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Biomedical subjects

G Tagariello

Publications and source records attributed to G Tagariello.

At least 19 recordsLinked to original sources
PubMed2006

Occurrence of inhibitors in previously untreated or minimally treated patients with haemophilia A after exposure to a plasma-derived solvent-detergent factor VIII concentrate.

A solvent-detergent virus-inactivated plasma-derived FVIII concentrate (SD-pdFVIII) has been employed for treatment of Italian patients with haemophilia A for 15 years. This product is a non-monoclonally purified, high purity FVIII concentrate, containing large amounts of von Willebrand factor (VWF). A retrospective survey was carried out in Italy in order to evaluate the immunogenicity of SD-pdFVIII in previously untreated patients (PUPs) or in minimally treated patients (MTPs), i.e. previously exposed for up to 5 days only to other plasma-derived concentrates. The survey included 99 patients with ages ranging from 6 to 64 years (median=21.3) of whom 31 PUPs and 68 MTPs, the latter with a median of four exposure days (EDs; range 1-5) to other plasma products. Surveyed patients had been exposed to SD-pdFVIII for a median of 83 EDs (range 21-1580). Seven patients (three PUPs and four MTPs), all with severe haemophilia, had developed inhibitors [7.1%, 95%; confidence interval: 3-14%] after a median of 11 EDs (range 4-22). Of them, two were low responders (<or=5 BU mL-1) and five high responders. Two low responders and one high responder tolerated inhibitors spontaneously; one high responder underwent immunotolerance treatment with complete, long-standing response. These findings show that SD-pdFVIII is at low risk of inhibitor development in PUPs and MTPs with severe and moderate haemophilia, the risk of inhibitor development being similar to that previously reported for other plasma-derived VWF-containing FVIII products.

Adolescent↗
PubMed2006

Tyr2105Cys mutation in exon 22 of FVIII gene is a risk factor for the development of inhibitors in patients with mild/moderate haemophilia A.

We report the case of a patient with mild haemophilia A, due to a Tyr2105Cys mutation in exon 22 of the C1 domain, who developed a high-titre factor VIII inhibitor (maximum titre 1600 BU) with recurrent severe haemorrhages and fatal intracranial bleeding. Based on published data, it appears that although this mutation occurs rarely in patients with mild or moderate haemophilia A, it is frequently associated with the development of high-titre inhibitors.

Blood Coagulation Factor Inhibitors↗
PubMed2004

Hepatitis C virus quasispecies in the natural course of HCV-related disease in patients with haemophilia.

Patients with haemophilia show high prevalence of hepatitis C infection but low rate of progressive liver disease when they are not co-infected with HIV. The balance between host immune system and hepatitis C virus (HCV) variability seems to play a major role in the evolution of the HCV-related disease. To address this point we have studied, in a group of selected patients with haemophilia, the composition and in some cases the evolution, of the highest variable envelope gene within the hypervariable region 1 (HVR1) of the HCV, which is the region more directly exposed to the host immune response. Five of 12 patients show a very high homogeneity of the HVR1 and four of those had severe progressive liver disease. These results seem to confirm the major role of the immunity in driving the variability of the HCV rather than the high degree of different HCV strains to which haemophiliacs have been in touch with, during their long-term replacement therapy. Our results seem in keeping with other studies on different type of patients, where a low degree of quasispecies variability has been demonstrated in relationship with the progression and the severity of their liver disease.

Adult↗
PubMed2004

Cases of surgery in high-responder haemophilia patients.

We present 11 cases of surgery in haemophilia patients with inhibitors (high responders). They were: one haemorroidectomy, one vesical surgery in a high responder, one adenoidectomy, seven orthopaedic procedures (one bone fixation of a femoral neck fracture, four total knee arthroplasties, two total knee arthroplasties), and one retroperitoneal haematoma that required emergency surgery. We conclude that surgery in haemophilia patients with inhibitor can be considered feasible but nevertheless remains difficult. When applied to high-responding patients the treatment must take into account both the haemorrhagic risk and the risk of anamnestic response. Use of activated fractions as first-line therapy makes it possible (if the titre of the antibody allows it) to resort to conventional replacement therapy with FVIII or FIX concentrates. NovoSeven or FEIBA can be equally used as first-line therapy including therapy for major surgeries. It can be useful to alternate one with the other in case of occurrence of haemorrhagic complications.

