Unusual clotting dynamics of plasma supplemented with iron(III)

Abstract

Abstract. Iron salts are used in the treatment of iron deficiency anemia. Diabetic patients are frequently anemic and treatment includes administration of iron. Anemic patients on hemodialysis are at an increased risk of thromboembolic coronary events associated with the formation of dense fibrin clots resistant to fibrinolysis. Moreover, in chronic kidney disease patients, high labile plasma iron levels associated with iron supplementation are involved in complications found in dialyzed patients such as myocardial infarction. The aim of the present study was to investigate whether iron treatment is involved in the formation of the fibrin clots. Clotting of citrated plasma supplemented with Fe 3+ was investigated by thromboelastometry and electron microscopy. The results revealed that iron modifies coagulation in a complex manner. FeCl 3 stock solution underwent gradual chemical modification during storage and altered the coagulation profile over 29 days, suggesting that Fe 3+ interacts with both proteins of the coagulation cascade as well as the hydrolytic Fe 3+ species. Iron extends clotting of plasma by interacting with proteins of the coagulation cascade. Fe 3+ and/or its hydrolytic species interact with fibrinogen and/or fibrin changing their morphology and properties. In general FeCl 3 weakens the fibrin clot while at the same time precipitating plasma proteins immediately after application. Fe 3+ or its derivatives induced the formation of insoluble coagulums in non-enzymatic reactions including albumin and transferrin. Iron plays a role in coagulation and can precipitate plasma proteins. The formation of coagulums resistant to lysis in non-enzymatic reactions can increase the risk of thrombosis, and extending clotting of plasma can prolong bleeding.

Evaluation of hypercoagulability with rotational thromboelastometry in children with iron deficiency anemia

“…The presence of a negative correlation between iron levels and MCF may mean, theoretically, that the clot firmness would decrease is iron levels increase, the reason for which may be hidden in the in vitro studies evaluating changes in the coagulation system due to the presence of iron ions. Jankun et al demonstrated that the in vitro addition of Fe +3 into the plasma resulted in prolonged coagulation and a relatively unstable fibrin formation, as a result of its interaction with the proteins of the coagulation cascade in the early period [37]. Platelet aggregation and thrombin levels were demonstrated to be decreased, and the clotting capacity of fibrinogen was found to be impaired when ferrous sulphate was added to plasma [38].…”

Coagulatory Defects in Type-1 and Type-2 Diabetes

“…Individuals with T1DM are deficient in iron; diabetes duration or sex had no influence on iron deficiency, but the menstrual cycle did [99,100]. For those individuals deficient in iron, treatment includes supplementation with Fe 3+ salt [101]. This has been shown to impact on coagulation by extending the clotting time of plasma (possibly by competing with calcium in binding coagulation factors), weakening the fibrin clot (by interacting with fibrinogen and fibrin), and inducing the precipitation of plasma proteins to form "insoluble coagulums" resistant to lysis (notably by binding and degrading serum albumin and possibly transferrin), thus increasing the risk of thrombosis [101].…”

“…For those individuals deficient in iron, treatment includes supplementation with Fe 3+ salt [101]. This has been shown to impact on coagulation by extending the clotting time of plasma (possibly by competing with calcium in binding coagulation factors), weakening the fibrin clot (by interacting with fibrinogen and fibrin), and inducing the precipitation of plasma proteins to form "insoluble coagulums" resistant to lysis (notably by binding and degrading serum albumin and possibly transferrin), thus increasing the risk of thrombosis [101]. In addition, Fe 3+ has been shown to initiate the conversion of fibrinogen into a fibrin-like polymer, parafibrin, that is resistant to proteolysis and so is deposited in blood vessels [102].…”

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

“…These molecules may interact with fibrinogen and change the mechanical properties of clots, which are essential to the effective function of fibrin. Clot properties that may vary include the pore size, fibrin diameter, rigidity, ease of fibrinolysis, and so on 208,396 (and some of these are correlated 361,397 ).…”