Neuropathy Progression Risk In Patients With Coagulation Abnormalities
Overview
Nearly half of individuals with diabetes develop diabetic peripheral neuropathy (DPN), which is associated with a concerning 53% survival rate within three years. Coagulation abnormalities have been suggested to play a role in the pathogenesis of microvascular complications, including DPN. Therefore, investigating the influence of coagulation function on the development and progression of DPN is critical.
The study analyzed data from 1,211 patients with type 2 diabetes, admitted to five medical centers in China between September 2018 and October 2022. DPN diagnosis was based on clinical symptoms and electromyography. Motor and sensory nerve conduction velocities (NCV) were assessed, and NCV sum scores were calculated for the median, ulnar, and peroneal nerves.
Patients with DPN displayed notable changes in coagulation function. Specifically, they showed prolonged thrombin time (p = 0.012), increased fibrinogen levels (p < 0.001), and shortened activated partial thromboplastin time (APTT; p = 0.026) compared to non-DPN controls. Further analysis revealed that elevated fibrinogen and D-dimer levels were negatively correlated with motor NCV, motor amplitude, and mean velocity. Fibrinogen also exhibited a significant association with higher Michigan Neuropathy Screening Instrument (MNSI) scores (β 0.140; p = 0.001). These findings were further validated in a separate cohort of 317 diabetic patients. Fibrinogen was found to be an independent risk factor for DPN (OR 1.172; p = 0.035). Interestingly, DPN development was slower until fibrinogen levels reached approximately 3.75 g/L, after which the risk rapidly increased.
In conclusion, the study highlights the importance of monitoring coagulation function in patients with type 2 diabetes, as it may help in predicting and preventing the onset of DPN in clinical settings.
Introduction
Diabetic peripheral neuropathy (DPN) is one of the most prevalent chronic complications associated with diabetes mellitus. It is estimated to affect 10%–15% of newly diagnosed diabetes patients, with its prevalence rising to 50% among all diabetic individuals. Notably, the three-year survival rate for diabetic patients with DPN stands at approximately 53%. DPN is characterized as a symmetrical, length-dependent sensorimotor polyneuropathy, driven by chronic hyperglycemia, metabolic disorders, cardiovascular risks, and microvascular changes. The symptoms of DPN, such as neuropathic pain, paresthesia, and sensory loss, increase the likelihood of burns, injuries, and diabetic foot ulcers. Research has also shown that neuropathy may emerge not only during diabetes but also in the prediabetic phase.
Several biomarkers have been identified as contributing to the diagnosis and prognosis of DPN. These include age, diabetes duration, hypertension, dyslipidemia, and smoking. Both type 1 and type 2 diabetics may experience a hypercoagulable state, characterized by elevated clotting factors and a prethrombotic environment. Studies suggest that even minimal systemic inflammation can damage both myelinated and unmyelinated nerve fibers, compromising the blood-nerve barrier and microvascular integrity. This has been identified as a potential mechanism leading to the onset of type 2 diabetes mellitus (T2DM) and its complications. However, detecting inflammatory markers is often technically challenging and costly, which limits their use in everyday clinical practice.
Disruption of coagulation function is known to exacerbate microvascular changes, thereby increasing the risk of DPN in patients with T2DM. Fibrinogen (FIB), the primary protein involved in blood clotting, has been strongly linked to chronic systemic inflammation, more so than hypercoagulability. Research has identified FIB as an independent risk factor for type 2 diabetic nephropathy, a major microvascular complication that can lead to kidney failure. Additionally, patients with a D-dimer level of ≥0.22 mg/L are reported to have a heightened risk of developing DPN. However, there has been limited research on the relationship between coagulation function and DPN severity, as measured by electromyography (EMG), and no studies have stratified this analysis by age.
In this retrospective study, we sought to explore the role of coagulation biomarkers in predicting the risk of DPN, based on EMG and neurological assessment, in Chinese patients with T2DM. Our objective was to evaluate the potential of these biomarkers in enhancing diagnosis and prognosis across various age groups.
