Platelet Turnover Research Articles

Real-time platelet P2Y12 receptor occupancy as a promising pharmacodynamics biomarker for bridging the gap between PK/PD of clopidogrel therapy

Clopidogrel effectively inhibits platelet aggregation in response to ADP by irreversibly binding to the platelet P2Y12 receptor through its active metabolite. However, the observed discrepancies between the pharmacokinetics (PK) and pharmacodynamics (PD) of clopidogrel present substantial challenges in individualizing of antiplatelet therapy. To address these challenges, a robust liquid chromatography–tandem mass spectrometry method has been developed to facilitate the real-time assessment of platelet P2Y12 receptor occupancy. This method has been validated in animal models, providing a reliable link between individual PK profiles and PD effects. Target receptor occupancy offers a comprehensive overview of interindividual variations in clopidogrel metabolism, regulation of P2Y12 receptor expression, and platelet turnover. Moreover, it directly correlates with the inhibitory effect on platelet aggregation. The levels of platelet P2Y12 occupancy accurately reflect the extent of clinical factors influencing the PD of clopidogrel, including dosage, drug–drug interactions (DDI), and type 2 diabetes mellitus (T2DM). As a normalized metric, platelet P2Y12 occupancy not only serves potential as a diagnostic tool for personalized clopidogrel therapy but also aids in elucidating the role of the P2Y12 signaling pathway in cases of abnormal on-treatment platelet reactivity.

Long-term pharmacodynamic and clinical effects of twice- versus once-daily low-dose aspirin in essential thrombocythemia: The ARES trial.

Patients with essential thrombocythemia (ET) are treated with once-daily low-dose aspirin to prevent thrombosis, but their accelerated platelet turnover shortens the antiplatelet effect. The short-term Aspirin Regimens in EsSential Thrombocythemia trial showed that twice-daily aspirin dosing restores persistent platelet thromboxane (TX) inhibition. However, the long-term pharmacodynamic efficacy, safety and tolerability of twice-daily aspirin remain untested. We performed a multicenter, randomized, open-label, blinded-endpoint, phase-2 trial in which 242 patients with ET were randomized to 100 mg aspirin twice- or once-daily and followed for 20 months. The primary endpoint was the persistence of low serum TXB2, a surrogate biomarker of antithrombotic efficacy. Secondary endpoints were major and clinically relevant non-major bleedings, serious vascular events, symptom burden assessed by validated questionnaires, and in vivo platelet activation. Serum TXB2 was consistently lower in the twice-daily versus once-daily regimen on 10 study visits over 20 months: median 3.9 ng/mL versus 19.2 ng/mL, respectively; p < .001; 80% median reduction; 95% CI, 74%-85%. No major bleeding occurred. Clinically relevant non-major bleedings were non-significantly higher (6.6% vs. 1.7%), and major thromboses lower (0.8% vs. 2.5%) in the twice-daily versus once-daily group. Patients on the twice-daily regimen had significantly lower frequencies of disease-specific symptoms and severe hand and foot microvascular pain. Upper gastrointestinal pain was comparable in the two arms. In vivo platelet activation was significantly reduced by the twice-daily regimen. In patients with ET, twice-daily was persistently superior to once-daily low-dose aspirin in suppressing thromboxane biosynthesis and reducing symptom burden, with no detectable excess of bleeding and gastrointestinal discomfort.

Shedding light on GPIbα shedding.

