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Lifestyle Intervention Improves Prothrombotic Coagulation Profile in Individuals at High Risk for Type 2 Diabetes.
Hörber, S, Lehmann, R, Fritsche, L, Machann, J, Birkenfeld, AL, Häring, HU, Stefan, N, Heni, M, Fritsche, A, Peter, A
The Journal of clinical endocrinology and metabolism. 2021;(8):e3198-e3207
Abstract
CONTEXT Patients with obesity and insulin resistance are at higher risk for arterial and venous thrombosis due to a prothrombotic state. OBJECTIVE The present study addressed whether this is reversible by lifestyle intervention and elucidated potential underlying associations. METHODS A total of 100 individuals with impaired glucose tolerance or impaired fasting plasma glucose participated in a 1-year lifestyle intervention, including precise metabolic phenotyping and MRS-based determination of liver fat content as well as a comprehensive analysis of coagulation parameters before and after this intervention. RESULTS During the lifestyle intervention, significant reductions in coagulation factor activities (II, VII, VIII, IX, XI, and XII) were observed. Accordingly, prothrombin time (PT%) and activated partial thromboplastin time (aPTT) were slightly decreased and prolonged, respectively. Moreover, plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (vWF), and also protein C and protein S decreased. Fibrinogen, antithrombin, D-dimer, and FXIII remained unchanged. Searching for potential regulators, especially weight loss, but also liver fat reduction, improved insulin sensitivity, and decreased low-grade inflammation were linked to favorable changes in hemostasis parameters. Independent of weight loss, liver fat reduction (FII, protein C, protein S, PAI-1, vWF), improved insulin sensitivity (protein S, PAI-1), and reduced low-grade inflammation (PT%, aPTT, FVIII/IX/XI/XII, vWF) were identified as single potential regulators. CONCLUSION Lifestyle intervention is able to improve a prothrombotic state in individuals at high risk for type 2 diabetes. Besides body weight, liver fat content, insulin sensitivity, and systemic low-grade inflammation are potential mechanisms for improvements in hemostasis and could represent future therapeutic targets.
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2.
Intravenous Vitamin K1 for the Correction of Prolonged Prothrombin Times in Non-Bleeding Critically Ill Patients: A Prospective Observational Study.
Dahlberg, S, Schött, U, Eriksson, EÄ, Tahirsylaj, Y, Schurgers, L, Kander, T
Nutrients. 2021;(8)
Abstract
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.
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Examining therapeutic equivalence between branded and generic warfarin in Brazil: The WARFA crossover randomized controlled trial.
Gomes Freitas, C, Walsh, M, Coutinho, EL, Vincenzo de Paola, AA, Atallah, ÁN
PloS one. 2021;(4):e0248567
Abstract
OBJECTIVES To determine whether the generic and branded warfarins used as anticoagulants in Brazil are therapeutic equivalents based on their international normalized ratio (INR) results. METHODS This crossover randomized controlled trial had four periods. We used the branded Marevan and two generic versions of warfarin sodium tablets, manufactured by União Química and Teuto laboratories, all purchased from retail drugstores. Eligible participants were outpatients from an anticoagulation clinic at a university hospital in São Paulo, Brazil. They had atrial fibrillation or flutter and had been using warfarin for at least 2 months with an INR therapeutic range of 2.0-3.0. Randomization was by numbered, opaque, sealed envelopes. Healthcare personnel and outcome assessors were blinded to treatments, but patients were not. The primary outcome was the variability in the INR (ΔINR) and secondary outcomes included mean INR. We accepted formulations as equivalent if the 95% confidence interval (CI) of the comparison of ΔINR between branded and generic formulations was within the limit of ±0.49. RESULTS One hundred patients were recruited and randomized to six sequences of treatment (four sequences with n = 17 and two sequences with n = 16). União Química generic warfarin had equivalent variability in the INR to Marevan (ΔINR +0.09 [95% CI -0.29 to +0.46], n = 84). Comparison between Teuto generic warfarin and Marevan was inconclusive (ΔINR +0.29 [95% CI -0.09 to +0.68], n = 84). CONCLUSIONS Marevan and União Química warfarin had equivalent therapeutic effectiveness and both could be confidently used for anticoagulation. The comparison between Marevan and TW was inconclusive and does not warrant a statement of equivalence. Our methods are especially important for comparing generic and branded drugs that raise concerns and may be subject of future investigations by regulatory agents. TRIAL REGISTRATION ClinicalTrials.gov NCT02017197.
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Treatment Effect of Regional Sodium Citrate Anticoagulation in Elderly Patients With High-Risk Bleeding Receiving Continuous Renal Replacement Therapy.
