
==== Front
Sci Rep
Sci Rep
Scientific Reports
2045-2322
Nature Publishing Group UK London

39232077
71490
10.1038/s41598-024-71490-4
Article
The impact of depression on platelet activation, cardiocerebral vascular events and arteriovenous fistula dysfunction in patients undergoing haemodialysis
Xu Ya 1
Zhang Shunjuan 1
Xia Wenyu 2
Xiong Ying 1
Wang Xianglei 1
Liu Yuhong 1
Li Zhengrong 1
Xia Yunfeng yunfengxia0920@126.com

1
1 https://ror.org/033vnzz93 grid.452206.7 0000 0004 1758 417X Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 40016 China
2 grid.448631.c 0000 0004 5903 2808 Duke Kunshan University, 2020 Data Science, Kunshan, 215300 China
4 9 2024
4 9 2024
2024
14 2056931 10 2023
28 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Depression is a common psychiatric disorder among patients undergoing maintenance haemodialysis (MHD). Depression may reportedly contribute to poor prognosis in several ways, including its effects on platelet function. We hypothesised that depression contributes to the occurrence of cardiocerebral vascular events (CCVE) and dysfunction of arteriovenous fistula (DAVF) in patients undergoing MHD through its effects on platelets. In this prospective cohort study, patients undergoing MHD were recruited and divided into depression and non-depression groups according to their Hamilton Depression Scale (HAMD) scores. The 286 enrolled patients had 103 occurrences of depressive symptoms (prevalence = 36.01%). Compared with the non-depression group, depression group had a significantly higher cumulative prevalence of CCVE and DAVF during follow-up. Cox regression analysis indicated that higher HAMD scores and lower plasma platelet distribution width (PDW) were common risk factors for CCVE and DAVF. Furthermore, HAMD scores were significantly negatively correlated with plasma PDW and was the main variable affecting changes in PDW, as indicated by multiple linear regression analysis. Depression may increase the risk of CCVE and DAVF in patients undergoing MHD by activating platelets. Plasma PDW may be a convenient indicator of platelet activation status and may predict the risk of CCVE and DAVF.

Keywords

Depression
Haemodialysis
Cardiocerebral vascular events
Arteriovenous fistula dysfunction
Platelet
Subject terms

Haemodialysis
Psychology
issue-copyright-statement© Springer Nature Limited 2024
==== Body
pmcCardiocerebral vascular events (CCVE) and dysfunction of arteriovenous fistula (DAVF) are two major categories of adverse events of concern for nephrologists. CCVE are the leading cause of death in patients undergoing maintenance haemodialysis (MHD). Its prevention and treatment are limited to the management of traditional risk factors such as hypertension, hyperlipidaemia, and diabetes mellitus etc. However, the efficacies of these approaches are considered insufficient. Other factors, such as depression, are also thought to be associated with cardiovascular mortality. Arteriovenous fistula (AVF) is the most popular vascular access currently used for haemodialysis. Compared with other vascular access, it can improve the prognosis for patients undergoing MHD1. Therefore, increasing the rate of AVF use and maintaining patency are particularly important. The Dialysis Outcomes and Practice Patterns Study has indicated that the primary patency rate (from establishing AVF to its dysfunction) in two years is only approximately 50% in many developed countries2. To better combat CCVE and DAVF beyond the management of traditional risk factors, identifying and actively preventing nonconventional risk factors for CCVE and DAVF may help achieve breakthroughs.

Depression is a common complication in patients undergoing MHD, accounting for 20–40% of all patients3. It may serve as a non-conventional risk factor for CCVE4. Depression diminishes patients’ adherence to treatment as well as beneficial diets and lifestyles5. Long-term depression may also lead to unfavourable pathological and physiological changes within the patient’s body6.

Platelets are involved in arteriovenous thrombosis and inflammatory responses, and their dysfunction is closely associated with the development of CCVE or DAVF7,8. Like neuronal cells, platelets contain signalling molecules that play important roles in the progression of depression, including 5-hydroxytryptamine (5-HT) transporter and brain-derived neurotrophic factor9. Increased 5-HT2A receptors10,11 and decreased 5-HT transporters12 have also been found in platelets of patients with depression, which may affect platelet transport, storage, and response to 5-HT. Mutations in the brain-derived neurotrophic factor gene are often accompanied by enhanced platelet aggregation capacity and an increased risk of thrombosis13. Based on the same material basis as platelets and central nervous system neurons, many clinical studies have shown an increase in platelet activation markers in patients with depression 1114−16, In a study involving 300 patients with cardiovascular disease comorbid with depression, it was noted that patients had higher serotonin receptor levels and more platelet aggregation compared to those with uncomplicated depression11. Similarly, some studies also confirmed that patients with coronary artery disease combined with depression had elevated platelet specific volume and higher levels of platelet activation markers17,18. It is suggested that depression-induced platelet activation triggers the release of related factors that exacerbate the progression of atherosclerosis, thereby increasing the risk of adverse cardiovascular events. Based on these findings, it is plausible to hypothesize that depression is also associated with platelet activation in patients undergoing MHD, which may further worsen cardiovascular outcomes.

The platelet aggregation test is the gold standard for detecting platelet function, but its cost is high in clinical practice, and patient compliance is poor. Decreased platelet distribution width (PDW) is associated with platelet activation19. Clinical studies have shown that PDW may be a sensitive diagnostic indicator for certain cardiovascular events in patients with chronic kidney disease20,21, which is also convenient and inexpensive. The impact of depression on platelet function, CCVE, and DAVF in patients undergoing MHD is currently unclear. This study aimed to conduct a preliminary exploration based on actual data from patients undergoing MHD at our blood purification centre.

Materials and methods

Study population

Patients undergoing MHD were recruited from the First Affiliated Hospital of Chongqing Medical University, China, between June 2022 and August 2023. These patients underwent dialysis for more than three months. At enrolment, their medical status was stable, and their expected survival period exceeded one year. The exclusion criteria were as follows: (1) patients with communication disorders or mental illnesses other than depression; (2) patients with cirrhosis, lymphoma, thrombocytopenic purpura, or other diseases that significantly affected platelet function; (3) patients with advanced malignant tumours, severe heart failure, or unstable medical conditions whose life expectancy did not exceed one year; and (4) patients unable or unwilling to cooperate with the researchers. All enrolled patients underwent routine haemodialysis through an AVF for 3–4 h, three times per week, and were routinely anticoagulated with unfractionated heparin or low-molecular-weight heparin in each dialysis session. Patients were administered other therapeutic medications, such as antihypertensive, anaemia-correcting, and phosphorus-reducing agents, according to their specific medical situations. This study was registered with the Clinical Trial Centre (NCT06070805) and approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University (permission number 2022–103). The study complied with the Declaration of Helsinki, and written informed consent was obtained from all participants.

