Challenges in ageing persons with haemophilia.

As treatments for individuals with inherited bleeding disorders improve, life expectancy increases and is approaching that of the normal population. Concomitant with this we are now seeing the problems of ageing in the bleeding disorder population. Although the clear-cut association between low clotting factor levels and risk of bleeding is well recognised, a relationship between high levels, some non-factor therapies and thrombotic risk also exists. The management of thrombosis in persons with inherited bleeding disorders is complex but manageable with modern treatments and collaboration in decision making between health care professionals and patients. Despite the improvements in treatment and reduction in bleeding, mostly musculoskeletal pain continues to be a major issue with advancing age. The management of pain amongst older people with haemophilia who may have multiple comorbidities should involve a person-centred, holistic, multi-disciplinary approach to support and optimise long-term physical functioning and overall quality of life.

Effects of sodium ferulate for injection on anticoagulation of warfarin in rats in vivo.

BACKGROUND: Herb-drug interactions may result in increased adverse drug reactions or diminished drug efficacy, especially for drugs with a narrow therapeutic index such as warfarin. The current study investigates the effects of sodium ferulate for injection (SFI) on anticoagulation of warfarin from aspects of pharmacodynamics and pharmacokinetics in rats and predicts the risk of the combination use. METHODS: Rats were randomly divided into different groups and administered single- or multiple-dose of warfarin (0.2 mg/kg) with or without SFI of low dose (8.93 mg/kg) or high dose (26.79 mg/kg). Prothrombin time (PT) and activated partial thromboplastin time (APTT) were detected by a blood coagulation analyzer, and international normalized ratio (INR) values were calculated. UPLC-MS/MS was conducted to measure concentrations of warfarin enantiomers and pharmacokinetic parameters were calculated by DAS2.0 software. RESULTS: The single-dose study demonstrated that SFI alone had no effect on coagulation indices, but significantly decreased PT and INR values of warfarin when the two drugs were co-administered (P < 0.05 or P < 0.01), while APTT values unaffected (P > 0.05). Cmax and AUC of R/S-warfarin decreased but CL increased significantly in presence of SFI (P < 0.01). The multiple-dose study showed that PT, APTT, INR, and concentrations of R/S-warfarin decreased significantly when SFI was co-administered with warfarin (P < 0.01). Warfarin plasma protein binding rate was not significantly changed by SFI (P > 0.05). CONCLUSIONS: The present study implied that SFI could accelerate warfarin metabolism and weaken its anticoagulation intensity in rats.

A decade of experience in over 300 surgically treated spine patients with long-term oral anticoagulation: a propensity score matched cohort study.

PURPOSE: The aim of this study was to investigate the risks and outcomes of patients with long-term oral anticoagulation (OAC) undergoing spine surgery. METHODS: All patients on long-term OAC who underwent spine surgery between 01/2005 and 06/2015 were included. Data were prospectively collected within our in-house Spine Surgery registry and retrospectively supplemented with patient chart and administrative database information. A 1:1 propensity score-matched group of patients without OAC from the same time interval served as control. Primary outcomes were post-operative bleeding, wound complications and thromboembolic events up to 90 days post-surgery. Secondary outcomes included intraoperative blood loss, length of hospital stay, death and 3-month post-operative patient-rated outcomes. RESULTS: In comparison with the control group, patients with OAC (n = 332) had a 3.4-fold (95%CI 1.3-9.0) higher risk for post-operative bleeding, whereas the risks for wound complications and thromboembolic events were comparable between groups. The higher bleeding risk was driven by a higher rate of extraspinal haematomas (3.3% vs. 0.6%; p = 0.001), while there was no difference in epidural haematomas and haematoma evacuations. Risk factors for adverse events among patients with OAC were mechanical heart valves, posterior neck surgery, blood loss > 1000 mL, age, female sex, BMI > 30 kg/m2 and post-operative PTT levels. At 3-month follow-up, most patients reported favourable outcomes with no difference between groups. CONCLUSION: Although OAC patients have a higher risk for complications after spine surgery, the risk for major events is low and patients benefit similarly from surgery.

Mortality of hospitalized patients with COVID-19: Effects of treatment options (vitamin D, anticoagulation, isoprinosine, ivermectin) assessed by propensity score matching, retrospective analysis.

