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.
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.
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.
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.
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.
Introduction
Hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) is complement-mediated due to the lack of complement inhibitors in the hemopoietic cell membranes, making complement inhibition the ...best approach to manage PNH. Three complement inhibitors are approved by the European Medicines Agency as targeted therapy for PNH: eculizumab and ravulizumab, two humanized monoclonal antibodies targeting the same complement 5 (C5) epitope, approved in 2007 and 2019, respectively, and the more recently approved cyclic peptide, the complement 3 (C3) inhibitor pegcetacoplan. Although national and international PNH treatment guidelines exist, they do not take into consideration the latest clinical trial evidence. Given the lack of evidence-based data for some clinical situations encountered in real life, we identified specific populations of patients who may benefit from switching to proximal C3 from terminal C5 inhibition.
Methods
The expert recommendations presented here were created using a Delphi-like process by a group of expert PNH specialists across Central Europe. Based on an initial advisory board meeting discussion, recommendations were prepared and reviewed as part of a Delphi survey to test agreement.
Results
Using a systematic approach, literature databases were searched for relevant studies, and 50 articles were reviewed by the experts and included as supporting evidence.
Conclusion
Implementation of these recommendations uniformly across healthcare institutions will promote the best use of complement inhibition in managing PNH, and has the potential to positively impact patient outcomes in Central Europe and worldwide.
Introduction
florio
®
HAEMO is a hemophilia treatment monitoring application (app) offering activity tracking and wearable device connectivity. Its use might support everyday activities for people ...with hemophilia. The aim of this study was to evaluate user satisfaction, long-term usage and the impact on data entry when pairing a wearable with a hemophilia monitoring app.
Methods
This is a follow-up of a two-part user survey conducted in Central Europe. People with hemophilia and parents/caregivers of children with hemophilia using florio HAEMO and who completed part one were invited to complete a second online questionnaire at least 4 months later.
Results
Fifty participants (83.3%) who completed part one of the survey continued to use the florio HAEMO app and completed part two. Of 14 participants who chose to use the app with a wearable, more than half (57.1%) were aged between 13 and 25 years. Overall, the results demonstrated that florio HAEMO is very easy or rather easy to use, especially for individuals pairing the app with a wearable. Most people using a wearable indicated that florio HAEMO was very or rather important in bringing certainty to daily activities (85.7%). Notably, 14 of 36 (38.9%) non-wearable users indicated that they would prefer to pair the app with a wearable in the future.
Conclusions
Adherence to the florio HAEMO app is maintained over an extended period of use. Pairing the app with a wearable might enable easier access to app features, increase data entry motivation and provide more certainty about daily activities for people with hemophilia.
Introduction
Continuous infusion (CI) of clotting factors has facilitated surgical procedures and intensive replacement therapy in haemophilia patients. This procedure could, however, be further ...optimized by using a short‐term central venous catheter (CVCs) instead of via peripheral venous access.
Aim
In this paper, we present our results on using a short‐term CVC in haemophilia patients during major surgical operations.
Methods
In total, 40 patients with haemophilia A or B (37 and 3, respectively), aged 21–81 years, underwent 67 surgeries with 65 CVCs. Patients requiring intensive treatment lasting over 5 days had the indications for CVC placement. The catheters were placed by experienced anaesthesiologists in the operating theatre under general anaesthesia and following activated partial thromboplastin time correction.
Results
No interruption of CI was observed and only one catheter had to be removed prematurely due to a suspected infection. There were no signs found for prosthesis or wound infection, nor was there any thrombosis documented.
Conclusion
Our study produced encouraging results regarding the use of short‐term CVCs in haemophilia patients. Even though our patient sample was small, the data corroborates short‐term CVCs to be safe and convenient for factor concentrate delivery in CI during major surgical operations.
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Introduction: Low molecular weight heparins (LMWH) have stable pharmacokinetics. However, physiologic changes during pregnancy can alter pharmacokinetics of LMWH and make the biodisponibility of ...the drug less predictable. When starting prophylactic treatment with LMWH in pregnant woman, most physicians calculate the initial LMWH dose based on the body weight and adapt the dose according to the weight gain. An alternative method is to monitor the anti-Xa activity and adjust the LMWH dose accordingly. LMWH are for the moment the only anticoagulant available for prophylaxis of venous thrombo-embolism in pregnant women and prevention of severe pregnancy complications. Therefore, we conducted a study addressing the rationality of performing an anti-Xa activity monitoring regularly during pregnancy.
Methods: We retrospectively analyzed data from pregnant women undergoing prophylaxis with LMWH followed at the Hemostasis and Thrombosis Unit of the Saint-Luc University Hospital Unit. All the patients that had anti-Xa activity done at least three times during pregnancy were included in the study. The measurements of anti-Xa were done regularly every 6 weeks and the dose of LMWH was increased in case of anti-Xa activity lower than 0.3 U/ml. Initial LMWH dose was calculated based on the patient body weight and the first measurement of anti-Xa done 10 days afterwards.
Results: Out of 173 women evaluated in the study, 79% needed LMWH dose adjustment. 97 patients (56%) had one dose adjustment, 35 patients (20%) two and 5 patients (3%) three. The first augmentation of LMWH dose was needed before the patient gained body weight in 36,5% of cases. The average increase of the LMWH dose was 49%, 100% and 116% for the one, two and three dose adjustments, respectively. Under-dosing of LMWH, defined as anti-Xa activity <0,2 U/mL, was present in 12% of patients on the first monitoring versus 3,5% on the last monitoring visit. No severe side effects occurred during the treatment. Five patients (3%) had unfavorable outcome of the pregnancy.
