..................................................................................................................9 List of publications ...............................................................................................11 Abbreviations ........................................................................................................13 Introduction ..........................................................................................................15 History ..........................................................................................................15 Different forms of vitamin K .......................................................................16 Sources of vitamin K and recommended daily intake ..................................17 Dietary sources ....................................................................................17 Vitamin K production by intestinal flora .............................................18 Recommended daily intake .................................................................18 Synthetic vitamin K concentrates ........................................................18 The vitamin K cycle .....................................................................................19 Intestinal absorption and transport of vitamin K ..........................................20 Vitamin K-dependent proteins (VKDPs) .....................................................20 Coagulation factors ..............................................................................20 Matrix Gla protein (MGP) ...................................................................21 Osteocalcin (OC) .................................................................................22 Growth arrest-specific gene 6 protein (Gas6) ......................................22 Gla rich protein (GRP) ........................................................................22 Markers of vitamin K status .........................................................................22 Implication of vitamin K’s involvement in disease ......................................23 Cardiovascular disease ........................................................................23 Sepsis ...................................................................................................24 Pulmonary disease ...............................................................................25 Osteoporosis ........................................................................................25 Cancer ..................................................................................................25 Neurodegenerative disease ..................................................................26 Normal haemostasis .....................................................................................26 Coagulopathy in perioperative and critically ill patients ..............................28 Aims .......................................................................................................................31 Study I ..........................................................................................................31 Study II .........................................................................................................31 Study III .......................................................................................................31 Study IV .......................................................................................................31 Study V .........................................................................................................31

Background Previous studies have indicated that vitamin K deficiency is common in non-bleeding critically ill patients with slightly prolonged prothrombin time-international normalized ratio (PT-INR). It has never been investigated thoroughly whether the administration of vitamin K to these patients could affect their PT-INR. Therefore, the aim of this registry study was to evaluate changes in PT-INR in response to vitamin K in critically ill patients with PT-INR in the range of 1.3–1.9. Methods Patients admitted to a mixed 9-bed general intensive care unit at a University Hospital, between 2013 and 2019 ( n = 4541) with a PT-INR between 1.3 and 1.9 at any time during the stay were identified. Patients who received vitamin K with appropriate sampling times for PT-INR and without exclusion criteria were matched with propensity score to patients from the same cohort who did not receive vitamin K (controls). PT-INR was measured at admission, within 12 h before vitamin K administration and 12–36 h following vitamin K administration. Exclusion criteria included pre-existing liver cirrhosis, any plasma or platelet transfusion, or > 1 unit red blood cell transfusion between PT-INR samplings. Results Propensity score matching resulted in two groups of patients with 129 patients in each group. PT-INR decreased in both groups (1.4 [1.3–1.4] in the vitamin K group and 1.4 [1.3–1.6] in the controls, p < 0.001 and p = 0.004, respectively). The decrease in PT-INR was slightly more pronounced in patients who received vitamin K (delta PT-INR − 0.10 [− 0.30 to − 0.10] in the vitamin K group and − 0.10 [− 0.20 to 0.10] in the controls, p = 0.01). Conclusion In critically ill patients with a PT-INR of 1.3–1.9, the administration of vitamin K resulted in a slightly larger decrease of PT-INR 12–36 h after administration compared to controls. Future studies should focus on identifying which patient populations may benefit most from vitamin K administration as well as whether vitamin K could be a better alternative than plasma or prothrombin complex concentrate to improve PT-INR before non-emergent invasive procedures.