Method
In the main cohort, patients who underwent nerve conduction studies were recruited from the First Affiliated Hospital of Wenzhou Medical University between September 2018 and October 2022. Individuals with type 2 diabetic peripheral neuropathy (DPN) were assigned to the DPN group (n = 614), while those with type 2 diabetes mellitus (T2DM) but no DPN were placed in the T2DM group (n = 280). A separate control group (n = 133) consisted of individuals without T2DM. For external validation, 196 patients with DPN and 121 patients with T2DM were recruited, totaling 317 patients across hospitals in Zhejiang and Henan Provinces between October 2021 and October 2022.
Clinical data were extracted from electronic health records, including demographics (age, BMI, smoking, hypertension), lab results (HbA1c, fasting glucose, cholesterol), and coagulation indicators (FIB, PT, TT, APTT, INR, D-dimer). The study was ethically approved, and all participants provided informed consent. In total, 1,211 patients were analyzed: 894 from Wenzhou and 317 from external hospitals.
To reduce confounding variables, patients refrained from substances and activities that could affect neurological function before testing. Nerve conduction studies were performed at controlled temperatures, measuring motor and sensory branches in the limbs, with abnormalities defined as conduction below 2.5 standard deviations from the control group. DPN was diagnosed based on abnormal nerve conduction paired with neurological symptoms or signs.
Peripheral nerve conduction velocities and amplitudes were standardized, with slow or low conduction defined by Z-scores below −1. The MNSI, comprising a 15-item questionnaire and foot examination (MNSIE), was used to assess neuropathy, with higher scores indicating more severe cases. T2DM was confirmed through blood glucose levels and medication history, and abnormal nerve conduction in two or more nerves confirmed DPN. All findings were evaluated by a panel of experienced neuromuscular specialists, ensuring diagnostic accuracy.
Inclusion Criteria
The study’s inclusion criteria were adults aged 18 and older with diabetes who had undergone nerve conduction tests and the Michigan Neuropathy Screening Instrument (MNSI).
Exclusion Criteria
Exclusion criteria included type 1 diabetes, lack of coagulation data, and severe medical conditions such as liver disease, venous thromboembolism, stroke, and non-diabetic neuropathies.
Statistical analysis
All statistical analyses were conducted using IBM SPSS software version 25.0 (IBM Corp., Armonk, NY, USA). For continuous variables with a normal distribution, the unpaired Student’s t-test was used, while the Wilcoxon rank-sum test or Kruskal-Wallis test was applied for non-normally distributed data. Categorical variables were analyzed using the Chi-square test or Fisher’s exact test, as appropriate. Normally distributed continuous variables were reported as mean ± standard error of the mean (mean ± SEM), and non-normally distributed variables were presented as medians with interquartile ranges (median, IQR). Categorical data were expressed as percentages.
To assess the correlation between FIB and EMG parameters, Spearman’s rank correlation was employed. Multiple linear regression analysis was conducted to explore the associations between coagulation function, abnormal nerve conduction, and MNSI exam results, adjusting for confounding variables such as age, diabetes duration, hypertension, hyperlipidemia, BMI, smoking status, FPG, HbA1c, TG, TC, and CRP. Additionally, multivariate logistic regression was used to evaluate the link between coagulation function and DPN risk, identifying serum FIB as an independent factor for DPN onset. Restricted cubic spline models with three knots (at the 10th, 50th, and 90th percentiles) were plotted to provide more precise estimates and examine potential nonlinear relationships.
Result
In a study conducted at the First Affiliated Hospital of Wenzhou Medical University, a total of 614 patients diagnosed with type 2 diabetic peripheral neuropathy (DPN), 280 patients with type 2 diabetes without DPN (T2DM), and 133 non-diabetic controls underwent electromyography (EMG) assessments. The findings revealed that the DPN group exhibited prolonged thrombin time (TT) and shorter activated partial thromboplastin time (APTT), alongside elevated fibrinogen (FIB) levels compared to the control group. Specifically, the DPN group had significantly higher FIB levels than the T2DM group, while no significant differences were observed in prothrombin time (PT), international normalized ratio (INR), or D-dimer levels across the groups.
