Factor XI deficiency: About 20 cases and literature review.

INTRODUCTION: Factor XI deficiency is a rare coagulation disorder with variable bleeding manifestations. AIM: To evaluate the correlation between the degree of factorXI deficiency and the clinical expression of the disease. METHODS: Retrospective study, spanning 10 years from January 1, 2010 to December 31, 2019, concerning patients followed at the Hemophilia Center at Aziza Othmana Hospital in Tunis. The data were collected from the medical records. The determination of PT, APTT, fibrinogen level and coagulation factors are performed by coagulometric technique on STA® compact / ACL TOP®. FactorXI deficiency was confirmed on two different samples. Statistical analysis of the clinical-biological correlation was performed using the chi-square test. The significance level was 0.05. RESULTS: Twenty patients were collected. The mean age of discovery was 25 years with a sex ratio (M/F) =0.33. The circumstances of discovery were incidental in 14 patients. A family history of bleeding was reported in 30% of cases. Eight patients underwent surgery, six of whom had a simple postoperative course. The APTT was prolonged and isolated in 75% of cases. The hemostasis test was normal in 5 cases. The average FactorXI level was 24%. The tendency to bleed did not seem to be correlated with FactorXI levels. CONCLUSION: Prospective multicenter studies including molecular study would be necessary to better elucidate this rare disorder.

[Tunisian National Protocol for Adult Hodgkin's Lymphoma Treatment: Results of a therapeutic regimen adapted to the 2-cycle CT response, about 444 patients]. / Protocole national Tunisien prospectif de traitement du Lymphome de Hodgkin de l'adulte : résultats d'un schéma thérapeutique adapté à la réponse par tomodensitométrie à 2 cycles, à propos de 444 patients.

OBJECTIVE: In Tunisia, the management of Adult Hodgkin's Lymphoma (HL) has been standardized since 1999. We propose in this study to report the therapeutic results of the national protocol of adult HL treatment (MDH2008). PATIENTS AND METHODS: Our study is prospective multicenter interesting 444 patients followed for HL between July 2008 and June 2013 and treated according to the MDH2008 protocol. The median age of our patients was 30 years. B symptoms were present in 62.8 % of our patients. According to the Ann Arbor classification, our patients were in stages I, II, III and IV in 3 %, 42 %, 26 % and 29 %, respectively. The MDH2008 protocol is based on a strategy adapted to the therapeutic response to 2 cycles of chemotherapy. RESULTS: Response≥75 % to 2 courses of chemotherapy was achieved in 43 % of patients and the response rate at the end of treatment was 92.1 %. Forty-eight patients (11.4 %) had primary failure. In the multi-variant study, bulky mediastinal mass (IMT≥0.35) was an independent predictive factor of primary failure (P: 0.000). Nineteen toxic deaths (4.35 %) were reported. The relapse rate was 7.8 %. Event free survival, relapse-free survival and overall survival at 5years were 75 %, 89 % and 90 %, respectively. Adaptation of the treatment to the 2 cycles response was effective in unfavorable early stages and advanced stages. CONCLUSION: Compared to MDH2002 (second version of Tunisian prospective protocol), the MDH2008 reduced the primary failure rate, the rate of toxic deaths with escalated BEACOPP and the rate of relapse in Tunisian patients.

Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study.

MABLE investigated the efficacy and safety of rituximab plus bendamustine or rituximab plus chlorambucil in fludarabine-ineligible patients with chronic lymphocytic leukemia. Patients received rituximab plus bendamustine or rituximab plus chlorambucil every four weeks for six cycles. Rituximab plus chlorambucil-treated patients without a complete response after Cycle 6 received chlorambucil monotherapy for at least six additional cycles or until complete response. The primary endpoint was complete response rate (confirmed by bone marrow biopsy) after Cycle 6 in first-line patients. Secondary endpoints included progression-free survival, overall survival, minimal residual disease, and safety. Overall, 357 patients were randomized (rituximab plus bendamustine, n=178; rituximab plus chlorambucil, n=179; intent-to-treat population), including 241 first-line patients (n=121 and n=120, respectively); 355 patients received treatment (n=177 and n=178, respectively; safety population). In first-line patients, complete response rate after Cycle 6 (rituximab plus bendamustine, 24%; rituximab plus chlorambucil, 9%; P=0.002) and median progression-free survival (rituximab plus bendamustine, 40 months; rituximab plus chlorambucil, 30 months; P=0.003) were higher with rituximab plus bendamustine than rituximab plus chlorambucil. Overall response rate and overall survival were not different. In first-line patients with a complete response, minimal residual disease-negativity was higher with rituximab plus bendamustine than rituximab plus chlorambucil (66% vs 36%). Overall adverse event incidence was similar (rituximab plus bendamustine, 98%; rituximab plus chlorambucil, 97%). Rituximab plus bendamustine may be a valuable first-line option for fludarabine-ineligible patients with chronic lymphocytic leukemia.

