Diphosphate-induced Platelet Aggregation Research Articles

Demand Ischemia due to Gastrointestinal Bleeding Secondary to Ticagrelor

Ticagrelor, an orally consumed antiplatelet medication, acts as an antagonist on the P2Y12 receptor preventing adenosine diphosphate-induced platelet aggregation. Gastrointestinal bleeding triggered by ticagrelor can lead to demand ischemia, as the demand for oxygen by the tissues surpasses the oxygen supply available following acute blood loss. A male patient in his 80s had his antiplatelet medication switched from clopidogrel to ticagrelor following a cardiac stent. He presented to the emergency department a few months later due to black stools and fatigue. The patient had a critically elevated initial troponin level of 780 ng/L which increased to 892 ng/L two hours later. Hemoglobin was low at 8.5 g/dL. The patient suspended usage of ticagrelor and switched back to clopidogrel. Three weeks later, he had an endoscopy, which demonstrated no active bleeding sources.

Can CYP2C19 genotyping improve antiplatelet therapy efficacy in real-life practice? Recent advances.

Clopidogrel remains the most widely used P2Y₁₂ receptor inhibitor worldwide and is often used in combination with aspirin for secondary prevention in patients with arterial disease. The drug is associated with a wide response variability with one on three patients exhibiting little or no inhibition of adenosine diphosphate-induced platelet aggregation. It is a prodrug that is mainly metabolized by hepatic cytochrome P450 (CYP) 2C19. Patients who carry a CYP2C19 loss-of-function (LoF) allele have reduced metabolism of clopidogrel that is associated with reduced platelet inhibition compared to non-carriers that is associated with increased risk for thrombotic event occurrences, particularly, stent thrombosis. The United States Food and Drug Administration (US FDA) issued a black box warning in the clopidogrel label highlighting the importance of presence of CYP2C19 LOF allele during the insufficient metabolism of clopidogrel and availability of other potent P2Y₁₂ inhibitor for the treatment in CYP2C19 poor metabolizers. Clinical trials have conclusively demonstrated greater anti-ischemic benefits of prasugrel/ticagrelor in the treatment of patients carrying the CYP2C19 LoF allele. However, uniform use of these more potent P2Y₁₂ inhibitors has been associated with greater bleeding and cost, and lower adherence. The latter information provides a strong rationale for personalizing P2Y₁₂ inhibitor therapy based on the laboratory determination of CYP2C19 genotype. However, cardiologists have been slow to take up pharmacogenetic testing possibly due to lack of provider and patient education, clear cardiology guidelines and, and lack of positive results from adequately sized randomized clinical trials. However, current evidence strongly supports genotyping of patients who are candidates for clopidogrel. Physicians should strongly consider performing genetic tests to identify LoF carriers and treat these patients with more pharmacodynamically predictable P2Y₁₂ inhibitors than clopidogrel.

An αIIbβ3 monoclonal antibody traps a semiextended conformation and allosterically inhibits large ligand binding

AbstractMonoclonal antibodies (mAbs) have provided valuable information regarding the structure and function of platelet αIIbβ3. Protein disulfide isomerase (PDI) has been implicated in αIIbβ3 activation and binds to thrombin-activated αIIbβ3. Using human platelets as the immunogen, we identified a new mAb (R21D10) that inhibits the binding of PDI to platelets activated with thrombin receptor–activating peptide (T6). R21D10 also partially inhibited T6-induced fibrinogen and PAC-1 binding to platelets, as well as T6- and adenosine 5'-diphosphate–induced platelet aggregation. Mutual competition experiments showed that R21D10 does not inhibit the binding of mAbs 10E5 (anti-αIIb cap domain) or 7E3 (anti-β3 β-I domain), and immunoblot studies indicated that R21D10 binds to β3. The dissociation of αIIbβ3 by EDTA had a minimal effect on R21D10 binding. Cryogenic electron microscopy of the αIIbβ3-R21D10 Fab complex revealed that R21D10 binds to the β3 integrin-epidermal growth factor 1 (I-EGF1) domain and traps an intermediate conformation of αIIbβ3 with semiextended leg domains. The binding of R21D10 produces a major structural change in the β3 I-EGF2 domain associated with a new interaction between the β3 I-EGF2 and αIIb thigh domains, which may prevent the swing-out motion of the β3 hybrid domain required for high-affinity ligand binding and protect αIIbβ3 from EDTA-induced dissociation. R21D10 partially reversed the ligand binding priming effect of eptifibatide, suggesting that it could convert the swung-out conformation into a semiextended conformation. We concluded that R21D10 inhibits ligand binding to αIIbβ3 via a unique allosteric mechanism, which may or may not be related to its inhibition of PDI binding.