Xun, K, Qiu, H, Jia, M, Lin, L, He, M, Li, D, Jin, D
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2021;:10760296211050640
Abstract
OBJECTIVE To investigate the safety and efficacy of regional citrate anticoagulation (RCA) on elderly patients at high risk of bleeding after continuous renal replacement therapy (CRRT). METHODS A total of 31 patients at high risk of bleeding who received CRRT in the intensive care unit were collected. The patients were divided into RCA group (n = 17) and no anticoagulation group (NA, n = 14) according to whether RCA was used or not. The levels of creatinine (Cr), blood urea nitrogen (BUN), prothrombin time (PT), activated partial thromboplastin time (APTT), total calcium (tCa), ionized calcium ion (iCa2+), sodium ion (Na+), bicarbonate ion (HCO3-), tCa/iCa2+ ratio, and pH were observed after treatment. The filter use time, number of filters used, filter obstruction events, clinical outcomes, and safety evaluation indexes were compared post-treatment. RESULTS After treatment, serum Cr and BUN levels, APTT and PT levels in the RCA group were significantly lower than the NA group. The tCa, iCa2+, HCO3-, tCa/iCa2+, and pH were within the normal range after RCA treatment while Na+ levels saw a significant increase. In the RCA group, the filter using time was significantly longer, with significantly reduced numbers of filter use within 72 h and filter disorder events. Additionally, patients in the RCA group showed significant recovery of renal function and a significant reduction in bleeding events and in-hospital mortality. CONCLUSION RCA treatment significantly improves clinical outcome of patients at high risk of bleeding after CRRT, safely and effectively prolongs the filter life and avoids coagulation incidences.
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5.
Antithrombotic strategies in elderly patients with acute coronary syndrome.
Dillinger, JG, Laine, M, Bouajila, S, Paganelli, F, Henry, P, Bonello, L
Archives of cardiovascular diseases. 2021;(3):232-245
Abstract
Elderly patients represent a growing proportion of the acute coronary syndrome population in Western countries. However, their frequent atypical symptoms at presentation often lead to delays in management and to misdiagnosis. Furthermore, their prognosis is poorer than that of younger patients because of physiological changes in platelet function, haemostasis and fibrinolysis, but also a higher proportion of comorbidities and frailty, both of which increase the risk of recurrent thrombotic and bleeding events. This complex situation, with ischaemic and haemorrhagic risk factors often being intertwined, may lead to confusion about the required treatment strategy, sometimes resulting in inadequate management or even to therapeutic nihilism. It is therefore critical to provide a comprehensive overview of our understanding of the pathophysiological processes underlying acute coronary syndrome in elderly patients, and to summarise the results from the latest clinical trials to help decision making for these high-risk patients.
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Comparison of Anticoagulation Quality between Acenocoumarol and Warfarin in Patients with Mechanical Prosthetic Heart Valves: Insights from the Nationwide PLECTRUM Study.
Menichelli, D, Poli, D, Antonucci, E, Cammisotto, V, Testa, S, Pignatelli, P, Palareti, G, Pastori, D, The Italian Federation Of Anticoagulation Clinics Fcsa,
Molecules (Basel, Switzerland). 2021;(5)
Abstract
Vitamin K antagonists are indicated for the thromboprophylaxis in patients with mechanical prosthetic heart valves (MPHV). However, it is unclear whether some differences between acenocoumarol and warfarin in terms of anticoagulation quality do exist. We included 2111 MPHV patients included in the nationwide PLECTRUM registry. We evaluated anticoagulation quality by the time in therapeutic range (TiTR). Factors associated with acenocoumarol use and with low TiTR were investigated by multivariable logistic regression analysis. Mean age was 56.8 ± 12.3 years; 44.6% of patients were women and 395 patients were on acenocoumarol. A multivariable logistic regression analysis showed that patients on acenocoumarol had more comorbidities (i.e., ≥3, odds ratio (OR) 1.443, 95% confidence interval (CI) 1.081-1.927, p = 0.013). The mean TiTR was lower in the acenocoumarol than in the warfarin group (56.1 ± 19.2% vs. 61.6 ± 19.4%, p < 0.001). A higher prevalence of TiTR (<60%, <65%, or <70%) was found in acenocoumarol users than in warfarin ones (p < 0.001 for all comparisons). Acenocoumarol use was associated with low TiTR regardless of the cutoff used at multivariable analysis. A lower TiTR on acenocoumarol was found in all subgroups of patients analyzed according to sex, hypertension, diabetes, age, valve site, atrial fibrillation, and INR range. In conclusion, anticoagulation quality was consistently lower in MPHV patients on acenocoumarol compared to those on warfarin.
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Effect of atorvastatin on lipogenic, inflammatory and thrombogenic markers in women with the metabolic syndrome.