Ectodomain shedding has been investigated since the late 1980s. The abundant and platelet specific GPIbα receptor is cleaved by ADAM17 resulting in the release of its ectodomain called glycocalicin. This review will address the role of glycocalicin as an end-stage marker of platelet turnover and storage lesion and will consider a potential function as effector in processes beyond hemostasis. Glycocalicin has been described as a marker for platelet senescence, turnover and storage lesion but is not routinely used in a clinical setting because its diagnostic value is nondiscriminatory. Inhibition of glycocalicin shedding improves posttransfusion recovery but little is known (yet) about potential hemostatic improvements. In physiological settings, GPIbα shedding is restricted to the intracellular GPIbα receptor subpopulation suggesting a role for shedding or glycocalicin beyond hemostasis. So far, all evidence represents glycocalicin as an end-stage biomarker of platelet senescence and a potential trigger for platelet clearance. The extensive list of interaction partners of GPIbα in fields beyond hemostasis opens new possibilities to investigate specific effector functions of glycocalicin.

Platelet microRNAs as Potential Novel Biomarkers for Antiplatelet Therapy with P2Y12 Inhibitors and Their Association with Platelet Function.

Patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) require dual antiplatelet therapy (DAPT). However, the response to treatment can vary considerably. Certain platelet microRNAs (miRs) are suspected to predict DAPT response and influence platelet function. This study aimed to analyze selected miRs' expressions and compare them among patients treated with different P2Y12 inhibitors while assessing their association with platelet activity and turnover parameters. We recruited 79 ACS patients post-PCI treated with clopidogrel, ticagrelor, or prasugrel, along with 18 healthy volunteers. Expression levels of miR-126-3p, miR223-3p, miR-21-5p, miR-197-3p, and miR-24-3p, as well as immature platelet fraction (IPF) and ADP-induced platelet reactivity, were measured and compared between groups. Analyses revealed significantly lower expressions of miR-126-3p, miR-223-3p, miR-21-5p, and miR-197-3p in patients treated with ticagrelor, compared to clopidogrel (fold changes from -1.43 to -1.27, p-values from 0.028 to 0.048). Positive correlations were observed between platelet function and the expressions of miR-223-3p (r = 0.400, p = 0.019) and miR-21-5p (r = 0.423, p = 0.013) in patients treated with potent drugs. Additionally, miR-24-3p (r = 0.411, p = 0.012) and miR-197-3p (r = 0.333, p = 0.044) showed correlations with IPF. The identified platelet miRs hold potential as biomarkers for antiplatelet therapy. (ClinicalTrials.gov number, NCT06177587).

Platelet functions in lymphatic filariasis patients

Filariasis is a chronic disease where parasitic worms survive in human hosts even for decades and lead to complications like lymphedema and elephantiasis. Despite the persistent existence of filarial parasites in human hosts, fatal and thrombotic complications are not known, unlike other parasitic diseases like malaria. This suggests that filarial parasites might be affecting the host's platelet functions. This study was conducted to examine platelet functions in confirmed filariasis patients and healthy controls. Results showed that filariasis patients had larger platelets, inhibited aggregation, and slower speed of aggregation, compared to controls. However, in vivo markers of platelet activation and degranulation (beta thromboglobulin and soluble P-selectin) were not affected. Observations suggested that there is increased platelet turnover, cellular apoptosis and inhibited platelet functions in filariasis patients compared to controls. Platelet function inhibition was not associated with the duration of disease, lymphedema-affected organs, or gender of patients. This study confirms that filarial parasites modulate platelet functions in human hosts.

Thrombopoietin levels in sepsis and septic shock-a systematic review and meta-analysis.

