Factor XI as a new target for prevention of thromboembolism in cardiovascular disease: a meta-analysis of randomized controlled trials.

Anticoagulant therapy is a mainstay in the management of patients with cardiovascular disease. The use of conventional anticoagulants carries potential side effects, mainly bleeding. Drugs targeting Factor XI (FXI) have been investigated in randomized controlled trials as a new option with more favorable outcomes. A comprehensive literature search was conducted to identify relevant studies comparing FXI inhibitors to placebo or standard therapy. The primary outcomes were incidence of all bleeding events, major bleeding, and thromboembolism. Secondary outcomes included incidence of all adverse events (AE), serious AE, and all-cause mortality. A total of 11 studies involving 10,536 patients were included. FXI inhibitors were associated with a trend toward reduction of bleeding events and incidence of thromboembolism compared to the control group (placebo/standard therapy). There was no statistically significant difference between both groups in terms of adverse events and all-cause mortality. When compared to enoxaparin, FXI inhibitors significantly reduced the risk of bleeding events (RR = 0.42, 95% CI: 0.23-0.76, P = 0.004) and thromboembolism (RR = 0.59, 95% CI: 0.44-0.77, P = 0.001). On the other hand, when compared to DOACs, FXI inhibitors were associated with a significant reduction in bleeding events but not thromboembolism. Whereas, compared to placebo, FXI inhibitors did not increase the risk of bleeding events, adverse events, or all-cause mortality (P > 0.05). FXI inhibitors could be a safer and more potent option for prevention of thromboembolism than conventional therapy.

The foundation for investigating factor XI as a target for inhibition in human cardiovascular disease.

Anticoagulant therapy is a mainstay in the management of patients with cardiovascular disease and related conditions characterized by a heightened risk for thrombosis. Acute coronary syndrome, chronic coronary syndrome, ischemic stroke, and atrial fibrillation are the most common. In addition to their proclivity for thrombosis, each of these four conditions is also characterized by local and systemic inflammation, endothelial/endocardial injury and dysfunction, oxidative stress, impaired tissue-level reparative capabilities, and immune dysregulation that plays a critical role in linking molecular events, environmental triggers, and phenotypic expressions. Knowing that cardiovascular disease and thrombosis are complex and dynamic, can the scientific community identify a common pathway or specific point of interface susceptible to pharmacological inhibition or alteration that is likely to be safe and effective? The contact factors of coagulation may represent the proverbial "sweet spot" and are worthy of investigation. The following review provides a summary of the fundamental biochemistry of factor XI, its biological activity in thrombosis, inflammation, and angiogenesis, new targeting drugs, and a pragmatic approach to managing hemostatic requirements in clinical trials and possibly day-to-day patient care in the future.

Factor XI: structure, function and therapeutic inhibition.

Arterial and venous thromboembolism is a major medical concern that requires therapeutic anticoagulation in various medical fields to prevent its drastic consequences. Despite significant advances in anticoagulant therapy, thrombosis remains a leading cause of morbidity and mortality worldwide. Traditional anticoagulants like heparin and vitamin K antagonists (VKAs) have shown efficacy in preventing and treating thrombosis but come with an inherent risk of bleeding due to their non-specific inhibition of multiple coagulation factors. Subsequent direct oral anticoagulants (DOACs), targeting specific factors such as Xa or thrombin, demonstrated improved safety profiles compared to VKAs, yet bleeding remains a concern. Accordingly, research is focused on developing anticoagulants with improved safety profiles. A safer class of anticoagulants would have broad appeal. The intrinsic pathway of coagulation, involving factor XI (FXI), has attracted attention as a potential target for safer anticoagulants. Preclinical studies and epidemiological data indicate that FXI deficiency or inhibition protects against thrombosis with minimal bleeding. Current research involves evaluating various FXI-directed strategies, and phase 2 studies have shown promising results in orthopedic surgery, atrial fibrillation, end-stage renal disease (ESRD), myocardial infarction, and ischemic stroke. Several agents, such as antisense oligonucleotides, monoclonal antibodies, small synthetic molecules, natural peptides, and aptamers, have been developed to inhibit FXI at different stages, offering potentially safer alternatives to traditional anticoagulants. However, the optimal balance between preventing thrombosis and the risk of bleeding associated with FXI inhibitors requires validation through extensive phase 3 clinical trials using definite clinical endpoints. Several of such trials are currently underway or planned to define the role of FXI inhibitors in clinical practice and determine the most suitable FXI inhibitor for each specific indication. The current review highlights the rationale behind developing FXI inhibitors, presenting the most advanced agents in development, summarizing completed clinical trials, and discussing ongoing research efforts.

