A study of the prevalence of vitamin K deficiency in patients with cancer referred to a hospital palliative care team and its association with abnormal haemostasis

Background:Many patients with advanced cancer are malnourished. Anorexia is common, as is the use of chemotherapy, which may cause nausea and poor appetite. Ten per cent of these patients experience haemorrhagic events.Aim:Since vitamin K deficiency (VKD) causes bleeding, to establish the prevalence of VKD in patients with advanced cancer receiving palliative care.Methods:Serum concentrations of vitamin K1 and undercarboxylated factor II (PIVKA-II) were determined in 46 (17 male/29 female) inpatients aged 26–85 (mean 58) years. INR and liver function tests (bilirubin, ALT, GGT and ALP) were also performed.Results:Vitamin K1 was below the lower limit of the reference range (0.33 nmol/l) in 22% of patients. 78% of patients had some degree of functional VKD indicated by raised (>0.2 AU/ml) PIVKA-II. Six patients (13%) had a prolonged INR, all of whom had raised PIVKA-II and GGT; 4 also had vitamin K1 <0.33 nmol/l. Three patients (6.5%) had clinically significant VKD characterised by INR >1.5, PIVKA-II >10 AU/ml, and undetectable vitamin K1.Conclusions:Patients with advanced cancer are prone to VKD which, while usually subclinical, may develop to a clinically relevant prolongation of the INR. Serum measurements of vitamin K1 and PIVKA-II can be used to detect VKD and monitor vitamin K status before an increased risk of bleeding develops.

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Vitamin K deficiency: an emerging player in the pathogenesis of vascular calcification and an iatrogenic consequence of therapies in advanced renal disease

AJP Renal Physiology ◽

10.1152/ajprenal.00278.2020 ◽

2020 ◽

Vol 319 (4) ◽

pp. F618-F623

Author(s):

David S. Levy ◽

Rickinder Grewal ◽

Thu H. Le

Keyword(s):

Bone Metabolism ◽

Vascular Calcification ◽

Vitamin K ◽

Hospital Admissions ◽

Fibroblast Growth Factor 23 ◽

Vitamin K Deficiency ◽

Increased Risk ◽

K Deficiency ◽

Human Aortic Valve

Vascular calcification is a known complication of chronic kidney disease (CKD). The prevalence of vascular calcification in patients with non-dialysis-dependent CKD stages 3–5 has been shown to be as high as 79% ( 20 ). Vascular calcification has been associated with increased risk for mortality, hospital admissions, and cardiovascular disease ( 6 , 20 , 50 , 55 ). Alterations in mineral and bone metabolism play a pivotal role in the pathogenesis of vascular calcification in CKD. As CKD progresses, levels of fibroblast growth factor-23, parathyroid hormone, and serum phosphorus increase and levels of 1,25-(OH)2 vitamin D decrease. These imbalances have been linked to the development of vascular calcification. More recently, additional factors have been found to play a role in vascular calcification. Matrix G1a protein (MGP) in its carboxylated form (cMGP) is a potent inhibitor of vascular calcification. Importantly, carboxylation of MGP is dependent on the cofactor vitamin K. In patients with CKD, vitamin K deficiency is prevalent and is exacerbated by warfarin, which is frequently used for anticoagulation. Insufficient bioavailability of vitamin K reduces the amount of cMGP available, and, therefore, it may lead to increased risk of vascular calcification. In vitro studies have shown that in the setting of a high-phosphate environment and vitamin K antagonism, human aortic valve interstitial cells become calcified. In this article, we discuss the pathophysiological consequence of vitamin K deficiency in the setting of altered mineral and bone metabolism, its prevalence, and clinical implications in patients with CKD.

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Functional vitamin K insufficiency, vascular calcification and mortality in advanced chronic kidney disease: A cohort study

PLoS ONE ◽

10.1371/journal.pone.0247623 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0247623

Author(s):

Lu Dai ◽

Longkai Li ◽

Helen Erlandsson ◽

Armand M. G. Jaminon ◽

Abdul Rashid Qureshi ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Vascular Calcification ◽

Vitamin K ◽

Matrix Gla Protein ◽

Vitamin K Deficiency ◽

Increased Risk ◽

Ckd Stage ◽

All Cause Mortality ◽

K Deficiency

Patients with chronic kidney disease (CKD) suffer from vitamin K deficiency and are at high risk of vascular calcification (VC) and premature death. We investigated the association of functional vitamin K deficiency with all-cause mortality and whether this association is modified by the presence of VC in CKD stage 5 (CKD G5). Plasma dephosphorylated-uncarboxylated matrix Gla-protein (dp-ucMGP), a circulating marker of functional vitamin K deficiency, and other laboratory and clinical data were determined in 493 CKD G5 patients. VC was assessed in subgroups by Agatston scoring of coronary artery calcium (CAC) and aortic valve calcium (AVC). Backward stepwise regression did not identify dp-ucMGP as an independent determinant of VC. During a median follow-up of 42 months, 93 patients died. Each one standard deviation increment in dp-ucMGP was associated with increased risk of all-cause mortality (sub-hazard ratio (sHR) 1.17; 95% confidence interval, 1.01–1.37) adjusted for age, sex, cardiovascular disease, diabetes, body mass index, inflammation, and dialysis treatment. The association remained significant when further adjusted for CAC and AVC in sub-analyses (sHR 1.22, 1.01–1.48 and 1.27, 1.01–1.60, respectively). In conclusion, functional vitamin K deficiency associates with increased mortality risk that is independent of the presence of VC in patients with CKD G5.

