A novel method for assessing the role of iron and its functional chelation in fibrin fibril formation: the use of scanning electron microscopy

Pretorius, Etheresia; Vermeulen, Natasha; Bester, Janette; Lipiński, Bogusław; Kell, Douglas B.

doi:10.3109/15376516.2012.762082

Cited by 62 publications

(64 citation statements)

References 70 publications

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“…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].…”

Section: Introductionmentioning

confidence: 95%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Nielsen

Pretorius

2014

Blood Coagulation &Amp; Fibrinolysis

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Two parallel lines of investigation elucidating novel mechanisms by which iron (scanning electron microscopy-based) and carbon monoxide (viscoelastic-based) enhance coagulation and diminish fibrinolysis have emerged over the past few years. However, a multimodal approach to ascertain the effects of iron and carbon monoxide remained to be performed. Such investigation could be important, as iron and carbon monoxide are two of the products of heme catabolism via heme oxygenase-1, an enzyme upregulated in a variety of disease states associated with thrombophilia. Human plasma was exposed to ferric chloride, carbon monoxide derived from carbon monoxide-releasing molecule-2, or their combination. Viscoelastic studies demonstrated ferric chloride and carbon monoxide mediated enhancement of velocity of growth, and final clot strength, with the combination of the two molecules noted to have all the prothrombotic kinetic effects of either separately. Parallel ultrastructural studies demonstrated separate types of fibrin polymer cross-linking and matting in plasma exposed to ferric chloride and carbon monoxide, with the combination sharing features of each molecule. In conclusion, we present the first evidence that iron and carbon monoxide interact with key coagulation and fibrinolytic processes, resulting in thrombi that begin to form more quickly, grow faster, become stronger, and are more resistant to lysis.

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Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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

Nielsen

Pretorius

2014

Blood Coagulation &Amp; Fibrinolysis

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“…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.…”

Section: Electrostatic Considerationsmentioning

confidence: 99%

“…Fibrin fibres were prepared for SEM according to methods published previously. 359,360 SEM analysis of healthy fibrin fibre morphology (Fig. 8A) shows individual fibres that form a typical netlike structure.…”

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confidence: 99%

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

Kell

Pretorius

2014

Integrative Biology

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Although the two phenomena are usually studied separately, we summarise a considerable body of literature to the effect that a great many diseases involve (or are accompanied by) both an increased tendency for blood to clot (hypercoagulability) and the resistance of the clots so formed (hypofibrinolysis) to the typical, 'healthy' or physiological lysis. We concentrate here on the terminal stages of fibrin formation from fibrinogen, as catalysed by thrombin. Hypercoagulability goes hand in hand with inflammation, and is strongly influenced by the fibrinogen concentration (and vice versa); this can be mediated via interleukin-6. Poorly liganded iron is a significant feature of inflammatory diseases, and hypofibrinolysis may change as a result of changes in the structure and morphology of the clot, which may be mimicked in vitro, and may be caused in vivo, by the presence of unliganded iron interacting with fibrin(ogen) during clot formation. Many of these phenomena are probably caused by electrostatic changes in the iron-fibrinogen system, though hydroxyl radical (OH ) formation can also contribute under both acute and (more especially) chronic conditions. Many substances are known to affect the nature of fibrin polymerised from fibrinogen, such that this might be seen as a kind of bellwether for human or plasma health. Overall, our analysis demonstrates the commonalities underpinning a variety of pathologies as seen in both hypercoagulability and hypofibrinolysis, and offers opportunities for both diagnostics and therapies.

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“…The coagulation cascade is the vital component that maintains the balance required for hemostasis by activating platelets and forming a hemostatic platelet plug as well as stabilizing fibrin networks, contributing to blood clot formation [27,28]. Laboratory-based investigations of fibrin structures, platelet morphology, and the fibrin clot in general has become a popular and powerful research tool as these structural findings could differ in and provide essential information on various diseased states possibly contributing to the discovery of new therapeutic targets [29,30].…”

Section: Discussionmentioning

confidence: 99%

The Effect of Sibutramine, a Serotonin-Norepinephrine Reuptake Inhibitor, on Platelets and Fibrin Networks of Male Sprague-Dawley Rats: A Descriptive Study

Schoor¹,

Oberholzer²,

Bester³

et al. 2014

Ultrastructural Pathology

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Sibutramine is used in the treatment of obesity due to its ability to influence feelings of hunger and satiety by inhibiting the re-uptake of serotonin and noradrenalin in the central nervous system (CNS). Sibutramine use has been associated with numerous adverse events in particular cardiovascular complications possibly due to the formation of thrombi. This ultrastructural descriptive study investigated the effect of sibutramine on blood coagulation, specifically the effect on morphology of platelets and fibrin networks using scanning electron microscopy. Male Sprague-Dawley rats treated with either a recommended therapeutic dose [low dosage 1.32 mg/kg] or a toxicological higher dose [high dosage 13.2 mg/kg] of sibutramine for 28 days were used and compared to control animals. Blood samples were collected and plasma smears were prepared for platelet evaluation. Following the addition of thrombin to the plasma samples, the morphology of the fibrin clots was evaluated. Platelet evaluation by scanning electron microscopy revealed morphology typical of a prothrombotic state with a characteristic excessive platelet activation in both low-dose (LD) and high-dose (HD) rats. The fibrin clots of sibutramine-treated rats, LD and HD revealed fused thick fibers with thin fibers forming a netlike structure over the thick fibers which differ considerably from the organized structure of the control animals. It can be concluded that sibutramine alters the ultrastructure of platelets and fibrin networks creating a prothrombotic state.

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A novel method for assessing the role of iron and its functional chelation in fibrin fibril formation: the use of scanning electron microscopy

Cited by 62 publications

References 70 publications

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

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

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

The Effect of Sibutramine, a Serotonin-Norepinephrine Reuptake Inhibitor, on Platelets and Fibrin Networks of Male Sprague-Dawley Rats: A Descriptive Study

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