Iron-Induced Fibrin in Cardiovascular Disease

Abstract

Accumulating evidence within the last two decades indicates the association between cardiovascular disease (CVD) and chronic inflammatory state. Under normal conditions fibrin clots are gradually degraded by the fibrinolytic enzyme system, so no permanent insoluble deposits remain in the circulation. However, fibrinolytic therapy in coronary and cerebral thrombosis is ineffective unless it is installed within 3-5 hours of the onset. We have shown that trivalent iron (FeIII) initiates a hydroxyl radical-catalyzed conversion of fibrinogen into a fibrin-like polymer (parafibrin) that is remarkably resistant to the proteolytic dissolution and thus promotes its intravascular deposition. Here we suggest that the persistent presence of proteolysis-resistant fibrin clots causes chronic inflammation. We study the effects of certain amphiphilic substances on the iron- and thrombin-induced fibrinogen polymerization visualized using scanning electron microscopy. We argue that the culprit is an excessive accumulation of free iron in blood, known to be associated with CVD. The only way to prevent iron overload is by supplementation with iron chelating agents. However, administration of free radical scavengers as effective protection against persistent presence of fibrin-like deposits should also be investigated to contribute to the prevention of cardiovascular and other degenerative diseases.

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

“…We found that the thrombelastographic, kinetic sine quo non of iron was a decrease in the onset time of coagulation and an increase in the velocity of thrombus growth [18]. The SEM signature of thrombi exposed to this small concentration of iron [18] demonstrated the typical changes previously mentioned [1][2][3][4][5][6]. Thus, the purpose of this study was to evaluate the effects of deferoxamine-mediated chelation on ironexposed plasma with thrombelastographic and SEMbased analyses.…”

“…When blood or plasma is exposed to iron addition, characteristic changes in thrombus formation are observed, which include fusion of fibrin polymers, matting, and even sheeting of fibrin [1][2][3][4][5][6]. This scanning electron micrographic (SEM) signature has also been documented in thrombi obtained from patients with diseases involving chronic iron overload [1,2,7,8].…”

Iron and carbon monoxide enhance coagulation and attenuate fibrinolysis by different mechanisms

“…HO-1 activity is also increased systemically in inflammatory disorders associated with thrombophilia, such as diabetes mellitus [21] and rheumatoid arthritis [22]. Critically, SEM-based investigations demonstrated that the fibrin matrix formed from blood obtained from individuals with diabetes mellitus [23] or rheumatoid arthritis [24] was very similar to that observed when normal blood was exposed to ferric chloride [2][3][4][5][6][7]. In a complementary fashion, using a viscoelastic methodology validated to detect carbon monoxide-mediated hypercoagulability in the setting of tobacco smoking [25], it was determined that a patient with a clotted ventricular assist device and hemolysis had carbon monoxide-mediated hypercoagulability, and upregulation of HO-1 was documented by increased carboxyhemoglobin concentrations [26].…”

“…First, it was posited, and then determined that iron modified fibrinogen, which enhanced coagulation and attenuated fibrinolysis as documented by spectrophotometric and scanning electron micrographic (SEM) techniques [1][2][3][4][5][6][7]. Second, it was serendipitously discovered that carbon monoxide enhanced fibrinogen-dependent coagulation via an associated heme(s) group and attenuated fibrinolysis via upregulation of a 2 -antiplasim activity and downregulation of plasmin activity via enzyme-associated heme(s) [8][9][10][11][12][13][14].…”

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

“…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. 3 and YCl 3 (final concentration 15 mM) were mixed with platelet rich plasma (PRP) from 6 healthy individuals prepared from blood drawn in citrate tubes.…”