Fatal superior vena cava rupture complicating dialysis catheter exchange.

Central vein stenosis (CVS) is a common and challenging complication in hemodialysis patients with chronic central venous catheters (CVCs). CVS often remains asymptomatic and is discovered incidentally during follow-up imaging. CVS symptoms include arm swelling, venous hypertension, impaired dialysis flow rates, and development of collateral veins. However, these symptoms can be nonspecific and overlap with other conditions, making the diagnosis challenging. Timely recognition and appropriate intervention are crucial to prevent complications and optimize patient outcomes. Diagnostic tools commonly used include duplex ultrasonography and venography to assess the degree and location of stenosis. Management strategies for CVS encompass a multidisciplinary approach involving nephrologists, interventional radiologists, and vascular surgeons. Initial conservative measures may include anticoagulation therapy, along with pharmacological interventions such as antiplatelet agents and thrombolytics. The endovascular approach is the first line for managing CVS by using balloon angioplasty either alone or in combination with stent placement, but CVS typically recurs frequently, requiring repeated interventions with an increased risk of complications. Additionally, alternative vascular access options such as arteriovenous fistulas or grafts may be considered. In this report, we describe a case of a 25-year-old woman who presented with an extensive history of multiple dialysis access failure for left internal jugular vein central venous tunneled catheter exchange. The procedure was complicated by a fatal superior vena cava rupture likely related to the dislodgment of the guidewire causing perforation into the pericardium space with subsequent cardiopulmonary collapse. The post-mortem autopsy showed severe organized stenosis of SVC and transmural defect above the SVC/atrial junction.

Catheter-based therapy for traumatic pseudoaneurysm of the anterior tibial artery.

Tibial artery pseudoaneurysms often result from penetrating or blunt trauma to the lower extremities, or after orthopedic and endovascular interventions. Clinically, these lesions manifest as an expanding pulsatile mass of the affected area accompanied with pain and erythema. Despite the rare occurrence, traumatic tibial pseudoaneurysms can be associated with significant morbidity including local discomfort, rupture, and lower limb ischemia. Duplex ultrasound is considered the gold standard for diagnosis. Treatment options include surgical repair, ultrasound-guided compression or thrombin injection, and endovascular repair. In this report, we describe a 42-year-old male who presented to our center with pulsatile swelling over the mid-lateral aspect of the left leg. The diagnosis of a large anterior tibial artery pseudoaneurysm was made on clinical basis and was confirmed with computed tomography angiography. The lesion was treated endovascularly with a covered stent graft. In conclusion, this case highlights the role of endovascular therapy as a surgery-sparing and minimally invasive approach in managing traumatic peripheral arterial pseudoaneurysms with excellent clinical outcomes.

Effect of Dapagliflozin in Patients with Heart Failure: A Systematic Review and Meta-Analysis.

Background: Heart failure (HF) is a major cause of recurrent hospitalization and death worldwide. Sodium-glucose cotransporter-2 inhibitors including dapagliflozin are anti-diabetic drugs with promising cardiovascular (CV) effects. We performed systematic review and meta-analysis of randomized controlled trials investigating the effects of dapagliflozin in heart failure patients. Methods: We searched PubMed, Scopus and ScienceDirect databases. A total of 1,567 studies from January 2017 to September 10, 2022, were screened. After applying exclusion criteria, 22 studies were retrieved for full-text screening, and nine of them were eligible for this meta-analysis. Effect estimates for dichotomous variables were expressed as risk ratio (RR) and 95% CI. The primary outcomes were the incidence of all-cause mortality, hospitalization due to HF, and CV death. This review was registered on PROSPERO with ID CRD42022347793. Results: A total of 14,032 patients were included. The overall risk ratio of all-cause mortality favored the dapagliflozin group over the placebo/standard therapy group (RR = 0.89, 95% CI: 0.82-0.97, P = 0.006) and the pooled studies were not heterogenous (I2 = 0%). Additionally, dapagliflozin significantly reduced the hospitalization due to heart failure (RR = 0.76, 95% CI: 0.70-0.84, P > 0.00001, I2 = 0%), cardiovascular death (RR = 0.87, 95% CI: 0.78-0.97, P = 0.01, I2 = 0%) and their composite outcomes. Conclusion: Dapagliflozin reduces the risk of all-cause mortality, heart failure hospitalizations and cardiovascular death in a wide range of heart failure patients.

Pickering syndrome in a patient with a single kidney: role of renal artery stenting.

