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1.
Blood Transfus ; 18(2): 152-158, 2020 03.
Article in English | MEDLINE | ID: mdl-31184581

ABSTRACT

BACKGROUND: Physical activity in people with haemophilia (PWH) reduces the development of severe arthropathy, but it must be performed after regular, proper prophylaxis. Strict adherence to treatment is crucial to achieving effectiveness and established outcomes. The primary aim of this study was to collect prospective data on adherence to prophylaxis for over 36 months. A secondary aim was to verify whether adherence correlates with physical activity. MATERIALS AND METHODS: Italian patients with severe haemophilia A treated on prophylaxis with octocog alfa were included in the study. Physical findings were assessed by the Haemophilia and Exercise Project (HEP)-Test-Q and the Early Prophylaxis Immunologic Challenge (EPIC)-Norfolk Physical Activity Questionnaire; orthopaedic status was assessed by the Hemophilia Joint Health Score (HJHS). Adherence was measured as percentage of empty vials returned with respect to the prescribed amount. RESULTS: Forty-two PWH were enrolled: 31% children, 21.4% adolescents, and 47.6% adults. Type, frequency and impact of physical activities differed among the three groups. The HEP-Test-Q showed the highest impairments in the domains "endurance" and "strength/co-ordination". Eight percent of patients were classified as adherent to prophylaxis. Among them, 50% had at least one bleeding episode in the year before enrolment; this percentage dropped during the three years of the study. While remaining stable in the "non-adherent" group, the HJHS score decreased in the "adherent" patients. The mean number of school/work days lost was lower in adherent patients (from 3.4±6.8 to 0.2±0.9) than in non-adherent ones. DISCUSSION: PWH with better orthopaedic scores reported better physical performance. Adherence to long-term prophylaxis proved to be high and correlated with a reduction in bleeds, target joints, school/work days lost, and with a performance improvement in endurance sports activities over time.


Subject(s)
Factor VIII/therapeutic use , Hemophilia A/prevention & control , Adolescent , Adult , Child , Exercise , Female , Hemophilia A/epidemiology , Humans , Italy/epidemiology , Male , Patient Compliance , Prospective Studies , Young Adult
2.
Blood Transfus ; 17(5): 391-398, 2019 09.
Article in English | MEDLINE | ID: mdl-30747707

ABSTRACT

BACKGROUND: There is a lack of prospective clinical trials specifically designed to evaluate the benefits of prophylaxis with vWF/FVIII concentrates in patients with inherited von Willebrand disease (vWD). The aim of the study was to compare efficacy of secondary long-term prophylaxis (PRO) with vWF/FVIII in the prevention of bleeding episodes in severe vWD patients to standard of care (on-demand treatment; ODT). MATERIALS AND METHODS: In this 12-month, phase III, open-label study (PRO.WILL), vWD patients (aged ≥6 years) were randomised to PRO (n=9; 5 completed) or ODT (n=10; 7 completed) treatment with Fanhdi®/Alphanate® (Grifols) according to current licensing status for use in vWD. We assessed the proportion of patients who did not present any spontaneous bleeding episode, adverse events (AEs) or thrombotic events. RESULTS: All patients on ODT had vWD type 2 or 3 vs 70% of patients on PRO. All ODT patients experienced bleeds vs 60% on PRO. PRO patients showed fewer bleeds (n=32 vs n=172 [112 in the same patient, mostly mucosal]; p<0.0001) and lower risk of bleeding (relative attributable risk estimate: -0.667; 95% CI: -2.374, -0.107; p<0.001). Most frequent bleeds in ODT and PRO groups were, respectively, epistaxis (n=52 vs n=15) and gastrointestinal (n=13 [9 in the same patient] vs n=1). While most bleeds lasted one day under ODT (31/32), only epistaxis did so in PRO group (14/15). No AEs due to study medication were observed. DISCUSSION: Despite the small sample size and the heterogeneity of the study population, patients on vWF/FVIII prophylaxis showed a reduction in bleeding risk and rate compared to on-demand treatment.


