Role of Platelet Activation in the Pathogenesis of Heart Failure in End-Stage Renal Disease Patients

Introduction: Heart failure (HF) is prevalent in patients with End-Stage Renal Disease (ESRD) with an incidence of approximately 40%. ESRD patients exhibit both quantitative and qualitative changes in platelets due to the uremic milleu and / or stress caused by the dialysis filtration membranes. Platelet Factor 4 (PF4) and Platelet Derived Growth Factor (PDGF) are released from the alpha granules of activated platelets and play a role in heparin neutralization and angiogenesis, respectively. The purpose of this study was to determine the interplay of platelets and their released mediators and their relevance to the pathogenesis of HF in ESRD patients.

Material and Methods: Under IRB approval, ninety blood samples from maintenance hemodialysis patients at Loyola University outpatient dialysis unit were collected prior to dialysis session and stored at -70°C. Twenty-five male and twenty-five female plasma samples from healthy individuals were obtained as a control (George King Biomedical Overland Park, KS). Maintenance hemodialysis patients' and healthy volunteers' plasma samples were used to profile PDGF-BB, Heparin anti Xa, and PF4 using commercial sandwich and competitive ELISA kits (R&D Systems, Minneapolis, MN | Hyphen Biomed, Neuville-sur-oise, France). In addition, patients' HF diagnoses, comorbidities, medications, and clinical laboratory parameters were reviewed through the patients' medical records.

Results: Plasma biomarkers PF4 (P < 0.0001; % change = 247.76) and heparin level as measured by an anti Xa methods were significantly increased (P < 0.05) in patients with ESRD in comparison to the values obtained in normal healthy volunteers. PDGF-BB was not found to be significantly increased (P = 0.4045 ; % change = 40.3%). PF4, Heparin levels, and PDGF-BB were not found to be significantly elevated in ESRD (+) HF vs ESRD (-) HF (P > 0). In male ESRD (+) CHF vs ESRD (-) HF, platelet counts were significantly decreased (P = 0.0476 ; % change = -16.5). Systolic BP and PLT count had a positive correlation in both male and female ESRD patients and in male ESRD (+) HF patients (P = 0.016 and P = 0.044, respectively), but not in female ESRD HF (+) patients (P = 0.172). PLT count and PDGF were found to have a positive correlation in ESRD HF (+) patients (P = 0.045). In ESRD (+) HF patients, PF4 had a positive correlation with proBNP (P = 0.045) and Heparin levels had a negative correlation with proBNP (P = 0.045).

Discussion: Elevated PF4 in the ESRD patients compared to normals suggest that there may be increased platelet granule release or an upregulation of PF4. The platelets may be activated due to dialysis procedure stress from the previous session, the uremic environment, or heparin-PF4 complexed with antibodies binding to the platelet surface. Elevated heparin levels in the ESRD patients compared to normal suggests that heparinization at dialysis session may lead to an anticoagulated state between sessions in several of these patients. Since these patients are continually heparinized, it is expected to see increased levels of platelet release products such as PF4 due to their mobilization from platelets. Activated platelets may lead to platelet exhaustion and thrombocytopenic responses. Interestingly thrombocytopenia is only noticed in male ESRD (+) HF patients suggesting gender differences and the potential role of hormonal regulation. These results suggest that both the quantitative and qualitative defects in platelets play an important role in the mediation of the pathogenesis of HF in ESRD patients underscoring the potential benefit of antiplatelet drugs.