Predicting the risk of recurrent venous thromboembolism: Impact and therapeutic consequences of inherited thrombophilia.

BACKGROUND: Over the past decades, thrombophilia testing in patients with venous thrombo-embolism has increased tremendously. However, the role of inherited thrombophilie in prediction the risk of recurrence remains controversial. Consequently, it is still unclear whether thrombophilia testing influences decisions regarding duration of anticoagulation in clinical practices. The aim of this study was to evaluate the impact if inherited thrombophilia on venous thrombosis treatment decisions and on predicting the risk of recurrence. METHODS: A retrospective longitudinal study (January 2011-Decembre 2016) including 131 patients with confirmed venous thrombo-embolism referred to the hematology laboratory from the internal medicine department for inherited thrombophilia screening was carried out. RESULTS: The mean age patients was 39.4 years and the sex ratio (M/F) was 0.61. Inherited thrombophilia was confirmed in 27.5% of patients. A long term anticoagulation was decided in 46.9% of patients with thrombophilia. There was no significant difference in the duration of anticoagulation between patients with or without thrombophilia. Thrombosis recurrence was recorded in 16 (17%) patients. The 24 years cumulative incidence of recurrence was 19% in patients with thrombophilia and 17% in those without (plog Rank= 0.6). Inherited thrombophilia was not associated with increased risk of recurrence after treatment withdrawal (Hazard ratio=1.31 IC (0.47-3.63); P=0.6). CONCLUSION: In clinical practice, inherited thrombophilia did not influence anticoagulation duration and was not associated with a higher venous thrombosis risk of recurrence. It seems to be less relevant for decision making than presumed.

Disseminated histoplasmosis diagnosed in the bone marrow of an HIV-infected patient: First case imported in Tunisia.

Histoplasmosis is a fungal infection caused by a dimorphic fungus, Histoplasma capsulatum. We report a first case of disseminated histoplasmosis in a 34-year-old woman, infected with human immunodeficiency virus (HIV), originating from Ivory Coast and living in Tunisia for 4 years. She was complaining from fever, chronic diarrhoea and pancytopenia. The Histoplasma capsulatum var. capsulatum was identified by direct microscopic examination of the bone marrow. She was treated by Amphotericin B, relayed by itraconazole. Even though a regression of symptoms and normalization of blood cell count (BCC), the patient died in a respiratory distress related to CMV hypoxemic pneumonia.

The international normalized ratio (INR): What reagent, what instrument? The assessment of the agreement between INR values according to different reagent/instrument combinations.

WHAT IS KNOWN AND OBJECTIVE: The international normalized ratio (INR) is widely used to monitor patients on vitamin K antagonists. This study aimed to assess the agreement of INR values obtained with different thromboplastin/instrument combinations. MATERIAL AND METHODS: International normalized ratio was determined on plasmas from 330 patients undergoing antivitamin K treatment (with acenocoumarol), using two calibration methods and four reagent/instrument combinations: Both Neoplastine CI and Neoplastine CI Plus on STA-R instrument from Diagnostica STAGO, Asnières, France; and both Thromborel S and Innovin on SYSMEX 2100i instrument from Siemens Health Care Diagnostics, Marbung, Germany. The agreement analysis was done using the Bland-Altman plot and the Cohen Kappa coefficient. RESULTS: The mean of the differences between the INR values and the limits of agreement were -0.07 [-0.51 to 0.38] for the Neoplastine CI plus and Neoplastine CI reagents, -0.08 [-1.18 to 1.03] for the Thromborel S and Innovin reagents when the INR was calculated, -0.1 [-1.15 to 0.95] for the Thromborel S and Innovin reagents when the INR was directly calibrated and -0.1 [-0.7 to 0.5] for the Neoplastine CI plus and Thromborel S. Cohen's kappa coefficients were 0.94, 0.76, 0.85 and 0.82, respectively. NEW FINDINGS AND CONCLUSION: The agreement between the four reagent/instrument combinations was high enough to classify patients as inefficaciously or efficaciously anticoagulated. The data interpretation should always be related to the clinical purpose.

The evaluation of the relevance of thrombin generation and procoagulant activity in thrombotic risk assessment in BCR-ABL-negative myeloproliferative neoplasm patients.

