Correlation between the outcome of vitrectomy for proliferative diabetic retinopathy and erythrocyte hematocrit level and platelet function

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Correlation between the outcome of vitrectomy for proliferative diabetic retinopathy and erythrocyte hematocrit level and platelet function

https://doi.org/10.21203/rs.3.rs-1638259/v1

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We investigated whether biomarkers such as red blood cell hematocrit (Hct), platelet count (PLT), mean platelet volume (MPV), and platelet distribution width (PDW) are useful as prognostic indicators of postoperative macular edema (ME) after vitrectomy for proliferative diabetic retinopathy (PDR). Forty-eight eyes of 43 patients with PDR who underwent vitrectomy between January 2018 and May 2020 were analyzed retrospectively. We divided them into two groups according to whether treatment was required for postoperative ME and compared the relationship between Hct, PLT, MPV, and PDW and the onset of postoperative ME. The group that received postoperative treatment (group T) comprised 13 eyes of 12 patients, and the group that did not (group N) comprised 35 eyes of 32 patients. The age (years) was 53.2 ± 9.9 in group T and 60.0 ± 11.4 in group N. When the Wilcoxon rank-sum test, Pearson chi-square test, and Fisher's exact test were performed for comparison between groups, significant differences were found in Hct (p = 0.04). Multivariate logistic regression analysis was performed, and a significant difference was found in Hct (< 0.01). These results suggest that Hct might be useful as a predictor of ME after PDR surgery.

Proliferative diabetic retinopathy (PDR) is the most severe form of diabetic retinopathy (DR) characterized by the formation of new blood vessels and causes tractional retinal detachment (RD) and neovascular glaucoma (NVG), resulting in severe visual impairment.¹

PDR may cause in approximately 10% of those with type 2 diabetes mellitus (DM) ^{2, 3} and in up to 50% of those with type 1 DM ^{2, 4} who have suffered from the diabetes for 15 years. The morbidity rate of PDR is slightly higher among patients with type 2 DM who need insulin to improve their condition and is lower among patients who do not.² Another important change that can cause as advanced DR is diabetic macular edema (DME). DME is caused by the destruction of the blood–retinal barrier, with blood plasma leakage from the macular small vessels. DME does not causes complete blindness, but it often brings on a severe loss of visual acuity. In a large population-based study, the rate of occurrence over 10 years of DME was 13.9% in patients with type 2 DM who did not need insulin, 25.4% in patients with type 2 DM who needed insulin, and 20.1% in patients with type 1 DM.⁵

In recent years, it has been reported that high red blood cell (RBC) hematocrit (Hct) levels correlate with the progression of chronic kidney disease and the risk of cardiovascular thrombosis.^{6 7} It has also been reported that there is a correlation between DR and Hct in the field of ophthalmology.⁸ Postoperative complications of PDR include ME, which has a significant impact on visual acuity prognosis. To the best of our knowledge, there has been no report on the correlation between postoperative ME and preoperative Hct. Meta-analyses performed by Ji et al. showed that there is a relationship between DR and platelet function.^{9, 10} The index of platelet function is called the platelet volume index (PVI), which includes the platelet count (PLT), mean platelet volume (MPV), and platelet distribution width (PDW). The PDW reflects the distribution width of platelet size, and the larger the value, the more heterogeneous the platelet volume. The PVI is deeply involved in cerebral thrombosis and myocardial infarction (MI).¹¹ In particular, large platelets have higher intracellular enzyme activity than smaller ones, have enhanced adhesion and release and agglutination ability, and are actively involved in thrombus formation.¹² Many studies showed the association between cardiovascular diseases (CVDs) such as MI and PVI, but not an association with DR.

Since Hct and PVI are straightforward parameters inexpensively obtained through blood sampling, and preoperative blood sampling is essential for surgery, we believed that Hct and PVI could be predictors of the minimally invasive prognosis in postoperative ME after PDR. Therefore, we investigated the relationship between PDR postoperative ME and preoperative Hct and PVI and examined whether these were helpful in predicting the postoperative prognosis of PDR.

Table 1 shows the patients’ baseline characteristics. The subjects of observation were 13 eyes in 12 patients in the postoperative treatment (T) group and 35 eyes in 32 patients in the no postoperative treatment (N) group. One patient was included both the T and N groups in the left and right eye, respectively. Gender, age, presence or absence of hyperlipidemia, oral hypoglycemic agent use, oral hyperlipidemia, oral anticoagulant use, oral antiplatelet agent use, preoperative logMAR (logarithm of the minimum angle of resolution) best-corrected visual acuity (BCVA), axial length, smoking history, body mass index (BMI), dialysis, the presence or absence of preoperative high systolic and diastolic blood pressure, fasting blood pressure, preoperative antivascular endothelial growth factor (anti-VEGF) vitreous injection, and preoperative panretinal photocoagulation (PRP) were compared between the two groups, and no significant differences were observed in any parameter (p > 0.05). However, there were significant differences in hypertension (HT), insulin use, and preoperative intraocular pressure (IOP) (p < 0.05, respectively). Seven eyes (53.9%) in group T and 30 eyes (85.7%) in group N (p = 0.04) were from patients with HT. Eight eyes (61.5%) in group T and 30 eyes (28.6%) in group N (p = 0.04) were from patients with insulin use. Preoperative IOP was 15.9 ± 2.9 (mean ± SD) in group T and 13.5 ± 3.5 in group N (p = 0.03).

