Use of hyperthermia in the treatment of cancer and viral infection has received renewed interest. However, the in vivo relationship between hyperthermia and direct versus indirect effects upon hemostasis are incompletely defined, although we do know that disseminated intravascular coagulation (DIC) is a common sequel to heat stroke. The purpose of the present study was to more precisely define the relationship between hyperthermia and derangements of hemostasis, thereby providing a guideline for the development of safe hyperthermia treatment regimens. The present investigation examined the in vivo effects of high-grade whole-body hyperthermia (WBH) (42.5 degrees C, 90 min) on hemostasis in a canine model. Induction of hyperthermia via extracorporeal circulation of heated blood (ECC-WBH) caused thrombocytopenia, increased plasma fibrin degradation products (FDPs), prolonged clotting times, increased serum liver enzymes, and evidence of spontaneous bleeding. However, when WBH was induced by peritoneal lavage (PL-WBH), transient thrombocytopenia was the only significant alteration. Temporal correlation between hemostatic alterations and elevations in serum alanine aminotransferase (ALT) levels in the ECC-WBH treatment group suggested that liver injury is responsible, at least in part, for the coagulopathy associated with high-grade hyperthermia and that in the absence of liver injury, identical degrees of hyperthermia cause only incidental decreases in platelet numbers.