INTRODUCTION: It has been recently suggested that microparticles (MP) play a role in the pathogenesis of thrombotic complications. This study aimed to assess the contribution of procoagulant activity expressed by circulating MP in thrombotic events in MPN patients. METHODS: Seventy-four MPN patients were enrolled in a trans-sectional study. The MP procoagulant activity was measured using two assays: (i) the thrombin generation (TG) assay used in different conditions with the addition of both tissue factor (TF) and phospholipids (PL) and with the addition of TF or PL alone and (ii) the PROCOAG-PPL assay. RESULTS: The mean age was 62 (26 men and 48 women). The prevalence of thrombotic events was 28%. When comparing patients with thrombosis to those without, age, sex, MPN type, cardiovascular risk factors, and history of thrombosis were not significantly associated with thrombosis. The JAK2 V617F mutation was significantly associated with thrombotic events (90% vs 67%; P=.04). Results from the TG assay and the PROCOAG-PPL assays did not demonstrate a significant association between the MP procoagulant activity and thrombotic events. CONCLUSION: The MP procoagulant activity did not predict thrombosis in MPN patients. The contribution of TG assay in the assessment of the thrombotic risk is still in debate.

[Hemovigilance: State 2007-2013 Tunis]. / Hémovigilance à Tunis (hôpital La Rabta) : bilan 2007­2013.

INTRODUCTION: Despite its lifesaving role, blood transfusion still has risks associated with it. Hemovigilance is a set of surveillance procedures of the transfusion chain intended to promote safe and effective use of blood components. This work aims to present a descriptive analysis of adverse reactions, which were notified over a period of 5 years (incidence and etiology); to identify malfunctions and to propose corrections. MATERIALS AND METHODS: All transfusion adverse reactions accidents reported to the blood bank of the hospital La Rabta (n=120) are explored (clinical and laboratory tests). RESULTS: The average age of patients with transfusion reaction was 51.2 years (25 days to 89 years). The transfusion accident rates ranged from 0.59 to 2.19 accidents/1000 labile blood products (LBP) distributed. The investigations were used to classify 71 % of accidents in different categories. The most prevalent reaction is the hemolytic reaction, n=24 (19.8 %), followed by allergic reactions, n=21 (17.5 %) and non-hemolytic feverish reaction, n=19 (15.8 %). Transfusion reactions of grade 1 severity were the most frequent (n=94); followed by those of grade 3 severity (n=16), accidents grade 4 (n=4) including two cases of acute pulmonary edema, one case of hyperkalemia, and the last case classified undetermined. CONCLUSION: These data are particularly rich in learning lessons. This study identified several levels failures: under-reporting of certain transfusion accidents, malfunctions at certain stages of the transfusion chain. In order to achieve an accurate statement of each transfusion reaction, it is important to plan in-service training.

[Nerve and deep vein compression by femoral artery pseudoaneurysm in a patient with multiple exostosis]. / Compression nerveuse et veineuse profonde par un faux anévrysme de l'artère fémorale superficielle au cours d'une exostose multiple.

The multiple exostosis is a hereditary bone tumour. Generally, its complications are benign and are related to compressing surrounding structures such as nerves and vessels. This is the case of a 52-year-old woman with a family history of multiple exostosis, which was complicated by a pseudoaneurysm of the right superficial femoral artery. The delay in diagnosis was allowed to develop this pseudoaneurysm which caused nervous and deep venous compression.

Myeloma after local external beam radiotherapy jet: Is it a new entity?

Multiple myeloma, also known as Kahler's disease, is a cancer of plasma cells that abnormally accumulate in bone marrow. Radiation therapy may be indicated in multiple myeloma to relieve pain, alleviate spinal cord compression or reduce tumor mass. We report the case of a patient presenting a multiple myeloma, treated with radiation therapy for a spinal cord compression, who developed, eleven months later, an in-field subcutaneous relapse. We called this phenomenon myeloma appearance after local external beam radiotherapy jet (MAALEJ). A review of literature was performed trying to explain this uncommon relapse feature.

Glucose-6-phosphate dehydrogenase deficiency in Tunisia: molecular data and phenotype-genotype association.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect. In this study, we aimed to perform a molecular investigation of G6PD deficiency in Tunisia and to associate clinical manifestations and the degree of deficiency with the genotype. A total of 161 Tunisian subjects of both sexes were screened by spectrophotometric assay for enzyme activity. Out of these, 54 unrelated subjects were selected for screening of the most frequent mutations in Tunisia by PCR/RFLP, followed by size-based separation of double-stranded fragments under non-denaturing conditions on a denaturing high performance liquid chromatography system. Of the 56 altered chromosomes examined, 75 % had the GdA(-) mutation, 14.28 % showed the GdB(-) mutation and no mutations were identified in 10.72 % of cases. Hemizygous males with GdA(-) mutation were mostly of class III, while those with GdB(-) mutation were mainly of class II. The principal clinical manifestation encountered was favism. Acute hemolytic crises induced by drugs or infections and neonatal jaundice were also noted. Less severe clinical features such as low back pain were present in heterozygous females and in one homozygous female. Asymptomatic individuals were in majority heterozygote females and strangely one hemizygous male. The spectrum of mutations seems to be homogeneous and similar to that of Mediterranean countries; nevertheless 10.72 % of cases remain with undetermined mutation thus suggesting a potential heterogeneity of the deficiency at the molecular level. On the other hand, we note a better association of the molecular defects with the severity of the deficiency than with clinical manifestations.

