Patrik Htun

Course of Platelet Activation and Platelet-Leukocyte Interaction in Cerebrovascular Ischemia

Background and Purpose— Platelet activation plays a crucial role in the pathophysiology of cerebral ischemia. The aim of this study was to investigate the contribution of platelet activation and leukocyte-platelet interactions to the disease. Methods— One hundred thirty-five patients with transient ischemic attack (TIA) or stroke were enrolled in this single-center study. They underwent cranial computer tomography within 24 hours of clinical onset and after 3 months, and systemic venous blood samples were drawn. Platelet activation (CD62P expression), leukocyte activation (L-selectin expression), and the appearance of platelet-specific antigens on leukocytes as an index of platelet-leukocyte aggregation were measured by flow cytometric techniques in the acute state and at 3-month follow-up. Results— Patients with a completed stroke or TIA had significantly increased circulating platelet-leukocyte aggregates, increased P-selectin expression on platelets, and decreased L-selectin expression in the acute state compared with the control group (healthy volunteers). No differences in regard to the tested activation markers could be detected between patients with stroke or TIA in the acute phase of the disease. However, platelet and leukocyte activations were normalized after 3 months in patients with TIA, whereas leukocyte activation (reduced L-selectin expression) remained in stroke patients. Conclusions— In patients with TIA and completed stroke, platelet and leukocyte activation is substantially enhanced in the acute phase of the disease. The sustained leukocyte activation observed in stroke but not in TIA patients at 3-month follow up might play a pathophysiological role in the course of the disease.

Low Responsiveness to Clopidogrel Increases Risk among CKD Patients Undergoing Coronary Intervention

Patients with CKD are at higher risk for major events after percutaneous coronary intervention (PCI) compared with subjects with normal renal function. The aims of this study were to evaluate responsiveness to clopidogrel in patients with CKD and to examine the effect of antiplatelet drug response on post-PCI outcome. We retrospectively evaluated a consecutive cohort of 1567 patients with symptomatic coronary artery disease undergoing PCI, 648 (41%) of whom had stage 3 to 5 CKD. We assessed responsiveness to clopidogrel by ADP-induced platelet aggregation after oral administration of a 600-mg clopidogrel loading dose and 100 mg of aspirin. In a multivariate survival analysis that included 1335 (85%) of the cohort, stage 3 to 5 CKD and low response to clopidogrel were independent predictors of the primary end point (composite of myocardial infarction, ischemic stroke, and death within 1 year). In summary, a low response to clopidogrel might be an additional risk factor for the poorer outcomes in patients with stage 3 to 5 CKD compared with patients with better renal function.

Impact of inflammatory markers on platelet inhibition and cardiovascular outcome including stent thrombosis in patients with symptomatic coronary artery disease.

BACKGROUND There is cumulative evidence that the degree of inflammation correlates with prognosis after percutaneous coronary interventions (PCI). Additionally, there is a cross-link between platelet activation and inflammatory pathways. The aim of the present analysis was to evaluate the association of inflammatory markers and effects of dual antiplatelet therapy on platelet function and outcome in patients undergoing PCI. METHODS AND RESULTS In a pilot study, 157 patients with symptomatic coronary artery disease (CAD) undergoing PCI were consecutively evaluated. Platelet response to clopidogrel and acetylsalicylic acid was assessed using whole blood multiple electrode aggregometry (MEA). Baseline levels of IL-6, RANTES and MCP-1 were measured by Bio-Plex Cytokine assay. C-reactive protein (CRP) was determined by Immunoassay. Levels of IL-6, RANTES, and CRP correlated well with ADP and arachidonic acid (AA)-induced MEA. In a second step, a retrospective analysis of a cohort of 903 PCI-patients was performed to evaluate the association of on-treatment residual platelet aggregation (RPA) and baseline CRP levels on the incidence of myocardial infarction (MI), death and stent thrombosis (ST). Patients suffering a subsequent event had a significantly higher level of baseline CRP and higher RPA compared to patients without events. After multivariate adjustment high baseline CRP and high RPA were independent predictors for combined major events and ST after PCI. CONCLUSION To our knowledge this is the first study linking inflammation, antiplatelet drug responsiveness and outcome in a large CAD-patient cohort. The results suggest a relevant interaction of these parameters and encourage multimodal therapeutic approaches to treat cardiovascular risk after PCI.

