Higher levels of circulating desphospho-uncarboxylated matrix Gla protein over time are associated with worse survival: the prospective Maastricht Intensive Care COVID cohort

Mark M G Mulder; Joep Schellens; Jan-Willem E M Sels; Frank van Rosmalen; Anne-Marije Hulshof; Femke de Vries; Ruud Segers; Casper Mihl; Walther N K A van Mook; Aalt Bast; Henri M H Spronk; Yvonne M C Henskens; Iwan C C van der Horst; Hugo Ten Cate; Leon J Schurgers; Marjolein Drent; Bas C T van Bussel

doi:10.1186/s40560-023-00712-0

Higher levels of circulating desphospho-uncarboxylated matrix Gla protein over time are associated with worse survival: the prospective Maastricht Intensive Care COVID cohort

J Intensive Care. 2023 Dec 18;11(1):63. doi: 10.1186/s40560-023-00712-0.

Authors

Mark M G Mulder^{1

2

3}, Joep Schellens⁴, Jan-Willem E M Sels^{4

5

6}, Frank van Rosmalen⁴, Anne-Marije Hulshof^{7

6}, Femke de Vries^{7

6}, Ruud Segers⁴, Casper Mihl^{8

6}, Walther N K A van Mook^{4

9

10}, Aalt Bast¹¹, Henri M H Spronk^{12

13

6}, Yvonne M C Henskens^{7

6}, Iwan C C van der Horst^{4

6}, Hugo Ten Cate^{12

13

6}, Leon J Schurgers^{12

6}, Marjolein Drent^#^{11

14

15}, Bas C T van Bussel^#^{4

6

16}

Affiliations

¹ Department of Intensive Care Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands. mark.mulder@mumc.nl.
² Department of Anaesthesiology, Maastricht University Medical Centre+, Maastricht, The Netherlands. mark.mulder@mumc.nl.
³ Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. mark.mulder@mumc.nl.
⁴ Department of Intensive Care Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands.
⁵ Department of Cardiology, Maastricht University Medical Centre+, Maastricht, The Netherlands.
⁶ Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
⁷ Central Diagnostic Laboratory, Maastricht University Medical Centre+, Maastricht, The Netherlands.
⁸ Department of Radiology and Nuclear Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands.
⁹ Academy for Postgraduate Medical Training, Maastricht University Medical Centre+, Maastricht, The Netherlands.
¹⁰ School of Health Professions Education, Maastricht University, Maastricht, The Netherlands.
¹¹ Department of Pharmacology and Toxicology, Maastricht University, Maastricht, The Netherlands.
¹² Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
¹³ Thrombosis Expert Centre Maastricht and Department of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands.
¹⁴ ILD Centre of Excellence, Department of Respiratory Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands.
¹⁵ ILD Care Foundation Research Team, Ede, The Netherlands.
¹⁶ Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands.

^# Contributed equally.

Abstract

Background: Extra-hepatic vitamin K-status, measured by dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP), maintains vascular health, with high levels reflecting poor vitamin K status. The occurrence of extra-hepatic vitamin K deficiency throughout the disease of COVID-19 and possible associations with pulmonary embolism (PE), and mortality in intensive care unit (ICU) patients has not been studied. The aim of this study was to investigated the association between dp-ucMGP, at endotracheal intubation (ETI) and both ICU and six months mortality. Furthermore, we studied the associations between serially measured dp-ucMGP and both PE and mortality.

Methods: We included 112 ICU patients with confirmed COVID-19. Over the course of 4 weeks after ETI, dp-ucMGP was measured serially. All patients underwent computed tomography pulmonary angiography (CTPA) to rule out PE. Results were adjusted for patient characteristics, disease severity scores, inflammation, renal function, history of coumarin use, and coronary artery calcification (CAC) scores.

Results: Per 100 pmol/L dp-ucMGP, at ETI, the odds ratio (OR) was 1.056 (95% CI: 0.977 to 1.141, p = 0.172) for ICU mortality and 1.059 (95% CI: 0.976 to 1.059, p = 0.170) for six months mortality. After adjustments for age, gender, and APACHE II score, the mean difference in plasma dp-ucMGP over time of ICU admission was 167 pmol/L (95% CI: 4 to 332, p = 0.047). After additional adjustments for c-reactive protein, creatinine, and history of coumarin use, the difference was 199 pmol/L (95% CI: 50 to 346, p = 0.010). After additional adjustment for CAC score the difference was 213 pmol/L (95% CI: 3 to 422, p = 0.051) higher in ICU non-survivors compared to the ICU survivors. The regression slope, indicating changes over time, did not differ. Moreover, dp-ucMGP was not associated with PE.

Conclusion: ICU mortality in COVID-19 patients was associated with higher dp-ucMGP levels over 4 weeks, independent of age, gender, and APACHE II score, and not explained by inflammation, renal function, history of coumarin use, and CAC score. No association with PE was observed. At ETI, higher levels of dp-ucMGP were associated with higher OR for both ICU and six month mortality in crude and adjusted modes, although not statistically significantly.

Keywords: COVID-19; Intensive care; Matrix Gla protein; Pulmonary embolism; Vitamin K deficiency.