Sickle cell disease (SCD) is an inherited blood disorder in which sickle hemoglobin (HbS) polymerizes, leading to red blood cell sickling and chronic hemolytic anemia, vaso-occlusive crises, and ...end-organ damage associated with early mortality. Despite standard of care, patients with SCD still experience complications and early mortality, highlighting remaining unmet treatment needs. Voxelotor is a first-in-class HbS polymerization inhibitor approved by the US Food and Drug Administration as a treatment for SCD and by the European Medicines Agency for hemolytic anemia due to SCD. In clinical studies, voxelotor has been shown to increase hemoglobin (Hb) and decrease hemolytic markers in patients with SCD. The objective of this study was to estimate the impact of voxelotor on the burden of SCD in France using a modeling approach, accounting for its anticipated adoption and diffusion over the next 5 years. We designed a sequential multi-cohort model to project and compare the cumulative incidence of SCD complications over a 20-year time horizon in a world with and without voxelotor. A distribution of patients was simulated across various levels of Hb response based on the phase 3 HOPE trial results, and relative risk reduction was adjusted using published meta-analysis results that projected risk reduction due to a 1 g/dL increase in Hb. In 6100 modeled patients with SCD treated with voxelotor, the model projected the number of deaths to decrease by 39.4%, with an increase of 1.8% in life-years gained. The model also projected life expectancy to increase by 15.8%, and incident cases of stroke, pulmonary hypertension, and chronic kidney disease to decrease by 19.8%, 24.5%, and 25.1%, respectively. The model suggests that improving Hb using a treatment such as voxelotor may have a positive public health impact by reducing the burden of SCD for patients and the healthcare system.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Optimal modalities for diagnosis, treatment, and surveillance of portal or splenic vein thrombosis have not yet been defined. The present retrospective study aimed to investigate the role of computed ...tomography performed systematically before and after laparoscopic splenectomy to assess the incidence of portal or splenic vein thrombosis, predictors, and outcomes.
Computed tomography scans were obtained from 170 patients undergoing elective laparoscopic splenectomy between 2005 and 2015. Pre- and postoperative splenic vein diameter was measured at the splenoportal junction and at a distance of 2, 4, 6 cm from it. Univariate and multivariate analyses were used to identify portal or splenic vein thrombosis risk factors and predictors of treatment outcome.
Overall, 68.2% of patients had benign hematologic diseases; 64.1% showed splenomegaly. Portal or splenic vein thrombosis occurred in 53.5% of patients (91/170), of whom 49.5% were asymptomatic. Preoperative splenic vein diameter measurements at 2, 4, and 6 cm from the splenoportal junction were significantly greater in portal or splenic vein thrombosis patients than in no-portal or splenic vein thrombosis patients. Patients with splenic vein diameter ≥8 mm at all measured sites had a greater risk of developing portal or splenic vein thrombosis (P = .009; odds ratio, 2.57; 95% confidence interval, 1.26–5.23). The majority of thromboses involved the distal splenic vein (45.1%, 41/91), and 41.7% of patients had thromboses located in multiple sites. Fully 71.4% showed complete resolution of portal or splenic vein thrombosis. Thrombus location at a single site predicted a favorable treatment outcome (P < .0001).
Portal or splenic vein thrombosis is a frequent complication of splenectomy that occurs asymptomatically in half of cases. Computed tomography could have an important role in identifying patients at risk of developing portal or splenic vein thrombosis as well as in predicting portal or splenic vein thrombosis resolution.
Transcranial Doppler (TCD) is used to detect children with sickle cell anemia (SCA) who are at risk for stroke, and transfusion programs significantly reduce stroke risk in patients with abnormal ...TCD. We describe the predictive factors and outcomes of cerebral vasculopathy in the Créteil newborn SCA cohort (n = 217 SS/Sβ0), who were early and yearly screened with TCD since 1992. Magnetic resonance imaging/magnetic resonance angiography was performed every 2 years after age 5 (or earlier in case of abnormal TCD). A transfusion program was recommended to patients with abnormal TCD and/or stenoses, hydroxyurea to symptomatic patients in absence of macrovasculopathy, and stem cell transplantation to those with human leukocyte antigen-genoidentical donor. Mean follow-up was 7.7 years (1609 patient-years). The cumulative risks by age 18 years were 1.9% (95% confidence interval 95% CI 0.6%-5.9%) for overt stroke, 29.6% (95% CI 22.8%-38%) for abnormal TCD, which reached a plateau at age 9, whereas they were 22.6% (95% CI 15.0%-33.2%) for stenosis and 37.1% (95% CI 26.3%-50.7%) for silent stroke by age 14. Cumulating all events (stroke, abnormal TCD, stenoses, silent strokes), the cerebral risk by age 14 was 49.9% (95% CI 40.5%-59.3%); the independent predictive factors for cerebral risk were baseline reticulocytes count (hazard ratio 1.003/L × 109/L increase, 95% CI 1.000-1.006; P = .04) and lactate dehydrogenase level (hazard ratio 2.78/1 IU/mL increase, 95% CI1.33-5.81; P = .007). Thus, early TCD screening and intensification therapy allowed the reduction of stroke-risk by age 18 from the previously reported 11% to 1.9%. In contrast, the 50% cumulative cerebral risk suggests the need for more preventive intervention.
