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1.
Early vascular ageing in chronic kidney disease: impact of inflammation, vitamin K, senescence and genomic damage.
Dai, L, Schurgers, LJ, Shiels, PG, Stenvinkel, P
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2020;(Suppl 2):ii31-ii37
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Abstract
Chronic kidney disease (CKD) is a clinical model of premature ageing characterized by cardiovascular disease, persistent uraemic inflammation, osteoporosis muscle wasting and frailty. The accelerated early vascular ageing (EVA) process mediated by medial vascular calcification (VC) is a hallmark of senescence as well as a strong predictor of cardiovascular morbidity and mortality in the CKD population. Current clinical therapeutic strategies and novel treatments for VC have not yet been proven to prevent or reverse VC progression in patients with CKD. Knowledge of the fundamental mechanism underlying EVA is urgently needed to identify and develop novel and efficient therapeutic targets for VC and EVA. An accumulating body of evidence indicates that deoxyribonucleic acid (DNA) damage-induced cellular senescence and 'inflammaging' may largely contribute to such pathological conditions characterized by accelerated EVA. Growing evidence shows that nuclear factor erythroid 2-related factor 2 (NRF2) signalling and vitamin K play a crucial role in counteracting oxidative stress, DNA damage, senescence and inflammaging, whereby NRF2 activation and vitamin K supplementation may provide a novel treatment target for EVA. In this review we discuss the link between senescence and EVA in the context of CKD, with a focus on the role of NRF2 and vitamin K in DNA damage signalling, senescence and inflammaging.
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Laboratory assessment of vitamin K status.
Card, DJ, Gorska, R, Harrington, DJ
Journal of clinical pathology. 2020;(2):70-75
Abstract
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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Factors Associated With the Choice of Oral Anticoagulant Class in the Older Patients: An Observational Study.
Pagès, A, Sabatier, R, Sallerin, B
Journal of cardiovascular pharmacology and therapeutics. 2020;(4):332-337
Abstract
AIM: Oral anticoagulants are the first-line drugs for treating thrombotic disorders related to nonvalvular atrial fibrillation and for treating deep vein thrombosis, diseases that increase in prevalence with age. Older patients have a greater risk of thrombotic and hemorrhagic events and are more prone to drug interactions. Given this backdrop, we wanted to determine the factors associated with the prescription of direct oral anticoagulants and vitamin K antagonists in older patients. METHODS We performed a cross-sectional observational study using a hospital prescription database. The study population consists of 405 older patients who were given oral anticoagulants. The 2 variables of interest were the prescription of 1 of the 2 classes of oral anticoagulants (direct oral anticoagulants vs vitamin K antagonists) and appropriateness of oral anticoagulant prescribing according to Summary of Product Characteristics (potentially inappropriate vs appropriate). RESULTS The factors associated with direct oral anticoagulant prescribing were the female gender (odds ratio [OR]: 1.87, 95% confidence interval [CI]: 1.22-2.88) and initiation during hospital stay (OR: 2.56, 95% CI: [1.52-4.32]). Stage 4 and 5 chronic kidney diseases (OR: 0.39, 95% CI: [0.19-0.79] and OR: 0.07, 95% CI: [0.01-0.53]) were factors favoring vitamin K antagonist prescription. Being 90 years of age or more (OR: 2.05, 95% CI: [1.06-3.98]) was a factor for potentially inappropriate anticoagulant prescribing. The gastroenterology department (OR: 2.91, 95% CI: [1.05-8.11]) was associated with potentially inappropriate anticoagulant prescribing. CONCLUSIONS Direct oral anticoagulants are the drugs of choice for anticoagulant treatment, including in older adults. The female gender and the initiation during hospital stay increased the chances of being prescribed a direct oral anticoagulant in older adults. Stage 4 and 5 chronic kidney disease increased the likelihood of having a vitamin K antagonist prescribed. Our study also revealed a persistence of potentially inappropriate oral anticoagulant prescriptions in older patients.
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Non-vitamin K antagonist oral anticoagulants (NOACs) in cancer patients with atrial fibrillation.