Subject(s)
Factor VIII/therapeutic use , Hemorrhage/prevention & control , von Willebrand Diseases/drug therapy , von Willebrand Factor/therapeutic use , Adolescent , Adult , Drug Combinations , Factor VIII/administration & dosage , Factor VIII/adverse effects , Female , Hemorrhage/drug therapy , Hemorrhage/etiology , Humans , Male , Middle Aged , Treatment Outcome , Young Adult , von Willebrand Diseases/complications , von Willebrand Diseases/prevention & control , von Willebrand Factor/administration & dosage , von Willebrand Factor/adverse effects
3.
Stem Cell Reports ; 11(6): 1391-1406, 2018 12 11.
Article in English | MEDLINE | ID: mdl-30416049

ABSTRACT

We generated patient-specific disease-free induced pluripotent stem cells (iPSCs) from peripheral blood CD34+ cells and differentiated them into functional endothelial cells (ECs) secreting factor VIII (FVIII) for gene and cell therapy approaches to cure hemophilia A (HA), an X-linked bleeding disorder caused by F8 mutations. iPSCs were transduced with a lentiviral vector carrying FVIII transgene driven by an endothelial-specific promoter (VEC) and differentiated into bona fide ECs using an optimized protocol. FVIII-expressing ECs were intraportally transplanted in monocrotaline-conditioned non-obese diabetic (NOD) severe combined immune-deficient (scid)-IL2rγ null HA mice generating a chimeric liver with functional human ECs. Transplanted cells engrafted and proliferated in the liver along sinusoids, in the long term showed stable therapeutic FVIII activity (6%). These results demonstrate that the hemophilic phenotype can be rescued by transplantation of ECs derived from HA FVIII-corrected iPSCs, confirming the feasibility of cell-reprogramming strategy in patient-derived cells as an approach for HA gene and cell therapy.


Subject(s)
Endothelial Cells/cytology , Hemophilia A/therapy , Induced Pluripotent Stem Cells/cytology , Animals , Antigens, CD34/metabolism , Biomarkers/metabolism , Cell Differentiation , Cell Proliferation , Disease Models, Animal , Endothelial Cells/transplantation , Factor VIII/metabolism , Fetal Blood/cytology , Fibroblasts/cytology , Hemophilia A/pathology , Humans , Induced Pluripotent Stem Cells/transplantation , Injections, Intraperitoneal , Liver/cytology , Mice , Microspheres , Phenotype , Portal Vein/metabolism , Tissue Donors
4.
Blood Transfus ; 16(4): 371-381, 2018 07.
Article in English | MEDLINE | ID: mdl-29313798

ABSTRACT

Recent advances in the care of von Willebrand's disease (vWD) have allowed the majority of patients to be managed adequately. Even in the more severe forms, it is now possible to control recurrent bleeding through secondary long-term prophylaxis with von Willebrand factor-containing concentrates. Moreover, in the setting of surgical prophylaxis, the combination of interdisciplinary management and close patient monitoring yields a positive outcome in nearly all cases, although safety concerns remain. In clinical practice, the effectiveness of therapy is hindered by the difficulties in making a rapid, yet accurate diagnosis, in identifying the subgroup of bleeders who may benefit most from a specific strategy, and in selecting the optimal product and regimen.Since specific guidelines for heavy bleeders requiring short- and long-term prophylaxis are still lacking, sharing the experience of experts dealing with vWD patients on a daily basis is crucial to fill gaps in information relating to patient management. To address this important issue, 13 Italian haematologists met in Milan on April, 2, 2016 and in Florence on July, 9, 2016. A 30-question survey constituted the input to discuss (i) optimisation of the diagnostic workflow for vWD, (ii) the characteristics of patients who may benefit from secondary long-term prophylaxis (in particular with the purified von Willebrand factor concentrate with a low content of factor VIII), (iii) the key elements to consider when selecting a concentrate and (iv) the pre-operative and post-operative management of vWD patients. A summary of the main points covered is provided in this report.


