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New Insights into the Pros and Cons of the Clinical Use of Vitamin K Antagonists (VKAs) Versus Direct Oral Anticoagulants (DOACs).

van Gorp RH, Schurgers LJ - Nutrients (2015)

Bottom Line: DOACs also display non-hemostatic vascular effects via protease-activated receptors (PARs).As atherosclerosis is characterized by a hypercoagulable state indicating the involvement of activated coagulation factors in the genesis of atherosclerosis, anticoagulation could have beneficial effects on atherosclerosis.Additionally, accumulating evidence demonstrates vascular benefit from high vitamin K intake.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. rick.vangorp@maastrichtuniversity.nl.

ABSTRACT
Vitamin K-antagonists (VKA) are the most widely used anticoagulant drugs to treat patients at risk of arterial and venous thrombosis for the past 50 years. Due to unfavorable pharmacokinetics VKA have a small therapeutic window, require frequent monitoring, and are susceptible to drug and nutritional interactions. Additionally, the effect of VKA is not limited to coagulation, but affects all vitamin K-dependent proteins. As a consequence, VKA have detrimental side effects by enhancing medial and intimal calcification. These limitations stimulated the development of alternative anticoagulant drugs, resulting in direct oral anticoagulant (DOAC) drugs, which specifically target coagulation factor Xa and thrombin. DOACs also display non-hemostatic vascular effects via protease-activated receptors (PARs). As atherosclerosis is characterized by a hypercoagulable state indicating the involvement of activated coagulation factors in the genesis of atherosclerosis, anticoagulation could have beneficial effects on atherosclerosis. Additionally, accumulating evidence demonstrates vascular benefit from high vitamin K intake. This review gives an update on oral anticoagulant treatment on the vasculature with a special focus on calcification and vitamin K interaction.

No MeSH data available.


Related in: MedlinePlus

Effects of vitamin K antagonists and direct oral anticoagulants on coagulation. (A) The coagulation cascade can be activated by both the intrinsic and extrinsic pathway, which finally results in activation of thrombin and subsequently fibrin formation. Vitamin K antagonists (VKA) induce anticoagulation via inhibiting activation of the coagulation factors depicted in red (factors X, IX, VII, and II). Direct oral anticoagulants (DOACs) induce anticoagulation via blocking the activity of coagulation factors Xa (rivaroxaban and apixaban) and IIa (dabigatran) depicted in blue; (B) Vitamin K cycle is required to carboxylate, and thus activate, vitamin K dependent proteins. Vitamin K is converted to vitamin hydroquinone (KH2), which is oxidized by γ-glutamylcarboxylase (3) to convert glutamate (Glu) residues in γ-carboxyglutamate (Gla) residues. This reaction results in vitamin K epoxide (K > O), which is recycled to vitamin K through vitamin K epoxide reductase (1). VKA disrupts the vitamin K cycle by inhibiting vitamin K epoxide reductase (VKOR) leading to depletion of vitamin K and uncarboxylated vitamin K dependent proteins. In the liver, the inhibition of warfarin can be circumvented via NAD(P)H quinone reductase (2), which can convert vitamin K into KH2 even in the presence of VKA. In extra-hepatic tissues NAD(P)H quinone reductase activity is ca. 100 fold less, resulting in inactive vitamin K dependent proteins in the presence of VKA; (C) DOACs induce anticoagulation via inhibiting the activity of FXa and FIIa via binding to the activation site.
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nutrients-07-05479-f001: Effects of vitamin K antagonists and direct oral anticoagulants on coagulation. (A) The coagulation cascade can be activated by both the intrinsic and extrinsic pathway, which finally results in activation of thrombin and subsequently fibrin formation. Vitamin K antagonists (VKA) induce anticoagulation via inhibiting activation of the coagulation factors depicted in red (factors X, IX, VII, and II). Direct oral anticoagulants (DOACs) induce anticoagulation via blocking the activity of coagulation factors Xa (rivaroxaban and apixaban) and IIa (dabigatran) depicted in blue; (B) Vitamin K cycle is required to carboxylate, and thus activate, vitamin K dependent proteins. Vitamin K is converted to vitamin hydroquinone (KH2), which is oxidized by γ-glutamylcarboxylase (3) to convert glutamate (Glu) residues in γ-carboxyglutamate (Gla) residues. This reaction results in vitamin K epoxide (K > O), which is recycled to vitamin K through vitamin K epoxide reductase (1). VKA disrupts the vitamin K cycle by inhibiting vitamin K epoxide reductase (VKOR) leading to depletion of vitamin K and uncarboxylated vitamin K dependent proteins. In the liver, the inhibition of warfarin can be circumvented via NAD(P)H quinone reductase (2), which can convert vitamin K into KH2 even in the presence of VKA. In extra-hepatic tissues NAD(P)H quinone reductase activity is ca. 100 fold less, resulting in inactive vitamin K dependent proteins in the presence of VKA; (C) DOACs induce anticoagulation via inhibiting the activity of FXa and FIIa via binding to the activation site.