Undas, A, Drabik, L
Anatolian journal of cardiology. 2020;(1):10-18
Abstract
Non-vitamin K antagonist oral anticoagulants (NOACs), or direct oral anticoagulants have not been tested in randomized trials conducted in patients with atrial fibrillation (AF), who had malignant disease. However, their use in cancer patients increases and real-life evidence for their effectiveness and safety in this vulnerable subset of patients is growing. The challenges of the use of NOACs in cancer patients with AF and the current expert opinions on this subject have been summarized in this review article.
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Joint association of vitamins D and K status with long-term outcomes in stable kidney transplant recipients.
van Ballegooijen, AJ, Beulens, JWJ, Keyzer, CA, Navis, GJ, Berger, SP, de Borst, MH, Vervloet, MG, Bakker, SJL
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2020;(4):706-714
Abstract
BACKGROUND Kidney transplant recipients (KTRs) experience substantial survival benefit compared with dialysis patients. However, their mortality and graft failure risk remain high. KTRs are often low in micronutrient status, including vitamins D and K. We investigated the association of both vitamins D and K status, and vitamin D treatment with all-cause mortality and death-censored graft failure. METHODS We studied 461 KTRs from a single-centre study at median 6.1 years after transplantation. At baseline, vitamins D and K concentrations were measured by 25-hydroxyvitamin D [25(OH)D] and dephosphorylated uncarboxylated matrix gla protein (dp-ucMGP) and patients were categorized into: 25(OH)D <50/≥50 nmol/L and median dp-ucMGP <1057/≥1057 pmol/L. RESULTS Mean age was 52 ± 12 years, and 122 KTRs (26%) had low vitamins D and K status. During median 9.8 years follow-up, 128 patients (28%) died and 48 (10%) developed death-censored graft failure. Low vitamins D and K status was associated with 2.33 (1.26-4.30) [hazard ratio (95% confidence interval)] increased mortality risk and 3.25 (1.17-9.08) increased graft failure risk compared with KTR with 25(OH)D ≥50 nmol/L and dp-ucMGP <1057 pmol/L. Dp-ucMGP was strongly associated with mortality (per 500 pmol/L increase): 1.41 (1.08-1.41) for vitamin D treatment versus no treatment 1.07 (0.97-1.18), and graft failure 1.71 (1.17-2.49) for vitamin D treatment versus 1.19 (1.05-1.36) no treatment, P-interaction <0.07 for vitamin D treatment (n = 44). CONCLUSIONS Combined vitamins D and K deficiency are highly prevalent and are associated with increased mortality and graft failure risk compared with high vitamins D and K status. Low vitamin K status was strongly associated with an increased risk of premature mortality and graft failure for patients treated with vitamin D versus no vitamin D treatment.
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Severe Hemorrhage Associated With Oral Anticoagulants.
Lindhoff-Last, E, Herrmann, E, Lindau, S, Konstantinides, S, Grottke, O, Nowak-Goettl, U, Lucks, J, Zydek, B, Heymann, CV, Birschmann, I, et al
Deutsches Arzteblatt international. 2020;(18):312-319
Abstract
BACKGROUND Few data have been published to date on outcomes after the common clinical experience of severe hemorrhage in orally anticoagulated patients. METHODS A prospective, multicenter observational study was carried out to investigate outcomes and management in a series of consecutive patients who sustained a severe hemorrhage under treatment with vitamin K antagonists (VKA) or direct oral anticoagulant drugs (DOAC). The primary endpoint was in-hospital death up to and including day 30 after hospital admission. The secondary endpoints were the duration of bleeding, in-hospital death due to hemorrhage (as defined by the study physician examining the patient's records), the use of antagonists, the extent of supportive measures used to stop the hemorrhage, and an assessment of causality. Consecutive patients were recruited until a predefined number of patients was reached in both groups. RESULTS Among 193 patients with severe hemorrhage, 97 had been taking a VKA, and 96 had been taking a DOAC. 13.0 % (95% confidence interval [8.6; 18.5]; 25/193) of the overall group patients died in the first 30 days after hospital admission, including 17.5% ([10.6; 26.6]; 17/97) in the VKA group and 8.3% ([3.7; 15.8]; 8/96) in the DOAC group (p = 0.085). The median duration of bleeding was 19.8 hours in the VKA group and 27.8 hours in the DOAC group (p = 0.632). The in-hospital mortality due to hemorrhage was higher in the VKA group than in the DOAC group (15.5% [15/97] versus 4.2% [4/97]; p = 0.014). Only the use of prothrombin complex concentrates (PCCs) lowered the median duration of hemorrhage in the two patient groups. In 35% (68/193) of the patients, the hemorrhage was caused by an external influence, most commonly a fall. CONCLUSION The in-hospital mortality was higher among patients treated with VKA than among patients treated with DOAC, although the difference failed to reach statistical significance.
