The Significance of Mean Platelet Volume in Assessing Amputation Risk in Patients with Diabetic Foot Ulcers: A Cohort Study

Abstract

Objective:

Diabetic foot ulcer is a condition associated with type 2 diabetes mellitus (T2DM). This study aims to examine the influence of mean platelet volume (MPV) on predicting amputation decisions in patients with diabetic foot ulcers.

Methods:

Patients with diabetic foot ulcers who presented to the tertiary healthcare facility from June 2023 to June 2024 were included. The first group comprises individuals who opted for amputation, whereas the second group includes patients without indications for amputation.

Results:

The mean age of patients with diabetic foot ulcers is 62.68 years, and the mean glycated hemoglobin A1c level is 9.62%. The initial group comprises 61 patients who opted for amputation, whereas the subsequent group includes 56 individuals who lacked an indication for amputation. The initial group exhibits markedly elevated values for MPV, total cholesterol, and low-density lipoprotein (LDL) (P = 0.001, P = 0.004, P = 0.020). Logistic regression research indicates that elevated levels of LDL and MPV substantially heighten the chance of amputation. The receiver operating characteristic curve study established the MPV cutoff value for amputation prediction at 11.2. The sensitivity and specificity of this value in predicting amputation were [β = 0.01, OR (odds ratio) = 1.01, 95% confidence interval (CI): 1.00–1.03, P = 0.006] for LDL and (β = 0.52, OR = 1.68, 95% CI: 1.18–2.39, P = 0.003) for MPV. Every unit increment in the MPV value corresponds to an approximate 68.8% elevation in the probability of amputation.

Conclusion:

In individuals with diabetic foot ulcers, MPV and LDL levels are independent variables affecting amputation and may function as predictors for amputation.

Introduction

Diabetes mellitus (DM) is a condition defined by inadequate insulin secretion or resistance to insulin’s effects.¹ The prevalence of DM in the population, which was 7% in the 1990s, has increased to around 14% by 2022. DM resulted in 1.6 million fatalities in 2021, with 530,000 of those deaths attributable to diabetes-related renal disease, and elevated blood glucose levels accounting for approximately 11% of cardiovascular mortality.² Type 2 diabetes mellitus (T2DM) is associated with numerous chronic consequences, including hypertension (HT), dyslipidemia, microvascular problems resulting from persistent hyperglycemia (nephropathy, retinopathy, and neuropathy), hepatic steatosis, and diabetic foot ulcers. In T2DM, hyperglycemia influences keratinocyte and fibroblast functions and significantly contributes to the development of diabetes-related foot problems and amputations. Moreover, elevated glycated hemoglobin A1c (HbA1c) levels frequently serve as a biomarker linked to impaired wound healing.³

Diabetic foot complications are a major source of morbidity. In individuals with T2DM and T1DM, the likelihood of having a foot ulcer may escalate to 34%.⁴ Approximately 18 million individuals globally experience diabetic foot ulcers each.⁵ Diabetes foot ulcers result in a significant frequency of hospital admissions and are linked to a heightened mortality risk relative to diabetes patients without foot ulcers.⁵ The initiating event typically commences with a skin injury resulting from modest trauma, which is potentially avoidable. The majority of diabetic foot ulcers can be averted via prompt identification and intervention, whereas 20% may necessitate amputation.⁶ Consequently, it underscores the necessity of more regular examinations to mitigate the risk of delayed diagnosis and surgical intervention.⁷

Amputations resulting from diabetic foot ulcers involve various indicators, including HbA1c, C-reactive protein (CRP), white blood cell (WBC) count, albumin levels, and erythrocyte sedimentation rate. Mean platelet volume (MPV) and platelet counts serve as indicators of diabetic foot ulcers.⁸ Large and oversized platelets exhibit heightened activity and a propensity to agglomerate. These platelets possess denser granules than smaller platelets, emit increased amounts of serotonin and β-thromboglobulin, and generate higher levels of thromboxane A2.⁹ A number of epidemiological research studies have shown that MPV value is a risk factor for amputation.¹⁰ Nonetheless, another research has indicated that there is no correlation between MPV value and diabetic foot amputation.^11,12 Despite the longstanding availability of routine lipid parameter evaluations, their clinical importance remains little clarified, and their diagnostic application has been constrained. Patients with complex T2DM exhibit elevated low-density lipoprotein (LDL) levels in comparison to those with uncomplicated T2DM.¹³ Results vary concerning whether MPV and cholesterol concentrations increase or remain stable in diabetic foot ulcers.^10
–12

