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1.
New Insights Into the Pathogenesis of Bullous Pemphigoid: 2019 Update.
Genovese, G, Di Zenzo, G, Cozzani, E, Berti, E, Cugno, M, Marzano, AV
Frontiers in immunology. 2019;:1506
Abstract
There are several lines of evidence indicating that the physiopathological bases of bullous pemphigoid (BP), the most common subepidermal autoimmune bullous disease, are hallmarked by the production of autoantibodies directed against the hemidesmosomal anchoring proteins BP180 and BP230. In contrast to the robustness of the latter assumption, the multifaceted complexity of upstream and downstream mechanisms implied in the pathogenesis of BP remains an area of intense speculation. So far, an imbalance between T regulatory cells and autoreactive T helper (Th) cells has been regarded as the main pathogenic factor triggering the autoimmune response in BP patients. However, the contributory role of signaling pathways fostering the B cell stimulation, such as Toll-like receptor activation, as well as that of ancillary inflammatory mechanisms responsible for blister formation, such as Th17 axis stimulation and the activation of the coagulation cascade, are still a matter of debate. In the same way, the pathomechanisms implied in the loss of dermal-epidermal adhesion secondary to autoantibodies binding are not fully understood. Herein, we review in detail the current concepts and controversies on the complex pathogenesis of BP, shedding light on the most recent theories emerging from the literature.
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2.
Lysis Timer: a new sensitive tool to diagnose hyperfibrinolysis in liver transplantation.
Roullet, S, Labrouche, S, Mouton, C, Quinart, A, Nouette-Gaulain, K, Laurent, C, Freyburger, G
Journal of clinical pathology. 2019;(1):58-65
Abstract
AIMS: Diagnosis of hyperfibrinolysis in orthotopic liver transplantation (OLT) remains challenging. Euglobulin clot lysis time (ECLT) is not adapted to clinical situations. ROTEM is specific but seldom sensitive to hyperfibrinolysis. The Lysis Timer assesses 'Global Fibrinolytic Capacity' in citrated plasma (GFC/LT). GFC/LT associates reagents for in vitro triggering of the clot (thrombin and calcium) and its lysis (tissue-plasminogenactivator (t-PA)), turbidity signal acquisition by the Lysis Timer, and dedicated software converting the digital signal into an optical curve. A visual check of the curves was systematic to ascertain the lysis time values calculated by the software. The primary aim of this prospective observational study was to evaluate the ability of GFC/LT to recognise hyperfibrinolysis during OLT. The secondary aim was to compare its results with ROTEM maximum lysis (EXTEM ML) and with standard laboratory tests. METHODS Thirty consecutive adult patients undergoing OLT were included (NCT03012633). Standard laboratory tests, ROTEM, GFC/LT, ECLT and fibrinolysis parameters were assayed at five sample times. RESULTS GFC/LT was correlated with ECLT, plasmin activator inhibitor 1 antigen and activity and t-PA activity (r=0.490, 0.681, 0.643 and -0.359, respectively). Hyperfibrinolysis was defined as ECLT ≤60 min. Receiver operating characteristic curve analysis showed that GFC/LT with a threshold of 31 min detected hyperfibrinolysis with a sensitivity of 0.88 (95% CI 0.73 to 0.96), a specificity of 0.68 (95% CI 0.56 to 0.78) and an area under the curve (AUC) of 0.85 (95% CI 0.74 to 0.94). EXTEM ML >12% did not detect hyperfibrinolysis (sensitivity 0.38 (95% CI 0.24 to 0.55), specificity 0.95 (95% CI 0.86 to 0.99) and AUC 0.60 (95% CI 0.46 to 0.75)). CONCLUSIONS GFC/LT recognised hyperfibrinolysis during OLT with a significant agreement with the other tests of fibrinolysis. TRIAL REGISTRATION NUMBER NCT03012633.
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3.
Dual versus triple antithrombotic therapy: is there a role for direct oral anticoagulants in arterial thrombosis?
Garcia-Ropero, A, Santos-Gallego, CG, Zafar, MU, Badimon, JJ
Drugs of today (Barcelona, Spain : 1998). 2019;(3):197-214
Abstract
The number of patients receiving dual antiplatelet therapy with an additional indication for long-term oral anticoagulation has substantially increased over time. This population is facing an unacceptable risk of bleeding events, particularly among elderly individuals, who are especially vulnerable to complications. Further strategies to minimize this bleeding risk, including various drug combinations, different dosage regimens and even numerous attempts to find the appropriate duration of the treatment, have been evaluated in a multitude of randomized control trials. Moreover, the recent incorporation of the direct oral anticoagulants (DOACs) to the therapeutic armamentarium may represent an alternative to treat such patients, since they have demonstrated to be noninferior to the classic vitamin K antagonists and with lower bleeding rates. The aim of this review is to summarize the most recent literature on the use of DOACs in patients with an indication for dual antiplatelet therapy (mostly subjects with coronary artery disease) and also an established indication for chronic anticoagulation (chiefly individuals with nonvalvular atrial fibrillation). The role of DOACs in ischemic heart disease alone is also discussed.