Table 2 shows the data from patients’ baseline blood tests. The Hct was 41.4 ± 5.7 in group T and 37.2 ± 5.6 in group N (p = 0.03). No significant differences were observed in any of the other parameters, i.e., hemoglobin A1c (HbA1c), fasting blood glucose, PLT, MPV, PDW, HbA1c, low-density lipoprotein cholesterol (LDL-chol), high-density lipoprotein cholesterol (HDL-chol), triglyceride (TG), creatinine value (Cr), estimated glomerular filtration rate (eGFR), hemoglobin (Hb), and blood urea nitrogen (BUN) (p > 0.05). Table 3 shows the patients’ characteristics after cataract surgery, internal limiting membrane (ILM) peeling, and gas tamponade by type of gas injected. The characteristics examined were postoperative logMAR BCVA, postoperative IOP, and observation period. A significant difference was observed only in postoperative IOP at 6 months (p = 0.04). Table 4 shows the multivariate logistic regression analysis for risk factors associated with PVI with metformin and statins as confounders. The p values were: PLT (10³/µl) = 0.85 (odds ratio [OR], 95% confidence interval [CI] 1.00 (1.00–1.00); MPV (fl) = 0.21 (OR [95% CI] = 0.55 [0.21–1.41]); PDW (fl) = 0.23 (OR [95% CI] = 2.93 [0.50–17.1]); oral statin use, eyes (%) = 0.67 (OR [95% CI] = 1.35 [0.36–5.29])’ and oral metformin use, eyes (%) = 0.63 (OR [95% CI] = 1.44 [0.33–6.23]). Multivariate logistic regression analysis was performed to rule out intravascular dehydration, a confounding factor for Hct (Table 5). The BUN/Cr ratio was used as an index of intravascular dehydration and showed a p value of = 0.13 (OR [95% CI] = 1.08 [0.98–1.22]), and the p value for Hct was < 0.01 (OR [95% CI] = 0.84 [0.71–0.96]). Figure 1 shows the receiver operating characteristic (ROC) curve obtained from the results of univariate logistic regression analysis with the objective variable of treatment for postoperative ME and the explanatory variable of Hct. The sensitivity was 69.2%, specificity 68.6%, area under the curve (AUC) 0.69, and cutoff value 39.3%.

This study investigated prognostic biomarkers for postoperative ME after PDR surgery, with the main focus on examining the usefulness of Hct and PVI as preoperative prognostic markers. Hct, but not PVI, showed a significant difference between the two groups of eyes (Table 2). Previous studies showed that metformin and statins lower MPV.^{13. 14} Therefore, we used metformin and statins as confounders, and performed multivariate logistic regression analysis for PVI (Table 4). However, there was no significant difference in PLT, MPV, and PDW in eyes from patients receiving those two agents. These results suggest that higher Hct might cause postoperative ME after PDR surgery. Romero et al. also reported the relationship between Hct and ME.⁸ Spade found that Muller cells are an important factor in the etiology of ME.¹⁵ Muller cells cross most of the thickness of the retina and are the major determinant of retinal fluid movement through the aquaporin 4 channel. The footplates of the Muller cells form the ILM of the retina, and Muller cell processes surround the retinal vessels of the superficial and deep vascular plexus. The fluid in the retina moves from the superficial vascular plexus toward the deep vascular plexus, and the excess is removed from the retina by being sent into the deep vascular plexus by the action of Muller cells. Deep vascular plexus occlusion might cause ME by blocking Muller cell function.

