The Gilded Clot: Review of Metal-Modulated Platelet Activation, Coagulation, and Fibrinolysis

Abstract

The processes of blood coagulation and fibrinolysis that in part maintain the physical integrity of the circulatory system and fluidity of its contents are complex as they are critical for life. While the roles played by cellular components and circulating proteins in coagulation and fibrinolysis are widely acknowledged, the impact of metals on these processes is at best underappreciated. In this narrative review we identify twenty-five metals that can modulate the activity of platelets, plasmatic coagulation, and fibrinolysis as determined by in vitro and in vivo investigations involving several species besides human beings. When possible, the molecular interactions of the various metals with key cells and proteins of the hemostatic system were identified and displayed in detail. It is our intention that this work serve not as an ending point, but rather as a fair evaluation of what mechanisms concerning metal interactions with the hemostatic system have been elucidated, and as a beacon to guide future investigation.

Keywords: activated partial prothrombin time; coagulation; fibrinogen; fibrinolysis; metal poisoning; metals; platelets aggregation; prothrombin time; thrombelastography.

Figure 1

Structures of various metal-containing compounds. Panel (A)—the metal cation contained in these four compounds is likely to directly bind to protein targets. Panel (B)—the metalloid and metal depicted in these two molecules are not likely to directly interact with proteins. As = arsenic, Ca = calcium, Cl = chloride, Fe = iron, Ga = gallium, Na = sodium, NH₃ = ammonia, NO₃ = nitrate, O = oxygen, Pt = platinum and W = tungsten.

Figure 2

Effects of metals on platelet activation. Metals depicted in green enhance activation, those displayed in red decrease activation, and elements that are blue have conflicting effects on platelet activation that may be concentration-dependent or dependent on the species source of the platelets.

Figure 3

Effects of metals on coagulation. Metals depicted in green enhance coagulation, those displayed in red decrease clotting, and elements that are blue have conflicting effects on coagulation that may be concentration-dependent or dependent on the species source of the plasma or blood. Metals seen at the top of the figure with the * are those without a specific site in the coagulation pathways identified. All metals have been defined in the text, but the depiction of iron was changed to improve the visual presentation. Fe⁺² = Fe(II) and Fe⁺³ = Fe(III). Please refer to the text for greater details about the specific coagulation enzymes and pathways depicted.

Figure 4

Effects of metals on fibrinolysis. Metals depicted in green enhance fibrinolysis, those displayed in red decrease clot dissolution, and elements that are blue have conflicting effects on fibrinolysis that may be concentration-dependent or dependent on the species source of the plasma or blood. Metals seen at the top of the figure with the * are those without a specific site in the fibrinolytic pathways identified. Green arrows indicate that the enzyme increases the indicated reaction and red arrows indicate that the enzyme inhibits the pathway indicated. All metals have been defined in the text, but the depiction of iron was changed to improve the visual presentation. Fe⁺² = Fe(II) and Fe⁺³ = Fe(III). Please refer to the text for greater details about the specific fibrinolytic enzymes and pathways depicted.