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4.
Recurrent Thrombosis With Direct Oral Anticoagulants in Antiphospholipid Syndrome: A Systematic Literature Review and Meta-analysis.
Sanchez-Redondo, J, Espinosa, G, Varillas Delgado, D, Cervera, R
Clinical therapeutics. 2019;(9):1839-1862
Abstract
PURPOSE The treatment of thrombosis in patients with antiphospholipid syndrome (APS) usually requires long-term anticoagulation with vitamin K antagonists. The effectiveness of direct oral anticoagulants (DOACs) in APS has not been fully addressed. The purpose of this research was to analyze the efficacy (thrombotic event-free time) and tolerability (bleeding events) of DOACs in patients with APS. METHODS We performed a descriptive analysis of a systematic review of data from patients with APS treated with DOACs reported in the literature, via EMBASE, PubMed, and the European League Against Rheumatism and American College of Rheumatology congresses. After systematic review, a meta-analysis of data from clinical trials was performed. FINDINGS A total of 728 patients, accounting for 731 courses of treatment with DOACs, were identified. The majority (48.3%) presented with triple anti-phospholipid antibody positivity. The prevalence of thrombosis during DOAC treatment was 13.9%. Analysis of risk factors for recurrent thrombosis suggested that a higher mean (SD) number of prior thrombotic events (1.80 [0.87] vs 1.67 [1.45]; P = 0.012), history of combined arterial and venous thrombosis (27.3% vs 9.2% [P < 0.0001]; odds ratio [OR] = 3.72 [95% CI, 1.91-7.25]), previous treatment with LMWH (9.8% vs 1.1% [P = 0.04]; OR = 9.95 [95% CI, 1.08-91.97]), use of immunosuppressant treatment (41.7% vs 12.7% [P = 0.03]; OR = 4.9 [95% CI, 1.21-19.76]), and no reason to switch anticoagulant treatment other than patient's decision (32% vs 2.8% [P = 0.001]; OR = 16.24 [95% CI, 3.16-83.52]) were associated with a high risk for re-thrombosis. Meta-Analysis did not show statistically relevant difference in risk of thrombosis or bleeding comparing warfarin with DOACs. IMPLICATIONS The findings from this systematic literature review and meta-analysis suggest that patients treated with DOACs and having risk factors such as history of recurrent thrombosis, a history of combined arterial and venous thrombosis, or a need for immunosuppressant treatment, may have higer ratio of thrombotic recurrence. There are limited data to inform decisions on the use of DOACs in patients with APS with different or no risk factors.
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5.
[Antithrombotic therapy and digestive endoscopy: a difficult management.].
De Francesco, V, Manta, R, Zullo, A
Recenti progressi in medicina. 2019;(11):535-542
Abstract
Antithrombotic therapy (antiplatelet and anticoagulant) is frequently used in clinical practice for the prevention of thromboembolic events in patients at risk, such as those with atrial fibrillation or pro-thrombotic conditions. On the other hand, endoscopic investigations on the upper digestive tract (gastroscopy, endoscopic retrograde colangiopancreatography) and lower (colonoscopy) are increasingly performed to prevent, diagnose and treat different diseases of digestive tract. Therefore, it is not uncommon for a patient to undergo endoscopic examination while taking antithrombotic therapy. The pharmacological management of these patients requires a careful balance between the haemorrhagic risk linked to the continuation of therapy and the hemorrhagic risk inherent to the endoscopic procedure, particularly when an operative procedure (polypectomy, sphincterotomy, etc.) is required. Beyond classical anticoagulants (vitamin K antagonists, dicumarolici), the so-called "direct-acting anticoagulants" have been recently introduced, and management of these drugs in before an endoscopic examination is different. Since endoscopic procedures are largely scheduled as "open access" directly by general practitioner, she/he is clearly involved in the management of these patients. This review aims to report the recommendations of international guidelines on this field, and to provide some schematic tools for performing a correct management of patients on antithrombotic therapy before gastrointestinal endoscopy.
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6.
Viscoelastic properties of plasma fibrin clots are similar in patients on rivaroxaban and vitamin K antagonists.