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Laboratory assessment of vitamin K status

Journal of Clinical Pathology ◽

10.1136/jclinpath-2019-205997 ◽

2019 ◽

Vol 73 (2) ◽

pp. 70-75 ◽

Cited By ~ 3

Author(s):

David John Card ◽

Renata Gorska ◽

Dominic Jon Harrington

Keyword(s):

Vitamin K ◽

Vitamin K Antagonists ◽

The Elderly ◽

Vitamin K Deficiency ◽

Laboratory Assessment ◽

Increased Risk ◽

K Deficiency ◽

Gla Domain ◽

Insight Into ◽

Abbott Architect

Vitamin K is required for the ɣ-carboxylation of specific glutamic acid residues within the Gla domain of the 17 vitamin K-dependent proteins (VKDPs). The timely detection and correction of vitamin K deficiency can protect against bleeding. Vitamin K also plays a role in bone metabolism and vascular calcification. Patients at increased risk of vitamin K deficiency include those with a restricted diet or malnutrition, lipid malabsorption, cancer, renal disease, neonates and the elderly. Coagulation assays such as the prothrombin time have been used erroneously as indicators of vitamin K status, lacking sufficient sensitivity and specificity for this application. The measurement of phylloquinone (K1) in serum is the most commonly used marker of vitamin K status and reflects abundance of the vitamin. Concentrations <0.15 µg/L are indicative of deficiency. Disadvantages of this approach include exclusion of the other vitamin K homologues and interference from recent dietary intake. The cellular utilisation of vitamin K is determined through measurement of the prevalence of undercarboxylated VKDPs. Most commonly, undercarboxylated prothrombin (Protein Induced by Vitamin K Absence/antagonism, PIVKA-II) is used (reference range 17.4–50.9 mAU/mL (Abbott Architect), providing a retrospective indicator of hepatic vitamin K status. Current clinical applications of PIVKA-II include supporting the diagnosis of vitamin K deficiency bleeding of the newborn, monitoring exposure to vitamin K antagonists, and when used in combination with α-fetoprotein, as a diagnostic marker of hepatocellular carcinoma. Using K1 and PIVKA-II in tandem is an approach that can be used successfully for many patient cohorts, providing insight into both abundance and utilisation of the vitamin.

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Vitamin K deficiency in cancer patients referred to a hospital palliative care team with bleeding and the impact of vitamin K replacement on laboratory indicators of vitamin K status

International Journal of Laboratory Hematology ◽

10.1111/ijlh.12035 ◽

2012 ◽

Vol 35 (4) ◽

pp. 457-459 ◽

Cited By ~ 2

Author(s):

D. J. Harrington ◽

L. Booth ◽

N. Dando ◽

L. Cottingham ◽

T. Beynon

Keyword(s):

Palliative Care ◽

Cancer Patients ◽

Vitamin K ◽

Palliative Care Team ◽

Care Team ◽

Vitamin K Deficiency ◽

K Deficiency ◽

The Impact

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Placental Transfer of Vitamin K1 and Its Implications in Fetal Hemostasis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647631 ◽

1988 ◽

Vol 60 (01) ◽

pp. 039-043 ◽

Cited By ~ 52

Author(s):

L Mandelbrot ◽

M Guillaumont ◽

M Leclercq ◽

J J Lefrère ◽

D Gozin ◽

...

Keyword(s):

Vitamin K ◽

High Performance ◽

Ultrasound Guidance ◽

Placental Transfer ◽

Vitamin K1 ◽

Vitamin K Deficiency ◽

Prothrombin Activity ◽

Oral Supplementation ◽

K Deficiency ◽

The Mean

SummaryVitamin K status was evaluated using coagulation studies and/ or vitamin IQ assays in a total of 53 normal fetuses and 47 neonates. Second trimester fetal blood samples were obtained for prenatal diagnosis under ultrasound guidance. Endogenous vitamin K1 concentrations (determined by high performance liquid chromatography) were substantially lower than maternal levels. The mean maternal-fetal gradient was 14-fold at mid trimester and 18-fold at birth. Despite low vitamin K levels, descarboxy prothrombin, detected by a staphylocoagulase assay, was elevated in only a single fetus and a single neonate.After maternal oral supplementation with vitamin K1, cord vitamin K1 levels were boosted 30-fold at mid trimester and 60 fold at term, demonstrating placental transfer. However, these levels were substantially lower than corresponding supplemented maternal levels. Despite elevated vitamin K1 concentrations, supplemented fetuses and neonates showed no increase in total or coagulant prothrombin activity. These results suggest that the low prothrombin levels found during intrauterine life are not due to vitamin K deficiency.

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Kinetic Aspects of the Interaction of Blood-Clotting Enzymes

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651250 ◽

1968 ◽

Vol 20 (01/02) ◽

pp. 078-087 ◽

Cited By ~ 34

Author(s):

H. C Hemker ◽

A. D Muller

Keyword(s):

Vitamin K ◽

Blood Clotting ◽

Experimental Results ◽

Factor X ◽

Clotting Factors ◽

Vitamin K Deficiency ◽

K Deficiency

SummaryPIVKA, the circulating anticoagulant protein found in vitamin K deficiency can, on kinetical grounds, be recognized as an analogue of factor X. The existence of analogues of other vitamin K-dependent clotting factors cannot be ruled out, but need not be assumed to explain the experimental results.

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