Analysis of fibrinogen concentrate pharmacokinetics and dosing for bleeds and surgery in adults, adolescents, and children with congenital afibrinogenaemia and hypofibrinogenaemia.

INTRODUCTION: Congenital afibrinogenaemia and hypofibrinogenaemia are rare coagulation disorders where clotting is impaired due to a lack of fibrinogen. Consequent bleeding episodes (BEs) are treated using human fibrinogen concentrate (HFC). AIM: This post-hoc analysis compared HFC pharmacokinetics (PK) and dosing between patient age groups and defined the in vivo recovery (IVR) for children with a- and hypofibrinogenaemia. METHODS: The analysis used data from the FORMA-01 (Phase 2), FORMA-02 and FORMA-04 (Phase 3) multinational, prospective, open-label studies in patients with a- and hypofibrinogenaemia. HFC PK in adults/adolescents (≥12 years; FORMA-01) and children (<12 years; FORMA-04) was examined. Haemostatic efficacy in BE treatment and perioperative prophylaxis was examined in FORMA-02 and FORMA-04 using an objective 4-point scale, with success defined as excellent/good. RESULTS: Median (range) age was 23 years for FORMA-01 (12-53; n = 22), 26.5 years for FORMA-02 (12-54; n = 25), and 6 years for FORMA-04 (1-10; n = 13). Mean PK parameters were lower for children (AUC, Cmax , IVR; p = .02), while clearance was higher. Median (range) total dose of HFC for all BEs was 59.41 mg/kg (32.12-273.80) in adults/adolescents and was 24% higher (ns) in children at 73.91 mg/kg (47.45-262.50). Treatment was successful in 98.9% of the 89 BEs in adults/adolescents and in 100% of the 10 BEs in children, with comparable results for perioperative prophylaxis. CONCLUSION: As expected, HFC PK differed between adults/adolescents and children. However, with the higher doses given to children, HFC showed similar efficacy across age groups. Dose adaptation based on age groups appears recommendable.

Comparative Effectiveness of Peg-Asparaginase and L-Asparaginase on Coagulation Markers Among Pediatric Patients with Acute Lymphoblastic Leukemia.

BACKGROUND: Asparaginase (ASP), a chemotherapy component in the acute lymphoblastic leukemia (ALL) treatment, could impair normal coagulation state. Usually, a decline in the levels of several coagulation factors occurs which ultimately could lead to thrombotic events and abnormal coagulation tests. In this study, we aimed to compare the effects of two different subtypes of ASP, pegylated asparaginase (PEG-ASP) and L-asparaginase (L-ASP) on coagulation markers and test among 40 pediatric patients with ALL. METHODS: In this cohort study a total of 40 pediatric patients with newly diagnosed ALL were enrolled and divided into two groups by simple randomization. In group A, 20 patients received PEG-ASP while in group B, 20 patients received L-ASP during the induction treatment. Coagulation markers included prothrombin time (PT), partial thrombin time (PTT), protein-C (Pr-C), protein-S (Pr-S), and antithrombin III (ATIII) and were assessed before start and after of induction chemotherapy. RESULTS: Coagulation profile including PT, PTT, INR, Pr-C, Pr-S, and ATIII before start of treatment were not statistically significant between the two groups. Anticoagulant factors decreased significantly after consuming both drugs. Tests for PT and INR of those who took L-ASP decreased significantly. Overall, when comparing the changes of the six studied factors, ATIII and Pr-C were the significant factors which were different between groups. CONCLUSIONS: ASP has a negative effect on anticoagulant factors including (ATIII, Pr-C, Pr-S). Additionally, the negative effect of L-ASP on anticoagulant factors was more prominent than PEG-ASP. Therefore, the risk of thrombosis probably was negligible in PEG-ASP in comparison with L-ASP.

Study of the Serum Immunoglobulin and Cell-Mediated Immunity in Patients with Congenital Severe Hemophilia.

