Peripheral neuropathy is associated with increased mean platelet volume in type 2 diabetic patients

Sir:

Mean platelet volume (MPV) is a recognized index of platelet activation [1]. Increased MPV has been reported in diabetic patients, especially in those with retinopathy and microalbuminuria, which are common microvascular complications [[1–3]]. Neuropathy is a further microvascular complication of diabetes, which leads to a considerable increase in morbidity and mortality [[4], [5]]. The present study was conducted to investigate the potential association between MPV and diabetic neuropathy in patients with type 2 diabetes mellitus.

This study included 163 patients divided into two groups A (patients with neuropathy) and B (patients without neuropathy), as summarized in Table I. The two groups were matched for age, sex, diabetes duration, HbA_1c, prevalence of retinopathy and prevalence of microalbuminuria. Exclusion criterion was detection of abnormal hematocrit and/or abnormal white blood cell count and/or abnormal platelet number. The study was approved by the institutional ethics committee and all patients gave their informed consent. Diabetes was diagnosed according to the American Diabetes Association criteria [6]. Microalbuminuria was defined as an albumin excretion rate ≥20 µg/min in the absence of uncontrolled hypertension and/or urinary tract infection [3]. Retinopathy was defined as at least two microaneurysms and/or retinal hemorrhage and/or other signs of retinal damage [3].

Table I.  Characteristics of patients included in the study.

Characteristic	Group A	Group B
Total patient number	81	82
Male	40	41
Female	41	41
Age (years, mean ± SD)	69.8 ± 10.4	68.7 ± 10.1
Diabetes duration (years, mean ± SD)	15.7 ± 5.6	15.3 ± 4.9
HbA1c (%, mean ± SD)	7.9 ± 1.3%	8.1 ± 1.4%
Microalbuminuria  (patients, %)	27 (33.33%)	26 (31.7%)
Retinopathy (patients, %)	48 (59.26%)	45 (54.88%)

Neuropathy was diagnosed by means of the diabetic neuropathy index (DNI) [[4], [7]]. The DNI is a standardized examination of feet appearance (deformity, dry skin, callus, infection and fissures), neuropathic ulceration, Achilles tendon reflexes and vibration perception at great toe using a 128-Hz tuning fork (normal score ≤2; worst score 8) [4]. In the present study patients with a DNI score higher than 2 were considered to have peripheral neuropathy [[4], [7]]. Peripheral neuropathy was considered moderate in patients with a DNI score between 2.5 and 4.5 (N = 48) and severe in those with a DNI score between 5 and 8 (N = 33) [7].

MPV was measured in blood samples anticoagulated with sodium citrate [3]. Each measurement was performed in two blood cell counters (Sysmex SF 3000 and Cell-Dyn 3700).

Statistical analysis was performed using SPSS (Statistical Package for Social Sciences) 11.0. MPV was a continuous variable with normal distribution. Data were expressed as mean ± standard deviation ( ± 1 SD). Comparison of MPV values between the two groups was made by unpaired t-test, while comparison between values with the two blood cell counters was made by paired t-test. Statistical significance was defined at a level of 5% (p < 0.05).

MPV was significantly (P = 0.03) higher in patients of group A (15.2 ± 1.6 fl) than in those of group B (11.3 ± 1.4 fl). In Group A, no significant difference (P = 0.78) in MPV was observed between patients with severe (15.7 ± 1.5 fl) and those with moderate neuropathy (15.1 ± 1.4 fl). There was no difference in MPV values measured with the two blood cell counters, both in Group A (Sysmex SF 3000, 15.2 ± 1.4 fl vs. Cell-Dyn 3700, 15.3 ± 1.2 fl, P = 0.96) and in Group B (Sysmex SF 3000, 11.1 ± 1.2 fl vs. Cell-Dyn 3700, 11.4 ± 1.1 fl, P = 0.9).

Increased MPV in the neuropathic group suggests platelet activation [[1–3]], in keeping with prior studies that have provided evidence for increased platelet aggregation and hyperproduction of prothrombotic factors in diabetic patients with neuropathy [[8], [9]]. Experimental studies in the streptozotocin-induced diabetic rat have also revealed increased platelet aggregation in association with neuropathy [[10], [11]]. More importantly, these studies have shown that treatment-induced amelioration of neuropathy was accompanied by improvement of platelet abnormalities [[10], [11]].

Among diabetic patients, increased MPV has been demonstrated in those with retinopathy [[2], [3]] and microalbuminuria [3], though not all studies agree [1]. Thus, increased MPV in a series of diabetic patients could be, partially at least, attributable to the higher prevalence of retinopathy or microalbuminuria. Nonetheless, the two groups in our study were matched for the prevalence of retinopathy and microalbuminuria. Accordingly, increased MPV in the neuropathic group could not be a biased result due to the presence of the other two microvascular complications. Moreover, our two groups were matched for HbA_1c, patient age and duration of diabetes, although studies have so far found no correlation between MPV and the aforementioned parameters [[1–3]]. Hence, it appears that increased MPV in the neuropathic group is actually correlated with neuropathy.

Interestingly, no association was observed in neuropathic patients between MPV and severity of neuropathy. This may, arguably, be explained by the complex pathophysiology of diabetic neuropathy [5]. Indeed, diabetes mellitus is thought to cause major disruption of several metabolic and vascular mechanisms, which contribute to the development of neuropathy [5]. For this reason, despite some evidence of a small role for platelet activation in the pathophysiology of neuropathy [[5], [8–11]], there is much more that remains to be determined [5]. Our finding, if confirmed upon replication, would suggest that there is increased platelet activation in neuropathic patients, irrespective of the severity of neuropathy.

In conclusion, increased MPV is associated with presence, but not with severity, of neuropathy in patients with type 2 diabetes mellitus. This finding might be of clinical value in the future, should further studies elucidate the contribution of platelet activation to the pathogenesis of diabetic neuropathy.