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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 anticoagulants and vitamin K on vascular calcification. (A) Mechanism by which vitamin K antagonist (VKA) induces calcification. VKA induces phenotypic switching of contractile to synthetic vascular smooth muscle cells (VSMCs) by increasing oxidative stress resulting in increased proliferation and migration. Synthetic VSMCs secrete uncarboxylated matrix Gla protein (ucMGP) as a result of vitamin K depletion induced by VKA. ucMGP is unable to inhibit bone morphogenetic protein (BMP) 2 and 4, a marker for osteochondrogenic differentiation. Osteochondrogenic VSMCs are prone to calcification. Additionally, ucMGP is directly associated with increased calcification; (B) Thrombin and factor Xa induce non-hemostasis signaling via protease-activated receptors (PARs). Activation of PARs on contractile VSMCs can induce phenotypic switching resulting in increased proliferation and migration. PAR signaling in these synthetic VSMCs increases oxidative stress and adhesion molecules and induces extracellular (ECM) remodeling thereby facilitating calcification; (C) DOAC treatment in combination with (D) supplemental vitamin K administration has the potential to prevent both hypercoagulability and inhibit vascular calcification.
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nutrients-07-05479-f002: Effects of anticoagulants and vitamin K on vascular calcification. (A) Mechanism by which vitamin K antagonist (VKA) induces calcification. VKA induces phenotypic switching of contractile to synthetic vascular smooth muscle cells (VSMCs) by increasing oxidative stress resulting in increased proliferation and migration. Synthetic VSMCs secrete uncarboxylated matrix Gla protein (ucMGP) as a result of vitamin K depletion induced by VKA. ucMGP is unable to inhibit bone morphogenetic protein (BMP) 2 and 4, a marker for osteochondrogenic differentiation. Osteochondrogenic VSMCs are prone to calcification. Additionally, ucMGP is directly associated with increased calcification; (B) Thrombin and factor Xa induce non-hemostasis signaling via protease-activated receptors (PARs). Activation of PARs on contractile VSMCs can induce phenotypic switching resulting in increased proliferation and migration. PAR signaling in these synthetic VSMCs increases oxidative stress and adhesion molecules and induces extracellular (ECM) remodeling thereby facilitating calcification; (C) DOAC treatment in combination with (D) supplemental vitamin K administration has the potential to prevent both hypercoagulability and inhibit vascular calcification.

Mentions: Human atherosclerotic plaques express elevated levels of PAR-1 [72], suggesting that PAR-1 plays a role in atherosclerosis development. In line with this hypothesis, thrombin induced PAR-1 activation can lead to VSMC migration and proliferation (Figure 2b). Moreover, thrombin elevates collagen production by VSMCs in a PAR-1 dependent manner [73], indicating a possible role for thrombin in plaque stability. Another feature of atherosclerotic plaque development is apoptosis. VSMCs that undergo apoptosis can generate thrombin via a process that accelerates the assembly of the prothrombinase complex [74]. In addition, thrombin generation is associated with vascular calcification [75].


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 anticoagulants and vitamin K on vascular calcification. (A) Mechanism by which vitamin K antagonist (VKA) induces calcification. VKA induces phenotypic switching of contractile to synthetic vascular smooth muscle cells (VSMCs) by increasing oxidative stress resulting in increased proliferation and migration. Synthetic VSMCs secrete uncarboxylated matrix Gla protein (ucMGP) as a result of vitamin K depletion induced by VKA. ucMGP is unable to inhibit bone morphogenetic protein (BMP) 2 and 4, a marker for osteochondrogenic differentiation. Osteochondrogenic VSMCs are prone to calcification. Additionally, ucMGP is directly associated with increased calcification; (B) Thrombin and factor Xa induce non-hemostasis signaling via protease-activated receptors (PARs). Activation of PARs on contractile VSMCs can induce phenotypic switching resulting in increased proliferation and migration. PAR signaling in these synthetic VSMCs increases oxidative stress and adhesion molecules and induces extracellular (ECM) remodeling thereby facilitating calcification; (C) DOAC treatment in combination with (D) supplemental vitamin K administration has the potential to prevent both hypercoagulability and inhibit vascular calcification.
© Copyright Policy
Related In: Results  -  Collection

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

nutrients-07-05479-f002: Effects of anticoagulants and vitamin K on vascular calcification. (A) Mechanism by which vitamin K antagonist (VKA) induces calcification. VKA induces phenotypic switching of contractile to synthetic vascular smooth muscle cells (VSMCs) by increasing oxidative stress resulting in increased proliferation and migration. Synthetic VSMCs secrete uncarboxylated matrix Gla protein (ucMGP) as a result of vitamin K depletion induced by VKA. ucMGP is unable to inhibit bone morphogenetic protein (BMP) 2 and 4, a marker for osteochondrogenic differentiation. Osteochondrogenic VSMCs are prone to calcification. Additionally, ucMGP is directly associated with increased calcification; (B) Thrombin and factor Xa induce non-hemostasis signaling via protease-activated receptors (PARs). Activation of PARs on contractile VSMCs can induce phenotypic switching resulting in increased proliferation and migration. PAR signaling in these synthetic VSMCs increases oxidative stress and adhesion molecules and induces extracellular (ECM) remodeling thereby facilitating calcification; (C) DOAC treatment in combination with (D) supplemental vitamin K administration has the potential to prevent both hypercoagulability and inhibit vascular calcification.
Mentions: Human atherosclerotic plaques express elevated levels of PAR-1 [72], suggesting that PAR-1 plays a role in atherosclerosis development. In line with this hypothesis, thrombin induced PAR-1 activation can lead to VSMC migration and proliferation (Figure 2b). Moreover, thrombin elevates collagen production by VSMCs in a PAR-1 dependent manner [73], indicating a possible role for thrombin in plaque stability. Another feature of atherosclerotic plaque development is apoptosis. VSMCs that undergo apoptosis can generate thrombin via a process that accelerates the assembly of the prothrombinase complex [74]. In addition, thrombin generation is associated with vascular calcification [75].

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