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Although desmopressin (DDAVP) is considered as the treatment of choice for many patients with mild hemophilia A, several aspects of DDAVP therapy remain unclear, including the rate and type of response and the molecular determinants of its clinical efficacy. To investigate these issues, we retrospectively studied all patients with mild hemophilia A followed up at the Parma Hemophilia Center. A total of 75 patients were enrolled who underwent a DDAVP test, and out of whom, 76% (57/75) had a complete or partial response. Response to DDAVP was significantly correlated to the patients' age (median age of responders and nonresponders: 24 and 18 y, respectively; p = 0.04) and type of mutation (all the 10 patients with mutations in the promoter region were nonresponders). The median basal factor VIII (FVIII):C level was significantly lower in responders than in nonresponders (0.14 vs. 0.19 IU/mL, respectively; p = 0.01); this was mainly due to nonresponders with promoter region mutations who had higher basal FVIII:C levels. During the 12-year follow-up, 82 of 237 (35%) bleeding episodes occurring in 27 responder patients were treated with 246 DDAVP infusions with complete or partial efficacy in 92% (75/82). Overall, 142 events were managed with 253 prophylactic DDAVP infusions, which were hemostatically effective in 96% of cases. No severe adverse reactions to DDAVP administration were recorded during the study period. These results document the safety and efficacy of DDAVP as a treatment or prevention of bleeding in patients with mild hemophilia A, also in the context of home treatment, and encourage the more widespread use of this product.

Treatment of patients with inherited bleeding disorders (PWIBD) in the emergency department (ED) is challenging. In 2010, a project was started involving all eight hemophilia centers (HC) and all 44 EDs of the Region of Emilia-Romagna (Italy) to improve emergency care for PWIBD. The project incorporates guidelines for emergency treatment, education for ED staff, and a dedicated Web site providing extensive information, proposing treatments, and sharing data with patients' electronic clinical records. A Web algorithm, accessible to PWIBD as well as ED and HC staff, suggests the first dose of concentrate for each type and severity of bleed or trauma. Following training courses in each ED, the network was activated. During 2012 and 2013, the site was visited 14,000 times, the EDs accessed the Web site 1,739 times, and used the algorithms 206 times. In two reference EDs, triage-assessment and triage-treatment times were reduced in 2013 and 2012 (27/20 and 110/71.5 minutes, respectively) and medical advice from the HC increased (54 vs. 24% cases). The main advantages of this system are better management of patients in ED (shorter triage-to-treatment times) and improved collaboration between HCs and EDs. The most critical point remaining is staff turnover in EDs, necessitating continual training.

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 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.

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 diagnostic value of a latex D-dimer test combined with strain-gauge plethysmography (SGP) was assessed in 425 patients referred to our vascular laboratory because of clinically suspected deep-vein thrombosis (DVT) of lower limbs, using venography as the reference standard. The inpatient/outpatient ratio was 236 189 . Adequate venograms were obtained in 401 patients and a DVT was diagnosed in 195 (49%). SGP results were borderline in 38 patients. In the 363 unequivocal cases, sensitivity of SGP was 88% and specificity 90%. The sensitivity of D-dimer latex test was 78% and the specificity 88%. Out of the 363 unequivocal cases, D-dimer test results were discordant with SGP in 88 cases, of whom 60% had DVT and 40% had not, and concordant in 275. The sensitivity of concordant results was 98% ( 124 127 ) and specificity 97% ( 143 148 ). Compared with strain-gauge plethysmography (plus venography in case of borderline results), the combined approach reduced the diagnostic errors (false positive plus false negative results) from 10% ( 40 401 ; 95% confidence interval, 7–13%) to 2% ( 8 401 ; 95% CI, 0.6–3.4%) albeit requiring a greater number of venographies, from 9% ( 38 401 ; 95% CI, 7–12%) to 31% ( 126 401 ; 95% CI, 27–36%). Most calf DVT (94%) were identified. We conclude that this test combination is valuable in the diagnosis of DVT in symptomatic patients, because of the high accuracy of concordant test results. Venography is required in case of borderline or discordant results.

BACKGROUND The optimal duration of oral anticoagulant therapy in patients with deep venous thrombosis (DVT) of the lower extremities remains uncertain. OBJECTIVE To assess whether tailoring the duration of anticoagulation on the basis of the persistence of residual thrombi on ultrasonography reduces the rate of recurrent venous thromboembolism (VTE) compared with the administration of conventional fixed-duration treatment in adults with proximal DVT. DESIGN Parallel, randomized trial from 1999 to 2006. Trained physicians who assessed outcomes were blinded to patient assignment status, but patients and providers were not. SETTING 9 university or hospital centers in Italy. PATIENTS 538 consecutive outpatients with a first episode of acute proximal DVT at completion of an uneventful 3-month period of anticoagulation. INTERVENTION Patients were randomly assigned (stratified by center and secondary vs. unprovoked DVT by using a computer-generated list that was accessible only to a trial nurse) to fixed-duration anticoagulation (no further anticoagulation for secondary thrombosis and an extra 3 months for unprovoked thrombosis) or flexible-duration, ultrasonography-guided anticoagulation (no further anticoagulation in patients with recanalized veins and continued anticoagulation in all other patients for up to 9 months for secondary DVT and up to 21 months for unprovoked thrombosis). For the primary outcome assessment, 530 patients completed the trial. MEASUREMENTS The rate of confirmed recurrent VTE during 33 months of follow-up. RESULTS Overall, 46 (17.2%) of 268 patients allocated to fixed-duration anticoagulation and 32 (11.9%) of 270 patients allocated to flexible-duration anticoagulation developed recurrent VTE (adjusted hazard ratio [HR], 0.64 [95% CI, 0.39 to 0.99]). For patients with unprovoked DVT, the adjusted HR was 0.61 (CI, 0.36 to 1.02) and 0.81 (CI, 0.32 to 2.06) for those with secondary DVT. Major bleeding occurred in 2 (0.7%) patients in the fixed-duration group and 4 (1.5%) patients in the flexible-duration group (P = 0.67). LIMITATIONS The trial lacked a double-blind design. The sample size was not powered to detect differences in bleeding between groups and to detect effectiveness of the intervention in the subgroups of patients with unprovoked and secondary DVT. Patients with previous thromboembolism, permanent risk factors for thrombosis, and thrombophilic abnormalities other than factor V Leiden and prothrombin mutation were excluded. CONCLUSION Tailoring the duration of anticoagulation on the basis of ultrasonography findings reduces the rate of recurrent VTE in adults with proximal DVT. PRIMARY FUNDING SOURCE None.

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.

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.

Absence of thromboembolic complications in patients with hereditary bleeding disorders undergoing major orthopaedic surgery without antithrombotic prophylaxis

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.

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.

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.