INTRODUCTION: SARS-CoV-2 respiratory infection is associated with significant morbidity and mortality, especially in hospitalized high-risk patients. We aimed to evaluate the effects of treatment options (vitamin D, anticoagulation, isoprinosine, ivermectin) on hospital mortality in non-vaccinated patients during the 2021 spring wave in the Czech Republic. METHODS: Initially, 991 patients hospitalized in the period January 1, 2021, to March 31, 2021, with PCR-confirmed SARS-CoV-2 acute respiratory infection in two university and five rural hospitals were included in the study. After exclusion of patients with an unknown outcome, a total of 790 patients entered the final analysis. The effects of different treatments were assessed in this cohort by means of propensity score matching. RESULTS: Of the 790 patients, 282 patients died in the hospital; 37.7% were male and 33.3% were female. Age, sex, state of the disease, pneumonia, therapy, and several comorbidities were matched to simulate a case-control study. For anticoagulation treatment, 233 cases (full-dose) vs. 233 controls (prophylactic dose) were matched. The difference in mortality was significant in 16 of the 50 runs. For the treatment with isoprinosine, ivermectin, and vitamin D, none of the 50 runs led to a significant difference in hospital mortality. CONCLUSION: Prophylactic-dose anticoagulation treatment in our study was found to be beneficial in comparison with the full dose. Supplementation with vitamin D did not show any meaningful benefit in terms of lowering the hospital mortality. Neither ivermectin nor, isoprinosine was found to significantly decrease hospital mortality.

Unraveling snake venom phospholipase A2: an overview of its structure, pharmacology, and inhibitors.

Snake bite is a neglected disease that affects millions of people worldwide. WHO reported approximately 5 million people are bitten by various species of snakes each year, resulting in nearly 1 million deaths and an additional three times cases of permanent disability. Snakes utilize the venom mainly for immobilization and digestion of their prey. Snake venom is a composition of proteins and enzymes which is responsible for its diverse pharmacological action. Snake venom phospholipase A2 (SvPLA2) is an enzyme that is present in every snake species in different quantities and is known to produce remarkable functional diversity and pharmacological action like inflammation, necrosis, myonecrosis, hemorrhage, etc. Arachidonic acid, a precursor to eicosanoids, such as prostaglandins and leukotrienes, is released when SvPLA2 catalyzes the hydrolysis of the sn-2 positions of membrane glycerophospholipids, which is responsible for its actions. Polyvalent antivenom produced from horses or lambs is the standard treatment for snake envenomation, although it has many drawbacks. Traditional medical practitioners treat snake bites using plants and other remedies as a sustainable alternative. More than 500 plant species from more than 100 families reported having venom-neutralizing abilities. Plant-derived secondary metabolites have the ability to reduce the venom's adverse consequences. Numerous studies have documented the ability of plant chemicals to inhibit the enzymes found in snake venom. Research in recent years has shown that various small molecules, such as varespladib and methyl varespladib, effectively inhibit the PLA2 toxin. In the present article, we have overviewed the knowledge of snake venom phospholipase A2, its classification, and the mechanism involved in the pathophysiology of cytotoxicity, myonecrosis, anticoagulation, and inflammation clinical application and inhibitors of SvPLA2, along with the list of studies carried out to evaluate the potency of small molecules like varespladib and secondary metabolites from the traditional medicine for their anti-PLA2 effect.

Gaps in guideline-recommended anticoagulation in patients with atrial fibrillation and elevated thromboembolic risk within an integrated healthcare delivery system.

BACKGROUND: Atrial Fibrillation (AF) is the leading cause of stroke, which can be reduced by 70% with appropriate oral anticoagulation (OAC) therapy. Nationally, appropriate anticoagulation rates for patients with AF with elevated thromboembolic risk are as low as 50% even across the highest stroke risk cohorts. This study aims to evaluate the variability of appropriate anticoagulation rates among patients by sex, ethnicity, and socioeconomic status within the Kaiser Permanente Mid-Atlantic States (KPMAS). METHODS: This retrospective study investigated 9513 patients in KPMAS's AF registry with CHADS2 score ≥ 2 over a 6-month period in 2021. RESULTS: Appropriately anticoagulated patients had higher rates of diabetes, prior stroke, and congestive heart failure than patients who were not appropriately anticoagulated. There were no significant differences in anticoagulation rates between males and females (71.8% vs. 71.6%%, [OR] 1.01; 95% CI, 0.93-1.11; P = .76) nor by SES-SVI quartiles. There was a statistically significant difference between Black and White patients (70.8% vs. 73.1%, P = .03) and Asian and White patients (68.3% vs. 71.6%, P = .005). After adjusting for CHADS2, this difference persisted for Black and White participants with CHADS2 scores of ≤3 (62.6% vs. 70.6%, P < .001) and for Asian and White participants with CHADS2 scores > 5 (68.0% vs. 79.3%, P < .001). CONCLUSIONS: Black and Asian patients may have differing rates of appropriate anticoagulation when compared with White patients. Characterizing such disparities is the first step towards addressing treatment gaps in AF.

Biomimetic platelet-camouflaged drug-loaded polypyrrole for the precise targeted antithrombotic therapy.

