Eyeworld

EW GLAUCOMA 122 March 2015 by Tony Realini, MD, MPH, EyeWorld Contributing Writer Do superactivated platelets explain disc hemorrhages in glaucoma? D isc hemorrhages are one of the mysteries of glaucoma. What causes them? Are they a sign of future dam- age to come or evidence of past damage? Why do some patients get them and others don't? Are they really more common in normal ten- sion glaucoma (NTG) than in high tension glaucoma? One thing is clear: The presence of a disc hemorrhage is a poor prog- nostic sign. In many major clinical trials, the appearance of a disc hem- orrhage was a significant predictor of glaucoma progression. A group of researchers in Chi- cago have discovered a potential explanation for the disc hemorrhage phenomenon in glaucoma: superac- tivated platelets. Platelets and superactivated platelets "Platelets are anucleate cell frag- ments derived from megakaryocytes that play an essential role in blood coagulation," explained Paulius Kuprys, BA, a researcher at the University of Illinois at Chicago. "Resting platelets patrol the vascu- lature and become activated when they encounter thrombogenic ele- ments. In some cases, they become superactivated. These superactivated platelets are phenotypically distinct from activated platelets and possess enhanced procoagulant and pro- thrombogenic activity." Superactivated platelets (SAPs) have been associated with system- ic diseases including Alzheimer's disease, transient ischemic attacks, and cortical stroke, among others, he said. "Individuals with Alzheimer's disease are at greater risk of devel- oping primary open-angle glaucoma (POAG) than those without Alzhei- mer's," he continued. "Furthermore, hemorrhages on both the optic nerve head and the nailfold capillary bed characterize POAG. The exact cause of these hemorrhages remains an enigma." These observations led the team to ask whether "elevated levels of SAPs might be observable in the blood of individuals with POAG," Mr. Kuprys said, which in turn might suggest that SAPs play a role in POAG. SAPs in glaucoma To test this hypothesis, the team determined the proportion of all platelets that were superactivated in a group of POAG and NTG patients and healthy control subjects. On average, 24% of the platelets in the peripheral blood of normal controls were SAPs, he said. In NTG, the number was similar at 27%. In POAG, however, 50% of all plate- lets were SAPs. POAG and normal control values were significantly dif- ferent (p=0.00133), while NTG and control values were similar (p=0.58). "POAG patients display an elevated level of SAPs, which are hypercoagulable," said Mr. Kuprys, "possibly playing a role in the dis- ease process by either leading to or limiting hemorrhages in the nailfold and optic nerve." Nailfold hemorrhages "Hemorrhages, dilated capillaries, and loss of capillaries in the nail- fold have been previously observed in both POAG and NTG patients," explained Paul A. Knepper, MD, PhD, lead researcher for the Chicago team. "These hemorrhages are tran- sient and last 5 to 10 days. Similarly, optic nerve hemorrhages are tran- sient and last 4 to 8 weeks." Dr. Knepper's group hypothe- sized that the presence of a nailfold hemorrhage—like a disc hemorrhage but easier to visualize in a screening setting—might have diagnostic or prognostic value for glaucoma. To test this hypothesis, nailfolds were evaluated in a large group of patients with POAG, NTG, and sec- ondary glaucomas as well as healthy control subjects. The group utilized video capillaroscopy to quantify vascular changes in the nailfold regions. "The vast majority of patients with POAG (96.8%), NTG (92.3%), and secondary glaucoma (75.0%) had video documented hemorrhag- es," Dr. Knepper said. "In contrast, only 17.6% of control subjects had microhemorrhages." Compared to controls, the POAG and NTG patients had 6-fold more nailfold hemorrhag- es (p<0.0001). Interestingly, NTG patients but not POAG patients had significantly more dilated capillaries and nailfold avascular zones than controls as well. Patients with sec- ondary glaucomas had inconsistent values relative to controls or primary glaucoma groups. These results were independent of comorbid systemic diseases and systemic medication use. "Our data suggests that there are distinct differences in the nailfold capillaroscopy between POAG, NTG, and secondary glaucoma," said Dr. Knepper. "Notably, hemorrhages are common in all 3 forms of glaucoma whereas avascular zones characterize NTG. Exactly why there are dif- ferences in nailfold capillary mor- phology underscores the theories of glaucoma pathophysiology, namely, the mechanical and the vascular theories." Practical applications The mechanical versus vascular debate has persisted in glaucoma for decades. Does elevated IOP cause cupping, which undermines vascular support and leads secondarily to the vascular changes and disc hemor- rhages, or does ischemia (evidenced by disc hemorrhages) cause cupping primarily? The answer remains elusive. While the data on SAPs and glaucoma is intriguing, more work is necessary to better characterize the relationship between these procoag- ulative elements and the glaucoma disease process. "We intend to examine the time course of SAPs relative to the various forms of glaucoma, as well as ex- plore the likelihood that SAPs might be the causative agent of the hemor- rhages we observe," said Mr. Kuprys. If causation can be established, "we intend to explore compounds that might be able to reduce levels of SAPs" in hopes of reducing glauco- ma progression, he added. In terms of nailfold hemor- rhages, it is intriguing that a quick, painless, non-invasive test might distinguish between people with and without glaucoma. "Video capillaroscopy may provide a quick and simple test to screen patients for NTG or POAG, and it may serve as an ancillary test in the management of POAG," Dr. Knepper said. While not likely useful as a single screening test, it may improve sensitivity and specificity of current screening techniques and warrants further exploration. EW Editors' note: Dr. Knepper and Mr. Kuprys have no financial interests related to their comments. Contact information Knepper: pknepper@northwestern.edu Kuprys: paulkuprys@gmail.com " We intend to examine the time course of SAPs relative to the various forms of glaucoma, as well as explore the likelihood that SAPs might be the causative agent of the hemorrhages we observe. " – Paulius Kuprys, BA

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