Inhibitors in Hemophilia B Santoro, Cristina; Quintavalle, Gabriele; Castaman, Giancarlo ...
Seminars in thrombosis and hemostasis,
09/2018, Letnik:
44, Številka:
6
Journal Article
Recenzirano
Hemophilia B (HB) is an X-linked bleeding disorder caused by deficiency of factor IX (FIX). Patients with the severe form (FIX <1%) account approximately for 30 to 45% of persons with HB and usually ...suffer from recurrent joint, soft-tissue, and muscle bleeds. The availability of safe plasma-derived and recombinant products has virtually abolished the risk of viral infections and the adoption of prophylactic regimens has attenuated the impact of hemophilic arthropathy. Therefore, the development of an inhibitor against FIX is currently the most serious complication that can still occur in the new generations of HB patients. The development of an inhibitor in HB is a rare event (1.5-3% of all patients) but is associated with a significant morbidity, related not only to the bleeding risk but also to the frequent occurrence of allergic/anaphylactic reactions and nephrotic syndrome. Due to the relative rarity of this event, few data exist about risk factors, pathophysiology, and clinical aspects of inhibitors in HB. The induction of immune tolerance is often unsuccessful and can be otherwise affected by many complications in patients with history of allergy or anaphylaxis. Therefore, alternative therapeutic strategies and new approaches are developing. The aim of this narrative review is to discuss current knowledge about risk factors, pathophysiology, and clinical aspects of this rare but serious complication.
Congenital fibrinogen disorders (CFD) include several types and subtypes of fibrinogen deficiency, resulting from monoallelic or biallelic mutations in one of the three fibrinogen genes. While it is ...relatively easy to make an accurate diagnosis based on activity and antigen levels of fibrinogen and genotype, prediction of the clinical phenotype is challenging. Even among patients with the same genotype, the clinical features are heterogeneous and unpredictable. The development of next-generation sequencing rises the possibility to integrate genetic modifiers to explain the subtle relationship between genotype and clinical phenotype. A recent development in integrative hemostasis assays can also help in the determination of patients at risk of bleeding or thrombosis. In this short review, we go through these topics and explain why CFD could be considered an oligogenic rather than a monogenic disease.
Objectives
To evaluate the efficacy of a salvage treatment with rituximab (RTX) in adults with primary immune thrombocytopenia (ITP), in terms of short‐term response and long‐term response (LTR, ...i.e., probability to achieve and maintain response) and to identify biological and clinical predictors of response.
Methods
We retrospectively evaluated the outcome of patients with primary ITP treated with standard dosage RTX (375 mg/m2 × 4) as salvage therapy in five Italian centers. One hundred and three patients, median age of 46 yr, were included. The median period of observation was 59 months.
Results
Response (R) and complete response (CR) were documented in 57 (55%) and 37 (36%) patients, respectively. Patients younger than 40 yr had a higher probability to achieve CR (P = 0.025). Younger women (age < 40 yr) had a significantly higher probability to achieve R and CR (P = 0.039 and P = 0.009, respectively). The estimated LTR rate was 36% and 31% after 48 and 72 months, respectively; female sex (P = 0.033) and younger age (P = 0.021) were associated with better LTR. Younger women had the highest LTR rate (P = 0.006). Response duration was associated with the obtainment of CR after RTX (CR vs. partial response, P = 0.002).
Conclusions
The effect of RTX salvage treatment appears higher in younger women, with LTR rate possibly approaching that of splenectomy.
Acquired Haemophilia A: An Intriguing Disease Mazzucconi, Maria Gabriella; Baldacci, Erminia; Ferretti, Antonietta ...
