Platelet Reactivity and Response to Aspirin and Clopidogrel in Patients with Platelet Count Disorders.

BACKGROUND: Platelet reactivity and response to antiplatelet drugs, acetylsalicylic acid (ASA) and clopidogrel, in patients with thrombocytopenia and thrombocythemia can have a potentially important effect on the outcome. The effectiveness and safety of antiplatelet drugs in such patients has not been well examined. Measuring the effect of ASA and clopidogrel on platelets could help guide the therapy. Nevertheless, platelet response to antiplatelet drugs is not routinely measured in platelet count disorders and relevant evidence is scarce. AIMS: The study aimed to measure platelet reactivity and response to ASA and clopidogrel in patients with platelet count disorders. MATERIALS AND METHODS: This was a cross-sectional study of consecutive patients hospitalized in cardiology and hematology departments in the years 2018-2019. The study included patients with thrombocytopenia (PLT < 150 G/L) and thrombocythemia (PLT > 450 G/L) on ASA or dual antiplatelet therapy (DAPT; ASA plus clopidogrel). Controls included patients on antiplatelet drugs with normal platelet count. Platelet reactivity was measured in whole blood (Multiplate aggregometer, Roche, Switzerland) using arachidonic acid (AA), adenosine-5'-diphosphate (ADP), and thrombin receptor agonist peptide-6 (TRAP) as agonists. Platelet aggregation was expressed in arbitrary units (AU). AA-induced aggregation was used as a measure of response to ASA with a cut-off above 30 AU showing high on-treatment platelet reactivity to ASA (HTPR-A). ADP-induced aggregation measured response to clopidogrel with a cut-off above 48 AU for high on-treatment platelet reactivity to clopidogrel (HTPR-C). TRAP-induced aggregation measured baseline platelet reactivity not affected by oral antiplatelet drugs. RESULTS: The study included 174 patients. There were 64 patients with thrombocytopenia, 30 patients with chronic thrombocythemia, and 80 controls. All patients were on 75 mg of ASA and 32% of them additionally on 75 mg of clopidogrel due to a history of recent coronary artery angioplasty. AA- and ADP-induced aggregation was comparable between thrombocytopenic patients and controls (median (IQR) 19 (7-28) vs. 23 (15-38) for AA AU and 32 (16-44) vs. 50 (32-71) for ADP AU, respectively), while it was significantly higher in thrombocythemic patients (median (IQR) 80 (79-118) for AA AU and 124 (89-139) for ADP AU). TRAP-induced aggregation showed significantly lowest aggregation in thrombocytopenic (median (IQR) 41 (34-60) for TRAP AU) and highest in thrombocythemic patients (median (IQR) 137 (120-180) for TRAP AU). HTPR-A was frequent in thrombocythemic patients in comparison with thrombocytopenic patients and controls (60% vs. 4% vs. 15%, respectively; p < 0.0002). HTPR-C was highly common in thrombocythemic patients and least common in thrombocytopenic ones in comparison with controls (80% vs. 8% vs. 40%, respectively; p < 0.001). CONCLUSION: Chronic thrombocytopenia does not significantly affect platelet reactivity and response to ASA and clopidogrel in comparison with controls. Thrombocytosis significantly increases platelet reactivity and attenuates response to both ASA and clopidogrel.

Original and generic clopidogrel: A comparison of antiplatelet effects and active metabolite concentrations in patients without polymorphisms in the ABCB1 gene and the allele variants CYPC19*2 and *3.

BACKGROUND: Ticagrelor and prasugrel are widely used as antiplatelet therapy after coronary angioplasty. However, there is a group of patients with indications for clopidogrel treatment. This population includes patients with chronic or acute coronary syndrome who are treated invasively and have contraindications to the use of novel antiplatelet drugs due to antithrombotic treatment (particularly with non-vitamin K antagonist oral anticoagulants). A wide range of generic forms of clopidogrel are available on the market. However, it is unclear whether they are as effective as the originator drug. OBJECTIVES: In the current study, we aimed to assess the concentrations of the active metabolite of clopidogrel and its effect on platelet aggregation inhibition in patients receiving the originator drug in comparison with those receiving generic clopidogrel. MATERIAL AND METHODS: We enrolled 22 healthy individuals without polymorphisms in the ABCB1 gene and the allele variants CYPC19*2 and CYPC19*3. All participants received a loading dose of clopidogrel (600 mg), followed by a maintenance dose of 75 mg for the next 3 days. On day 3, blood samples were obtained 1 h after drug administration to assess active metabolite concentrations using liquid chromatography with tandem mass spectrometry. In each participant, platelet aggregation was assessed with light transmission aggregometry after 5-µmol/L and 10-µmol/L adenosine diphosphate (ADP) stimulation. Assays were performed for the originator clopidogrel and 2 different generic groups. RESULTS: The mean ± standard deviation (SD) concentrations of active clopidogrel did not differ between the originator drug and 2 generic products with clopidogrel (12.7±5 pg/µL compared to 13.0 ±4 pg/µL compared to 14.4 ±4 pg/µL). Platelet aggregation inhibition after stimulation with 5 µmol/L and 10 µmol/L ADP was similar for all preparations. CONCLUSIONS: In comparison with original clopidogrel, the use of its generic form does not affect the blood concentrations of the active metabolite or its antiplatelet effect.

