ASPI and TRAP reagents. Results Patients with CAD and DM2 were significantly older and had the highest BMI. All patients with CAD were on acetylsalicylic acid, and 95% of CAD patients were on high-dose statins. Total cholesterol, LDL-c, Apolipoprotein A1, and Apolipoprotein B did not change during the OFTT, irrespective of the group. However, HDL-c decreased statistically significantly three and five hours after the fat loading with a peak after five hours (3.46±0.4 mg/dL, p&amp;lt;0.001). The lowest HDL-c was in the CAD and DM2 group (p=0.006). Triglycerides (TG) increased significantly during the OFTT, with a peak after 5 hours (130.2±14.5 mg/dL, p&amp;lt;0.001) irrespective of the group. There was no difference in TG concentration between the groups. Differences stayed statistically significant even after adjustment for age and BMI. Platelet activity increased after fat loading, as shown by a significantly increased thrombocyte count after three hours (p&amp;lt;0.001). Platelet activity measured by multiplate test with ADP (7.16±2.17 AU, p=0.005), ASPI (4.60±1.40 AU, p=0.005), and TRAP (11.41±3.10 AU, p=0.001) reagents increased statistically significant three hours after the fat loading. The platelet activity measured by all three reagents remained increased even after the adjustment for age and BMI (ADP: 7.14±2.10 AU, p=0.004, ASPI: 4.60±1.40 AU, p=0.006, TRAP: 11.40±3.10 AU, p=0.002). Moreover, the platelet activity measured by ADP (−13.12±4.93, p=0.030), and TRAP (−14.6±15.51, p=0.031) reagents was lower in the control group. When adjusted for age and BMI, there was no difference in the platelet activity between the three groups. Conclusion This study showed that fatty meal causes worsening of lipid profile and leads to increased platelet activity in subjects irrespective of cardiovascular risk profile. Funding Acknowledgement Type of funding sources: None.

Platelet protease activated receptor 4 (PAR 4) receptor genotype is associated with an increased risk of preterm birth

BackgroundPlatelet protease activated receptor‐4 (PAR4) Thr120 is a common genetic variant associated with increased platelet activity. Increased platelet activity is implicated in the pathogenesis of preeclampsia and preterm birth. ObjectiveCompare the rate of preeclampsia and preterm birth in pregnant individuals homozygous for PAR4 Thr120 variant vs not. Study DesignThis is a prospective cohort study of patients who delivered November 2020–July 2021. Maternal blood collected on admission for PAR4 genotyping. The primary outcome was the rate of preeclampsia/gestational hypertension in those with Thr/Thr genotype compared with Ala/Thr or Ala/Ala. Secondary outcomes included rates of preterm birth and placental pathology. ResultsThree hundred and twenty singletons were included and 52 (16.3%) were PAR4 Thr/Thr. Those PAR4 Thr/Thr were more likely to be Black (67.3% vs 29.5%, p < .001), younger (28 ± 6 vs 31 ± 6, p = .004), and have higher body mass index (35.2 ± 6.8 vs 33.1 ± 7.4, p = .047). There was no difference in preeclampsia/gestational hypertension (19.2% vs 22.8%, p = .705). Those Thr/Thr had a significantly higher rate of preterm birth (15.4% vs 3.7%, adjusted odds ratio [aOR] 4.04 [1.47–11.10], p = .007), indicated preterm birth because of fetal growth restriction or preeclampsia (5.8% vs 0.4%, aOR 10.03 [1.48–67.87], p = .02), spontaneous preterm birth (7.7% vs 2.2%, aOR 4.81 [1.27–18.27], p = .02), and placental intervillous thrombosis (18.5% vs 7.9%, aOR 4.12 [1.14–14.92], p = .03). ConclusionPlatelet receptor PAR4 Thr120 is a common variant associated with an increased risk of placental vascular pathology and preterm birth in homozygous individuals. Although a cohort study cannot establish causation, this strong association warrants further exploration.

Increased platelet activation and platelet-inflammasome engagement during chikungunya infection

Chikungunya fever is a viral disease transmitted by mosquitoes of the genus Aedes. The infection is usually symptomatic and most common symptoms are fever accompanied by joint pain and swelling. In most cases symptoms subside within a week. However, severe prolonged and disabling joint pain, that may persist for several months, even years, are reported. Although the pathogenesis of Chikungunya infection is not fully understood, the evolution to severe disease seems to be associated with the activation of immune mechanisms and the action of inflammatory mediators. Platelets are recognized as inflammatory cells with fundamental activities in the immune response, maintenance of vascular stability and pathogenicity of several inflammatory and infectious diseases. Although the involvement of platelets in the pathogenesis of viral diseases has gained attention in recent years, their activation in Chikungunya has not been explored. The aim of this study was to analyze platelet activation and the possible role of platelets in the amplification of the inflammatory response during Chikungunya infection. We prospectively included 132 patients attended at the Quinta D’Or hospital and 25 healthy volunteers during the 2016 epidemic in Rio de Janeiro, Brazil. We observed increased expression of CD62P on the surface of platelets, as well as increased plasma levels of CD62P and platelet-derived inflammatory mediators indicating that the Chikungunya infection leads to platelet activation. In addition, platelets from chikungunya patients exhibit increased expression of NLRP3, caspase 4, and cleaved IL-1β, suggestive of platelet-inflammasome engagement during chikungunya infection. In vitro experiments confirmed that the Chikungunya virus directly activates platelets. Moreover, we observed that platelet activation and soluble p-selectin at the onset of symptoms were associated with development of chronic forms of the disease. Collectively, our data suggest platelet involvement in the immune processes and inflammatory amplification triggered by the infection.