Subject(s)
von Willebrand Diseases/diagnosis , von Willebrand Diseases/prevention & control , Congresses as Topic , Humans , Italy , Practice Guidelines as Topic , von Willebrand Diseases/epidemiology
5.
Mol Ther ; 25(8): 1815-1830, 2017 08 02.
Article in English | MEDLINE | ID: mdl-28552407

ABSTRACT

Hemophilia A (HA) is an X-linked bleeding disease caused by factor VIII (FVIII) deficiency. We previously demonstrated that FVIII is produced specifically in liver sinusoid endothelial cells (LSECs) and to some degree in myeloid cells, and thus, in the present work, we seek to restrict the expression of FVIII transgene to these cells using cell-specific promoters. With this approach, we aim to limit immune response in a mouse model by lentiviral vector (LV)-mediated gene therapy encoding FVIII. To increase the target specificity of FVIII expression, we included miRNA target sequences (miRTs) (i.e., miRT-142.3p, miRT-126, and miRT-122) to silence expression in hematopoietic cells, endothelial cells, and hepatocytes, respectively. Notably, we report, for the first time, therapeutic levels of FVIII transgene expression at its natural site of production, which occurred without the formation of neutralizing antibodies (inhibitors). Moreover, inhibitors were eradicated in FVIII pre-immune mice through a regulatory T cell-dependent mechanism. In conclusion, targeting FVIII expression to LSECs and myeloid cells by using LVs with cell-specific promoter minimized off-target expression and immune responses. Therefore, at least for some transgenes, expression at the physiologic site of synthesis can enhance efficacy and safety, resulting in long-term correction of genetic diseases such as HA.


Subject(s)
Hemophilia A/genetics , Hemophilia A/immunology , Immune Tolerance/genetics , Immunosuppression Therapy , Animals , CD11b Antigen/genetics , Disease Models, Animal , Endothelial Cells/metabolism , Factor VIII/genetics , Factor VIII/immunology , Factor VIII/metabolism , Gene Expression , Genes, Reporter , Genetic Vectors/genetics , Immunization , Immunosuppression Therapy/methods , Isoantibodies/blood , Isoantibodies/immunology , Lentivirus/genetics , Male , Mice , Mice, 129 Strain , Mice, Inbred BALB C , Mice, Inbred C57BL , Organ Specificity/genetics , Promoter Regions, Genetic , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Transduction, Genetic , Transgenes , Whole Blood Coagulation Time
6.
Adv Ther ; 34(3): 620-637, 2017 03.
Article in English | MEDLINE | ID: mdl-28194578

ABSTRACT

Edoxaban is the fourth non-vitamin K antagonist oral anticoagulant now available for clinical use in the prevention of stroke/systemic embolism in atrial fibrillation (AF) and in the treatment of venous thromboembolism (VTE), after the completion of large-scale randomized comparative clinical trials with the vitamin K antagonist warfarin. Edoxaban has some peculiar pharmacological properties and outcome data. Here a group of experts in AF and VTE answers a set of questions on its practical use, trying to define the profile of patients that would be most appropriate for its use.


Subject(s)
Atrial Fibrillation , Pyridines/pharmacology , Thiazoles/pharmacology , Venous Thromboembolism , Age Factors , Anticoagulants/pharmacology , Atrial Fibrillation/complications , Atrial Fibrillation/drug therapy , Comparative Effectiveness Research , Humans , Medication Therapy Management , Practice Guidelines as Topic , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & control , Warfarin/pharmacology
7.
Thromb Haemost ; 115(3): 543-50, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26582077