Chronic myeloid leukemia patients in Tunisia: epidemiology and outcome in the imatinib era (a multicentric experience).

Data are limited in developing countries regarding the clinicopathologic features and response to therapy of chronic myeloid leukemia (CML) in the era of imatinib (IM). The objective of this study is to report on the clinicoepidemiologic features of CML in Tunisia, to evaluate the long-term outcome of patients in chronic (CP) or accelerated phase (AP) treated with IM 400 mg daily as frontline therapy, and to determine imatinib's efficacy and safety. From October 2002 to December 2014, 410 CML patients were treated with IM in six Tunisian departments of hematology. Response (hematologic, cytogenetic, and molecular responses) and outcome-overall survival (OS), event-free survival (EFS), and progression-free survival (PFS)-were evaluated. The following prognostic factors were analyzed for their impact on the European leukemia net (ELN) response, OS, EFS, and PFS at 5 years: age, sex, leukocyte count, Sokal score, European Treatment and Outcome Study (EUTOS) score, CML phase, time to starting IM, and impact of adverse events. The median age was 45 years (3-85 years). Two hundred ten (51.2%) patients were male. Splenomegaly was present in 322 of the 410 (79%). Additional cytogenetic abnormalities were encountered in 25 (6.3%) patients. At diagnosis, 379 (92.4%) patients were in CP, 31 (7.6%) were in AP. The Sokal risk was low in 87 (22.5%), intermediate in 138 (35.7%), and high in 164 patients (41.9%). The EUTOS risk was low in 217 (74%), and high in 77 (26%) patients. The rates of cumulative complete cytogenetic response (CCyR), major molecular response (MMR), and molecular response 4/5 log (MR4.5) in CP/AP-CML patients were 72, 68.4, and 46.4%, respectively. The median time to reach CCyR, MMR, and MR4.5 was 6 months (3-51), 18 months (3-72), and 24 months (3-100), respectively. According to the ELN criteria, optimal, suboptimal response, and failure were noted in 206 (51.8%), 61 (15.3%), and 125 (31.4%) patients, respectively. Five-year event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) were 81, 90, and 90%, respectively. By multivariate analysis, AP, high EUTOS risk, and baseline WBC ≥ 150G/l remained independent predictive factors of non-optimal response to IM. The adverse events (AE) of IM were moderate and tolerable. With the caveats that the monitoring of the disease was not optimal, response rates were similar to those reported in previous studies. It is clear to us that improvements should be made in treatment of AP-CML and high Sokal risk group of CP-CML. The frontline use of second-generation tyrosine kinase inhibitor (TKI) is expected to improve the results of the first-line treatment of these high-risk Tunisian patients, but cost and accessibility of this therapy remain the problems in developing countries.

The Glanzmann's Thrombasthenia in Tunisia: A Cohort Study.

BACKGROUND: The Glanzmann's thrombasthenia (GT) is a rare autosomal-recessive bleeding disorder with uncommon neonatal revelation. It is due to abnormalities of quantitative and/or qualitative αIIbß3 integrin. This cell adhesion receptor is essential for platelet aggregation and allows the formation of a hemostatic plug if the vessel is damaged by injury. The clinical picture of GT is variable, with mucocutaneous bleeding due to non-functional platelets. Management requires a good expertise in bleeding disorders. We describe the clinical and the epidemiological data of GT in Aziza Othmana Hospital Hemophilia Center. METHODS: This was a retrospective study of all patients with GT monitored and treated in our hemophilia center during the period of 2011 - 2015. RESULTS: Twenty-seven patients among the 35 patients included in our hemophilia center registry were studied. The most common sign encountered is the gingival bleeding. In our women cohort, one completed her pregnancy. The consanguinity is present with a frequency of 62%. Treatments used depending on the case are tranexamic acid, platelet transfusion, packed red blood cells and rFVIIa, respectively. CONCLUSION: GT is relatively frequent in Tunisia and especially in the North of the country which can be explained by the high consanguinity in our population.

Tunisian adult's Hodgkin lymphoma Study Group.