BACKGROUND: It has been shown that a close relationship exists between the immune system and coagulation cascade. Hemophilia A is an X-linked, recessive bleeding disorder caused by deficiency of functional plasma clotting factor VIII that is classically treated with factor VIII replacement therapy. Despite this, some patients produce inhibitors or antibodies against epitopes of infused factor VIII, indicating the activation of the adaptive immune system. The aim of this study was to evaluate the change in the T cell frequency and serum immunoglobulin level in patients with congenital hemophilia A, especially those who produce inhibitors against factor VIII. METHODS: This is a cross-sectional, case-control study on congenital hemophilia A patients with severe factor VIII deficiency. Twenty-eight hemophilia A male patients were randomly selected along with twenty age-matched healthy males, as the control group. Serum immunoglobulin concentration was measured by nephelometry (for IgG, IgA and IgM) and enzyme-linked immunosorbent assay (ELISA) (for IgE) and the frequency of CD4+ and CD8+ T cells were calculated using a flow cytometry method. RESULTS: Serum IgG was significantly higher in hemophilic patients compared to controls (14.35 ± 3.60, vs. 12.4 ± 1.72, p = 0.014). Among IgG subtypes, the IgG1 antibody was significantly higher in hemophilia patients than control group (p < 0.001). The frequency of CD4+ as well as CD8+ T cells did not significantly differ between patients and control group (p > 0.05). There was no significant difference between patients with and without inhibitors re-garding serum immunoglobulin level, different IgG subtypes, the frequency of CD4+ and CD8+ T cells as well as CD4/CD8 ratio (p > 0.05). CONCLUSIONS: Patients with hemophilia A have high levels of serum immunoglobulin especially IgG1. Therefore, further larger studies along with close observation and evaluation of the presence of serum inhibitor is recommended every 3 months.

The Zinc and Copper Levels in Thalassemia Major Patients, Receiving Iron Chelation Therapy.

Essential trace elements deficiency including zinc and copper are frequently reported in the literature, but the results are controversial. The aim of this study was to evaluate zinc and copper levels in thalassemia major (TM) patients who were on regular transfusion and iron chelation therapy. In a case-control cross-sectional study 43 TM patients and 43 age-matched and sex-matched healthy controls were examined. Patients were selected by convenience sampling method from TM patients who were registered in Thalassemia Clinic during 6 months. Serum zinc and copper levels were evaluated in all subjects. Zinc and copper dietary intake were also assessed. The median zinc level in the participants was significantly lower than the control group (35 [6.3 to 298] vs. 173 [3.1 to 584] µg/dL; P<0.05), but the mean copper level was significantly higher in the patients in comparison with the control group (260±118 vs. 201±69 µg/dL; P<0.05). In contrast, the mean zinc and copper dietary intake in the patient's group were significantly lower than the control group. The mean serum zinc and copper levels in the patient's group were not different according to iron chelation therapy type. Also, zinc and copper levels in the patient's group were not statistically significant based on ferritin level, age, and duration of therapy. Essential trace elements level change and deficiency might occur in TM patients. Hence, routine assessment of these elements is recommended for better management.

A randomised controlled trial of oral zinc sulphate for primary dysmenorrhoea in adolescent females.

BACKGROUND: Primary dysmenorrhoea, the most common gynaecologic problem of adolescent females, is commonly treated with nonsteroidal anti-inflammatory drugs or oral contraceptive pills. AIM: To compare the effect of zinc sulphate with that of placebo on the control of pain severity and duration in adolescent girls with primary dysmenorrhoea. MATERIALS AND METHODS: In a three-month randomised double-blind placebo-controlled clinical trial, 120 adolescent females with primary dysmenorrhoea were randomly divided into two groups of sixty: an intervention group (zinc) and a control group (placebo). Zinc was administered in the form of a capsule containing 50 mg/day zinc sulphate beginning on the first day of menses and continuing until three days prior to the end of menses. Each month, the duration and severity of primary dysmenorrhoea were determined. Severity scoring was performed by using a 0-10 scaling system. RESULTS: In the first month, the duration of pain was significantly lower in the zinc group compared with the placebo group (P-value = 0.044), while there was no significant difference in pain severity between the groups (P-value = 0.497). In the second and third month, pain severity and duration in the zinc group were significantly lower than the placebo group (P-value <0.001). CONCLUSION: Both pain duration and pain severity were decreased by taking oral zinc. The results of our interventional study suggests that zinc may be used to treat primary dysmenorrhoea in adolescents.

Comparison of thrombin generation assay with conventional coagulation tests in evaluation of bleeding risk in patients with rare bleeding disorders.

Based on the premise that the capacity of plasma to generate thrombin in vitro is a comprehensive and precise functional test of the clotting system, we designed a cross-sectional, single-center study involving 83 patients with rare bleeding disorders (RBDs) to compare the usefulness of the thrombin generation (TG) assay versus conventional tests including prothrombin time (PT) and activated partial thromboplastin time (aPTT) in predicting bleeding risk in patients with RBD in southern Iran. The TG parameters consisted of endogenous thrombin potential, lag time, peak, time to peak (ttPeak), and start tail. The area under the receiver-operating characteristic (ROC) curve showed statistically significant associations between bleeding risk and lag time, ttPeak, and start tail. We determined cutoff values for these 3 TG parameters and obtained a negative predictive value of 86% to 90% in patients with RBD who had a bleeding score (BS) ≤13. The ROC curves for the association of PT and aPTT with BS did not indicate any significant association. Correlation analysis supported the results of ROC curve analysis, only lag time, ttPeak, and start tail showed significant positive correlations with BS (P < .05). Disease severity based on plasma factor activity was significantly associated with prolonged lag time and ttPeak and with prolonged PT (P <.05). We suggest that TG assay is a potentially more useful tool for predicting the bleeding risk in patients with RBD. However, the small sample size in different RBD subgroups precluded subgroup analysis. Prospective multicenter studies with larger numbers of patients are therefore advisable.

