GAPP Italy: "A survey on asthma on Italian physicians and patients"

Guidelines recognize the importance of achieving and maintaining asthma control: the treatment strategies nw available allow the control of the great majority of patients with asthma but despite many efforts only 5% of patients achieve guideline-defined asthma control. The GAPP (The Global Asthma Physician and Patient survey) is a global quantitative survey with the aiim of identifying barriers to optimal management of asthma. Physicians and adult patients with persistent asthma have been interviewed with closed-ended questions questionnaire. This study has been conducted in 16 countries. In Italy the survey has revealed that physicians prescribe a combination of ICS and LABA more often in the other countries. They consider ICS the first-line treatment for mild persistent asthma. They are not completely satified with ICS because of local and systemic side effects. At the same time, the reason why patients change asthma medication is the potential for side effects. The two group responses were found to differ about the time spent discussing how to improve the management of asthma. A better communication between physician and patient and a new treatment option with lower side effect profile could be the key point to achieve asthma control in a larger number of patients.     

Inhibitors in haemophilia B: the Italian experience

The prevalence of inhibitors in haemophilia B is significantly lower than that of patients with haemophilia A. However, the peculiar occurrence of allergic reactions associated with the onset of inhibitor in haemophilia B (HB) may render immune tolerance a risky procedure. We have carried out a detailed survey among all the Italian Hemophilia Centers to analyse all the patients with HB and inhibitors. A total of eight patients were reported among 282 living patients (2.8%) with severe factor IX (FIX) deficiency (FIX < 1 U dL^?1). In addition, two deceased patients were also identified. Six patients carried nonsense mutations while in four partial or complete gene deletions were detected. Three patients (one deceased) had history of allergic/anaphylactic reaction upon substitutive treatment, which in one case was recurrent and resolved after switching to plasma derived FIX. Immune tolerance was adopted in five patients and in four complete response was achieved while in the remaining it was partial. No nephrotic syndrome was observed. Our data confirm that inhibitors in HB occur in patients with null mutations or complete/partial gene deletion. Immune tolerance can be achieved also in HB patients, without allergic reactions or nephrotic syndrome upon replacement therapy.     

Prenatal diagnosis of haemophilia B: the Italian experience

This article describes prenatal diagnosis (PND) of haemophilia B (HB) within the framework of Italian haemophilia centres and genetics laboratories. The study details the experience from six haemophilia genetic centres (three in the North, one in the Centre and two in the South of Italy) and summarizes the different techniques used to perform PND of HB during the last 15 years. To date, the Italian HB database includes 373 characterized unrelated patients and their genetic information has permitted the identification of 274 carriers of childbearing age. This database represents the main instrument for timely and precise PND. Sixty‐six prenatal diagnoses were performed on 52 HB carriers whose average age at the time was 34 (ranging from 24 to 44 years). In 44 cases, genetic counselling for carrier status determination was performed before pregnancy, while eight were not studied prior to pregnancy. Foetal samples were obtained by chorionic villus sampling in 52 cases, by amniocentesis in 12 while two were diagnosed by analysis of free foetal DNA obtained from maternal peripheral blood. In 35 (53%) pregnancies the foetus was female. For 31 men (47%), haemophilia status was determined by analysis of previously determined informative markers or familial mutations (12 affected and 19 unaffected). There may be more than one laboratory involved in the PND diagnostic pathway (providing DNA extraction, karyotype analysis, gender determination, maternal contamination detection, molecular diagnosis and sequencing). Good communication between all the parties, coordinated by the haemophilia centre, is essential for a successful and rapid process.     

