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Zhao Heng, 1,* Zhang Lidan, 2,* Liu Lifang, 1 Li Chunqing, 3 Song Weili, 3 Peng Yongyang, 1 Zhang Yunliang, 1 Li Dan 41 Endocrinology Laboratory, First Baoding Central Hospital, Baoding, Hebei Province, 071000; 2 Baoding First Department of Nuclear Medicine, Central Hospital, Baoding, Hebei 071000; 3 Outpatient Department of Baoding First Central Hospital, Baoding, Hebei Province, 071000; 4 Department of Ophthalmology, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000 *These authors have contributed equally to this work. Corresponding author: Li Dan, Department of Ophthalmology, Hebei University Hospital, Baoding, Hebei, 071000 Tel +86 189 31251885 Fax +86 031 25981539 Email [email protected] Zhang Yunliang Endocrinology Laboratory, Baoding First Central Hospital, Baoding, Hebei Province 071000 People’s Republic of China Tel +86 151620373737373737375axe Email protected ] Purpose: This study aims to describe the levels of glycosylated hemoglobin (HbA1c), D-dimer (DD) and fibrinogen (FIB) in different types of diabetic retinopathy (DR). Method: A total of 61 diabetic patients, who received treatment in our department from November 2017 to May 2019, were selected. According to the results of non-mydriatic fundus photography and fundus angiography, patients were divided into three groups, namely non-DR (NDR) group (n=23), non-proliferative DR (NPDR) group (n=17) and proliferative DR ( PDR) group (n=21). It also includes a control group of 20 people who tested negative for diabetes. Measure and compare HbA1c, DD and FIB levels respectively. Results: The average values of HbA1c were 6.8% (5.2%, 7.7%), 7.4% (5.8%, 9.0%) and 8.5% (6.3%), 9.7%) in the NDR, NPDR and PDR groups, respectively. The control value was 4.9% (4.1%, 5.8%). These results indicate that there are significant statistical differences between the groups. In the NDR, NPDR, and PDR groups, the average values of DD were 0.39 ± 0.21 mg/L, 1.06 ± 0.54 mg/L, and 1.39 ± 0.59 mg/L, respectively. The result of the control group was 0.36 ± 0.17 mg/L. The values of the NPDR group and the PDR group were significantly higher than those of the NDR group and the control group, and the PDR group value was significantly higher than that of the NPDR group, indicating that the difference between the groups was significant (P<0.001). The average values of FIB in the NDR, NPDR, and PDR groups were 3.07 ± 0.42 g/L, 4.38 ± 0.54 g/L, and 4.46 ± 1.09 g/L, respectively. The result of the control group was 2.97 ± 0.67 g/L. The difference between the groups was statistically significant (P <0.05). Conclusion: The levels of blood HbA1c, DD, and FIB in the PDR group were significantly higher than those in the NPDR group. Keywords: glycosylated hemoglobin, HbA1c, D-dimer, DD, fibrinogen, FIB, diabetic retinopathy, DR, microangiopathy
Diabetes mellitus (DM) has become a multiple disease in recent years, and its complications can cause multiple system diseases, among which microangiopathy is the main cause of death in diabetic patients. 1 Glycated hemoglobin (HbA1c) is the main marker of blood glucose control, which mainly reflects the average blood glucose level of patients in the first two or three months, and has become the internationally recognized gold standard for long-term blood glucose monitoring of diabetes. In the coagulation function test, D-dimer (DD) can specifically reflect the secondary hyperfibrinolysis and hypercoagulability in the body, as a sensitive indicator of thrombosis. Fibrinogen (FIB) concentration can indicate the prethrombotic state in the body. Existing studies have shown that monitoring the coagulation function and HbA1c of patients with DM plays a role in judging the progression of disease complications, 2,3 especially microangiopathy. 4 Diabetic retinopathy (DR) is one of the most common microvascular complications and a major cause of diabetic blindness. The advantages of the above three types of examinations are that they are simple to operate and are widely popular in clinical settings. This study observes the HbA1c, DD, and FIB values of patients with different degrees of DR, and compares them with the results of non-DR DM patients and non-DM physical examiners, so as to explore the significance of HbA1c, DD and FIB. FIB testing is used to monitor the occurrence and development of DR.
This study selected 61 diabetic patients (122 eyes) who were treated in the outpatient department of Baoding First Central Hospital from November 2017 to May 2019. The inclusion criteria of patients are: Diabetes patients diagnosed according to the “Guidelines for Prevention and Treatment of Type 2 Diabetes in China (2017)”, and healthy physical examination subjects for diabetes are excluded. The exclusion criteria are as follows: (1) pregnant patients; (2) patients with prediabetes; (3) patients under 14 years of age; (4) there are special drug effects, such as the recent application of glucocorticoids. According to their non-mydriatic fundus photography and fluorescein fundus angiography results, the participants were divided into the following three groups: The non-DR (NDR) group included 23 patients (46 eyes), 11 males, 12 females, and age 43-76 years old. Years old, average age 61.78±6.28 years; non-proliferative DR (NPDR) group, 17 cases (34 eyes), 10 males and 7 females, 47-70 years old, average age 60.89±4.27 years; proliferative DR ( There were 21 cases (42 eyes) in the PDR group, including 9 males and 12 females, aged 51-73 years, with an average age of 62.24±7.91 years. A total of 20 people (40 eyes) in the control group were negative for diabetes, including 8 males and 12 females, aged 50-75 years, with an average age of 64.54±3.11 years. All patients had no complicated macrovascular diseases such as coronary heart disease and cerebral infarction, and recent trauma, surgery, infection, malignant tumors or other general organic diseases were excluded. All participants provided written informed consent to be included in the study.