Grouping methods

The Hamilton Rating Scale for Depression (HAMD) was used to assess the depressive status of all enrolled patients. The HAMD Depression Scale, developed by Hamilton in 1960, has good reliability and validity and can be used to diagnose depression, assess severity, and measure treatment effectiveness22. The scale mainly includes cognitive disturbance, sleep disturbance, anxiety/somatisation, weight, diurnal variation, retardation, and other dimensions, and the 24 items cover almost all symptoms of depression23. Depression scoring was performed by a trained researcher during dialysis through observation and communication. Patients were assigned to the non-depression (NDP) group if their HAMD score was < 8 or to the depression (DP) group if their HAMD score was ≥ 8.

Data collection

General clinical data, including sex, age, primary disease, duration of dialysis, blood pressure, body mass index, history of alcohol consumption or smoking, comorbidities (including history of cardiocerebrovascular disease, diabetes, and stroke), and use of platelet inhibitor medications, were collected. Several laboratory tests were conducted during the enrolment and study period, including platelet count, mean platelet volume, PDW, platelet-large cell ratio, platelet crit, haemoglobin, calcium, phosphorus, intact parathyroid hormone, creatinine, triglyceride, total cholesterol, high-density lipoprotein, low-density lipoprotein, C-reactive protein (CRP), and beta-2 microglobulin. Based on the results of the repeated examinations conducted over the entire study period, the mean value of each index was calculated for the final analysis.

Follow-up and definition of endpoints

The patients were monitored for health changes during each dialysis session, and information regarding the occurrence of CCVE and DAVF during the follow-up period was collected and compared between the groups. CCVE were defined as the first occurrence of angina pectoris, myocardial infarction, episodes of heart failure requiring clinical intervention, arrhythmic episodes with clinically significant symptoms, transient ischaemic attack, cerebral infarction, or cerebral haemorrhage during the observational period. DAVF was diagnosed if a patient presented with one or more of the following conditions rendering the AVF unsatisfactory for effective haemodialysis: (1) loss of AVF murmur on clinical auscultation; (2) notable weakening or disappearance of pulsation in the AVF; (3) echocardiography showing interruption of blood flow, thrombosis within the fistula, or stenosis of the venous outflow tract at or near the anastomotic site; or (4) maximum blood flow < 200 mL/min in the AVF during dialysis.

Statistical methods

Normally distributed values were assessed using histograms. Normally distributed measures are expressed as mean ± standard deviation. An independent sample t-test was used to compare two groups, and analysis of variance (ANOVA) was used to compare multiple groups. Non-normally distributed measures are expressed as medians. Comparisons between two groups were performed using the Mann–Whitney U test, and comparisons among multiple groups were performed using the Kruskal − Wallis test. Categorical variables are expressed as numbers of cases and percentages (%), and comparisons between groups were performed using the chi-square test or Fisher’s exact test, as appropriate. Based on the analytical results of the intergroup comparisons, statistical methods such as the Cox regression model, Kaplan–Meier analysis, and multiple linear regression models were used to analyse the risk factors for CCVE and DAVF, the effect of depression on patient survival status, and laboratory indices associated with changes in plasma PDW levels. Statistical analyses were performed using SPSS 26.0, and p < 0.05 was considered statistically significant.

Results

Comparison of baseline characteristics between the NDP and DP groups

There were approximately 500 patients undergoing long-term dialysis in our dialysis centre, and we included all patients who met the inclusion criteria and were willing to participate in the study. Finally, 297 patients undergoing dialysis were enrolled, 286 of whom were included in the statistical analysis. Of the 11 excluded patients, six had a significant loss of laboratory tests due to poor compliance, one underwent kidney transplantation in the middle of follow-up, and four were transferred to other dialysis centres. According to the HAMD scores, 103 of 286 (approximately 36%) patients were assigned to the DP group, and 183 were assigned to the NDP group (Fig. 1). The general clinical data and laboratory indicators of the groups are shown in Tables 1 and 2 separately, and the proportion of primary diseases is shown in Fig. 2. Compared with the NDP group, the DP group experienced more cardiovascular and cerebrovascular diseases. Lower diastolic blood pressure, blood creatinine, serum albumin, intact parathyroid hormone, and PDW were observed in the DP group compared with the NDP group. The differences between the groups were statistically significant (p < 0.05).Fig. 1 Flow chart for the methodology. NDP non-depression (HAMD < 8); DP depression (HAMD ≥ 8); PDW platelet distribution width; CCVE cardio-cerebral vascular events; DAVF dysfunction of arteriovenous fistula.

Table 1 Basic information of the included patients undergoing MHD according to the HAMD scores.

Variable	All patients (n = 286)	NDP group (n = 183)	DP group (n = 103)	t/z/χ2	p-value	
Age (y)	57.64 ± 14.44	56.83 ± 14.29	59.09 ± 14.65	−1.27	0.205a	
Male (%)	122 (43)	76 (42)	46 (45)	0.26	0.607b	
BMI (Kg/m2)	22.47 ± 3.35	22.59 ± 3.47	22.25 ± 3.12	0.84	0.400a	
Smoke (%)	127 (44)	79 (43)	48 (47)	0.32	0.575b	
Drink (%)	102 (36)	63 (34)	39 (38)	0.34	0.560b	
Time on dialysis (months)	64.55 ± 45.90	66.3 ± 46.32	61.9 ± 45.24	0.73	0.466c	
With diabetes mellitus (%)	83 (29)	47 (26)	36 (35)	2.75	0.097b	
With cardio-cerebrovascular disease (%)	129 (45)	68 (37)	61 (59)	12.96	0.000*	
SBP (mmHg)	139.82 ± 15.25	139.45 ± 15.14	140.50 ± 15.52	−0.56	0.576a	
DBP (mmHg)	75.30 ± 10.32	76.22 ± 10.62	73.65 ± 9.61	2.04	0.042a*	
Antiplatelets user (%)	149 (52)	90 (49)	59 (57)	1.73	0.188b	
Data are shown as numbers (percentages) or x¯±s.

NDP non-depression (HAMD < 8); DP depression (HAMD ≥ 8); SBP systolic BP; DBP diastolic BP.

*p-value < 0.05 shows a statistically significant difference. a, Independent samples t-test; b, Chi-square test; c, Mann–Whitney U test.

Table 2 Laboratory testing parameters of the included patients undergoing MHD according to HAMD scores.