A survey of patients with acquired haemophilia in a haemophilia centre over a 28-year period

Data of patients with acquired inhibitors to clotting factors seen in a haemophilia centre from 1970-98 was collected. Twenty-four patients with anti-factor VIII antibodies and four with acquired von Willebrand disease case records were evaluable. Two-thirds of the patients were females and their age ranged from 2 to 92 years (median 69). There was no correlation between the inhibitor titres and the severity or the pattern of bleeding. Porcine factor VIII and activated prothrombin complex were both effective for acute bleeds. Prednisolone and cyclophosphamide proved valuable for suppression of the antibodies without adverse effects even in the elderly group of patients. Three deaths were directly related to bleeding. This review has shown the life-threatening nature of this acquired bleeding disorder, its variable clinical presentation and the importance of early referral to a specialist centre for appropriate therapy.     

Acquired haemophilia: experience of two Italian centres with 17 new cases

Summary . Acquired haemophilia is a rare but often catastrophic haemorrhagic disorder associated with a high mortality rate. No single therapeutic approach has been consistently successful and clinical experience remains mainly anecdotal. This report describes 17 new cases diagnosed at two Italian haemophilia centres between 1979 and 1995.
There was no difference in sex distribution. Mean age at diagnosis was 50 years. Fifty-nine per cent of cases had associated disorders and 29% developed an inhibitor post-partum. Eleven (64%) patients required substitutive therapy. Desmopressin was successfully used in five cases for minor bleeding. Immunosuppressive drugs (steroid, cyclophosphamide or experimental therapy) were used in 14 (82%) cases. Eight of 15 (52%) evaluable cases achieved complete remission (four post-partum). Fatal haemorrhage occurred in 2/15 (13%) of patients within 2 days from diagnosis.
Acquired haemophilia is a severe coagulopathy. Prompt diagnosis with characterization and intensive treatment is usually required. However, particular subsets of patients such as those with inhibitor occurring post-partum or with low inhibitor titre at diagnosis usually show a more favourable clinical outcome.     

Pain management in patients with haemophilia: a European survey

Summary. There are no evidence-based guidelines on pain management in people with haemophilia (PWH), who may suffer acute, disabling pain from haemarthroses and chronic arthropathic pain. To review evidence and to investigate current clinical practice in pain assessment and management in PWH the European Haemophilia Therapy Standardisation Board undertook a literature review and a survey in 22 Haemophilia Treatment Centres (HTC), using a questionnaire and seven clinical scenarios. Consensus was sought on pain assessment and management in PWH. Few clinical studies on pain management in PWH were identified. The HTCs care for 1678 children (47% severe haemophilia, 84% on prophylaxis, 17% with arthropathy and 8% with chronic pain) and 5103 adults (44% severe haemophilia, 40% on prophylaxis, 67% with arthropathy and 35% with chronic pain). Analgesics are prescribed by HTCs in 80% of cases (median; range 0-100%) and in 10% (median; range 0-80%) are bought over the counter. Pain and analgesic use are assessed when reported by patients and at check-ups. Only eight centres use a specific pain scale and/or have specific pain guidelines. Two HTCs arrange regular consultations with pain specialists. For acute pain, the preferred first-line drug is paracetamol for children, and paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) for adults. Children with chronic pain are treated with paracetamol or NSAIDs, whereas adults usually receive Cox-2 inhibitors. Second-line therapy is heterogeneous. There is little published evidence to guide pain assessment and management in PWH, and clinical practice varies considerably across Europe. General and specific recommendations are needed.     

A survey of patients with acquired haemophilia in a haemophilia centre over a 28‐year period

Data of patients with acquired inhibitors to clotting factors seen in a haemophilia centre from 1970–98 was collected. Twenty‐four patients with anti‐factor VIII antibodies and four with acquired von Willebrand disease case records were evaluable. Two‐thirds of the patients were females and their age ranged from 2 to 92 years (median 69). There was no correlation between the inhibitor titres and the severity or the pattern of bleeding. Porcine factor VIII and activated prothrombin complex were both effective for acute bleeds. Prednisolone and cyclophosphamide proved valuable for suppression of the antibodies without adverse effects even in the elderly group of patients. Three deaths were directly related to bleeding. This review has shown the life‐threatening nature of this acquired bleeding disorder, its variable clinical presentation and the importance of early referral to a specialist centre for appropiate therapy.     

