Effect of zoledronic acid on markers of bone turnover and mineral density in osteoporotic patients with beta-thalassaemia.

Osteoporosis has emerged as an important cause of morbidity in patients with thalassemia major. Studies regarding the efficacy of bisphosphonates in thalassemia-induced osteoporosis have yielded conflicting results. We performed this prospective study to evaluate the efficacy of zoledronic acid in osteoporotic patients with thalassemia major. Patients, 29, were given 1 mg zoledronic acid intravenously every 3 months for a total of four doses. Twenty age- and sex-matched healthy blood donors served as controls. Before each infusion and 3 months after the last infusion, we determined serum levels of osteoprotegerin (OPG), N-terminal cross-linking telopeptide of type I collagen (NTX), osteocalcin (OC) and insulin-like growth factor 1 (IGF-1). Bone mineral density (BMD) of the lumbar spine was measured at baseline and after the treatment's completion. At baseline, OPG did not differ significantly between patients and controls (p=0.2), NTX were higher in patients although not significantly (p=0.139), whereas, OC levels were significantly higher and IGF-1 levels significantly lower in patients than in controls (p<0.001 and p<0.006, respectively). Zoledronic acid administration resulted in a significant decrease in NTX, OC and IGF-1 (p<0.05, p<0.001 and p<0.05, respectively) and in a significant increase in OPG and BMD (p<0.05 for both comparisons). The change in NTX, osteocalcin and IGF-1 became significant as early as 3 months after the first administration of zoledronic acid, while the change in OPG reached significance only after three infusions. Our study supports the effectiveness of bisphosphonates in the treatment of thalassemia-induced osteoporosis.

Uneventful cesarean delivery with administration of factor XI concentrate in a patient with severe factor XI deficiency.

Factor XI (FXI) is a procoagulant factor and antifibrinolytic agent, and its absence causes a bleeding tendency. FXI deficiency is autosomal in inheritance, with severe FXI deficiency in homozygotes and partial deficiency in heterozygotes. A 24-year-old primigravida with an uneventful pregnancy and no history of bleeding manifestations was admitted to our department at 38 weeks of gestation. Her blood count and serum biochemistry findings were normal except for a coagulation screen, which revealed a prolonged activated partial thromboplastin time (APTT) of 63 seconds (normal range, 24-35 seconds). The measured FXI coagulant activity of 8 IU/dL (reference range, 70-150 IU/dL) established a diagnosis of severe FXI deficiency. The breech presentation of the fetus prompted the decision for cesarean delivery under general anesthesia. We administered a single dose of FXI concentrate (15 IU/kg), which corrected the APTT to 34 seconds. The cesarean delivery was uncomplicated, and postpartum recovery of the mother and her baby was uneventful with no bleeding complications. The finding of an isolated prolonged APTT should prompt obstetricians to consider FXI deficiency. The appropriate use of factor FXI concentrate in managing obstetric patients with FXI deficiency can minimize potential bleeding complications and ensure an optimal outcome for both mother and neonate.

A case of successful management with splenectomy of intractable ascites due to congenital dyserythropoietic anemia type II-induced cirrhosis.

The congenital dyserythropoietic anemias comprise a group of rare hereditary disorders of erythropoiesis, characterized by ineffective erythropoiesis as the predominant mechanism of anemia and by characteristic morphological aberrations of the majority of erythroblasts in the bone marrow. Congenital dyserythropoietic anemia type II is the most frequent type. All types of congenital dyserythropoietic anemias distinctly share a high incidence of iron loading. Iron accumulation occurs even in untransfused patients and can result in heart failure and liver cirrhosis. We have reported about a patient who presented with liver cirrhosis and intractable ascites caused by congenital dyserythropoietic anemia type II. Her clinical course was further complicated by the development of autoimmune hemolytic anemia. Splenectomy was eventually performed which achieved complete resolution of ascites, increase of hemoglobin concentration and abrogation of transfusion requirements.

Reduced bone mineral density in patients with haemophilia A and B in Northern Greece.