Variable	All patients (n = 286)	NDP group (n = 183)	DP group (n = 103)	t /z	p-value	
β 2 M(mg/L)	33.50 (27.70, 39.40)	34.10 (27.80, 39.40)	33.36 (27.00, 40.30)	-0.36	0.723c	
TG (mmol/L)	1.52 (0.99, 2.13)	1.51 (0.96, 2.15)	1.58 (1.17, 2.13)	-1.25	0.212c	
TC (mmol/L)	3.71 (3.09, 4.48)	3.69 (3.17, 4.37)	3.88 (3.03, 4.59)	-0.09	0.930c	
LDL-C (mmol/L)	1.97 (1.47, 2.51)	2.01 (1.54, 2.58)	1.92 (1.38, 2.44)	-1.52	0.129c	
HDL-C (mmol/L)	1.11 (0.89, 1.35)	1.09 (0.89 ,1.32)	1.07 (0.84 ,1.35)	-0.08	0.936c	
Cr (μmol/L)	966.15 ± 252.68	991.61 ± 256.78	920.58 ± 239.71	2.27	0.024a*	
BUN (mmol/L)	21.93 ± 6.50	22.07 ± 6.21	21.67 ± 7.00	0.50	0.618a	
Alb (g/L)	41.62 ± 3.98	42.24 ± 3.74	40.52 ± 4.17	3.59	0.000a*	
CRP (mg/ml)	3.38 (2.04, 6.36)	3.20 (2.04, 3.20)	3.80 (2.17, 6.77)	-1.49	0.136c	
iPTH (pg/ml)	293.30 (178.50, 457.40)	332.00 (178.53, 458.67)	266.13 (162.07, 457.40)	-2.32	0.020c*	
Ca (mmol/L)	2.17 ± 0.16	2.16 ± 0.17	2.18 ± 0.15	-0.53	0.596a	
P (mmol/L)	1.78 ± 0.41	1.79 ± 0.38	1.76 ± 0.46	0.68	0.499a	
Hb (g/L)	114.99 ± 14.11	115.61 ± 13.58	113.89 ± 15.00	0.99	0.324a	
PLT (× 109/L)	175.28 ± 49.79	175.68 ± 48.96	174.58 ± 51.46	0.18	0.857a	
MPV (fl)	10.14 ± 1.03	10.08 ± 1.01	10.24 ± 1.08	-1.27	0.206a	
PDW (fl)	15.63 (14.20, 16.20)	15.80 (14.30, 16.23)	15.27 (14.06, 16.10)	-2.38	0.018c*	
PCT (%)	0.18 ± 0.05	0.18 ± 0.05	0.18 ± 0.05	-0.04	0.966a	
Data are shown as x¯±s or median.

NDP non-depression (HAMD < 8); DP depression (HAMD ≥ 8); β2M β2 Micro globulin; TG triglyceride; TC total cholesterol; LDL-C low-density lipoprotein; HDL-C high-density lipoprotein; Cr creatinine; BUN blood urea nitrogen; Alb albumin; CRP C-reactive protein; iPTH intact parathyroid hormone; Ca calcium; P phosphate; Hb haemoglobin; PLT platelet count; MPV mean platelet volume; PDW platelet distribution width; P-LCR platelet-large cell ratio; PCT platelet crit.

*p-value < 0.05 shows a statistically significant difference. a, Independent samples t-test; c, Mann–Whitney U test.

Fig. 2 The proportion of primary disease in the NDP and DP groups. NDP non-depression (HAMD < 8); DP depression (HAMD ≥ 8).

Comparison of CCVE and DAVF occurrence

The median follow-up duration was 274 days (237–376), during which 47 CCVE occurred, including 14 acute coronary syndromes, 16 acute heart failures, 10 cerebral infarctions, four cerebral haemorrhages, and three other CCVE (Fig. 3). CCVE were reported in 10% (18/183) and 28% (29/103) of patients in the NDP and DP groups, respectively (χ2 = 15.93, p < 0.001). DAVFs were reported in 9% (17/183) and 22% (23/103) of patients in the NDP and DP groups, respectively (χ2 = 9.32, p = 0.002). The incidence of CCVE and DAVF was significantly higher in the DP group than in the NDP group (Fig. 4).Fig. 3 The composition of cardiocerebral vascular events in all patients undergoing MHD during follow-up. Note Data are shown as percentages. ACS acute coronary syndrome.

Fig. 4 Comparison of the occurrence of CCVE and DVAF in the NDP and NDP groups. Note Data are presented as percentages. The chi-square test was used for comparisons between groups. n denotes the achievement of the patients/overall patients. NDP non-depression (HAMD < 8); DP depression (HAMD ≥ 8); CCVE cardio-cerebral vascular events; DAVF dysfunction of arteriovenous fistula.

Analysis of risk factors for CCVE and DAVF

A multivariate Cox regression analysis model was constructed, incorporating CCVE as a dependent variable and using the HAMD score, age, history of cardiovascular and cerebrovascular diseases, diabetes mellitus, diastolic blood pressure, PDW, blood calcium, creatinine, triglycerides, intact parathyroid hormone, CRP, and albumin as independent variables. Higher HAMD scores, advanced age, and lower PDW were independent prognostic indicators for CCVE. Using the same Cox regression model and replacing the dependent variable from CCVE with DAVF, we found that higher HAMD scores, hypertriglyceridaemia, and lower PDW were independent prognostic indicators of DAVF (Table 3). Kaplan–Meier survival curves also showed a statistically significantly greater cumulative incidence of CCVE and DAVF in the DP group than in the NDP group (Fig. 5).Table 3 Univariate and multivariate Cox regression predicting CCVE and DAVF in patients undergoing MHD.