1 CECOS, Service dHistologie, Biologie de la Reproduction et Cytogénétique EA 1533 (UPMC), Hôpital Tenon (APHP), Paris
2 Service de Chirurgie, Institution Nationale des Invalides, Paris
3 Centre de ...la Drépanocytose, Hôpital Henri Mondor (APHP), Créteil
4 Département de Santé Publique, Hôpital Tenon (APHP), UPMC, Paris
5 CECOS, Service dHistologie, Biologie de la Reproduction et Cytogénétique, Hôpital Cochin (APHP), Paris
6 Service dHématologie, Hôpital Tenon (APHP), Paris, France
Correspondence: Jacqueline Mandelbaum, Service dHistologie, Biologie de, la Reproduction et Cytogénétique, CECOS Hôpital Tenon 4, rue de la, Chine 75020 Paris, France. E-mail: jacqueline.mandelbaum{at}tnn.aphp.fr
Background: Recent progress in the treatment of sickle cell disease, in particular the use of hydroxyurea, has considerably modified the prognosis of this disease. Many more patients now reach reproductive age. The objective of this study was to assess the potential impact of hydroxyurea on the semen of patients.
Design and Methods: In this retrospective multicenter study, we evaluated the sperm parameters and fertility of 44 patients and analyzed the potential impact of hydroxyurea.
Results: We report data from the largest series so far of semen analyses in patients with sickle cell disease: 108 samples were analyzed, of which 76 were collected before treatment. We found that at least one sperm parameter was abnormal in 91% of the patients before treatment, in agreement with published literature. All sperm parameters seemed to be affected in semen samples collected during hydroxyurea treatment, and this impairment occurred in less than 6 months, later reaching a plateau. Furthermore, after hydroxyurea cessation, while global results in 30 patients were not statistically different before and after hydroxyurea treatment, in four individuals follow-up sperm parameters did not seem to recover quickly and the total number of spermatozoa per ejaculate fell below the normal range in about half the cases.
Conclusions: The observed alterations of semen parameters due to sickle cell disease seem to be exacerbated by hydroxyurea treatment. Until prospective studies reveal reassuring findings, we suggest that a pre-treatment sperm analysis be performed and sperm cryopreservation be offered to patients before hydroxyurea treatment.
Key words: sickle cell disease, hydroxyurea, sperm, male fertility.
Red blood cell (RBC) transfusion is a major therapy for sickle cell disease (SCD). Patients are at risk of forming antibodies to RBC antigens, which can result in the impossibility to find compatible ...units and can cause hemolytic transfusion reactions. This retrospective study investigates the evolution of RBC consumption and the frequencies, specificities, and chronology of the appearance of antibodies in a population of patients consistently receiving RH (C, D, E, c, e) and K-matched RBC units (RBCus) from a predominantly European donor population. Over the 11-year period in the Paris area, 6496 patients received transfusion at least once for a total of 239 944 units. Antibodies were made by 1742 patients. The first antibodies of a patient were predictive of subsequent immunization. By the 17th RBCu transfused (by the 20th, excluding warm autoantibodies), 75% of the patients who would make antibodies had made their first. By the 16th, 90% who would make antibodies to a high frequency antigen had made their first antibody to these antigens. Females made their first antibodies slightly earlier than males. Patients who received multiple transfusions (>50 units) had a higher immunization prevalence than those who rarely received transfusion (<12 units) but fewer clinically significant antibodies. Patients with SCD and prophylactic RH-K matching not immunized by the 20th RBCu are likely to have a low alloimmunization risk (to antigens other than RH-K), that is, be low responders, especially relative to the most clinically significant antibodies. This number of 20 units is a point before which close monitoring of patients is most important but remains open to future adjustment.