The studies, however, have often involved patients with or without T2DM. The quantity of papers only including patients with T2DM is restricted. This study intends to examine the impact of MPV value in assessing surgical risk in individuals with diabetic foot ulcers diagnosed with T2DM who are candidates for amputation or medicinal therapy.

Materials and Methods

The study examined individuals aged 18 and older with T2DM who presented to the endocrinology and internal medicine outpatient clinics, were admitted to the endocrinology and internal medicine wards, or were referred from the emergency department between June 2023 and June 2024.

Criteria for inclusion

The study comprised patients aged 18 and older diagnosed with T2DM and foot ulcers.

Criteria for exclusion

Individuals with peripheral artery disease, those who had already undergone amputation or declined amputation when advised, those utilizing beta blockers, and nondiabetic individuals were excluded from the study.

Research methodology

The principal objective is to assess the impact of MPV on the likelihood of amputation in diabetic foot ulcers. The secondary objective examines the influence of platelet count on amputation in diabetic foot ulcers.

A total of 117 patients with T2DM who fulfilled the criteria were identified. The data in the study were sourced from patient records within the hospital system. The hemogram, biochemistry, and hormone panels of the study participants were quantified spectrophotometrically utilizing autoanalyzers in the biochemistry laboratory of Bursa Yüksek İhtisas Training and Research Hospital, Health Sciences University, whereas HbA1c levels were assessed chromatographically. The patients were categorized into two groups according to whether an amputation decision was rendered within the preceding week, and MPV along with other laboratory values were documented. The choice for amputation was made in accordance with the protocols established by the American Academy of Orthopaedic Surgeons.¹³ The research was performed retrospectively, and the investigators affirm compliance with the Helsinki Declaration.

The ethical committee approval for this study was granted by Bursa Yüksek İhtisas Training and Research Hospital of Health Sciences University, under decision number 2024-TBEK-2024/08-01.

Statistical examination

The IBM SPSS Statistics 23 software package was utilized for data analysis in the study. The analysis commenced with an examination of descriptive statistics and the normality distributions of the data. In relationship studies, the chi-squared test was employed to compare categorical variables, while the Independent Samples t-test, a parametric method, was utilized for comparing categorical and continuous variables due to the normal distribution of the data. During the analysis, instances with a P-value below 0.05 were deemed statistically significant. In the analysis, cases with a P-value below 0.05 were deemed statistically significant.

Results

Table 1 presents the comparisons of demographic factors between the amputated and non-amputated groups. Table 1 indicates that only the gender variable exhibited a significant difference between the amputee and nonamputee participant groups (P = 0.018), but the data for coronary artery disease, smoking, and blood pressure variables were comparable in both groups.

Table 1.

Demographic Variables and Comorbidities

Variables	Amputations(n = 61)	Nonamputee(n = 56)	P
Age (years)	62.16 ± 11.95	63.21 ± 12.74	0.6
Gender (male/female) n (%)	50/11 (58.80/34.40)	35/21 (41.20/65.60)	0.018
Coronary artery disease			0.8
Bypass n (%)	7 (46.7)	8 (53.3)
Stent n (%)	17 (56.7)	13 (43.3)
None n (%)	37 (51.4)	35 (48.6)
Smoking (%)	59.6	40.4	0.1
Hypertension (%)	51.7	48.3	0.9

Comparison of laboratory characteristics between amputee and nonamputee participant groups

Table 2 delineates the comparison of laboratory characteristics between the amputated and non-amputated participant groups. Table 2 indicates that only total cholesterol, LDL, and MPV variables exhibited statistically significant differences among the participant groups (P = 0.004). The results of creatinine, glucose, total cholesterol, LDL, high-density lipoprotein (HDL), hemoglobin, mean corpuscular volume, CRP, WBC, neutrophils, lymphocytes, and platelets were uniformly distributed throughout both groups.