Velarde, GP, Choudhary, N, Bravo-Jaimes, K, Smotherman, C, Sherazi, S, Kraemer, DF
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2021;(2):634-640
Abstract
BACKGROUND AND AIM Specific drug therapy to target the underlying proinflammatory and prothrombotic state in patients with metabolic syndrome (MS) is lacking. We sought to study the effect of high-intensity atorvastatin on markers of lipogenesis, inflammation and thrombogenesis, in women with MS in the absence of cardiovascular disease or diabetes. METHODS AND RESULTS This randomized double-blinded controlled trial included 88 women with MS (according to National Cholesterol Education Panel Adult Treatment Panel III criteria) and low atherosclerotic cardiovascular risk. Participants were randomized to receive atorvastatin 80 mg or matching placebo. Thrombogenic, lipogenic and inflammatory markers were collected at the time of enrollment, after a 6-week dietary run-in phase (time of randomization), and at 6- and 12-weeks after randomization. At 6 weeks post-randomization, there was significant reduction in total cholesterol, low density lipoprotein cholesterol, triglycerides, apolipoprotein-B (Apo-B) and Apo-B/Apo-A1 ratio in the atorvastatin arm compared to placebo. This difference persisted at 12-weeks post randomization. There was no significant difference in fasting blood glucose, high-density lipoprotein cholesterol, high sensitivity C-reactive protein, serum leptin, Apo-A1, intercellular adhesion molecule 1 and platelet activity. A significant increase in vascular adhesion molecule 1 at 6 and 12 weeks was seen within the atorvastatin arm. No difference was observed in blood pressure and waist circumference. CONCLUSIONS In conclusion, high-intensity atorvastatin has an early and significant impact on lipoproteins and apolipoproteins but did not lower inflammatory, thrombogenic or biomarkers of platelet activity and aggregation in women with MS. The use of statins for primary prevention in these patients should be further explored.
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A review of oral anticoagulants, old and new, in major bleeding and the need for urgent surgery.
Milling, TJ, Ziebell, CM
Trends in cardiovascular medicine. 2020;(2):86-90
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Abstract
Oral anticoagulants, old and new, are effective therapies for prevention and treatment of venous thromboembolism and reduction of stroke risk in patients with atrial fibrillation. However, blocking elements of the clotting cascade carries an inherent risk of bleeding. Also, anticoagulated patients sometimes require urgent surgery or invasive procedures. This has led to the emergence of a body of scientific literature on the reversal of anticoagulation in these two settings. Traditionally, vitamin K antagonists (VKAs), which indirectly inactivate clotting factors II, VII, IX and X (and natural anticoagulant proteins C and S), had been the mainstay of oral anticoagulation for half a century. Only a few years ago, the US Food and Drug Administration (FDA) approved a specific VKA reversal agent, 4-Factor Prothrombin Complex Concentrate (4F-PCC). The last decade has seen the rise of non-Vitamin K oral anticoagulants (NOACs), which target specific factors, i.e. Factors IIa and Xa. Investigators have rapidly developed reversal agents for these agents as well, idarucizumab for the Factor IIa inhibitor dabigatran (Pradaxa) and andexanet alfa for the entire class of Factor Xa inhibitors (FXaIs), currently four drugs: rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Savaysa) and betrixaban (Bevyxxa). Clinicians still use off-label PCC for reversing FXaIs in some settings, and a universal reversal agent, ciraparantag, remains in development. This review summarizes the safety and efficacy of these reversal agents in the setting of anticoagulant-associated major bleeding and the need for urgent surgery.
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Regional Citrate Anticoagulation for Continuous Renal Replacement Therapy - A Safe and Effective Low-Dose Protocol.
Poh, CB, Tan, PC, Kam, JW, Siau, C, Lim, NL, Yeon, W, Cui, HH, Ding, HT, Song, XY, Yan, P, et al
Nephrology (Carlton, Vic.). 2020;(4):305-313
Abstract
AIMS: Regional citrate anticoagulation (RCA) is the preferred mode of anticoagulation for continuous renal replacement therapy (CRRT). Conventional RCA-CRRT citrate dose ranges from 3 to 5 mmol/L of blood. This study explored the effectiveness of an RCA protocol with lower citrate dose and its impact on citrate-related complications. METHODS This prospective observational study compared two RCA-CRRT protocols in the intensive care unit. RCA Protocol 1 used an initial citrate dose of 3.0 mmol/L while Protocol 2 started with 2.5 mmol/L. The citrate dose was titrated by sliding scale to target circuit-iCa 0.26-0.40 mmol/L. Calcium was re-infused post-dialyzer and titrated by protocol to target systemic-iCa 1.01-1.20 mmol/L. RESULTS Two hundred RCA-CRRT sessions were performed (81 Protocol 1; 119 Protocol 2). The median age was 65.4 years and median APACHE-II score was 23. Citrate dose for Protocol 1 was significantly higher than Protocol 2 in the first 12 h. The circuit clotting rate was similar in both arms (Protocol 1: 9.9%; Protocol 2: 9.2%; P = 0.881). With Protocol 2, circuit-iCa levels were 2.42 times more likely to be on target (P = 0.003) while the odds of hypocalcaemia was 4.67 times higher with Protocol 1 (P < 0.001). There was a wider anion gap was noted with Protocol 1, which suggests a propensity for citrate accumulation with higher citrate exposure. CONCLUSION The RCA protocol with a lower initial citrate dose of 2.5 mmol/L blood had less citrate-related complications with no loss of efficacy. A more precise RCA prescription at the start of treatment avoids unnecessary citrate exposure and improves safety.
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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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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.