Increased platelet reactivity in Klinefelter men: something new to consider

Abstract

SUMMARYPatients with Klinefelter syndrome (KS) exhibit an increased cardiovascular risk, but underlying mechanisms are largely unknown. The present cross-sectional study has been conducted to evaluate platelet reactivity and the expression of platelet activation markers (8-iso-prostaglandin F2a[8-iso-PGF2a] and 11-dehydro-thromboxane-B₂[11-dehydro-TXB2]) in KS patients and healthy controls. Twenty-three consecutive KS patients under testosterone replacement therapy have been included as case group and 46 agematched healthy males recruited among hospital staff served as controls. Light transmission aggregometry was performed in both cases and controls and maximal platelet aggregation (max-A%) was defined as maximal light transmittance reached within 5 min after the addition of 0.2 or 0.4 mM arachidonic acid (AA). A ≥ 50% irreversible light transmittance (LT-50%) following platelet stimulation defined an adequate platelet aggregation and AC-50% was defined as the minimal agonist concentration needed to achieve LT-50%. The AC-50% was 0.26 mM AA for KS and 0.36 mM for controls (p < 0.001). Whereas AA (0.2 mM) induced LT-50% in 69.6% of KS and in 15.2% of controls (p < 0.001), the stimulation with AA (0.4 mM) determined LT-50% in all cases and controls. However, max-A% was higher in KS than in controls both after AA (0.2 mM) (65.61% vs. 46.30%, p = 0.002,) and after AA (0.4 mM) (96.43% vs. 81.04%, p < 0.001). 8-iso-PGF2a and 11-dehydro-TXB2 were higher in KS than in controls (446.54 pg/mg creatinine vs. 230.00 pg/mg creatinine, p < 0.001 and 1278.36 pg/mg creatinine vs. 595.08 pg/mg creatinine, p = 0.001, respectively) and AC-50% inversely correlated with 8-iso-PGF2a (q = À0.548, p < 0.001) and with 11-dehydro-TXB2 (q = À0.523, p < 0.001). In a linear regression model, KS independently predicted a lower AC-50% (b = À0.597, p < 0.001) and higher levels of 8-iso-PGF2a (b = 0.709, p < 0.001) and 11-dehydro-TXB2 (b = 0.605, p < 0.001). In contrast, no correlation has been found between max-A%, testosterone and estradiol levels in KS. We observed increased platelet reactivity in KS. This might, at least in part, explain the increased thrombotic risk associated with this disease.

Klinefelter Syndrome: Integrating Genetics, Neuropsychology, and Endocrinology

“…Furthermore, Di Minno et al recently demonstrated increased platelet aggregation in testosterone-treated men with KS compared with controls (144). We, on the other hand, have in an ongoing study found no evidence for increased platelet aggregation in a group of untreated men with KS (155).…”

Klinefelter syndrome and testosterone treatment: a national cohort study on thrombosis risk

“…Thrombotic risk in men with KS could be affected directly by the presence of an extra X chromosome, subsequent hypogonadism, and the induction of a vicious cycle of truncal obesity and insulin insensitivity (1,13). This unfavourable metabolism then leads to increased risk of disease entities associated with cardiovascular risk and furthermore skewing of the haemostatic balance (14) and increased platelet aggregation (15). Testosterone treatment could reduce thrombotic risk by counteracting the vicious metabolic cycle present in KS (16).…”

Klinefelter syndrome: cardiovascular abnormalities and metabolic disorders

“…In a recent study, twenty-three consecutive KS patients under testosterone replacement therapy were included in a case control study to evaluate platelet reactivity and the expression of platelet activation markers (8-iso-prostaglandin F2a[8-iso-PGF2a] and 11-dehydro-thromboxane-B2[11-dehydro-TXB2]). The authors found increased platelet reactivity in KS and no correlation between the percentage of maximal aggregability, testosterone and estradiol levels [32].…”

“…Several observational studies, published in the last 40 years, have highlighted a close association between KS, metabolic diseases and T2DM. Moreover, these metabolic diseases, in association with other important disorders (such as lung and cerebrovascular diseases, thrombotic events, and osteoporosis), contribute in increasing mortality of patients with KS [5,32].…”

“…In adult KS patients, several studies have shown an elevated prevalence of MetS (diagnosed by the National Cholesterol Education Program criteria), hyperlipidaemia (especially hypertriglyceridaemia) insulin resistance and hyperinsulinemia, and even overt T2DM [42][43][44]. These patients have an increased cardiovascular risk that cannot be only referred to these metabolic conditions, but also, at least in part, to an increased platelet activity [32]. Conversely, blood hypertension is not a frequent finding in patients with KS as recently reported [11].…”