The effects of P2Y12 adenosine receptors' inhibitors on central and peripheral chemoreflexes.

Introduction: The most common side effect of ticagrelor is dyspnea, which leads to premature withdrawal of this life-saving medication in 6.5% of patients. Increased chemoreceptors' sensitivity was suggested as a possible pathophysiological explanation of this phenomenon; however, the link between oversensitization of peripheral and/or central chemosensory areas and ticagrelor intake has not been conclusively proved. Methods: We measured peripheral chemoreceptors' sensitivity using hypoxic ventilatory response (HVR), central chemoreceptors' sensitivity using hypercapnic hyperoxic ventilatory response (HCVR), and dyspnea severity before and 4 ± 1 weeks following ticagrelor initiation in 11 subjects with chronic coronary syndrome undergoing percutaneous coronary intervention (PCI). The same tests were performed in 11 age-, sex-, and BMI-matched patients treated with clopidogrel. The study is registered at ClinicalTrials.com at NCT05080478. Results: Ticagrelor significantly increased both HVR (0.52 ± 0.46 vs. 0.84 ± 0.69 L min-1 %-1; p < 0.01) and HCVR (1.05 ± 0.64 vs. 1.75 ± 1.04 L min-1 mmHg-1; p < 0.01). The absolute change in HVR correlated with the change in HCVR. Clopidogrel administration did not significantly influence HVR (0.63 ± 0.32 vs. 0.58 ± 0.33 L min-1%-1; p = 0.53) and HCVR (1.22 ± 0.67 vs. 1.2 ± 0.64 L min-1 mmHg-1; p = 0.79). Drug-related dyspnea was reported by three subjects in the ticagrelor group and by none in the clopidogrel group. These patients were characterized by either high baseline HVR and HCVR or excessive increase in HVR following ticagrelor initiation. Discussion: Ticagrelor, contrary to clopidogrel, sensitizes both peripheral and central facets of chemodetection. Two potential mechanisms of ticagrelor-induced dyspnea have been identified: 1) high baseline HVR and HCVR or 2) excessive increase in HVR or HVR and HCVR. Whether other patterns of changes in chemosensitivities play a role in the pathogenesis of this phenomenon needs to be further investigated.

Preliminary Assessment of Intra-Aneurysm Sac Pressure During Endovascular Aneurysm Repair as an Early Prognostic Factor of Aneurysm Enlargement.

Purpose: Numerous cases of abdominal aortic aneurysm (AAA) enlargement, and even rupture, despite endovascular aneurysm repair (EVAR), have been documented. This has been linked to increased aneurysm sac pressure (ASP). We decided to conduct further research with the aim to identify correlations between ASP during EVAR and subsequent aneurysm enlargement. Patients and Methods: This experimental prospective study included 30 patients undergoing EVAR of infrarenal AAAs. Invasive ASP measurements were done using a thin pressure wire. Aortic pressure (AP) was measured using a catheter placed over the wire. Systolic pressure index (SPI), diastolic pressure index (DPI), mean pressure index (MPI), and pulse pressure index (PPI) were calculated both for ASP and AP. The results of follow-up computed tomography angiography (CTA) at 3 months were compared with baseline CTA findings. Results: During EVAR, a significant reduction was observed for SPI (from 98% to 61%), DPI (from 100% to 87%), MPI (from 99% to 74%), and PPI (from 97% to 34%). There were no significant correlations of pressure indices with an aneurysm diameter, cross-sectional area, velocity, thrombus shape and size, number of patent lumbar arteries, length and diameter of aneurysm neck, diameter of the inferior mesenteric artery, as well as diameter and angle of common iliac arteries. On the other hand, aneurysm neck angulation was significantly inversely correlated with reduced PPI. After combining CTA findings with pressure measurements, we identified a positive correlation between PPI and aneurysm enlargement (ratio of the cross-sectional area at the widest spot at baseline and at 3 months after EVAR). Conclusion: The study showed that ASP can be successfully measured during EVAR and can facilitate the assessment of treatment efficacy. In particular, PPI can serve as a prognostic factor of aneurysm enlargement and can help identify high-risk patients who remain prior monitoring.

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.

Sealing of Coronary Perforations With a Second-Generation Covered Stent Graft - Results From the PAST-PERF Registry.

