Thrombomodulin and catecholamines as post-mortem indicators of hypothermia

Abstract Hypothermia deaths pose a difficult challenge from the medico-legal point of view because no specific traces are left on the cadaver to be examined post-mortem. The concentrations of urinary catecholamines, adrenaline and noradrenaline increase in various stressful situations including cold stress, and high levels have been considered to be suggestive of lethal hypothermia. There is, however, a need for a better hypothermia indicator. A potential candidate could be thrombomodulin (TM), an endothelially expressed protein whose plasma concentration has been shown to elevate in response to hypothermia. TM and catecholamine levels were studied in short-term cold exposure (human subjects, n = 7), in mild and severe hypothermia with or without rewarming (rats, n = 96) and in hypothermia deaths compared with deaths from cardiovascular diseases, traumas and other causes (autopsy cases, total n = 552). Myocardial thrombomodulin transcript expression was increased in severely hypothermic rats, but was lower in hypothermia deaths than in other causes. The circulating TM level was transiently reduced in severe hypothermia. The myocardial and urinary TM protein levels were reduced in lethal hypothermia compared with other causes of death. TM and catecholamine levels correlated significantly in blood and urine both in living subjects and post-mortem examination. In severely hypothermic rats, there was an inverse relationship between plasma adrenaline concentration and myocardial thrombomodulin transcript level. The results suggest that TM expression and secretion are altered by hypothermia, possibly linked to the actions of catecholamines. Analysing the post-mortem catecholamine and TM levels provides evidence of ante-mortem cold stress in suspected hypothermia deaths. Further studies should be conducted in order to reveal the exact mechanisms behind the regulation of TM on cell level.%%%%Tiivistelma Paleltumiskuolemat ovat oikeuslaaketieteellisesti haastavia, koska vainajaan ei jaa paleltumiseen viittaavia yksiselitteisia loydoksia. Virtsan katekoliamiinien, adrenaliinin ja noradrenaliinin, pitoisuudet kasvavat stressitilanteissa kuten kylmaaltistuksessa. Korkeita pitoisuuksia on pidetty paleltumiseen viittaavana tekijana. Paremmalle paleltumista osoittavalle merkkiaineelle on kuitenkin selkea tarve. Eras mahdollinen merkkiaine voisi olla trombomoduliini (TM), joka on endoteelisolujen tuottama proteiini. Sen plasmapitoisuuden on aiemmin osoitettu nousevan alilampoisyystilassa. TM- ja katekoliamiinitasoja tutkittiin lyhyessa kylmaaltistuksessa (koehenkilot, n = 7) seka lievassa ja vaikeassa alilampoisyystilassa joko lammityksen jalkeen tai ilman lammitysta (rotat, n = 96). Lisaksi verrattiin paleltumisen, sydan- ja verisuonitautien, vammojen seka muiden syiden aiheuttamia kuolemia (ruumiinavausaineisto, n = 552). Sydanlihaksen trombomoduliini-transkriptin taso oli kohonnut vaikeasti alilampoisilla rotilla, mutta se oli matalampi paleltumiskuolemissa kuin muissa kuolemissa. Veren TM-taso oli hetkellisesti alentunut…