The natural history of mild haemophilia: a 30-year single centre experience.

Although up to 50% of all haemophilic patients followed at haemophilia treatment centres (HTCs) are affected by a mild factor VIII (FVIII) or factor IX (FIX) defect, published data regarding the natural history of these disorders are scarce. To fill this lack of information, a retrospective single centre study was conducted. All cases with mild haemophilia (75 A and 7 B) followed at the regional reference HTC of Parma were evaluated. The patients' median age at diagnosis was 11.5 years and their median age at first bleeding was 5.5 years; 95% of patients had a history of haemorrhagic problems during their life. Twenty-three percent of patients were infected by HCV, and none by HIV. Genetic analysis was performed in 80 patients (97% haemophilia A and 100% haemophilia B) and 21 different mutations were characterized. Eleven percent of patients had never received treatment, whereas 67% were treated with plasma-derived or recombinant FVIII/FIX concentrates (4% developed inhibitors). desmopressin (DDAVP) was used in 80% of the haemophilia A patients. The response to DDAVP was closely related to the patients' genetic profile, as 60% of non-responders had a mutation in the F8 promoter region. Patients with mild haemophilia may experience a variety of medical problems, sometimes challenging for the physicians, during their lifetime. The HTCs play an important role in the management of these patients, whose diagnosis is often delayed. The HTCs should improve patients' knowledge and consideration of their disease and encourage them to maintain regular contact with their haemophilia care provider.

A web-based clinical record 'xl'Emofilia' for outpatients with haemophilia and allied disorders in the Region of Emilia-Romagna: features and pilot use.

The treatment of haemophilia in developed countries is based on home self-infusion of concentrates. Improving communication between haemophilia centres (HC) and patients is very important. The Hub Centre (Parma) designed a new outpatient clinical record, 'xl'Emofilia', as part of a project 'Web Connections of the Region's HC' funded by Emilia-Romagna Health Authority. It is a web-based application suited to the needs of HC, which shares the databases of the region's HC, integrated with regional and national registries that can be accessed from anywhere. Data are managed with the 'https' protocol. Significant innovations are 'pathways' that help with the entry of data and 'problem list', which is a summary (updated automatically) of the patient's clinically significant data that can be consulted at a glance. With a 'web identity' (a personal USB key for secure web access), patients can record bleeds and home infusions, consult their own data and allow access to their general practitioners or in emergency departments anywhere in the world (also in English language). In December 2006, the HC started to use 'xl'Emofilia' and 673 clinical records are now active. Since April 2007, 50 pilot patients have been trained and are successfully using the system. A questionnaire administered to these patients on their level of satisfaction with the system and its ease of use gave excellent results. Our web-based system facilitates communication between patients and HC, improves the quality of care and enables patients to use these information at any time and from anywhere in the world.

A web-based registry of inherited bleeding disorders in the region of Emilia-Romagna: results at three and a half years.

A Registry of inherited bleeding disorders was set up in the Region of Emilia-Romagna (RER) to collect information about these diseases and to improve the quality of care. From January 2003, the eight Haemophilia Centres (HC) in the RER began to use computerized clinical records; every 6 months, they send data to Parma Hospital to be processed and published in a website (http://www.registroemofiliarer.it). Great efforts are made to ensure high quality of data. Results of general interest are included in a free 'public area' and more sensitive data in a 'reserved area' (open only to HC and to health authorities). A total of 610 individuals are included: 249 haemophilia A (HA), 63 haemophilia B (HB), 173 von Willebrand's disease, 69 rare bleeding disorders, seven platelet disorders and 49 haemophilia carriers; 131 were genotyped, 188 were tested for inhibitors (16 affected). The most frequent bleeding was haemarthrosis. The joint score (evaluated in 104 haemophiliacs) was higher in severe HA. There were 22 HIV-positive and 182 hepatitis C virus-positive patients (21% have chronic hepatitis, two hepatocellular carcinoma). In 2005, two patients received primary prophylaxis, 47 secondary prophylaxis, four children were on immune-tolerance induction. From 2003 to 2005 the use of recombinant products was greatly increased and the majority of patients received them. The mean clotting factor consumption for prophylaxis was higher than on-demand treatment. The main features of registry are to collect high quality and comprehensive data of all patients followed by HC, to improve quality of care and it's availability on the web.

A comparative study on the quality of oral anticoagulant therapy (warfarin versus acenocoumarol).