The aim of this study was to evaluate the effects of vitamin K1 on various vitamin K-dependent proteins in critically ill patients with prolonged Owren PT. We included critically ill non-bleeding adult patients without liver failure or anticoagulation treatment, with Owren PT > 1.2, who were prescribed intravenous vitamin K1. Blood was drawn at baseline and at 20–28 h after vitamin K1 administration. At both time points, we measured various vitamin K-dependent proteins and coagulation assays. ClinicalTrials.gov; Identifier: NTC3782025. In total, 52 patients were included. Intravenous vitamin K1 reduced Owren PT, Quick PT, protein induced by vitamin K absence/antagonist-II and desphospho-uncarboxylated matrix Gla protein (dp-ucMGP), but not to normal levels. Concomitantly, there were increases in thrombin generation and the activity of coagulation factors II, VII, IX and X that was only counteracted with a small increase in Protein C activity. In conclusion, the results suggest that vitamin K1 strengthens coagulation as measured by PT decrease and increases in the activity of vitamin K-dependent clotting factors and thrombin generation. The decreased dp-ucMGP, and its potential positive short- and long-term non-coagulative effects, merits further research.

This review summarizes the involvement of vitamin K and the extrahepatic Gla proteins matrix Gla protein (MGP), Os-teocalcin (OC) and growth arrest-specific gene 6 protein (Gas6) in the development and progression of diabetes: in particular, complications related to angiopathy and inflammation. High vitamin K intake has been associated with a decreased risk of type 2 diabetes. Furthermore, in type 2 diabetic patients, the extent of artery calcification correlates to levels of the uncarboxylated Gla protein MGP, and supplementation with vitamin K has been shown to reduce oxidative stress markers as well as metabolic risk markers for diabetes.

Background: Matrix Gla protein (MGP) is an extrahepatic protein that is dependent on glutamate carboxylation, a vitamin K-dependent process. Its dysfunctional form, desphospho-uncarboxylated-MGP, has been associated with increased arterial calcification and stiffness. The aim of this study was to measure the degree of postoperative carboxylation of MGP and two other Gla proteins in patients scheduled for abdominal or orthopaedic surgery. Methods: Forty patients undergoing abdominal or orthopaedic surgery were included. Blood samples were collected preoperatively and four days after the surgery. Desphospho-carboxylated MGP (dp-cMGP), desphospho-uncarboxylated MGP (dp-ucMGP), carboxylated osteocalcin (OC) (cOC), uncarboxylated OC (ucOC), and uncarboxylated prothrombin (PIVKA-II) were analysed. Results: Preoperatively, 29 patients had dp-ucMGP levels above the reference values. Patients with pre-existing cardiovascular comorbidities had higher dp-ucMGP preoperatively compared with patients with no record of cardiovascular disease. Postoperatively, this number increased to 36 patients, and median dp-ucMGP levels increased (p < 0.0001) and correlated to a PIVKA-II increase (r = 0.44). On the other hand, dp-cMGP levels did not significantly alter. Decreased levels of ucOC and cOC were seen after surgery (p = 0.017 and p = 0.0033, respectively). Comorbidities, possible nutritional defects, and complications affecting Gla protein activity and function were identified. Conclusions. Dp-ucMGP was high preoperatively, and had further increased postoperatively. This pattern was linked to several comorbidities, possible nutritional defects, and postoperative complications, which motivates further research about potential interactions between perioperative corrective treatments with vitamin K supplements, cardiovascular biomarkers, and incidents of stroke and myocardial infarction events.

BACKGROUND:Vitamin K is a cofactor for proteins involved in cardiovascular health, bone metabolism and cancer. Measuring uncarboxylated prothrombin, also termed as "protein induced by vitamin K absence or antagonism for factor II (PIVKA-II)", has been used to assess vitamin K status. High levels may indicate vitamin K deficiency. The aim of this study was to measure PIVKA-II and prothrombin time (PT-INR) in intensive care (ICU) patients and correlate vitamin K status with mortality.METHODS:Ninety-five patients admitted to the ICU had blood samples taken near admission and every third day. In addition to PIVKA-II and PT-INR, critical-care severity scores were computed.RESULTS:The median baseline PIVKA-II was 4.97 μg/L compared to the upper reference of 2.0 μg/L. PIVKA-II further increased at days 3 and 6, (median 7.88 μg/L, p = .047 and median 8.14 μg/L, p = .011) predominantly in cardiac arrest patients (median 21.4 μg/L, day 3).CONCLUSION:Intensive care patients have increased PIVKA-II levels at admission, which increases during the ICU stay, especially in cardiac arrest patients. There were no correlations between PIVKA-II and PT-INR, SOFA score or mortality. Further studies are needed to determine why PIVKA-II increases and whether high PIVKA-II levels in ICU patients affect long-term mortality or morbidity.