BACKGROUND: The PAST-PERF registry was initiated to collect data on the PK Papyrus covered stent, a second-generation device for the treatment of coronary artery perforations with enhanced mechanical properties, but with limited available data. METHODS: Patients treated for coronary artery perforations with the PK Papyrus stent at 14 international centers were retrospectively identified. The primary effectiveness outcome was successful sealing of the perforation. The primary safety outcome was a composite of all-cause mortality, definite or probable stent thrombosis, myocardial infarction and target lesion revascularization. RESULTS: Among the 94 included patients, 72.3% (68/94) had Ellis type III and cavity spilling perforations. Complete sealing was achieved in 93.6% (n = 88), and no sealing could be achieved in 3.2% (n = 3, including one patient with a geographical miss and one patient in whom the device could not be implanted). Pericardiocentesis was required in 25.0% (n = 23), emergency cardiac surgery was needed in 7.6% (n = 7), acute stent thrombosis was observed in 1.1% (n = 1), and in-hospital mortality occurred in 11.7% (n = 11). The median follow-up duration was 283 (IQR:40;670) days. At 6 and 12 months, the incidence of the primary safety endpoint was 26.6% [95%CI:18.6;37.1] and 32.0% [95%CI:22.8;43.4], mortality 15.0% [95%CI:9.0;24.6] and 19.0% [95%CI:11.3;30.0], and target lesion revascularization 5.5% [95%CI:2.0;14.6] and 7.7% [95%CI:3.1;18.2]. Two definite stent thrombosis occurred, one during the procedure and one on post-procedure day 233. CONCLUSIONS: The registry demonstrates favorably high rates of successful stent delivery and sealing of coronary perforations using a second-generation covered stent with low target lesion revascularization and stent thrombosis rates. ANNOTATED TABLE OF CONTENT: The PAST-PERF registry demonstrates favorably high rates of successful stent delivery and sealing of coronary perforations using a second-generation covered stent with low target lesion revascularization and stent thrombosis rates. Specifically, complete sealing was achieved in 93.6% of patients (n = 88/94), and no sealing could be achieved in 3.2% (n = 3, including one patient with a geographical miss and one patient in whom the device could not be implanted). The 12-month mortality was 19.0% [95%CI:11.3;30.0], the rate of target lesion revascularization was 7.7% [95%CI:3.1;18.2], and two definite stent thromboses occurred (one during procedure and one on post-procedure day 233).

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.

Platelet inhibition with standard vs. lower maintenance dose of ticagrelor early after myocardial infarction (ELECTRA): a randomized, open-label, active-controlled pharmacodynamic and pharmacokinetic study.

AIMS: Currently available data indicate that reduction of ticagrelor maintenance dose (MD) 1-3 years after acute myocardial infarction (AMI) not only provides sufficient platelet inhibition but also can improve ticagrelor's safety profile. The aim of this study was to compare the antiplatelet effect of reduced and standard ticagrelor MD in stable patients beginning 1 month after AMI. METHODS AND RESULTS: In a single-centre, randomized, open-label, active-controlled trial, on Day 30 following AMI, 52 patients (26 in each study arm) were assigned in a 1:1 ratio to receive either reduced (60 mg b.i.d) or standard (90 mg b.i.d) ticagrelor MD for the following 2 weeks. On Day 45 after AMI the antiplatelet effect of ticagrelor was evaluated with the VASP assay and Multiplate, and there were no significant differences in platelet inhibition between patients on reduced vs. standard MD [VASP: 10.4 (5.6-22.2) vs. 14.1 (9.4-22.1) platelet reactivity index; P = 0.30; Multiplate: 30.0 (24.0-39.0) vs. 26.5 (22.0-35.0) U; P = 0.26]. Likewise, no differences were found regarding the prevalence of on-ticagrelor high platelet reactivity between patients on ticagrelor 60 mg b.i.d vs. 90 mg b.i.d (VASP: 4% vs. 8%; P = 0.67; Multiplate: 15% vs. 8%; P = 0.54). Administration of reduced MD resulted in proportionally lower plasma concentrations of ticagrelor and its active metabolite on Day 45 after AMI. CONCLUSION: These results suggest that lowering ticagrelor MD 1 month after AMI confers an adequate antiplatelet effect that is comparable to the standard dose. The tested strategy warrants further research to assess its clinical efficacy and safety. CLINICALTRIALS.GOV IDENTIFIER: NCT03251859.

Low platelet activity predicts 30 days mortality in patients undergoing heart surgery.