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Efficacy and safety of direct oral anticoagulants (DOACs) versus vitamin K antagonist (VKA) among patients with atrial fibrillation and hypertrophic cardiomyopathy: a systematic review and meta-analysis.
Rujirachun, P, Charoenngam, N, Wattanachayakul, P, Winijkul, A, Owattanapanich, W, Ungprasert, P
Acta cardiologica. 2020;(8):724-731
Abstract
Background/objectives: Long-term oral anticoagulant therapy is recommended for patients with hypertrophic cardiomyopathy (HCM) who develop atrial fibrillation (AF) to prevent cardioembolic complications. In patients with non-valvular AF, direct oral anticoagulants (DOACs) has been proved to be non-inferior to adjusted-dose vitamin K antagonist (VKA). However, the role of DOACs in patients with AF in the setting of HCM has not been fully established.Methods: A comprehensive literature review was conducted by searching for published articles indexed in MEDLINE and EMBASE databases from inception through 1 May 2019. Eligible studies must start with recruitment of patients with AF in the setting of HCM who received either DOACs or VKA. The studies must follow them for the occurrence of ischaemic stroke. Hazard ratio (HR) and confidence interval (CI) of developing ischaemic stroke between the two groups must be reported. Pooled HR was calculated using a random-effect, generic inverse variance method of DerSimonian and Laird.Results: A total of three retrospective cohort studies with 4,418 participants met the eligibility criteria and were included into the meta-analysis. A significantly lower risk of all-cause death was observed in the DOACs group than in the VKA group with the pooled HR of 0.43 (95% CI, 0.33-0.58, I2 = 0%). However, the risk of ischaemic stroke among patients with AF and HCM who received DOACs was not significantly different from those who received VKA with the pooled HR of 0.95 (95% CI, 0.73-1.22, I2 = 0%). Both major bleeding and intracranial bleeding were also not significantly different between those who received DOACs versus those who received VKA with the pooled HR of 0.94 (95% CI, 0.70-1.26, I2 = 0%) and 0.61 (95% CI, 0.27-1.37, I2 = 0%), respectively.Conclusions: The current study found that the risk of all-cause death was significantly reduced but the risk of ischaemic stroke, major bleeding and intracranial bleeding were not significantly different between patients with AF and HCM who had received DOACs and those who received VKA.
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8.
The rebirth of the contact pathway: a new therapeutic target.
Srivastava, P, Gailani, D
Current opinion in hematology. 2020;(5):311-319
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Abstract
PURPOSE OF REVIEW Anticoagulation with vitamin-K antagonists or direct oral anticoagulants is associated with a significant risk of bleeding. There is a major effort underway to develop antithrombotic drugs that have a smaller impact on hemostasis. The plasma contact proteins factor XI (FXI) and factor XII (FXII) have drawn considerable interest because they contribute to thrombosis but have limited roles in hemostasis. Here, we discuss results of preclinical and clinical trials supporting the hypothesis that the contact system contributes to thromboembolic disease. RECENT FINDINGS Numerous compounds targeting FXI or FXII have shown antithrombotic properties in preclinical studies. In phase 2 studies, drugs-targeting FXI or its protease form FXIa compared favorably with standard care for venous thrombosis prophylaxis in patients undergoing knee replacement. While less work has been done with FXII inhibitors, they may be particularly useful for limiting thrombosis in situations where blood comes into contact with artificial surfaces of medical devices. SUMMARY Inhibitors of contact activation, and particularly of FXI, are showing promise for prevention of thromboembolic disease. Larger studies are required to establish their efficacy, and to establish that they are safer than current therapy from a bleeding standpoint.
