How Protein Depletion Balances Thrombosis and Bleeding Risk in the Context of Platelet's Activatory and Negative Signaling.

Platelets are small cell fragments that play a crucial role in hemostasis, requiring fast response times and fine signaling pathway regulation. For this regulation, platelets require a balance between two pathway types: the activatory and negative signaling pathways. Activatory signaling mediators are positive responses that enhance stimuli initiated by a receptor in the platelet membrane. Negative signaling regulates and controls the responses downstream of the same receptors to roll back or even avoid spontaneous thrombotic events. Several blood-related pathologies can be observed when these processes are unregulated, such as massive bleeding in activatory signaling inhibition or thrombotic events for negative signaling inhibition. The study of each protein and metabolite in isolation does not help to understand the role of the protein or how it can be contrasted; however, understanding the balance between active and negative signaling could help develop effective therapies to prevent thrombotic events and bleeding disorders.

Implementing a pharmacogenomic-driven algorithm to guide antiplatelet therapy among Caribbean Hispanics: a non-randomised clinical trial.

OBJECTIVES: To assess whether genotype-guided selection of oral antiplatelet drugs using a clinical decision support (CDS) algorithm reduces the rate of major adverse cardiovascular and cerebrovascular events (MACCEs) among Caribbean Hispanic patients, after 6 months. DESIGN: An open-label, multicentre, non-randomised clinical trial. SETTING: Eight secondary and tertiary care hospitals (public and private) in Puerto Rico. PARTICIPANTS: 300 Caribbean Hispanic patients on clopidogrel, both genders, underwent percutaneous coronary intervention (PCI) for acute coronary syndromes, stable ischaemic heart disease and documented extracardiac vascular diseases. INTERVENTIONS: Patients were separated into standard-of-care (SoC) and genotype-guided (pharmacogenetic (PGx)-CDS) groups (150 each) and stratified by risk scores. Risk scores were calculated based on a previously developed CDS risk prediction algorithm designed to make actionable treatment recommendations for each patient. Individual platelet function, genotypes, clinical and demographic data were included. Ticagrelor was recommended for patients with a high-risk score ≥2 in the PGx-CDS group only, the rest were kept or de-escalated to clopidogrel. The intervention took place within 3-5 days after PCI. Adherence medication score was also measured. PRIMARY AND SECONDARY OUTCOMES: The occurrence rate of MACCEs (primary) and bleeding episodes (secondary). Statistical associations between patient time free of events and predictor variables (ie, treatment groups, risk scores) were tested using Kaplan-Meier survival analyses and Cox proportional-hazards regression models. RESULTS: The genotype-guided group had a clinically lower but not significantly different risk of MACCEs compared with the SoC group (8.7% vs 10.7%, p=0.56; HR=0.56). Among high-risk score patients, genotype-driven guidance of antiplatelet therapy showed superiority over SoC in reducing MACCE incidence 6 months postcoronary stenting (adjusted HR=0.104; p< 0.0001). CONCLUSIONS: The potential benefit of implementing our PGx-CDS algorithm to significantly reduce the incidence rate of MACCEs in post-PCI Caribbean Hispanic patients on clopidogrel was observed exclusively among high-risk patients, with apparently no evident effect in other patient groups. TRIAL REGISTRATION NUMBER: NCT03419325.

Comparando a segurança da oclusão do apêndice atrial esquerdo, ablação por cateter e procedimentos combinados para a abordagem da fibrilação atrial: uma metanálise em rede / Comparing the safety of left atrial appendage occlusion, catheter ablation, and combined procedures for the management of atrial fibrillation: a network meta-analysis