Lower extremity deep venous thrombosis (LEDVT) affects patient's quality of life for a long time, and even causes pulmonary embolism, which threatens human health. Current anticoagulant drugs in clinical treatment are hampered by the risk of bleeding due to poor targeting and low drug penetration. Here, we used platelet (PLT)-like biological targeting to enhance the delivery and accumulation of nanomedicines in thrombus and reduce the risk of bleeding. Meanwhile, the parallel strategy of "thrombus thermal ablation and anticoagulation" was applied to increase the permeability of drugs in thrombus and achieve the optimal antithrombotic effect. Polypyrrole (PPy) and rivaroxban (Riv, an anticoagulant drug) were co-assembled into platelet membrane-coated nanoparticles (NPs), PLT-PPy/Riv NPs, which actively targeted the thrombotic lesion at multiple targets in the platelet membrane and were thermally and drug-specific thrombolysed by 808 nm laser irradiation. The combination therapy resulted in up to 90% thrombolysis in a femoral vein thrombosis model compared to single phototherapy or drug therapy. The results showed that the nanoformulation provided a new direction for remote precise and controlled sustained thrombolysis, which was in line with the trend of nanomedicine towards clinical translation.

[Optimal processing technology of Zhangbang vinegar-processed Olibanum with multi-indicator-response surface methodology and anticoagulant effect evaluation].

This study first optimized the processing technology for Zhangbang vinegar-processed Olibanum and investigated its in vitro anticoagulant activity. A multi-index-response surface methodology was used, with yield, powder yield, and the relative percentage of the content of six non-volatile components [11-keto-boswellic acid(KBA), 3-acetyl-11-keto-boswellic acid(AKBA), ß-elemonic acid, α-boswellic acid(α-BA), ß-boswellic acid(ß-BA), and α-acetyl-boswellic acid(α-BA)] and three volatile components(octyl acetate, incensole, and incensole acetate) as evaluation indicators. Analytical hierarchy process(AHP) combined with coefficient of variation method was used to calculate the weight of each indicator and calculate the comprehensive score(OD). Furthermore, response surface methodology was used to investigate the effects of frying temperature(A), burning time(B), rice vinegar dosage(C), and steaming time(D) on the processing technology of vinegar-processed Olibanum. Vinegar-steamed Olibanum was prepared according to the optimal processing technology for in vitro anticoagulant experiments. The results showed that the weights of octyl acetate, incensole, incensole acetate, KBA, AKBA, ß-elemonic acid, α-BA, ß-BA, α-ABA, yield, and powder yield were 0.358 2, 0.104 5, 0.146 4, 0.032 9, 0.123 7, 0.044 4, 0.022 1, 0.042 2, 0.110 1, 0.012 2, and 0.0032, respectively. The optimal processing technology for Zhangbang vinegar-processed Olibanum was as follows. Olibanum(50 g) with a particle size of 1-5 mm was continuously stir-fried at a low heat of 150-180 ℃ until in a gel-like state, ignited for burning for 15 s, sprayed with 7.5 g of rice vinegar(15%), and steamed for 3 min without fire. Subsequently, the cover was removed, and the product was continuously stir-fried at 150-180 ℃ until in a soft lump shape, removed, cooled, and crushed. The results of the in vitro anticoagulant experiments showed that compared with the blank group, both Olibanum and vinegar-processed Olibanum significantly prolonged the activated partial thromboplastin time(APTT), thrombin time(TT), and prothrombin time(PT) of rat platelet-poor plasma(PPP), and the effect of vinegar-processed Olibanum was significantly better than that of Olibanum(P<0.05). The optimized processing technology for Zhangbang vinegar-processed Olibanum is stable, feasible, and beneficial for the further development and utilization of Olibanum slices. At the same time, using the content of volatile and non-volatile components, yield, and powder yield as indicators, and verifying through pharmacological experiments, the obtained results are more reasonable and credible, and have positive guiding significance for the clinical application of characteristic processed Olibanum products.

Antithrombin III supplementation during neonatal and pediatric extracorporeal membrane oxygenation.

BACKGROUND: Bleeding and thrombosis are common extracorporeal membrane oxygenation (ECMO) complications associated with increased mortality. Heparin is the most commonly used ECMO anticoagulant, employed in 94% of cases. Reduced antithrombin III (AT3) levels could decrease heparin effectiveness. Neonates have inherently lower levels of AT3 than adults, and pediatric patients on ECMO can develop AT3 deficiency. One potential approach for patients on ECMO with AT3 deficiency is exogenous AT3 supplementation. However, there is conflicting data concerning the use of AT3 for pediatric and neonatal patients on ECMO. METHODS: We analyzed the Bleeding and Thrombosis during ECMO database of 514 neonatal and pediatric patients on ECMO. We constructed daily regression models to determine the association between AT3 supplementation and rates of bleeding and thrombosis. Given the physiological differences between pediatric patients and neonates, we constructed separate models for each. RESULTS: AT3 administration was associated with increased rates of daily bleeding among pediatric (adjusted odds ratio [aOR] 1.59, p < 0.01) and neonatal (aOR 1.37, p = 0.04) patients. AT3 supplementation did not reduce the rate of thrombosis for either pediatric or neonatal patients. CONCLUSION: AT3 administration was associated with increased rates of daily bleeding, a hypothesized potential complication of AT3 supplementation. In addition, AT3 supplementation did not result in lower rates of thrombosis. We recommend clinicians utilize caution when considering supplementing patients on ECMO with exogenous AT3.