Serological investigation for hepatitis E virus infection in the patients with chronic maintenance hemodialysis from southwest of Iran.

BACKGROUND AND OBJECTIVES: A global distribution has been shown for hepatitis E virus (HEV) infection. Although the fecal-oral was considered as the primary infection route, there is controversial evidence for increased risk of the infection and consequent problems in patients on maintenance hemodialysis (HD) with suppressed immunity. The aim is to find if the prevalence of anti-HEV IgG, in patients with maintenance HD is higher than normal population in southwest of Iran. MATERIALS AND METHODS: During November and December 2010, in a cross-sectional study we compared the seroprevalence of HEV among 80 patients with maintenance HD and 276 healthy individuals from Jahrom and Shiraz, Southwest of Iran. In addition to the clinical and laboratory records, serum samples were tested for the presence of IgG anti-HEV antibody by enzyme immunoassay (ELISA) test. The Chi-square, the Student's 't' and Fisher's exact tests were used for the statistical analysis. RESULTS: ELISA tests detected anti-HEV antibody in five males of the patients (6.3%) and in eight of the healthy controls (2.9%, 6 males and 2 female) which statistically were not different. The mean levels of the aspartate aminotransferase and the alanine aminotransferase in the sera of the patients were 19.96±11.08U/L and 23.93±14.26 IU/L, respectively. However, no one of the individuals with positive anti-HEV antibody showed elevated liver enzymes. Moreover, there was not a significant association between positive anti-HEV antibody result, age and the history of the hemodialysis. CONCLUSIONS: We did not observe statistically significant higher anti-HEV prevalence among patients with chronic HD; however, more safety precaution is needed to keep HD patients from the risk of possible exposure to HEV infection.

Comparative study of hypogonadism in beta-thalassemia intermedia patients with and without hydroxyurea.

BACKGROUND: We aimed at evaluating the effect of long-term use of hydroxyurea (HU) on gonad function in patients with beta-thalassemia intermedia (beta-TI) in Iran. METHODS: Seventy-five beta-TI patients aged ≥11 years, mean serum ferritin level of <1000 ng/dL in the recent 5 years, and taking HU with a dose of 8-15 mg per kg body weight per day for at least 5 years were randomly selected during 2010 in southern Iran. Thirty-one beta-TI patients without HU were considered as a control group. Serum levels of prolactin, luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol were measured. An expert endocrinologist examined all participants and reviewed their hormonal profile. RESULTS: The mean age of the participants was 22.7 ± 5.1 years (age range of 12-41 years). Overall, 10 patients with hypogonadotropic hypogonadism were detected including seven patients (9.3%) with HU and three patients (9.7%) without HU. The difference between the two groups was not statistically significant (P = 0.605). CONCLUSION: It appears that long-term use of HU at a dose of 8-15 mg per kg body weight per day has no effect on gonad function in beta-TI patients. However, further prospective studies and large clinical trials are needed to confirm this subject.

Clinical response of patients with sickle cell anemia to cromolyn sodium nasal spray.

Sickle cell anemia is the most common heritable hematological disease affecting humans. Although hydroxyurea is the most commonly used antisickling agent, several previous studies suggest that cromolyn sodium also prevents sickling when administered acutely. However, no previous studies have evaluated the safety or efficacy of prolonged administration of cromolyn to patients with sickle cell anemia. The purpose of this study, therefore, was to test the hypothesis that prolonged administration of cromolyn alone or in combination with hydroxyurea would decrease the incidence of pain crises and/or alter the chronic pain seen in patients with this disease. In this crossover, single-blind, in vivo and in vitro study, 17 patients with sickle cell disease were studied. Each patient had to fill out a standard pain chart. Every 3 months the patients' medications changed in the following manner: The first 3 months the patients used cromolyn sodium nasal spray; the second 3 months they received placebo nasal spray; the third 3 months they received cromolyn sodium nasal spray and hydroxyurea capsule; and the last 3 months they received hydroxyurea capsule and placebo nasal spray. The least pain was felt with the mixture of hydroxyurea capsule and cromolyn sodium nasal inhaler. Furthermore, with the other combinations of medications, there were no significant statistical changes in the number of sickled red blood cells. Every combination used in this survey had positive effects on decreasing the pain. cromolyn sodium nasal spray is significantly efficient in decreasing sickle cell crisis as well as pain intensity in patients with sickle cell anemia.