INTRODUÇÃO: O fechamento percutâneo transcateter do apêndice atrial esquerdo surgiu recentemente como uma alternativa segura e eficaz à terapia anticoagulante de longo prazo na prevenção de AVC e na redução dos riscos de sangramento em pacientes com FA não valvular. No entanto, o papel da combinação do fechamento percutâneo transcateter do apêndice atrial esquerdo e ablação por cateter em um único procedimento ainda não está claro. OBJETIVOS: Neste estudo, os autores buscaram comparar a segurança do fechamento percutâneo transcateter do apêndice atrial esquerdo, ablação por cateter e o procedimento combinando-os em pacientes com fibrilação atrial. MÉTODOS: As bases de dados MEDLINE, EMBASE e a Cochrane Central foram revisadas sistematicamente em busca de estudos que relatassem o desfecho de complicações periprocedimentos na ablação por cateter e oclusão do apêndice atrial esquerdo em uma abordagem "one-stop". O procedimento combinado dessas abordagens, o fechamento percutâneo transcateter do apêndice atrial esquerdo e a ablação por cateter isoladamente foram analisados. Foi realizada uma metaanálise em rede bayesiana para estimar os efeitos relativos entre tratamentos utilizando razão de risco (RR) e para classificar cada um de acordo com a "Surface Under the Cumulative Ranking Curve" (SUCRA). RESULTADOS: Identificamos 11 ensaios relevantes representando 3343 participantes. A avaliação dos valores SUCRA indicou que apenas o LAAC (0,84) emergiu como o tratamento mais eficaz para a redução das complicações periprocedimento, seguido por apenas ablação (0,60) e abordagem combinada (0,05). O risco de complicações periprocedimento foi maior para o grupo apenas ablação (RR 0,73; intervalo credível [CrI] 0,45, 1,1) e menor para o grupo LAAC (RR 0,62; CrI 0,35, 1,0) quando comparados ao grupo combinado. Na comparação indireta entre os grupos LAAC apenas e ablação apenas, não houve significância estatística (Odds Ratio [OR] 1,1; CrI 0,27, 4,4; p=0,60). CONCLUSÃO: Nesta metanálise de rede, a abordagem combinada do fechamento percutâneo transcateter do apêndice atrial esquerdo e da ablação por cateter foi associada a um aumento de complicações periprocedimentos quando comparado aos procedimentos isoladamente. Portanto, deve-se avaliar cuidadosamente os benefícios e riscos de realizar esses procedimentos em conjunto, levando em consideração a segurança do paciente.

Fondaparinux versus Enoxaparin in the Treatment of Obese Patients with Acute Coronary Syndrome. / Fondaparinux versus Enoxaparina no Tratamento de Pacientes Obesos com Síndrome Coronariana Aguda.

BACKGROUND: Fondaparinux is an effective and safe anticoagulant in the treatment of acute coronary syndromes (ACS). However, due to the low representation of obese individuals in clinical trials, the effects of applying the results of this drug to this population remain uncertain. OBJECTIVES: To compare Fondaparinux to Enoxaparin in the treatment of obese patients with ACS. METHODS: This is a retrospective cohort study, including obese individuals (BMI ≥ 30 Kg/m2) admitted with non-ST-segment elevation myocardial infarction (NSTEMI) or unstable angina (UA) and treated with Fondaparinux or Enoxaparin between 2010 and 2020. The Fondaparinux and Enoxaparin groups were compared for their clinical and laboratory characteristics using chi-square and Mann-Whitney tests, as appropriate. The incidence of primary outcomes (death, reinfarction, stroke, major bleeding) was compared between groups. P-value < 0.05 was considered significant for all analyses. RESULTS: A total of 367 obese patients with NSTEMI or UA were included, of whom 258 used Fondaparinux and 109 used Enoxaparin. Mean age was 64 ± 12 years, and 52.9% were male. The prevalence of diabetes, hypertension, dyslipidemia, prior coronary artery disease, prior stroke, and implementation of invasive strategy was similar between groups. The incidence of the primary outcome was 4.7% in the Fondaparinux group and 5.5% in the Enoxaparin group (p = 0.729). There was no difference between groups when analyzing the components of the primary outcome separately. CONCLUSION: In a sample of obese patients with NSTEMI or UA, there was no difference in the occurrence of the composite outcome (death, stroke, reinfarction, major bleeding) between patients who used Fondaparinux or Enoxaparin.