Variable	Cardio-cerebral vascular events	Dysfunction of arteriovenous fistula	
Univariate cox regression	Multivariate cox regression	Univariate cox regression	Multivariate cox regression	
HR (95% CI)	p-value	HR (95% CI)	p-value	HR (95% CI)	p-value	HR (95% CI)	p-value	
HAMD	1.058 (1.029–1.088)	0.000	1.038 (1.002–1.075)	0.038*	1.046 (1.013–1.081)	0.01	1.037 (1.000–1.075)	0.048*	
Age	1.084 (1.057–1.111)	0.000	1.053 (1.020–1.087)	0.001*	1.011 (0.989–1.033)	0.34	1.000 (0.969–1.031)	0.982	
CCVD	0.165 (0.080–0.342)	0.000	0.434 (0.198–0.952)	0.037*	0.639 (0.343–1.189)	0.16	0.929 (0.457–1.889)	0.838	
DM	0.242 (0.135–0.435)	0.000	0.579 (0.305–1.099)	0.095	0.939 (0.469–1.882)	0.86	1.233 (0.560–2.715)	0.604	
DBP	0.930 (0.905–0.956)	0.000	0.971 (0.929–1.014)	0.179	0.979 (0.950–1.009)	0.17	0.975 (0.935–1.017)	0.239	
PDW	0.930 (0.905–0.956)	0.000	0.832 (0.698–0.992)	0.040*	0.851 (0.732–0.990)	0.04	0.815 (0.690–0.962)	0.016*	
Ca	0.762 (0.125–4.658)	0.77	0.720 (0.076–6.873)	0.776	0.224 (0.033–1.503)	0.12	0.311 (0.037–2.640)	0.285	
Cr	0.998 (0.997–1.000)	0.01	1.000 (0.999–1.002)	0.753	0.999 (0.998–1.000)	0.09	0.999 (0.998–1.000)	0.169	
TG	1.146 (0.984–1.333)	0.08	1.107 (0.922–1.328)	0.276	1.258 (1.103–1.434)	0.001	1.287 (1.104–1.501)	0.001*	
iPTH	0.998 (0.997–1.000)	0.02	0.999 (0.998–1.001)	0.226	1.000 (0.999–1.001)	0.82	1.000 (0.999–1.001)	0.653	
CRP	1.020 (1.010–1.030)	0.000	1.012 (0.998–1.026)	0.095	0.996 (0.962–1.032)	0.83	0.974 (0.916–1.035)	0.392	
Alb	0.882 (0.831–0.937)	0.000	0.993 (0.916–1.075)	0.855	0.976 (0.903–1.054)	0.54	1.029 (0.938–1.129)	0.549	
CCVD cardiovascular and cerebrovascular diseases; DM diabetes mellitus; DBP diastolic BP; PDW platelet distribution width; Ca calcium; Cr creatinine; TG triglyceride; iPTH intact parathyroid hormone; CRP C-reactive protein; Alb albumin.

*p-value < 0.05 shows a statistically significant difference.

Fig. 5 Cumulative incidence curves for CCVE (a) and DAVF (b) for patients undergoing MHD with different patterns of depressive symptoms. NDP non, depression (HAMD < 8); DP depression (HAMD ≥ 8); CCVE cardiocerebral vascular events; DAVF dysfunction of arteriovenous fistula.

Analysis of relevant factors affecting changes in plasma PDW levels

We categorised all patients into three groups according to plasma PDW levels and analysed the differences in laboratory parameters among the groups. Statistical analysis revealed significant differences across the subgroups in HAMD scores, time on dialysis, intact parathyroid hormone concentrations, and diastolic blood pressure (Table 4). Spearman’s correlation analysis indicated a negative correlation between PDW and HAMD scores (r =  − 0.15, p = 0.014). However, no significant correlation was observed between other platelet factors and HAMD scores. A multifactorial linear regression analysis model was constructed with PDW as the dependent variable and HAMD score, time on dialysis, antiplatelet therapy use, diastolic blood pressure, intact parathyroid hormone, CRP, albumin, BMI, and HDL-C as the independent variables. Changes in PDW were significantly correlated with HAMD scores, dialysis duration, and diastolic blood pressure (Table 5).Table 4 MHD patients cohort characteristics by PDW tertile.

	Low PDW group
(9.13–14.63fL)	Middle PDW group
(14.64–16.07fL)	High PDW group
(16.08–17.93fL)	p-value	
HAMD	4.00 (1.00, 11.25)	4.00 (2.00, 10.00)	3.00 (1.00, 9.75)	0.044c*	
Age (y)	57.11 ± 16.34	58.32 ± 13.12	57.81 ± 13.62	0.849a	
Time on dialysis (months)	42.00 (15.00, 64.00)	64.50 (24.75, 113.75)	67.50 (39.00, 100.25)	0.000c*	
SBP (mmHg)	142.11 ± 14.42	137.70 ± 15.28	140.41 ± 15.80	0.093a	
DBP (mmHg)	76.88 ± 9.84	72.81 ± 10.52	76.51 ± 10.29	0.007a*	
β 2 M (mg/L)	34.10 (27.35, 38.75)	32.50 (27.76, 41.00)	34.82 (28.89, 40.22)	0.730c	
TG (mmol/L)	1.53 (0.96, 2.33)	1.57 (1.17, 2.15)	1.42 (0.90, 2.10)	0.160c	
TC (mmol/L)	3.68 (3.03, 4.50)	3.75 (3.28, 4.59)	3.83 (3.05, 4.31)	0.544c	
LDL, C (mmol/L)	1.83 (1.46, 2.25)	2.08 (1.62, 2.68)	1.98 (1.45, 2.56)	0.309c	
HDL, C (mmol/L)	1.11 (0.93, 1.31)	1.06 (0.84, 1.32)	1.15 (0.93, 1.41)	0.105c	
Cr (μmol/L)	955.42 ± 239.17	962.00 ± 237.54	982.26 ± 283.18	0.760a	
BUN (mmol/L)	21.35 ± 6.82	22.30 ± 6.30	22.14 ± 6.38	0.563a	
Alb (g/L)	41.16 ± 4.28	41.33 ± 4.04	42.43 ± 3.54	0.070a	
CRP (mg/ml)	4.04 (2.47, 7.65)	3.57 (1.79, 6.40)	2.89 (1.90, 5.95)	0.091c	
iPTH (pg/ml)	250.75 (151.73, 382.70)	368.03 (221.43, 603.10)	292.28 (180.40, 506.05)	0.001c*	
Ca (mmol/L)	2.15 ± 0.15	2.19 ± 0.16	2.17 ± 0.18	0.357a	
P (mmol/L)	1.75 ± 0.39	1.80 ± 0.42	1.79 ± 0.42	0.619a	
Hb (g/L)	115.29 ± 14.19	114.31 ± 15.13	115.52 ± 13.40	0.859a	
PDW platelet distribution width, β2M β2 microglobulin; TG triglyceride; TC total cholesterol; LDL C, low-density lipoprotein; HDL C, high-density lipoprotein; Cr creatinine; BUN blood urea nitrogen; Alb albumin; CRP C, reactive protein; iPTH intact parathyroid hormone; Ca calcium; P phosphate; Hb haemoglobin.

Data are shown as x¯±s or median.

*p-value < 0.05 shows a statistically significant difference. a, ANOVA; c, Kruskal − Wallis test.

Table 5 Multivariate linear regression analysis of factors influencing PDW.