Sepsis is a life-threatening condition implicating an inadequate activation of the immune system. Platelets act as modulators and contributors to immune processes. Indeed, altered platelet turnover, thrombotic events, and changes in thrombopoietin levels in systemic inflammation have been reported, but thrombopoietin-levels in sepsis and septic-shock have not yet been systematically evaluated. We therefore performed a meta-analysis of thrombopoietin (TPO)-levels in patients with sepsis. Two independent reviewers screened records and full-text articles for inclusion. Scientific databases were searched for studies examining thrombopoietin levels in adult sepsis and septic-shock patients until August 1st 2022. Of 95 items screened, six studies met the inclusion criteria, including 598 subjects. Both sepsis and severe sepsis were associated with increased levels of thrombopoietin (sepsis vs. control: standardized mean difference 3.06, 95 % CI 1.35-4.77; Z=3.50, p=0.0005) (sepsis vs. severe sepsis: standardized mean difference-1.67, 95 % CI-2.46 to-0.88; Z=4.14, p<0.0001). TPO-levels did not show significant differences between severe sepsis and septic shock patients butdiffered between sepsis and inflammation-associated non-septic controls. Overall, high heterogeneity and low sample size could be noted. Concluding, increased levels of thrombopoietin appear to be present both in sepsis and severe sepsis with high heterogeneity but thrombopoietin does not allow to differentiate between severe sepsis and septic-shock. TPO may potentially serve to differentiate sepsis from non-septic trauma and/or tissue damage related (systemic) inflammation. Usage of different assays and high heterogeneity demand standardization of methods and further large multicenter trials.

Towards a greater understanding of reduced response to aspirin in children with congenital heart disease post-cardiac surgery using immature platelet fraction

ObjectiveA high platelet turnover rate may produce a population of platelets that confers an inadequate response to aspirin. We aimed to investigate the relationship between residual platelet aggregation and platelet turnover in paediatric cardiology patients on aspirin monotherapy by evaluating the fraction of immature platelets as a marker for turnover and secondly to test the predictive value of the immature platelet fraction (IPF) to classify patients as responsive or non-responsive to aspirin. MethodsSixty patients divided into two age categories (≤90 days, >90 days of age) were included in this prospective observational study. Patients were then stratified into tertiles using their IPF level. Platelet studies included thromboelastography with platelet mapping (TEGPM). ResultsThe overall incidence of ‘inadequate response to aspirin’ was 38 % in our patient cohort recently post-cardiac surgery a consequence that warrants further study. The frequency of inadequate response to aspirin was higher in the upper tertile of IPF when compared to the lower tertile, (88 %) versus (4 %) respectively (p < 0.05). The ‘cut off’ for IPF was determined to be 3.9 % with a sensitivity of 95.7 %, and a specificity of 92.9 % (area under the curve of 0.955 [CI 0.896–1.014, p < 0.05]). ConclusionThis study demonstrates that inadequate response to aspirin occurs in approximately 38 % of patients undergoing specific high-risk congenital cardiac procedures using the dosing practice of a national centre. This study supports the hypothesis that an elevated platelet turnover may result in aspirin being less effective in patients who are recently post cardiac surgery. These data are of direct translational relevance.

PB0891 Impact of Enhanced Platelet Turnover on Platelet Reactivity in Healthy Humans

PB0891 Impact of Enhanced Platelet Turnover on Platelet Reactivity in Healthy Humans

High Immature Platelet Fraction is Associated with Early Neurological Deterioration in Acute Ischemic Stroke (P3-5.007)

<h3>Objective:</h3> To investigate the association between the level of immature platelet fraction (IPF) and the prevalence of early neurological deterioration (END) in acute ischemic stroke patients. <h3>Background:</h3> Early neurological deterioration (END) in acute ischemic stroke is a common event. However, the underlying pathophysiological bases are heterogenous and hard to explain. Immature platelet fraction (IPF) is the useful marker of increased platelet production and turnover which could occur in patients with increased platelet activation. High value of IPF was reported in acute coronary syndrome. <h3>Design/Methods:</h3> A total 1655 of acute ischemic stroke patients in single tertiary academic center was enrolled from January 2013 to October 2018 via stroke registry. IPF levels were quantified by whole blood flow cytometry with automated assays (Sysmex XE-2100™). High IPF was defined as the IPF level was more than 5%. Early neurological deterioration was defined as an increment change of at least one point in motor power or total National Institute of Health Stroke Scale (NIHSS) score deterioration ≥2 points within the first week after admission. <h3>Results:</h3> A total of 72 patients (4.4%) experienced END. END was more prevalent in the patients with high IPF [13 (11.7%) vs 59 (3.8%), p&lt;0.0001]. Multivariate logistic regression analysis showed high IPF was an independent predictor of the prevalence of END (adjust odds ratio = 1.32; 95% confidence interval = 1.03–1.70). <h3>Conclusions:</h3> A high IPF levels was associated with the prevalence of END in acute ischemic stroke patients. Future investigation might be needed to evaluate the effective treatment of the high IPF in acute phase of ischemic stroke. <b>Disclosure:</b> Bang-Hoon Cho has nothing to disclose. The institution of Sung-Wook Yu has received research support from Yuhan.