FUNDAMENTO: O fondaparinux é um anticoagulante eficaz e seguro usado no tratamento de síndromes coronarianas agudas (SCAs). No entanto, devido à baixa representatividade de indivíduos obesos em ensaios clínicos, os efeitos de se aplicar os resultados desse medicamento nesta população continuam incertos. OBJETIVOS: Comparar o fondaparinux à enoxaparina no tratamento de obesos com SCA. MÉTODOS: Este é um estudo do tipo coorte retrospectivo, incluindo indivíduos obesos (IMC ≥ 30 Kg/m2) internados com Infarto do Miocárdio sem Elevação do Segmento ST (IAMSSST) ou Angina Instável (AI) e tratados com fondaparinux ou enoxaparina entre 2010 e 2020. Os grupos que receberam fondaparinux e enoxaparina foram comparados quanto suas características clínicas e laboratoriais usando o teste do qui-quadrado e o teste de Mann-Whitney, conforme apropriado. A incidência dos desfechos primários (morte, reinfarto, acidente vascular cerebral, sangramento maior) foi comparada entre os grupos. Um p<0,05 foi considerado estatisticamente significativo em todas as análises. RESULTADOS: Um total de 367 pacientes obesos com IAMSSST ou AI foi incluído, dos quais 258 usaram fondaparinux e 109 usaram enoxaparina. A idade média foi 64 ± 12 anos, 52,9% eram do sexo masculino. A prevalência e diabetes, hipertensão, dislipidemia, doença arterial coronariana prévia, acidente vascular cerebral prévio, e implementação de estratégia invasiva foi similar entre os grupos. A incidência do desfecho primário foi 4,7% no grupo fondaparinux e 5,5% no grupo enoxaparina (p = 0,729). Não houve diferença entre os grupos quando os componentes do desfecho primário foram analisados separadamente. CONCLUSÃO: Em uma amostra de pacientes obesos com IAMSSST ou AI, não houve diferença na ocorrência do desfecho composto (morte, acidente vascular cerebral, reinfarto, sangramento maior) entre os pacientes que utilizaram fondaparinux ou enoxaparina.

Selective embolization with autologous fat to treat massive bleeding secondary to percutaneous renal biopsy.

Bleeding following a percutaneous renal biopsy is a complication that can be life-threatening. Embolization of the bleeding artery is a procedure that can limit the damage; however, embolization devices can be costly or not immediately available. This is why we present the case of a 25-year-old man with a history of multiple thromboses who underwent a renal biopsy due to suspected systemic lupus erythematosus. Five days after the procedure, he developed hypovolemic shock. A CT scan was performed due to suspected hemorrhage and showed active bleeding at the renal biopsy site. Since embolization devices were not immediately available, selective embolization of the bleeding artery was successfully performed using autologous fat. It is known that embolization with coils is the most frequently used interventional procedure to stop bleeding secondary to renal biopsies. However, embolization with autologous fat is a proven technique to stop bleeding in coronary perforations. In this case, we adapted this technique to treat an actively bleeding renal artery secondary to a renal biopsy. Based on this case, we consider that this technique may be an alternative when coil embolization is not available.

An alternative method for comparing hemorrhagic activity of snake venoms following one of the 3R's principles.

Venom-induced hemorrhage analysis usually is performed by Minimum Hemorrhagic Dose (MHD), however a similar method can be used to compare venoms with fewer laboratory animals. Our work compared the MHD of five different venoms, with the size of hemorrhagic spot, finding good correlations in the results. Considering the 3Rs principle, we propose the use of the hemorrhagic spot method to compare hemorrhagic activity of snake venoms, rather than using the MHD method, since the first one needs 5 times less animals than the other.

Aspirin use in patients with elevated lipoprotein(a): Impact on cardiovascular events and bleeding.

The role of aspirin in cardiovascular primary prevention remains controversial. There are physiological reasons to explore its potential benefits in patients with high levels of lipoprotein(a) [Lp(a)], mainly due to its antifibrinolytic properties and interactions with platelets. The primary objective of this systematic review was to evaluate the cardiovascular benefits and bleeding risks associated with aspirin use in patients who have elevated Lp(a) levels but no history of cardiovascular disease. This systematic review was conducted following PRISMA guidelines. We performed a literature search to identify studies assessing the cardiovascular benefits and bleeding risks of aspirin use in patients with elevated Lp(a) levels (or a related genetic variant) who have no history of cardiovascular disease. Five studies (49,871 individuals) were considered for this systematic review. Three studies assessed the impact of aspirin use in relation to genetic variants associated with elevated Lp(a) levels (SNP rs379822), while the remaining two studies directly measured plasma levels of Lp(a). The endpoints evaluated varied among the studies. Overall, the findings consistently show that carriers of the apolipoprotein(a) variant or patients with Lp(a) levels > 50 mg/dL experience a reduction in cardiovascular risk with aspirin use. No significant bleeding issues were observed, although such events were reported in only two studies. This systematic review suggests that aspirin use in patients with elevated Lp(a) levels and no prior cardiovascular history may reduce cardiovascular risk. The available data on bleeding risk is insufficient.