Despite advanced techniques and improved clinical outcomes, patient survival following coronary artery bypass grafting (CABG) is still a major concern. Therefore, predicting future CABG mortality represents an unmet medical need and should be carefully explored. The objective of this study is to assess whether pre-CABG platelet activity corresponds with 30 days mortality post-CABG. Retrospective analyses of platelet biomarkers and death at 30 days in 478 heart surgery patients withdrawn from aspirin or/and clopidogrel. Platelet activity was assessed prior to CABG for aspirin (ASPI-test) with arachidonic acid and clopidogrel (ADP-test) utilizing Multiplate impedance aggregometer. Most patients (n = 198) underwent conventional CABG, off-pump (n = 162), minimally invasive (n = 30), artificial valve implantation (n = 48) or valves in combination with CABG (n = 40). There were 22 deaths at 30 days, including 10 in-hospital fatalities. With the cut-off value set below 407 area under curve (AUC) for the ASPI-test, the 30-day mortality was 5.90% for the lower cohort and 2.66% for patients with significantly higher platelet reactivity (P = 0.038). For the ADP-test with a cut-off at 400AUC, the 30-day mortality was 9.68% for the lower cohort and 3.66% for patients with higher platelet reactivity, representing a borderline significant difference (P = 0.046). Aside from the platelet indices, patients who received red blood cell (RBC) concentrate had a highly significant (P < 0.0001) risk of death at 30 days. Both aspirin and clopidogrel tests were useful in predicting 30 days mortality following heart surgery, suggesting the danger of diminished platelet activity prior to CABG in such high-risk patients. These preliminary evidence supports early discontinuation of antiplatelet therapy for elective CABG and requires adequately powered randomized trials to test the hypothesis and potentially improve survival.

Relationship between high on aspirin platelet reactivity and oxidative stress in coronary artery by-pass grafted patients.

The aim of the study was to assess the responsiveness of blood platelets to acetylsalicylic acid (ASA) in patients following coronary artery bypass grafting (CABG) surgery with relation to oxidative and antioxidative plasma status. The study included 37 patients treated with the CABG procedure. During the first 24 h after CABG patients were given 300 mg of ASA with the following dose of 150 mg daily. The blood was collected before the procedure and 10 days after. Whole blood platelet aggregation induced with arachidonic acid, collagen and adenosine diphosphate (ADP) was performed together with whole blood generation of thromboxane B2 (TxB2). Oxidative stress was measured before and 10 days after CABG with total oxidative plasma status (TOS) and total antioxidative status of the plasma (TAS). TOS/TAS index was calculated. We observed a significant increase in the TOS and TOS/TAS index and ADP-induced aggregation 10 days after CABG in comparison with its level before operation. There was a significant decrease in the arachidonic acid-induced aggregation and serum TxB2 level. Patients with ADP-induced and collagen-induced aggregation in the upper quartile had significantly higher TOS and TOS/TAS index before (ADP) and after the operation (ADP and collagen). There were 19 patients (51%) with high on aspirin platelet reactivity after CABG who had also higher TOS and TOS/TAS index and lower TAS value in comparison with aspirin responders. Despite ASA use, increased oxidative stress after CABG can overcome its antiplatelet effect and increase platelet activation through other pathways.

Predicting Bleeding Risk by Platelet Function Testing in Patients Undergoing Heart Surgery.

BACKGROUND: Predicting bleeding events in patients with coronary artery bypass grafting (CABG) represents an unmet medical need that may improve CABG outcomes. HYPOTESIS: To assess the potential link between platelet function testing and bleeding risk in patients undergoing CABG. METHODS: Platelet aggregation and clinical outcomes in 478 patients treated with aspirin and/or clopidogrel were retrospectively analyzed. Platelet activity was assessed prior to CABG with arachidonic acid (ASPI Test), and adenosine diphosphate(ADP Test) utilizing multiple-electrode aggregometry. RESULTS: In the study group of 478 patients, mean age was 65.2±15.2 years; 138 were women. The majority of patients (n = 198) underwent on-pump surgery, with 162 undergoing off-pump and 30 undergoing minimally invasive surgery. Forty-eight patients received artificial valve implantation alone, and 40 received valve implantation in combination with CABG. The analysis of the entire pool revealed that an ASPI test value <407 area under curve per minute (AUC*min) may be useful in predicting postoperative drainage. In CABG patients only, an ASPI test value <271 AUC*min predicted the need for red blood cell concentrate transfusion following surgery. In patients who stopped clopidogrel for up to 5 days before surgery, the ADP test failed to exhibit prognostic utility for predicting bleeding risk. CONCLUSIONS: In patients undergoing heart surgery, an ASPI test value <407 AUC*min may predict higher postoperative drainage, whereas <271 AUC*min may be linked to postoperative use of red blood cell concentrate.

