Reduced Vitamin K Status as a Potentially Modifiable Risk Factor of Severe Coronavirus Disease 2019
Anton S M Dofferhoff, Ianthe Piscaer, Leon J Schurgers, Margot P J Visser, Jody M W van den Ouweland, Pim A de Jong, Reinoud Gosens, Tilman M Hackeng, Henny van Daal, Petra Lux, Cecile Maassen, Esther G A Karssemeijer, Cees Vermeer, Emiel F M Wouters, Loes E M Kistemaker, Jona Walk, Rob Janssen, Anton S M Dofferhoff, Ianthe Piscaer, Leon J Schurgers, Margot P J Visser, Jody M W van den Ouweland, Pim A de Jong, Reinoud Gosens, Tilman M Hackeng, Henny van Daal, Petra Lux, Cecile Maassen, Esther G A Karssemeijer, Cees Vermeer, Emiel F M Wouters, Loes E M Kistemaker, Jona Walk, Rob Janssen
Abstract
Background: Respiratory failure and thromboembolism are frequent in severe acute respiratory syndrome coronavirus 2-infected patients. Vitamin K activates both hepatic coagulation factors and extrahepatic endothelial anticoagulant protein S, required for thrombosis prevention. In times of vitamin K insufficiency, hepatic procoagulant factors are preferentially activated over extrahepatic proteins. Vitamin K also activates matrix Gla protein (MGP), which protects against pulmonary and vascular elastic fiber damage. We hypothesized that vitamin K may be implicated in coronavirus disease 2019 (COVID-19), linking pulmonary and thromboembolic disease.
Methods: A total of 135 hospitalized COVID-19 patients were compared with 184 historic controls. Inactive vitamin K-dependent MGP (desphospho-uncarboxylated [dp-uc] MGP) and prothrombin (PIVKA-II) were measured inversely related to extrahepatic and hepatic vitamin K status, respectively. Desmosine was measured to quantify the rate of elastic fiber degradation. Arterial calcification severity was assessed using computed tomography.
Results: dp-ucMGP was elevated in COVID-19 patients compared with controls (P < .001), with even higher dp-ucMGP in patients with poor outcomes (P < .001). PIVKA-II was normal in 82.1% of patients. dp-ucMGP was correlated with desmosine (P < .001) and with coronary artery (P = .002) and thoracic aortic (P < .001) calcification scores.
Conclusions: dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insufficiency, which was related to poor outcome; hepatic procoagulant factor II remained unaffected. These data suggest pneumonia-induced extrahepatic vitamin K depletion leading to accelerated elastic fiber damage and thrombosis in severe COVID-19 due to impaired activation of MGP and endothelial protein S, respectively.
Keywords: COVID-19; elastic fibers; factor II; matrix Gla protein; vitamin K.
© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
Source: PubMed