High Hct levels are thought to inhibit the action of nitric oxide (NO)^{16, 17} and correlate with the progression of chronic kidney disease and the risk of cardiovascular thrombosis.¹⁸ NO has a vasodilatory effect dependent on the vascular endothelium, and decreased NO activity may inhibit vasodilation and cause obstruction of the deep vasculature by blood cells.¹⁶ Higher Hct could cause obstruction of the deep retinal vasculature and lead to ME by blocking Muller cell function. It was reported that higher Hct levels increase blood viscosity.^{19. 20} Moreover, increased blood viscosity might cause vascular occlusion. Shiga et al. showed that blood viscosity is affected by Hct concentration, the erythrocyte deformation phenomenon, and depletion of erythrocyte aggregation.²¹ A high Hct concentration increases blood viscosity by increasing collision between RBCs.²² RBCs deform in blood vessels to reduce flow resistance, although increased blood viscosity decreases the deformability of RBCs. When RBC deformability decreases, the flow resistance also increases the viscosity of blood.²³ The increase in viscosity reduces the rate of blood slippage in the blood vessels, and the low-rate area causes the assembly of RBCs, which leads to a further increase in viscosity.^{23, 24}

As described above, the decrease in NO action and increase in blood viscosity might cause a reduction in blood flow in the deep retinal vasculature, which impairs the water excretion action of Muller cells and causes ME. In addition, it has been reported that smoking,^{25, 26, 27} HT, hyperglycemia,²⁸ DM,²⁹ elevated HbA1c, insulin use, alcohol intake,³⁰ total cholesterol, and LDL-chol³¹ are involved in the severity of DR and arteriosclerosis. Therefore, these factors might reduce the action of NO in the blood vessels, increase blood viscosity, and increase the risk of ME.

Insulin use was significantly higher in group T than in group N (Table 1, p = 0.04). Several reports identified insulin use as a risk factor for DME,^{2, 32} and our result supported that finding. Insulin use may reflect poor glycemic control, and it was reported that hyperglycemia reduces vascular endothelial function^{33, 34} and that DM reduces the use of NO.³⁵ Therefore, insulin use might be a risk for PDR postoperative ME. As shown in Tables 1 and 3, high preoperative (p = 0.03) and postoperative IOP (p = 0.04) might be a risk factor for PDR postoperative ME. In this study, patients with obvious preoperative NVG were excluded, but it is possible that not all patients underwent gonioscopy and that our groups included hidden NVG. In a future study, it will be necessary to perform gonioscopy on all patients at the screening stage.

Unexpectedly, the group without HT in the present study did not require treatment (p = 0.04). HT is a risk factor for DR, heart disease, and CVD.³⁵ It was also reported to be a risk factor for DME.³⁶ Further studies with larger sample sizes may be necessary to determine the role of HT in PDR.

Table 4 showed the results of multivariate logistic regression analysis for PVI. Metformin and statins lower MPV, suggesting that they may act as confounders of PVI. As a result of multivariate logistic regression analysis, even after removing the effects of these confounding factors, no significant difference was found in each parameter of PVI.

Table 5 shows the results of multivariate logistic regression analysis for Hct. Both the BUN/Cr ratio and Hct are used as indicators of intravascular dehydration, and it is possible that intravascular dehydration may act as a confounding factor for Hct. Therefore, confounding factors were excluded by using the BUN/Cr ratio as an index of intravascular dehydration. The results showed that Hct might be useful as a preoperative predictor of PDR postoperative ME. To investigate the performance of Hct as a predictor of the prognosis of PDR postoperative ME, univariate logistic regression analysis was performed and a ROC curve was created (Fig. 1). The ROC curve showed that the AUC was 0.69 (p = 0.03), and the cutoff value of Hct was 39.3%. The sensitivity based on this cutoff value was 69.2%, and the specificity was 68.6%. Although the AUC of 0.69 was somewhat low in terms of test performance, Hct might be useful as a predictor of PDR postoperative ME. Insulin use and preoperative IOP might also be useful prognostic factors.

In conclusion, no significant difference in PVI was found between the two groups in this study. Although the AUC was 0.69, and the predictive power was relatively low (cutoff value = 39.3%), Hct might be useful as a predictor of ME after PDR surgery. The decrease in blood flow in the deep retinal plexus might inhibit the water-removing action of Muller cells in the retina and cause ME. Two possible causes of decreased blood flow in deep retinal blood vessels are vascular dilatation disorder due to reducing NO action caused by decreased vascular endothelial cell function, and vascular occlusion due to increased blood viscosity. No significant results were obtained in this study on the risk factors for arteriosclerosis such as HT, high LDL-chol, low HDL-chol, hyperlipidemia, and hyperglycemia, although those factors might cause a decrease in vascular endothelial function and an increase in blood viscosity and therefore could be predictors of ME after PDR surgery.

This study was conducted in a small number of eyes, and it will be necessary to conduct further studies in the future involving more eyes from a larger patient group.

Patients

This retrospective observational study examined 48 eyes in 43 patients who underwent pars plana vitrectomy (PPV) for PDR at St. Marianna University School of Medicine from January 2018 to May 2020. Data were obtained by tracking patient charts. The patients were divided into two groups depending on the presence or absence of anti-VEGF vitreous injection and/or triamcinolone acetonide subtenon (STTA) injection for postoperative ME. The eyes were divided into the T group and N group and the correlation with preoperative Hct was compared between them. PPV was performed for complications of PDR such as fundus invisible vitreous hemorrhage (VH), progressive RD, and fibrovascular membrane (FVM). Exclusion criteria were a history of past vitreous surgery, the presence of existing NVG, and the use of intraoperative silicon oil.