Postoperative myocardial injury and platelet reactivity in patients undergoing vascular surgery: The platelet reactivity and postoperative myocardial injury after major vascular surgery (PROMISE) study

BackgroundPostoperative myocardial injury (PMI) after major vascular surgery, detected by elevated cardiac troponin (cTn), has been associated with morbidity and mortality. It is unclear whether the pathophysiology of PMI is determined by increased platelet activity. ObjectiveTo examine the relationship between platelet activation (P-selectin expression) and PMI in patients undergoing elective open abdominal aortic surgery. MethodsThis prospective, single-centre, observational, cohort study included 33 patients undergoing elective open abdominal aortic surgery between March 2018 and April 2021. Patients were routinely treated with aspirin. Unstimulated platelet activation was measured by platelet bound P-selectin expression (range 0–100 %). Explorative coagulation measurements were: stimulated platelet aggregation measured with the VerifyNow® assay (aspirin cartridge), with the Multiplate® analyzer (ASPI, ADP and TRAP) and stimulated coagulation status evaluated by the TEG® Hemostasis Analyzer System (global hemostasis cartridge). The primary outcome was cTn release assessed by the fifth generation high-sensitive cTn assay. Multivariable generalized linear mixed models were used to evaluate the association between platelet function and cTn concentrations over time. ResultsTen patients (30.3 %) developed PMI. Increased P-selectin expression directly after surgery was associated with the cTn concentrations over 48 h (β = 1.39 (1.1–1.75), P = 0.0064). No association was found between P-selectin measured later after surgery (at 24 h or 48 h) and cTn concentrations. Furthermore, there was no association between the explorative coagulation parameters and cTn release. ConclusionPlatelet reactivity, assessed by P-selectin expression measured directly after surgery is associated with PMI, assessed by elevated cTn concentrations in the early postoperative period in patients undergoing elective open abdominal aortic surgery.

Arterial stiffness, endothelial dysfunction and impaired fibrinolysis are pathogenic mechanisms contributing to cardiovascular risk in ANCA-associated vasculitis

Cardiovascular disease is a complication of systemic inflammatory diseases including anti-neutrophil cytoplasm antibody-associated vasculitis (AAV). The mechanisms of cardiovascular morbidity in AAV are poorly understood, and risk-reduction strategies are lacking. Therefore, in a series of double-blind, randomized case-control forearm plethysmography and crossover systemic interventional studies, we examined arterial stiffness and endothelial function in patients with AAV in long-term disease remission and in matched healthy volunteers (32 each group). The primary outcome for the case-control study was the difference in endothelium-dependent vasodilation between health and AAV, and for the crossover study was the difference in pulse wave velocity (PWV) between treatment with placebo and selective endothelin-A receptor antagonism. Parallel invitro studies of circulating monocytes and platelets explored mechanisms. Compared to healthy volunteers, patients with AAV had 30% reduced endothelium-dependent vasodilation and 50% reduced acute release of endothelial active tissue plasminogen activator (tPA), both significant in the case-control study. Patients with AAV had significantly increased arterial stiffness (PWV: 7.3 versus 6.4 m/s). Plasma endothelin-1 was two-fold higher in AAV and independently predicted PWV and tPA release. Compared to placebo, both selective endothelin-A and dual endothelin-A/B receptor blockade reduced PWV and increased tPA release in AAV in the crossover study. Mechanistically, patients with AAV had increased platelet activation, more platelet-monocyte aggregates, and altered monocyte endothelin receptor function, reflecting reduced endothelin-1 clearance. Patients with AAV in long-term remission have elevated cardiovascular risk and endothelin-1 contributes to this. Thus, our data support a role for endothelin-blockers to reduce cardiovascular risk by reducing arterial stiffness and increasing circulating tPA activity.

Oxidised Low-Density Lipoprotein-Induced Platelet Hyperactivity-Receptors and Signalling Mechanisms.

Dyslipidaemia leads to proatherogenic oxidative lipid stress that promotes vascular inflammation and thrombosis, the pathologies that underpin myocardial infarction, stroke, and deep vein thrombosis. These prothrombotic states are driven, at least in part, by platelet hyperactivity, and they are concurrent with the appearancxe of oxidatively modified low-density lipoproteins (LDL) in the circulation. Modified LDL are heterogenous in nature but, in a general sense, constitute a prototype circulating transporter for a plethora of oxidised lipid epitopes that act as danger-associated molecular patterns. It is well-established that oxidatively modified LDL promote platelet activation and arterial thrombosis through a number of constitutively expressed scavenger receptors, which transduce atherogenic lipid stress to a complex array of proactivatory signalling pathways in the platelets. Stimulation of these signalling events underlie the ability of modified LDL to induce platelet activation and blunt platelet inhibitory pathways, as well as promote platelet-mediated coagulation. Accumulating evidence from patients at risk of arterial thrombosis and experimental animal models of disease suggest that oxidised LDL represents a tangible link between the dyslipidaemic environment and increased platelet activation. The aim of this review is to summarise recent advances in our understanding of the pro-thrombotic signalling events induced in platelets by modified LDL ligation, describe the contribution of individual platelet scavenger receptors, and highlight potential future challenges of targeting these pathways.