Iron-enhanced coagulation is attenuated by chelation A thrombelastographic and ultrastructural analysis

Abstract

bIncreased circulating ferritin and free iron have been found in a variety of disease states associated with thrombophilia. When blood or plasma is exposed to iron addition, characteristic changes in thrombus formation are observed by scanning electron microscopy, which include fusion of fibrin polymers, matting, and even sheeting of fibrin. A primary mechanism posited to explain iron-mediated hypercoagulability is hydroxyl radical formation and modification of fibrinogen; however, iron has also been demonstrated to bind to fibrinogen. We have recently demonstrated that iron enhances coagulation, manifested as a decrease in the time of onset of coagulation. Using clinically encountered concentrations of iron created by addition of FeCl 3 to human plasma, we demonstrated that iron-mediated changes in reaction time determined by thrombelastography or changes in thrombus ultrastructure were significantly, but not completely, reversed by iron chelation with deferoxamine. Thus, reversible iron binding to fibrinogen mechanistically explains a significant portion of coagulation kinetic and ultrastructural hypercoagulability. Further investigation is needed to determine whether residual iron binding or other iron-mediated effects is responsible for hypercoagulability observed after chelation.

The simultaneous occurrence of both hypercoagulability and hypofibrinolysis in blood and serum during systemic inflammation, and the roles of iron and fibrin(ogen)

“…149,380,381 As one would also expect from Debye-Hückel theory, it binds divalent cations such as Ca 2+ 380,392,398,399 and Zn 2+ 404 ; the trivalent iron ion is especially effective. 389,406 It has also been suggested that added ferric iron can carry out Fenton chemistry by reacting with peroxide that may be formed in a variety of ways. 171,353,359,407,408 Thus both electrostatic phenomena and hydroxyl radical formation may modify the fibrinogen structure in such a way that its kinetics of polymerisation, and the structure of the fibrin products, is altered substantially.…”

Effect of Iron and Carbon Monoxide on Fibrinogenase‐like Degradation of Plasmatic Coagulation by Venoms of Six Agkistrodon Species

“…Specifically, it has been revealed that plasmatic fibrinogen exposed to iron and CO forms thrombi that are structurally different from plasma without such exposures, and coagulation commences earlier, with greater formation velocity and final clot strength compared to clots that are iron-and CO-na€ ıve [19]. CO binds to haeme(s) bound to fibrinogen [20], and iron and haeme have been found to bind to fibrinogen by other investigators [21], with chelation of iron noted to reverse both structural and coagulation kinetic changes in plasma thrombi [22]. Iron and CO enhance fibrinogen by separate mechanisms; iron decreases the time to onset of coagulation and increases the velocity of clot formation without affecting final clot strength, whereas CO increases the velocity of clot formation and increases clot strength without affecting the time to onset of coagulation [19].…”

Novel Diagnostic and Monitoring Tools in Stroke: an Individualized Patient-Centered Precision Medicine Approach

“…To prepare PPP, citrated WB samples are centrifuged for 15 min at 227.5 g, plasma is aspirated into Eppendorf tubes, which are once again centrifuged at 5600 g for 10 min. PPP techniques are described in detail in selected references [33][34][35][36] . PPP is typically frozen for at least 24 h (or longer until enough samples for a particular study have been collected), thawed, and then exposed to calcium as described above.…”