Emna Gouider

High body mass index is an independent predictor of differentiation syndrome in patients with acute promyelocytic leukemia

Increased BMI has been correlated to an increased incidence of APL, but not to the occurrence of differentiation syndrome (DS) in APL. We consecutively treated 39 APL patients with ATRA and idarubicin (according to PETHEMA regimen). Median age was 26 years. Forty-one percent patients were classified as intermediate risk, and 59% as high risk according to Sanzs score. Thirty-three patients (85%) reached CR. Eleven of the 36 patients evaluable for DS (30.5%) developed this syndrome (severe in 7 cases, moderate in 4, and fatal in 3 cases) within a median of 12 days (range 3-23) of ATRA onset. Six of the 9 (66.6%) patients with BMI>or=30 developed DS vs. 5 of 27 (18.5%) with BMI<30 (p=0.012). Other predictors of DS in univariate analysis were: age>or=40 year (p=0.033), baseline WBC>or=20 x 10(9)/l (p=0.003), and creatinine>1.4 mg/dl (p=0.009). In multivariate analysis, BMI>or=30 remained an independent predictor of DS in addition to baseline WBC>or=20 x 10(9)/l.

Predictive factors of all-trans-retinoic acid related complications during induction therapy for acute promyelocytic leukemia

Abstract Background: The combination of all-trans-retinoic acid (ATRA) and chemotherapy has made acute promyelocytic leukemia (APL) a highly curable leukemia. However, several complications are reported with this treatment the most serious and life threatening being Retinoic Acid Syndrome (RAS). We aimed at identifying factors that could predict complications caused by ATRA during induction treatment of APL. Patients: Forty-two patients with confirmed APL (by t(15;17) and/or PML/RARA) treated at our institution (University hospital of Tunis) between January 1998 and June 2006 using two consecutive protocols: European APL93 trial (24 patients) until February 2004 and Spanish PETHEMA LPA99 trial (18 patients) more recently. Induction regimen consisted of ATRA 45 mg/m2/d until CR combined to DNR 60 mg/m2/d×3+Cytarabine 200 mg/m2/d×7 (APL93) and Idarubicin 12 mg/m2 d2, 4, 6, 8 (LPA99). Prednisone (0·5 mg/kg d1–d15) was added if WBC >10×109/L to prevent RAS in LPA 99. Results: Median age was 36 yr (7–64 yr), M/F=16/26 (0·61), median WBC was 2·4×109/L (range 0·6–100×109/L). WBC >10×109/L was noted in 14 patients (33%). Additional cytogenetic abnormalities were seen in 12/42 (28%). Median body mass index (BMI=weight/height2:N 20–25) was 24 kg/m2 (range 16–40 kg/m2), BMI >30 was noted in nine patients (8F and 1M). Thirty-three patients achieved CR (78·57%):18/24 (75%) in APL93 versus 15/18 (83%) in LPA99. Nine patients (21·42%) had early death. Causes of early death were: RAS (6) and CNS hemorrhage (3). Complications due to ATRA were: RAS (10), Scrotal ulcerations (3), Sweet syndrome (2), Perineal ulcerations (1), and Pseudotumor cerebri (1). Prognostic factors for complications of ATRA (Fisher exact test) were: BMI >35 (p=0·055), induction treatment without cytarabine (LPA99 trial) (p=0·047), whereas age (p=0·74), gender (p=0·51), initial WBC (p=0·47), and additional cytogenetic abnormalities (p=0·83) were not predictive. Retinoic Acid Syndrome was more reported in patients with initial WBC >10×109/L (p=0·08). Conclusion: We found high BMI (>35) in female and treatment without Cytarabine to increase the risk of developing complications with ATRA.

A first case of congenital TTP on the African continent due to a new homozygous mutation in the catalytic domain of ADAMTS13

Hereditary thrombotic thrombocytopenic purpura (TTP) is a rare disorder characterized by occlusive microvascular thrombosis, consumptive thrombocytopenia, and microangiopathic hemolytic anemia. Homozygous or compound heterozygous mutations in the ADAMTS13 gene result in a congenital severe ADAMTS13 deficiency and subsequent accumulation of ultra-large von Willebrand factor multimers, which tend to form platelet thrombi in the microcirculation. We report a first case of congenital TTP on the African continent with a new, homozygous mutation in the metalloprotease domain of ADAMTS13. An initially oligo-symptomatic presentation was followed by acute exacerbation with ischemic stroke and acute renal failure highlighting the severity of this syndrome.