Mentions: In 1856 Rudolf Virchow, often regarded as the founder of modern pathology, delineated three major components that were responsible for the formation of emboli in the venous circulation. These three elements, now known as Virchow’s triad, can be briefly summarized as: (1) changes in the composition of blood; (2) alterations in the vessel wall; and (3) disruption of the blood flow. Coagulation is a protective response after vascular injury to prevent bleeding [1] and can be initiated via either the so-called intrinsic or extrinsic pathways, which although simplistic, are still useful schematic models of the coagulation process (Figure 1a). Both pathways are characterized by a series of enzymatic events whereby the activation of members of a hierarchical chain of coagulation enzymes (called coagulation factors) are successively activated by the preceding factor in the chain. Although the initiation steps are different, both pathways converge and lead to activation of pro-thrombin (FII) to produce thrombin (FIIa). An important feature of this coagulation cascade is that it functions as a biochemical amplifier [2] in which the final product, thrombin catalyses the production of fibrin which forms a meshwork clot [3]. The coagulation events leading to the formation of a blood clot (thrombus) that adheres to the wall of a blood vessel and obstructs the flow of blood is termed thrombosis. Thrombosis can take place in both arteries and veins. Atherothrombosis is the term describing the occlusion of a blood vessel by a ruptured atherosclerotic plaque [4,5]. Arterial thrombosis can lead to stroke and myocardial infarction. In contrast to arterial thrombosis, venous thrombosis is associated with dysregulation of coagulation proteins and manifests in deep-vein thrombosis and pulmonary embolism [6]. Obesity and diabetes mellitus are risk factors for both arterial and venous thrombosis whereas other risk factors such as smoking, hypertension and hyperlipidemia increase only the risk for arterial thrombosis [6]. Oral anticoagulant drugs are prescribed to patients to reduce the risk and incidence of both arterial and venous thrombosis, although mainly for the latter.


New Insights into the Pros and Cons of the Clinical Use of Vitamin K Antagonists (VKAs) Versus Direct Oral Anticoagulants (DOACs).

van Gorp RH, Schurgers LJ - Nutrients (2015)

Effects of vitamin K antagonists and direct oral anticoagulants on coagulation. (A) The coagulation cascade can be activated by both the intrinsic and extrinsic pathway, which finally results in activation of thrombin and subsequently fibrin formation. Vitamin K antagonists (VKA) induce anticoagulation via inhibiting activation of the coagulation factors depicted in red (factors X, IX, VII, and II). Direct oral anticoagulants (DOACs) induce anticoagulation via blocking the activity of coagulation factors Xa (rivaroxaban and apixaban) and IIa (dabigatran) depicted in blue; (B) Vitamin K cycle is required to carboxylate, and thus activate, vitamin K dependent proteins. Vitamin K is converted to vitamin hydroquinone (KH2), which is oxidized by γ-glutamylcarboxylase (3) to convert glutamate (Glu) residues in γ-carboxyglutamate (Gla) residues. This reaction results in vitamin K epoxide (K > O), which is recycled to vitamin K through vitamin K epoxide reductase (1). VKA disrupts the vitamin K cycle by inhibiting vitamin K epoxide reductase (VKOR) leading to depletion of vitamin K and uncarboxylated vitamin K dependent proteins. In the liver, the inhibition of warfarin can be circumvented via NAD(P)H quinone reductase (2), which can convert vitamin K into KH2 even in the presence of VKA. In extra-hepatic tissues NAD(P)H quinone reductase activity is ca. 100 fold less, resulting in inactive vitamin K dependent proteins in the presence of VKA; (C) DOACs induce anticoagulation via inhibiting the activity of FXa and FIIa via binding to the activation site.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663607&req=5