Adenoidectomy↗
PubMed2004

Consensus perspectives on surgery in haemophilia patients with inhibitors: summary statement.

Summary. Participants in an international workshop on surgery in haemophilia patients with inhibitors developed a consensus summary of the findings and conclusions of the meeting. In the consensus, participants agreed upon revised definitions for minor and major surgery, including an intermediate degree of surgery. An evaluation system of intraoperative and postoperative bleeding was developed. Recommended doses of FEIBA((R)) and rFVIIa (both in bolus injections and in continuous infusion) for surgery were agreed. Participants also agreed on the main blood tests to be performed peri-operatively. They also suggested the need of a prospective evaluation in the future. Finally, the approximate number of surgical procedures and costs performed on haemophilia patients with inhibitors were analysed.

Adult↗
PubMed2003

Concurrent total hip and knee replacements in a patient with haemophilia with inhibitors using recombinant factor VIIa by continuous infusion.

The introduction of activated recombinant factor VIIa (rFVIIa) has allowed elective surgery to be safely performed in haemophiliacs with inhibitors. The main problems associated with its use are the short half-life, necessitating frequent intravenous injections, and its very high cost. Here we describe, for the first time, the performance of total hip and knee replacements in a haemophiliac with inhibitors at the same operation. The amount of rFVIIa concentrate used (8.57 mg) was similar to that normally used for a single joint replacement. The use of continuous infusion allowed for easier administration and further contributed to the reduction in cost as it avoids the peak levels associated with bolus injections.

Adult↗
PubMed2003

Intra-articular rifamycin in haemophilic arthropathy.

Synoviorthesis is the intra-articular injection of chemical or radioactive substances able to produce fibrosis of hypertrophied synovium, which has proved effective in the treatment of chronic haemophilic synovitis. Between September 1999 and October 2001 we treated 28 outpatients (25 with haemophilia A, three with haemophilia B). Our treatment was focused on pain and functional limitation of joints. A schedule was adopted to treat each joint using intra-articular rifamycin once a week, repeated five times. Patients were covered with factor replacement on demand. Oral analgesia was offered as required because of acute but transient painful inflammatory reaction. Their median age was 34 years (range 15-60 years). The indication for synoviorthesis was chronic synovitis characterized by recurrent haemarthroses, persistent pain and limited range of motion (ROM). Thirty-five joints were treated with a total of 169 injections, including six joints (20%) in patients with inhibitors. In five patients two joints were treated in the same session. Thirty procedures were completed: 24 (80%) were considered effective (as excellent or good), while six were considered insufficient (20%). Pain was reduced in 96% of cases and in 70% the ROM was improved. In our experience intra-articular infiltration with rifamycin appears to be effective in reducing joint pain and in improving the ROM. The procedure presents a low risk of bleeding, can be used for patients with inhibitors and multiple joints can be treated without any additional cost.

Adolescent↗
PubMed2002

Large FVIII gene deletion confers very high risk of inhibitor development in three related severe haemophiliacs.

Haemophilia A displays a broad heterogeneity of genetic defects and of clinical severity. Inhibitor development is the main complication of replacement therapy in severe cases and most patients with inhibitors have gross gene rearrangement or point mutations, which hamper the production of normal circulating factor VIII (FVIII). We have investigated three related severe haemophilia A patients, all of whom have high titre inhibitors. By using long-range polymerase chain reaction (PCR) for FVIII gene inversion, we observed an unusual pattern in these patients. We therefore decided to screen the whole FVIII gene by conformation-sensitive gel electrophoresis. A large FVIII gene deletion spanning exon 2 to exon 25 was identified and we were able to obtain a 18.5 kb PCR product, which is specific for this mutation and useful for determining the carrier state in this family. All three haemophiliacs carrying this very large gene deletion show similar clinical history and very high-titre inhibitors, supporting the observation that inhibitor development seems to be an inherited characteristic. On the basis of our observations we think that this subgroup of patients at very high risk of inhibitor development should be identified by mutation analysis whenever possible, before the beginning of replacement therapy.

Adult↗
PubMed2001

Persistence of parvovirus B19 DNA in synovium of patients with haemophilic arthritis.

