41 research outputs found
Product type and other environmental risk factors for inhibitor development in severe hemophilia A
No full textThe development of FVIII inhibitory antibodies is currently the most challenging complication of treatment, affecting similar to 30% of severe hemophilia A patients. These inhibitors inactivate FVIII, rendering the treatment ineffective, causing disability and increasing morbidity and mortality. Inhibitor development results from a complex multicausal immune response involving both genetic and environmental risk factors. One of the most important modifiable risk factors is the source of FVIII products, eg, plasma-derived or recombinant FVIII. Other environmental risk factors, such as age at first treatment, regimen, and intensity of treatment, could contribute to inhibitor development. Severe bleeds, surgery, concomitant infections, or vaccinations may all be events initiating danger signaling resulting in an immune reaction towards administered FVIII. All in all, the etiology of inhibitor development still remains unclear. The risk factors have been stratified into genetic and environmental, but there are no definitive data to determine the impact of each of them
Risk factors for inhibitor development in severe hemophilia A
No full textAlthough significant advances in hemophilia treatment have improved patient outcomes and quality of life, one of the greatest complications in severe hemophilia A is the development of anti-Factor VIII (FVIII) antibodies that inhibit FVIII activity in almost 30% of previously untreated patients (PUPs). Inhibitors make very difficult the management of patients and increase their morbidity and mortality reducing drastically their quality of life. Numerous studies have investigated the mechanisms leading to the development of FVIII inhibitors. However, the etiology of their onset is complex and not yet fully understood. Inhibitors develop from a multicausal immune response involving both genetic (unmodifiable) and environmental (modifiable) factors. F8 gene mutations are the most important genetic risk factor, with null mutations being associated with the highest risk of inhibitor development. Immune response genes (e.g. the human leukocyte antigen complex) and proteins (e.g. cytokines) were studied without any strong confirmation of their role in modulating of inhibitor development. Type of FVIII product is the most important modifiable risk factor. The plasma-derived products containing von Willebrand factor were recently suggested to determine a lower incidence of inhibitor development than recombinant products in PUPs, in the first 50 exposure days (EDs). Other environmental factors including, age at first treatment, treatment intensity and the danger signal effect (surgery, severe bleeds, vaccinations and infections) has also been postulated as an explanation for environment-related inhibitor risk. This review reports the current knowledge on genetic and environmental risk factors on inhibitor development in patients with severe hemophilia A
Pitfalls in molecular diagnosis in a family with severe factor VII (FVII) deficiency-misdiagnosis by direct sequence analysis using a PCR product
No full textMolecular diagnostic tests are becoming a routine analysis in many laboratories. These modern analyses are
widely used in clinical medicine, forensic, genetic and prenatal diagnosis and also in preimplantation genetic
diagnosis. The accuracy of analysis is highly dependent on the success achieved in minimising genotyping
errors. The pitfalls in molecular diagnostic tests can be due to a simple technique such as the polymerase chain
reaction (PCR) used universally. This technique is routinely used for its apparent accuracy, but it is also a
well-known source of errors. We report an error introduced during PCR reaction that leads to a wrong sequence
result and consequently to a ‘false’ molecular result in a next prenatal diagnosis in a family with severe factor
VII (FVII) deficiency. This error was verified using an unsuitable primer design in a rich repetitive sequence
of the FVII gene that leads to a false annealing and then to a wrong molecular diagnosis. It is essential to link
closely molecular data with clinical and phenotype analysis in order to avoid false-negative or false-positive
results, which is of great importance to diagnosis and molecular preventio
Management of pregnancy and delivery in women with inherited bleeding disorders
No full textWomen with inherited bleeding disorders present a wide spectrum of clinical symptoms that vary from mild or moderate bleeding tendency to severe episodes. Monthly haemostatic changes affect these women during menstruation and ovulation. These events may be associated with significant bleeding and pain leading to the limitations in conducting daily activities and adverse effect on quality of life. Likewise, pregnancy and delivery are critical times for affected women. During pregnancy, they may be at greater risk of miscarriage and bleeding complications. In particular, recurrent miscarriage was observed in women with type 3 von Willebrand disease, afibrinogenaemia and severe factor XIII deficiency, and an optimal therapeutic plan is required during their pregnancy. Precautions must be taken at delivery in these women, since they could be at risk of bleeding. The lack of adequate information makes it very difficult to prepare evidence-based guidelines for the prevention of bleedings in affected women and their treatment. A multidisciplinary team of obstetricians, haematologists and paediatricians is required with a good knowledge of these disorders and an awareness of the potential maternal neonatal complication
Knowledge and attitudes toward gene therapy of a cohort of Italian patients with hemophilia