Hyperresponsiveness of platelets in ischemic stroke

Platelet activation and aggregation are critical in the pathogenesis of acute ischemic cerebrovascular diseases. The aim of our study was to characterize platelet function in patients with acute ischemic stroke or transient ischemic attack (TIA), and to evaluate the effect of platelet activation on clinical outcome. One hundred thirty-eight consecutive patients with TIA (n = 74) or stroke (n = 64) were enrolled in this study. Platelet aggregation in response to ADP, epinephrine, arachidonic acid, or collagen, and expression of platelet activation receptors (CD62P, CD63, LIBS-1 and PAC-1) in the acute phase and at three months follow-up were evaluated. Platelets derived from stroke patients were more hyperaggregable in response to agonists in the acute phase compared to TIA patients (p[ADP] = 0.002, p[arachidonic acid] = 0.047, p[epinephrine] = 0.020). Platelet activation was enhanced in the acute phase irrespective of the severity of the disease (stroke or TIA) and returned to baseline levels three months later. Persistent elevated platelet activation at three months follow-up (PAC-1) was associated with increased incidence of recurrent stroke (median, [interquartile range] 3.4, [3.0-5.2] versus 2.9, [2.3-4.0], p = 0.048). In conclusion, platelets are hyperactive in acute stroke compared with TIA. A more intensified dual antiplatelet therapy may be of benefit for stroke patients.

Haemodialysis impairs clopidogrel but not aspirin responsiveness in patients with end-stage renal disease. Results of a pilot study.

Dual antiplatelet therapy (DAPT) with aspirin (ASA) and clopidogrel (Clp) is the standard treatment to reduce ischaemic coronary events, but in patients with end-stage renal disease (ESRD) the efficacy of Clp remains unclear. Patients with ESRD are at higher risk for coronary artery disease (CAD) and also their post-interventional outcome is worse compared to patients with normal renal function. Little is known about the influence of haemodialysis (HD) on ASA and Clp responsiveness. To assess the effect of HD on ASA- and Clp-responsiveness in patients with documented CAD and ESRD, 31 patients with ESRD (mean age 66.5 ± 1.8 years, 23 male) on DAPT were evaluated for their ASA and Clp responsiveness with the Verify Now System (Accumetrics Inc.) We measured the antiplatelet effect in all ESRD patients at three time points: T1: just before HD; T2: directly after HD; T3: steady state on a HD free day one week after T1. In our study at baseline 10 (32.3%) patients were ASA-low responder (ASA-LR) and 14 (45.2%) patients Clp-low responder (Clp-LR). There was a significant difference in the PRU values before (T1) and immediately after HD (T2) [PRU T1=234 (169; 274) vs PRUT2= 247 (199; 278); pT1,2=0.036; ]. Results were shown as median ARU T1 (25th, 75th percentile) or median PRU T1 (25th, 75th percentile). Hence HD seems to impair responsiveness to Clp, resulting in an increase of 6.5 % Clp-LR. No significant differences in the ARU values at the different time-points were found.

Platelet activation is less enhanced in the new balloon expandable Edwards Sapien 3 valve compared to its predecessor model (Edwards Sapien XT)

Stroke and thromboembolic events after transfemoral aortic valve replacement (TAVR) continue to be a problem. The aim of our study was to compare platelet aggregation (Agg) and platelet activation (PA) observed with two different catheter valves, the ESV-XT and the newer ESV-3 valve in patients (pts) undergoing TAVR on dual antiplatelet therapy (DAPT). A total of 174 patients with severe aortic stenosis and high surgical risk successfully underwent TAVR (60 ESV-XT; 114 ESV-3). Platelet Agg and PA (CD62P expression) were evaluated before and the following three days after TAVR under DAPT. Platelet Agg was inhibited to the same extent in both valve types and there was no significant difference in platelet drop between both valve types between day 0 and day 3 [ESV-XT vs ESV-3: median (25th-75th percentile): platelet count (x1000): 55 (42-74) vs 61(42-93), p=0.280]. However, there was an enhanced CD62P expression directly after TAVR with the ESV-XT compared to the ESV-3 [CD62P (MIF): 7.4 (6.8-8.6) vs 6.6 (6-7.9), p=0.014]. Surface expression of platelet CD62P was associated with the occurrence of residual aortic regurgitation (AR) and was significantly higher in patients with residual AR [CD62P (mild AR) vs CD 62P (no or trace AR): 7.9 (7.3-9.1) vs 7.1 (6.4-8.0), p < 0.001)]. PA was significantly enhanced in patients with the ESV-XT compared to the ESV-3 valve and was associated with the amount of residual AR which was significantly reduced by ESV-3. This may have implications for thromboembolic events following TAVR procedure.