Reduced vitamin K status may play a role in the pathogenesis of coronavirus disease 2019 (COVID-19) through interacting with both elastic fiber metabolism and the coagulation cascade, thus linking pulmonary and thromboembolic disease, according to a study published in Clinical Infectious Diseases.
“These data suggest a mechanism of pneumonia-induced extrahepatic vitamin K depletion leading to accelerated elastic fiber degradation and thrombosis formation,” wrote Anton S M Dofferhoff, MD, Department of Internal Medicine, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands, and colleagues. “An intervention trial is now needed to assess whether vitamin K administration improves outcome in patients with COVID-19 by increasing pulmonary MGP [matrix Gla protein] and endothelial protein S activation.”
The study included 135 patients hospitalized for COVID-19 in the Canisius-Wilhelmina Hospital between March 12 and April 15, 2020, who were compared with 184 historical controls. Patient data was extracted from hospital records, and vitamin K antagonist (VKA) usage was determined from pharmacy and anticoagulant clinic records.
Investigators measured inactive vitamin K-dependent MGP (dp-ucMGP) and prothrombin (PIVKA-II), which are inversely related to extrahepatic and hepatic vitamin K status, respectively. Desmosine was also measured to quantify the rate of elastic fiber degradation, while arterial calcification severity was assessed by computed tomography (CT).
Maximum dp-ucMGP levels were significantly higher in COVID-19 patients compared to healthy controls (p<0.001), with the difference remaining significant after adjustment for age, sex, and use of VKAs. The levels of dp-ucMGP were even higher in COVID-19 patients with poor outcomes (1998 pmol/L, 95% CI: 1737 to 2296), defined as invasive ventilation and/or death, compared to those with good outcomes (1157 pmol/L, 95% CI: 1022 to 1312, mean fold change 1.73, 95% CI, 1.43 to 2.08, p<0.001), defined as discharge from the hospital without the need for invasive ventilation. Significance was maintained after adjustments (p<0.001). Meanwhile, PIVKA-II levels were normal in 82.1% of patients, mildly elevated in 13.0%, moderately in 4.1% and severely in 0.8% of COVID-19 patients not using VKA.
In addition, dp-ucMGP was correlated with desmosine (p<0.001), and coronary artery (p=0.002) and thoracic aortic (p<0.001) calcification scores. Levels of plasma desmosine were significantly higher in COVID-19 patients with poor (430 ng/L, 95% CI 384 to 481) compared to good outcomes (342 ng/L, 95% CI 310 to 379; mean fold change 1.25, 95% CI, 1.07 to 1.47, p=0.004). In addition, thoracic and coronary aortic calcification scores were significantly higher in COVID-19 patients with poor outcome compared to those with good outcomes, but both lost significance after adjustments.
“Indirectly quantified extrahepatic vitamin K status is severely reduced in COVID-19 patients. Data suggest pneumonia-induced vitamin K depletion leading to accelerated elastic fiber damage and thrombosis risk due to impaired vitamin K-dependent activation of MGP and endothelial protein S, respectively,” the authors reported, adding “it is reasonable to assume that vitamin K administration reduces dp-ucMGP in COVID-19. Whether improving dp-ucMGP results in better outcome of COVID19 remains to be evaluated.”
They noted that “as low vitamin K levels are found in comorbidities that are related to poor outcome of COVID-19, we were unable formally to determine whether vitamin K insufficiency truly predisposes patients to the development of severe COVID-19 or whether it is merely an epiphenomenon. However, the latter seems highly unlikely given the extreme elevation of dp-ucMGP levels in COVID-19 patients, which was much more pronounced than in hypertensive, diabetic, cardiovascular and [chronic obstructive pulmonary disease] patients without COVID-19. The strong correlation that we found between vitamin K status and the rate of elastic fiber degradation also suggests causality.”
“The major strength of our study is the use of robust biomarkers and quantitative CT assessment,” the authors stated, but they suggested their findings were “limited by the fact that it is impossible to determine which proportion of circulating dp-ucMGP and [desmosine] levels originated from the lungs, as both biomarkers are not tissue specific. Therefore, there is urgent need for experimental data to better link vitamin K insufficiency specifically with COVID-19-related lung pathologies.”