Response to Dual Antiplatelet Therapy Does Not Impact Bleeding Risks in Patients Undergoing Oral Surgery after Acute Coronary Syndromes.

INTRODUCTION: Oral surgery (OS) in patients on antecedent dual antiplatelet therapy (DAPT) may be associated with extra bleeding risks. Monitoring platelet activity in such patients may be beneficial for safety when performing OS. OBJECTIVES: The aim of this study was to assess whether platelet function during DAPT impacted the risk of bleeding following OS in patients with acute coronary syndromes (ACS). PATIENTS AND METHODS: Patients who required OS on top of DAPT with aspirin and clopidogrel (n = 55) for invasively treated ACS were included. The control group (n = 33) consisted of patients who underwent OS with no antiplatelet agent. Platelet aggregation before OS was assessed with a Multiplate® analyzer. Bleeding during OS and at days 1, 3, 7 and 10 after surgery was serially evaluated. RESULTS: All 88 patients completed the study. An incomplete response to aspirin or clopidogrel was observed in 43.6% of the patients. In 11% of the cases, an excessive response to clopidogrel was demonstrated. No excessive bleeding upon OS was exhibited in either group during the entire follow-up. Platelet aggregation values and the use of DAPT did not impact the performance of OS. CONCLUSION: Therapy with clopidogrel and aspirin after ACS does not seem to increase the risk of real-life bleeding following OS, regardless of the platelet activity response to DAPT. © 2015 S. Karger AG, Basel.

Activated Hemostatic Biomarkers in Patients with Implanted Left Ventricle Assist Devices: Are Heparin and/or Clopidogrel Justified?

BACKGROUND: Adequate anticoagulation represents a major problem for left ventricle assist device (LVAD) utilization in patients awaiting heart transplantation as well as for regeneration of the native heart. The proper management of hemostatic abnormalities during LVAD support may improve survival by reducing the incidence of hemorrhagic and/or thromboembolic complications. CASE REPORT: A 40-year-old man with implanted pulsatile LVAD due to dilated cardiomyopathy received aspirin and warfarin. The patient underwent serial weekly monitoring of hemostatic biomarkers including international normalization ratio, prothrombin time, prothrombin activity, activated partial thromboplastin time, fibrinogen, D-dimer, platelet aggregation induced by adenosine diphosphate and arachidonic acid, platelet count, and mean platelet volume. The external pump was exchanged three times - twice because of a clot formation in the blood chamber of the pump, and once according to the standard protocol. RESULTS: LVAD use was consistently associated with enhanced adenosine diphosphate-induced platelet aggregation independent from the timing of clot formation or external pump exchange. Among coagulation indices, increased D-dimer holds predictive value for clot formation. The fibrinogen level peaked before the first pump exchange and was twice as high than the average values. Gradual improvement in exercise capacity was observed 2 years after implantation, after which the patient underwent a controlled stress test in the stop mode of the LVAD and the device was successfully explanted. CONCLUSIONS: Serial assessment of hemostatic biomarkers may benefit and triage LVAD patients. Consistent platelet activation during long-term LVAD may justify the addition of clopidogrel, while high D-dimer and/or elevated fibrinogen may indicate adding heparin to the conventional antithrombotic regimen. Randomized evidence is needed to test such a hypothesis.

Aspirin 'resistance': impact on no-reflow, platelet and inflammatory biomarkers in diabetics after ST-segment elevation myocardial infarction.