No full textBackground: Gene therapy (GT) has recently become a new therapeutic option for hemophilia A and B. However, patient levels of knowledge and attitudes toward it are poorly understood. A general lack of knowledge and education has been highlighted in previous studies. To date, no studies focused on patient attitudes toward GT, priorities, concerns, and information needs, nor how these factors might influence their willingness to accept it. Objectives: To evaluate knowledge and attitudes toward GT of an Italian cohort of patients with hemophilia. Methods: A questionnaire was administered to patients with hemophilia A and B to evaluate: (1) clinical data; (2) GT knowledge; (3) willingness to accept GT, perceived benefits and concerns, and information needs. Results: Eighty-five patients participated in the study; 64 with severe hemophilia A and 4 with severe hemophilia B. Participants appeared to know only general information on GT, but little about its detailed functioning. The avoidance of frequent infusions and the reduction of bleeding episodes seem to be the most relevant expected benefits. The possibility of failing or losing effectiveness of GT over time was the main concern. Regarding willingness to undergo GT, 54.4% of respondents gave a negative response, mainly due to fear that treatment will lose effectiveness over time, fear of side effects, and lack of GT knowledge. Greater knowledge increased the acceptability of this disruptive therapy among patients with severe hemophilia. Conclusion: Overall, Italian patients with hemophilia showed poor knowledge of GT. However, it seems that greater knowledge was associated with a greater willingness to have GT
Exploring nonreplacement therapies’ impact on hemophilia and other rare bleeding disorders
No full textThe management of hemophilia, von Willebrand disease (VWD), and rare coagulation disorders traditionally relied on replacement therapies, such as factor concentrates, to address clotting factor deficiencies. However, in recent years, the emergence of nonreplacement therapies has shown promise as an adjunctive approach, especially in hemophilia, and also for patients with VWD and rare bleeding disorders. This review article offers an overview of nonreplacement therapies, such as FVIII-mimicking agents and drugs aimed at rebalancing hemostasis by inhibiting natural anticoagulants, particularly in the management of hemophilia. The utilization of nonreplacement therapies in VWD and rare bleeding disorders has recently attracted attention, as evidenced by presentations at the International Society on Thrombosis and Haemostasis 2023 Congress. Nonreplacement therapies provide alternative methods for preventing bleeding episodes and enhancing patients' quality of life, as many of them are administered subcutaneously and allow longer infusion intervals, resulting in improved quality of life and comfort for patients
Updates on Novel Non-Replacement Drugs for Hemophilia
No full textOver the last decade, the world of hemophilia has experienced an unprecedented therapeutic advance, thanks to the progress in bioengineering technologies, leading to the introduction of drugs with novel mechanisms of action based on restoring thrombin generation or coagulation factor VIII mimicking. Apart from the bispecific monoclonal antibody emicizumab, already approved for patients with severe hemophilia A with and without inhibitors, novel non-replacement drugs designed to reduce the treatment burden of patients with hemophilia A or B with or without inhibitors are undergoing evaluation in clinical trials. Thanks to their innovative mechanism of action and subcutaneous administration, these drugs promise to provide effective bleeding protection together with improved adherence and improve health-related quality of life for patients with hemophilia. On the other hand, rare thromboembolic events have been reported with some of these drugs and warrant continuous post-marketing surveillance and investigation of predisposing factors, although the overall safety profile of most of these drugs is good. Finally, new challenges need to be faced in the clinical and laboratory monitoring of the hemostatic status in patients treated with these innovative therapies. In this review, we provide an update on the available data on novel non-replacement drugs currently undergoing evaluation in clinical trials for patients with hemophilia
Psychological and cognitive factors involved in decision‐making process of haemophilia carriers in reproductive choices
No full textIntroductionHaemophilia carriers (HCs) face a multitude of psychological challenges, mainly linked to the possibility of having an affected child. Important reproductive decisions such as opting for pre-implantation genetic testing, or choosing prenatal diagnosis and then whether to continue or interrupt pregnancy in case of affected male fetus, have to be taken into consideration. Notwithstanding, the role of psychological characteristics on such decision-making process needs further investigation. AimThe aim of this study was to investigate whether HCs' beliefs and emotions about haemophilia and cognitive factors such as decision-making style, risk perception, coping strategies in response to stress, and need for cognitive closure might modulate HCs' reproductive decisions. MethodsParticipants were interviewed about their beliefs and emotions on haemophilia and filled an on-line standardized questionnaire on cognitive variables. Sixty HCs participated in this study. ResultsResults show that HCs with high distress for haemophilia given by negative childhood experiences for one or more family member illness and by high concern for their children's health, and with psychological traits characterized by logical (versus emotional) reasoning, active coping style and high need for certainty, tend to choose diagnostic prenatal tests over routine pregnancy analysis. ConclusionThis study highlighted the influence of negative early-life experience with haemophilia and of several cognitive factors in HCs choice of prenatal test
A rare inherited coagulation disorder : combined homozygous factor VII and factor X deficiency
No full textThe combined presence in the homozygous state of more than one recessively transmitted coagulation defect may rarely occur in countries with a high rate of consanguinity. In an Iranian family consisting of two parents (second cousins) and two affected siblings, initial phenotypic analysis led to a diagnosis of mild FX deficiency (10–19% FX activity,
42–54% FX:Ag), and genotyping revealed a new homozygous missense mutation in the
corresponding gene (Ser3Cys). As both of the sibs had a severe bleeding history that was not compatible with mild deficiency of FX, further phenotypic analysis revealed the
additional presence of severe FVII deficiency (<1% FVII activity; 63–111% FVII:Ag) associated with the homozygous missense gene mutation Cys310Phe. In this kindred, lack of identification of the double coagulation defect might have led not only to incomplete understanding of the clinical phenotype but also to an incorrect prenatal diagnosis