Subsequent analyses indicated a notable inverse relationship between FIB levels and various EMG parameters, including nerve conduction velocities (NCV) and amplitudes in both upper and lower limbs, after controlling for potential confounders. FIB levels demonstrated strong correlations with reduced mean motor nerve amplitude (MNAmp), mean motor nerve conduction velocity (MNCV), mean sensory nerve amplitude (SNAmp), and mean sensory nerve conduction velocity (SNCV). Furthermore, D-dimer levels were also linked to diminished motor NCV and amplitude.
In an external validation cohort of 196 patients with DPN and 121 with T2DM, the DPN group showed higher scores on the Michigan Neuropathy Screening Instrument (MNSI) and increased FIB levels. Regression analyses confirmed that elevated FIB levels were negatively associated with motor amplitude values, MNAmp, MNCV, SNAmp, and SNCV.
Additionally, multivariate analyses highlighted a significant correlation between FIB levels and MNSI scores, suggesting a link to the severity of neuropathy. No significant associations were noted with other coagulation markers. Logistic regression further established that FIB levels independently predicted the risk of developing DPN in type 2 diabetes patients, whereas other coagulation indicators showed no significant associations.
Further examination of EMG parameters stratified by FIB levels indicated that as FIB levels increased, the age and prevalence of DPN also rose. Significant disparities in motor and sensory nerve conduction metrics were noted across different FIB tertiles. Age-stratified analyses reaffirmed that FIB was consistently associated with decreased NCV and amplitudes across all age groups.
Exploratory analyses using restricted cubic spline regressions demonstrated a nonlinear relationship between elevated FIB levels and DPN risk. The risk of DPN decreased until FIB levels reached approximately 3.75 g/L, after which it increased. This trend was particularly evident in the 55–65 age group. Overall, the findings suggest that elevated fibrinogen levels are associated with increased severity and risk of DPN in type 2 diabetes patients, highlighting the need for further research into the underlying mechanisms and potential clinical implications.
Conclusion
The study investigated the connection between coagulation function, diabetic peripheral neuropathy (DPN), and nerve conduction parameters among 1,211 individuals from five hospitals. Findings revealed that fibrinogen (FIB) and D-dimer levels were negatively correlated with electromyography (EMG) results after accounting for confounding factors. Elevated FIB levels were positively linked to higher Michigan Neuropathy Screening Instrument (MNSI) scores, indicating a worsening condition, a relationship that was also confirmed in an external cohort of 317 diabetic patients. Notably, FIB emerged as an independent predictor of DPN in type 2 diabetes mellitus (T2DM) patients and correlated with disease severity, illustrated by reduced nerve conduction velocities (NCV) and amplitudes.
The analysis suggested that dysfunction in coagulation plays a significant role in developing diabetic microvascular complications. The study highlighted diabetes-induced thrombotic tendencies and chronic systemic inflammation as potential mechanisms contributing to neuropathy. Key coagulation indicators, such as prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and D-dimer, were assessed. Chronic conditions, including hyperlipidemia and hyperglycemia, promote systemic inflammation, leading to platelet activation and a disordered coagulation system, exacerbating diabetes and increasing DPN risks.
Additionally, the study emphasized the importance of the duration of diabetes in developing DPN, noting that patients with longer disease histories are at a heightened risk of microvascular complications. It identified that older age groups, particularly those aged 55-65, are particularly susceptible to abnormal nerve conduction, suggesting the need for regular DPN screenings in these populations.
However, the study acknowledged limitations, including its cross-sectional nature and the exclusion of type 1 diabetes patients, which may affect the generalizability of the results. It called for further longitudinal research to clarify the pathophysiological role of FIB in T2DM and DPN and to establish a clearer risk threshold for FIB levels. Overall, the research underscores that elevated coagulation factors, especially FIB, could be critical in the onset and progression of DPN among Chinese patients with T2DM, highlighting the potential for monitoring coagulation function as a therapeutic strategy.
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