Renal artery stenosis (RAS) is associated with hypertension and high mortality rates. With its prevalence and associated risk of death, it is important to screen for patients displaying symptoms of RAS. RAS has a wide spectrum of clinical manifestations and is usually resistant to medical therapy. Of these clinical manifestations is Pickering syndrome which is characterized by bilateral renal arterial occlusion inflow lesions, flash pulmonary edema, acute kidney injury, and hypertensive emergencies in the setting of a preserved left ventricle function. Stenting techniques have been used extensively to treat symptomatic renal artery stenosis with excellent primary patency rate, however have failed to demonstrate a long-term benefit over the optimal medical management alone in randomized trials. However, accumulating evidence suggests that stenting is justified in specific patient subgroups that have severe occlusive renal artery stenoses with significant clinical sequelae, including flash pulmonary edema, acute ischemic kidney injury, and uncontrolled hypertension. In this report we discuss the case of a 32-year-old male who presented to our center with recurrent flash pulmonary edema and hypertensive emergency and was found to have RAS, which responded well to renal artery stenting. In conclusion, correcting the renal arterial inflow stenosis is beneficial and warranted in selective clinical scenarios.

Three-dimensional echocardiography of the tricuspid valve.

Due to the proportionally high mortality rates associated with isolated tricuspid valve surgery, the invasive treatment of such pathology, historically, has been left largely unaddressed. Recently, there has been an appreciation for the mortality and morbidity of tricuspid valve disease, giving rise to the movement towards identifying less invasive, transcatheter approaches for treatment. Due to the technical complexity of these procedures along with the uniqueness and variability of tricuspid valve anatomy, a better appreciation of the tricuspid valve anatomy and pathology is required for pre-procedural planning. While two-dimensional echocardiography serves as the initial non-invasive modality for tricuspid valve evaluation, three-dimensional echocardiography provides a complete en face view of the tricuspid valve and surrounding structures, as well contributes further information regarding disease etiology and severity. In this review, we discuss the utility of three-dimensional echocardiography as a supplement to two-dimensional imaging to better assess tricuspid valve disease and anatomy to aide in future innovative therapies.

Family planning in the Sudan: a pilot project success story.

PIP: In 1980, the Department of Community Medicine of the University of Khartoum designed an operations research project to test the possibility of getting village midwives to be involved in the delivery of maternal and child health and family planning (MCH/FP) services. From 1981-1983 the project was implemented by the University of Khartoum in cooperation with the Ministry of Health. The project area covered 100 km. It encompassed a largely agrarian population of 93,000 in 90 villages north of Khartoum along the banks of the Nile. The focus was on training and supervising village midwives. Information was provided on contraceptives for birth spacing, distribution of oral contraceptives, and referral for other methods. Also provided to midwives was information for mothers on oral rehydration therapy for children with diarrhea, and distribution of oral rehydration solution packets. Nutrition education was given midwives with emphasis on breastfeeding and weaning procedures. Information was also supplied about vaccination for children under 5 years of age (in collaboration with the Sudan Expanded Program on Immunization). The project was expensive, particularly regarding incentive payments for supervisors and midwives. The project had a very good start, but when incentive payments were withdrawn, it almost collapsed. At first, what midwives could do to provide maternal and child health services was targeted, but as the project went on, there was more concern for involvement of midwives in broader rural health delivery. The project area was a conservative, Islamic one. An extension area was selected 5 hours travelling time from Khartoum in Shendi District of Nile Province. The project was begun in 60 villages of 75,000 inhabitants. The land stretched for 120 km along both banks of the Nile. In the extension area, a small fee (US$.025) was charged per cycle, half going to the midwives, and half towards the health teams' expenses. 21 health zones were created, and a health team created for each. Registers of women aged 15-49 and children 3 years have been set up for each health zone. There have been very good results in the management of diarrhea.^ieng

Planificación de la familia en el Sudán: Exito de un proyecto piloto / Family planning in Sudan: A pilot proyect success story

Un proyecto piloto ejecutado en el Sudán para determinar la aceptabilidad de la planificación familiar en las aldeas islámicas a orillas del Nilo ha sido un completo éxito, hasta el punto que, en lugar de desaparecer como suelen hacerlo los proyectos piloto, sigue siendo parte integrante del servicio de salud

Family planning in the Sudan: a pilot project success story

A pilot project in the Sudan to determine the acceptability of family planning in the Islamic villages along the Nile has proved completely successful- so much so that instead of expiring as most pilot projects do, it continues as an integral part of the health service