Redefining Clinically Significant Hematuria After Holmium Enucleation of the Prostate.

Introduction and Objective: Holmium laser enucleation of the prostate (HoLEP) is often offered for symptomatic prostatic enlargement at high risk for bleeding. However, prior studies define clinically significant hematuria (CSH) narrowly as the need for blood transfusion or significant decrease in hemoglobin. We sought to evaluate risk factors contributing to a broader definition of CSH, which may contribute to alteration of clinical course. Methods: We analyzed 164 patients in a prospectively maintained database who underwent HoLEP at a single institution across two surgeons from November 2020 to April 2023. HoLEP was performed using Moses 2.0 (Boston Scientific) laser and the Piranha enucleation system (Richard Wolf). We defined CSH broadly as follows: clot retention, return to operating room, perioperative management variation due to hematuria, or continued gross hematuria past 1 month postoperatively. Univariable and multivariable ANOVAs were used. Multivariable analysis of CSH risk based on the use of antiplatelet (AP) agents or anticoagulants included correction for age, enucleation time (surrogate for case difficulty), and prostate volume. Results: 17.7% (29/164) of our patients developed CSH after HoLEP. Longer enucleation time was a mild risk factor for developing CSH (multivariate odds ratio [OR] 1.01, p = 0.02). The strongest predictor of CSH was the use of anticoagulation or AP agents (OR 2.71 p < 0.02 on univariable analysis, OR 2.34 p < 0.02 on multivariable analysis), even when aspirin 81 mg was excluded. Conclusion: With a broadened definition, 18% of patients developed CSH following HoLEP, which impacted the clinical course. Our data suggest that the current definition of significant hematuria is too narrow and does not capture many patients whose clinical course is affected by hematuria. While safe, anticoagulants and APs significantly predicted an increased CSH risk, and patients should be counseled accordingly.

Phyllanthus emblica (Amla) methanolic extract regulates multiple checkpoints in 15-lipoxygenase mediated inflammopathies: Computational simulation and in vitro evidence.

Amla (Phyllanthus emblica) has long been used in traditional folk medicine to prevent and cure a variety of inflammatory diseases. In this study, the antioxidant activity (DPPH scavenging and reducing power), anti-inflammatory activity (RBC Membrane Stabilization and 15-LOX inhibition), and anticoagulation activity (Serin protease inhibition and Prothrombin Time assays) of the methanolic extract of amla were conducted. Amla exhibited a substantial amount of phenolic content (TPC: 663.53 mg GAE/g) and flavonoid content (TFC: 418.89 mg GAE/g). A strong DPPH scavenging effect was observed with an IC50 of 311.31 µg/ml as compared to standard ascorbic acid with an IC50 of 130.53 µg/ml. In reducing power assay, the EC50 value of the extract was found to be 196.20 µg/ml compared to standard ascorbic acid (EC50 = 33.83 µg/ml). The IC50 value of the RBC membrane stabilization and 15-LOX assays was observed as 101.08 µg/ml (IC50 of 58.62 µg/ml for standard aspirin) and 195.98 µg/ml (IC50 of 19.62 µg/ml for standard quercetin), respectively. The extract also strongly inhibited serine protease (trypsin) activity with an IC50 of 505.81 µg/ml (IC50 of 295.44 µg/ml for standard quercetin). The blood coagulation time (PTT) was found to be 11.91 min for amla extract and 24.11 min for standard Warfarin. Thus, the findings of an in vitro study revealed that the methanolic extract of amla contains significant antioxidant, anti-inflammatory, and anticoagulation activity. Furthermore, in silico docking and simulation of reported phytochemicals of amla with human 15-LOXA and 15-LOXB were carried out to validate the anti-inflammatory activity of amla. In this analysis, epicatechin and catechin showed greater molecular interaction and were considerably stable throughout the 100 ns simulation with 15-lipoxygenase A (15-LOXA) and 15-lipoxygenase B (15-LOXB) respectively.

Evaluation of the efficacy and associated complications of regional citrate anticoagulation in neonates: experience from a fourth level neonatal intensive care unit.