BACKGROUND: The no-reflow (NR) phenomenon exists despite percutaneous coronary intervention (PCI), and is especially prevalent in diabetics. The causes(s) of NR are not fully elucidated, but may be associated with impaired residual platelet and inflammatory reactivity during dual-antiplatelet therapy. OBJECTIVE: To assess the relationship between dual-antiplatelet therapy, NR and conventional biomarkers suggestive of platelet and inflammatory response in diabetics following ST-segment elevation myocardial infarction (STEMI) treated with PCI. METHODS: Sixty diabetics with (n = 27) and without NR (n = 33) were prospectively enrolled. All patients were treated with clopidogrel and aspirin. Platelet and inflammatory biomarkers were assessed serially in the peripheral blood and right atrium before and after PCI and then at 24 h, 7 days and 30 days. RESULTS: Arachidonic acid (AA)-induced platelet aggregation and the serum thromboxane B2 level before and after PCI (in the peripheral and right atrium blood) were significantly higher in the NR patients than in those with no NR. AA-induced aggregation >100 (AUC*min) before PCI predicted NR in diabetic patients with 96.2% sensitivity and 38.5% specificity (AUC 0.66; 95% CI 0.52-0.71; p = 0.029). There were no other correlations between NR and platelet reactivity (collagen, adenosine diphosphate, thrombin receptor agonist peptide-induced aggregation, vasodilator-stimulated phosphoprotein platelet reactivity index, soluble P-selectin, soluble CD40 ligand, platelet-derived growth factor AB and the level of platelet-monocyte aggregates) or between NR and inflammatory indices (i.e. high-sensitivity C-reactive protein, interleukin 6 and interleukin 10). CONCLUSION: An inadequate response to aspirin, but not to clopidogrel, may be associated with the occurrence of the NR phenomenon in diabetics with STEMI who have been treated with primary PCI.

Thrombin generation and platelet reactivity at hospital discharge and 6-month outcome after the acute coronary syndrome in diabetic and nondiabetic patients.

OBJECTIVES: Increased plasma thrombogenesis and blood platelet reactivity are associated with a worse outcome in patients with the acute coronary syndrome (ACS). The aim of this study was to test the clinical utility of combining a thrombin generation test and platelet aggregation in predicting future ischemic events after ACS. METHODS: The study included patients hospitalized due to ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention with stent implantation. Blood for platelet aggregation and thrombin generation was collected at hospital discharge. We performed whole-blood platelet aggregation with arachidonic acid (AA), collagen, adenosine diphosphate and thrombin receptor-activating peptide (TRAP) as agonists and the thrombin generation test using a fluorescence method. Patients were followed for up to 6 months. The combined end point of the study consisted of death, stroke, myocardial infarction or repeated target vessel revascularization. RESULTS: The study enrolled 161 patients. The end point occurred in 30 patients (18.6%). Thrombin generation showed a significantly prolonged lag time, time to thrombogram peak and start of the tail of the thrombogram in diabetic patients who reached the study end point but not in nondiabetics. End point occurrence was not connected with platelet reactivity at hospital discharge in the whole group. In the diabetic subgroup, increased platelet aggregation induced with AA and TRAP at hospital discharge was connected with a more frequent occurrence of the study end point. CONCLUSIONS: In diabetic patients after STEMI, thrombin generation measures as well as TRAP- and AA-induced platelet aggregation at hospital discharge are associated with an ensuing ischemic event during the 6-month follow-up.

Fatal sepsis and systemic inflammatory response syndrome after off-label prasugrel: a case report.

Aggressive dual antiplatelet therapy is associated not only with more bleeding, impaired wound healing, and potentially more solid cancer rates but it also causes higher infection risks including sepsis, and systemic inflammatory response syndrome (SIRS). This may be especially true considering the alarming off-label use of prasugrel. A 65-year-old white male patient with a history of myocardial infarction treated with percutaneous coronary intervention and implantation of 2 bare metal stents, was treated with off-label clopidogrel for 4 years, including a double daily dose (150 mg) for the initial 13 months. Still on clopidogrel, the patient was hospitalized with suspected pneumonia. A diagnostic cardiac catheterization revealed a 60%-70% blockage of the mid left anterior descending, but there was no need for coronary intervention. At discharge, clopidogrel 75 mg/d was switched over to off-label prasugrel 10 mg/d on top of aspirin (81 mg/d). On day 3 after prasugrel was given, a football-sized bruise appeared on the patient's lower right abdomen, but computed tomography results were unremarkable. On day 6 after administration of prasugrel, the patient became dizzy, disoriented, confused, experienced difficulty breathing, severe headache, weakness, intensive petechial rash covering the entire body, and breathing difficulty requiring ventilation. Within 24 hours, the patient was unable to correctly identify his age; his eyes were pale in color to almost colorless and when hearing a sound he would turn his entire head toward the sound and he appeared to be blind. His lungs, liver, and kidneys began to show signs of failure over the next 5-9 days. Sixteen days after the administration of the first prasugrel dose, the patient died of sepsis complicated with SIRS. Aggressive off-label use of clopidogrel (double dose for 13 months, and >4 years overall duration), followed by off-label switchover to the highest daily dose (10 mg) prasugrel may trigger sepsis and fatal SIRS. The mechanism responsible for such harmful association is probably indirect, and involves the weakening of platelet-neutrophil-endothelial crosstalk necessary to combat infections, and/or keep inflammation from spreading.