Clinical and Molecular Characteristics of Megakaryocytes in Myelodysplastic Syndrome.

Objective Myelodysplastic syndrome (MDS) is a malignant clonal disorder of hematopoietic stem cells which is characterized by morphologic dysplasia. However, the pathological characteristics of megakaryocytes (MKs) in MDS patients with gene mutation are not well established. Methods Bone marrow MK specimens from 104 patients with primary MDS were evaluated, and all patients were distributed into two groups according to gene mutation associated with functional MKs. The morphologic and cellular characteristics of MKs and platelets were recorded and compared. Results The more frequently mutated genes in MDS patients were TUBB1 (11.54%), VWF (8.65%), NBEAL2 (5.77%), and the most common point mutation was TUBB1 p.(R307H) and p.(Q43P). Patients with MK mutation showed a decrease in adenosine diphosphate-induced platelet aggregation, high proportion of CD34 + CD61 + MKs (10.00 vs. 4.00%, p = 0.012), and short overall survival (33.15 vs. 40.50 months, p = 0.013). Further, patients with a higher percent of CD34 + CD61 + MKs (≧20.00%) had lower platelet counts (36.00 × 10 9 /L vs. 88.50 × 10 9 /L, p = 0.015) and more profound emperipolesis ( p = 0.001). By analyzing RNA-sequencing of MKs, differentially expressed mRNA was involved in physiological processes including platelet function and platelet activation, especially for MDS patients with high percent of CD34 + CD61 + MKs. The high levels of expression of CD62P, CXCL10, and S100A9 mRNA, shown by RNA sequencing, were validated by PCR assay. Conclusion High proportion of CD34 + CD61 + MKs was a poor prognostic factor in MDS patients with MK mutation. CD62P, CXCL10, and S100A9 may be the potential targets to evaluate the molecular link between gene defects and platelet function.

Clinical prediction factors of nonchronic total occlusion lesion progression in patients with unstable angina receiving percutaneous coronary intervention for chronic total occlusion lesions

BackgroundIn this study, we investigated clinical prediction factors of nonchronic total occlusion lesion (NCTOL) progression in patients who underwent percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) lesions. MethodsIn total, 450 patients with unstable angina (mean age = 57.1 ± 9.2 years) who underwent PCI for CTO lesions between January 2016 and December 2018 at Beijing Anzhen Hospital were enrolled in this study. A clinical and angiographic follow-up examination was performed 12 months postoperatively. The patients were divided into NCTOL progression (145 cases) and control (305 cases) groups based on the outcome of the 12-month angiographic follow-up. The clinical and angiographic features of the participants were analyzed. ResultsThe adenosine diphosphate-induced platelet aggregation (ADP-IPA) rate and levels of lipoprotein (a) (Lp(a)) in the NCTOL progression group were significantly higher than those in the control group (51.89 ± 14.81 vs. 39.63 ± 17.12, P < 0.01; 0.22 ± 0.26 vs. 0.14 ± 0.18, P < 0.05, respectively). Logistic regression showed that the ADP-IPA rate (odds ratio = 1.047, 95 % confidence interval: 1.014–1.082, P = 0.005) and Lp(a) (odds ratio = 11.972, 95 % confidence interval: 1.230–116.570, P = 0.033) were independent predictors of NCTOL progression. Partial correlation analysis demonstrated that the ADP-IPA rate was positively correlated with NCTOL progression (r = 0. 351, P < 0.001). Receiver operating characteristic curve showed that the boundary point of the ADP-IPA rate to predict NCTOL progression was 30 % (sensitivity, 86.2 %; specificity, 68.9 %). ConclusionsNCTOL progression is an important cause of recurrent PCI in patients with coronary artery disease after PCI for CTO lesions. The ADP-IPA rate is a useful predictor for NCTOL progression in patients with unstable angina who undergo PCI for CTO lesions.

No impact of polymorphism in the phosphodiesterase 5A gene in Cavalier King Charles Spaniels on pimobendan-induced inhibition of platelet aggregation response.