Surgical Technique

All surgeries were performed by three skilled surgeons. All patients underwent standard PPV under regional anesthesia. In patients with cataract, phacoemulsification and aspiration were performed simultaneously, and an acrylic foldable intraocular lens was placed in the capsular bag. All PPVs were conducted using a 25-gauge or 27-gauge 3-port system (Alcon Constellation; Vision System, Fort Worth, TX) and a high-speed vitreous cutter (10,000 cycles/minute), with intravitreal injection of triamcinolone acetonide to visualize the vitreous gel and vitreoretinal adhesions. A valved cannula entry system was used. In cases with FVM, segmentation was performed after core vitrectomy, followed by delamination of FVM and removal of the posterior hyaloid face. We shaved vitreous base under scleral depression, and blood clots in the peripheral vitreous were also removed as much as we could. Intraoperative bleeding was controlled either by increasing the reflux pressure or endodiathermy. An endolaser was applied to complete PRP up to the ora serrata. When performing ILM peeling, brilliant blue G was used in all cases.

In some patients with combined traction-rhegmatogenous RD or RD caused by iatrogenic tear, fluid–air exchange was performed. In severe cases, sulfur hexafluoride (SF6) gas was injected at the end of surgery. Patients who underwent fluid–gas exchange were instructed to remain face down for 3 to 7 days. For patients taking an anticoagulant for underlying systemic disease, the anticoagulant was discontinued for 1 week preoperatively if possible and resumed within 2 weeks postoperatively.

Clinical Data Analysis

Postoperative ME was defined as occurring within 12 months after surgery. Preoperative examination parameters were age, gender, PLT, MPV, PDW, HbA1c, axial length, preoperative IOP, preoperative logMAR BCVA, Hct, Hb, Cr, eGFR, LDL-chol, HDL-chol, TG, BUN, pulse pressure, mean blood pressure, BUN/Cr ratio, systolic blood pressure, diastolic blood pressure, fasting blood glucose, BMI, HT, whether an oral antiplatelet, oral anticoagulant, oral hypoglycemic, oral metformin, oral statin, and oral diuretic was used, whether insulin was used, smoking habit, presence or absence of artificial dialysis, preoperative PRP and preoperative anti-VEGF vitreous injection, preoperative lens condition, whether cataract surgery and/or ILM peeling was performed, whether intraoperative gas replacement was performed and the type of gas, postoperative logMAR BCVA (at 1, 3, 6, 12 months), and observation period (months). We divided the two groups according to the presence or absence of postoperative ME treatment (groups T and N, respectively) and compared the results between them.

Statistical Analysis

Statistical processing was performed using JMP 13 (SAS Institute Inc., Cary, NC, USA). The Wilcoxon rank-sum test, Pearson chi-square, test and Fisher's exact test were performed to compare significant differences between the two groups. A p value of < 0.05 was considered statistically significant. Multivariate logistic regression analysis was performed considering metformin and high statins as confounders of PVI. To rule out intravascular dehydration as a confounding factor, multivariate logistic regression analysis was performed using the BUN/Cr ratio as an indicator of intravascular dehydration. To evaluate the test performance of Hct and calculate the cutoff value, univariate logistic regression analysis was performed, and the ROC curve was extracted. The AUC was calculated from the ROC curve obtained, and the cutoff value was calculated using the Youden index.

Ethical approval and consent to participate

This study complied with the tenets of the Declaration of Helsinki and was approved by the St. Marianna University School of Medicine Bioethics Committee. We fully explained the necessity for surgery and the possibility of complications to patients who needed surgical treatment for the diagnosis of PDR and obtained their consent.

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Acknowledgments

We would like to thank Mr. Takahiko Ueno for directing by statistical methods.

Author Contributions

K.S., T.J., and J.K. designed the study, and J.K. and H.T. performed surgery; K.S., T.J., R.S., N.U. and K.K. collected the data; K.S. and J.K. generated the figures and tables; K.S., J.K., Y.N, T.K., Y.K., and H.T. drafted and revised the manuscript; and all approved the final manuscript.

Conflict of Interest Statement

The authors have no conflicts of interest to disclose.

Funding Sources

The entire study was performed and completed at the Department of Ophthalmology, St. Marianna University School of Medicine, Kanagawa, Japan, without any support from grants or other funding.

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Tables 1 to 5 are available in the Supplementary Files section

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Correlation between the outcome of vitrectomy for proliferative diabetic retinopathy and erythrocyte hematocrit level and platelet function

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