Activation of factor XII-dependent pathways in human plasma by hematin and protoporphyrin.

Intravenous administration of hematin is effective in the treat- ment of acute exacerbations of the inducible porphyrias. In the course of such treatment, coagulopathies have occurred that are characterized by prolongation of prothrombin time, partial thromboplastin time, and formation of fibrin split products. In experiments in vitro with normal human plasma, we observed that hematin and protoporphyrin activated Factor XII-dependent pathways of coagulation and fibrinolysis, and that they generated kallikrein activity. Incubation of protoporphyrin with purified Factor XII resulted in activation as measured by amidolysis of a chromogenic substrate. Neither coproporphyrin, uroporphyrin, 5-aminolevulinic acid, porphobilinogen, or bilirubin activated Factor XII-dependent pathways. Exposure of serum containing added uroporphyrin, coproporphyrin, and protoporphyrin, but not hematin, to ultraviolet light (405 nm) resulted in activation of the classical pathway of the complement system. On the other hand, exposure of plasma containing uroporphyrin or coproporphyrin to ultraviolet light did not result in activation of Factor XII-dependent pathways. are characterized by accumulation of heme precursors, which lead to a wide variety of sequelae, especially in the brain, liver, and skin, which occur via largely undefined mechanisms (1, 2). Injury to skin, particularly after solar exposure, is charac- teristic of congenital erythropoietic porphyria, protoporphyria, and porphyria cutanea tarda. Recent data suggest that the skin changes may be due to activation of the classical pathway of the complement system (3-6). Another group of porphyrias, the inducible porphyrias, is usually not associated with skin lesions. These patients profit from hematin injections in periods of exacerbations of their disease (7). In some patients, admin- istration of hematin has been associated with prolongation of prothrombin time, partial thromboplastin time (PTT), and evidence of fibrinolysis (8). These observations suggested to us that hematin and perhaps other porphyrin compounds might