[Pediatric Hodgkin disease in North Tunisia: clinical and therapeutic study]. / La maladie de Hodgkin de l'enfant dans le Nord Tunisien : étude clinique et thérapeutique.

PURPOSE: To assess the epidemiological, clinical and therapeutic aspects of pediatric Hodgkin disease (HD) and to study prognosis factors. PATIENTS AND METHODS: We retrospectively reviewed the medical records of children (≤18 years) with HD treated between 1st January 1994 and 31st December 2004. Chemotherapy was undertaken in different departments of hematology and oncology in the North of the country and radiotherapy was centralized at the Salah-Azaïz National Cancer Institute. RESULTS: One hundred fourteen consecutively treated patients were collected. Median age was 12 years (4-18 years) and sex-ratio was 2.25. Peripheral lymphadenopathy was the predominant circumstance of HD detection (82.5%). The predominant histologic type was nodular sclerosing (56%). Treatment included chemotherapy and involved-field radiotherapy. With a mean follow-up of 23.5 months, relapse rate was 12.2%. Five-year overall survival (OS) and event-free survival (EFS) rates were 95% and 76%, respectively. Five-year OS was 98.2% and 90.8% for early and advanced stages respectively. In multivariate analysis, stage IV (P=0.029) and early response to initial treatment (P=0.003) retained statistical significance for EFS whereas the only prognostic factor for OS was stage IV (P=0.002). The long-term side effects were rare. No secondary tumor was noted. CONCLUSION: Combined-modality therapy using chemotherapy and involved-field radiotherapy was effective and well-tolerated in early stage pediatric HD. Stage IV patients should be referred to specialized units for intensive treatment. The short median follow-up in our study cannot allow considering long-term effects.

[Chorea revealing a polycytemia vera]. / Chorée révélant une polyglobulie primitive.

Neurological manifestations in polycytemia vera are common. However, chorea is an exceptionally revealing feature of this disease. We report a 78-year-old man who presented with headache and an abnormal movement disorder corresponding to chorea. Laboratory findings showed increased levels of hemoglobin at 20 g/dl and hematocrit at 62.3%. An elevated erythrocyte mass to twice the normal value demonstrated the absolute erythrocytosis. A JAK2 V617F gene mutation was identified. A diagnosis of polycytemia vera-associated chorea was obtained. Clinical and biological outcomes were favorable after therapeutic phlebotomy and treatment with hydroxyurea. We recommend a complete blood cell count in elderly patient presenting with chorea to eliminate a diagnosis of polycytemia vera.

Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia.

BACKGROUND: CBL missense mutations have recently been associated with juvenile myelomonocytic leukaemia (JMML), an aggressive myeloproliferative and myelodysplastic neoplasm of early childhood characterised by excessive macrophage/monocyte proliferation. CBL, an E3 ubiquitin ligase and a multi-adaptor protein, controls proliferative signalling networks by downregulating the growth factor receptor signalling cascades in various cell types. METHODS AND RESULTS: CBL mutations were screened in 65 patients with JMML. A homozygous mutation of CBL was found in leukaemic cells of 4/65 (6%) patients. In all cases, copy neutral loss of heterozygosity of the 11q23 chromosomal region, encompassing the CBL locus, was demonstrated. Three of these four patients displayed additional features suggestive of an underlying developmental condition. A heterozygous germline CBL p.Y371H substitution was found in each of them and was inherited from the father in one patient. The germline mutation represents the first hit, with somatic loss of heterozygosity being the second hit positively selected in JMML cells. The three patients display a variable combination of dysmorphic features, hyperpigmented skin lesions and microcephaly that enable a 'CBL syndrome' to be tentatively delineated. Learning difficulties and postnatal growth retardation may be part of the phenotype. CONCLUSION: A report of germline mutations of CBL in three patients with JMML is presented here, confirming the existence of an unreported inheritable condition associated with a predisposition to JMML.

[Efficacy of imatinib in FIP1L1-PDGFRA positive hypereosinophilic syndrome]. / Efficacité de l'imatinib dans les syndromes hyperéosinophiliques associés au transcrit FIP1L1-PDGFRA.

Hypereosinophilic syndromes (HES) are a heterogeneous group of disorders characterized by marked peripheral blood and tissue eosinophilia resulting in organ damage. Recent advances in molecular biology have led to the identification of a FIP1L1-PDGFRA fusion gene as a recurrent abnormality in some patients with HES. This fusion gene results from a cryptic 4q12 interstitial deletion involving an 800 kb region. Recent reports indicate that this subtype of HES is imatinib responsive with rapid and complete haematological remissions. Here we report two patients successfully treated with imatinib.