ABSTRACT

The development of an inhibitory antibody in non-severe haemophilia A patients may aggravate the bleeding phenotype considerably. Effective treatment of bleeding episodes may be challenging, with ensuing severe complications. At present, evidence is scarce for optimal treatment of bleeding episodes in this patient group. The aim of this study was to describe the incidence and the treatment of bleeding episodes in inhibitor patients in a population-based unselected cohort of non-severe haemophilia A patients with clinically relevant inhibitors. Data were available for 100 of the 107 non-severe haemophilia A patients (factor VIII (FVIII) baseline, 2-40 IU/dl) from 29 centres in Europe and one centre in Australia who had developed a clinically relevant inhibitor between 1980 and 2011. The majority (89 %) of the patients were treated during the inhibitor period for bleeding episodes or a surgical intervention: 66 % needed treatment for bleeding episodes, at a median annual bleeding rate (ABR) of 1.1 (interquartile range (IQR) 0.1-2.5) and a median total of 2 (IQR 1-6) bleeding episodes. Compared to the median ABR before inhibitor development of 0.095 bleeds per year (IQR 0.02-0.42), the increase in ABR is more than a 10-fold. More than 90 % of the bleeding episodes were treated with only one type of product, most frequently (51 %) FVIII concentrates. This study provides the incidence of bleeding episodes and treatment choices in non-severe haemophilia A patients with inhibitors. The 10-fold increase to a median ABR of 1.1 episodes per year emphasizes the impact of inhibitor development for non-severe haemophilia A patients.


Subject(s)
Hemophilia A/drug therapy , Hemophilia A/epidemiology , Hemorrhage/drug therapy , Adolescent , Adult , Antibodies/chemistry , Cohort Studies , Factor VIII/analysis , Factor VIII/antagonists & inhibitors , Female , Humans , Incidence , Middle Aged , Phenotype , Young Adult
8.
Clinicoecon Outcomes Res ; 7: 17-25, 2015.
Article in English | MEDLINE | ID: mdl-25565871

ABSTRACT

PURPOSE: Prophylaxis with von Willebrand factor (VWF)/factor VIII (FVIII) concentrates is a potential approach for patients with severe von Willebrand disease (VWD). As far as we are aware, to date there have been no pharmacoeconomic analyses in order to assess the economic impact of treatments for severe VWD. The analysis presented here estimates the cost-benefit ratio of VWF with a low FVIII content when compared with VWF/FVIII concentrates currently used in Italy for long-term prophylaxis in patients with severe VWD. METHODS: A cost-consequence analysis was undertaken to assess the economic impact of the treatment of severe VWD from the perspective both of the Italian National Health Service and society. The analysis was based on four case reports of long-term prophylaxis with VWD with VWF/FVIII concentrates and VWF with a low FVIII content. The costs per patient included direct and indirect costs for each treatment. RESULTS: Considering the four case reports, health care costs (without cost of treatment) and indirect costs per patient per year were lower with VWF with a low FVIII content than VWF/FVIII concentrates. The total health care costs (without cost of treatment) and indirect costs avoided with VWF with a low FVIII content per patient per year ranged from €2,295 to €17,530 and from €1,867 to €4,978, respectively. CONCLUSION: VWF with a low FVIII content seems to be a cost-effective treatment option for patients with severe VWD. Although the drug cost per se is higher, the use of VWF with a low FVIII content is associated with decreased consumption of hospital resources and fewer lost working days due to bleedings and consequently with an improvement of the quality of life of the patients.

