Paper Brings Understanding to Vitamin K and New Anticoagulants

Vitamin K expert Dr. Leon Schurgers and his colleague Dr. Henri M.H. Spronk have published a new paper in Thrombosis & Haemeostasis examining the new generation of anticoagulants. A key takeaway being that, unlike their predecessors, these treatments can be used with Vitamin K without hesitation.

Vitamin K-antagonists (VKA) and heparins have been anticoagulants for prevention and treatment of thromboembolitic events for some 70 years. VKA are still the most widely used anticoagulant drugs to treat patients at risk of arterial and venous thrombosis, but due to unfavorable pharmacokinetics of VKA, direct thrombin, and factor Xa (FXa) inhibitors, non-vitamin K-antagonist oral anticoagulants (NOACs) have been introduced into the clinic as alternatives to VKA.

In the article, “Differential cellular effects of old and new oral anticoagulants: consequences to the genesis and progression of atherosclerosis”, Dr. Schurgers discusses that while VKA has proven effective, the treatment has several shortcomings, in particular that VKA are not restricted to vitamin K-dependent coagulation factors and inhibit vitamin K-dependent proteins involved in other physiological process, such as bone metabolism and vascular function.

“The best studied side-effect of VKA is on Matrix Gla-protein (MGP), a strong inhibitor of vascular calcification,” Dr. Schurgers writes.

He then examines NOACs, which are small synthetically made molecules against one clotting factor [i.e. thrombin (or factor IIa) or factor Xa]. They bind selectively and with high affinity to the active site of the enzyme, thereby inhibiting the turnover of the natural substrates.

“Direct thrombin inhibition is straightforward by inhibition of the key regulator of coagulation,” says Dr. Schurgers. “Factor Xa inhibition is based on reducing the thrombin burst in the propagation of coagulation.”

Examining the pleiotropic effects of anticoagulants, the authors explain that long-term treatment with VKA induces and accelerates vascular calcification. The first pre-clinical data are from the mid-1990s, in which the combined treatment of vitamin K with VKA resulted in a severe vascular vitamin K deficiency, with concomitant medial vascular calcification.

It took until 2004 before the effect of VKA on vascular calcification in the clinical setting was revealed. Today, the association between VKA use and vascular calcification has been confirmed in several trials.

“Although both VKA and NOACs act as anticoagulants, their mode of action suggests differences in pleiotropic effects. Whereas VKA treatment is mainly associated with enhanced calcification, NOACs treatment might have an effect on atherosclerosis progression in humans via PAR signaling,” Dr. Schurgers concludes. “In short, while VKA cannot be used with vitamin K, this new generation of anticoagulants can.”

Reference: Leon J. Schurgers; Henri M. H. Spronk. Differential cellular effects of old and new oral anticoagulants: consequences to the genesis and progression of atherosclerosis. Thromb Haemost. 2014; 112.

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