DR patients meet the diagnostic criteria issued by the Ophthalmology Division of the Ophthalmology Branch and the Chinese Medical Association. 5 We used a non-mydriatic fundus camera (Canon CR-2, Tokyo, Japan) to record the posterior pole of the fundus of the patient. And took a 30°–45° fundus photo. A well-trained ophthalmologist provided a written diagnosis report based on the images. In the case of DR, use Heidelberg Retinal Angiography-2 (HRA-2) (Heidelberg Engineering Company, Germany) for fundus angiography, and use seven-field early treatment diabetic retinopathy study (ETDRS) fluorescein angiography (FA) to Confirm NPDR or PDR. According to whether the participants showed retinal neovascularization, the participants were divided into NPDR and PDR groups. Non-DR diabetes patients were labeled as NDR group; patients who tested negative for diabetes were regarded as control group.
In the morning, 1.8 mL of fasting venous blood was collected and placed in an anticoagulation tube. After 2 hours, centrifuge for 20 minutes to detect HbA1c level.
In the morning, 1.8 mL of fasting venous blood was collected, injected into an anticoagulation tube, and centrifuged for 10 min. The supernatant was then used for DD and FIB detection.
HbA1c detection is carried out using Beckman AU5821 automatic biochemical analyzer and its supporting reagents. Diabetes cut-off value>6.20%, normal value is 3.00%~6.20%.
The DD and FIB tests were performed using the STA Compact Max® automatic coagulation analyzer (Stago, France) and its supporting reagents. The positive reference values are DD> 0.5 mg/L and FIB> 4 g/L, while the normal values are DD ≤ 0.5 mg/L and FIB 2-4 g/L.
The SPSS Statistics (v.11.5) software program is used to process the results; the data are expressed as mean±standard deviation (±s). Based on the normality test, the above data conforms to the normal distribution. One-way analysis of variance was performed on the four groups of HbA1c, DD, and FIB. In addition, the statistically significant levels of DD and FIB were further compared; P <0.05 indicates that the difference is statistically significant.
The ages of subjects in the NDR group, NPDR group, PDR group, and control group were 61.78±6.28, 60.89±4.27, 62.24±7.91, and 64.54±3.11 years old, respectively. The age was normally distributed after the normal distribution test. One-way analysis of variance showed that the difference was not statistically significant (P=0.157) (Table 1).
Table 1 Comparison of baseline clinical and ophthalmological characteristics between the control group and the NDR, NPDR and PDR groups
The average HbA1c of the NDR group, NPDR group, PDR group and control group were 6.58±0.95%, 7.45±1.21%, 8.04±1.81% and 4.53±0.41%, respectively. The HbA1cs of these four groups are normally distributed and tested by the normal distribution. Using one-way analysis of variance, the difference was statistically significant (P<0.001) (Table 2). Further comparisons between the four groups showed significant differences between the groups (P<0.05) (Table 3).
The average values of DD in the NDR group, NPDR group, PDR group, and control group were 0.39±0.21mg/L, 1.06±0.54mg/L, 1.39±0.59mg/L and 0.36±0.17mg/L, respectively. All DDs are normally distributed and tested by normal distribution. Using one-way analysis of variance, the difference was statistically significant (P<0.001) (Table 2). Through further comparison of the four groups, the results show that the values of the NPDR group and the PDR group are significantly higher than the NDR group and the control group, and the value of the PDR group is significantly higher than the NPDR group, indicating that the difference between the groups is significant (P< 0.05). However, the difference between the NDR group and the control group was not statistically significant (P>0.05) (Table 3).
The average FIB of NDR group, NPDR group, PDR group and control group were 3.07±0.42 g/L, 4.38±0.54 g/L, 4.46±1.09 g/L and 2.97±0.67 g/L, respectively. The FIB of these four groups Shows a normal distribution with a normal distribution test. Using one-way analysis of variance, the difference was statistically significant (P<0.001) (Table 2). Further comparison between the four groups showed that the values of the NPDR group and the PDR group were significantly higher than those of the NDR group and the control group, indicating that the differences between the groups were significant (P<0.05). However, there was no significant difference between the NPDR group and the PDR group, and the NDR and the control group (P>0.05) (Table 3).
In recent years, the incidence of diabetes has increased year by year, and the incidence of DR has also increased. DR is currently the most common cause of blindness. 6 Severe fluctuations in blood glucose (BG)/sugar can cause a hypercoagulable state of blood, leading to a series of vascular complications. 7 Therefore, to monitor the BG level and coagulation status of diabetic patients with the development of DR, researchers in China and other places are very interested.