9.
Haemophilia ; 20(2): e128-35, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24533954

ABSTRACT

Despite great advances in haemophilia care in the last 20 years, a number of questions on haemophilia therapy remain unanswered. These debated issues primarily involve the choice of the product type (plasma-derived vs. recombinant) for patients with different characteristics: specifically, if they were infected by blood-borne virus infections, and if they bear high or low risk of inhibitor development. In addition, the most appropriate treatment regimen in non-inhibitor and inhibitor patients compel physicians operating at the haemophilia treatment centres (HTCs) to take important therapeutic decisions, which are often based on their personal clinical experience rather than on evidence-based recommendations from published literature data. To know the opinion on the most controversial aspects in haemophilia care of Italian expert physicians, who are responsible for common clinical practice and therapeutic decisions, we have conducted a survey among the Directors of HTCs affiliated to the Italian Association of Haemophilia Centres (AICE). A questionnaire, consisting of 19 questions covering the most important topics related to haemophilia treatment, was sent to the Directors of all 52 Italian HTCs. Forty Directors out of 52 (76.9%) responded, accounting for the large majority of HTCs affiliated to the AICE throughout Italy. The results of this survey provide for the first time a picture of the attitudes towards clotting factor concentrate use and product selection of clinicians working at Italian HTCs.


Subject(s)
Hemophilia A/epidemiology , Hospitals, Special , Medical Staff, Hospital , Practice Patterns, Physicians'/statistics & numerical data , Blood Coagulation Factors/therapeutic use , Health Care Surveys , Hemophilia A/drug therapy , Humans , Italy , Surveys and Questionnaires
10.
Semin Thromb Hemost ; 39(7): 794-802, 2013 Oct.
Article in English | MEDLINE | ID: mdl-24014070

ABSTRACT

Life expectancy for persons with hemophilia (PWH) has considerably increased in the last decades as a direct result of the availability of modern therapies to control the clotting defect. Because their life expectancy now matches that of the general population, PWH are experiencing age-related comorbidities, such as, cardiovascular diseases, metabolic syndrome, renal diseases, sexuality issues, malignancies, and neurologic problems, that until recently have been rarely seen in this group of patients. In this article, we present a summary of the current knowledge on the aging PWH along with the clinical approaches that may be integrated into the routine comprehensive care of these patients for preventing, diagnosing, and monitoring age-related comorbidities. In general, patients with and without hemophilia should receive similar care, with close collaboration between the physician treating PWH and the specialty expert treating the comorbid disease.


Subject(s)
Hemophilia A/therapy , Age Factors , Comorbidity , Hemophilia A/drug therapy , Hemophilia A/prevention & control , Humans , Life Expectancy
11.
Blood ; 122(11): 1954-62, 2013 Sep 12.
Article in English | MEDLINE | ID: mdl-23926300

ABSTRACT

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A.


Subject(s)
Antibodies, Neutralizing/immunology , Factor VIII/genetics , Factor VIII/immunology , Hemophilia A/genetics , Hemophilia A/immunology , Mutation, Missense , Adolescent , Adult , Factor VIII/therapeutic use , Follow-Up Studies , Genotype , Hemophilia A/drug therapy , Humans , Kaplan-Meier Estimate , Middle Aged , Retrospective Studies , Risk Factors , Time Factors , Treatment Outcome , Young Adult
12.
Crit Rev Oncol Hematol ; 83(1): 11-20, 2012 Jul.
Article in English | MEDLINE | ID: mdl-21964312

ABSTRACT

The introduction of clotting factor concentrates led to major advances in hemophilia care. Rather than simply providing an alternative to plasma-derived concentrates, the introduction in the 1990s of recombinant concentrates added value to replacement therapy particularly with respect to prophylaxis and immune-tolerance induction. While the safety of plasma-derived concentrates has improved considerably, these concentrates may still pose an infectious risk through as-yet unknown pathogens and poor impurity constituent characterization. Recombinant concentrates are increasingly used because of their benefits in pathogen safety, convenience and the potential for unfettered supply. Yet worldwide they remain accessible only to a limited number of patients due to fear of the potential for inhibitor development, overestimation of their costs and underestimation of their benefits. This article reviews the characteristics and properties of recombinant FVIII concentrates to help physicians and patient representatives promote the right of access of patients to the safest products.


