BLOOD-COAGULATION AND ACUTE IRON TOXICITY - REVERSIBLE IRON-INDUCED INACTIVATION OF SERINE PROTEASES INVITRO

  • 1 January 1984
    • journal article
    • research article
    • Vol. 103  (4) , 524-533
Abstract
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 Fe concentration comparable to those of previous animal investigations, coagulopathy [the dose-related prolongation of the prothrombin, thrombin and partial thromboplastin time, in human plasma] was reproduced in vitro. Studies of the mehcanism by which Fe prevents a normal plasma coagulation revealed that the proenzymes of the coagulation cascade and fibrinogen were not damaged by Fe. Fibrinogen coagulability and fibrin monomer aggregation were unaffected by very high Fe concentrations. Thrombin was markedly inhibited by Fe in its clotting effect on fibrinogen and, specifically, in its fibrinopeptide A-generating capacity, the inhibitory effect being reversible on Fe removal by EDTA chelation and gel filtration. Thrombin generation in the presence of Fe was reduced as well, indicating an inhibition of 1 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 (Fe3+) citrate, is likely that the coagulopathy occurring in Fe poisoning is the consequence of a general, physiologically important phenomenon: the susceptibility of serine proteases to nontransferrin-bound Fe3+.