In our Center for the Surveillance of Anticoagulant Treatment, most of the 1700 patients followed-up are traditionally treated with acenocoumarol, while warfarin is administered nowadays to an increasing proportion of patients. To assess if the difference in the pharmacokinetics of these two drugs may determine a different laboratory quality of treatment, a retrospective study was performed on the computerized files of all 142 patients on treatment with warfarin for more than 100 days and on a control group of 142 patients treated with acenocoumarol, matched for age, sex, disease state and duration of oral anticoagulant therapy (OAT). The study considered 7071 assays for a total of 432 patient-years of treatment. The overall quality of treatment was significantly better in patients treated with warfarin (72% of controls within the therapeutic range versus 67% on acenocoumarol, p < 0.001). Also the individual quality of therapy, which was assessed as the percentage of patients with 75% or more assays in range, was in favour of warfarin (50.7% vs 34.5%, p < 0.05). Warfarin therapy was more stable and fewer assays were required for treatment monitoring. Confounding factors possibly influencing the treatment stability, such as interfering drugs, diagnostic or therapeutical procedures requiring withdrawal of anticoagulation, were evaluated and no significant difference between the two groups was found. The difference in the laboratory quality of OAT was marked in patients treated for prevention of arterial thromboembolism, while it was negligible in patients with venous thromboembolic disease, whose mean duration of OAT was considerably shorter. Since there is no evidence that acenocoumarol is more efficacious or safer than warfarin, the latter seems to be preferable for patients who are candidate to very prolonged OAT.

Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis.

To evaluate the role of low-molecular weight heparin (LMWH) as an alternative to oral anticoagulants in the prevention of recurrent venous thromboembolism, we compared in a randomized trial conventional warfarin treatment with a three-month course of enoxaparin 4000 anti-Xa units once a day subcutaneously. 187 patients with symptomatic deep-vein thrombosis (DVT), diagnosed by strain-gauge plethysmography plus D-dimer latex assay and confirmed by venography in most cases, were treated with full-dose subcutaneous heparin for ten days and then randomized to secondary prophylaxis. During the 3-month treatment period, 6 of the 93 patients who received LMWH (6%) and 4 of the 94 patients on warfarin (4%) had symptomatic recurrence of venous thromboembolism confirmed by objective testing (p = 0.5; 95% confidence interval [CI] for the difference, -3% to 7%). Four patients in the LMWH group had bleeding complications as compared with 12 in the warfarin group (p = 0.04; 95% CI for the difference, 4% to 14%). In the 9-month follow-up period, during which 34 patients on warfarin prolonged treatment for other 3 months and 14 up to one year, 10 patients in the enoxaparin group and 4 patients in the warfarin group suffered a documented recurrence of venous thromboembolism. Of these 14 late recurrences, just one occurred in patients with postoperative DVT. After one year there were 16 recurrences (17%) in the LMWH group and 8 (9%) in the warfarin group (p = 0.07; 95% CI for the difference, 1% to 16%).(ABSTRACT TRUNCATED AT 250 WORDS)

Duplex ultrasound diagnosis of symptomatic proximal deep vein thrombosis of lower limbs.

Real time ultrasound (US) was used to examine 165 consecutive inpatients with clinically suspected deep vein thrombosis of lower limbs. In order to evaluate accuracy, the results of non-invasive techniques were compared with ascending venography, performed in all patients. Assessment included only femoro-popliteal veins, because of difficulty in visualizing calf vein with US. Diagnosis of thrombosis was based on noncompressibility of the examined veins; pulsed Doppler provided further information by evaluating blood flow. In our series Duplex ultrasound was very accurate in detecting acute thrombosis of the proximal veins, sensitivity being 97% and specificity 98%. With US it is also possible to detect conditions that mimic deep vein thrombosis, such as muscular rupture, hematoma, popliteal cyst or compressive tumors. In conclusion US is considered a valid alternative to contrast venography in the diagnosis of proximal vein thrombosis of lower limbs.

Warfarin induced dermatitis and venous thrombosis in a patient with Protein S deficiency.

A case of warfarin-induced dermatitis in a 79 year-old patient with Protein S deficiency is described. Both total Protein S antigen and free Protein S were moderately reduced (about 50%). The skin lesion did not progress to frank necrosis and it was associated with elevated creatin phosphokinase (CPK) levels in plasma and with thrombosis of the anterior tibial vein localized to the area of dermatitis (probably warfarin-induced deep venous thrombosis). After warfarin withdrawal and beginning of heparin therapy, serum CPK rapidly normalized and the skin lesion improved.