Subject(s)
Factor VIII/therapeutic use , Hemophilia A/drug therapy , Blood Component Removal , Clinical Trials as Topic , Cross Infection/prevention & control , Cross Infection/transmission , Disease Management , Drug Administration Schedule , Drug Contamination/prevention & control , Factor VIII/economics , Factor VIII/pharmacokinetics , Hemophilia A/immunology , Humans , Immune Tolerance , Plasma/chemistry , Practice Guidelines as Topic , Virus Diseases/prevention & control , Virus Diseases/transmission
13.
Haemophilia ; 18(1): 39-45, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21752159

ABSTRACT

Intracranial haemorrhage (ICH) is the most serious bleeding symptom in haemophiliacs, resulting in high rates of mortality and disabling sequelae. The Association of Italian Haemophilia Centres carried out a retrospective survey (1987-2008) of ICH occurring in haemophiliacs with the goals to establish: (i) incidence, location of bleeding, death rate and disabling sequels; (ii) risk factors for ICH; and (iii) treatment used during the acute phase of ICH and for recurrence prevention. A total of 112 ICH episodes had occurred in 88 patients (78 haemophilia A, 10 haemophilia B), 24 of whom experienced recurrences. The cumulative hazard of ICH for the whole cohort over the entire follow-up period was 26.7 per 1000 patients, and the annualized rate of ICH was 2.50 events per 1000 patients (95% CI 1.90-3.31). The risk of ICH was higher in the youngest children (24.4 per 1000, 95% CI 12.7-47.0 in the first year of age and 14.9, 95% CI 7.1-31.4 in the second year of age) and then progressively rose again after the age of 40. Univariate, bivariate (age-adjusted) and multivariate analysis investigating the effects of patient characteristics on ICH occurrence showed that haemophilia severity and inhibitor status were strongly associated with ICH [severe vs. mild, HR 3.96 (2.39-6.57); inhibitor vs. non-inhibitor 2.52 (1.46-4.35)]. HCV infection was also associated with the risk of ICH [HR 1.83 (1.25-2.69)]. Therapeutic suggestions based upon our experience to control ICH recurrence are provided.


Subject(s)
Hemophilia A/complications , Hemophilia B/complications , Intracranial Hemorrhages/epidemiology , Adolescent , Adult , Age Distribution , Aged , Autoantibodies/blood , Blood Coagulation Factors/therapeutic use , Child , Child, Preschool , Cohort Studies , Hemophilia A/immunology , Hemophilia B/immunology , Humans , Incidence , Infant , Infant, Newborn , Intracranial Hemorrhages/prevention & control , Italy/epidemiology , Male , Middle Aged , Prevalence , Retrospective Studies , Risk Factors , Surveys and Questionnaires , Young Adult
14.
Ann Hematol ; 89(7): 691-9, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20146064

ABSTRACT

The clinical impact of polycythemia vera (PV) diagnostic and therapeutic guidelines is still undetermined. In particular, the recommended target of hematocrit (Hct) <0.45 has been recently questioned and alkylating drugs are still used for elderly patients. We revised, according to WHO criteria, 300 PV diagnosis and evaluated the impact on clinical outcome of median Hct and of the strategy to administer anti-thrombotic prophylaxis and to avoid alkylating chemotherapy in almost all patients. Of 226 patients with WHO-confirmed diagnosis (median age 66), 91.3% survived at the median follow-up of 5.84 years and 77.5% are projected alive at 13 years. Eighteen percent had major thrombosis and 2.7% acute myeloid leukemia. Twenty-two percent of patients maintained an Hct <0.45: their overall and thrombosis-free survival are similar to those of patients with a 0.45-0.48 value. Conversely, an Hct >0.48 and a "high thrombotic risk" according to ECLAP criteria were both significantly associated to shorter survival and higher thrombosis risk. Chemotherapy reduced thrombotic events without affecting survival. Our study revealed suboptimal compliance to published guidelines. However, in our casistic characterized by wide use of anti-platelet- and avoidance of alkylating drugs, patients' survival, although analyzed retrospectively, seemed to have improved compared to old literature data. The optimal Hct target was not clearly defined, although a value <0.48 looks highly advisable.


