What is the role of coumarins in blood clotting?

Coumarin (1,2-benzopyrone or 2H-1-benzopyran-2-one) and coumarin derivatives are natural compounds widely available in plants as a heteroside or free form. A total of 800 coumarin derivative compounds that were naturally found were obtained from about 600 genera of 100 families to date. Coumarin and its derivatives are frequently found in the seeds, roots and leaves of many plant species belonging to families (especially Rutaceae and Apiaceae) in the Dicotyledonae class of the division of Spermatophyta. It was originally isolated from Melilotus officinalis and is a natural substance in plants. Coumarin is widely found in cinnamon, soybean sprouts, strawberries, and cherries.

Coumarin can be used as a spice and in medicine as a flavouring agent. The coumarin derivative warfarin is used to kill rodents, and this drug has anticoagulant functions. Coumarin drugs are structurally similar to vitamin K. Coumarin-like drugs bind to vitamin K epoxide reductase complex 1 in the liver and block the conversion of inactive oxidative vitamin K into active reducing vitamin K. Active vitamin K is involved in the effects of coagulation factors II (reducing prothrombin production), VII, IX, and X. One side effect of warfarin is bleeding, which may be caused by its interaction with other drugs or food, resulting in enhanced anticoagulation effect. Coumarins are effective for the prevention and treatment of venous and arterial thrombosis but may cause bleeding (especially if overdosed) or thrombosis (especially if under-dosed)[1].

Hemostasis is a process in which a series of reactions occur in the body to stop wound bleeding. The process of hemostasis is divided into three steps: vascular spasm, platelet plug formation, and clot formation. Coagulation is part of the hemostasis process. Coagulation (or clotting) is how blood thickens into a gel-like consistency. This is the body’s way of stopping bleeding when needed. The coagulation cascade is divided into intrinsic and extrinsic pathways, which converge to a final common pathway to activate factor X, leading to fibrin formation. The intrinsic pathway consists of factors I, II, IX, X, XI, and XII. The extrinsic pathway consists of factors I, II, VII, and X. The common pathway consists of factors I, II, V, VIII, and X. Many factors circulate in the blood as zymogens and are activated into serine proteases. These serine proteases act as catalysts, cleaving the next zymogen into more serine proteases and finally activating fibrinogen. Researchers have explored the anticoagulant mechanism of coumarin derivatives primarily to inhibit the activation of coagulation factors[2].

Lu et al. investigated the effects of six coumarin derivatives on the platelet aggregation induced by adenosine diphosphate (ADP). We found that the six coumarin derivatives inhibited the active form of GPIIb/IIIa on platelets and hence inhibited platelet aggregation. We found that 7-hydroxy-3-phenyl 4H-chromen-4-one (7-hydroxyflavone) had the most severe effect. In addition, the downstream signal transduction of the ADP receptor was further analyzed, including the release of calcium ions and the regulation of cAMP, which were inhibited by the six coumarin derivatives selected in this study. These results suggest that coumarin derivatives inhibit coagulation by inhibiting the synthesis of coagulation factors and may also inhibit platelet aggregation.

References

[1] F. DENTALI, M. CROWTHER, W. AGENO. “Treatment of coumarin-associated coagulopathy: a systematic review and proposed treatment algorithms.” Journal of Thrombosis and Haemostasis 4 9 (2006): 1853–1863.

[2] Ping-Hsun Lu. “Coumarin Derivatives Inhibit ADP-Induced Platelet Activation and Aggregation.” Molecules (2022).