Risk of venous thromboembolism and stroke associated with oral contraceptives. Role of congenital thrombophilias.

To assess the risk of thromboembolism in women using oral contraceptives (OCs), we identified through computer search in the hospitals of the province of Parma, Italy, all women aged 15-44 who were resident in the province and had a documented thromboembolic event in the years 1989-93. The number of users and nonusers of OCs was estimated by the drug sale data for the province and by the demographic statistics. In cases with venous thromboembolism (VT) the prevalence of concomitant deficiency of antithrombin III, protein C, protein S, and of factor V gene mutation Arg506GIn was evaluated. The incidence rate of VT was 37/59,603 woman-years in users (0.62 per 1000) and 13/303,954 woman-years in nonusers (0.042 per 1000), for a relative risk (RR) of 14.5 (95% confidence interval: 7.8-27.1; P < 0.001); the rate of stroke per 1000 woman-years was 0.17 in users and 0.036 in nonusers (RR = 4.6; 2.9-10.7; P < 0.01). A congenital thrombophilia involving the protein C anticoagulant system was documented in about 25% of young women developing venous thromboembolism while on OCs.

Dental procedures in adult patients with hereditary bleeding disorders: 10 years experience in three Italian Hemophilia Centers.

Excessive bleeding after dental procedures are one of the most frequent complications occurring in patients with hereditary bleeding disorders. In this retrospective study we collected data from 10 years of experience in the oral care of patients with congenital haemorrhagic disorders in three Italian Hemophilia Centers. Between 1993 and 2003, 247 patients with inherited bleeding disorders underwent 534 dental procedures including 133 periodontal treatments, 41 conservative dentistry procedures, 72 endodontic treatments and 288 oral surgery procedures. We recorded 10 bleeding complications (1.9%), most of which occurred in patients with severe/moderate haemophilia A undergoing multiple dental extractions. Thus, our protocol of management of patients with hereditary bleeding tendency undergoing oral treatment or surgery has been shown to be effective in preventing haemorrhagic complications.

Computer assisted anticoagulant therapy.

The constantly workload increase has led to the development of Computerised Decision Support Systems (CDSS) for a better management of patient care. Many clinical situations have been investigated to verify the utility of CDSS: few have demonstrated stable effects. One area where success has been reported is the field of oral anticoagulation management. CDSS system has demonstrated to be able to improve the treatment quality in comparison to manual method. In the future scenario of oral anticoagulant management CDSS will have a pivotal part, the constant increase of patients number and their pressure on thrombosis centres had led to the development of alternative models for delivery OAT: Primary care, General Practitioner, Patient self testing and self management and the use of CDSS has been central to the decentralisation process and may be useful in maintaining the efficacy and quality of anticoagulant control. GP with the aid of CDSS are able to deliver OAT as well as expert physician of Thrombosis Centre in terms of time spent by patient in therapeutic range.

[Arteriosclerosis obliterans of the lower limbs. Epidemiological study of the risk factors]. / Arteriosclerosi obliterante degli arti inferiori. Studio epidemiologico sui fattori di rischio.

Chronic arterial occlusive disease of lower limbs is recognized as a typical multifactorial disease, but the role of some risk factors is still debated, because contrasting results have been obtained in epidemiological studies. We investigated the prevalence of hypercolesterolemia, hypertriglyceridemia, hypertension, smoking habits and diabetes in a population of 172 patients with peripheral arterial disease admitted to the III and V Medical Division of the "Ospedale Regionale" of Parma in the period January 1979 - April 1983, and in a control group of 174 subjects comparable for age and sex, free of clinical symptoms or signs of atherosclerosis. Statistically significant (p less than 0,005) increases in the prevalence of hypercolesterolemia, hypertriglyceridemia, smoking and hypertension were found in vascular patients compared with controls, the relative risk for the various considered factors being respectively: 6.40; 4.72; 4.03; 3.16.

Risk of acute cerebrovascular events related to low oestrogen oral contraceptive treatment.

