Blood coagulation and acute iron toxicity. Reversible iron-induced inactivation of serine proteases in vitro.
Coagulopathy is a hallmark of severe ferrous sulfate poisoning in humans and laboratory animals. Although nontransferrin-bound Fe3+ is thought to initiate the disorder, little is known about how it interferes with blood coagulation. At iron concentrations comparable to those of previous animal investigations, we reproduced the coagulopathy, in other words, the dose-related prolongation of the prothrombin, thrombin, and partial thromboplastin time, in human plasma in vitro. Studies of the mechanism by which iron prevents a normal plasma coagulation revealed that the proenzymes of the coagulation cascade and fibrinogen were not damaged by iron. Fibrinogen coagulability and fibrin monomer aggregation were unaffected by very high iron concentrations. Instead, thrombin was markedly inhibited by iron in its clotting effect on fibrinogen and, specifically, in its fibrinopeptide A-generating capacity, the inhibitory effect being reversible upon iron removal by EDTA chelation and gel filtration. Thrombin generation in the presence of iron was reduced as well, indicating an inhibition of one or several other enzymes of the intrinsic coagulation cascade. Because the amidolytic activity of human thrombin as well as factor Xa, kallikrein, and bovine trypsin was also reversibly suppressed by ferrous sulfate as well as ferric citrate, we consider it likely that the coagulopathy occurring in iron poisoning is the consequence of a general, physiologically important phenomenon: the susceptibility of serine proteases to nontransferrin-bound Fe3+.
D000814:Aniline Compounds / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects*; D002850:Chromatography, Gel; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000494:pharmacology; D005296:Ferrous Compounds / Q000506:poisoning*; D005340:Fibrinogen / Q000378:metabolism; D005344:Fibrinopeptide A / Q000096:biosynthesis; D006801:Humans; D066298:In Vitro Techniques; D007501:Iron / Q000506:poisoning*; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; D013917:Thrombin / Q000096:biosynthesis
D000814:Aniline Compounds; D005296:Ferrous Compounds; D011480:Protease Inhibitors; C019498:4-nitroaniline; D005344:Fibrinopeptide A; C020748:ferrous sulfate; D005340:Fibrinogen; D004492:Edetic Acid; D007501:Iron; D012697:Serine Endopeptidases; D013917:Thrombin