RESUMO
OBJECTIVE: To evaluate whether treatment patterns for endophthalmitis after cataract surgery in American Academy of Ophthalmology IRIS® (Intelligent Research in Sight) Registry patients are in line with evidence-based guidelines established by the 1995 Endophthalmitis Vitrectomy Study (EVS), which showed that patients who present with light perception (LP) vision have better visual outcomes with immediate vitrectomy (VIT) compared with vitreous tap with antibiotic injection (TAP). DESIGN: Retrospective cohort study. SUBJECTS: Intelligent Research in Sight Registry patients undergoing cataract surgery between 2014 and 2022 (identified by Current Procedural Terminology codes), presenting with endophthalmitis (identified by International Classification of Diseases 10 codes) within 42 days postcataract surgery, and having a record of being treated with VIT or TAP on the same or 1 day after endophthalmitis diagnosis were identified. METHODS: Potential covariates of age, sex, race, ethnicity, geographic region, insurance status, and visual acuity on the day of endophthalmitis diagnosis were evaluated using multivariable logistic regression. MAIN OUTCOME MEASURES: Treatment with VIT or TAP. RESULTS: Of the 2425 patients who met the inclusion criteria, 14% (345) underwent VIT and 86% (2080) underwent TAP. Notably, 80% of patients (1946) presented with endophthalmitis within 14 days from cataract surgery (median = 6 days). Notably, 66% (173/263) of the patients presenting with LP vision underwent TAP instead of VIT. In a multivariable logistic regression model, receiving VIT instead of TAP was positively associated with poor vision at endophthalmitis presentation (LP - odds ratio [OR] = 5.4; confidence interval [CI], 2.9-10.6; counting fingers, hand motions - OR = 1.9; CI, 1.1-3.6) versus (20/20-20/40) vision; Asian versus White race (OR = 2.6; CI, 1.3-5.2); Hispanic versus non-Hispanic ethnicity (OR = 1.9; CI, 1.1-3.2); living in the West (OR = 1.6; CI, 1.1-2.2) and Midwest (OR = 1.5; CI, 1.1-2.0) (vs. South), but not with age, sex, and insurance coverage (P > 0.05). CONCLUSIONS: In the IRIS Registry, treatment patterns for postcataract surgery endophthalmitis did not match evidence-based recommendations of the EVS, a randomized controlled clinical trial. More work is needed to evaluate whether the current treatment patterns are optimal for patients with postcataract surgery endophthalmitis. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
RESUMO
The critical role of G protein-coupled receptor kinase 2 (GRK2) in regulating cardiac function has been well documented for >3 decades. Targeting GRK2 has therefore been extensively studied as a novel approach to treating cardiovascular disease. However, little is known about its role in hemostasis and thrombosis. We provide here the first evidence that GRK2 limits platelet activation and regulates the hemostatic response to injury. Deletion of GRK2 in mouse platelets causes increased platelet accumulation after laser-induced injury in the cremaster muscle arterioles, shortens tail bleeding time, and enhances thrombosis in adenosine 5'-diphosphate (ADP)-induced pulmonary thromboembolism and in FeCl3-induced carotid injury. GRK2-/- platelets have increased integrin activation, P-selectin exposure, and platelet aggregation in response to ADP stimulation. Furthermore, GRK2-/- platelets retain the ability to aggregate in response to ADP restimulation, indicating that GRK2 contributes to ADP receptor desensitization. Underlying these changes in GRK2-/- platelets is an increase in Ca2+ mobilization, RAS-related protein 1 activation, and Akt phosphorylation stimulated by ADP, as well as an attenuated rise of cyclic adenosine monophosphate levels in response to ADP in the presence of prostaglandin I2. P2Y12 antagonist treatment eliminates the phenotypic difference in platelet accumulation between wild-type and GRK2-/- mice at the site of injury. Pharmacologic inhibition of GRK2 activity in human platelets increases platelet activation in response to ADP. Finally, we show that GRK2 binds to endogenous Gßγ subunits during platelet activation. Collectively, these results show that GRK2 regulates ADP signaling via P2Y1 and P2Y12, interacts with Gßγ, and functions as a signaling hub in platelets for modulating the hemostatic response to injury.
Assuntos
Hemostáticos , Trombose , Difosfato de Adenosina/farmacologia , Animais , Plaquetas/metabolismo , Humanos , Camundongos , Agregação Plaquetária , Trombose/metabolismoRESUMO
Rebalancing the hemostatic system by targeting endogenous anticoagulant pathways, like the protein C (PC) system, is being tested as a means of improving hemostasis in patients with hemophilia. Recent intravital studies of hemostasis demonstrated that, in some vascular contexts, thrombin activity is sequestered in the extravascular compartment. These findings raise important questions about the context-dependent contribution of activated PC (APC) to the hemostatic response, because PC activation occurs on the surface of endothelial cells. We used a combination of pharmacologic, genetic, imaging, and computational approaches to examine the relationships among thrombin spatial distribution, PC activation, and APC anticoagulant function. We found that inhibition of APC activity, in mice either harboring the factor V Leiden mutation or infused with an APC-blocking antibody, significantly enhanced fibrin formation and platelet activation in a microvascular injury model, consistent with the role of APC as an anticoagulant. In contrast, inhibition of APC activity had no effect on hemostasis after penetrating injury of the mouse jugular vein. Computational studies showed that differences in blood velocity, injury size, and vessel geometry determine the localization of thrombin generation and, consequently, the extent of PC activation. Computational predictions were tested in vivo and showed that when thrombin generation occurred intravascularly, without penetration of the vessel wall, inhibition of APC significantly increased fibrin formation in the jugular vein. Together, these studies show the importance of thrombin spatial distribution in determining PC activation during hemostasis and thrombosis.
Assuntos
Hemostáticos , Trombose , Animais , Anticoagulantes/farmacologia , Células Endoteliais/metabolismo , Fibrina/metabolismo , Hemostasia , Humanos , Camundongos , Proteína C/farmacologia , Trombina/metabolismo , Trombose/metabolismoRESUMO
Hemostatic thrombi develop a characteristic architecture in which a core of highly activated platelets is covered by a shell of less-activated platelets. Here we have used a systems biology approach to examine the interrelationship of this architecture with transport rates and agonist distribution in the gaps between platelets. Studies were performed in mice using probes for platelet accumulation, packing density, and activation plus recently developed transport and thrombin activity probes. The results show that intrathrombus transport within the core is much slower than within the shell. The region of slowest transport coincides with the region of greatest packing density and thrombin activity, and appears prior to full platelet activation. Deleting the contact-dependent signaling molecule, Sema4D, delays platelet activation, but not the emergence of the low transport region. Collectively, these results suggest a timeline in which initial platelet accumulation and the narrowing gaps between platelets create a region of reduced transport that facilitates local thrombin accumulation and greater platelet activation, whereas faster transport rates within the shell help to limit thrombin accumulation and growth of the core. Thus, from a systems perspective, platelet accumulation produces an altered microenvironment that shapes thrombus architecture, which in turn affects agonist distribution and subsequent thrombus growth.