The Tunisian adult's Hodgkin lymphoma (HL) Study Group was created in 1999. It aimed to improve the management of this curable hematologic malignancy by standardizing the diagnosis, assessment of disease, treatment management and therapeutic evaluation in different Tunisian centers (Hematology, oncology and radiotherapy).Since 1998, four versions of the prospective national protocol for treating adult Hodgkin lymphoma have succeeded (MDH99, MDH2002, MDH2008, MDH2015). Each version was based on the results of the previous version and analyzed according to new data from the literature. Due to this national study group, the number of patients lost to follow decreased significantly (30% before the creation of the group and only 3% for patients treated with MDH2008), the complete and uncertain response rates have improved (75% before the creation of the group and 92% in patients treated with MDH2008) with dramatically improved rates of overall survival from 57% to 90%. On the other hand there was an improvement of toxic death rate (13% of toxic deaths in MDH2002 to 4.37% in the MDH2008) with a decrease of the respective rate of primary failure and relapse by 17% and 12.5% in MDH2002 against the 11.4% and 7.8% in the MDH2008. This resulted in an improvement in overall survival (90%) and event-free survival at 5 years (75%). Now with the introduction of positron emission tomography in Tunisia, we hope yet to finalize the assessment of response and thus better adapt the treatment of this disease. Our objective remains the improvement of event-free survival rate to reach 80%.

[Impact of early lymphopenia on the risk of febrile neutropenia and hematological toxicity]. / Impact de la lymphopénie précoce sur la survenue de neutropenia fébrile et de toxicité hématologique.

BACKGROUND: Hematologic toxicity is a severe complication of chemotherapy. The objective of our study is to evaluate the impact of early lymphopenia on the risk of occurrence of febrile neutropenia and hematological toxicity after aggressive chemotherapy for Hodgkin lymphoma or high grade non-Hodgkin lymphoma. METHODS: This prospective study involved 42 patients who received 193 cycles of chemotherapy in 2009. We assessed the impact of lymphopenia on day 1 and 8 on the risk of occurrence of febrile neutropenia. We also investigated the relation between the occurrence of hematologic toxicity after the first cycle and the subsequent cycles. RESULTS: Febrile neutropenia was observed in 25% of cycles. Grade 3/4 hematologic toxicity occurred in 63% of cycles. Growth factors were used in 79% of cycles. Lymphopenia ≤ 700/mm3 on day1 and 8 was noted in 21% and 65% of cycles. If the lymphocyte count was ≤700/mm3 on day1, the risk of febrile neutropenia was significantly higher (p=0.042) and the mean duration of antibiotic therapy longer (p = 0.013). Lymphopenia ≤700/mm3 on day 8 was associated with a greater risk of febrile neutropenia in univariate analysis (OR=2.4; p=0.02). Moreover analyzes showed that this factor was significantly associated with increase in hematologic toxicity (p=0.02), duration of neutropenia (p=0.001) and duration of antibiotics (p=0.05). Hematologic toxicity during the first cycle was predictive of its occurrence in subsequent cycles of chemotherapy (p=0.028). CONCLUSION: Our results confirmed the impact of early lymphopenia on the occurrence of febrile neutropenia and hematologic toxicity after aggressive chemotherapy for Hodgkin lymphoma or high grade non Hodgkin lymphoma.

Monocentric study of Willebrand's disease in Tunisia: assets and difficulties.

BACKGROUND: Von Willebrand's disease (VWD) is the most commonly inherited bleeding disorder. It is characterized by clinical, biological and molecular heterogeneity. In certain types of the disease, diagnosis can be difficult. AIM: We report the clinico-biological characteristics of VWD's patients and analyze diagnosis difficulties. METHODS: 33 cases were diagnosed in the laboratoryfrom February to May, 2011. Screening hemostasis included the measuring of FVIII: C, VWF: Ag and VWF: RCo. Blood cell count and blood group were performed in all cases. RESULTS: Mean age at diagnosis is 13 years [10 months -43 years]. The sex ratio M/F is 0.5. The patients are classified type 3 VWD in 52% of the cases, type 2 VWD in 30 % of the cases and type 1 VWD in 18 % of the cases. The diagnosis of type 2B VWD suspected in combination of the ratio VWF:RCo / VWF: Ag <0,7 and thrombocytopenia in one case. Required tests for positive diagnosis and distinction between the primary categories of VWD are available. Specialized tests will allow a best characterization variants type 2 VWD for a better therapeutic approach.

Primary adrenal lymphoma.