When the hemoglobin in red blood cells is combined with blood sugar, glycosylated hemoglobin is produced, which usually reflects the patient’s blood sugar control in the first 8-12 weeks. The production of HbA1c is slow, but once it is completed, it is not easily broken down; therefore, its presence helps diabetes blood glucose monitoring. 8 Long-term hyperglycemia may cause irreversible vascular changes, but HbAlc is still a good indicator of blood glucose levels in diabetic patients. 9 HbAlc level not only reflects the blood sugar content, but also is closely related to the blood sugar level. It is related to diabetic complications such as microvascular disease and macrovascular disease. 10 In this study, the HbAlc of patients with different types of DR were compared. The results showed that the values of the NPDR group and the PDR group were significantly higher than those of the NDR group and the control group, and the value of the PDR group was significantly higher than that of the NPDR group. Recent studies have shown that when HbA1c levels continue to rise, it affects the ability of hemoglobin to bind and carry oxygen, thereby affecting retinal function. 11 Increased HbA1c levels are associated with an increased risk of diabetic complications, 12 and decreased HbA1c levels can reduce the risk of DR. 13 An et al.14 found that the HbA1c level of DR patients was significantly higher than that of NDR patients. In DR patients, especially PDR patients, the levels of BG and HbA1c are relatively high, and as the levels of BG and HbA1c increase, the degree of visual impairment in patients increases. 15 The above research is consistent with our results. However, HbA1c levels are affected by factors such as anemia, hemoglobin life span, age, pregnancy, race, etc., and cannot reflect the rapid changes in blood glucose in a short period of time, and has a “delay effect”. Therefore, some scholars believe that its reference value has limitations. 16
The pathological features of DR are retinal neovascularization and blood-retinal barrier damage; however, the mechanism of how diabetes causes the onset of DR is complicated. It is currently believed that the functional damage of smooth muscle and endothelial cells and the abnormal fibrinolytic function of retinal capillaries are the two basic pathological causes of patients with diabetic retinopathy. 17 The change of coagulation function may be an important indicator for judging retinopathy. The progression of diabetic microangiopathy. At the same time, DD is a specific degradation product of fibrinolytic enzyme to cross-linked fibrin, which can quickly, simply, and cost-effectively determine the concentration of DD in plasma. Based on these and other advantages, DD testing is usually performed. This study found that the NPDR group and the PDR group were significantly higher than the NDR group and the control group by comparing the average DD value, and the PDR group was significantly higher than the NPDR group. Another Chinese study shows that the coagulation function of diabetic patients will not change initially; however, if the patient has microvascular disease, the coagulation function will change significantly. 4 As the degree of DR degradation increases, the DD level gradually rises and reaches a peak in PDR patients. 18 This finding is consistent with the results of the current study.
Fibrinogen is an indicator of hypercoagulable state and decreased fibrinolytic activity, and its increased level will seriously affect blood coagulation and hemorheology. It is a precursor substance of thrombosis, and FIB in the blood of diabetic patients is an important basis for the formation of hypercoagulable state in diabetic plasma. The comparison of the average FIB values in this study shows that the values of the NPDR and PDR groups are significantly higher than the values of the NDR and control groups. Another study found that the FIB level of DR patients is much higher than that of NDR patients, indicating that the increase of FIB level has a certain effect on the occurrence and development of DR and may accelerate its progress; however, the specific mechanisms involved in this process are not yet complete. clear. 19,20
The above results are consistent with this study. In addition, related studies have shown that the combined detection of DD and FIB can monitor and observe changes in the body’s hypercoagulable state and hemorheology, which is conducive to the early diagnosis, treatment and prognosis of type 2 diabetes with diabetes. Microangiopathy 21
It should be noted that there are several limitations in the current research that may affect the results. Since this is an interdisciplinary study, the number of patients who are willing to undergo both ophthalmology and blood tests during the study period is limited. In addition, some patients who require fundus fluorescein angiography need to control their blood pressure and must have a history of allergies before the examination. Refusal to check further resulted in loss of participants. Therefore, the sample size is small. We will continue to expand the observation sample size in future studies. In addition, eye examinations are only performed as qualitative groups; no additional quantitative examinations are performed, such as optical coherence tomography measurements of macular thickness or vision tests. Finally, this study represents a cross-sectional observation and cannot reflect changes in the disease process; future studies require further dynamic observations.
In summary, there are significant differences in blood HbA1c, DD, and FIB levels in patients with different degrees of DM. The blood levels of the NPDR and PDR groups were significantly higher than the NDR and euglycemic groups. Therefore, in the diagnosis and treatment of diabetic patients, the combined detection of HbA1c, DD, and FIB can increase the detection rate of early microvascular damage in diabetic patients, facilitate the assessment of the risk of microvascular complications, and help early diagnosis of diabetes with retinopathy.
This study was approved by the Ethics Committee of the Affiliated Hospital of Hebei University (approval number: 2019063) and was carried out in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants.
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