Continuous kidney replacement therapy (CKRT) use has increased in recent years, but anticoagulation is a challenge for neonates. Regional citrate anticoagulation (RCA) is rarely preferred in neonates because of citrate accumulation (CA) and metabolic complications. We aimed to demonstrate the efficacy and safety of RCA in neonates. We retrospectively analyzed the medical records of 11 neonates treated with RCA-CKRT between 2018 and 2023. The initial dose of RCA was 2.1-3 mmol/l, and then, its dose was increased according to the level of ionized calcium (iCa+2) in the circuit and patients. The total/iCa+2 ratio after-treatment > 2.5 was indicated as CA. We evaluated to citrate dose, CA, circuit lifespan, and dialysis effectivity. The median gestational age was 39 (36.4-41.5) weeks, the median body weight (BW) was 3200 (2400-4000) grams, and the mean postnatal age was 4 (2-24) days. The most common indication for CKRT was hyperammonemia (73%). All neonates had metabolic acidosis and hypocalcemia during CKRT. Other common metabolic complications were hypophosphatemia (90%), hypokalemia (81%), and hypomagnesemia (63%). High dialysate rates with a median of 5765 ml/h/1.73 m2 allowed for a rapid decrease in ammonia levels to normal. Four patients (36.3%) had CA, and seven (63.7%) did not (non-citrate accumulation, NCA). Mean BW, median postnatal age, biochemical parameters, coagulation tests, and ammonia levels were similar between the CA and NCA groups. Low pH, low HCO3, high lactate, and SNAPPE-II scores could be associated with a higher T/iCa ratio. CONCLUSION:  RCA was an efficient and safe anticoagulation for neonates requiring CKRT. Metabolic complications may occur, but they could be managed with adequate supplementation. WHAT IS KNOWN: • Continuous kidney replacement therapy (CKRT) has become popular in recent years due to its successful treatment of fluid overload, electrolyte imbalance, metabolic acidosis, multi-organ failure, and hyperleucinemia/hyperammonemia associated with inborn errors of metabolism. • The need for anticoagulation is the major difficulty in neonatal CKRT. In adult and pediatric patients, regional citrate anticoagulation has been shown to be effective. WHAT IS NEW: • RCA is an effective and safe anticoagulation method for neonates who require CKRT. • Electrolyte imbalances and metabolic acidosis could be managed with adequate supplementation and appropriate treatment parameters such as citrate dose, blood flow rate, and dialysate flow rate.

Thromboembolic and hemorrhagic complications in patients with prosthetic heart valves cared for in a tertiary care center. What have we learned?

BACKGROUND: Heart valve replacement surgery with mechanical or biological prostheses entails a risk of thromboembolism and bleeding complications. OBJECTIVE: To determine the complications related to complementary anticoagulation therapy and the probability of risk. METHODS: One-hundred and sixty-three patients who underwent heart valve replacement between 2002 and 2016 with either mechanical or biological prostheses, and who received vitamin K antagonists after hospital discharge, were studied. Anticoagulation therapy was categorized into optimal and non-optimal according to INR values prior to the development of complications. Patients with comorbidities and other risk factors for thrombosis and/or bleeding were excluded. RESULTS: In total, 68.7 % of patients received mechanical prostheses, and 31.3 %, biological prostheses (p ≤ 0.001); 25.2 % experienced the complications that motivated the study (p ≤ 0.001), which were hemorrhagic in 48.8 %, thromboembolic in 26.8 %, and of both types in 24.4 % (relative risk = 4.229). Among the patients with complications, 95.1 % received mechanical prostheses, and 4.9 %, biological (p = 0.005); non-optimal INR was identified in 49.7 % (p ≤ 0.001). CONCLUSIONS: Given the high risk of thromboembolic and hemorrhagic complications, valve prostheses must be carefully chosen, and care priorities should include prevention and follow-up, especially in those patients who require anticoagulation therapy.

ANTECEDENTES: El reemplazo valvular por prótesis mecánicas o biológicas implica riesgo de tromboembolismo y complicaciones hemorrágicas. OBJETIVO: Determinar las complicaciones relacionadas con la terapia de anticoagulación complementaria y la probabilidad de riesgo en pacientes portadores de prótesis valvulares del corazón. MÉTODOS: Se estudiaron 163 pacientes entre 2002 y 2016, portadores de prótesis mecánicas y biológicas, quienes recibieron antagonistas de la vitamina K posterior al egreso hospitalario. La terapia de anticoagulación se categorizó en óptima y no óptima conforme a los valores de INR previos a las complicaciones. Fueron excluidos los pacientes con comorbilidades y otros factores de riesgo de trombosis y/o sangrado. RESULTADOS: a 68.7 % de los pacientes se les colocó prótesis mecánica y a 31.3 %, biológica (p ≤ 0.001); 25.2 % presentó las complicaciones motivo de estudio (p ≤ 0.001), hemorrágicas en 48.8 %, tromboembólicas en 26.8 % y de ambos tipos en 24.4 % (riesgo relativo = 4.229); a 95.1 % de los pacientes con complicaciones se les colocó prótesis mecánica y a 4.9 %, biológica (p = 0.005); 49.7 % presentó INR no óptimo (p ≤ 0.001). CONCLUSIONES: Ante riesgo alto de complicaciones tromboembólicas y hemorrágicas, la elección de las prótesis valvulares, la prevención y el seguimiento son prioridades, principalmente en quienes requieren terapia de anticoagulación.

Initial therapeutic anticoagulation with rivaroxaban compared to prophylactic therapy with heparins in moderate to severe COVID-19: results of the COVID-PREVENT randomized controlled trial.