Kopytek, M, Zabczyk, M, Natorska, J, Siudut, J, Malinowski, KP, Ptaszek, P, Glajcar, A, Goralczyk, T, Undas, A
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society. 2019;(1)
Abstract
Unfavorable fibrin clot features have been observed in patients with venous thromboembolism (VTE). We investigated whether rivaroxaban, a direct factor Xa inhibitor, and vitamin K antagonists (VKAs) can improve plasma clot viscoelastic properties. We studied four age- and sex-matched groups: 25 healthy controls, 15 VTE patients taking rivaroxaban 20 mg/day (blood concentration, 145 (67 - 217) ng/ml), 15 VTE patients taking VKA (INR: 2 - 3), and 15 VTE patients who stopped oral anticoagulant therapy (OAT). Using a hybrid rheometier the storage (G') and loss (G") moduli were evaluated in citrated plasma after addition of 5 pmol/l tissue factor. Fiber thickness within clots was assessed using scanning electron microscopy. Higher G' but not G" was observed for VTE patients taking rivaroxaban (+34%; post hoc, P = 0.029) compared to controls. As reflected by lower G' and G", patients taking rivaroxaban (-19% and -30%; post hoc, P = 0.0013 and P < 0.0001, respectively) formed less stiff and viscous clots compared to VTE patients after OAT withdrawal, also after adjustment for fibrinogen. VTE patients treated with rivaroxaban and VKA had similar clot viscoelastic properties (post hoc, P = 0.85 for G' and P = 0.29 for G"). G' and G" correlated with plasma rivaroxaban concentrations (r = -0.67, P = 0.005 and r = -0.59, P = 0.021, respectively), and the time from the last dose of rivaroxaban intake (r = 0.59, P = 0.02 and r = 0.58, P = 0.022, respectively). G' and G" showed no association with INR in patients on VKAs. G' or G" were not associated with fibrin diameter on scanning electron microscopy images in either group. Our preliminary study shows that both rivaroxaban and VKA improve clot viscoelastic properties in VTE patients, which might contribute to their antithrombotic effects. G' and G" may reflect specific clot physical features, beyond key plasma clot characteristics, which highlights benefits from comprehensive plasma clot analysis in patients with thrombotic diseases.
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7.
Triple versus double antithrombotic therapy in patients with atrial fibrillation and stent implantation: a meta‑analysis of randomized trials.
Grajek, S, Olasińska-Wiśniewska, A, Michalak, M, Ritter, SS
Kardiologia polska. 2019;(9):837-845
Abstract
BACKGROUND Appropriate double (DT) and triple (TT) antithrombotic therapy in patients with atrial fibrillation and stent implantation is unclear. AIM: The aim of the study was to perform a meta‑analysis of studies comparing DT and TT in patients with atrial fibrillation and stent implantation. METHODS Of the 450 reports, 5 randomized trials were included in the meta‑analysis: WOEST, ISAR‑REACT, PIONEER AF‑PCI, RE‑DUAL PCI, and AUGUSTUS, with a total of 9931 patients. RESULTS Treatment efficacy, as assessed by the incidence of major adverse cardiac events, did not differ significantly between both therapeutic strategies: 8.98% for DT vs 8.71% for TT (odds ratio [OR], 1.02; 95% CI, 0.86-1.21). The incidence of hemorrhagic complications was significantly lower in patients treated with DT than TT (13.1% and 21.0%, respectively; OR, 0.57; 95% CI, 0.47-0.70). In over 90% of patients, DT included clopidogrel along with an oral anticoagulant (non-vitamin K antagonist oral anticoagulant or vitamin K antagonist). CONCLUSIONS The results of our meta‑analysis are clearly in line with the current trend of the fastest possible reduction in the use of TT in favor of DT. Almost half lower risk of hemorrhagic complications during DT compared with TT, with similar efficacy of the 2 strategies, provides an argument for the wider use of DT in patients with AF and stent implantation.
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8.
Coagulation, Thrombogenesis, and Insulin Resistance Markers in Increased-Cardiovascular-Risk Subjects Consuming Improved-Fat Meat Products.