Myeloproliferative Neoplasms and Aspirin: Does Increased Platelet Turnover Matter?

Platelet aggregation tests and the analysis of thromboxane A2 metabolites [serum thromboxane B2 (TXB2) and urine 11-dehydro TXB2] are used to evaluate the efficacy of aspirin. In myeloproliferative neoplasms (MPNs), the immature platelet fraction (IPF) rises due to enhanced platelet turnover, and this has been thought to reduce the efficacy of aspirin. This phenomenon is overcome by the recommendation of aspirin intake in divided doses. We aimed to evaluate aspirin efficacy in patients who were receiving aspirin treatment of 100 mg/day. Thirty-eight MPN patients and 30 control patients (non-MPN patients who received a single daily dose of aspirin at 100 mg for nonhematological conditions) were enrolled. IPF, serum TXB2, and urine 11-dehydro TXB2 levels were measured and aggregation tests with arachidonic acid and adenosine diphosphate were performed by light transmission aggregometry (LTA). Mean IPF and TXB2 levels were higher in the MPN group (p=0.008 and p=0.003, respectively). IPF levels were lower in patients on cytoreductive therapy in the MPN group (p=0.001), but these values were similar between patients on hydroxyurea and the non-MPN group (p=0.72). TXB2 levels did not differ according to hydroxyurea treatment status but were higher in the MPN group compared to non-MPN patients (23.63 ng/mL and 19.78 ng/mL, respectively; p=0.04). TXB2 values were higher in patients with essential thrombocythemia and a history of thrombotic events (p=0.031). No difference was observed in LTA between the MPN and non-MPN patient groups (p=0.513). Higher levels of IPF and TXB2 in the MPN patient group indicated platelets that could not be inhibited by aspirin. It was observed that patients under cytoreductive therapy had lower IPF values, but the expected decrease in TXB2 levels was not observed. These findings suggest that a lack of response to aspirin may be due to additional intrinsic factors rather than increased platelet turnover.

Cytometry and analytical methods in COVID‐19 diagnostics and potential treatment: A special issue on Cytometry Part A

Cytometry and analytical methods in <scp>COVID</scp>‐19 diagnostics and potential treatment: A special issue on Cytometry Part A

Decreased Platelet Reactivity and Function in a Mouse Model of Human Pancreatic Cancer.

Cancer patients have increased thrombosis and bleeding compared with the general population. Cancer is associated with activation of both platelets and coagulation. Mouse models have been used to study the dysregulation of platelets and coagulation in cancer. We established a mouse model of pancreatic cancer in which tissue factor-expressing human pancreatic tumors (BxPC-3) are grown in nude mice. Tumor-bearing mice have an activated coagulation system and increased venous thrombosis compared to control mice. We also showed that tumor-derived, tissue factor-positive extracellular vesicles activated platelets ex vivo and in vivo. In this study, we determined the effect of tumors on a platelet-dependent arterial thrombosis model. Unexpectedly, we observed significantly reduced carotid artery thrombosis in tumor-bearing mice compared to controls. In addition, we observed significantly increased tail bleeding in tumor-bearing mice compared to controls. These results suggested that the presence of the tumor affected platelets. Indeed, tumor-bearing mice exhibited a significant decrease in platelet count and an increase in mean platelet volume and percentage of reticulated platelets, findings that are consistent with increased platelet turnover. Levels of the platelet activation marker platelet factor 4 were also increased in tumor-bearing mice. We also observed decreased platelet receptor expression in tumor-bearing mice and reduced levels of active αIIb/β3 integrin in response to PAR4 agonist peptide and convulxin in platelets from tumor-bearing mice compared with platelets from control mice. In summary, our study suggests that in tumor-bearing mice there is chronic platelet activation, leading to thrombocytopenia, decreased receptor expression, and impaired platelet adhesive function.