A progressive arthropathy develops commonly in haemophiliacs and its pathogenesis is not fully understood. Human parvovirus B19 has been associated with several diseases including acute and chronic arthropathy and some studies suggest its implication in chronic inflammatory diseases of the joints such as rheumatoid arthritis. In haemophiliacs parvovirus B19 infection occurs very frequently because of its transmission with plasma derivatives. In order to assess a role of B19 virus in haemophilic arthritis, synovial tissue samples from patients with haemophilia with arthritis and from patients, nonhaemophiliacs, with arthrosis or with joint trauma were examined for B19 DNA by nested PCR. In addition, the prevalence of antibody to parvovirus B19 NS1 protein as a possible serological marker of persistent B19 infection was tested and the association of the outcome of parvovirus infection with genetic diversity of B19 P6 promoter sequences was investigated. B19 DNA was detected in the synovial tissue of 31% of haemophiliacs with progressive arthropathy and of 5% of control patients. Fourteen out of 17 patients (82%) with haemophilic arthritis and with B19 DNA in their synovial membranes had IgG antibodies against the nonstructural protein NS1 of parvovirus B19. On the other hand, 19% of patients with haemophilia with B19 PCR negative synovial tissue and 21% of controls showed anti-NS1 antibodies. The P6 promoter presented specific sites of point mutations shared frequently by isolates from patients with haemophilia and arthritis. These results indicate that B19 DNA can persist in the synovial membranes of patients with haemophilic arthritis significantly more frequently in comparison to control individuals with arthrosis or joint trauma and show a correlation between anti- NS1 antibody presence and B19 DNA persistence in the synovial tissue.

Adolescent↗
PubMed2001

Mild bleeding diathesis in a boy with combined severe haemophilia B (C(10400)-->T) and heterozygous factor V Leiden.

Haemophilia B patients with factor IX (FIX) activity < 1% are usually characterized by severe bleeding episodes early in life. We report a case of sporadic severe haemophilia B, clinically characterized by mild bleeding diathesis. The presence of anamnestic thrombophlebitis in the patient's mother prompted us to investigate a possible associated hypercoagulable condition. Resistance to activated protein C due to factor V R506Q mutation was present in the mother and in the propositus, in the homozygous and heterozygous form, respectively. Molecular analysis of the FIX gene led to the identification of a nonsense mutation resulting in a stop codon at position 50, previously described and usually responsible for a severe pattern of haemophilia B. The implications of this unusual association are discussed.

Activated Protein C Resistance↗
PubMed2000

Recombinant FVIIa (NovoSeven) continuous infusion and total hip replacement in patients with haemophilia and high titre of inhibitors to FVIII: experience of two cases.

In this report we describe our experience of total hip replacement in two patients with severe haemophilia A and high titres of inhibitors to FVIII. We used rFVIIa replacement therapy by continuous infusion to perform the surgery. The total amount of rFVIIa used in these two patients was very similar but the manner of administration was quite different. In our experience, it is an advantage to use a higher dose for shorter periods than a lower dose for a longer treatment period. Tranexamic acid by continuous infusion, and parallel saline infusion were useful for good haemostasis and avoided local thrombophlebitis in the side of rFVIIa infusion.

Adult↗
PubMed2000

Experience of a single Italian center in genetic counseling for hemophilia: from linkage analysis to molecular diagnosis.

BACKGROUND AND OBJECTIVE: We describe our three year experience in genetic counseling at the Castelfranco Veneto Hemophilia Center, Italy. DESIGN AND METHODS: A total of 258 individuals were involved in the study of 142 females. These formed 40 families with hemophilia A and 6 families with hemophilia B. Following pedigree analysis, the FVIII inversion was first examined in severe hemophilia A patients by polymerase chain reaction (PCR) analysis. DNA polymorphisms were used to track the affected gene through the remaining families. In uninformative cases, we initiated analysis of the FVIII or FIX gene coding region by conformation sensitive gel electrophoresis and DNA sequencing to identify the mutation responsible for the disease. RESULTS: The FVIII gene inversion was present in 16 of the 32 patients (50%) affected by severe hemophilia A and was informative for 44 females. For hemophilia A, 45 cases (55%) were informative by linkage analysis, however 37 (45%) were uninformative because of lack of key individuals, homozygosity, or sporadic disease. Information from extragenic linked polymorphisms alone was present in 9 cases (6%). For hemophilia B, linkage analysis was informative in only 50% of females (8 out of 16). To date, nine mutations have been identified in patients with hemophilia A and three in patients with hemophilia B. Six novel missense mutations in hemophilia A are discussed briefly. INTERPRETATION AND CONCLUSIONS: Using this approach we are now able to offer accurate genetic analysis to virtually all families with hemophilia.

