Figure 1.

Infusion of heme in different formulations (i.e., hematin, hemin, heme arginate (Normosang^®), Panhematin^®) leads to coagulation disorders in animals (1911–1978; rats, guinea pigs, rabbits, cats, and dogs) and humans (1975–2015). Heme infusions of rather high concentrations (10–180 mg/kg) were shown to cause bleeding symptoms in animals, such as hemorrhage and coagulopathy, whereas administration of comparatively low concentrations (1.2–6 mg/kg) resulted in prothrombotic symptoms, such as vaso-occlusion and thrombophlebitis. The transition between bleeding and thrombotic events seems to be smooth, since there are also studies that report both effects in the same study (10–25 mg/kg hematin) [141,143]. Moreover, there are single exceptions (three studies) that also report bleeding upon administration of lower hematin (3.5–9 mg/kg) [140,162] or heme arginate (2–3 mg/kg) [168] concentrations.