BACKGROUND: COVID-19 is associated with a prothrombotic state. Current guidelines recommend prophylactic anticoagulation upon hospitalization. METHODS: COVID-PREVENT, an open-label, multicenter, randomized, clinical trial enrolled patients (≥ 18 years) with moderate to severe COVID-19 and age-adjusted D-dimers > 1.5 upper limit of normal (ULN). The participants were randomly assigned (1:1) to receive either therapeutic anticoagulation with rivaroxaban 20 mg once daily or thromboprophylaxis with a heparin (SOC) for at least 7 days followed by prophylactic anticoagulation with rivaroxaban 10 mg once daily for 28 days or no thromboprophylaxis. The primary efficacy outcome was the D-dimer level and the co-primary efficacy outcome the 7-category ordinal COVID-19 scale by WHO at 7 days post randomization. The secondary outcome was time to the composite event of either venous or arterial thromboembolism, new myocardial infarction, non-hemorrhagic stroke, all-cause death or progression to intubation and invasive ventilation up to 35 days post randomization. RESULTS: The primary efficacy outcome D-dimer at 7 days was not different between patients assigned to therapeutic (n = 55) or prophylactic anticoagulation (n = 56) (1.21 mg/L [0.79, 1.86] vs 1.27 mg/L [0.79, 2.04], p = 0.78). In the whole study population D-dimer was significantly lower at 7 days compared to baseline (1.05 mg/L [0.75, 1.48] vs 1.57 mg/L [1.13, 2.19], p < 0.0001). Therapy with rivaroxaban compared to SOC was not associated an improvement on the WHO 7-category ordinal scale at 7 days (p = 0.085). Rivaroxaban improved the clinical outcome measured by the score in patients with a higher baseline D-dimer > 2.0 ULN (exploratory analysis; 0.632 [0.516, 0.748], p = 0.026). The secondary endpoint occurred in 6 patients (10.9%) in the rivaroxaban group and in 12 (21.4%) in the SOC group (time-to-first occurrence of the components of the secondary outcome: HR 0.5; 95% CI 0.15-1.67; p = 0.264). There was no difference in fatal or non-fatal major or clinically relevant non-major bleeding between the groups. CONCLUSIONS: Therapeutic anticoagulation with rivaroxaban compared to prophylactic anticoagulation with a heparin did not improve surrogates of clinical outcome in patients with moderate to severe COVID-19. Whether initial rivaroxaban at therapeutic doses might be superior to thromboprophylaxis in patients with COVID-19 and a high risk as defined by D-dimer > 2 ULN needs confirmation in further studies.

Complicaciones tromboembólicas y hemorrágicas en pacientes portadores de prótesis valvulares del corazón en un centro de tercer nivel. ¿Qué hemos aprendido? / Thromboembolic and hemorrhagic complications in patients with prosthetic heart valves at third level care center. What have we learned?

Resumen Antecedentes: El reemplazo valvular por prótesis mecánicas o biológicas implica riesgo de tromboembolismo y complicaciones hemorrágicas. Objetivo: Determinar las complicaciones relacionadas con la terapia de anticoagulación complementaria y la probabilidad de riesgo en pacientes portadores de prótesis valvulares del corazón. Métodos: Se estudiaron 163 pacientes entre 2002 y 2016, portadores de prótesis mecánicas y biológicas, quienes recibieron antagonistas de la vitamina K posterior al egreso hospitalario. La terapia de anticoagulación se categorizó en óptima y no óptima conforme a los valores de INR previos a las complicaciones. Fueron excluidos los pacientes con comorbilidades y otros factores de riesgo de trombosis y/o sangrado. Resultados: a 68.7 % de los pacientes se les colocó prótesis mecánica y a 31.3 %, biológica (p ≤ 0.001); 25.2 % presentó las complicaciones motivo de estudio (p ≤ 0.001), hemorrágicas en 48.8 %, tromboembólicas en 26.8 % y de ambos tipos en 24.4 % (riesgo relativo = 4.229); a 95.1 % de los pacientes con complicaciones se les colocó prótesis mecánica y a 4.9 %, biológica (p = 0.005); 49.7 % presentó INR no óptimo (p ≤ 0.001). Conclusiones: Ante riesgo alto de complicaciones tromboembólicas y hemorrágicas, la elección de las prótesis valvulares, la prevención y el seguimiento son prioridades, principalmente en quienes requieren terapia de anticoagulación.

Abstract Background: Heart valve replacement surgery with mechanical or biological prostheses entails a risk of thromboembolism and bleeding complications. Objective: To determine the complications related to complementary anticoagulation therapy and the probability of risk. Methods: One-hundred and sixty-three patients who underwent heart valve replacement between 2002 and 2016 with either mechanical or biological prostheses, and who received vitamin K antagonists after hospital discharge, were studied. Anticoagulation therapy was categorized into optimal and non-optimal according to INR values prior to the development of complications. Patients with comorbidities and other risk factors for thrombosis and/or bleeding were excluded. Results: In total, 68.7 % of patients received mechanical prostheses, and 31.3 %, biological prostheses (p ≤ 0.001); 25.2 % experienced the complications that motivated the study (p ≤ 0.001), which were hemorrhagic in 48.8 %, thromboembolic in 26.8 %, and of both types in 24.4 % (relative risk = 4.229). Among the patients with complications, 95.1 % received mechanical prostheses, and 4.9 %, biological (p = 0.005); non-optimal INR was identified in 49.7 % (p ≤ 0.001). Conclusions: Given the high risk of thromboembolic and hemorrhagic complications, valve prostheses must be carefully chosen, and care priorities should include prevention and follow-up, especially in those patients who require anticoagulation therapy.