Table 2.

Distribution of Laboratory Values among Categories in the Study Population

Variable	Amputations	Nonamputee	P
HbA1c (%)	9.31 ± 2.25	10.01 ± 2.65	0.128
Glucose (mg/dL)	239.36 ± 126.71	255.45 ± 118.61	0.4
Creatinine (mg/dL)	2.92 ± 1.18	1.77 ± 2.12	0.4
CRP (mg/dL)	141.70 ± 88.18	130.57 ± 86.41	0.4
MPV (fl)	10.58 ± 1.17	9.78 ± 1.39	0.001^**
WBC (mcL)	14.68 ± 6.96	13.98 ± 6.66	0.5
NEU (mcL)	12.04 ± 6.92	11.41 ± 6.28	0.6
PLT (mcL)	371.70 ± 137.24	355.21 ± 159.70	0.5
Lymphocyte (mcL)	4.19 ± 2.03	1.62 ± 0.92	0.3
MCV (fl)	82.11 ± 9.04	82.95 ± 11.28	0.6
Hemoglobin (g/dL)	10.49 ± 1.92	10.62 ± 2.18	0.7
Total cholesterol (mg/dL)	172.03 ± 37.69	154.21 ± 43.67	0.020^**
LDL (mg/dL)	102.66 ± 32.01	83.50 ± 37.76	0.004^**
HDL (mg/dL)	37.72 ± 12.82	35.96 ± 11.16	0.4

P < 0.05.

CRP, c-reactive protein; HbA1c, glycated hemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MCV, mean corpuscular volume; MPV, mean platelet volume; NEU, neutrophil, PLT, platelet; WBC, white blood cell.

MPV distributions based on smoking

In the amputation group, 28 of 61 patients (45%) are smokers, whereas in the nonamputation group, 19 of 56 patients (33%) are smokers. No statistically significant difference was seen in MPV distribution between smokers and nonsmokers (P = 0.2).

MPV distributions based on LDL values

The average LDL values in the amputation group were 102.66 ± 32.01 mg/dL, while in the nonamputation group, the average was 83.50 ± 37.76 mg/dL. A link and association between LDL levels and MPV levels has been established (r = 0.081, P = 0.004).

Amputation status categorized by gender

The initial group comprises 61 patients designated for amputation (11 women, 50 men), whereas the subsequent group includes 56 patients without an indication for amputation (21 women, 35 men). A notable correlation exists between gender and amputation (P = 0.018). The male gender constitutes a risk factor for amputation.

Factors indicating association with amputation

The average total cholesterol levels in the amputation group were 172.03 ± 37.69 mg/dL, while in the nonamputation group, they were 154.21 ± 43.67 mg/dL (P = 0.020). A notable correlation exists between total cholesterol and MPV (r = 0.022, P = 0.020). Total cholesterol and LDL vary according to MPV levels (Table 3).

Table 3.

Correlation Analysis of Amputation and Other Parameters

Variable	Correlation significance	Amputation
MPV	rp	0.2830.002
Gender	rp	0.0100.913
Age	rp	0.0460.623
HbA1c	rp	0.0290.759
Total cholesterol	rp	0.0220.816
LDL	rp	0.0810.384
HDL	rp	−0.0850.362

Regression analysis

Regression analysis revealed that LDL and MPV are significant independent factors influencing amputation (Table 4).

Table 4.

Logistic Regression Analysis Results of Independent Variables Associated with Amputation

Dependent variable	Independent variable	β	P	OR	OR (95% CI)
Amputation	Age	−0.019	0.281	0.981	0.947–1.016
	Gender	−0.836	0.091	0.433	0.165–1.142
	HbA1c	−0.151	0.105	0.860	0.716–1.032
	LDL	0.017	0.006	1.017	1.005–1.030
	Smoking	0.390	0.369	0.677	0.289–1.584
	MPV	0.523	0.003	1.688	1.189–2.395

CI, confidence interval.

