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Hereditary angioedema is a rare, genetic disorder characterized by painful, debilitating and potentially life-threatening angioedema attacks in subcutaneous and submucosal tissue. While usually unpredictable, attacks can be provoked by a variety of triggers including physical injury and certain medication and are often preceded by prodromal symptoms. Hereditary angioedema has a profound influence on the patients' lives. The fundamental cause of hereditary angioedema in almost all patients is a mutation in the SERPING1 gene leading to a deficiency in C1-inhibitor. Subsequently, the contact activation cascade and kallikrein-kinin pathway are insufficiently inhibited, resulting in excessive bradykinin production triggering vascular leakage. While C1-inhibitor is an important regulator of the intrinsic coagulation pathway, fibrinolytic system and complement cascade, patients do not have an increased risk of coagulopathy, autoimmune conditions or immunodeficiency disorders. Hereditary angioedema is diagnosed based on C1-inhibitor level and function. Genetic analysis is only required in rare cases where hereditary angioedema with normal C1-inhibitor is found. In recent years, new, highly specific therapies have greatly improved disease control and angioedema-related quality of life. This article reviews the clinical picture of hereditary angioedema, the underlying pathophysiology, diagnostic process and currently available as well as investigational therapeutic options. [ABSTRACT FROM AUTHOR]

Hereditary angioedema (HAE) is a rare, potentially life‐threatening genetic disorder characterized by recurrent attacks of swelling. Local vasodilation and vascular leakage are stimulated by the vasoactive peptide bradykinin, which is excessively produced due to dysregulation of the activated factor XII (FXIIa)‐driven kallikrein–kinin system. There is a need for novel treatments for HAE that provide greater efficacy, improved quality of life, minimal adverse effects, and reduced treatment burden over current first‐line therapies. FXIIa is emerging as an attractive therapeutic target for interference with HAE attacks. In this review, we draw on preclinical, experimental animal, and in vitro studies, providing an overview on targeting FXIIa as the basis for pharmacologic interference in HAE. We highlight that there is a range of FXIIa inhibitors in development for different therapeutic areas. Of these, garadacimab, an FXIIa‐targeted inhibitory monoclonal antibody, is the most advanced and has shown potential as a novel long‐term prophylactic treatment for patients with HAE in clinical trials. The evidence from these trials is summarized and discussed, and we propose areas for future research where targeting FXIIa may have therapeutic potential beyond HAE. [ABSTRACT FROM AUTHOR]

This systematic review examines the outcomes and measurement tools used in recent studies on prophylaxis for hereditary angioedema (HAE). The review found that there is significant variation in the outcomes selected, which can make it difficult to compare trials and may introduce bias in outcome reporting. The primary outcome most commonly chosen was "time-normalized attack frequency," but there were differences in how this measurement was timed and adjudicated. The review emphasizes the need for consistent outcomes in HAE research and provides recommendations for improving outcome selection and measurement in future studies. The authors disclose potential conflicts of interest and the research did not receive specific funding. [Extracted from the article]

Background: Hereditary angioedema (HAE) is a potentially fatal disease characterized by unpredictable, recurrent, often disabling swelling attacks. In a randomized phase 2 study, donidalorsen reduced HAE attack frequency and improved patient quality‐of‐life (ISIS721744‐CS2, NCT04030598). We report the 2‐year interim analysis of the phase 2 open‐label extension (OLE) study (ISIS 721744‐CS3, NCT04307381). Methods: In the OLE, the on‐treatment study period consisted of fixed (weeks 1–13, donidalorsen 80 mg subcutaneously every 4 weeks [Q4W]) and flexible (weeks 17–105, donidalorsen 80 mg Q4W, 80 mg every 8 weeks [Q8W], or 100 mg Q4W) dosing periods. The primary outcome was incidence and severity of treatment‐emergent adverse events (TEAEs). The secondary outcomes included efficacy, pharmacodynamic, and quality‐of‐life assessments. Results: Seventeen patients continued in the OLE study. No serious TEAEs or TEAEs leading to treatment discontinuation were reported. Mean monthly HAE attack rate was 96% lower than the study run‐in baseline rate (mean, 0.06/month; 95% confidence interval [CI], 0.02–0.10; median, 0.04 on‐treatment vs. mean, 2.70/month; 95% CI, 1.94–3.46; median, 2.29 at baseline). Mean monthly attack rate for Q8W dosing (n = 8) was 0.29 (range, 0.0–1.7; 95% CI, −0.21 to 0.79; median, 0.00). Mean plasma prekallikrein and D‐dimer concentrations decreased, and Angioedema Quality of Life Questionnaire total score improved from baseline to week 105 with donidalorsen. Conclusion: The 2‐year interim results of this phase 2 OLE study of donidalorsen in patients with HAE demonstrated no new safety signals; donidalorsen was well tolerated. There was durable efficacy with a 96% reduction in HAE attacks. [ABSTRACT FROM AUTHOR]