A variant in the canine phosphodiesterase (PDE) 5A gene (PDE5A:E90K) is associated with decreased concentrations of circulating cyclic guanosine monophosphate (cGMP) and response to PDE5 inhibitor treatment. Pimobendan is a PDE inhibitor recommended for medical treatment of certain stages of myxomatous mitral valve disease (MMVD) in dogs. PDE5A:E90K polymorphism attenuates the inhibitory effect of pimobendan on in vitro platelet aggregation and increases basal platelet aggregation in Cavalier King Charles Spaniels (CKCS). Selected clinical variables (MMVD severity, sex, age, hematocrit, platelet count in platelet-rich plasma [PRP], and echocardiographic left ventricular fractional shortening [LV FS]) will not show an association with results. Fifty-two privately owned CKCS with no or preclinical MMVD. Using blood samples, we prospectively assessed PDE5A genotype using Sanger sequencing and adenosine diphosphate-induced platelet aggregation response (area under the curve [AUC], maximal aggregation [MaxA], and velocity [Vel]) with and without pimobendan using light transmission aggregometry. Dogs also underwent echocardiography. Pimobendan inhibited platelet function as measured by AUC, MaxA, and Vel at a concentration of 10 μM (P < .0001) and Vel at 0.03 μM (P < .001). PDE5A:E90K polymorphism did not influence the inhibitory effect of pimobendan or basal platelet aggregation response. The PDE5A:E90K polymorphism did not influence in vitro basal platelet aggregation response or the inhibitory effect of pimobendan on platelet aggregation in CKCS. Dogs with the PDE5A:E90K polymorphism did not appear to have altered platelet function or response to pimobendan treatment.

Evaluation of herb-drug interactions between compound Danshen dripping pills and clopidogrel based on the pharmacokinetics and pharmacodynamics in rats.

Compound Danshen dripping pills (CDDP), a well-known traditional Chinese medicine, is widely used to prevent and treat cardiovascular diseases. CDDP is usually prescribed in combination with clopidogrel (CLP), but the herb-drug interactions are rarely reported. This study evaluated the effects of CDDP on the pharmacokinetics and pharmacodynamics of coadministered CLP, and ensured the safety and efficacy of their usage. The trial design included a single-dose administration and multidose test for 7 consecutive days. Wistar rats received CLP alone or CLP combined with CDDP. After the final dose, plasma samples were collected at various time points, and the active metabolite H4 of CLP was analyzed by ultrafast liquid chromatography coupled with triple quadrupole tandem mass spectrometry. The main pharmacokinetic parameters of Cmax (maximum [or peak] serum concentration), Tmax (peak plasma time), t1/2 (half-time), AUC0-∞ (area under the concentration-time curve from dosing (time 0) to infinite time), and AUC0-t (area under the concentration-time curve from dosing [time 0] to time t) were calculated using the non-compartment model. In addition, prothrombin time, activated partial thromboplastin time, bleeding time, and adenosine diphosphate-induced platelet aggregation were evaluated for anticoagulation and antiplatelet aggregation activity. In this study, we found that CDDP had no significant effect on the metabolism of CLP in rats. In pharmacodynamic studies, the combination group showed significant synergistic antiplatelet activity compared with the CLP or CDDP groups alone. Based on pharmacokinetic and pharmacodynamic results, CDDP and CLP have synergistic effects on antiplatelet aggregation and anticoagulation.

O11 | In vitro and in vivo effects of dapagliflozin on adenosine diphosphate induced platelet aggregation response in Göttingen minipigs

Journal of Veterinary Pharmacology and TherapeuticsVolume 46, Issue S1 p. 33-33 ORAL PRESENTATIONS O11 | In vitro and in vivo effects of dapagliflozin on adenosine diphosphate induced platelet aggregation response in Göttingen minipigs First published: 11 June 2023 https://doi.org/10.1111/jvp.13177Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume46, IssueS1Special Issue: 15th International Congress of the European Association for Veterinary Pharmacology and Toxicology held Bruges, Belgium, July 2–5, 2023June 2023Pages 33-33 RelatedInformation