Central venous access devices for paediatric patients with haemophilia: a single-institution experience

Summary.  Use of a central venous access device (CVAD) can facilitate early introduction of home-based infusion of factor concentrate for long-term prophylaxis or immune tolerance therapy in children with bleeding disorders. The aim was t o review outcomes associated with use of CVAD. Retrospective review of paediatric patients with bleeding disorders was observed at the Mayo Clinic Comprehensive Hemophilia Center. Thirty-seven CVAD were placed in 18 patients (haemophilia A [ n  = 15], type 3 von Willebrand disease [ n  = 2] and haemophilia B [ n  = 1]). Follow-up was for 45 952 CVAD days, and median time that CVAD remained in place was 1361 days per device. Factor VIII (FVIII) inhibitors were present in 4 of the 15 patients. Ten CVAD-related infections occurred (median, 672 days; range, 72–1941 days), of which six were in one patient with FVIII inhibitors. Overall infection rate was 0.22 (95% confidence interval [CI], 0.10–0.40) per 1000 CVAD days, with 0.11 infections in patients without FVIII inhibitors compared with a pooled incidence of 0.66 (95% CI, 0.44–0.97) reported in the literature. Indications for removal of 27 CVAD were blockage, change to peripheral venous access, catheter displacement, infection, leak in the port septum, short catheter and skin erosion. No clinically apparent thrombosis or sequelae of thrombosis were observed. Infection is the most common complication associated with CVAD use and is increased in patients who have inhibitors. The low rate of clinically apparent thrombosis reflects our practice of not screening for thrombosis. The low infection rate reflects our practice of using and reinforcing the aseptic technique.     

F8 gene mutation profile and ITT response in a cohort of Italian haemophilia A patients with inhibitors

Anti factor VIII (FVIII) antibodies represent the main complication of replacement therapy in severe cases of haemophilia and most patients with inhibitor have gross gene rearrangements or point mutations that hamper the production of normal circulating FVIII. In this study we have investigated 82 haemophilia A patients with inhibitors. Seventy six were severe, three were moderate and three were mild. We screened the patients for the causative mutations using long range PCR for the recurrent intron 22 inversion (invint22), multiplex PCR for intron 1 inversion (invint1) and conformation sensitive gel electrophoresis followed by DNA sequencing for all other mutation types in the F8 gene. Diverse genetic defects were detected in the severe cases (with a predominance of severe molecular defects): F8 gene inversions, large deletions and non-sense mutations account for 71% of the mutations. Only missense and splicing mutations were identified in the non-severe patients and we confirmed that the presence of inhibitors correlates well with the presence of severe mutations, but a proportion of severe patients develops inhibitors despite the presence of diverse less severe mutations. When we have analysed the subgroup of patients who underwent immunetolerance, we have found that F8 gene large deletions are likely to be a high risk factor also for immunetolerance therapy unresponsiveness, while no clear evidence has been demonstrated for other mutation types.     

Surgery in patients with haemophilia and high responding inhibitors: Izmir experience

Summary. This report evaluates the haemostatic efficacy of recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (APCC) in patients with haemophilia and high responding inhibitors who underwent major and minor surgery. Data pertaining to surgeries from 2001 to 2009 at a single centre were retrospectively analysed. During this period, 53 surgical procedures were performed in 30 haemophiliacs with high responding inhibitors. Mean age was 16.2 ± 9.4 years. Eleven major surgeries in 4 patients, 41 radioisotope synovectomies (RS) and one circumcision classified as minor surgery in 28 patients were performed. Among the major surgery procedures, four were treated with rFVIIa, five with APCC and two with sequential use of APCC and rFVIIa. We used rFVIIa at the dosage of 80–120 μg kg^?1 every 2 h and APCC 100 IU kg^?1 every 12 h for the major surgery. When performing RS, we used rFVIIa in 18 patients with 26 target joints and APCC in 9 patients with 15 target joints. Three consecutive doses of rFVIIa (90 μg kg^?1) were used at 2‐h intervals followed by additional three doses at 6‐h intervals. The initial dose of APCC was 75 IU kg^?1 followed by a second and third dose of 50 IU kg^?1 at 12‐h intervals. APCC and rFVIIa demonstrated excellent efficacy in our major and minor surgical interventions [100% (22/22) and 94% (31/33), respectively]. We had only two bleeding complications with rFVIIa. There were no thromboembolic complications. APCC and rFVIIa provide an effective and safe first line haemostatic therapy for inhibitor‐positive haemophiliacs, allowing both major and minor surgery to be successfully performed.     