Bleeding recurrence risk among hospitalized patients undergoing therapeutic plasma exchange: a multi-center study.

BACKGROUND: In hospitalized patients undergoing therapeutic plasma exchange (TPE), it is not known how TPE-associated bleeding risk is impacted by a prior bleeding episode. Therefore, to assess the prevalence and predictors of bleeding recurrence, we analyzed data from the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III). MATERIALS AND METHODS: Using a retrospective cross-sectional analysis of REDS-III public use files, we identified hospitalized adults who had a major bleeding episode prior to their first TPE procedure. Patients were classified into two cohorts based on bleeding recurrence (no-recurrence vs recurrence). After identifying potential predictors, we used multiple imputation by chained equations to impute variables with <30% missing data. Variable selection was optimized using a 10-fold cross validated least absolute shrinkage and selection operator. Final predictors were identified by fitting a logistic regression model. RESULTS: In 310 patients with major bleeding prior to TPE initiation, bleeding recurred in 121 (39.0%). We identified the following seven unique predictors: 1) >10 TPE procedures (OR 2.23); 2) intensive care unit stay (OR 1.35); 3) thrombocytopenia (OR 1.26); 4) surgery (OR 1.22); 5) hepatic disease (OR 1.21); 6) 6-10 TPE procedures (OR 1.04); and 7) Asian race (OR 1.01). We also identified the following five interactions: 1) surgery and therapeutic anticoagulation (OR 1.50); 2) 6-10 TPE procedures and therapeutic anticoagulation (OR 1.05); 3) 6-10 TPE procedures and antiplatelets (OR 1.02); 4) >10 TPE procedures and antiplatelets (OR 1.00); and 5) albumin-only TPE and antiplatelets (OR 0.53). When assessed for adjusted performance, the prediction model had a C-statistic of 0.617 (95% CI 0.613-0.619) and Brier Score of 0.342 (95% CI 0.340-0.347). DISCUSSION: In this study assessing predictors of bleeding recurrence among hospitalized patients undergoing TPE, we identified seven variables and five interactions. These findings should be validated in future studies.

Evaluation of variants in the ENTPD1 and ENTPD2 genes in athletic horses with exercise-induced pulmonary haemorrhage.

BACKGROUND: Exercise-induced pulmonary haemorrhage (EIPH) in athletic horses is characterized by the presence of blood from the lungs in the tracheobronchial tree after intense exercise. Despite the high prevalence of EIPH in horses, the primary aetiology remains unknown. Variants in the genes encoding CD39 and CD39L1 (ENTPD1 and ENTPD2, respectively) were previously reported as potential genetic causes involved in EIPH pathogenesis. However, the role of these variants in haemostatic functions is unknown. RESULTS: To investigate the association between EIPH and missense variants in the ENTPD1 (rs1152296272, rs68621348, and rs68621347) and ENTPD2 genes (rs782872967), 76 Thoroughbred horses diagnosed with EIPH and 56 without clinical signs of EIPH (control group) by trachea-bronchial endoscopy were genotyped. The rs1152296272 and rs68621347 variants were linked, which explained why the same results were found in all horses. Approximately 96% and 95% of the EIPH and control horses, respectively, carried at least one nonreference allele for these variants. In contrast, 100% of the control horses and 96% of the EIPH horses were homozygous for the reference allele for the rs68621348 variant. In the EIPH group, 1.5% of the horses were homozygotes and 24% were heterozygous for the nonreference allele of the rs782872967 variant. In the control group, the nonreference allele of this variant was observed only in heterozygotes (16%). There were no significant differences between groups for any of the variants. CONCLUSIONS: The variants previously described in the genes encoding the CD39 and CD39L1 enzymes were highly present in the studied population. However, no association was found between the occurrence of EIPH and the presence of these variants in Thoroughbred horses in this study.

Antithrombotic Strategies in Atrial Fibrillation After ACS and/or PCI: A 4-Way Comparison From AUGUSTUS.