Receiver operating characteristic curve analysis

The study aimed to assess the efficacy of the MPV value in forecasting amputation. The research established a cutoff value of 11.1 for MPV. At this threshold value, the sensitivity of MPV for predicting amputation was established at 34%, while the specificity was recorded at 91%. The area under the curve (AUC) indicating the accuracy of MPV in differentiating amputation was determined to be 0.66 (95% confidence interval: 0.56–0.76), and this finding was statistically significant (P = 0.002) (Fig. 1).

FIG. 1.

ROC curve illustrating the relationship between MPV value and amputation. Area under the curve (AUC) = 0.66, P = 0.002 (95% CI: 0.56–0.76). CI, confidence interval; MPV, mean platelet volume; ROC, receiver operating characteristic.

Discussion

This study examined the correlation between MPV levels and diabetic foot amputation. The findings demonstrated a distinct correlation among total cholesterol, LDL, gender, and MPV levels with the heightened risk of diabetic foot amputation. Recognizing risk factors for diabetic foot amputation can enhance primary prevention, facilitate early diagnosis and treatment, improve survival rates among diabetic patients, and diminish morbidity. Risk factors for amputation in diabetic patients include age, gender, hyperlipidemia, MPV, ischemic heart disease, HT, pulmonary arterial hypertension, nephropathy, length of diabetes, and HbA1c, among others.¹⁴ Nevertheless, there are discrepancies among research indicating that MPV levels serve as a risk factor for diabetic foot amputation.

Larger platelets exhibit heightened activity and a propensity to aggregate. These platelets possess denser granules than smaller platelets, emit increased amounts of serotonin and β-thromboglobulin, and generate greater quantities of thromboxane A2.⁹ Consequently, patients with elevated MPV levels heighten the risk of amputation by aggravating lower extremity ischemia. Kapukaya and associates identified MPV as statistically significant in assessing the risk of amputation.¹⁰ A study by Mardia and associates revealed no difference in MPV levels between the diabetic foot group and the nondiabetic foot group.¹¹ The research by Rachmanadi et al. revealed that a drop in MPV values in T2DM foot amputations correlates with an elevated risk of chronic ischemia in the extremities, hence increasing the likelihood of amputation.¹² This study contrasts diabetes and nondiabetic groups, differing from earlier studies as diabetic people were included in both groups. Furthermore, our study’s findings align with those of Kapukaya and associates. The Kapukaya study indicated that MPV values were markedly elevated in individuals with diabetic foot ulcers who underwent amputations (P = 0.028). Nonetheless, a definitive MPV cutoff number was not disclosed in the previously described study. The research by Rachmanadi and associates indicated that patients with a MPV of ≥9.8 fL exhibited a diminished chance of experiencing critical limb ischemia. In our study, receiver operating characteristic (ROC) curve analysis established an MPV cutoff value of 11.1. Additional research examines whether MPV is a substantial risk factor at a specific threshold while presenting a definitive cutoff value derived from ROC analysis can mitigate ambiguities in the literature.

Dyslipidemia constitutes a significant risk factor for cardiovascular illnesses. In individuals with DM, there is frequently an elevation in LDL and very low-density lipoprotein, along with a reduction in HDL, signifying compromised lipoprotein metabolism. Elevated LDL levels in T2DM impair blood circulation in the lower extremities due to their atherogenic properties, increasing the risk of amputation.¹⁵

The American Diabetes Association’s 2019 guidelines stipulate that all diabetes individuals with a 10-year atherosclerotic cardiovascular risk over 10% should get high-dose statin therapy alongside lifestyle modifications. In those with an LDL-C concentration ≥100 mg/dL, the cardiovascular risk escalates.¹⁶

Patients with complex T2DM exhibit elevated LDL levels in comparison to those with uncomplicated T2DM. Vincent and colleagues’ investigation found that the group with diabetic foot ulcers exhibited elevated LDL levels compared to the other group, identifying it as an independent risk factor for amputation.¹⁵ Conversely, Callaghan and associates found no correlation between LDL levels and the likelihood of amputation.¹⁷ Elevated LDL is a risk factor for lower extremity amputation.¹⁸