Association of serum PCSK9 levels with platelet function in patients with acute coronary syndromes.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein (LDL) homeostasis and plays a key role in acute coronary syndrome (ACS). The cardioprotective effect of PCSK9 inhibition extends beyond LDL cholesterol reduction, involving regulation of platelet function by not yet unraveled mechanisms. Oxidized-LDL (ox-LDL) is increased during ACS and induces platelet activation via binding to platelet surface. We will evaluate serum PCSK9 and its correlation with platelet reactivity and platelet-ox-LDL binding in Chinese ACS patients. In this pilot cross-sectional study, we will enroll 115 Chinese participants aged 30 to 75 years with ACS. Blood sample will be obtained after the first maintenance dose of aspirin and clopidogrel during morning time. Serum PCSK9 will be measured by an enzyme-linked immunoadsorbent assay. Platelet reactivity will be assessed by; Platelet activation (P-selectin and GPIIbIIIa expression using flow cytometry) and; Platelet aggregation using light transmission aggregometry in response to various stimuli. On-treatment platelet reactivity is measured by adenosine diphosphate-induced platelet aggregation. Binding of ox-LDL to platelet will be evaluated by flow cytometry. Spearman correlations will be used to determine association of serum PCSK9 with platelet functional parameters and platelet-ox-LDL binding. Additionally, continuous PCSK9 levels will be categorized into tertiles of equal size to investigate its association with on-treatment platelet reactivity. This study will reveal possible relationship between serum PCSK9 and platelet reactivity in the setting of ACS which may shed light on therapeutic potential in platelet inhibition by targeting PCSK9. The study will also explore the association of serum PCSK9 and platelet-ox-LDL binding, an important mechanism for platelet-LDL interplay, to provide mechanistic insight into PCSK9-mediated regulation of platelet reactivity.

The role of the hydrogen sulfide donor in adenosine diphosphate-induced platelet aggregation in patients with coronary heart disease

Introduction. Platelet activation is the initial stage of thrombotic complications in pathological conditions, primarily in atherosclerotic cardiovascular diseases. Endogenous hydrogen sulfide (H2S) is an antiplatelet agent, but the specific ways to realize its effects are not studied enoughAim: To study the effect of H2S on adenosine diphosphate (ADP)-induced platelet aggregation in patients with coronary heart disease (CHD) with blockers of Na+,K+,2Cl- cotransporter (NKCC), an anion exchanger, and a phosphodiesterase (PDE) inhibitor of cyclic nucleotides.Material and Methods. The study included 22 patients with CHD. The control group included 14 healthy volunteers. Platelet aggregation was determined by turbidimetric method. The degree of aggregation (%) and the size of aggregates (rel. units) were measured. ADP (2 μM) was an aggregation inductor. In some cases the incubation medium contained the hydrogen sulfide donor NaHS (1–100 μM) and aggregation modifierResults. The H2S donor at a concentration of 100 μM reduced the parameters of ADP-dependent platelet aggregation in healthy volunteers and increased it in patients with coronary artery disease. NKCC and anion exchanger blockers, as well as a PDE inhibitor, reduced ADP-dependent platelet aggregation in healthy volunteers. The combined action of these agents and NaHS enhanced the inhibitory effects of the applied modifiers. The results obtained for platelet aggregation in patients with coronary artery disease differed in different directionConclusion. The obtained data indicate that the antiaggregation effect of H2S is realized through the effect on the NKCC and anion exchanger, as well as due to the effect on the links of the signaling system mediated by cyclic nucleotides.

Choline and trimethylamine N-oxide impair metabolic activation of and platelet response to clopidogrel through activation of the NOX/ROS/Nrf2/CES1 pathway

BackgroundTrimethylamine N-oxide (TMAO), a gut microbe–generated metabolite, elicits thrombotic events by enhancing platelet reactivity; however, no studies have reported the effects of TMAO on the metabolism of and response to clopidogrel. ObjectivesTo determine whether choline and TMAO could significantly impair metabolic activation of and platelet response to clopidogrel in choline- or TMAO-fed mice and the mechanisms involved. MethodsMale mice were fed with vehicle control (Ctrl), TMAO, choline alone or in combination with 3,3-dimethyl-1-butanol, N-acetyl-L-cysteine, or ML385 for 14 days and then treated with Ctrl or a single oral dose of clopidogrel. Plasma TMAO, protein levels of clopidogrel-metabolizing enzymes in the liver, plasma concentrations of clopidogrel and its metabolites, and adenosine diphosphate–induced platelet aggregation and activation were measured. In addition, HepG2 cells were treated with Ctrl or TMAO alone or in combination with N-acetyl-L-cysteine, ML385, or apocynin, and CES1, reactive oxygen species (ROS), and Nrf2 protein levels were measured, respectively. ResultsTMAO significantly increased Ces1 protein expression and activity and clopidogrel hydrolysis in the liver as well as intracellular ROS and CES1 levels and Nrf2 nucleus translocation in HepG2 cells but decreased the formation of clopidogrel active metabolite and impaired platelet response to clopidogrel. Furthermore, concomitant use of 3,3-dimethyl-1-butanol, N-acetyl-L-cysteine, or ML385 effectively reversed choline- or TMAO-induced impairment of inhibition of platelet aggregation by clopidogrel in mice, respectively. ConclusionsCholine and TMAO impair the metabolic activation of and platelet response to clopidogrel through the activation of the NOX-dependent ROS/Nrf2/CES1 pathway, suggesting novel strategies for overcoming clopidogrel resistance from bench to bedside.