Subject(s)
Hematocrit , Polycythemia Vera , Thrombosis , Adolescent , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Female , Follow-Up Studies , Humans , Leukemia, Myeloid, Acute/blood , Leukemia, Myeloid, Acute/complications , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Platelet Aggregation Inhibitors , Polycythemia Vera/blood , Polycythemia Vera/complications , Polycythemia Vera/drug therapy , Polycythemia Vera/mortality , Practice Guidelines as Topic , Retrospective Studies , Survival Rate , Thrombosis/blood , Thrombosis/complications , Thrombosis/drug therapy , Thrombosis/mortality
15.
Exp Hematol ; 34(12): 1680-6, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17157165

ABSTRACT

OBJECTIVE: Nonlymphoma-associated bcl-2/IgH rearrangements (NLABRs) are frequently amplified by PCR in blood of lymphoma-free subjects (LFS), but the temporal kinetics and phenotypic nature of NLABR-positive cells are unknown. To address these issues we prospectively monitored a panel of NLABR-positive LFS. METHODS: LFS have been studied by nested PCR, real-time PCR, and DNA sequencing. Cell selection studies were also performed to define the nature of NLABR-bearing clones. RESULTS: Of 125 donors, 16 (12.8%) were found to be bcl-2/IgH positive and were monitored at least every 6 months for a median time of 22 months (range 6-50). In half of the subjects the same NLABR detected initially was again reamplified at follow-up thrice or more. In 5, the same NLABR was constantly amplified in every follow-up sample. With a median follow-up of 22 months (range 9-50), no stable disappearance of a recurrent clone has been so far recorded. Real-time PCR indicated that persistent NLABR-positive clones are stable over time in the same subject. Cell separation studies indicate that NLABRs belong to CD19+, CD5-, CD23-, CD10+/- cells. CONCLUSIONS: Our results indicate that NLABR-positive clones are persistent populations phenotypically related to follicular lymphoma (FL). This suggests the existence of a FL-related clonal expansion of undetermined significance, which might be either a premalignant or a nonmalignant counterpart of FL.


Subject(s)
Immunoglobulin Heavy Chains/genetics , Leukocytes, Mononuclear/metabolism , Lymphoma, Follicular/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Translocation, Genetic , Adult , Aged , Aged, 80 and over , Cell Separation , Clone Cells , Female , Follow-Up Studies , Humans , Immunoglobulin Heavy Chains/metabolism , Immunophenotyping , Male , Middle Aged , Polymerase Chain Reaction/methods , Proto-Oncogene Proteins c-bcl-2/metabolism
16.
Dig Dis Sci ; 47(2): 427-31, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11855562

ABSTRACT

Thirty patients affected by hemophilia A or B or von-Willebrand's disease and chronic posttransfusional active HCV hepatitis who developed major side effects during the course of a previous treatment with recombinant interferon-alpha (IFN-alpha) were studied. In all patients IFN-alpha therapy had to be discontinued and those who achieved a primary serologic and viral response to HCV relapsed within a few months. After a washout period, patients were retreated with human leukocyte IFN-alpha, 6 MU thrice weekly for 12 months. In about 90% of patients, a primary response, with normal AST and GGT values and undetectable HCV-RNA, was achieved within the third month of treatment and for the entire duration of treatment none of the patients had to discontinue therapy because of severe adverse reactions. During posttherapy follow-up only one patient relapsed. The human leukocyte IFN-alpha regimen looks to be very effective and safe for carriers of inherited clotting disorders who developed major side effects with recombinant IFN-alpha therapy for HCV-related chronic hepatitis.


Subject(s)
Hemophilia A/complications , Hemophilia B/complications , Hepatitis C, Chronic/drug therapy , Interferon Type I/adverse effects , Interferon-alpha/therapeutic use , von Willebrand Diseases/complications , Follow-Up Studies , Hepatitis C, Chronic/complications , Humans , Recombinant Proteins , Time Factors
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