Seroprevalency of transfusion-transmitted infections in first-time volunteer and replacement donors in Tunisia

BACKGROUNDnReplacement donors are considered as having a major risk of transmission of infections to recipients mainly by the World Health Organisation.nnnSTUDY DESIGN AND METHODSnSeroprevalency of HBV, HCV, HIV and syphilis were determined in 19,783 whole blood donations collected in the Tunisian National Blood Transfusion Centre during the year 2010 (12,968 [65.55%] replacement donations and 6815 [34.44%] voluntary blood donations). For HBV, HCV and syphilis, we performed a univariate analysis to determine whether age, sex and type of donation were risk factors, then multivariate logistic regression, to see if these factors were independent.nnnRESULTSnMean age of donors was 30.1 years (replacement donors 34.5 years, first time non-remunerated donors 34.5 years, P<0.001). The predominant age group was 30-39 years (35.51%) in replacement donors and 20-29 years (54.15%) in first time non-remunerated donors. Male gender was significantly predominant (73.00% men vs 27.00% women, P<10(-6)). There were significantly more men among replacement donors (82.27% vs 55.38%, P<10(-3)). There were more women in the age groups 18-19 and 20-29 years. Only one HIV seropositive donation was noted in a male first time non-remunerated donor aged 18. Replacement type of donation, male sex and age were three independent risk factors for the HBs Ag carriage. For anti-HCV antibodies and TPHA, only replacement type of donation and age were found out to be risk factors and only age was independent.nnnCONCLUSIONnIn Tunisia, replacement blood donors were at higher risk of infection transmission, but only for hepatitis B.

Transfusion-related acute lung injury (TRALI) during remission induction course of acute myeloid leukemia: A possible role for all-transretinoic-acid (ATRA)?

Transfusion-related acute lung injury (TRALI) is a clinical syndrome characterized by sudden onset of respiratory distress due to pulmonary edema during or following transfusion. Two proposed pathophysiologic mechanisms for TRALI were proposed: the antibody hypothesis and the two-event hypothesis. The two-event hypothesis postulates that a pathway to neutrophil activation and aggregation can occur without leukocyte antibodies. We report a case of TRALI occurring during remission induction course of acute myeloid leukemia in a 27-year-old woman who received All-transretinoic-acid (ATRA). We postulate that ATRA may have played a role in this life-threatening complication by priming neutrophil and enhancing their adherence and their activation in the pulmonary endothelium. TRALI improved with non-invasive ventilation support and use of high dose corticosteroids.

First report of molecular diagnosis of Tunisian hemophiliacs A: Identification of 8 novel causative mutations

AbstractIntroductionHemophilia A is an X linked recessive hemorrhagic disorder caused by mutations in the F8 gene that lead to qualitative and/or quantitative deficiencies of coagulation factor VIII (FVIII). Molecular diagnosis of hemophilia A is challenging because of the high number of different causative mutations that are distributed throughout the large F8 gene. Molecular studies of these mutations are essential in order to reinforce our understanding of their pathogenic effect responsible for the disorder.AimIn this study we have performed molecular analysis of 28 Tunisian hemophilia A patients and analyzed the F8 mutation spectrum.MethodsWe screened the presence of intron 22 and intron 1 inversion in severe hemophilia A patients by southern blotting and polymerase chain reaction (PCR). Detection of point mutations was performed by dHPLC/sequencing of the coding F8 gene region. We predict the potential functional consequences of novel missense mutations with bioinformatics approaches and mapping of their spatial positions on the available FVIII 3D structure.ResultsWe identified 23 different mutations in 28 Tunisian hemophilia A patients belonging to 22 unrelated families. The identified mutations included 5 intron 22 inversions, 7 insertions, 4 deletions and 7 substitutions. In total 18 point mutations were identified, of which 9 are located in exon 14, the most mutated exonic sequence in the F8 gene. Among the 23 mutations, 8 are novel and not deposited in the HAMSTeRS database nor described in recently published articles.ConclusionThe mutation spectrum of Tunisian hemophilia A patients is heterogeneous with the presence of some characteristic features.Virtual slidesThe virtual slide(s) for this article can be found here:n http://www.diagnosticpathology.diagnomx.eu/vs/1693269827490715

Factor VIII haplotypes frequencies in Tunisian hemophiliacs A.