To establish if an association exists between use of oral contraceptives (OC) and the occurrence of cerebral arterial thromboembolism, cerebral venous thrombosis and retinal vein/artery thrombosis, we identified all women aged 15-44 years resident in the province of Parma, Italy, who were hospitalized because of a documented cerebral or retinal thromboembolic event during the period 1989-1993. The numbers of users and nonusers of OC were estimated from drug sale data and demographic statistics for the province. There were 21 cases of cerebral arterial thromboembolism during the study period: 10 in OC users and 11 in nonusers, for an estimated incidence rate of 1.70 and 0.35 per 10,000 woman-years OC of use and nonuse, respectively (RR=4.8, 95% CI = 1.8-9.0). Eight cases of cerebral venous thrombosis were observed: 6 in OC users and 2 in nonusers (both in puerperium), for an incidence rate of 1.00 and 0.06 per 10,000 woman-years, respectively (RR=16.7, 95% CI = 3.3-81.4). Finally, 13 cases of retinal vein/artery thrombosis were found: 1 in OC users and 12 in nonusers, for an incidence rate of 0.17 and 0.37 per 10,000 woman-years, respectively (RR=0.46, 95% CI = 0.06-3.7). In our population study the use of low oestrogen OC was associated with an increased risk of cerebral venous thrombosis and ischemic stroke, but not of retinal vein/artery thrombosis.

The Natural History of Hepatitis C Virus Infection in Hemophiliacs.

Hepatitis C virus (HCV) infection is an important cause of morbidity and mortality in patients affected by hereditary bleeding disorders and treated with non-virus inactivated clotting factor concentrates during the 1970s. Since the onset of the infection is known (first treatment with large-pool non-virus inactivated blood products) these patients are a unique model for studying the natural history of HCV infection and associated complications. The course of Hepatitis can be accurately assessed in these patients because they are regularly followed at hemophilia centers with laboratory, clinical and instrumental tests. In this review, we briefly report the present knowledge about the natural course of HCV infection in hemophiliacs, by analyzing the prevalence of HCV infection, the genotype distribution and the risk factors involved in the progression of chronic Hepatitis into severe liver disease as cirrhosis, liver decompensation and hepatocellular carcinoma. Understanding the natural evolution of HCV infection in hemophiliacs helps us to understand better the natural history of HCV infection and to improve the treatment approach to all HCV infected patients.

Interferon and ribavirin in HIV-negative haemophiliacs with chronic hepatitis C who were nonresponders to a previous interferon treatment.

Between January 1999 and December 2001, 33 HIV-negative haemophiliacs with interferon-nonresponsive chronic hepatitis C were treated with interferon (IFN) alpha2b (5 MU three times weekly) and ribavirin (1-1.2 g daily) for 12 months. Four patients (12.1%) dropped out of the study due to adverse effects. At the end of therapy, normalization of ALT occurred in 14/33 treated patients (42.4%) and HCV-RNA was cleared in 12 (36.4%). Eleven patients (33.3%) became sustained responders. Genotype 1 was the only factor associated with a poor response to therapy (P < 0.001). Our study shows that IFN and ribavirin combination therapy is effective in HIV-negative chronically HCV-infected haemophiliacs who do not respond to a previous IFN treatment.

The natural history of chronic hepatitis C in a cohort of HIV-negative Italian patients with hereditary bleeding disorders.

This study looked at 102 anti-hepatitis C virus (HCV)-positive, hepatitis B virus (HBV)-negative, and HIV-negative patients (median age, 45.1 years; range, 15-71) affected by hereditary bleeding disorders who have been infected with HCV for 15 to 34 years (median, 25.1). All these patients were infected before the mid 1980s because of non-virally inactivated pooled blood products. Fourteen patients (13.7%) were HCV-RNA negative with no signs of liver disease and were considered to have cleared the virus. Eighty-eight patients (86.3%) were HCV-RNA positive. The HCV genotype distribution was 1a in 20.5%, 1b in 36.4%, 2 in 17.0%, 3 in 15.9%, 4 in 3.4%, and mixed in 6.8% of cases. Twenty-four patients (23.5%) had serum cryoglobulins, symptomatic in 4 cases, and associated with liver disease and with genotype 1. Among the 88 HCV-RNA-positive patients, 15 (17.0%) had normal alanine aminotransferase levels and abdominal ultrasound, 61 (69.3%) had nonprogressive chronic hepatitis, and 12 (13.7%) had severe liver disease (6 [6.9%] liver cirrhosis, 4 [4.5%] hepatic decompensation, and 2 [2.3%] hepatocellular carcinoma) after a follow-up period of 25 years. There were 3 (3.4%) liver-related deaths. HCV genotype 1, patient's age at evaluation, duration of infection, and severity of congenital bleeding disorder were associated with more advanced liver disease. The results confirm the slow progression of HCV infection in HIV-negative hemophiliacs.