Platelet polyphosphate level is elevated in patients with chronic primary thrombocytopenia: A preliminary study.

BACKGROUND: Platelets are key players in hemostasis. These blood cells contain different types of granules. Recently, there has been a growing interest in the role of inorganic polyphosphate (polyP) structures stored in dense granules of platelets and secreted during platelet activation. OBJECTIVES: To measure platelet polyP levels in patients with thrombocytopenia and thrombocythemia, and to examine the relationship of this indicator with platelet aggregation. MATERIAL AND METHODS: The study included 36 patients with hematological disorders (26 with primary chronic thrombocytopenia and 10 with essential thrombocythemia (ET)) and 40 healthy subjects. Platelet reactivity was measured using whole blood impedance aggregometry. The polyP levels were isolated from lysed platelets, which were obtained from citrated platelet-rich plasma. The procedure included inactivating endogenous phosphatases, removing phosphate units derived from DNA and proteins, and finally hydrolyzing them into monophosphate units. A colorimetric assay using malachite green and ammonium molybdate was performed in order to quantify polyP levels. RESULTS: The polyP concentrations were significantly higher in the patients with thrombocytopenia than in the patients with thrombocythemia or the controls. The polyP level was not correlated with the level of aggregation. CONCLUSIONS: The higher polyP levels observed in the patients with low platelet counts may indicate the existence of a compensatory mechanism that prevents excessive bleeding in such patients. Our study provides evidence of an essential role of polyP in platelet function and the coagulation process.

Response to antiplatelet therapy in patients undergoing invasive treatment due to acute coronary syndrome complicated by cardiogenic shock.

INTRODUCTION: There are limited data on platelet reactivity and response to antiplatelet drugs in patients with cardiogenic shock. AIM: To assess platelet reactivity on dual antiplatelet therapy with acetylsalicylic acid (ASA) and ticagrelor, a novel potent P2Y12 receptor inhibitor, in patients with cardiogenic shock in the course of acute coronary syndrome (ACS) who received invasive treatment. MATERIAL AND METHODS: We enrolled 12 consecutive patients with ACS complicated by cardiogenic shock. To assess response to antiplatelet therapy during cardiogenic shock, only patients with symptoms persisting for at least 3 days and who completed a 5-day follow-up were included in the study. Patients received a loading dose of ASA (300 mg) and ticagrelor (180 mg), followed by a maintenance dose (ASA, 1 × 75 mg; ticagrelor, 2 × 90 mg). Blood samples for platelet function tests were collected. Platelet aggregation was assessed with a Multiplate whole-blood impedance aggregometer. Arachidonic acid (AA), adenosine diphosphate (ADP), and thrombin receptor-activating peptide (TRAP) were used as aggregation agonists. RESULTS: Response to antiplatelet therapy assessed by aggregometry showed numerically higher on-ASA platelet reactivity on day one and statistically significant higher on-ticagrelor platelet reactivity on day one in comparison with following days. There were 2 patients with high on ASA platelet reactivity and 3 with high on ticagrelor platelet reactivity, but only on the day one. CONCLUSIONS: Some patients with cardiogenic shock in the course of ACS treated invasively show a lower response to ASA and ticagrelor only on the first day after invasive treatment, with a good response on subsequent days.

Effect of Aldosterone Antagonism on Exercise Tolerance in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Impaired functional capacity is a hallmark of patients with heart failure with preserved ejection fraction (HFpEF). Despite the association of HFpEF with reduced myocardial compliance attributed to fibrosis, spironolactone has not been shown to alter outcomes-perhaps reflecting the heterogeneity of underlying pathological mechanisms. OBJECTIVES: The authors sought to identify improvement in exercise capacity with spironolactone in the subset of patients with HFpEF with exercise-induced increase in ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e') reflecting elevation of left ventricular (LV) filling pressure. METHODS: In this randomized, blinded, parallel-group, placebo-controlled trial, 150 subjects (age 67 ± 9 years) with exertional dyspnea (New York Heart Association functional class II to III, left ventricular ejection fraction >50%, diastolic dysfunction, and exertional E/e' >13), excluding those with ischemic heart disease, were recruited in a tertiary cardiology center. Patients were randomized to 6 months of oral spironolactone 25 mg/day or matching placebo. Primary outcomes were improvements in peak oxygen uptake (VO2) and exertional E/e' ratio, and secondary outcomes were improvements in exercise blood pressure response and global LV longitudinal strain. RESULTS: At follow-up, 131 patients completed therapy-64 taking spironolactone and 67 placebo. At baseline, subjects had substantial exercise limitation (peak VO2 64 ± 17% predicted). The spironolactone group showed improvement in exercise capacity (increment in peak VO2 [2.9 ml/min/kg (95% confidence interval [CI]: 1.9 to 3.9 ml/min/kg) vs. 0.3 ml/min/kg (95% CI: -0.5 to 1.1 ml/min/kg); p < 0.001], anaerobic threshold [2.0 ml/min/kg (95% CI: 0.9 to 3.2 ml/min/kg) vs. -0.9 ml/min/kg (95% CI: -3.4 to 1.6 ml/min/kg); p = 0.03], and O2 uptake efficiency [0.19 (95% CI: 0.06 to 0.31) vs. -0.07 (95% CI: -0.17 to 0.04); p = 0.002]), with reduction in exercise-induced increase in E/e' (-3.0 [95% CI: -3.9 to -2.0] vs. 0.5 [95% CI: -0.6 to 1.6]; p < 0.001). There was a significant interaction of spironolactone and change in E/e' on VO2 (p = 0.039). CONCLUSIONS: In patients with HFpEF and abnormal diastolic response to exertion, improvement in exercise E/e' mediates the beneficial effect of spironolactone on exercise capacity. Identification of exercise-induced increase in LV filling pressure in patients with HFpEF may define a subgroup with warranting trial of spironolactone.