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The Relationship between Vitamin K and Osteoarthritis: A Review of Current Evidence.
Chin, KY
Nutrients. 2020;(5)
Abstract
Vitamin K is a cofactor of γ-glutamyl carboxylase, which plays an important role in the activation of γ-carboxyglutamate (gla)-containing proteins that negatively regulate calcification. Thus, vitamin K status might be associated with osteoarthritis (OA), in which cartilage calcification plays a role in the pathogenesis of the disease. This review collates the evidence on the relationship between vitamin K status (circulating or dietary intake level of vitamin K, or circulating uncarboxylated gla proteins) and OA from human observational studies and clinical trial, to examine its potential as an agent in preventing OA. The current literature generally agrees that a sufficient level of vitamin K is associated with a lower risk of OA and pathological joint features. However, evidence from clinical trials is limited. Mechanistic study shows that vitamin K activates matrix gla proteins that inhibit bone morphogenetic protein-mediated cartilage calcification. Gla-rich proteins also inhibit inflammatory cascade in monocytic cell lines, but this function might be independent of vitamin K-carboxylation. Although the current data are insufficient to establish the optimal dose of vitamin K to prevent OA, ensuring sufficient dietary intake seems to protect the elderly from OA.
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Intracerebral hemorrhage outcomes in patients using direct oral anticoagulants versus vitamin K antagonists: a meta-analysis.
Ahmed, A, Ahmed, R, Ali, SS, Patel, U, Shahid, I, Zafar, M, Sharma, A, Ashraf, A, Jani, V
Clinical neurology and neurosurgery. 2020;:106146
Abstract
BACKGROUND The objective of this paper is to assess the clinical outcomes between non-traumatic intracerebral hemorrhage(ICH) in patients using direct oral anticoagulants(DOAC) versus vitamin K antagonists(VKA) for non-valvular atrial fibrillation. We also evaluated the predictors of the poor post-ICH outcomes. METHODS We have performed pooled meta-analysis to assess long-term clinical outcomes in patients with DOAC-ICH as compared to those with VKA-ICH. A systematic literature search was conducted by searching the full-text English literature in PubMed, EMBASE, and Cochrane databases for observational studies reporting outcomes on interest. MOOSE guidelines were used to collect data till December 31, 2019 and random effects analysis was carried out to account for heterogeneity. For outcomes, risk ratios(RR) and the mean differences were pooled using a random-effects model and weighted mean differences (WMDs), respectively. RESULTS Seventeen studies met the inclusion criteria (n = 25,354 patients; DOAC-ICH arms = 5,631; VKA-ICH arm = 19,273). Patients with DOAC-ICH had smaller hematoma volumes (WMD=-9.59; 95%CI=-15.33--3.85; I2 = 68.6%) and reduced mortality rate at discharge (RR = 0.82; 95%CI = 0.71-0.96; I2 = 9.4%). There was no significant difference between the two groups in rate of hematoma expansion (RR = 0.79; 95%CI = 0.56-1.11; I2 = 50.9%), unfavorable functional outcome(Modified Rankin Scale) at discharge (RR = 0.82; 95%CI = 0.56-1.18; I2 = 80.2%), unfavorable outcome at 3-months (RR = 0.77; 95%CI = 0.56-1.06; I2 = 63.9), and mortality at 3-months (RR = 0.90; 95%CI = 0.73-1.10; I2 = 35∙8%). Multivariate meta-regression revealed that the average age of patient population had a significantly negative correlation with(RR=-0.202; p = 0.017) hematoma expansion. CONCLUSION We conclude that use of DOAC is associated with reduced hematoma volume and mortality rate at discharge. Age is a predictor of the poor outcome of hematoma expansion.