Subclinical vitamin K deficits refer to carboxylation defects of different types of vitamin K-dependent hepatic and extrahepatic so-called Gla proteins without prolongation of the prothrombin time. This condition has been reported in different clinical situations due to insufficient supply or malabsorption of vitamin K as well as drug interactions. This review discusses the effects of different vitamin K subspecies on tumour growth and the possible anti-tumour effects of increased vitamin K intake. Blocking carboxylation of vitamin K-dependent proteins with warfarin anticoagulation - what are the risks/benefits for carcinogenesis? Previous studies on both heparin and low molecular weight heparin blocking of the vitamin K-dependent factors X and II have shown tumour suppressive effects. Vitamin K has anti-inflammatory effects that could also impact carcinogenesis, but little data exists on this subject.

Subclinical vitamin K deficits refer to carboxylation defects of different types of vitamin K-dependent hepatic and extrahepatic so-called Gla proteins without prolongation of the prothrombin time. This condition has been reported in different clinical situations due to insufficient supply or malabsorption of vitamin K as well as drug interactions. This review discusses the effects of different vitamin K subspecies on tumour growth and the possible anti-tumour effects of increased vitamin K intake. Blocking carboxylation of vitamin K-dependent proteins with warfarin anticoagulation – what are the risks/benefits for carcinogenesis? Previous studies on both heparin and low molecular weight heparin blocking of the vitamin K-dependent factors X and II have shown tumour suppressive effects. Vitamin K has anti-inflammatory effects that could also impact carcinogenesis, but little data exists on this subject.

Vitamin K is known for supporting the carboxylation of hepatic coagulation proteins. Levels of proteins induced by vitamin K absence for factor II (PIVKA-II) reflect hypocarboxylated prothrombin and can be used to detect subclinical vitamin K deficiency. The aim of this study was to determine the prevalence of perioperative subclinical vitamin K deficiency among neurosurgical patients using PIVKA-II and investigate the existence of any correlation to standard coagulation assays. Also, the antitumor effects of vitamin K were reviewed. Thirty-five patients undergoing brain tumor resection were included. Blood samples were drawn preoperatively, at the end of surgery and in the morning after surgery. In addition to PIVKA-II, factor II and the Owren and Quick prothrombin times were analyzed. Seventeen of 35 patients had elevated PIVKA-II levels before surgery, which continued to be above normal range postoperatively. Median PIVKA-II and Owren prothrombin time (PT-INR) were increased on the morning day 1 postoperatively compared to before surgery, whereas Quick end-stage prothrombin time (EPT) decreased and factor II was unaffected. Postoperative complications were connected to high PIVKA-II increases. Positive correlations between PIVKA-II and factor II and body mass index (BMI) were found. In conclusion, PIVKA-II was increased in many patients preoperatively and then increased by the morning following surgery. Standard coagulation assays were largely non-pathological. Correlations were demonstrated between PIVKA-II and factor II and BMI. The effect of perioperative treatment with different vitamin K supplements should be investigated in future studies, as well as clinical trials evaluating their antitumor effects.

Background: Type 2 diabetes can often be managed by healthier diet and exercise in early stages of the disease, but as it progresses oral medication is needed and later on the patients will require insulin to survive. Vitamin K is a fat soluble vitamin that is a cofactor in gamma-carboxylation and activation of coagulation proteins produced in the liver. There are also extrahepatic proteins named Gla proteins that require vitamin K to be activated. Previous studies suggest that some of these proteins have a connection to calcification of vessels, bone mineralization, metabolic syndrome and diabetes, but results are conflicting.