Celada, P, Olmedilla-Alonso, B, Delgado-Pando, G, Raposo, R, Jiménez-Colmenero, F, Garcimartín, A, Sánchez-Muniz, FJ
Journal of the American College of Nutrition. 2019;(4):334-341
Abstract
OBJECTIVES Cardiovascular disease (CVD) risk is prevalent in high-meat-product consumers. The effect of consuming lipid-improved pâtés/frankfurters on plasma low-density lipoprotein (LDL)-cholesterol, thromboxane A2 (as TXB2), prostacyclin I2 (as 6-keto-PGF1α), activated partial thromboplastin time, fibrinogen, antithrombin, and insulin-resistance/sensitivity markers in volunteers at high CVD risk was studied. SUBJECTS/METHODS Eighteen male volunteers enrolled in a blind crossover-controlled study consumed improved products during three 4-week periods: reduced fat (RF), n-3-enriched-RF (n-3RF), and normal fat (NF), separated by 4-week washouts. RESULTS Fibrinogen and 6-keto-PG1α decreased (p < 0.05) following the RF period; LDL-cholesterol, TXB2, and 6-keto-PGF1α decreased (p < 0.05) after the n-3RF-period, while LDL-cholesterol, fibrinogen, TXB2, insulin, and Homostatic Model Assessment-insulin resistance (HOMA-IR) increased (at least p < 0.05) and QUICKI (Quantitative Insulin Sensitivity Check Index) decreased (p < 0.05) during the NF period. The rates of changes of fibrinogen, TXB2, 6-keto-PGF1α, and HOMA-IR differ between groups (repeated-measures test p < 0.05). Fibrinogen, insulin, and HOMA-IR differed significantly (p < 0.05) between RF and n-3RF period versus NF period, while that of TXB2 and 6-keto-PGF1α differed between n-3RF and NF periods (p < 0.05). CONCLUSIONS The consumption of n-3RF meat products, followed by RF ones, partially reduced thrombogenesis, coagulation, and insulin-resistance markers. Thus, the inclusion of lipid-improved pâtés/frankfurters might be recommended into dietary strategies in at-CVD-risk volunteers.
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9.
Vitamin K antagonists and emergencies.
Lapostolle, F, Siguret, V, Martin, AC, Pailleret, C, Vigué, B, Zerbib, Y, Tazarourte, K
European journal of emergency medicine : official journal of the European Society for Emergency Medicine. 2018;(6):378-386
Abstract
The recent emergence of 'non-VKA' oral anticoagulants may have led to some forgetting that vitamin K antagonists (VKA) are by far the most widely prescribed oral anticoagulants worldwide. Consequently, we decided to summarize the information available on them. This paper presents the problems facing emergency physicians confronted with patients on VKAs in 10 points, from pharmacological data to emergency management. Vitamin K antagonists remain preferable in many situations including in the elderly, in patients with extreme body weights, severe chronic kidney or liver disease or valvular heart disease, and in patients taking VKAs with well-controlled international normalized ratios (INRs). Given the way VKAs work, a stable anticoagulant state can only be achieved at the earliest 5 days after starting therapy. The induction phase of VKA treatment is associated with the highest risk of bleeding; validated algorithms based on INR values have to be followed. VKA asymptomatic overdoses and 'non-severe' hemorrhage are managed by omitting a dose or stopping treatment plus administering vitamin K depending on the INR. Major bleeding is managed using a VKA reversal strategy. A prothrombin complex concentrate infusion plus vitamin K is preferred to rapidly achieve an INR of up to 1.5 and maintain a normal coagulation profile. The INR must be measured 30 min after the infusion. Before an invasive procedure, if an INR of less than 1.5 (<1.3 in neurosurgery) is required, it can be achieved by combining prothrombin complex concentrate and vitamin K. A well-codified strategy is essential for managing patients requiring emergency invasive procedures or presenting bleeding complications.
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10.
Dalteparin anticoagulation in paediatric home haemodialysis.
Lutkin, M, Stronach, L, Yadav, P, Hothi, DK
Pediatric nephrology (Berlin, Germany). 2018;(12):2337-2341
Abstract
BACKGROUND The aim of this study was to investigate whether dalteparin is a safe and effective anticoagulant for paediatric home haemodialysis (HD) and to assess the determinants of dosing. METHODS Data were collected for all children (< 18 years) undergoing home HD from 2011 to 2017 at one large paediatric nephrology centre in the UK. All children had anticoagulation with dalteparin sodium according to a standardised protocol. Dalteparin safety was assessed by monitoring for accumulation, adequate clearance of dalteparin and adverse events. Dalteparin efficacy was assessed through monitoring for clot formation in dialysis circuits. Potential determinants of dalteparin dosing were assessed. RESULTS Eighteen children were included, their median age at start was 12 years, and 50% were male. Eighty-three percent of children had four home HD sessions each week, with a median total dialysis hours of 20 h/week. Thirty-three percent of children had nocturnal home HD. Median dalteparin dose at 12-month follow-up was 40 IU/kg (range 8-142 IU/kg). Factors associated with higher dalteparin dosing requirements included a younger age of the child (p < 0.01), a lower blood flow rate (p < 0.01) and the use of a central venous line for dialysis access (p = 0.038). No children had evidence of bioaccumulation of dalteparin or inadequate clearance. No significant bleeding or adverse events were reported. CONCLUSIONS Dalteparin is a safe and effective anticoagulant when used for paediatric home HD. In this study, there was no evidence of bioaccumulation or significant adverse events. Further research is required to directly compare dalteparin with unfractionated heparin (UFH) and evaluate anticoagulant choice for paediatric home HD.