Platelet kinetics in patients with chronic immune thrombocytopaenia treated with thrombopoietin receptor agonists.

Thrombopoietin receptor agonists (TPO-RAs) increase platelet counts (PC) in the majority of patients with chronic immune thrombocytopaenia (ITP). Platelet kinetics study (PKS) might contribute to the understanding of mechanisms that lead to durable response. To evaluate the effects of TPO-RAs on PKS parameters in chronic ITP patients. Fifteen chronic ITP patients, aged 59 years [range: 22-84], female/male: 10/5, splenectomised 7/15, were treated with TPO-RAs (eltrombopag/romiplostim: 11/4). Durable response was defined as PC ≥30 × 109 /L at 6months. Autologous 111 Indium-oxinate PKS was performed before and 5 months after TPO-RAs initiation. Accordingly, platelet survival (PS), platelet turnover, production ratio and sequestration site were assessed. Durable response was achieved in 13/15 of patients (eltrombopag/romiplostim: 10/3). Pre-treatment parameters were: PC 10 × 109 /L [range: 1-110], PS 0.5 days [range: 0.1-1.7 (normal values: 7-10)], platelet turnover 30 857 Plt/μL/day [range: 944-103 500] and platelet production ratio 0.64 [range: 0.01-3.2 (normal values: 1 ± 0.2)]. Post-treatment assessment showed significantly higher: PC 92.5 × 109 /L [range: 28-260, p=.001], PS 2.2 days [range: 0.1-3.6, p=.008], platelet turnover 70 213 Plt/μL/day [range: 2800-462 236, p=.02] and platelet production ratio 1.8 [range: 0.5-37.9, p=.011] compared to the pre-treatment values. Platelet sequestration site altered in 3/15 treated with TPO-RAs. TPO-RAs could increase PC by simultaneous increasing of platelet production and decreasing of platelet destruction.

Aspirin in essential thrombocythemia. For whom? What formulation? What regimen?

Essential thrombocythemia (ET) is a BCR-ABL1-negative myeloproliferative neoplasm, the most common clinical manifestations of which include arterial and venous thrombosis, bleeding and vasomotor/microvascular disturbances. Low-dose (81-100 mg) aspirin once daily, which irreversibly inhibits platelet thromboxane A2 (TxA2) production by acetylating cyclo-oxygenase-1, is the recommended treatment for the control of vascular events in all ET risk categories, except patients at very low risk, who need aspirin for treatment of vasomotor/microvascular disturbances only. Simple observation should be preferred over aspirin prophylaxis in low-risk patients with platelet counts >1,000x109/L or harboring CALR mutations. Plain aspirin should be preferred over enteric coated aspirin because some ET patients display poor responsiveness ("resistance") to the latter. When treated with a once daily aspirin regimen, adequate inhibition of platelet TxA2 production (measured as serum thromboxane B2 level) does not persist for 24 h in most patients. This phenomenon is associated with the patients' platelet count and the number (but not the fraction) of circulating immature reticulated platelets with non-acetylated cyclo-oxygenase-1 and is therefore consequent to high platelet production (the hallmark of ET), rather than increased platelet turnover (which is normal in ET). Twice daily aspirin administration overcame this problem and proved safe in small studies. Although additional data on gastrointestinal tolerability will be useful, the twice daily regimen could already be implemented in clinical practice, considering its favorable risk/benefit profile. However, patients whose platelet count has been normalized could still be treated with the once daily regimen, because they would otherwise be unnecessarily exposed to a potential small risk of gastrointestinal discomfort.

