Background/Purpose: Patients with systemic lupus erythematosus (SLE) are at increased risk for widespread endothelial dysfunction, vascular thromboses, and premature cardiovascular disease.  Enhanced platelet activation and interaction with the vascular endothelium may represent a common predisposition.  This study was initiated to evaluate platelet phenotype and effect on endothelial cell function in SLE and healthy subjects.  

Methods: Platelet phenotype was assessed using assays of platelet aggregation and markers of platelet activity in 50 SLE patients (mean age 41.1 ± 13.0, 81% female and 46% white) and age/sex matched healthy controls off antiplatelet therapy.  SLEDAI ranged from 0 to 22 (mean 5.3 ± 4.0).  Serum was collected for circulating soluble P-selectin and RANTES (chemokines from activated platelets).  Agnostic (array) and candidate (qPCR) gene transcripts were identified following cotreatment of resting and thrombin-stimulated platelets from SLE patients and controls with normal endothelial cells (HUVECs).

Results: Compared to healthy controls, SLE patients had increased monocyte platelet aggregation, leukocyte platelet aggregation, light transmission platelet aggregation both with and without submaximal ADP, collagen, and arachidonic acid (P<0.05 for each comparison).  Platelet activation did not associate with any ACR criteria or concomitant SLEDAI.  However, patients with active renal disease compared to those without renal disease had significantly higher values of both sP-selectin (37.0 ± 18.6 ng/ml vs 20.6 ± 13.7, P=0.01) and RANTES (45.2 ± 13.7 ng/ml vs 29.9 ± 7.6, P=0.03) reflecting in vivo platelet activation.  Predicted by serum levels, in ex vivo experiments using healthy platelets, SLE sera increased P-selectin expression (35.9%±8.6 vs. 28.0%±7.0, SLE vs control, P<0.01). Based on agnostic RNA array on HUVECs incubated with resting platelets from SLE vs healthy controls, endothelial adhesion molecules SELE, VCAM1, ICAM1, and cytokine IL8 and chemokine CXCR7, were among the top ten upregulated genes. KLF2 (0.69 + 0.02), a repressor of NFkB transcription factor was attenuated compared with CD146, a pan endothelial cell marker, 1.04 +0.08, p=0.034). Decreased expression of genes encoding proteins with immunomodulatory function including HMOX1, PROCR, HDAC5, and CALML4 were also noted following incubation of SLE platelets compared to controls.  Validation by qPCR confirmed that cotreatment of HUVECs with resting platelets from SLE vs controls resulted in a mean fold increase in IL-8 gene expression (12.46 ± 2.55 (SE) and 4.23 ± 0.74, respectively, P<0.01) and ICAM-I (3.02 ± 0.5 vs. 1.31 ± 0.3, P =0.02). ICAM1 gene expression trended higher in patients with SLEDAI >4 compared to those with SLEDAI ≤4 (3.42 ± 0.7 vs 2.25 ± 0.19 , P=0.09).

Conclusion: Platelet activity measurements are increased in SLE, irrespective of accompanying disease activity which supports observations that premature atherosclerosis is not fully explained by overt clinical activity. Platelets from subjects with SLE increase pro-inflammatory gene expression by endothelial cells, suggesting a role for the platelet-endothelial interface in the pathogenesis of the more insidious vascular manifestations of disease.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/platelet-activation-and-endothelial-reactivity-in-the-pathogenesis-of-tissue-inflammationinjury-in-systemic-lupus-erythematosus/