Mediterranean journal of hematology and infectious diseases,
07/2020, Letnik:
12, Številka:
1
Journal Article
Odprti dostop
Acquired Haemophilia A is a rare acquired bleeding disorder caused by Factor VIII autoantibodies, which neutralise FVIII activity. These inhibitors differ from alloantibodies against FVIII, which can ...occur in congenital Haemophilia A after repeated exposures to plasma-derived or recombinant FVIII products. In most cases, the disease occurs suddenly in subjects without a personal or familiar history of bleedings, with symptoms that may be mild, moderate, or severe. However, only laboratory alterations are present in ~ 30% of patients. The incidence varies from 1 to 4 cases per million/year; more than 80% of patients are elderly, males and females are similarly affected. There is a small peak of incidence related to pregnancy in young women aged 20–40 years. The disease may be underdiagnosed in the elderly. The diagnostic algorithm is based on an isolated prolonged activated partial thromboplastin time, normal thrombin time, absence of Lupus Anticoagulant, and a mixing test that reveals the presence of an inhibitor: the finding of reduced FVIII activity and the detection of neutralising autoantibodies against FVIII lead to the diagnosis. The disease is idiopathic in 44%–63% of cases, while in the others etiological factors are present. Bleeding prevention and treatment are based on therapeutic tools as by-passing agents, recombinant porcine FVIII concentrate or, in a limited number of cases, FVIII concentrates and desmopressin. As soon as the diagnosis has been made, immunosuppressive therapy must be started to eradicate the inhibitor. Better knowledge of the disease, optimal management of bleeding and eradication of the inhibitor have significantly reduced morbidity and mortality in most patients.
1 Institute of Hematology, Catholic University, Rome
2 Dept. of Hematology, University of Florence, Florence
3 Hematology Department and Hemophilia and Thrombosis Center, San Bortolo Hospital, ...Vicenza
4 Hematology Division and Bone Marrow Transplantation Unit, San Gerardo Hospital, University of Milano-Bicocca, Monza
5 Dept. of Hematology-Oncology, Ospedali Riuniti, Bergamo
6 Hematology Unit, Santa Maria Nuova Hospital, Reggio Emilia
7 the Dept. of Biomedical Sciences, Section of Hematology, University of Catania, Catania
8 Institute of Hematology, Dept. of Cellular Biotechnology and Hematology, University La Sapienza, Rome
9 Hematology and Thrombosis Unit, San Paolo Hospital, University of Milan, Milan
10 Institute of Hematology and Oncology L. and A. Seràgnoli, University of Bologna, Bologna
11 Laboratory of Epidemiology of Cardiovascular Disease, Dept. of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy
Correspondence: Valerio De Stefano, Institute of Hematology, Catholic University, Largo Gemelli 8, 00168 Rome, Italy. E-mail: valerio.destefano{at}rm.uni-catt.it
Background: Prior thrombosis is a well-established risk factor for re-thrombosis in polycythemia vera and essential thrombocythemia but scarce data are available on the rate of re-thrombosis and the optimal strategy for prevention of recurrence.
Design and Methods: We retrospectively estimated the rate of recurrence in a multicenter cohort of 494 patients (poly-cythemia vera/essential thrombocythemia 235/259) with previous arterial (67.6%) or venous thrombosis (31%) or both (1.4%). First thrombosis was cerebrovascular disease in 191 cases, acute coronary syndrome in 106, peripheral arterial thrombosis in 44, and venous thromboembolism in 160. Microcirculatory events were not computed.
Results: Thrombosis recurred in 166 patients (33.6%), with an incidence of 7.6% patient-years. Sex, diagnosis (polycythemia vera or essential thrombocythemia), and presence of vascular risk factors did not predict recurrence, whereas age >60 years did (multivariable hazard ratio HR, 1.67; 95% confidence interval CI 1.19–2.32). Increased leukocyte count at the time of the first thrombosis was a risk factor for recurrence in patients <60 years old (HR 3.55; 95% CI 1.02–12.25). Cytoreduction halved the risk in the overall cohort (HR 0.53; 95% CI 0.38–0.73) and the combination with antiplatelet agents or oral anticoagulants was more effective than administration of single drugs. Significant prevention of rethrombosis was independently achieved in patients with venous thromboembolism by both oral anticoagulants (HR 0.32; 95% CI 0.15–0.64) and antiplatelet agents (HR 0.42; 95% CI 0.22–0.77), in those with acute coronary syndrome by cytoreduction (HR 0.30; 95% CI 0.13–0.68), and in those with cerebrovascular disease by antiplatelet agents (HR 0.33; 95% CI 0.16–0.66). The overall incidence of major bleeding was 0.9% patient-years and rose to 2.8% in patients receiving both antiplatelet and anti-vitamin K agents.
Conclusions: In patients with polycythemia vera and essential thrombocythemia, cytoreduction protects against recurrent thrombosis, particularly after acute coronary syndrome. The contemporary use of oral anticoagulants (after venous thromboembolism) or antiplatelet agents (after cerebrovascular disease or venous thromboembolism) further improves the protective effect. Such findings call for prospective studies aimed at investigating whether strategies tailored according to the type of first thrombosis could improve prevention of recurrences.