U.S. survey of surgical capabilities and experience with surgical procedures in patients with congenital haemophilia with inhibitors

General guidelines exist for the use of recombinant activated factor VII (rFVIIa) to maintain haemostasis during surgery in congenital haemophilia A and B patients with high responding inhibitors (CHwI). Individual surgical plans are required and based upon historical therapy response, adverse events and anticipated procedure. Surgical interventions are feasible, yet it remains unclear how many US hemophilia treatment centres (HTCs) perform procedures in this fragile population. To better understand the US HTC surgical experience in CHwI patients and the number/types of procedures performed, a 21-question survey was sent to 133 US HTCs, with follow-up for response clarification and to non-responders. 98/133 HTCs (74%) responded, with 87 currently treating CHwI patients. In the last decade, 76/85 HTCs performed 994 surgeries on CHwI patients. Sites were experienced in the following procedures: central line insertion/removal (73 HTCs), dental (58), orthopaedic (52), abdominal (23), cardiovascular (14) and otolaryngologic (11). Experience with orthopaedic surgeries included synovectomies - arthroscopic (23 HTCs), radioisotopic (22), and open (7); joint replacement (18); fracture repair (14); and arthrodesis (8). Treatment modalities included rFVIIa bolus (83 HTCs) or continuous infusions (9), plasma-derived activated prothrombin complex concentrate (pd-aPCC) (55), antifibrinolytics (51), topical haemostatic agents (29), factor VIII (16) and fibrin sealants (14). Protocols for bypassing agents were used by 31/92 (33%) HTCs. Most US HTCs surveyed care for CHwI patients (74%) and have experience in minor surgery; fewer HTCs reported complex orthopaedic surgical experience. Identification of best practices and surgical barriers is required to guide future initiatives to support these patients.     

Managing oral anticoagulant therapy in patients with mechanical heart valves undergoing elective surgery: results of a survey conducted among Italian physicians.

The optimal perioperative anticoagulation management in patients on warfarin therapy is poorly defined because of the lack of randomized trials. Because guidelines are heterogeneous, we hypothesized that treatment strategies are not uniform in clinical practice. During the Annual Meeting of the Italian Federation of Anticoagulation Clinics, a questionnaire with four different clinical scenarios was distributed. Two scenarios described the cases of patients with a mechanical heart valve in the mitral position and additional risk factors for systemic embolism, one undergoing major surgery (case 1) and one undergoing minor surgery (case 3). Two scenarios described patients with an aortic mechanical heart valve, one undergoing major surgery (case 2) and one minor surgery (case 4). Different preoperative and postoperative management options were offered. Treatment options for all scenarios were the same. Of the 300 questionnaires distributed, 72 were returned (24%). Outpatient full-dose low molecular weight heparin (LMWH) was the most selected strategy in the preoperative phase. It was chosen by 90.3% of participants in case 3, 87.5% in case 1, 62.5% in case 2, and 52.8% in case 4. In the postoperative phase, full-dose LMWH remained the most selected option for cases 1 (75%) and 3 (70.8%), whereas low-dose LMWH was selected by the majority for cases 2 (50%) and 4 (61.1%). Even among expert clinicians, the management of perioperative anticoagulation is heterogeneous. In particular, the definition of risk categories and the optimal intensity of antithrombotic drugs remain to be assessed by well-designed prospective studies.