Thrombus remodelling by reversible and irreversible P2Y12 inhibitors

Pharmacological inhibition of the platelet ADP-receptor P2Y12 is a cornerstone in the prevention of atherothrombotic events in adult patients with acute coronary syndrome (ACS). Thienopyridines such as clopidogrel and prasugrel exert their antithrombotic effect by means of active metabolites that irreversibly inhibit P2Y12. Due to the short half-life of these metabolites, a subpopulation of ADP-responsive platelets will form in between dosing. With increased platelet turnover rate or poor patient compliance, the fraction of ADP-responsive platelets will increase, potentially increasing the risk for new thrombotic events. In contrast, the reversible P2Y12 inhibition produced by direct-acting ADP blockers such as ticagrelor and cangrelor inhibit the entire platelet population. In this study, we evaluated the impact of these pharmacological differences on thrombus formation in an ex vivo flow chamber model. A customized image analysis pipeline was used for automatized, large-scale identification and tracking of single platelets incorporated into the thrombus, enabling quantitative analysis of the relative contribution of inhibited and uninhibited platelets to thrombus growth and consolidation. Comparative experiments were conducted using the irreversible and reversible P2Y12 inhibitors prasugrel active metabolite (PAM) and ticagrelor, respectively. Our results show that PAM inhibited thrombus platelet recruitment more gradually than ticagrelor, with a slower onset of inhibition. Further, we show that the presence of a small fraction (<10%) of uninhibited platelets did not abrogate the antithrombotic effect of PAM to any significant extent. Finally, we demonstrate a gradual enrichment of inhibited platelets in the thrombus shell due to selective recruitment of inhibited platelets to the thrombus periphery.

Laboratory Markers of Platelet Production and Turnover

Platelets are formed from bone marrow megakaryocytes, circulate in blood for 7-10 days, and then are destroyed in the spleen and/or liver. Platelet production depends on the megakaryocyte population state in the bone marrow: number and size of the cells. The platelet turnover, i.e., the number of platelets passing through the bloodstream in a certain time, is determined by both the rate of their production and the rate of their destruction. The review considers laboratory markers, which are used to assess platelet production and turnover in the patients with hematologic and cardiovascular pathologies. These markers include some characteristics of platelets themselves: (i) content of reticulated ("young") forms in the blood detected by their staining with RNA dyes; (ii) indicators of the platelet size determined in hematology analyzers (mean volume, percentage of large forms) and in flow cytometers (light scattering level). Alterations of platelet production and turnover lead to the changes in blood plasma concentrations of such molecules as thrombopoietin (TPO, main mediator of megakaryocyte maturation and platelet formation in the bone marrow) and glycocalicin (soluble fragment of the membrane glycoprotein Ib detached from the surface of platelets during their destruction). Specific changes in the markers of platelet production and turnover have been observed in: (i) hypoproductive thrombocytopenias caused by suppression of megakaryocytes in the bone marrow; (ii) immune thrombocytopenias caused by accelerated clearance of the autoantibody-sensitized platelets; and (iii) thrombocytosis (both primary and reactive). The paper presents the data indicating that in patients with cardiovascular diseases an increased platelet turnover and changes in the corresponding markers (platelet size indexes and content of reticulated forms) are associated with the decreased efficacy of antiplatelet drugs and increased risk of thrombotic events, myocardial infarction, and unstable angina (acute coronary syndrome).

New functions of C3G in platelet biology: Contribution to ischemia-induced angiogenesis, tumor metastasis and TPO clearance.