Haemophilia A and B has been associated with increased prevalence of low bone mass (67-86%). The aim of this study was to estimate the prevalence of bone disease in haemophiliacs and its association with potential risk factors. Adult patients with haemophilia A and B followed-up in the Haemophilia Centre of Northern Greece were included. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) in lumbar spine (LS), femoral neck (FN), total hip (TH) and great trochanter (GT). One-hundred four male patients (aged 45.8 ± 15.1 years) and 50 controls (aged 44.9 ± 12.8 years) were screened. Low BMD was diagnosed in 28 patients (26.9%) and 10 controls (20%) (p=0.0001). Patients had lower BMD in TH (p=0.007), FN (p=0.029) and GT (p=0.008) than controls, without differences in LS. BMD was positively associated with the severity of haemophilia, history of herpes virus C or human immunodeficiency virus and level of physical activity, and negatively with the level of arthropathy. In multiple-regression analysis, only the level of physical activity and 25-hydroxyvitamin D [25(OH)D] significantly predicted BMD. Half of the patients had vitamin D deficiency. In conclusion, our study showed increased prevalence of low BMD in haemophiliacs. The levels of physical activity and 25(OH)D independently predicted low BMD.

Treatment of congenital fibrinogen deficiency: overview and recent findings.

Afibrinogenemia is a rare bleeding disorder with an estimated prevalence of 1:1,000,000. It is an autosomal recessive disease resulting from mutations in any of the 3 genes that encode the 3 polypeptide chains of fibrinogen and are located on the long arm of chromosome 4. Spontaneous bleeding, bleeding after minor trauma and excessive bleeding during interventional procedures are the principal manifestations. We review the management of afibrinogenemia. Replacement therapy is the mainstay of treatment of bleeding episodes in these patients and plasma-derived fibrinogen concentrate is the agent of choice. Cryoprecipitate and fresh frozen plasma are alternative treatments that should be used only when fibrinogen concentrate is not available. Secondary prophylactic treatment may be considered after life-threatening bleeding whereas primary prophylactic treatment is not currently recommended. We also discuss alternative treatment options and the management of surgery, pregnancy and thrombosis in these patients. The development of new tests to identify higher risk patients and of safer replacement therapy will improve the management of afibrinogenemia in the future.

Low protein Z levels, but not the intron F G79A polymorphism, are associated with unexplained pregnancy loss.

INTRODUCTION: The present case-control study was designed in order to investigate the association between plasma protein Z (PZ) levels, the intron F G79A polymorphism and unexplained pregnancy loss. MATERIALS AND METHODS: 51 women with at least two consecutive or three non-consecutive fetal losses between the 8th and 12th week of gestation and 47 apparently healthy parous women of reproductive age with no history of pregnancy loss (controls) were enrolled. Allele frequencies of the PZ intron F G79A polymorphism and PZ levels were measured. RESULTS: PZ levels (mg/L) were significantly lower in cases (mean +/- S.D. 1.28 +/- 0.56) than controls (1.97 +/- 0.76, p < 0.001) and in carriers of the A allele (1.46 +/- 0.62), compared to GG homozygous subjects (1.72 +/- 0.81, p = 0.044). A higher proportion of cases (41.2%) were PZ-deficient (<1 mg/L), compared to controls (10.6%, p = 0.001). No significant difference in the frequency of at least one A allele carriers was observed between cases (39.2%) and controls (40.4%). CONCLUSION(S): It is possible that low PZ levels are a novel risk factor for unexplained recurrent miscarriage or fetal death. The presence of the F 79A allele is associated with significantly lower PZ levels, but, in the present study, was unrelated to unexplained early pregnancy loss.

Is the use of rFVIIa safe and effective in bleeding neonates? A retrospective series of 8 cases.

BACKGROUND: Recombinant activated factor VII (rFVIIa), originally developed for the treatment of life-threatening bleeding in hemophilic patients with inhibitors to factors VIII or IX, has been increasingly used to control hemorrhage unresponsive to conventional treatment, in the absence of a defined coagulopathy or thrombocytopathy. To date, clinical experience of rFVIIa administration in neonates, especially preterms, is rather limited, because of the lack of controlled studies and based solely on some published case reports and 1 prospective pilot study. The objective of this study was to retrospectively evaluate the clinical outcome of newborns treated with recombinant activated factor VII for intractable bleeding or severe coagulation disturbances, resistant to conventional hemostatic therapy. METHODS: The medical records of 8 neonates treated with rFVIIa (100 micro g/kg) were retrospectively reviewed for the course of hemorrhage and the hemostatic interventions performed before and up to 24 hours after the administration rFVIIa. Coagulation parameters of 3 different time-points were assessed and compared: before administration of any blood product (time-point 1), before administration of the first dose of rFVIIa (time-point 2), and 4 hours after the administration of the last dose of rFVIIa (time-point 3). The safety and tolerability profile of rFVIIa in bleeding neonates was also evaluated. RESULTS: Six preterm and 2 term patients were included in the study. Seven patients presented with refractory bleeding and 1 was diagnosed with severe coagulopathy unresponsive to the conventional treatment. Prompt hemostasis was achieved in half of the patients with their coagulation profile being restored within 4 hours after the administration of the first dose of rFVIIa. Improvement in prothrombin time, activated partial thromboplastin time, and fibrinogen after rFVIIa administration was statistically significant, as compared with that observed after conventional treatment. No major safety issues were observed during the study. All 8 patients survived and had their hemorrhage or coagulopathy controlled within 4 hours after transfusion of the last dose of rFVIIa. CONCLUSIONS: In this study, the hemostatic agent rFVIIa was well-tolerated and behaved in a safe and efficacious manner in all infants treated for life-threatening bleeding and coagulation disorders. Future prospective controlled trials are needed to determine the efficacy, safety, tolerability, and possibly the optimal dose and timing of rFVIIa administration.