Endothelial biomarkers and platelet reactivity on ticagrelor versus clopidogrel in patients after acute coronary syndrome with and without concomitant type 2 diabetes: a preliminary observational study

BackgroundPleiotropic effects have been implicated in clinical benefits of ticagrelor compared to thienopyridine P2Y12 antagonists. There are conflicting data regarding effects of ticagrelor vs. thienopyridine P2Y12 blockers on endothelial function. Our aim was to compare endothelial biomarkers and their relations with platelet reactivity in real-world patients after acute coronary syndrome (ACS) on maintenance dual antiplatelet therapy (DAPT) with ticagrelor or clopidogrel stratified by diabetes status.MethodsBiochemical indices of endothelial dysfunction/activation and platelet reactivity by multiple electrode aggregometry were compared in 126 stable post-ACS subjects (mean age: 65 ± 10 years, 92 men and 34 women), including patients with (n = 61) or without (n = 65) coexistent type 2 diabetes (T2DM) on uneventful maintenance DAPT with either ticagrelor (90 mg b.d.) or clopidogrel (75 mg o.d.) in addition to low-dose aspirin. Exclusion criteria included a complicated in-hospital course, symptomatic heart failure, left ventricular ejection fraction < 40% and relevant coexistent diseases except for well-controlled diabetes, mild renal insufficiency or hypertension.ResultsClinical characteristics were similar in patients on ticagrelor (n = 62) and clopidogrel (n = 64). The adenosine diphosphate-induced platelet aggregation and circulating soluble P-selectin (sP-selectin) were decreased in ticagrelor users irrespective of T2DM status (p < 0.001 and p < 0.01 for platelet reactivity and sP-selectin, respectively). Plasma levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) were lower in T2DM subjects on ticagrelor vs. clopidogrel (758 ± 162 vs. 913 ± 217 µg/L, p < 0.01). In contrast, plasma sVCAM-1 was similar in non-diabetic patients on ticagrelor and clopidogrel (872 ± 203 vs. 821 ± 210 µg/L, p > 0.7). The concentrations of sE-selectin, monocyte chemoattractant protein-1 and asymmetric dimethylarginine did not differ according to the type of P2Y12 antagonist regardless of T2DM status. Platelet reactivity was unrelated to any endothelial biomarker in subjects with or without T2DM.ConclusionsOur preliminary findings may suggest an association of ticagrelor-based maintenance DAPT with favorable endothelial effects compared to clopidogrel users in stable post-ACS patients with T2DM. If proven, this could contribute to more pronounced clinical benefits of ticagrelor in diabetic subjects.

Low-Temperature Storage of Placenta Affects Anti-Inflammatory and Wound Healing Properties of Its Extracts

Here we have studied the effect of low-temperature storage of the placenta at different temperatures on anti-inflammatory activity of its extracts in cell models of erythrocyte thermohemolysis and adenosine-5’-diphosphate-induced platelet aggregation. The wound-healing effect of cryopreserved placental extracts was also evaluated in rat thermal burn model. When preserving placenta for up to a month, the temperature of storage was shown to cause no significant impact on the percentage of inhibition of erythrocyte thermohemolysis and platelet aggregation by the extracts. Placental storage for three months at –20°C decreased anti-inflammatory activity of its extracts, and led to its complete loss during 6 months. Placental cryopreservation at –196°C enabled to preserve the anti-inflammatory and wound-healing activity. The cryopreserved placenta-derived extracts showed a pronounced positive effect on reparative process at third-degree (B) skin burn injury in rats.

A study of microRNA-223 in evaluating platelet reactivity in patients with acute ischemic stroke.

