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Michael Giovingo, Nicholas Maxwell Pfahler, Indre Bielskus, Paul A Knepper; Primary open-angle glaucoma: A phenotype with two faces. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5165.
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Primary open-angle glaucoma (POAG) is clinically divided into two forms: high-tension (HTG) and normal-tension (NTG), although most glaucoma specialists consider them to be the same phenotype and disease process. The extent to which vascular abnormalities in HTG and NTG differ remains unclear. This study tested the hypothesis that HTG than NTG subjects would exhibit differential platelet abnormalities.
Blood samples were obtained from control (n=25), POAG (n=25), and NTG (n=10) subjects recruited from John. H. Stroger, Jr. Cook County Hospital and Zaparackas and Knepper, Ltd after obtaining informed consent and Institutional Review Board approval. Superactivated platelet (SAP) and transglutaminase-active platelet (TAP) levels induced by thrombin and convulxin in vitro were measured by flow cytometry. The effect of TLR4 inhibitors resveratrol, quercetin, and curcumin (RQC) on SAP and TAP levels was determined. Thrombin sensitivity (the dose at which an intermediate clotting response occurred) and Aβ response (the percent of subjects who clotted in response to the thrombin sensitivity dose plus Aβ) were measured by cone-plate rheometry at a low shear rate.
SAP levels were significantly increased in HTG (51.5±6.3%, p<0.0001) but not NTG subjects (35.1±6.7%, p=0.41) compared to controls (34.0±5.6%) and were associated with visual field loss in HTG. TAP levels were also significantly increased in HTG (28.8±4.6%, p=0.008) but not NTG (23.8±6.3%, p=0.86) compared to controls (23.5±3.9%). RQC exhibited synergistic inhibition in control and HTG but not NTG subjects. The thrombin sensitivity dose was significantly lower in HTG (0.005±0.007 U/mL, p<0.0001) but not NTG subjects (0.03±0.03 U/mL, p=0.08) compared to controls (0.05±0.03 U/mL). The Aβ response was significantly lower in NTG (37.5%) compared to HTG (87.5%) (OR, 95% CI: 0.09, 0.01-1.08, p=0.03).
The results are the first evidence that SAP and TAP levels and the platelet clotting response to thrombin are significantly increased in HTG compared to NTG subjects, suggesting that platelet dysfunction may effectively differentiate the two types of POAG. HTG is driven by danger-associated molecular patterns leading to trabecular meshwork fibrosis via TLR4 signaling, whereas NTG is predominantly a vascular/endothelial dysfunction-driven disease process.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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