Skin involvement in Hodgkin's disease.

Hodgkin's disease involving the skin is an unusual occurrence and is found in 0.5-3.4 percent of these patients. The most common clinical presentation is of single or multiple dermal or subcutaneous nodules. The mechanisms usually implicated include direct extension from an underlying nodal focus, hematogenous dissemination, and, most often, retrograde lymphatic spread, distal to involved lymph nodes. We report the case of a patient with refractory Hodgkin's disease who presented with skin involvement.

Prevention of hepatitis B reactivation with lamivudine in hepatitis B virus carriers with hematologic malignancies treated with chemotherapy--a prospective case series.

Administration of immunosuppressive treatment in hepatitis B virus carriers with malignancies is associated with the risk of hepatitis B reactivation. This complication is more frequent in patients with hematologic malignancies because administration of corticosteroids, the mainstay of treatment of these patients, is an independent risk factor for hepatitis B reactivation. When lamivudine is given prior to chemotherapy, it prevents the viral replication during the immunosuppression period; therefore, it might reduce the risk of hepatitis B exacerbation. We performed a prospective study to assess the efficacy of prophylactic administration of lamivudine in this setting. Ten hepatitis B virus carriers with hematologic malignancies were included in this study; seven were HBsAg positive, and three had isolated antiHBc and detectable HBV-DNA levels. Nine patients were given corticosteroids after the administration of lamivudine. Lamivudine was given per os at a dose of 100 mg once daily. In four patients that had not been previously treated with chemotherapy, lamivudine was started 19 days (median) (range, 0-35 days) prior to the onset of chemotherapy. The administration of lamivudine has not stopped since in any of our patients. After a median follow-up of 15 months (range 6-38 months), no hepatitis B reactivation was observed. HBV-DNA levels were decreased in all 6 patients who had detectable HBV-DNA at baseline. Lamivudine was well tolerated. Chemotherapy regimens were administered as planned, and their effectiveness was not compromised by lamivudine. In conclusion, prophylactic administration of lamivudine should be considered as a means of reducing the frequency of hepatitis B reactivation in hepatitis B virus carriers with hematologic malignancies who are being treated with chemotherapy.

Elevated levels of serum vascular endothelial growth factor in patients with polycythaemia vera.

Angiogenesis seems to be a prominent event of myeloproliferative diseases. There are few reported data on angiogenesis and the significance of its stimulator, the vascular endothelial growth factor (VEGF), in polycythaemia vera (PV). We report our observation of elevated serum VEGF levels in patients suffering from PV. Twenty patients with PV and 20 age-matched healthy subjects were enrolled. VEGF levels were measured by a quantitative sandwich enzyme immunoassay. Serum VEGF levels in PV were found to be very significantly higher than in healthy individuals (569.7 +/- 101.2 vs. 164.7 +/- 32.8 pg/ml, p = 0.001). We found no correlation between VEGF and haemoglobin, platelet or leucocyte counts in the patient group. Different therapeutic regimens had no influence on VEGF levels. However, in the control group, we observed a positive correlation between VEGF levels and platelet counts (r = 0.52, p = 0.02). Platelet counts did not differ between patients and healthy subjects. We also evaluated platelet-poor plasma VEGF levels in 10 patients and in all healthy individuals. We found very low levels of VEGF, approximately zero in most cases, in both groups and there was obviously no difference between the two groups. Our results indicate that VEGF is overproduced in PV. However, follow-up studies are needed to verify the role of this factor.