Comparison between five-year mortality of patients with and without red blood cell transfusion after percutaneous coronary intervention for ST-elevation acute myocardial infarction.

BACKGROUND: Red blood cell (RBC) transfusion can be lifesaving. However, in many clinical cases, including acute coronary syndromes, percutaneous coronary interventions (PCI), cardiac surgery, and acute critical care, detrimental effects (excess death and myocardial infarction [MI], and also lung infections) have been observed in patients after a RBC transfusion. AIM: To evaluate the long-term impact on the prognosis of patients who received a RBC transfusion after PCI for the treatment of ST-segment elevation MI (STEMI). METHODS: Between 1999 and 2004, 2,415 consecutive patients, with an STEMI treated with PCI, were included in the analysis. The patients were divided into two groups: 82 patients with a RBC transfusion (3.5%) and 2,333 without a RBC transfusion (96.5%). RESULTS: The in-hospital mortality rate was 15.8% and 4.2% (p < 0.0001) and the five-year mortality rate was 42.7% and 19% (p < 0.0001) for patients who received and who did not receive a RBC transfusion, respectively. Moreover, multivariate analysis revealed that, after correction for baseline differences, RBC transfusion was an independent predictor of five-year mortality in patients treated with PCI (HR 1.45; 95% CI 1.0-2.1; p = 0.04). CONCLUSIONS: Red blood cell transfusion is associated with higher five-year mortality in STEMI patients treated with PCI.

[The plant anticoagulants with perspective to use in treatment of thrombosis]. / Antykoagulanty pochodzenia roslinnego z perspektywa wykorzystania w leczeniu zakrzepic.

The diseases of blood circulation system--cardiovascular diseases are the main causes of mortality in developing, low and middle-income countries all over the world. The specialists recommend the prophylaxis to avoid the dangerous complications connected with these diseases, what can reduce the final treatment costs. All over the world there is continuous research of novel, therapeutically better, more effective anticoagulant or anti-platelet agents, with multiple targets, without so many side effects. Plant material is a good source to do this kind of research. The authors show the results of their few years research on polyphenolic-polysaccharide plant conjugates, isolated from medicinal plants, popular in Poland, which is continuing in the framework of the project WROVASC--Integrated Center of Cardiovascular Medicine. This research group has been working on isolation, structure characterization and biological activity of these macromolecular compounds. Because of anticoagulant, antioxidant as well as anti-platelet properties of these plant structures they are promising to be a new source of the innovative therapeutic agent.

Gastrointestinal adverse events after dual antiplatelet therapy: clopidogrel is safer than ticagrelor, but prasugrel data are lacking or inconclusive.

Current guidelines offer a choice of P2Y12 receptor antagonist among clopidogrel, prasugrel or ticagrelor on top of aspirin (ASA) for dual antiplatelet therapy (DAPT) in patients after acute coronary syndromes (ACS). However, the comparative risks of gastrointestinal (GI) adverse events during DAPT are not clear. Two large ACS trials (TRITON and PLATO) provide a valuable opportunity to directly match the risks of GI complications among current antiplatelet regimens. We compared the rates of GI adverse events after prasugrel and ticagrelor versus clopidogrel based on the Food and Drug Administration (FDA) clinical safety reviews. When compared with ticagrelor, clopidogrel is safer with regard to GI-related risks including fewer overall GI/anal bleeding events and spontaneous GI hemorrhagic episodes, less nausea, vomiting, dyspepsia and diarrhea, and a lower rate of presence of Helicobacter pylori. Among GI symptoms, only constipation was more common after clopidogrel than following ticagrelor. There were extrahepatic risks observed with ticagrelor but not with prasugrel when compared to clopidogrel. Prasugrel unquestionably caused more bleeding from the GI tract and GI malignancies than clopidogrel. However, the entire spectrum of GI effects of prasugrel is much less well known and mostly based on sponsor analysis rather than FDA-verified numbers. Among 3 DAPT options on top of ASA, clopidogrel seems to represent the safest alternative, although comprehensive data on direct prasugrel-associated GI effects are lacking or inconclusive.