Our study’s findings reveal that hyperlipidemia correlates with an increased risk of major amputations, suggesting that vascular health complications in the lower extremities predispose patients to limb loss. Hyperlipidemia is the primary risk factor identified in a study by Wouters and associates.¹⁹ Total cholesterol levels serve as a prognostic indicator for amputation in patients with diabetic foot ulcers, and the heightened risk of amputation linked to elevated total cholesterol in our study aligns with prior research findings.²⁰

This study revealed that male diabetes patients had a greater risk of amputation than their female counterparts, indicating that gender disparities affect amputation risk in diabetic individuals. Research by Saltoğlu, Pickwell, and Cervantes indicates that the male gender elevates the risk of amputation relative to the female gender.^21,22 Numerous research have revealed no distinction between the two.^23
–25 Personal self-care varies between genders, which may elucidate the disparity in amputation risk. The hormonal protective function of estrogen may contribute to immunological disparities between men and women, leading to this outcome.²⁶

Diabetic foot ulcers and amputations diminish the quality of life for individuals with T2DM, elevating morbidity and mortality rates.²⁷ Moreover, the management of problems incurs a financial burden.²⁸ In this setting, the prompt identification of risk factors and the therapy of the disease have more significance.²⁹ Consequently, a straightforward method is required to assess the risk of amputation in diabetic foot conditions or diabetic foot ulcers. A multitude of research has examined the elevation of MPV and the factors that contribute to it. MPV is recognized as an independent indicator of diabetic foot ulcers.¹⁰

In certain investigations, the MPV value was seen to be reduced in instances of inflammation.^30
–32 Conversely, another study revealed a correlation between MPV values and acute phase reactants.^33–34 The alteration in MPV value during inflammation remains ambiguous. Furthermore, an increase in platelet consumption due to inflammation leads to a heightened discharge of immature platelets. Immature platelets are discharged from the bone marrow into circulation, exhibiting bigger size and elevated RNA content compared to mature platelets.^35–36 This is indicated by an elevated MPV rate in the total blood count. Consequently, it remains ambiguous whether the elevated MPV resulting from secondary inflammation associated with diabetic foot amputation is a causative factor or a consequence of the amputation risk. Numerous studies in the literature indicate that the MPV value serves as a biomarker in disorders associated with ischemia and thrombosis, hence corroborating the findings of our study.^37,38

In our study, HbA1c levels exhibited no significant difference between the amputation group and the nonamputation group. Although elevated HbA1c levels are associated with a heightened risk of amputation, the elevated MPV levels seen in our investigation, despite the lack of differentiation, underscore that MPV serves as an independent risk factor for amputation.³⁹

This study has certain limitations; as it is a retrospective analysis, data about the Wagner–Meggitt Classification and the three subtypes (neuropathic, neuroischemic, and ischemic) of diabetic foot ulcer classifications could not be obtained. Simultaneously, data such as body mass index remained inaccessible, and analysis was confined to a restricted number of patients. If the study design is prospective, it is posited that a more extensive investigation might be undertaken by including diabetic foot categories.

Conclusion

Patients with diabetic foot ulcers who have undergone amputation exhibit elevated MPV levels compared to those who have not been amputated. The MPV value is expected to serve as an indicator in the development of amputation in diabetic foot ulcers. This issue requires validation through prospective and controlled investigations.

Footnotes

Acknowledgments

The authors thank all authors and patients who contributed to this publication.

Authors’ Contributions

A.E. and M.G.: Conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, resources, software, supervision, validation, visualization, writing—original draft, and writing—review and editing. Z.A.A.: Project administration, resources, and software. F.A.: Supervision, validation, and visualization. M.K.: Writing—original draft, writing—review and editing, and conceptualization. A.D.: Data curation, funding acquisition, and investigation. H.E.Y.: Methodology, project administration, and resources. F.G.: Software, supervision, and validation. M.F.Ş.: Visualization, writing—original draft, and writing—review and editing. O.E.: Conceptualization, data curation, and formal analysis.

Author Disclosure Statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.

Funding Information

No financial support was received for this article.

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