BACKGROUND: The optimal antithrombotic regimen for patients with atrial fibrillation (AF) who had an acute coronary syndrome (ACS) or have undergone percutaneous coronary intervention (PCI) is not known. OBJECTIVES: The authors sought to determine which antithrombotic regimen best balances safety and efficacy. METHODS: AUGUSTUS, a multicenter 2 × 2 factorial design randomized trial compared apixaban with vitamin K antagonist (VKA) and aspirin with placebo in patients with AF with recent ACS and/or PCI treated with a P2Y12 inhibitor. We conducted a 4-way analysis comparing safety and efficacy outcomes in the 4 randomized groups. The primary outcome was a composite of all-cause death, major or clinically relevant nonmajor bleeding, or hospitalization for cardiovascular causes over 6-month follow-up. Secondary outcomes included individual components of the primary endpoint. RESULTS: A total of 4,614 patients were enrolled. All patients were treated with a P2Y12 inhibitor. The primary endpoint occurred in 21.9% of patients randomized to apixaban plus placebo, 27.3% randomized to apixaban plus aspirin, 28.0% randomized to VKA plus placebo, and 33.3% randomized to VKA plus aspirin. Rates of major or clinically relevant nonmajor bleeding and hospitalization for cardiovascular causes were lower with apixaban and placebo compared with the other 3 antithrombotic strategies. There was no difference between the 4 randomized groups with respect to all-cause death. CONCLUSIONS: In patients with AF and a recent ACS and/or PCI, an antithrombotic regimen that included a P2Y12 inhibitor and apixaban without aspirin resulted in a lower incidence of the composite of death, bleeding, or cardiovascular hospitalization than regimens including VKA, aspirin, or both. (An Open-label, 2 x 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Aspirin Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention; NCT02415400).

Predictors of bleeding and thrombotic events among patients admitted to the hospital with COVID-19 and elevated D-dimer: insights from the action randomized clinical trial

Therapeutic anticoagulation showed inconsistent results in hospitalized patients with COVID-19 and selection of the best patients to use this strategy still a challenge balancing the risk of thrombotic and hemorrhagic outcomes. The present post-hoc analysis of the ACTION trial evaluated the variables independently associated with both bleeding events (major bleeding or clinically relevant non-major bleeding) and the composite outcomes thrombotic events (venous thromboembolism, myocardial infarction, stroke, systemic embolism, or major adverse limb events). Variables were assessed one by one with independent logistic regressions and final models were chosen based on Akaike information criteria. The model for bleeding events showed an area under the curve of 0.63 (95% confidence interval [CI] 0.53 to 0.73), while the model for thrombotic events had an area under the curve of 0.72 (95% CI 0.65 to 0.79). Non-invasive respiratory support was associated with thrombotic but not bleeding events, while invasive ventilation was associated with both outcomes (Odds Ratio of 7.03 [95 CI% 1.95 to 25.18] for thrombotic and 3.14 [95% CI 1.11 to 8.84] for bleeding events). Beyond respiratory support, creatinine level (Odds Ratio [OR] 1.01 95% CI 1.00 to 1.02 for every 1.0 mg/dL) and history of coronary disease (OR 3.67; 95% CI 1.32 to 10.29) were also independently associated to the risk of thrombotic events. Non-invasive respiratory support, history of coronary disease, and creatinine level may help to identify hospitalized COVID-19 patients at higher risk of thrombotic complications.ClinicalTrials.gov: NCT04394377.

Validation of the RIETE, Kuijer, and HAS-BLED Models to Assess 3-Month Bleeding Risk in Anticoagulated Patients Diagnosed with Venous Thromboembolic Disease.