nutrients-07-05479-f001: Effects of vitamin K antagonists and direct oral anticoagulants on coagulation. (A) The coagulation cascade can be activated by both the intrinsic and extrinsic pathway, which finally results in activation of thrombin and subsequently fibrin formation. Vitamin K antagonists (VKA) induce anticoagulation via inhibiting activation of the coagulation factors depicted in red (factors X, IX, VII, and II). Direct oral anticoagulants (DOACs) induce anticoagulation via blocking the activity of coagulation factors Xa (rivaroxaban and apixaban) and IIa (dabigatran) depicted in blue; (B) Vitamin K cycle is required to carboxylate, and thus activate, vitamin K dependent proteins. Vitamin K is converted to vitamin hydroquinone (KH2), which is oxidized by γ-glutamylcarboxylase (3) to convert glutamate (Glu) residues in γ-carboxyglutamate (Gla) residues. This reaction results in vitamin K epoxide (K > O), which is recycled to vitamin K through vitamin K epoxide reductase (1). VKA disrupts the vitamin K cycle by inhibiting vitamin K epoxide reductase (VKOR) leading to depletion of vitamin K and uncarboxylated vitamin K dependent proteins. In the liver, the inhibition of warfarin can be circumvented via NAD(P)H quinone reductase (2), which can convert vitamin K into KH2 even in the presence of VKA. In extra-hepatic tissues NAD(P)H quinone reductase activity is ca. 100 fold less, resulting in inactive vitamin K dependent proteins in the presence of VKA; (C) DOACs induce anticoagulation via inhibiting the activity of FXa and FIIa via binding to the activation site.
Mentions: In 1856 Rudolf Virchow, often regarded as the founder of modern pathology, delineated three major components that were responsible for the formation of emboli in the venous circulation. These three elements, now known as Virchow’s triad, can be briefly summarized as: (1) changes in the composition of blood; (2) alterations in the vessel wall; and (3) disruption of the blood flow. Coagulation is a protective response after vascular injury to prevent bleeding [1] and can be initiated via either the so-called intrinsic or extrinsic pathways, which although simplistic, are still useful schematic models of the coagulation process (Figure 1a). Both pathways are characterized by a series of enzymatic events whereby the activation of members of a hierarchical chain of coagulation enzymes (called coagulation factors) are successively activated by the preceding factor in the chain. Although the initiation steps are different, both pathways converge and lead to activation of pro-thrombin (FII) to produce thrombin (FIIa). An important feature of this coagulation cascade is that it functions as a biochemical amplifier [2] in which the final product, thrombin catalyses the production of fibrin which forms a meshwork clot [3]. The coagulation events leading to the formation of a blood clot (thrombus) that adheres to the wall of a blood vessel and obstructs the flow of blood is termed thrombosis. Thrombosis can take place in both arteries and veins. Atherothrombosis is the term describing the occlusion of a blood vessel by a ruptured atherosclerotic plaque [4,5]. Arterial thrombosis can lead to stroke and myocardial infarction. In contrast to arterial thrombosis, venous thrombosis is associated with dysregulation of coagulation proteins and manifests in deep-vein thrombosis and pulmonary embolism [6]. Obesity and diabetes mellitus are risk factors for both arterial and venous thrombosis whereas other risk factors such as smoking, hypertension and hyperlipidemia increase only the risk for arterial thrombosis [6]. Oral anticoagulant drugs are prescribed to patients to reduce the risk and incidence of both arterial and venous thrombosis, although mainly for the latter.

Bottom Line: DOACs also display non-hemostatic vascular effects via protease-activated receptors (PARs).As atherosclerosis is characterized by a hypercoagulable state indicating the involvement of activated coagulation factors in the genesis of atherosclerosis, anticoagulation could have beneficial effects on atherosclerosis.Additionally, accumulating evidence demonstrates vascular benefit from high vitamin K intake.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. rick.vangorp@maastrichtuniversity.nl.

ABSTRACT
Vitamin K-antagonists (VKA) are the most widely used anticoagulant drugs to treat patients at risk of arterial and venous thrombosis for the past 50 years. Due to unfavorable pharmacokinetics VKA have a small therapeutic window, require frequent monitoring, and are susceptible to drug and nutritional interactions. Additionally, the effect of VKA is not limited to coagulation, but affects all vitamin K-dependent proteins. As a consequence, VKA have detrimental side effects by enhancing medial and intimal calcification. These limitations stimulated the development of alternative anticoagulant drugs, resulting in direct oral anticoagulant (DOAC) drugs, which specifically target coagulation factor Xa and thrombin. DOACs also display non-hemostatic vascular effects via protease-activated receptors (PARs). As atherosclerosis is characterized by a hypercoagulable state indicating the involvement of activated coagulation factors in the genesis of atherosclerosis, anticoagulation could have beneficial effects on atherosclerosis. Additionally, accumulating evidence demonstrates vascular benefit from high vitamin K intake. This review gives an update on oral anticoagulant treatment on the vasculature with a special focus on calcification and vitamin K interaction.

No MeSH data available.


Related in: MedlinePlus