Key words: polycythemia vera, essential thrombocythemia, recurrent thrombosis, cytoreductive treatment, antiplatelet treatment, oral anticoagulant treatment.
Related Article
Prevention of thrombosis in polycythemia vera and essential thrombocythemia
Raffaele Landolfi, Leonardo Di Gennaro
Haematologica 2008 93: 331-335.
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Direct oral anticoagulants (DOACs) are widely used for the treatment and secondary prophylaxis of venous thromboembolism (VTE). Nowadays, DOACs represent the gold standard for long-term ...anticoagulation, with low-intensity DOACs administration becoming increasingly used worldwide in such scenario. Albeit low-intensity apixaban and rivaroxaban are approved for clinical usage as secondary VTE prophylaxis, there are few literature data regarding their efficacy and safety with a long follow-up.
The aim of our study was to evaluate the efficacy and safety of low-dose DOACs for VTE secondary prophylaxis in patients at high risk of VTE recurrence.
We retrospectively evaluated patients who required long-term anticoagulant secondary prophylaxis to prevent recurrent VTE, treated with apixaban 2.5 mg BID or rivaroxaban 10 mg daily with a follow-up ≥ 12 months.
The examined patients were 323. The median low-dose DOAC administration time was 25.40 months (IQR 13.93-45.90). Twelve (3.7%) VTE recurrences were observed; 21 bleeding events were registered (6.5%), including one episode of Major bleeding (MB) (0.3%), 8 Clinically relevant nonmajor bleeding (CRNMB) (2.5%) and 12 minor bleeding (3.7%). No statistically significant difference in the rate of VTE recurrence and/or bleeding events emerged between the rivaroxaban and apixaban groups. Patients included in the study for multiple episodes of VTE presented a significantly higher risk of a new VTE recurrence during low-intensity DOAC.
Our data suggest that low-dose DOACs may be effective and safe in secondary VTE prophylaxis in patients at high risk of VTE recurrence; however, attention might be needed in their choice in such a scenario for patients who experienced multiple episodes of VTE.
Recent advances in the development of factor VIII (FVIII) concentrates offer patients with hemophilia the opportunity to switch to products considered safer or with improved properties. In some ...cases, product switch occurs due to side effects, convenience issues, or economic reasons affecting clinical choices. Reluctance to change FVIII concentrates is shown by patients and also by their physicians, because of concerns in particular about the risk of inhibitor development. A literature review was performed to retrieve the best evidence regarding safety issues of switching FVIII concentrate in patients with severe hemophilia A. Product switch was not associated with an increased inhibitor risk in four studies in patients during the first 50 to 75 exposure days, or in three studies reporting national switches in Canada and United Kingdom. The latter, the only available study comparing switcher and nonswitcher patients, showed an inhibitor incidence similar to that historically reported in the United Kingdom. In 16 phase III clinical trials and 6 postmarketing studies of FVIII concentrates, few de novo inhibitors were detected in previously treated patients, mostly transient and low-titer, with some additional recurrent inhibitors in patients with previous positive testing. On the whole, although rigorous controlled studies are lacking, literature data do not support increased risk of inhibitor development or other safety issues related to product switch. Therefore, in the presence of clinical needs, the advantages of switching FVIII products should not be missed because of perceived more than evidence-based challenges, in particular in this era of products with improved properties recently introduced or available in few years. Caution, however, is suggested in patients with high inhibitor risk, including in those in concomitance with surgery or intensive treatment. A careful inhibitor testing prior to and after product switch is always needed, to identify real de novo inhibitors and to gather further information in the current evolving scenario, in particular comparing switch and nonswitch patients.
Over the last 2 years, different cases of immune thrombocytopenia (ITP) in patients affected by SARS‐CoV2 have been reported. The management of SARS‐CoV2 in subjects with simultaneous or previous ITP ...can be challenging because of the great involvement of the haemostatic system in this viral infection. In this report, we describe the management and outcome of patients with newly diagnosed (ND), chronic and previous ITP, infected by COVID‐19, referred to the Haematology Institute of University Hospital Policlinico Umberto I in Rome. Steroids + immunoglobulins for ND or relapsed ITP and continuation of home therapy for chronic ITP are advised, although further knowledge is required.
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