OBJECTIVE: To evaluate the discriminative ability and calibration of the RIETE, Kuijer, and HAS-BLED models for predicting 3-month bleeding risk in patients anticoagulated for venous thromboembolism (VTE). METHODS: External validation study of a prediction model based on a retrospective cohort of patients with VTE seen at the Hospital Universitario San Ignacio, Bogotá (Colombia) between July 2021 and June 2023. The calibration of the scales was evaluated using the Hosmer-Lemeshow test and the ratio of observed to expected events (ROE) within each risk category. Discriminatory ability was assessed using the area under the curve (AUC) of a ROC curve. RESULTS: We analyzed 470 patients (median age 65 years, female sex 59.3%) with a diagnosis of deep vein thrombosis in most cases (57.4%), 5.7% bleeding events were observed. Regarding calibration, adequate calibration cannot be ruled out given the limited number of events. The discriminatory ability was limited with an area under the curve (AUC) of 0.48 (CI 0.37-0.59) for Kuijer Score, 0.58 (CI 0.47-0.70) for HAS-BLED and 0.64 (CI 0.51-0.76) for RIETE. CONCLUSION: The Kuijer, HAS-BLED, and RIETE models in patients with VTE generally do not adequately estimate the risk of bleeding at three months, with a low ability to discriminate high-risk patients. Cautious interpretation is recommended until further evidence is available.

Direct oral anticoagulants in embolic stroke of undetermined source: an updated meta-analysis.

The efficacy and safety of direct oral anticoagulants (DOAC) in patients with embolic stroke of undetermined source (ESUS) remains unclear. We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCT) comparing DOACs versus aspirin in patients with ESUS. Risk ratios (RR) and 95% confidence intervals (CI) were computed for binary endpoints. Four RCTs comprising 13,970 patients were included. Compared with aspirin, DOACs showed no significant reduction of recurrent stroke (RR 0.95; 95% CI 0.84-1.09; p = 0.50; I2 = 0%), ischemic stroke or systemic embolism (RR 0.97; 95% CI 0.80-1.17; p = 0.72; I2 = 0%), ischemic stroke (RR 0.92; 95% CI 0.79-1.06; p = 0.23; I2 = 0%), and all-cause mortality (RR 1.11; 95% CI 0.87-1.42; p = 0.39; I2 = 0%). DOACs increased the risk of clinically relevant non-major bleeding (CRNB) (RR 1.52; 95% CI 1.20-1.93; p < 0.01; I2 = 7%) compared with aspirin, while no significant difference was observed in major bleeding between groups (RR 1.57; 95% CI 0.87-2.83; p = 0.14; I2 = 63%). In a subanalysis of patients with non-major risk factors for cardioembolism, there is no difference in recurrent stroke (RR 0.98; 95% CI 0.67-1.42; p = 0.90; I2 = 0%), all-cause mortality (RR 1.24; 95% CI 0.58-2.66; p = 0.57; I2 = 0%), and major bleeding (RR 1.00, 95% CI 0.32-3.08; p = 1.00; I2 = 0%) between groups. In patients with ESUS, DOACs did not reduce the risk of recurrent stroke, ischemic stroke or systemic embolism, or all-cause mortality. Although there was a significant increase in clinically relevant non-major bleeding, major bleeding was similar between DOACs and aspirin.

Effect of combined red and infrared wavelengths on inflammation, hemorrhage, and muscle damage caused by Bothrops leucurus snake venom.

To evaluate the effects of red and infrared wavelengths, separately and combined, on the inflammatory process and collagen deposition in muscle damage caused by B. leucurus venom. 112 mice were inoculated with diluted venom (0.6mg/kg) in the gastrocnemius muscle. The animals were divided into four groups: one control (CG) and three treatments, namely: 1) red laser (λ=660 nm) (RG), 2) infrared laser (λ=808 nm) (IG) and 3) red laser (λ=660 nm) + infrared (λ=808 nm) (RIG). Each group was subdivided into four subgroups, according to the duration of treatment application (applications every 24 hours over evaluation times of up to 144 hours). A diode laser was used (0.1 W, CW, 1J/point, ED: 10 J/cm2). Both wavelengths reduced the intensity of inflammation and the combination between them significantly intensified the anti-inflammatory response. Photobiomodulation also changed the type of inflammatory infiltrate observed and RIG had the highest percentage of mononuclear cells in relation to the other groups. Hemorrhage intensity was significantly lower in treated animals and RIG had the highest number of individuals in which this variable was classified as mild. As for collagen deposition, there was a significant increase in RG in relation to CG, in RIG in relation to CG and in RIG in relation to IG. Photobiomodulation proved to be effective in the treatment of inflammation and hemorrhage caused by B. leucurus venom and stimulated collagen deposition. Better results were obtained with the combined wavelengths.

