F. A. Scaraggi

A prospective randomized trial of high and standard dosages of recombinant factor VIIa for treatment of hemarthroses in hemophiliacs with inhibitors.

Summary.  Aim: A multicenter randomized open‐label crossover prospective trial was designed to compare the efficacy, safety, and cost of standard and high dosages of recombinant factor VIIa (rFVIIa) for home treatment of hemarthroses in hemophiliacs with inhibitors. Methods: Patients were instructed to treat, within 6 h from the onset of bleeding, four consecutive hemarthroses of ankles, knees, or elbows, either with the rFVIIa standard dose of 90 μg kg−1 (repeated as necessary every 3 h) or with a single high dose of 270 μg kg−1. Patients who did not achieve a clinical success within 9 h continued rFVIIa treatment with repeated standard doses. Response to treatment was assessed for up to 48 h by patients/caregivers, who reported on a Visual Analogue Scale (VAS) graded from 0 to 100 the improvement in symptoms and also rated the responses as effective, partially effective or ineffective. Success was defined a treatment course rated as effective and with a VAS score ≥70 and failure a treatment course rated as ineffective and VAS score ≤30, whereas treatment courses that did not fulfill these criteria were considered partial responses. Results: Twenty hemophiliacs with inhibitors were originally enrolled (median age: 27 years), 18 of them treated 32 hemarthroses assigned to the standard‐dosage and 36 to the high‐dosage regimen, during the study period of 18 months. Forty‐eight hemarthroses (71%) occurred in target joints. Success rates for standard‐ and high‐dosage regimens were similar: 31% and 25% at 9 h, 53% and 50% at 24 h, 66% and 64% at 48 h, the end point for outcome assessment. The median number of rFVIIa infusions needed to achieve a successful course was significantly greater for the standard‐dosage (n = 3) than for the high‐dosage regimen (n = 1), and the median amount of rFVIIa ultimately used per successful course was identical (270 μg kg−1). Conclusion: Our results indicate that a high‐dosage regimen with rFVIIa for home treatment of hemarthroses is effective, safe, does not imply an increased consumption of rFVIIa and requires the infusion of a smaller number of rFVIIa doses. Its convenience is particularly relevant in cases with difficult venous access and in hemorrhages into target joints.

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

Summary.  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 (≤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.

Influence of factor VIII/von Willebrand complex on the activated protein C-resistance phenotype and on the risk for venous thromboembolism in heterozygous carriers of the factor V Leiden mutation.

High factor VIII plasma levels have been shown to represent a common increased risk for venous thromboembolism (VTE) and may cause an activated protein C (APC) resistance in the absence of the factor V Leiden mutation, but there are no studies specifically aimed to establish if high factor VIII and von Willebrand factor (vWF) concentrations may influence the APC sensitivity ratio (APC-SR) and increase the risk for VTE in the presence of the factor V Leiden mutation. For this purpose, we performed a retrospective case-control study to investigate the influence of the procoagulant factor VIII (VIII:C) and the antigen of vWF (vWF:Ag) on the normalized APC-SR (n-APC-SR) and on the risk for VTE, in two selected groups of 30 symptomatic (Group I) and 32 asymptomatic (Group II) related heterozygotes for the factor V Leiden mutation. Differences between the two groups (Group I versus Group II) were: n-APC-SR, 0.57+/-0.06 versus 0.63+/-0.08, P = 0.001; factor VIII:C, 1.49+/-0.42 versus 1.13+/-0.28 IU/ml, P<0.001; vWF:Ag, 1.46+/-0.53 versus 1.26+/-0.32 IU/ml, NS. As a whole (Group I + Group II), Pearson correlation coefficients were: n-APC-SR versus factor VIII:C, r = -0.410, P = 0.001; n-APC-SR versus vWF:Ag, r = -0.309, P = 0.01; factor VIII:C versus vWF:Ag, r = +0.640, P<0.0001. The relative risk for VTE in individuals with the factor VIII:C concentration > 1.5 IU/ml was 2.5 (95% confidence interval 1.6-3.9). We concluded that high factor VIII:C levels, probably in the effect of vWF, play a determinant role in worsening the APC-resistance phenotype and represent a common additional risk factor for VTE in heterozygous carriers of the factor V Leiden mutation.

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.

Long‐term immunogenicity and safety of an inactivated hepatitis A vaccine in haemophilic patients

Summary. As a consequence of recent outbreaks of HAV infection by blood products, 91 patients, haemophiliacs and subjects with bleeding disorders (10 of whom were also anti‐HIV positive) susceptible to HAV infection received a formalin‐inactivated hepatitis A vaccine (HAVRIX 720 Elisa Units, SmithKline Beecham). Subcutaneous injections were given in the deltoid region at 0, 1 and 6 months. The seroconversion rates and litres, expressed in GMT IU/1, were determined at 1, 2, 6, 7, 12, 18 and 24 months. No adverse reactions to the vaccine were observed. The highest percentage of responders observed was 98.7% in anti‐HIV negative and 71.4% in anti‐HIV positive patients. The anti‐HAV GMT titres were higher in anti‐HIV negative than in anti‐HIV positive patients. The inactivated hepatitis A vaccine is safe, clinically well tolerated, and provides long‐term protection against HAV infection.

Treatment with recombinant activated factor VII in a patient with hemophilia A and an inhibitor: advantages of administration by continuous infusion over bolus intermittent injections.