C3G is a Rap1 guanine nucleotide exchange factor that controls platelet activation, aggregation, and the release of α-granule content. Transgenic expression of C3G in platelets produces a net proangiogenic secretome through the retention of thrombospondin-1. In a physiological context, C3G also promotes megakaryocyte maturation and proplatelet formation, but without affecting mature platelet production. The aim of this work is to investigate whether C3G is involved in pathological megakaryopoiesis, as well as its specific role in platelet mediated angiogenesis and tumor metastasis. Using megakaryocyte-specific C3G knockout and transgenic mouse models, we found that both C3G overexpression and deletion promoted platelet-mediated angiogenesis, induced by tumor cell implantation or hindlimb ischemia, through differential release of proangiogenic and antiangiogenic factors. However, only C3G deletion resulted in a higher recruitment of hemangiocytes from the bone marrow. In addition, C3G null expression enhanced thrombopoietin (TPO)-induced platelet production, associated with reduced TPO plasma levels. Moreover, after 5-fluorouracil-induced platelet depletion and rebound, C3G knockout mice showed a defective return to homeostatic platelet levels, indicating impaired platelet turnover. Mechanistically, C3G promotes c-Mpl ubiquitination by inducing Src-mediated c-Cbl phosphorylation and participates in c-Mpl degradation via the proteasome and lysosome systems, affecting TPO internalization. We also unveiled a positive role of platelet C3G in tumor cell-induced platelet aggregation, which facilitated metastatic cell homing and adhesion. Overall, these findings revealed that C3G plays a crucial role in platelet-mediated angiogenesis and metastasis, as well as in platelet level modulation in response to pathogenic stimuli.

Personalized allocation of acetylsalicylic acid therapy for secondary prevention of coronary artery disease.

BackgroundA single-daily dose of 75 mg of acetylsalicylic acid inhibits 100% of thromboxane-B2 synthesis within 30–60 min. Thromboxane-B2 synthesis then recovers slowly as new platelets are released from the bone marrow. Normally, only 10% of the platelets are replaced daily by new platelets entering circulation. Hence, 24 h after a dose of acetylsalicylic acid, thromboxane-B2 synthesis is still suppressed by more than 90%. Hence, there is an adequate anti-platelet effect even after 24 h of acetylsalicylic acid intake. However, some patients treated with once-daily acetylsalicylic acid may have an incomplete 24-h suppression of thromboxane-B2 synthesis due to increased platelet turnover. The response could be improved in such patients by twice-daily acetylsalicylic acid administration. This study aimed to identify such a group of patients who would benefit from a twice-daily dose of acetylsalicylic acid.Materials and methodsSerum thromboxane-B2 levels were measured in 79 patients with coronary artery disease receiving 75 mg of acetylsalicylic acid for secondary prophylaxis. Serum levels of thromboxane-B2 were measured after 4 and 24 h of acetylsalicylic acid intake. Patients were then classified into three groups: steady suppression group (serum thromboxane B2 is adequately suppressed at 4 and 24 h), i.e., adequate response to acetylsalicylic acid; fast recovery group (more than 10% rise in serum thromboxane-B2 levels at 24-h when compared to at 4-h) and non-responders (serum thromboxane-B2 levels of >3,100 pg/ml after 4 h of acetylsalicylic acid intake). Patients in the fast recovery group were given twice-daily acetylsalicylic acid and thromboxane-B2 levels were re-measured.ResultsA total of 20 patients (24.3%) had steady suppression of thromboxane-B2 and 11 patients (13.9%) belonged to the fast recovery group, i.e., thromboxane-B2 levels were adequately suppressed at 4 h but had recovered by more than 10% at 24 h; which was adequately suppressed by twice-daily acetylsalicylic acid (p 0.004). A total of 48 patients (60.8%) were non-responders.ConclusionTwice-daily acetylsalicylic acid may be beneficial if serum thromboxane-B2 levels at 4 h are <3,100 and >3,100 pg/ml at 24 h. If thromboxane-B2 levels at 4 and 24 h is <3100 pg/ml but if there is a >10% rise in serum thromboxane B2 at 24 h as compared to that at 4 h, then twice-daily acetylsalicylic acid should be considered. However, if thromboxane-B2 at 4 and 24 h is >3,100 pg/ml consider switching over to a P2Y12 inhibitor.