Background: Hereditary angioedema (HAE) with C1‐inhibitor deficiency (HAE‐C1‐INH) is characterized by recurrent, debilitating episodes of swelling. Sebetralstat, an investigational oral plasma kallikrein inhibitor, demonstrated promising efficacy for on‐demand treatment of HAE‐C1‐INH in a phase 2 trial. We describe the multipronged approach informing the design of KONFIDENT, a phase 3 randomized, placebo‐controlled, three‐way crossover trial evaluating the efficacy and safety of sebetralstat in patients aged ≥12 years with HAE‐C1‐INH. Methods: To determine an optimal endpoint to measure the beginning of symptom relief in KONFIDENT, we engaged patients with HAE on clinical outcome measures and subsequently conducted analyses of phase 2 outcomes. Sample size was determined via a simulation‐based approach using phase 2 data. Results: Patient interviews revealed a strong preference (71%) for the Patient Global Impression of Change (PGI‐C) over other measures and indicated a rating of "A Little Better" as a clinically meaningful milestone. In phase 2, a rating of "A Little Better" demonstrated agreement with attack severity improvement and resolution on the Patient Global Impression of Severity and had better sensitivity than "Better." Simulations indicated that 84 patients completing treatment would ensure at least 90% power for assessing the primary endpoint of time to beginning of symptom relief defined as a PGI‐C rating of at least "A Little Better" for two time points in a row. Conclusions: Patient feedback and phase 2 data support PGI‐C as the primary outcome measure in the phase 3 KONFIDENT trial evaluating sebetralstat, which has the potential to be the first oral on‐demand treatment for HAE‐C1‐INH attacks. [ABSTRACT FROM AUTHOR]

Emerging studies in the literature describe an association between high-fat, low-carbohydrate diets and severe hypercholesterolemia consistent with the levels observed in patients with (homozygous) familial hypercholesterolemia (FH). High levels of low-density lipoprotein cholesterol (LDL-C) may result from the reduced clearance of LDL particles from the circulation, the increased production of their precursor, or a combination of both. The increased intake of (saturated) fat and cholesterol, combined with limited to no intake of carbohydrates and fiber, are the main features of diets linked to hypercholesterolemia. However, several observations in previous studies, together with our observations from our lipid clinic, do not provide a definitive pathophysiological explanation for severe hypercholesterolemia. Therefore, we review these findings and possible pathophysiological explanations as well as opportunities for future research. Altogether, clinicians should rule out high-fat, low-carbohydrate diets as a possible cause for hypercholesterolemia in patients presenting with clinical FH in whom no mutation is found and discuss dietary modifications to durably reduce LDL-C levels and cardiovascular disease risk. [ABSTRACT FROM AUTHOR]

Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up‐to‐date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1 inhibitor (type 1) and HAE with dysfunctional C1 inhibitor (type 2), by providing guidance on common and important clinical issues, such as: (1) How should HAE be diagnosed? (2) When should HAE patients receive prophylactic on top of on‐demand treatment and what treatments should be used? (3) What are the goals of treatment? (4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast‐feeding women? and (5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients. [ABSTRACT FROM AUTHOR]

Hereditary angioedema (HAE) is a rare disease that causes episodic attacks of subcutaneous and submucosal edema, which can be painful, incapacitating, and potentially fatal. These attacks are mediated by excessive bradykinin production, as a result of uncontrolled activation of the plasma kallikrein/kinin system, which is caused by a C1 esterase inhibitor deficiency or dysfunction in HAE types 1 and 2, respectively. For many years, treatment options were limited to therapies with substantial adverse effects, insufficient efficacy, or difficult routes of administration. Increased insights in the pathophysiology of HAE have paved the way for the development of new therapies with fewer side effects. In the last two decades, several targeted novel therapeutic strategies for HAE have been developed, for both long-term prophylaxis and on demand treatment of acute attacks. This article reviews the advances in the development of more effective and convenient treatment options for HAE and their anticipated effects on morbidity, mortality, and quality of life. The emergence of these improved treatment options will presumably change current HAE guidelines, but adherence to these recommendations may become restricted by high treatment costs. It will therefore be essential to determine the indications and identify the patients that will benefit most from these newest treatment generations. Ultimately, current preclinical research into gene therapies may eventually lead the way towards curative treatment options for HAE. In conclusion, an increasing shift towards the use of highly effective long-term prophylaxis is anticipated, which should drastically abate the burden on patients with hereditary angioedema. [ABSTRACT FROM AUTHOR]