BackgroundThe development of inhibitors against factor 8 (F8) is the most serious complication of replacement therapy with F8 in children with severe hemophilia. It was suggested that mismatched F8 replacement therapy may be a risk factor for the development of anti-factor F8 alloantibodies. Recently four single nucleotide polymorphisms (SNPs) encoding six distinct haplotypes, designated H1 through H6, were studied in different populations. Two SNPs are components of the A2 and C2 immunodominant-inhibitor epitopes.The aim of this study is to determine the different types of haplotypes in relation with inhibitors developments and their frequencies in our Tunisian hemophiliac population.Materials and methods95/116 Tunisian patients with hemophilia A undergoing treatment at Hemophilia Treatment Center, Aziza Othmana hospital, participate in this study. Among them only six patients develop inhibitors. The four SNPs were amplified and sequenced.Results and DiscussionIn a total of 77 patients, we identified the H1, H2, H3 and the infrequent H5 haplotypes. The H1 and H2 haplotypes, which have the same amino acid sequence in the recombinant F8 molecules used clinically, are the most represented with the frequency of 0.763 and 0.157 respectively. This distribution is almost similar to that of Caucasians in which the frequencies are respectively 0.926 and 0.074, whereas it is 0.354 and 0.374 among Subsaharians. Four patients with inhibitors studied here have the H1 haplotype. For one patient who has a large deletion including the exon 10 we cant identify his haplotype. Theses frequencies may explain partially the low level of inhibitors in our patients.

Treatment of acute promyelocytic leukemia with PETHEMA LPA 99 protocol: a Tunisian single center experience

Abstract Acute promyelocytic leukemia (APL) has now become the most curable of all subtypes of acute myeloid leukemia. A cure rate of 75–80% can be anticipated with a combination of all-trans retinoic acid (ATRA) and anthracyclines. In Tunisia, the ATRA era began in 1998 with the use, consecutively, of two regimens of a combination of ATRA with anthracycline and cytarabine (APL93), and without cytarabine (LPA99). From 2004, 39 patients with confirmed APL either by t(15;17) or PML/RARA were treated by the PETHEMA LPA 99 trial. The rationale of this protocol by avoiding cytarabine is to reduce death in complete remission (CR) without increasing the incidence of relapse. Thirty-three patients achieved CR (84·6%). The remaining six patients were considered as failure due to early death: three caused by differentiation syndrome (DS) and three died from central nervous system hemorrhage. Baseline blood cell count (WBC) >10 × 109/l (P=0·26) and creatinine >1·4 mg/dl (P=0·42) were not predictive of mortality. DS was observed in 11 patients (30·5%) with a median onset time of 12 days (range: 3–23 days) and median WBC of 29 × 109/L (range: 1·2 × 109–82·7 × 109/l). DS was severe in seven cases, moderate in four, and fatal in three cases. Body mass index ≥30 (P=0·044) and baseline WBC ≥20 × 109/l (P=0·025) are independent predictors of DS. The median follow-up of this study is 36 months. Thirty patients are alive in continuous complete remission; two patients died in CR from septic shock and secondary myelodysplastic syndrome respectively; one patient died 47 months after achieving two relapses. Event free survival from diagnosis was 80% and overall survival was 82%. Our results are quite acceptable and can be improved by reducing mortality rate.

Molecular analysis in two Tunisian families with combined factor V and factor VIII deficiency

Summary.u2002 Combined factor V (FV) and factor VIII (FVIII) deficiency (F5F8D) is a rare autosomal recessive disorder caused by mutations in LMAN1 or MCFD2 genes which encode proteins that form a complex involved in the transport of FV and FVIII from the endoplasmic reticulum to Golgi apparatus. We report two novel mutations in MCFD2 gene and one recurrent mutation in LMAN1 gene that caused combined FV and FVIII deficiency in two unrelated Tunisian Muslim families. For the first family two patients were homozygous for a new missense mutation Asp81His in exon 3 of MCFD2 and heterozygous for a second new missense mutation Val100Asp in the same exon. Replacement respectively of the hydrophilic Asp residue with hydrophobic positively charged His and of the hydrophobic neutral Val residue with the Asp residue most likely disrupts the MCFD2–LMAN1 interaction, thus leading to the disease phenotype. For the second family a reported Arg202X mutation in exon 5 in the LMAN1 gene was identified in the homozygous state.

Small insertion (c.869insC) within F13A gene is dominant in Tunisian patients with inherited FXIII deficiency due to ancient founder effect

such as this. Some other causes of nerve compression in haemophilia should be considered in clinical evaluation, the most important is haemophilic arthropathy. The mechanism was well known and it started from repeated haemarthrosis, which caused synovitis then resulted in further inflammatory response, cartilage destruction, synovial fibrosis and epiphyseal over growth due to hyperaemia. Some surgical interventions can be considered for haemophilic arthropathy, such as joint debridement, alignment osteotomy, arthrodesis, total joint arthroplasty and nerve release. In our case, the X-ray of right elbow was consistent with haemophilic arthropathy, but the nerve compression symptom was not related to it. The case we report has some distinctive aspect for us to the following considerations: 1.This is the first reported case of a haemophilic patient with symptomatic ulnar nerve compression not caused by hematoma, intra-articular haemorrhage or joint contracture, but by lymphoid hyperplasia. 2. Musculoskeletal ultrasound has proved a valuable tool for detecting superficial mass in differentiate hematoma, cyst lesion or lymphoid hyperplasia.