A simplified protocol of regional citrate anticoagulation with phosphate-containing solutions in infants and children treated with continuous kidney replacement therapy.

BACKGROUND: Regional citrate anticoagulation (RCA) is the preferred modality of anticoagulation used in continuous kidney replacement therapy (CKRT) in adults and less extensively in children. Potential metabolic complications limit widespread use in infants, neonates, and in children with liver failure. METHODS: We report our experience with a simplified protocol in 50 critically ill children, infants, and neonates, some of them with liver failure, with commercially available solutions containing phosphorous and higher concentration of potassium and magnesium. RESULTS: RCA allowed attainment of a mean filter lifetime of 54.5 ± 18.2 h, 42.5% of circuits lasted more than 70 h, and scheduled change was the most frequent cause of CKRT interruption. Patient Ca++ and circuit Ca++ were maintained in the target range with mean values of 1.15 ± 0.13 mmol/l and 0.38 ± 0.07 mmol/l, respectively. No session had to be stopped because of metabolic complications. The most frequent complications were hyponatremia, hypomagnesemia, and metabolic acidosis mostly related to primary disease and critical illness. No session had to be stopped because of citrate accumulation (CA). Transitory CA occurred in 6 patients and was managed without requiring RCA interruption. No patients with liver failure presented CA episodes. CONCLUSIONS: In our experience, RCA with commercially available solutions was easily applied and managed in critically ill children, even in patients with low weight or with liver failure. Solutions containing phosphate and higher concentrations of magnesium and potassium allowed reduction of metabolic derangement during CKRT. Prolonged filter life was ensured with no detrimental effects on patients and reduced staff workload. A higher resolution version of the Graphical abstract is available as Supplementary information.

Simplified regional citrate anticoagulation protocol for CVVH, CVVHDF and SLED focused on the prevention of KRT-related hypophosphatemia while optimizing acid-base balance.

BACKGROUND: Hypophosphatemia is a common electrolyte disorder in critically ill patients undergoing prolonged kidney replacement therapy (KRT). We evaluated the efficacy and safety of a simplified regional citrate anticoagulation (RCA) protocol for continuous venovenous hemofiltration (CVVH), continuous venovenous hemodiafiltration (CVVHDF) and sustained low-efficiency dialysis filtration (SLED-f). We aimed at preventing KRT-related hypophosphatemia while optimizing acid-base equilibrium. METHODS: KRT was performed by the Prismax system (Baxter) and polyacrylonitrile AN69 filters (ST 150, 1.5 m2, Baxter), combining a 18 mmol/L pre-dilution citrate solution (Regiocit 18/0, Baxter) with a phosphate-containing solution (HPO42- 1.0 mmol/L, HCO3- 22.0 mmol/L; Biphozyl, Baxter). When needed, phosphate loss was replaced with sodium glycerophosphate pentahydrate (Glycophos™ 20 mmol/20 mL, Fresenius Kabi Norge AS, Halden, Norway). Serum citrate measurements were scheduled during each treatment. We analyzed data from three consecutive daily 8-h SLED-f sessions, as well as single 72-h CVVH or 72-h CVVHDF sessions. We used analysis of variance (ANOVA) for repeated measures to evaluate differences in variables means (i.e. serum phosphate, citrate). Because some patients received phosphate supplementation, we performed analysis of covariance (ANCOVA) for repeated measures modelling phosphate supplementation as a covariate. RESULTS: Forty-seven patients with acute kidney injury (AKI) or end stage kidney disease (ESKD) requiring KRT were included [11 CVVH, 11 CVVHDF and 25 SLED-f sessions; mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score 25 ± 7.0]. Interruptions for irreversible filter clotting were negligible. The overall incidence of hypophosphatemia (s-P levels <2.5 mg/dL) was 6.6%, and s-P levels were kept in the normality range irrespective of baseline values and the KRT modality. The acid-base balance was preserved, with no episode of citrate accumulation. CONCLUSIONS: Our data obtained with a new simplified RCA protocol suggest that it is effective and safe for CVVH, CVVHDF and SLED, allowing to prevent KRT-related hypophosphatemia and maintain the acid-base balance without citrate accumulation. TRIAL REGISTRATION: NCT03976440 (registered 6 June 2019).

In Vitro Anti-Venom Potentials of Aqueous Extract and Oils of Toona ciliata M. Roem against Cobra Venom and Chemical Constituents of Oils.