Primary non-Hodgkin's lymphoma of the adrenal gland is rare. We report the case of a 56-year-old patient suffering from B symptoms. The CT scan showed a bilateral adrenal mass without any lymph nodes. Scan-guided biopsies led to the diagnosis of diffuse large B-cell lymphoma. The medullar biopsy eliminated a secondary lymphoma. The patient was treated by immunochemotherapy with a complete response before autologous stem cell transplantation.

[Accidental shortening time of high dose methotrexate infusion: case report and literature review]. / Raccourcissement accidentel du temps de perfusion de méthotrexate à haute dose : cas clinique et revue de la littérature.

Methotrexate (MTX) is a folic acid antagonist used at high-dose intravenously on 24 hours (24h) in the treatment of the acute lymphoblastic leukemia (ALL). To prevent potential toxicity, MTX is usually administered following the application of preventive measures. We report a case of an accidental shortening time for high dose MTX infusion and a literature review of accidental intoxications by the MTX. This case illustrates the importance of the respect of MTX high dose infusion time and the major role played by the therapeutic drug monitoring.

[Quality of life during menstruation in women with an inherited bleeding disorder: report of 31 cases]. / Qualité de vie pendant les menstruations chez les patientes portueses d'un troble héréditaire de l'hémostase: a propos de 31 patientes.

BACKGROUND: Menstruations, by their abundance and their duration, can be a source of impaired quality of life. Women with inherited bleeding disorders appear to be, specially at risk. AIM: Assess the impact of menstrual blood loss on the quality of life for women with inherited bleeding disorders. METHODS: 31 women with various inherited bleeding disorders were interviewed. They completed a quality of life questionnaire. RESULTS: Von Willebrand disease was the most frequent inherited bleeding disorder in our population (38.7%). 54.8% of patients had a menstrual period more than 6 days 61.3% of them consider their menstrual flow to be normal. The general condition apart of the menstrual period was considered medium to poor in 35.5% of patients. The average score assessing the impact of menstruation on daily life was of 5.00 ± 3.47. Only 19.35% of patients felt that dysmenorrhea significantly affect their quality of life. Impaired quality of life was seen in 64.5% of patients according to score Aand in 41.9% of them according to score B. During menstruation 22.6% of the patients didn't do to work or to school because of the menstrual flow. On the other hand, 48.4% of patients were hospitalized at least once for a heavy menstrual flow. CONCLUSION: The quality of life during menstruation, in women with an inherited bleeding disorder, according to the different scores appear altered. Although because of the small size of our study population, we could not prove correlation between the importance of menstrual blood loss and the impairment of quality of life.

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

INTRODUCTION: Hemophilia 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. AIM: In this study we have performed molecular analysis of 28 Tunisian hemophilia A patients and analyzed the F8 mutation spectrum. METHODS: We 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. RESULTS: We 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. CONCLUSION: The mutation spectrum of Tunisian hemophilia A patients is heterogeneous with the presence of some characteristic features. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/1693269827490715.

Identification of genetic defects underlying FVII deficiency in 10 patients belonging to eight unrelated families of the North provinces from Tunisia.

Inherited factor VII (FVII) deficiency is a rare disorder characterized by a bleeding phenotype varying from mild to severe. To date, more than 200 mutations have been described along the F7 gene encoding for FVII. The aim of this study was the identification of genetic defects underlying FVII deficiency in 10 patients belonging to eight unrelated families of the North provinces from Tunisia. Mutation detection was performed by sequencing the whole F7 gene coding region, exon-intron boundaries and about 400 bp of the promoter region. We identified 5 mutations in five unrelated families; the novel p.F328Y mutation and the reported mutations: p.R304Q, p.M298I, IVS1aG > A and p.G-39G. For the remaining 5 patients we didn't identified any mutations using PCR/Sequencing protocol. In conclusion, this study represents the first comprehensive molecular series of FVII deficiency affected patients in Tunisia from the North. We will try in the future to continue the molecular study for Tunisian patients from Center and South provinces in order to have a complete idea about the FVII deficiency mutational profile in our country. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1288044089753085.

Molecular cytogenetic study of derivative chromosome 9 deletion in chronic myeloid leukemia patients.

