Seminars in thrombosis and hemostasis最新文献

Chronic liver disease is a frequently encountered disorder and a major concern worldwide with a complex pathophysiology, which often affects the hemostatic system. Such alterations, which affect both primary and secondary hemostasis, are heterogenous, including pro-hemorrhagic (i.e., decreased coagulation factors, increased fibrinolysis, thrombocytopenia and platelet dysfunction) and pro-thrombotic (i.e., decreased natural anticoagulants) changes. As a consequence of this unstable balance, patients with liver cirrhosis may experience both hemorrhagic complications and venous thromboembolic events, which are often unpredictable and whose management is particularly challenging for clinicians. This narrative review will address the most recent advances in the pathophysiology of key derangements of hemostasis in patients with chronic liver disease, focusing on their clinical implications and management.

Hemophilia B is the first bleeding disorder for which gene therapy clinical programs began. Presently, adenovirus-associated vectors represent the best means to deliver the transgene, and their administration by intravenous route has been used in recent clinical trials. The natural occurring factor IX (FIX) Padua variant, which allows for a 5- to 8-fold higher activity of FIX, while maintaining a normal protein concentration, was subsequently used to enhance the level of transgene expression. All the recent trials using this variant showed good results, and accumulating data suggest that long-term expression durability could be maintained at a significant hemostatic level. However, the risk of loss of transgene expression associated to immune response with liver enzymes elevation remains a concern, especially as to the efficacy and duration of immunosuppressive treatment. Notwithstanding this limitation, the results of clinical trials suggest that gene therapy in hemophilia B has the potential to provide long-term benefits with sustained factor activity levels predicted to last several years in many patients.

Hemophilia is a rare X-linked congenital bleeding disorder due to a deficiency of factor VIII (hemophilia A [HA]) or factor IX (hemophilia B [HB]). Replacement and nonreplacement treatments are available but have limitations. Gene therapy (GT) provides an effective, long-term, single-dose treatment option, now approaching clinical practice. This study aimed to understand patient perspectives on GT for HA and HB in Italy using a qualitative questionnaire distributed through Italian patient associations, addressing patient views on daily life, treatments, unmet needs, quality of life (QoL), and GT for hemophilia. In total, 141 participants had HA, and 14 had HB (severe 78.6%). Daily life was most affected by pain and/or joint function limitations (57.5% of participants), high infusion frequency (42.5%), management of breakthrough bleeding episodes (40.3%), and anxiety/fear of severe or sudden bleeding (38.8%). Despite current treatments, about half of the participants experienced three or more annual bleeding episodes. Most participants knew of GT (87.2%) and expected improvements in QoL (60.5%), reduced frequency of current treatments (53.5%), and a permanent cure (49.1%); 46.4% were unaware of its once-off dosage and 46.4% were not concerned about the costs they anticipated to be associated with GT. Although several fears were reported, 25.0% of participants were willing to undergo GT with the support of a multidisciplinary team. This survey provided valuable insight into patient perspectives on hemophilia and GT in Italy. Overall, relevant proportions of patients still experience limitations affecting their daily life. Most were positive about GT and anticipated improvements in their clinical outcomes and QoL.

People with nonsevere hemophilia (PWNSH) are phenotypically more diverse than those with severe hemophilia. Perceptions relating to a "nonsevere" phenotype have contributed to fewer research initiatives, fewer guidelines on optimal management, and a lack of standards for surveillance and clinical assessment for affected individuals. In many cases, episodes of abnormal bleeding could, if investigated, have led to earlier diagnosis. Furthermore, the major recent developments in therapy for hemophilia have largely focused on severe disease and, as a group, PWNSH have not been included in many key clinical trials. Benefiting people with severe disease, innovative replacement therapies have generally targeted factor levels that are above those present in a large proportion of PWNSH. Therapeutic advances can lead to improvement in phenotype for people with severe hemophilia over that currently experienced by many PWNSH. As a result, we are approaching a point where PWNSH may, in many countries, have a higher risk of bleeding and restriction in lifestyle than those with severe disease but with more limited therapeutic options. Given the multiple major advances in treatment for people with hemophilia, it is timely to review the aspects of nonsevere disease, to ensure equity in care and management for all individuals with this condition.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder with highly variable penetrance, affecting up to 1 in 5,000 individuals. It is characterized by the presence of abnormal blood vessels that can lead to excessive bleeding-most frequently recurrent nosebleeds (epistaxis), skin and mucosal telangiectasias (small, dilated blood vessels), as well as arteriovenous malformations (AVMs) that can form in various organs, particularly the lungs, liver, and brain. HHT is caused by loss-of-function mutations in the BMP9-10/ENG/ALK1/SMAD4 signaling pathway, an important mediator of vascular quiescence. HHT possesses significant challenges for affected individuals, as the complications can range from mild to life-threatening events, depending on the severity and location of the vascular abnormalities. Despite this bleeding disorder being not uncommon, nowadays no specific treatment is as yet available for HHT and most current therapies include repurposed drugs. The aim of this review was to show therapeutic advances on the basis of recent promising clinical trials for HHT.

Historically, the aim of treatment for hemophilia, the congenital X-linked hemorrhagic disorder due to deficiencies of coagulation Factor (F) VIII (hemophilia A) or FIX (hemophilia B), has been the replacement through factor concentrates, whose regular administration (i.e., prophylaxis) has been shown to be highly effective in preventing bleeding complications and it is currently considered the gold standard of hemophilia treatment. However, continuous technological progress (i.e., plasma-derived factor concentrates, recombinant standard and extended half-life [EHL] products) has allowed clinicians operating at hemophilia treatment centers to individualize the management of persons with hemophilia, improving outcomes, adherence to therapy, and their quality of life. The achievement of normal hemostasis, the final goal that now seems possible with new-generation EHL products, non-replacement and gene therapies, will translate into normalization of life for persons with hemophilia, also addressing health equity (i.e., rendering them indistinguishable from their healthy peers). The evolution of hemophilia treatment and, in parallel, of therapeutic targets in the management of hemophilia patients over the last decades will be critically discussed in this narrative review.

Type 3 von Willebrand disease (VWD), the most severe form of VWD, is an inherited recessive bleeding disorder caused by the complete deficiency of von Willebrand factor (VWF). The reported prevalence is 1 per million but varies worldwide according to the frequency of consanguineous marriages. The clinical phenotype is characterized not only by mucocutaneous bleedings, but also by hemarthroses and muscle hematoma, as in patients with moderate hemophilia. Long-term prophylaxis with factor (F)VIII/VWF concentrates is recommended in patients with a history of severe and frequent bleeds. A rare complication of replacement therapy is the development of alloantibodies against VWF, with the consequences of an ineffective therapy and risk of anaphylactic reactions upon treatment. Emicizumab is the first bispecific monoclonal antibody that mimics FVIII coagulant activity and is approved for prophylaxis of bleeding in patients with inherited hemophilia A with or without inhibitors and recently also for acquired hemophilia. In this manuscript we report and discuss available data in the literature on the use of emicizumab in type 3 VWD and describe the case of a female patient with type 3 VWD with a history of alloantibodies against VWF and posttransfusion anaphylaxis, recently and successfully put on off-label prophylaxis with emicizumab.