There are high mortality and morbidity rates from poisonous snakebites globally. Many medicinal plants are locally used for snakebite treatment in Uganda. This study aimed to determine the in vitro anti-venom activities of aqueous extract and oils of Toona ciliata against Naja melanoleuca venom. A mixture of venom and extract was administered intramuscularly in rats. Anticoagulant, antiphospholipase A2 (PLA2) inhibition assay, and gel electrophoresis for anti-venom activities of oils were done. The chemical constituents of the oils of ciliata were identified using Gas chromatography-tandem mass spectroscopy (GC-MS/MS). The LD50 of the venom was 0.168 ± 0.21 µg/g. The venom and aqueous extract mixture (1.25 µg/g and 3.5 mg/g) did not cause any rat mortality, while the control with venom only (1.25 µg/g) caused death in 1 h. The aqueous extract of T. ciliata inhibited the anticoagulation activity of N. melanoleuca venom from 18.58 min. to 4.83 min and reduced the hemolytic halo diameter from 24 to 22 mm. SDS-PAGE gel electrophoresis showed that oils completely cleared venom proteins. GC-MS/MS analysis showed that the oils had sesquiterpene hydrocarbons (60%) in the volatile oil (VO) and oxygenated sesquiterpenes (48.89%) in the non-volatile oils (NVO). Some major compounds reported for the first time in T. ciliata NVOs were: Rutamarin (52.55%), ß-Himachalol (9.53%), Girinimbine (6.68%) and Oprea1 (6.24%). Most compounds in the VO were reported for the first time in T. ciliata, including the major ones Santalene (8.55%) and Himachal-7-ol (6.69%). The result showed that aqueous extract and oils of T. ciliata have anti-venom/procoagulant activities and completely neutralized the venom. We recommend a study on isolation and testing the pure compounds against the same venom.

Short- and long-term risks of photoselective laser vaporization of the prostate: a population-based comparison with transurethral resection of the prostate.

BACKGROUND: Transurethral resection of the prostate (TURP) is the standard surgical treatment for benign prostate enlargement (BPE). Photoselective vaporization of the prostate (PVP) is an alternative, but there is limited real-life evidence of PVP risks. OBJECTIVE: To compare short- and long-term risks of PVP to those of TURP in the treatment of BPE. MATERIALS AND METHODS: Consecutive patients who underwent elective PVP or TURP between 2006 and 2018 in 20 hospitals in Finland were retrospectively studied using a combination of national registries (n = 27,408; mean age 71 years). Short-term risks were postoperative mortality, major adverse cardiovascular events (MACE), and reoperations for bleeding. Long-term risks were reoperations for BPE or any urethral operations within 12 years. Differences between treatment groups were balanced by inverse probability of treatment weighting. Risks were analyzed using the Kaplan-Meier method and Cox regression. RESULTS: There were no differences in postoperative mortality or MACE between the study groups. Reoperations for bleeding were less frequent after PVP (0.9%, HR: 0.72, p = 0.042). Bleeding was more likely in patients with atrial fibrillation (number needed to treat [NNT] for PVP vs TURP: 61). Cumulative incidence for reoperation was higher after PVP (23.5%) than after TURP in long-term follow-up (17.8%; HR: 1.20, p < 0.0001, NNT: -31.7). CONCLUSIONS: PVP is associated with lower postoperative bleeding risk but higher long-term reoperation risk than TURP. Patients with high bleeding risk and a low likelihood of needing reoperation appear most suitable for laser vaporization.KEY MESSAGEPVP is associated with lower postoperative bleeding risk but higher long-term reoperation risk than TURP. PVP appears an attractive treatment option, especially for patients with high bleeding risk and a low likelihood of needing a reoperation.

The Impact of Clinical Pharmacy Services on Direct Oral Anticoagulant Medication Selection and Dosing in the Ambulatory Care Setting.

Background: Off-label dosing of direct oral anticoagulants (DOACs) is both common and associated with adverse patient outcomes. Evidence describing best practices to support optimal direct oral anticoagulant (DOAC) dosing is limited. Objective: To describe the impact of clinical pharmacist intervention on DOAC prescribing. Methods: This retrospective study was a descriptive analysis conducted within an integrated healthcare system with a centralized, pharmacist-led Anticoagulation Management Service (AMS). Patients prescribed a DOAC between January 1, 2020 and December 31, 2020 were included. Pharmacy dispensing reports were generated for pharmacist review and anticoagulant drug therapy changes were recommended to physicians where appropriate. The primary objective was to describe the number and type of recommendations made. Secondary objectives were to determine the provider acceptance rate based on the intervention type and on clinical vs formulary recommendations. Results: Clinical pharmacists made 147 recommendations for 2331 unique patients included in the analysis. Twenty-three recommendations (16%) were to decrease the dose, 46 (31%) were to increase the dose, 14 (10%) were to change the medication due to clinical scenario, 62 (42%) were to change the medication due to cost, and 2 (1%) were another issue. One hundred twenty-three (84%) recommendations were accepted. The provider acceptance rate was similar for clinical and formulary recommendations (85% and 82% respectively). Conclusion: Implementation of report-driven clinical pharmacist intervention led to an improvement in appropriate DOAC medication selection and dosing.