Hemorrhage-inducing activity

TNF was originally identified because of its cytotoxic activity against some tumor cell lines and its ability to induce hemorrhagic necrosis of solid tumors in various animal models. However, the clinical use of TNF as an anticancer drug has been so far limited by its severe cardiovascular side effects. Therefore, TNF treatment is limited to regional and local administration of high doses of TNF, often in combination with chemotherapy, as accomplished in isolated limb and isolated hepatic perfusion (ILP and IHP, respectively) [5]. In the case of ILP, typically metastases are treated, patients benefit from this procedure by salvage of limbs from a loss by amputation. 

Asahi M, Asahi K, Wang X, Lo EH. Reduction of tissue plasminogen activator-induced hemorrhage and brain injury by free radical spin trapping after embolic focal cerebral ischemia in rats. J Cereb Blood Flow Metab 2000 20 452 57. 

Absolute contraindications to warfarin include active bleeding, hemorrhagic tendencies, pregnancy, and a history of warfarin-induced skin necrosis. It should be used with great caution in patients with a history of GI bleeding, recent neurosurgery, alcoholic liver disease, severe renal... 

Exposure of rats to carbon tetrachloride (up to 160 mg/kg/day for 10 days) by gavage did not alter the primary antibody response to sheep red blood cells, lymphoproliferative responses to mitogen or mixed leukocytes, natural killer cell activity, or cytotoxic T lymphocyte responses also, spleen and thymus weights were comparable to controls (Smialowicz et al. 1991). In rats exposed twice weekly for 4-12 weeks to 3,688 mg/kg/day, there was histologic evidence of hemorrhage, hemosiderin deposition, and lymphocyte depletion in the pancreaticoduodenal lymph node (Doi et al. 1991), an effect which may be secondary to induced hepatic damage. 

We speculate that ischemia induces changes in the tubulo-interstitium by such factors as oxidative stress, apoptosis, an increase in intracellular Ca, complement activation, ICAM-1 expression, and inflammation, in a region controlled by the blood vessels, thereby influencing the blood vessels and prolonging vascular spasm. Coronary spasm persists for 15min, and cerebrovascular spasm in the presence of subarachnoid hemorrhage persists for a week in some patients. Therefore, renovascular spasm may persist for a long period. 

It is interesting to note that following spontaneous subarachnoid hemorrhage (SAH), body temperature falls and then rises immediately after the SAH-induced transient global cerebral ischemia without cardiac arrest (57). This may be a natural cerebral protection mechanism activated by the body shortly after the insult. 

There is also experimental evidence that central DA neurons may be involved in inhibiting activated vasopressin secretion. In normal hydrated rats icv administration of DA suppresses anesthesia-induced vasopressin secretion (Forsling and Williams, 1984). Conversely, icv injection of a DA antagonist enhances vasopressin secretion in response to hemorrhage (Yamaguchi et al., 1990). No information is availability, however, regarding the identity of diencephalic neurons mediating the suppressive effects of DA on stimulated vasopressin release. 

Our understanding on the underlying mechanism of this novel cancer treatment was significantly advanced by the discovery in 1975 that bacterial endotoxin induced the production and release of an anti-tumor activity from host cells like macrophages. This activity caused hemorrhagic necrosis of transplanted tumors in mice and killed transformed cell lines (Carswell et al, 1975). The promise of TNF as a cancer cure prompted many laboratories to search the molecular identity of TNF, which eventually led to the purification, characterization and cloning of TNF (Beutler and Cerami, 1986 Pennica et al., 1984 Shirai et al., 1985 Wang et al, 1985). 

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