Variable	β	SE	p	Lower	Upper	
HAMD (per 1 increase)	−0.030	0.015	0.048*	−0.060	0.000	
Time on dialysis (per 1 month increase)	0.010	0.002	0.000*	0.005	0.014	
DBP (per 1 mmHg increase)	−0.027	0.010	0.008*	−0.047	0.007	
iPTH (per 1 pg/ml increase)	0.000	0.000	0.457	0.000	0.001	
CRP (per 1 mg/ml increase)	−0.002	0.009	0.816	−0.019	0.015	
Antiplatelet drugs use (vs no)	0.060	0.206	0.772	−0.347	0.467	
Alb (per 1 g/L increase)	0.052	0.028	0.064	−0.003	0.108	
BMI (per 1 kg/m2 increase)	−0.017	0.032	0.587	−0.080	0.045	
HDL, C (per 1 mmol/L increase)	0.433	0.283	0.127	−0.125	0.991	
DBP diastolic blood pressure; iPTH intact parathyroid hormone; CRP C-reactive protein; Alb albumin; HDL, C, high-density lipoprotein.

β, Regression coefficient; SE, standard error of β; Lower and upper, 95% confidence interval.

*p-value < 0.05 shows a statistically significant difference.

Discussion

CCVE and DAVF are the most concerning clinical events in patients undergoing MHD, while the former is the leading cause of death in over 50% of patients undergoing MHD who ultimately die24, and the latter directly shuts down the “lifeline” to regular dialysis. Given that patients have a limited number of vessels suitable for AVF, preventing DAVF and maximising longevity are important. CCVE and DAVF are closely associated with vasculopathy and varying degrees of coagulopathy, as well as related conditions, such as stenosis, embolism, or haemorrhage, in patients undergoing dialysis. Currently, clinical measures for the prevention and management of CCVE and DVAF include controlling blood pressure and glucose levels, lowering blood lipids, and using platelet inhibitors. However, these therapeutic measures predominantly focus on managing traditional risk factors and exhibit limited efficacy. The effects of nonconventional risk factors, such as depression, have not received sufficient attention from the public.

Depression is a common psychiatric disorder among patients undergoing MHD. Several studies have indicated that depression may promote CCVE through its effect on platelet function25. The present study also reported depressive symptoms in 36% of the patients undergoing MHD. Compared with non-depressed patients, depressed patients experienced a greater rate of comorbid cardiovascular disease; significantly lower levels of blood creatinine, albumin, parathyroid hormone, PDW, and diastolic blood pressure; and higher cumulative incidence rates of CCVE and DAVF during follow-up. Cox regression analysis indicated that higher HAMD scores and lower plasma PDW levels were common risk factors for CCVE and DAVF in patients undergoing MHD. Studies have shown that PDW is a marker of inflammatory thrombosis in several diseases26–28. In this study, changes in plasma PDW were significantly and negatively correlated with HAMD scores in patients undergoing MHD. Previous studies have also reported that plasma PDW levels are negatively correlated with platelet p-selectin, platelet/leukocyte aggregates, and vascular hemophilic factor levels and positively correlated with clotting time19. These findings suggest that diminished plasma PDW levels may be a marker of platelet activation.

Depression often leads to decreased appetite, malnutrition, and low medication adherence, all of which are important triggers for the development of CCVE29,30. A prospective cohort study has reported that depression is an independent risk factor for cardiovascular and all-cause mortality in patients undergoing MHD and that CCVE are a direct cause of cardiovascular and all-cause mortality31, in agreement with the results of our study. Our study also revealed notably lower serum albumin and creatinine concentrations in depressed patients than in non-depressed patients, suggesting that depression may impair nutritional status. Malnutrition, chronic inflammation, and atherosclerosis mutually reinforce clinical syndromes, leading to poor prognosis in patients undergoing MHD32. Malnutrition can exacerbate metabolic disorders, promote the progression of chronic inflammatory states and atherosclerosis, and lead to severe cardiovascular and cerebrovascular pathologies33.

The effects of depression in patients are not restricted to malnutrition or atherosclerosis. Long-term depression may be associated with platelet activation, thus disrupting the balance of the coagulation process and subsequently increasing susceptibility to CCVE in patients undergoing MHD34. The dysregulated metabolism of 5-HT in neuronal cells is a crucial mechanism in the pathogenesis of depression. The dense granules within platelets contain most of the 5-HT in the body. Moreover, the storage, transport, and metabolism of 5-HT within platelets are similar to those observed in central nervous system neuronal cells and may underlie the effects of depression on platelet function35,36. Platelet activation plays a very important role in chronic inflammation, atherosclerosis, and thrombosis and may also potentially link depression, immune dysfunction, and coagulation complications37. A study has found that patients with cardiovascular disease and higher depression scores showed higher platelet 5-HT2A receptor density and were more likely to experience adverse cardiac events during follow-up11. A meta-analysis has also indicated that antidepressant use is an independent risk factor for haemorrhagic adverse events in patients with cardiovascular disease16. This study revealed a significant association between higher depression scores and lower plasma PDW. It was found in the Cox risk-proportionality model that both higher depression scores and lower plasma PDW were risk factors for the development of CCVE and DAVF, suggesting that depression may contribute to the occurrence of CCVE and DAVF, partly by platelet activation. Previous studies have reported that patients with emotional disorders, such as depression, have lower plasma PDW levels than healthy controls and have demonstrated a significant negative correlation between PDW and patient depression scores38. Another study has reported that plasma PDW is strongly associated with the occurrence of ST-elevation myocardial infarction in young patients with coronary artery disease39. In patients with chronic kidney disease not undergoing dialysis, a prospective cohort study has found that a lower PDW was an independent risk factor for cardiovascular events21. Based on prior findings combined with those of this study, we believe that PDW is an affordable and easily determined parameter with high potential to serve as a useful laboratory marker for assessing platelet function and thrombosis risk in patients undergoing MHD.

This study had some limitations. First, as this was a single-centre study with a small sample size, the findings require further confirmation. Second, owing to the relatively short follow-up period, only CCVE and DAVF were used as endpoints, and cardiovascular and all-cause deaths were not included in the analysis. Owing to patient noncompliance and budget constraints, the evaluation of platelet function was relatively limited, requiring further verification of the results through more accurate methods. This study revealed the mutual influence and possible mechanism between depression and malnutrition inflammatory syndrome, CCVE, DAVF, and platelet activation; however, the actual mechanism requires further confirmation.

Conclusion

This study is the first to simultaneously analyse the possible mechanisms of depression and its effects on CCVE and DAVF in patients undergoing MHD. Our results suggest that depression may increase the risk of CCVE and DAVF in patients undergoing MHD by activating platelets. Plasma PDW may be a convenient indicator of platelet activation status and may predict the risk of CCVE and DAVF. These findings provide insights in the prevention of CCVE and DAVF in MHD patients in the future.