To investigate the relationship between plasma microRNA-223 expression and platelet reactivity in patients with acute ischemic stroke (AIS) and to evaluate its predictive value in clopidogrel resistance or high on-treatment platelet reactivity (HTPR). A total of 120 patients with acute ischemic stroke were screened in this study, and 60 patients were included in the acute ischemic stroke group according to the inclusion criteria and platelet reactivity after clopidogrel treatment. control group was 60 non-ischemic stroke patients hospitalized. The levels of phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and adenosine diphosphate-induced platelet aggregation (ADP-PAg) in platelets were detected by flow cytometry. The expression level of plasma microRNA-223 was detected before and after clopidogrel treatment using quantitative real-time polymerase chain reaction (PcR). The AIS group was then divided into the clopidogrel non-HTPR and the clopidogrel HTPR groups based on the relative inhibition rate. We found that: 1) the VASP platelet reactivity index (PRI) was positively correlated with ADP-PAg; 2) before administration, the plasma microRNA-223 expression level and VASP-PRI were higher in the AIS group than in the control group; 3) after administration, the expression level of microRNA-223 was negatively correlated with VASP-PRI; 4) before and after treatment, the plasma microRNA-223 expression level in the clopidogrel HTPR group was lower than in the non-AIS patients; 5) before treatment, there was an interaction between the expression level of microRNA-223 in the plasma and the cYP2c19 loss-of-function (LOF) allele. The study showed that decreased plasma microRNA-223 expression levels in AIS patients indicate an increased risk of clopidogrel HTPR. carrying cYP2c19 LOF alleles may result in the microRNA-223 expression being more distinct. The combined detection of plasma microRNA-223 and cYP2c19 gene polymorphisms may be effective in predicting the occurrence of clopidogrel HTPR in patients with AIS.

Natural Sources of Inhibition of Adenosine Diphosphate-Induced Platelet Aggregation

Natural Sources of Inhibition of Adenosine Diphosphate-Induced Platelet Aggregation

Editor's Summaries of the Articles Published in This Issue of Phytopharmacological Communications

In this issue, Iram and colleagues described their study on the anti-inflammatory potential of Medicago laciniata, Afzal and her colleagues rationalized the traditional use of Peganum harmala in cardiovascular diseases, Aisha and her colleagues summarized studies showing inhibition of tau by medicinal plants and phytocompounds isolated from them for the treatment of Alzheimer’s disease, Zia-Ul-Hq et al, compiled investigations in which adenosine diphosphate-induced platelet aggregation is shown to be inhibited by medicinal plants, and Ullah and his colleagues reviewed studies showing potential calcium channel blockers from medicinal plants and provided their insights and recommended their further investigation in clinical trials.

Гемостаз та запалення у пацієнтів із політравмою

Актуальність. Причинами смерті при тяжких травмах є як ушкодження, несумісні з життям, так і тяжкі кровотечі. Коагулопатію, асоційовану з травмою, виявляють у 46 % пацієнтів уже на місці події та у 60 % пацієнтів — при надходженні на лікування. Мета: встановити наявність зв’язку між показниками загальної відповіді організму на запалення та показниками судинно-тромбоцитарного і коагуляційного гемостазу у пацієнтів з політравмою. Матеріали та методи. Проведено проспективне обсерваційне дослідження 20 пацієнтів віком від 19 до 55 років з політравмою, які перебували на лікуванні у відділенні анестезіології з ліжками інтенсивної терапії в Комунальному некомерційному підприємстві «8-ма міська клінічна лікарня м. Львова». Пацієнтів оцінювали за Injury Severity Score (ISS) та шкалою APACHE II (Acute Physiology And Chronic Health Evaluation II) з урахуванням тривалості синдрому загальної відповіді організму на запалення і лікування у відділенні інтенсивної терапії (ВІТ) та госпіталізації. Етапи дослідження: надходження на лікування у ВІТ (d1), третя доба (d3), п’ята доба (d5). Основними оцінюваними клінічними маркерами були показники: загальної відповіді організму на запалення, судинно-тромбоцитарного гемостазу (внутрішньосудинна активація тромбоцитів, агрегація тромбоцитів, індукована адреналіном і аденозиндифосфатом), коагуляційного гемостазу (міжнародне нормалізоване відношення, активований частковий тромбопластиновий час, рівень загального фібриногену та D-димерів). Результати. Встановлено наявність вірогідного (p &lt; 0,05) позитивного кореляційного зв’язку між співвідношенням рівнів дискоехіноцитів до сфероехіноцитів та рівнем загального фібриногену на етапі d1, а також тенденцію (p = 0,09) до наявності позитивного кореляційного зв’язку між цим співвідношенням та температурою тіла пацієнта. Виявлено вірогідний (p &lt; 0,05) зворотний кореляційний зв’язок між цим співвідношенням і рівнем тяжкості стану пацієнтів за шкалою APACHE II та прямий вірогідний (p &lt; 0,05) кореляційний зв’язок із тривалістю госпіталізації у ВІТ, а також тенденції до зворотного кореляційного зв’язку з тяжкістю ушкоджень за шкалою ISS (p = 0,07) та до прямого кореляційного внаслідок Systemic Inflammatory Response Syndrome (SIRS) (p = 0,12). Висновки. У пацієнтів із політравмою встановлено: наявність вірогідного (p &lt; 0,05) позитивного кореляційного зв’язку між співвідношенням дискоехіноцити/сфероехіноцити та рівнем загального фібриногену; тенденцію (p = 0,09) до позитивного кореляційного зв’язку між цим співвідношенням та температурою тіла пацієнта; вірогідний (p &lt; 0,05) зворотний кореляційний зв’язок з рівнем тяжкості стану пацієнтів за шкалою APACHE II; прямий вірогідний (p &lt; 0,05) кореляційний зв’язок з тривалістю госпіталізації у ВІТ; тенденцію (p = 0,07) до зворотного кореляційного зв’язку з тяжкістю ушкоджень за шкалою ISS та тенденцію (p = 0,12) до прямого кореляційного зв’язку з тривалістю SIRS.