Physiologically based modelling of the antiplatelet effect of aspirin: A tool to characterize drug responsiveness and inform precision dosing.

A computational approach involving mathematical modeling and in silico experiments was used to characterize the determinants of extent and duration of platelet cyclooxygenase (COX)-1 inhibition by aspirin and design precision dosing in patients with accelerated platelet turnover or reduced drug bioavailability. To this purpose, a recently developed physiologically-based pharmacokinetics (PK) and pharmacodynamics (PD) model of low-dose aspirin in regenerating platelets and megakaryocytes, was used to predict the main features and determinants of platelet COX-1 inhibition. The response to different aspirin regimens in healthy subjects and in pathological conditions associated with alterations in aspirin PK (i.e., severely obese subjects) or PD (i.e., essential thrombocytemya patients), were simulated. A model sensitivity analysis was performed to identify the main processes influencing COX-1 dynamics. In silico experiments and sensitivity analyses indicated a major role for megakaryocytes and platelet turnover in determining the extent and duration of COX-1 inhibition by once-daily, low-dose aspirin. They also showed the superiority of reducing the dosing interval vs increasing the once-daily dose in conditions of increased platelet turnover, while suggested specific dose adjustments in conditions of possible reduction in drug bioavailability. In conclusion, the consistency of our model-based findings with experimental data from studies in healthy subjects and patients with essential thrombocythemia supports the potential of our approach for describing the determinants of platelet inhibition by aspirin and informing precision dosing which may guide personalized antithrombotic therapy in different patient populations, especially in those under-represented in clinical trials or in those associated with poor feasibility.

Association between platelet indices and risk of preeclampsia in pregnant women

We aimed to examine the association between the platelet indices and the risk of preeclampsia (PE) at different gestational weeks (GW) to explore the feasibility of early prediction of PE with these indices. About 7314 normotensive pregnant women and 396 PE patients were included and platelet indices, including platelet count (PC), plateletcrit (PCT), platelet distribution width (PDW), mean platelet volume (MPV) at different gestational weeks (1–12, 13–28, 29–32, 33–36 and 37–41 GW) were compared in two statistical methods. Patients with PE tended to have higher means of PC, PCT, PDW and MPV than normal pregnant women at early stage of pregnancy. The odds of PE were significantly increased with the increase of PC, PCT, PDW and MPV both at 13–28 GW and 29–32 GW, which indicated that increased values of PC, PCT, PDW and MPV at 13-32 GW were associated with greater subsequent risk of preeclampsia. Increased PC, PCT, PDW and MPV may have potential to predict preeclampsia before the disease onset. Impact Statement What is already known on this subject? Previous studies indicated that preeclampsia patients may have decreased platelet count (PC), plateletcrit (PCT) and increased platelet distribution width (PDW) and mean platelet volume (MPV). Increased PDW and MPV or decreased PC/MPV may have predictive values for PE. What do the results of this study add? The discrepancy with previous studies lay in the increased values of PC and PCT in PE patients at early stage of pregnancy. The study indicated that increased PC, PCT, PDW and MPV may have potential to predict preeclampsia far ahead of the disease onset. The results may reflect the abnormal turnover of platelets in PE patients. What are the implications of these findings for clinical practice and/or further research? These findings may help to guide early interventions before progress to overt preeclampsia by predicting onset of preeclampsia via easily available platelet indices in early weeks of gestation, which is especially valuable in areas lacking medical resources. The inconsistency with previous studies can facilitate researchers to further explore the coagulation mechanism beneath preeclampsia and pay more attention to the dynamic changes of platelet indices and other coagulation indices during pregnancy.