Supplementary Information

Supplementary Information 1.

Supplementary Information 2.

Supplementary Information 3.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-024-71490-4.

Acknowledgements

We would like to thank Editage (www.editage.cn) for English language editing.

Author contributions

Y.X.: Conceptualization; data curation; formal analysis; investigation; methodology; visualization; writing—original draft. S.Z.: Conceptualization; investigation. W.X.: Conceptualization; investigation. Y.X.: Conceptualization; investigation. X.W.: Conceptualization; investigation. Y.L.: Conceptualization; investigation. Z.L.: Conceptualization; investigation. Y.X.: Conceptualization; methodology; writing—review and editing; project administration; supervision.

Data availability

All data generated or analysed during this study are included in this published article and its Supplementary Information files.

Competing interests

The authors declare no competing interests.

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Roca Tey R Vascular access for haemodialysis: An unresolved issue Nefrologia. 2010 30 280 287 10.3265/Nefrologia.pre2010.Apr.10349 20514096
Roca Tey, R. Vascular access for haemodialysis: An unresolved issue. Nefrologia. 30, 280–287. 10.3265/Nefrologia.pre2010.Apr.10349 (2010).20514096 10.3265/Nefrologia.pre2010.Apr.10349
2. Pisoni RL International comparisons of native arteriovenous fistula patency and time to becoming catheter-free: Findings from the dialysis outcomes and practice patterns study (DOPPS) Am. J. Kidney Dis. 2021 77 245 254 10.1053/j.ajkd.2020.06.020 32971192
Pisoni, R. L. et al. International comparisons of native arteriovenous fistula patency and time to becoming catheter-free: Findings from the dialysis outcomes and practice patterns study (DOPPS). Am. J. Kidney Dis. 77, 245–254. 10.1053/j.ajkd.2020.06.020 (2021).32971192 10.1053/j.ajkd.2020.06.020
3. Palmer S Prevalence of depression in chronic kidney disease: systematic review and meta-analysis of observational studies Kidney Int. 2013 84 179 191 10.1038/ki.2013.77 23486521
Palmer, S. et al. Prevalence of depression in chronic kidney disease: Systematic review and meta-analysis of observational studies. Kidney Int. 84, 179–191. 10.1038/ki.2013.77 (2013).23486521 10.1038/ki.2013.77
4. Jiang W Depression and cardiovascular disorders in the elderly Clin. Geriatr. Med. 2020 36 211 219 10.1016/j.cger.2019.11.003 32222297
Jiang, W. Depression and cardiovascular disorders in the elderly. Clin. Geriatr. Med. 36, 211–219. 10.1016/j.cger.2019.11.003 (2020).32222297 10.1016/j.cger.2019.11.003
5. Theofilou P Medication adherence in Greek hemodialysis patients: The contribution of depression and health cognitions Int. J. Behav. Med. 2013 20 311 318 10.1007/s12529-012-9231-8 22407452
Theofilou, P. Medication adherence in Greek hemodialysis patients: The contribution of depression and health cognitions. Int. J. Behav. Med. 20, 311–318. 10.1007/s12529-012-9231-8 (2013).22407452 10.1007/s12529-012-9231-8
6. Tian N Chen N Li PK-T Depression in dialysis Curr. Opin. Nephrol. Hypertens. 2021 30 600 612 10.1097/MNH.0000000000000741 34456238
Tian, N., Chen, N. & Li, P.K.-T. Depression in dialysis. Curr. Opin. Nephrol. Hypertens. 30, 600–612 (2021).34456238 10.1097/MNH.0000000000000741
7. Kaplan ZS Jackson SP The role of platelets in atherothrombosis Hematol. Am. Soc. Hematol. Educ. Program. 2011 2011 51 61 10.1182/asheducation-2011.1.51
Kaplan, Z. S. & Jackson, S. P. The role of platelets in atherothrombosis. Hematol. Am. Soc. Hematol. Educ. Program. 2011, 51–61. 10.1182/asheducation-2011.1.51 (2011).10.1182/asheducation-2011.1.51
8. Viecelli AK The pathogenesis of hemodialysis vascular access failure and systemic therapies for its prevention: Optimism unfulfilled Semin. Dial. 2018 31 244 257 10.1111/sdi.12658 29178510
Viecelli, A. K. et al. The pathogenesis of hemodialysis vascular access failure and systemic therapies for its prevention: Optimism unfulfilled. Semin. Dial. 31, 244–257. 10.1111/sdi.12658 (2018).29178510 10.1111/sdi.12658
9. Canobbio I Blood platelets: Circulating mirrors of neurons? Res. Pract. Thromb. Haemost. 2019 3 564 565 10.1002/rth2.12254 31624775
Canobbio, I. Blood platelets: Circulating mirrors of neurons?. Res. Pract. Thromb. Haemost. 3, 564–565. 10.1002/rth2.12254 (2019).31624775 10.1002/rth2.12254
10. Mendelson SD The current status of the platelet 5-HT(2A) receptor in depression J. Affect. Disord. 2000 57 13 24 10.1016/s0165-0327(99)00177-9
Mendelson, S. D. The current status of the platelet 5-HT(2A) receptor in depression. J. Affect. Disord. 57(13), 24. 10.1016/s0165-0327(99)00177-9 (2000).10.1016/s0165-0327(99)00177-9
11. Williams MS Platelet serotonin signaling in patients with cardiovascular disease and comorbid depression Psychosom. Med. 2019 81 352 362 10.1097/PSY.0000000000000689 30855555
Williams, M. S. et al. Platelet serotonin signaling in patients with cardiovascular disease and comorbid depression. Psychosom. Med. 81, 352–362 (2019).30855555 10.1097/PSY.0000000000000689
12. Williams MS Platelets and depression in cardiovascular disease: A brief review of the current literature World J. Psychiatry. 2012 2 114 123 10.5498/wjp.v2.i6.114 24175177
Williams, M. S. Platelets and depression in cardiovascular disease: A brief review of the current literature. World J. Psychiatry. 2, 114–123. 10.5498/wjp.v2.i6.114 (2012).24175177 10.5498/wjp.v2.i6.114
13. Amadio P BDNFVal66met polymorphism: A potential bridge between depression and thrombosis Eur. Heart J. 2017 38 1426 1435 10.1093/eurheartj/ehv655 26705390
Amadio, P. et al. BDNFVal66met polymorphism: A potential bridge between depression and thrombosis. Eur. Heart J. 38, 1426–1435. 10.1093/eurheartj/ehv655 (2017).26705390 10.1093/eurheartj/ehv655