Direct Oral Anticoagulants versus Vitamin K Antagonists for Left Ventricular Thrombus: A Meta-Analysis with Trial Sequential Analysis. / Anticoagulantes Orais Diretos versus Antagonistas da Vitamina K para Trombo Ventricular Esquerdo: Uma Metanálise com Análise Sequencial de Ensaios.

BACKGROUND: Vitamin K antagonists (VKAs) are the recommended first-line treatment for left ventricular thrombus (LVT); however, direct oral anticoagulants (DOACs) have been considered an alternative therapy. OBJECTIVES: To evaluate the efficacy and safety of DOACs compared with VKAs therapy in patients with LVT. METHODS: PubMed, Embase, and Cochrane were systematically searched for randomized clinical trials or cohort studies that compared DOACs versus VKAs for LVT. Risk ratios (RRs) were computed for binary endpoints, with 95% confidence intervals (95% CIs). Statistical significance was defined as p value < 0.05. RESULTS: A total of 4 randomized clinical trials and 29 cohort studies were included, with 4,450 patients assigned to either DOACs or VKAs. There was no significant difference between groups for stroke or systemic embolic (SSE) events (RR 0.84; 95% CI 0.65 to 1.07; p = 0.157), stroke (RR 0.73; 95% CI 0.48 to 1.11; p = 0.140), systemic embolic (SE) events (RR 0.69; 95% CI 0.40 to 1.17; p = 0.166), thrombus resolution (RR 1.05; 95% CI 0.99 to 1.11; p = 0.077), any bleeding (RR 0.78; 95% CI 0.60 to 1.00; p = 0.054), clinically relevant bleeding (RR 0.69; 95% CI 0.46 to 1.03; p = 0.066), minor bleeding (RR 0.73; 95% CI 0.43 to 1.23; p = 0.234), major bleeding (RR 0.87; 95% CI 0.42 to 1.80; p = 0.705), and all-cause mortality (RR 1.05; 95% CI 0.79 to 1.39; p = 0.752). Compared with VKAs, rivaroxaban significantly reduced SSE events (RR 0.35; 95% CI 0.16 to 0.91; p = 0.029) and SE events (RR 0.39; 95% CI 0.16 to 0.95; p = 0.037). CONCLUSIONS: DOACs had a similar rate of thromboembolic and hemorrhagic events, as well as thrombus resolution, compared to VKAs in the treatment of LVTs. Rivaroxaban therapy had a significant reduction in thromboembolic events, compared to VKAs.

International Society on Thrombosis and Haemostasis clinical practice guideline for treatment of congenital hemophilia A and B based on the Grading of Recommendations Assessment, Development, and Evaluation methodology.

BACKGROUND: Hemophilia is a rare congenital bleeding disorder that results from complete or partial deficiency of blood coagulation factor (F)VIII (hemophilia A) or FIX (hemophilia B) due to pathogenic variants in their coding genes. Hemophilia requires complex management. To date, there is no evidence-based clinical practice guideline on hemophilia treatment based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. OBJECTIVES: This evidence-based clinical practice guideline from the International Society on Thrombosis and Haemostasis aims to provide an overview of evidence and support patients, caregivers, hematologists, pediatricians, other clinicians, researchers, and stakeholders in treatment decisions about congenital hemophilia A and B. METHODS: The International Society on Thrombosis and Haemostasis formed a multidisciplinary guideline panel of physicians and patients with global representation, balanced to minimize potential bias from conflicts of interest. The panel prioritized a set of clinical questions and outcomes according to their importance for clinicians and patients. A methodological team supported the guideline development process, including searching for evidence and performing systematic reviews. The GRADE approach was used, including GRADE Evidence to Decision frameworks. The recommendations were subject to public comment. RESULTS: The panel selected 13 questions, of which 11 addressed the treatment of hemophilia A and 2 the treatment of hemophilia B. Specifically, the panel addressed questions on prophylactic and episodic treatment with FVIII concentrates, bypassing agents, and nonfactor therapy (emicizumab) for hemophilia A (with and without inhibitors) as well as immune tolerance induction for hemophilia A. For hemophilia B, the panel addressed questions on prophylactic and episodic treatment of bleeding events with FIX concentrates. Agreement was reached for all 13 recommendations, of which 7 (54%) were based on evidence from randomized clinical trials, 3 (23%) on observational studies, and 3 (23%) on indirect comparisons. CONCLUSION: Strong recommendations were issued for prophylactic over episodic treatment for severe and moderately severe hemophilia A and B. Only conditional recommendations were issued for the remaining questions. Future research should focus on direct treatment comparisons and the treatment of hemophilia B with and without inhibitors. Future updates of this guideline will provide an updated evidence synthesis on the current questions and focus on new FVIII and FIX concentrates, novel nonfactor therapies, and gene therapy for severe and nonsevere hemophilia A and B.