Kidney microcirculation response to adenosine stimulation in renal artery stenosis.

The purpose of this study was to assess the vasoconstrictive effects of adenosine in the kidney microcirculation in hypertensive patients with renal artery stenosis (RAS). Twelve patients with resistant hypertension and moderate RAS were selected for the study. In all patients, systolic, diastolic and mean translesional pressure gradients, distal pressure (Pd), aortic pressure (Pa) and Pd/Pa ratio were measured using a pressure guidewire at baseline and after intrarenal bolus administration of 400 µg adenosine. We observed significant changes in mean translesional pressure gradient and systolic Pd after pharmacological stimulation. The results suggest that in hypertensive patients with RAS, vasomotor activity of the kidney microcirculation may be preserved.

Expression of Proinflammatory Factors, Proangiogenic Factors and Endostatin in Patients with Heart Failure and Different Grades of Collateral Circulation Development.

BACKGROUND: The process of collateral vessel maturation is stimulated by numerous factors affecting the endothelium and smooth muscle cells building the vessel wall. Looking for arteriogenesis stimulating factors means looking for a potential innovative heart failure treatment method in the patients unresponsive to traditional therapies. OBJECTIVES: The purpose of this study was to assess the changes in serum concentrations of pro-inflammatory factor IL-6, growth factors FGF (FGFa, FGFb, FGFbH), HGF, VEGF and endostatin in heart failure patients in relation to the coronary collaterals development stage. MATERIAL AND METHODS: This study included 22 patients with chronic heart failure NYHA II or III (mean age 62.5 ± 11.6 years) and 8 control patients (mean age 58.4 ± 10.7 years). Coronary angiography was performed and the presence and grade of collateral circulation was assessed by a four-level scale proposed by Rentrop and Cohen. The level of the studied factors was determined in the blood samples collected during the angiographic procedure. RESULTS: The concentration of IL-6 was significantly higher in the heart failure patients than in the control group (p < 0.001) and in NYHA III vs. NYHA II patients (p < 0.02). Patients with heart failure and collaterals grade 1 or 2 exhibited higher serum concentrations of FGFbH (from p < 0.03 to p < 0.01). The serum VEGF level in NYHA III patients was significantly higher than in NYHA II individuals (from p < 0.03 to p < 0.01). CONCLUSIONS: Higher levels of IL-6 and FGFbH were observed in patients with heart failure. Collaterals formation seems to be associated with the activation of pro-inflammatory factors, growth factors and endostatin.

Left main aneurysm and what's next?

The purpose of the case report is to present a case of a 65-year-old male, referred for coronary angiography because of a typical chest pain. The coronary angiography showed an aneurysm of the left main coronary artery. Despite the absence of obvious ischemic symptoms and because of the potential complications of the aneurysm with a width of 15 mm, the patient underwent surgery.

[Neurohormonal effects following treatment with dopamine. More advantages or disadvantages?]. / Neurohormonalne nastepstwa leczenia dopamina. Wiecej korzysci czy dzialarí ubocznych?

Due to a big amount of dopaminergic receptors set in the vertebrate central nervous system (CNS), endogenously freed dopamine determines motor and cognitive activities of an organism. It influences neurohormonal regulation of the body, among all, other catecholamines' production; it also regulates kidney's functioning, the cardiovascular system and alimentary canal. Dopamine (a natural catecholamine) containing specimens are often used for the sake of intensive medical care. A particular effect, which is natriuretic, inotropic and vasopressive, is expected under inpatient treatment conditions depending on a selected dose. In practice, however, a potential influence of such treatment on neurohormonal processes, among all, an impact on hypothalamo-hypophyseal-adrenal axis is rarely taken into account. Considering numerous adverse events, a risk of renal failure development and blood redistribution disorders in the mucous membrane of the gastrointestinal tract, a negative impact on the respiratory system, as well as in the event of insufficient evidence for dopamine's effectiveness in both prevention and acute renal failure) treatment, dopamine's implementation in so called diuretic doses is controversial. Its implementation as a drug with the vasopressor effect must be reconsidered and individualised.