Агрегационная способность тромбоцитов у пациентов с гипертонической болезнью в сочетании с неалкогольной жировой болезнью печени на фоне ожирения

Актуальность. Активация тромбоцитов и их агрегации являются важнейшими процессами в патофизиологии ишемической болезни сердца. Зависимость смертности от сердечно-сосудистой заболеваемости может усугубляться присутствием других сопутствующих сердечно-сосудистых факторов риска, в том числе гипертонической болезнью (ГБ), ожирением, неалкогольной жировой болезнью печени (НАЖБП). Цель работы: изучить наличие тромбофилических изменений крови у пациентов с гипертонической болезнью и сопутствующим ожирением и неалкогольной жировой болезнью печени путем определения агрегационной способности тромбоцитов. Материалы и методы. Обследован 91 пациент. Средний возраст — (57,9 ± 9,4) года. Выделено три группы пациентов: I — 36 больных ГБ II стадии с сопутствующей НАЖБП, II — 28 пациентов с НАЖБП без ГБ, III группа — 27 пациентов с ГБ II стадии без сопутствующей НАЖБП. Результаты. Выявлено достоверное увеличение степени спонтанной агрегации у пациентов во всех группах по сравнению с группой контроля: у пациентов с ГБ II ст. — в 3 раза (p &lt; 0,05), у пациентов с НАЖБП — в 4,2 раза (p &lt; 0,001), у пациентов с НАЖБП + ГБ II ст. — в 7 раз (p &lt; 0,01). Степень АДФ-индуцированной агрегации тромбоцитов достоверно возрастала во всех группах пациентов: в группе ГБ II ст. увеличивалась на 116 % (p &lt; 0,05), в группе НАЖБП + ГБ II ст. — на 93 % (р &lt; 0,001), при самостоятельной НАЖБП — на 71,7 % (p &lt; 0,05). Степень агрегации, индуцированной арахидоновой кислотой, достоверно снижалась на 8,3 % (p &lt; 0,05) в группе пациентов с НАЖБП + ГБ II ст. Выводы. При гипертонической болезни наблюдалось увеличение функциональной активности тромбоцитов, выраженность которой значительно возрастала при присоединении НАЖБП. У пациентов с изолированной НАЖБП также наблюдалось статистически значимое усиление спонтанной агрегации тромбоцитов, что позволяет рассматривать НАЖБП как один из факторов риска тромбофилических изменений первичного звена гемостаза.

Budget impact analysis of antiplatelet therapy with cangrelor in patients with acute coronary artery disease undergoing percutaneous coronary intervention in Portugal