Chromosome Inversion↗
PubMed1999

Safety and efficacy of high-purity concentrates in haemophiliac patients undergoing surgery by continuous infusion.

In this study we explore the feasibility of high-purity double-inactivated concentrates by continuous infusion for the treatment of haemophiliacs in a group of patients undergoing different surgical procedures. The patients were enrolled in the study on the basis of their transfusion history, which was well known due to their long-term follow up at our Haemophilia Center. We did not perform a pre-operative pharmacokinetic study because one of the aims of this study was to demonstrate that continuous infusion can become a first choice standard treatment in patients with haemophilia. Fourteen haemophilia A and one haemophilia B patients who needed at least 5 days of replacement therapy were monitored for haemostatic efficacy, post-operative factor VIII and factor IX levels and evaluated for safety and flexibility of the products. The infusion rate of 3 IU kg-1 h-1 was demonstrated to be sufficient to ensure haemostasis and patients did not need additional bolus infusion during the post-operative period. Our study demonstrates the safety and feasibility of high-purity concentrates in patients undergoing surgery by continuous infusion, also in the absence of a previous pharmacokinetic study.

Adult↗
PubMed1999

Serological markers of autoimmunity in patients with hemophilia A: the role of hepatitis C virus infection, alpha-interferon and factor VIII treatment in skewing the immune system toward autoreactivity.

The aim of this study was to investigate whether the immune system of patients with hemophilia A is skewed toward an aspecific activation and to identify the causative factors. It is well known that an immune derangement does exist in patients with hemophilia A. At least three factors potentially play a role: hepatitis C virus (HCV) infection, alpha-interferon therapy and the administration of factor VIII (FVIII). Sixty human immunodeficiency virus (HIV)-negative patients with severe or moderate hemophilia A were studied retrospectively. The serological markers of autoimmunity were evaluated and the results correlated with anti-HCV antibodies, FVIII treatment and alpha-interferon therapy. The role of these factors in the development of the anti-FVIII antibody was estimated concomitantly. The prevalence of autoantibodies and anti-FVIII antibodies was higher in HCV-positive than in HCV-negative patients before any treatment, although the difference was not statistically significant. The administration of FVIII further influenced the development of autoantibodies both in HCV-negative and HCV-positive patients, with no difference being observed between the two groups. As expected, fewer HCV-negative than HCV-positive patients developed anti-FVIII antibodies after administration of FVIII (31.8% versus 38%, respectively). Therapy with alpha-interferon did not seem to enhance significantly the risk of developing autoantibodies nor anti-FVIII antibodies. We observed a high prevalence of humoral signs of autoimmunity among patients with hemophilia A. Treatment with FVIII concentrate is probably the most important triggering factor. Monitoring these patients for autoimmune manifestations is recommended.

Adolescent↗
PubMed1997

A multicenter controlled, randomized, open trial of interferon alpha2b treatment of anti-human immunodeficiency virus-negative hemophilic patients with chronic hepatitis C. Hepatitis Study Group of the Association of Italian Hemophilia Centers.

There is limited information about the long-term efficacy of prolonged therapy (more than 6 months) with interferon alpha in hemophilic patients with chronic hepatitis C who are not coinfected with the human immunodeficiency virus (HIV-1). One hundred and seven hemophiliacs were randomly assigned to 3 million U of interferon alpha2b three times weekly for 12 months or no therapy. The patients were followed up for at least 12 months posttreatment. Response was assessed by both serial alanine aminotransferase (ALT) levels and hepatitis C virus (HCV)-RNA measured by reverse transcribed polymerase chain reaction (RT-PCR) method. Before treatment, serum levels of HCV-RNA were measured quantitatively by second-generation branched-DNA assay and the HCV genotype was determined by RT-PCR. Serum HGV-RNA, a marker of infection with the hepatitis G virus, was also measured by RT-PCR. Normalization of ALT was sustained and serum HCV-RNA was cleared in 6 of 45 treated patients, compared with none of the 50 untreated controls (13% v 0% P < .01). Low pretreatment viremia was the only feature that was associated with an increased likelihood of sustained response (P < .01). This study shows that multitransfused hemophiliacs with chronic hepatitis C not coinfected with HIV-1 respond at low rates to prolonged interferon therapy.

Adolescent↗