The aims of this study are to investigate the frequency of derivative chromosome 9 (der (9)) deletion in Tunisian patients with chronic myeloid leukemia (CML) and to assess the correlation between this deletion and the cytogenetic response for patients treated with hydroxyurea (HU) or imatinib (IM). Karyotype analysis of 336 patients with CML was performed with R-banding technique. Fluorescence in situ hybridization (FISH) was carried using home-brew probes 17L7 and 248J22 for detecting, respectively, adjacent 5'ABL and 3'BCR deletions on der(9). Cytogenetic study demonstrated typical t(9;22)(q34;q11) translocation in 89.6% and variant translocation in 10.4% of patients. Interphase FISH studies showed deletion of der(9) in 59 (17.6%) of the 336 patients, 23 (39%) of them had variant rearrangements. There are 19 patients with solely 5'ABL deletion and 40 with concomitant 5'ABL and 3'BCR deletions. Cytogenetic response was evaluated during 18 months with HU or IM therapy. Our results demonstrate that (a) 3'BCR deletion is associated with 5'ABL deletion in all patients with der(9) deletions, (b) the 5'ABL and 3'BCR deletions arise simultaneously with t(9;22), (c) deletions on der(9) chromosome were frequently encountered in older patients and in patients presenting variant rearrangements, (d) both 5'ABL and 3'BCR deletions were associated with cytogenetic response failure in patients treated with HU, however, patients treated with IM and carrying der(9) deletions presented better cytogenetic response.

Treatment of Acute Promyelocytic Leukemia with AIDA Based Regimen. Update of a Tunisian Single Center Study.

In Tunisia, the ATRA era began in 1998 with the use, consecutively, of two regimens combining ATRA and an anthracycline with cytarabine (APL93), and without cytarabine (LPA99). From 2004, 51 patients with confirmed APL either by t(15;17) or PML/RARA were treated according to the PETHEMA LPA 99 trial. Forty three patients achieved CR (86%). The remaining seven patients had early death (one died before treatment onset): four caused by differentiation syndrome (DS) and three died from central nervous system hemorrhage. Multivariate analysis revealed that female gender (P=0.045), baseline WBC> 10 G/L (P=0.041) and serum creatinine > 1.4mg/dl (P=0.021) were predictive of mortality during induction. DS was observed in 16 patients (32%) after a median onset time of 15 days from treatment onset (range, 2-29). Body mass index ≥ 30 (P=0.01) remained independent predictor of DS. Occurrence of hypertensive peaks significantly predicted occurrence of DS (P=0.011) and was significantly associated with high BMI (p=0.003). With a median follow-up of 50 months, 5 year cumulative incidence of relapse, event free and overall survival were 4.7%, 74% and 78%, respectively.

Factor VIII haplotypes frequencies in Tunisian hemophiliacs A.

BACKGROUND: The 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 METHODS: 95/116 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 DISCUSSION: In 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 can't identify his haplotype. Theses frequencies may explain partially the low level of inhibitors in our patients.

Risk factors of septic shock in patients with hematologic malignancies and Pseudomonas infections.

Pseudomonas is a clinically significant and opportunist pathogen, usually associated in causing high mortality nosocomial infections. The aim of this study was to determine the risk factors associated with septic shock in patients diagnosed with hematologic malignancies and Pseudomonas infections. A total of 80 Pseudomonas isolates (77 Pseudomonas aeruginosa) were collected from 66 patients aged 2-64 years: 52 with acute leukemia (79%), 7 with lymphoma (10.5%), and 7 with other hematologic disorders (10.5%), between 2001 and 2009. The median age of the patients was 30 years. Isolates were collected mostly from bloodstreams (45%) and skin lesions (31.5%). The median time for microbiologic documentation was 8 days (range 0-35 days) from onset of neutropenia. At least 11 patients (16.6%) had recurrent (≥2) infections. The clinical symptoms observed were skin lesions (34%), diarrhea (20%), isolated fever (18%), and respiratory symptoms (14%). The isolates tested were found resistant to piperacillin/tazobactam (43%), ceftazidime (31%), imipenem-cilastatin (26%), ciprofloxacin (25%), and amikacin (26%). Septic shock occurred in 16.2% of episodes (13/80). Crude mortality due to septic shock occurred in 19.6% of patients (13/66). The median time for response to antibiotic therapy in the remaining 80.4% of patients (53/66) was 2.5 days. Univariate analysis revealed that factors associated with septic shock were: fever for ≥3 days in patients on antibiotic therapy (P = 0.019), serum lactate >5 mmol (P = 0.05), hemoglobin level <50 g/l (P = 0.042), hypoproteinemia <50 g/l (P = 0.01), procalcitonin >10 ng/ml (P = 0.031), and hypophosphatemia (P = 0.001). Multivariate analysis revealed that hypophosphatemia (P = 0.018), hypoproteinemia (P = 0.028), and high serum lactate (P = 0.012) are significant factors, independently associated with increased risk of septic shock in patients with hematologic malignancies and Pseudomonas infections.