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Ferrer, Barcelona, Spain Background Cangrelor is a novel, intravenous, potent, fast onset, direct-acting, P2Y12 receptor antagonist that blocks adenosine diphosphate-induced platelet activation and aggregation with a half-life of 3-6 min. Co-administered with acetylsalicylic acid, it is indicated for reducing thrombotic cardiovascular events in patients with coronary artery disease (CAD) (ST-elevation myocardial infarction (STEMI), non-STEMI, stable CAD) undergoing percutaneous coronary intervention (PCI) who have not received an oral P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) prior to PCI procedure and in whom oral therapy with P2Y12 inhibitors is not feasible or desirable. Purpose To assess the economic implications of incorporating cangrelor into the hospital formulary for the acute care of CAD patients undergoing PCI in Portugal. Methods A budget impact model (BIM) was developed. The 3-year pharmacological and clinical event costs of two hypothetical scenarios, without and with cangrelor in the formulary for the total PCI population (base case) in Portugal were compared. Also, the primary PCI (STEMI) and a PCI population with special needs (ie. unable to swallow) were assessed as complementary setups. Epidemiological, efficacy (stent thrombosis, myocardial infarction (MI), ischaemia-driven revascularization, death), safety (Thrombolysis in Myocardial Infarction (TIMI) bleeding criteria) and costs (€, 2019) data were based on clinical trials, meta-analyses and on Portuguese registries. Only the costs of pre-treatment with oral P2Y12 inhibitors and glycoprotein IIb-IIIa inhibitors (GPI) for bail-out were considered. One-way sensitivity analysis established the effect of uncertainty on BIM results. Results The model assumes that the total PCI population grows from 13,422 to 14,370 adults (age 65 years, mean) over three years in Portugal. Pre-treatment with oral P2Y12 inhibitors increases from 9,932 to 10,634 patients, and uptake of cangrelor rises from 0.80% to 1.40% in the same period. The number of total PCI patients receiving cangrelor grows from 79 to 149. At current usage of antithrombotics and at existing pharmacological and management costs, adding cangrelor into the hospital formulary represents 115 thousand € over 3 years in Portugal. Results are most sensible to the percentage of patients on GPI bail-out. Conclusions Under BIM assumptions, introducing cangrelor for the acute care of CAD patients undergoing PCI represents a safe and affordable option in Portugal, particularly when the required control of thrombosis is not certain with oral pre-treatment.

Budget impact analysis of antiplatelet therapy with cangrelor in patients with acute coronary artery disease undergoing percutaneous coronary intervention in Belgium

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Ferrer, Barcelona, Spain Background Cangrelor is a novel, intravenous, potent, fast onset, direct-acting, P2Y12 receptor antagonist that blocks adenosine diphosphate-induced platelet activation and aggregation with a half-life of 3-6 min. Co-administered with acetylsalicylic acid, it is indicated for reducing thrombotic cardiovascular events in patients with coronary artery disease (CAD) (ST-elevation myocardial infarction (STEMI), non-STEMI, stable CAD) undergoing percutaneous coronary intervention (PCI) who have not received an oral P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) prior to PCI procedure and in whom oral therapy with P2Y12 inhibitors is not feasible or desirable. Purpose To assess the economic implications of incorporating cangrelor into the hospital formulary for the acute care of CAD patients undergoing PCI in Belgium. Methods A budget impact model (BIM) was developed. The 3-year pharmacological and clinical event costs of two hypothetical scenarios, without and with cangrelor in the formulary for the total PCI population (base case) in Belgium were compared. Also, the primary PCI (STEMI) and a PCI population with special needs (e.g., unable to swallow) were assessed as complementary setups. Epidemiological, efficacy (stent thrombosis, myocardial infarction (MI), ischaemia-driven revascularization, death), safety (Thrombolysis in Myocardial Infarction (TIMI) bleeding criteria) and costs (€, 2019) data were based on clinical trials, meta-analyses and on Belgian registries. Only the pharmacological costs of pre-treatment (preload) with oral P2Y12 inhibitors and glycoprotein IIb-IIIa inhibitors (GPI) for bail-out were considered. One-way sensitivity analysis established the effect of uncertainty on BIM results. Results The model assumes that the primary PCI population grows from 4,790 to 4,935 adults (age 68 years, mean) over three years in Belgium. Pre-treatment with oral P2Y12 inhibitors increases from 3,544 to 3,652 patients, and uptake of cangrelor rises from 20.60% to 38.30% in the same period. The number of primary PCI patients receiving cangrelor grows from 730 to 1,399. At current usage of antithrombotics and at existing pharmacological and management costs, adding cangrelor into the hospital formulary represents 1.1 million euros over 3 years in Belgium. 6 additional stent thromboses, 3 ischaemia-driven revascularisations and 2 cardiovascular related deaths are avoided while three extra minor bleedings occur over 3 years. Similar pharmacoeconomic findings emerge in the base case and complementary setups. Results are most sensible to the percentage of patients on GPI bail-out. Conclusions Under BIM assumptions, introducing cangrelor for the acute care of CAD patients undergoing primary PCI represents a safe and affordable option in Belgium, particularly when the required control of thrombosis is not certain with oral pre-treatment.