Keywords: efficacy; hereditary angioedema; outcomes; swelling; treatment EN efficacy hereditary angioedema outcomes swelling treatment 2222 2224 3 07/04/22 20220701 NES 220701 ACKNOWLEDGEMENTS The authors thank Nerissa P. Denswil for her help with the construction of the search strategies. Outcomes measuring treatment response were predominantly either time-based (e.g., time to symptom relief) or symptom-based (e.g., change in severity at a predefined time point). [Extracted from the article]

Background: The PEmb-QoL is a validated 40-item questionnaire to quantify health-related quality of life in patients having experienced pulmonary embolism (PE). It covers six health dimensions: frequency of complaints, activities of daily living limitations, work-related problems, social limitations, intensity of complaints, and emotional complaints. Originally developed in Dutch and English, we sought to prospectively validate the psychometric properties of a French version of the PEmb-QoL. Methods: We performed a forward and backward translation of the English version of the PEmb-QoL into French. French-speaking consecutive adult patients with an acute, objectively confirmed PE admitted to the emergency department of a Swiss university hospital between 08/2009 and 09/2011 were recruited telephonically. We used standard psychometric tests and criteria to evaluate the acceptability, reliability, and validity of the French version of the PEmb-QoL. We also performed an exploratory factor analysis. Results: Overall, 102 patients were enrolled in the study. The French version of the PEmb-QoL showed good reliability (internal consistency, item–total and inter-item correlations), reproducibility (test-retest reliability), and validity (convergent, discriminant) in French-speaking patients with PE. The exploratory factor analysis suggested three underlying dimensions: limitations in daily activity (items 4b-m, 5a-d), symptoms (items 1a-h and 7), and emotional complaints (items 9a-f and j). Conclusion: We successfully validated the French version of the PEmb-QoL questionnaire in patients with PE. Our results show that the PEmb-QoL is a valuable tool for assessing health-related quality of life after PE in French-speaking patients. [ABSTRACT FROM AUTHOR]

Background: Low-molecular-weight heparin (LMWH) is the drug of choice to prevent venous thrombosis in pregnancy, but the optimal dose for prevention while avoiding bleeding is unclear. This study investigated whether therapeutic doses of LMWH increase the incidence of postpartum haemorrhage (PPH) in a retrospective controlled cohort. Methods: All pregnant women who received therapeutic doses of LMWH between 1995 and 2008 were identified in the Academic Medical Center, Amsterdam, The Netherlands. The controls were women registered for antenatal care in the same hospital who did not use LMWH during pregnancy, matched by random electronic selection for age, parity and delivery date to LMWH users. The incidence of PPH (blood loss >500 ml), severe PPH (blood loss >1000 ml) and median blood loss were compared in two cohorts of LMWH users and non-users. Results: The incidence of PPH was 18% in LMWH users (N=95) and 22% in non-users (N=524) (RR 0.8; 95% CI 0.5 to 1.4). The incidence of severe PPH was 6% in both groups (RR 1.2; 0.5 to 2.9). The median amount of blood loss differed only in normal vaginal deliveries. It was 200 ml in LMWH users and 300 ml in non-users (difference −100 ml; 95% CI −156 to −44). Conclusion: Therapeutic doses of LMWH in pregnancy were observed not to be associated with a clinically meaningful increase in the incidence of PPH or severe PPH in women delivered in this hospital, although this observation may be confounded by the differential use of strategies to prevent bleeding. A randomised controlled trial is necessary to provide a definite answer about the optimal dose of LMWH in pregnancy. [ABSTRACT FROM AUTHOR]

In patients with diabetes, metabolic disorders disturb the physiological balance of coagulation and fibrinolysis, leading to a prothrombotic state characterized by platelet hypersensitivity, coagulation disorders and hypofibrinolysis. Hyperglycemia and insulin resistance cause changes in platelet number and activation, as well as qualitative and/or quantitative modifications of coagulatory and fibrinolytic factors, resulting in the formation of fibrinolysis-resistant clots in patients with diabetes. Other coexisting factors like hypoglycemia, obesity and dyslipidemia also contribute to coagulation disorders in patients with diabetes. Management of the prothrombotic state includes antiplatelet and anticoagulation therapies for diabetes patients with either a history of cardiovascular disease or prone to a higher risk of thrombus generation, but current guidelines lack recommendations on the optimal antithrombotic treatment for these patients. Metabolic optimizations like glucose control, lipid-lowering, and weight loss also improve coagulation disorders of diabetes patients. Intriguing, glucose-lowering drugs, especially cardiovascular beneficial agents, such as glucagon-like peptide-1 receptor agonists and sodium glucose co-transporter inhibitors, have been shown to exert direct anticoagulation effects in patients with diabetes. This review focuses on the most recent progress in the development and management of diabetes related prothrombotic state. [ABSTRACT FROM AUTHOR]