Ischaemic and haemorrhagic risk distribution in real-life patients with acute coronary syndromes.

BACKGROUND: Effective treatment of non-ST-segment elevation acute coronary syndromes (NSTEACS) requires careful assessment of both ischaemic and bleeding risks. We aimed to analyse risk distribution and evaluate antiplatelet prescription behaviours in real-life settings. METHODS: Data from 1100 NSTEACS patients in Buenos Aires, Argentina, from the Buenos Aires I Registry, with a 15-month follow-up, were analysed. In-hospital and 6-month GRACE scores, CRUSADE, and Precise DAPT scores were calculated. RESULTS: The mean age was 65.4 ± 11.5 years with a majority being male (77.2%). In-hospital mortality was 2.7%, primarily due to cardiovascular causes (1.8%). Bleeding events occurred in 20.9% of patients, with 4.9% classified as ≥ BARC 3. Predominance of low bleeding (71.3%) and ischaemic (55.8%) risks on admission was observed. At 6 months, the low-risk Precise category (70.9%) and GRACE (44.1%) categories prevailed. Linear correlation analysis showed a moderately positive correlation (r = 0.61, p < .05) between ischaemic-haemorrhagic risks. Regarding the prescription of antiplatelet agents, in the low ischaemic-haemorrhagic risk group, there was a predominance of aspirin + clopidogrel (41.2%) over other high-potency antiplatelet regimens (aspirin + ticagrelor or prasugrel). In the low ischaemic and high haemorrhagic risk group, aspirin and clopidogrel were also predominant (58%). CONCLUSIONS: Our analysis underscores the significant relationship between ischaemic and haemorrhagic risks during NSTEACS hospitalisation. Despite the majority of patients falling into the low-intermediate risk category, the prescription of P2Y12 inhibitors in real-life settings does not consistently align with these risks.

Incidence of venous thromboembolism and bleeding in patients with malignant central nervous system neoplasm: Systematic review and meta-analysis.

Central nervous system (CNS) malignant neoplasms may lead to venous thromboembolism (VTE) and bleeding, which result in rehospitalization, morbidity and mortality. We aimed to assess the incidence of VTE and bleeding in this population. METHODS: This systematic review and meta-analysis (PROSPERO CRD42023423949) were based on a standardized search of PubMed, Virtual Health Library and Cochrane (n = 1653) in July 2023. After duplicate removal, data screening and collection were conducted by independent reviewers. The combined rates and 95% confidence intervals for the incidence of VTE and bleeding were calculated using the random effects model with double arcsine transformation. Subgroup analyses were performed based on sex, age, income, and type of tumor. Heterogeneity was calculated using Cochran's Q test and I2 statistics. Egger's test and funnel graphs were used to assess publication bias. RESULTS: Only 36 studies were included, mainly retrospective cohorts (n = 30, 83.3%) from North America (n = 20). Most studies included were published in high-income countries. The sample size of studies varied between 34 and 21,384 adult patients, mostly based on gliomas (n = 30,045). For overall malignant primary CNS neoplasm, the pooled incidence was 13.68% (95%CI 9.79; 18.79) and 11.60% (95%CI 6.16; 18.41) for VTE and bleeding, respectively. The subgroup with elderly people aged 60 or over had the highest incidence of VTE (32.27% - 95%CI 14.40;53.31). The studies presented few biases, being mostly high quality. Despite some variability among the studies, we observed consistent results by performing sensitivity analysis, which highlight the robustness of our findings. CONCLUSIONS: Our study showed variability in the pooled incidence for both overall events and subgroup analyses. It was highlighted that individuals over 60 years old or diagnosed with GBM had a higher pooled incidence of VTE among those with overall CNS malignancies. It is important to note that the results of this meta-analysis refer mainly to studies carried out in high-income countries. This highlights the need for additional research in Latin America, and low- and middle-income countries.