Conclusions: This study demonstrates that regular monitoring of anti-Xa activity can help in maintaining the prophylactic levels of LMWH throughout the pregnancy. We also showed that the reduction of the anti-Xa activity is not always directly correlated with the weight gain in pregnant women. Therefore we recommend that LMWH dose adjustment should not be made based solely on the weight gain of the patient during pregnancy.
No relevant conflicts of interest to declare.
Introduction: Continuous infusion (CI) of clotting factor concentrate has facilitated surgical procedures and intensive replacement therapy in hemophilia patients. The advantage of CI over bolus ...infusions is ability to maintain steady-state levels of coagulation factors and moreover, to reduce the total amount of factor concentrate spent. CI is commonly delivered through a peripheral vein. However, a significant number of hemophilia patients have distorted peripheral veins which can compromise continuous flow of factor concentrate needed for successful treatment. Also, thrombophlebitis at the site of venous access, an adverse effect of CI previously reported, can further impair the delivery of factor concentrate in CI and make the future use of the vein for concentrate administration impossible or difficult. Use of central venous catheter can ease the application of CI. By searching the literature, we found only a few case reports describing the use of temporary non-tunneled central venous catheters (CVC) for administrating CI in patients with hemophilia.
The aim of this study was to evaluate the efficacy and safety of short-term used non-tunneled CVC for CI during surgical procedures in hemophilia patients.
Methods: In this study we have retrospectively studied patients with hemophilia that had temporarily used non-tunneled CVC for CI of factor concentrate during and after major surgery in the Saint-Luc University Hospital in Brussels between August 2000 and April 2014. The indication for CVC usage was a major surgery with anticipated need for CI of factor concentrate longer than 5 days.
CVC was inserted by an experienced anesthesiologist in the operating room after the induction of general anesthesia and normalization of APTT. Before the CVC insertion, the patient would have already received bolus of clotting factor concentrate and have the CI started through the peripheral vein. Upon placement, the CI was switched to the CVC. The CVC was kept in place until leaving hospital or cessation of the need for continuous infusion.
Results: During the study period, 40 male patients with hemophilia A or B (37 and 3 patients, respectively) underwent 67 major surgical procedures covered by CI of factor concentrate delivered through CVC. Patients, age 21 -81, had severe, mild or moderate disease (33, 5 and 2 patients, respectively). Patients had altogether 65 CVC for 67 surgical procedures. The same catheter was used for 3 surgeries and 16 patients had CVC placed more than once; 14 patients twice, one patient three times and one ten times. Patients underwent orthopedic surgery (79%), gastrointestinal surgery (15%) and cardiovascular surgery (5%) while one patient (1%) had surgery of urinary tract. The CVC were placed in the right jugular vein (58%), the left jugular vein (18%), the left subclavian vein (8%) and right subclavian vein (3%), while the data were missing in 6 patients. Median duration of catheter was 12 days, with range from 5 to 107 days. No CVC was removed prematurely and no malfunctions of catheters were recorded. Moreover, no complications related to the CVC were noted whatsoever. We searched for bleeding at the site of puncture of the catheter, signs of local infection, pneumothorax following placement of CVC, catheter thrombosis, malfunction of the catheter and surgical site infection. Finally, most of the patients reported satisfaction related to the use of CVC for CI of factor concentrate.
Conclusions: Based on results of this study, we can conclude that the use of short-term non-tunneled CVC should be considered in patients with hemophilia undergoing major surgery with the need for prolonged CI of factor concentrates. By placing CVC we can ensure undisturbed flow of factor concentrate during CI and preserve peripheral veins for the future concentrate administration.
No relevant conflicts of interest to declare.
Non-Saccharomyces wine yeasts are recognized for their ability to enhance the aroma complexity of wines. New trends in winemaking have highlighted the concept of microbiological terroir thus ...encouraging the use of indigenous non-Saccharomyces starter cultures in mixed fermentations with Saccharomyces cerevisiae to overcome the lack of authenticity and provide the wines with unique regional character and distinct aromatic profiles. In this study, 257 indigenous non-Saccharomyces isolates were obtained for the first time from 11 Maraština vineyards located within the winegrowing region of Dalmatia (Croatia). The isolates were identified at the molecular level and characterized for desirable oenological traits such as growth at different temperatures, high ethanol and SO2 tolerance, and for negative features such as high hydrogen sulphide (H2S) and acetic acid production as well as hydroxycinnamic acid decarboxylase (HCDC) activity. Among 27 identified species, those from Aureobasidium genera prevailed, followed by Metschnikowia, Hanseniaspora and Lachancea. The representatives from different species showed high SO2 (up to 250 mg/L) and ethanol (up to 12%) tolerance, low acetic acid, and medium-low H2S production. The HCDC activity was detected exclusively among Metschnikowia, Aureobasidium and Kabatiella species. Some regionally distinct characteristics within the isolates from the same species were observed. The encouraging insights into potential new starter cultures emerged after the evaluation of enzymatic activities of selected isolates. Most of them showed high leucine and valine arylamidase activity, whereas Hanseniaspora and Metschnikowia isolates were additionally characterized by high β-glucosidase and esterase activity, respectively.
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•Indigenous non-Saccharomyces yeasts were isolated from Croatian Maraština grapes.•Among 257 isolates, 27 different species were identified and characterized.•Potential candidates for development as starter cultures were found.•Hanseniaspora isolates showed high β-glucosidase activity.•Some regionally distinct characteristics within the species were observed.