14. Musselman DL Platelet activation and secretion in patients with major depression, thoracic aortic atherosclerosis, or renal dialysis treatment Depress. Anxiety. 2002 15 91 101 10.1002/da.10020 12001177
Musselman, D. L. et al. Platelet activation and secretion in patients with major depression, thoracic aortic atherosclerosis, or renal dialysis treatment. Depress. Anxiety. 15, 91–101. 10.1002/da.10020 (2002).12001177 10.1002/da.10020
15. Morel-Kopp M-C The association of depression with platelet activation: evidence for a treatment effect J. Thromb. Haemost. 2009 7 573 581 10.1111/j.1538-7836.2009.03278.x 19192119
Morel-Kopp, M.-C. et al. The association of depression with platelet activation: Evidence for a treatment effect. J. Thromb. Haemost. 7, 573–581. 10.1111/j.1538-7836.2009.03278.x (2009).19192119 10.1111/j.1538-7836.2009.03278.x
16. Nochaiwong S Use of serotonin reuptake inhibitor antidepressants and the risk of bleeding complications in patients on anticoagulant or antiplatelet agents: A systematic review and meta-analysis Ann. Med. 2022 54 80 97 10.1080/07853890.2021.2017474 34955074
Nochaiwong, S. et al. Use of serotonin reuptake inhibitor antidepressants and the risk of bleeding complications in patients on anticoagulant or antiplatelet agents: A systematic review and meta-analysis. Ann. Med. 54, 80–97. 10.1080/07853890.2021.2017474 (2022).34955074 10.1080/07853890.2021.2017474
17. Peng M Association of BDNF gene polymorphisms with co-morbid depression in coronary heart disease and its mechanism of platelet activity Chin. J. Clin. Psychol. 2018 26 230 233 10.16128/j.cnki.1005-3611.2018.02.005
Peng, M. et al. Association of BDNF gene polymorphisms with co-morbid depression in coronary heart disease and its mechanism of platelet activity. Chin. J. Clin. Psychol. 26, 230–233. 10.16128/j.cnki.1005-3611.2018.02.005 (2018).10.16128/j.cnki.1005-3611.2018.02.005
18. Delle Chiaie R Persistence of subsyndromal residual symptoms after remission of major depression in patients without cardiovascular disease may condition maintenance of elevated platelet factor 4 and β-thromboglobulin plasma levels J. Affect. Disord. 2013 150 664 667 10.1016/j.jad.2013.03.017 23611535
Delle Chiaie, R. et al. Persistence of subsyndromal residual symptoms after remission of major depression in patients without cardiovascular disease may condition maintenance of elevated platelet factor 4 and β-thromboglobulin plasma levels. J. Affect. Disord. 150, 664–667. 10.1016/j.jad.2013.03.017 (2013).23611535 10.1016/j.jad.2013.03.017
19. Izzi B Platelet distribution width is associated with p-selectin dependent platelet function: Results from the moli-family cohort study Cells. 2021 10 2737 10.3390/cells10102737 34685717
Izzi, B. et al. Platelet distribution width is associated with p-selectin dependent platelet function: Results from the moli-family cohort study. Cells. 10, 2737. 10.3390/cells10102737 (2021).34685717 10.3390/cells10102737
20. Su N The relationship between platelet distribution width and new-onset cardiovascular disease events in patients with peritoneal dialysis Ren. Fail. 2022 44 1640 1648 10.1080/0886022X.2022.2130802 36285366
Su, N. et al. The relationship between platelet distribution width and new-onset cardiovascular disease events in patients with peritoneal dialysis. Ren. Fail. 44, 1640–1648. 10.1080/0886022X.2022.2130802 (2022).36285366 10.1080/0886022X.2022.2130802
21. Yu Z The association between platelet indices and cardiovascular events in chronic kidney disease patients without dialysis Int. Urol. Nephrol. 2021 53 961 971 10.1007/s11255-020-02696-4 33387224
Yu, Z. et al. The association between platelet indices and cardiovascular events in chronic kidney disease patients without dialysis. Int. Urol. Nephrol. 53, 961–971. 10.1007/s11255-020-02696-4 (2021).33387224 10.1007/s11255-020-02696-4
22. Zheng YP Validity and reliability of the Chinese Hamilton Depression Rating Scale Br. J. Psychiatry 1988 152 660 664 10.1192/bjp.152.5.660 3167442
Zheng, Y. P. et al. Validity and reliability of the Chinese Hamilton Depression Rating Scale. Br. J. Psychiatry 152, 660–664. 10.1192/bjp.152.5.660 (1988).3167442 10.1192/bjp.152.5.660
23. Sun XY Li YX Yu CQ Li LM Reliability and validity of depression scales of Chinese version: A systematic review Zhonghua Liu Xing Bing Xue Za Zhi 2017 38 1 110 116 28100388
Sun, X. Y., Li, Y. X., Yu, C. Q. & Li, L. M. Reliability and validity of depression scales of Chinese version: A systematic review. Zhonghua Liu Xing Bing Xue Za Zhi. 38, 110–116 (2017).28100388
24. Collins, A. J. et al. US Renal Data System 2013 Annual Data Report. https://www.niddk.nih.gov/about-niddk/strategic-plans-reports/usrds/prior-data-reports/2013(2014).
25. Amadio P Zarà M Sandrini L Ieraci A Barbieri SS Depression and cardiovascular disease: The viewpoint of platelets Int. J. Mol. Sci. 2020 21 e7560 10.3390/ijms21207560
Amadio, P., Zarà, M., Sandrini, L., Ieraci, A. & Barbieri, S. S. Depression and cardiovascular disease: The viewpoint of platelets. Int. J. Mol. Sci. 21, e7560. 10.3390/ijms21207560 (2020).10.3390/ijms21207560
26. Xia W Chen W Tu J Ni C Meng K Prognostic value and clinicopathologic features of platelet distribution width in cancer: A meta-analysis Med. Sci. Monit. 2018 24 7130 7136 10.12659/MSM.913040 30291788
Xia, W., Chen, W., Tu, J., Ni, C. & Meng, K. Prognostic value and clinicopathologic features of platelet distribution width in cancer: A meta-analysis. Med. Sci. Monit. 24, 7130–7136. 10.12659/MSM.913040 (2018).30291788 10.12659/MSM.913040
27. Zaccardi F Platelet mean volume, distribution width, and count in type 2 diabetes, impaired fasting glucose, and metabolic syndrome: a meta-analysis Diabetes Metab. Res. Rev. 2015 31 402 410 10.1002/dmrr.2625 25421610
