Victims of lethal hypothermia have decreased levels of thrombomodulin in myocardium and urine

Abstract

Severe cold stress has been shown to cause changes in the expression and secretion of thrombomodulin (TM), an endothelial protein regulating haemostasis and inflammation. To further evaluate TM as a cold stress indicator, relative TM mRNA and TM protein levels in the myocardium and the concentrations of TM in serum and urine were analysed in different causes of death (hypothermia main cause, n = 80; hypothermia contributory cause, n = 26; cardiovascular disease (CVD) main cause, n = 94; trauma main cause, n = 45; other main cause, n = 25). Urinary catecholamine concentrations and myocardial heat shock factor 1 (HSF1) transcript levels were also studied. The TM mRNA and the TM protein levels in myocardium and urine were significantly lower in hypothermia deaths than those in the controls. Post-mortem interval did not correlate with urinary TM concentration. The sensitivity and specificity of urinary TM assay to detect hypothermia deaths were 70.8 and 70.3 %, respectively. Catecholamine concentrations in urine correlated significantly with TM concentration in urine and TM mRNA levels in all groups excluding CVD deaths. There were no differences in the HSF1 transcript levels and no correlation to TM levels. These findings provide further evidence that cold stress and hypothermia affect TM expression and secretion and that they are possibly linked to catecholamine action. Thus, measuring post-mortem TM levels may provide additional support to diagnosing hypothermia in medico-legal examination. The results may also provide additional knowledge for the treatment of hypothermic patients and the use of hypothermia for medical purposes.

Urinary thrombomodulin and catecholamine levels are interrelated in healthy volunteers immersed in cold and warm water

“…In our previously conducted study with rats, mild hypothermia was associated with lower urinary and higher circulating TM levels compared with severe hypothermia. 6 However, the urine of lethal hypothermia victims contained lower TM concentrations 7 than the baseline values measured in the present study. These findings would suggest that the elimination of TM is diminished in the first phases of cold exposure, possibly reflecting an increased need in the circulation.…”

“… 6 Significant correlations between TM and catecholamine levels were also seen in autopsy material. 7 These findings suggested that there could be a regulatory link between catecholamines and TM during severe cold exposure, possibly via protein kinase A signaling pathway.…”

“… 6 In autopsy material, lethal hypothermia was associated with low myocardial TM transcript and TM protein levels as well as low urinary TM level compared with other causes of death. 7 Furthermore, the circulating TM levels have been shown to increase in patients with induced milder hypothermia compared with normothermic patients after approximately a 2-hour period. 8 However, no changes were seen in healthy subjects immediately after a 10-minute dry cold exposure.…”

RNU6B, a frequent reference in miRNA expression studies, differentiates between deaths caused by hypothermia and chronic cardiac ischemia

“…Although the expression of RNUs has been found to be prone to variation in varying conditions, RNU6B has proved to be more stable than many other small ncRNAs in tumor pathology [16]. A reliable reference is needed also in hypothermia research, since cold temperature is known to alter gene expression levels [17][18][19][20]. We found Cq values of RNU6B to be significantly higher in hypothermia than in chronic ischemic heart disease in the myocardium.…”

Updated review of postmortem biochemical exploration of hypothermia with a presentation of standard strategy of sampling and analyses

“…Pakanen et al have described that lethal hypothermia is associated with low myocardial TM transcript and TM protein levels as well as low urinary TM level compared with other causes of death. They also demonstrate a postmortem stability of TM during at least 24 h. Using urinary TM as a biomarker, with a cut-off at 15.5 ng/mL, they found sensitivity and specificity at 70.8% and 70.3%, respectively [54].…”