Recent studies have shown that treatment with a continuous infusion of recombinant activated factor VII (rFVIIa) is far more convenient than administration by bolus intermittent injections and may allow a substantial reduction in the dose. We present the case of a 26-year-old patient with hemophilia A, who had a high-titer inhibitor to both human and porcine factor VIII, and who had recently been admitted to hospital because of a bilateral severe ilio-psoas hematoma. Two subsequent courses of treatment with rFVIIa by bolus intermittent injection showed only a partial efficacy. A further administration of rFVIIa was therefore carried out using a continuous infusion regimen that proved to be fully efficacious. During the continuous infusion course levels of factor VII coagulant activity were in the range 18.2-5.2 U/ml, while the prothrombin time, expressed as an International Normalized Ratio, remained within the range 0.57-0.71. The continuous infusion, compared with the administration of the bolus intermittent infusion, reduced the amount of rFVIIa required by approximately 40-50%. Statistical analysis demonstrated that there was a strong positive correlation between the rate of infusion of rFVIIa and levels of factor VII coagulant activity (r = +0.941; P < 0.001), and a very significant negative correlation between levels of factor VII coagulant activity and prothrombin time values (r = -0.897; P < 0.001). In accordance with previous findings, our experience confirms that, when prolonged therapy is required, treatment with rFVIIa by continuous infusion is more convenient than administration of bolus intermittent injections, and may allow the saving of a large amount of drug. Moreover, we suggest potential additional advantages of the continuous infusion regimen over bolus intermittent injections, such as a better efficacy and a stronger correlation between prothrombin time and factor VII coagulant activity levels.

The prevalence of hepatitis C virus types in patients of the same geographic area, according to the source of infection and liver disease

BACKGROUND The duration and stage of hepatitis C might be associated with the source of infection and hepatitis C virus (HCV) types. OBJECTIVE We studied the relationship among the different HCV types, source, duration, and stage of infection in 100 patients from the Apulia, southern Italy, selected from consecutive clinical records. They were 20 parenterally infected haemophiliacs with 10-20 years of disease history, but without cirrhosis; 20 patients (matched for sex, age and disease) and without known risk factor for parenteral infections; 60 patients with community acquired infection (ten with CAH and ten with cirrhosis with less than 20 years disease history; 20 with cirrhosis and hepatocellular carcinoma (HCC) and more than 20 years of liver disease and 20 matched cases with cirrhosis without HCC). RESULTS Type 1 and 2 HCVs had comparable prevalence in patients with long lasting and recent HCV infection, 56 and 64%, 26 and 30% respectively. HCV type 3 was found in 6.5-12% of the patients with recent HCV infection, but it was not detected in those with infection longer than 20 years. Type 1 b HCV was more frequently found in HCC patients (68% of cases) than in the other forms of liver disease. The opposite was observed for HCV types (2 and 3). CONCLUSIONS The prevalence of the different HCV types appears associated with the source and duration of the infection. The interesting association between HCV type 1 b and HCC prompts further studies in larger series of patients.

DEFIBROTIDE IN THE TREATMENT OF RAYNAUD'S PHENOMENON IN PATIENTS WITH PROGRESSIVE SYSTEMIC SCLEROSIS OR ESSENTIAL MIXED CRYOGLOBULINEMIA

Abstract Defibrotide, a polydeoxyribonucleotide extracted from mammalian organs, enhances natural fibrinolysis and prostacyclin generation. The aim of this study was to evaluate the effects of this drug in patients with Raynauds phenomenon suffering from progressive systemic sclerosis (PSS) or essential mixed cryoglobulinemia. Fourteen patients (four men and 10 women, aged 33 to 64 years) were enrolled in the study. Defibrotide was administered as follows: 1200 mg daily was infused over 2 hours for 7 days, 200 mg BID was injected intramuscularly for an additional 21 days, and 400 mg BID was administered orally for the final 12 weeks. The frequency and severity of Raynauds attacks were monitored during the treatment using in-clinic questionnaires and patients daily diaries. At baseline and after 1, 4, and 16 weeks of treatment, patients underwent a cold stress test, hand thermography, digital plethysmography, capillaroscopy, and cutaneous oxymetry. Blood coagulation and fibrinolysis studies were also performed. Overall clinical and instrumental assessment revealed a subjective and objective response in all patients. Statistical analysis of fibrinolytic parameters globally examined did not show any significant change at fixed times during treatment. In the PSS group, the stratified analysis demonstrated a trend toward improvement of atrest euglobulin clot lysis time, but specific assays, such as tissue plasminogen activator and plasminogen activator inhibitor-1, were not modified. The improved fibrinolysis induced by defibrotide in the PSS patients may be due to the drugs influence on the intrinsic fibrinolytic mechanism. Our study indicates that defibrotide may provide a new and interesting approach to the pharmacologic treatment of Raynauds phenomenon associated with progressive systemic sclerosis or essential mixed cryoglobulinemia.

Factor XI deficiency: two novel mutations in asymptomatic Italian patients

Summary.  Factor XI (FXI) deficiency is a rare bleeding disorder, resulting in a wide range of bleeding manifestations, from asymptomatic bleeding to injury‐related bleeding. To identify mutations in FXI‐deficient patients and to establish a possible relationship between clinical phenotype and genotype, we studied two patients from Southern Italy with FXI deficiency. They were identified by presurgical or routine laboratory screening. None of them showed bleeding. Three different mutations were detected (Glu117Stop, Cys118Arg and Trp497Gly); two of them were novel (Cys118Arg and Trp497Gly). One patient (with severe FXI levels) showed a compound heterozygosity (Glu117Stop with Cys118Arg). Two novel missense mutations were highly conserved among different species. In our patients, bleeding tendency did not appear to be correlated with FXI levels or with a single mutation in heterozygosis. On the other hand, the compound heterozygosis might explain low FXI levels, but it is not associated with bleeding. Our data confirm that a severe FXI deficiency is not necessarily associated with bleeding.