Zaccardi, F. et al. Platelet mean volume, distribution width, and count in type 2 diabetes, impaired fasting glucose, and metabolic syndrome: A meta-analysis. Diabetes Metab. Res. Rev. 31, 402–410. 10.1002/dmrr.2625 (2015).25421610 10.1002/dmrr.2625
28. Weymann A Platelets cellular and functional characteristics in patients with atrial fibrillation: A comprehensive meta-analysis and systematic review Med. Sci. Monit. Basic. Res. 2017 23 58 86 10.12659/msmbr.902557 28302997
Weymann, A. et al. Platelets cellular and functional characteristics in patients with atrial fibrillation: A comprehensive meta-analysis and systematic review. Med. Sci. Monit. Basic. Res. 23, 58–86. 10.12659/msmbr.902557 (2017).28302997 10.12659/msmbr.902557
29. Cukor D Rosenthal DS Jindal RM Brown CD Kimmel PL Depression is an important contributor to low medication adherence in hemodialyzed patients and transplant recipients Kidney Int. 2009 75 1223 1229 10.1038/ki.2009.51 19242502
Cukor, D., Rosenthal, D. S., Jindal, R. M., Brown, C. D. & Kimmel, P. L. Depression is an important contributor to low medication adherence in hemodialyzed patients and transplant recipients. Kidney Int. 75, 1223–1229. 10.1038/ki.2009.51 (2009).19242502 10.1038/ki.2009.51
30. Koo J-R Association of depression with malnutrition in chronic hemodialysis patients Am. J. Kidney Dis. 2003 41 1037 1042 10.1016/s0272-6386(03)00201-4 12722038
Koo, J.-R. et al. Association of depression with malnutrition in chronic hemodialysis patients. Am. J. Kidney Dis. 41, 1037–1042. 10.1016/s0272-6386(03)00201-4 (2003).12722038 10.1016/s0272-6386(03)00201-4
31. Van Dijk S How baseline, new-onset, and persistent depressive symptoms are associated with cardiovascular and non-cardiovascular mortality in incident patients on chronic dialysis J. Psychosom Res. 2013 74 511 517 10.1016/j.jpsychores.2013.03.001 23731749
Van Dijk, S. et al. How baseline, new-onset, and persistent depressive symptoms are associated with cardiovascular and non-cardiovascular mortality in incident patients on chronic dialysis. J. Psychosom Res. 74, 511–517. 10.1016/j.jpsychores.2013.03.001 (2013).23731749 10.1016/j.jpsychores.2013.03.001
32. Stenvinkel P Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure Kidney Int. 1999 55 1899 1911 10.1046/j.1523-1755.1999.00422.x 10231453
Stenvinkel, P. et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int. 55, 1899–1911. 10.1046/j.1523-1755.1999.00422.x (1999).10231453 10.1046/j.1523-1755.1999.00422.x
33. Graterol Torres F Evolving concepts on inflammatory biomarkers and malnutrition in chronic kidney disease Nutrients. 2022 14 4297 10.3390/nu14204297 36296981
Graterol Torres, F. et al. Evolving concepts on inflammatory biomarkers and malnutrition in chronic kidney disease. Nutrients. 14, 4297. 10.3390/nu14204297 (2022).36296981 10.3390/nu14204297
34. Tagliarini C Carbone MG Pagni G Marazziti D Pomara N Is there a relationship between morphological and functional platelet changes and depressive disorder? CNS. Spectr. 2022 27 157 190 10.1017/S1092852920001959 33092669
Tagliarini, C., Carbone, M. G., Pagni, G., Marazziti, D. & Pomara, N. Is there a relationship between morphological and functional platelet changes and depressive disorder?. CNS. Spectr. 27, 157–190. 10.1017/S1092852920001959 (2022).33092669 10.1017/S1092852920001959
35. Andres AH Rao ML Ostrowitzki S Entzian W Human brain cortex and platelet serotonin2 receptor binding properties and their regulation by endogenous serotonin Life Sci. 1993 52 313 321 10.1016/0024-3205(93)90223-p 8423711
Andres, A. H., Rao, M. L., Ostrowitzki, S. & Entzian, W. Human brain cortex and platelet serotonin2 receptor binding properties and their regulation by endogenous serotonin. Life Sci. 52, 313–321. 10.1016/0024-3205(93)90223-p (1993).8423711 10.1016/0024-3205(93)90223-p
36. Stahl SM Woo DJ Mefford IN Berger PA Ciaranello RD Hyperserotonemia and platelet serotonin uptake and release in schizophrenia and affective disorders Am. J. Psychiatry. 1983 140 26 30 10.1176/ajp.140.1.26 6401198
Stahl, S. M., Woo, D. J., Mefford, I. N., Berger, P. A. & Ciaranello, R. D. Hyperserotonemia and platelet serotonin uptake and release in schizophrenia and affective disorders. Am. J. Psychiatry. 140, 26–30. 10.1176/ajp.140.1.26 (1983).6401198 10.1176/ajp.140.1.26
37. Ponomarev ED Fresh evidence for platelets as neuronal and innate immune cells: Their role in the activation, differentiation, and deactivation of Th1, Th17, and Tregs during tissue inflammation Front. Immunol. 2018 9 406 10.3389/fimmu.2018.00406 29599771
Ponomarev, E. D. Fresh evidence for platelets as neuronal and innate immune cells: Their role in the activation, differentiation, and deactivation of Th1, Th17, and Tregs during tissue inflammation. Front. Immunol. 9, 406. 10.3389/fimmu.2018.00406 (2018).29599771 10.3389/fimmu.2018.00406
38. Wei Y Characteristics of platelet-associated parameters and their predictive values in Chinese patients with affective disorders BMC Psychiatry. 2022 22 150 10.1186/s12888-022-03775-9 35216557
Wei, Y. et al. Characteristics of platelet-associated parameters and their predictive values in Chinese patients with affective disorders. BMC Psychiatry. 22, 150. 10.1186/s12888-022-03775-9 (2022).35216557 10.1186/s12888-022-03775-9
39. Cetin MS Platelet distribution width and plateletcrit: novel biomarkers of ST elevation myocardial infarction in young patients Kardiol. Pol. 2017 75 1005 1012 10.5603/KP.a2017.0135 28715073
Cetin, M. S. et al. Platelet distribution width and plateletcrit: Novel biomarkers of ST elevation myocardial infarction in young patients. Kardiol. Pol. 75, 1005–1012. 10.5603/KP.a2017.0135 (2017).28715073 10.5603/KP.a2017.0135