[Chemotherapy against polycythemia due to a cyanotic congenital heart disease in adults. One case report]. / Chimiotherapie anti-erythrocytaire dans les cardiopathies congenitales cyanogenes de l'adulte. A propos d'une observation.

BACKGROUND: Hydroxyurea has largely been utilized in the management of primary polycythemia. It is certainly efficient in the short and medium terms side effects are marked by a leukemogenic risk. AIM: In this study we report the case in which hydroxyrea was for the first time used in the reatment of secondary polycythemia due to cyanotic congenital heart disease. CASE: Our patient was a 22-years-old man suffering from pulmonary atresia with ventricular septal defect, and for whom ther was no available surgical option. Because of severe symptomatic and demanding polycythemia requiring frequent phlebotomies, we decided to use hydroxyurea at the dose of Igr a day. Eight months later, ther was obvious clinical improvement with stable hematocrit levels below 60% and with only 3 phlebotomies in 8 months. CONCLUSION: Hydroxyurea seems to be an eddicient there alternative therapy for seconday polycythemia caused by incurable cyantic congenital heart disease.

FIP1L1-PDGFRA positive chronic eosinophilic leukemia in Tunisian patients.

Hypereosinophilic syndromes (HES) are a heterogenous group of rare disorders characterized by sustained and otherwise unexplained overproduction of eosinophils with organ involvement and consecutive dysfunction. Detection of the FIP1L1-PDGFRA fusion gene or the corresponding cryptic 4q12 deletion in HES supports the diagnosis of chronic eosinophilic leukemia (CEL) and provides a molecular explanation for the pathogenesis of this disorder. We screened seven Tunisian patients fulfilling the WHO criteria of HES for the presence of the FIP1L1-PDGFRA fusion gene using nested reverse transcription polymerase chain reaction on peripheral blood samples. Four of the seven patients were positive for this fusion gene. Sequence analysis revealed a substantial heterogeneity of the fusion transcripts due to the involvement of several FIP1L1 exons. All patients were male. The median age at diagnosis was 24 years (range, 18-50); one patient had a history of hypereosinophilia of more than 10 years. Two patients had clinically important and symptomatic eosinophilic endomyocardial disease with thrombotic events. Splenomegaly was constant in FIP1L1-PDGFRA positive CEL but not in the other HES patients (only 1/3).

[Ovarian irradiation in recurrent endometriosis]. / Irradiation ovarienne pour endométriose réfractaire inopérable.

We describe a case of a young woman with a history of an aplastic anaemia in which pelvic radiotherapy was used successfully in the management of a recurrent and inoperable endometriosis. The use of therapeutic pelvic or ovarian irradiation in endometriosis may be considered, when surgical and medical treatments have been exhausted and have failed.

Prevalence of inherited prothrombotic abnormalities and central venous catheter-related thrombosis in haematopoietic stem cell transplants recipients.

In this prospective study, we assessed the incidence of central venous catheter (CVC)-related thrombosis in haematopoietic stem cell transplant (HSCT) recipients. We determined the contribution of inherited prothrombotic abnormalities in blood coagulation to CVC-related thrombosis in these patients. The study was conducted between May 2002 and September 2004. CVCs were externalized, nontunneled, polyurethane double lumen catheters. Before catheter insertion, laboratory prothrombotic markers included factor V Leiden, the prothrombin gene Gly20210A mutation, plasma antithrombin levels, and protein C and S activity. All patients were systematically examined by ultrasonography just before, or <24 h after, catheter removal, and in case of clinical signs of thrombosis. A total of 171 patients were included during the 28-month study period. Five (2.9%) and three (1.7%) patients had evidence of protein C and protein S deficiency, respectively. Only one patient had an antithrombin deficiency (0.6%). In total, 10 patients (5.8%) were heterozygous for the factor V Leiden mutation, and one patient had heterozygous prothrombin G20210A mutation (0.6%). We observed a CVC-related thrombosis in 13 patients (7.6%). Thrombosis was diagnosed in four out of 20 patients (20%) with a inherited prothrombotic abnormality compared to nine of 151 patients (6%) who did not have a thrombophilic marker (relative risk 3.3 CI 95% 1.1-9.9). Our results suggest that inherited prothrombotic abnormalities contribute substantially to CVC-related thrombosis in HSCT recipients. In view of physicians' reluctance to prescribe prophylactic anticoagulant treatment in these patients, a priori determination of inherited prothrombotic abnormalities may form a basis to guide these treatment decisions.

First-line thalidomide-dexamethasone therapy in preparation for autologous stem cell transplantation in young patients (<61 years) with symptomatic multiple myeloma.

Thalidomide-dexamethasone therapy was given in patients (<61 years) with previously untreated symptomatic multiple myeloma. The aim of this study was to assess the efficacy and toxicity of this combination as first-line therapy, and to determine its effect on stem cell collection and engraftment. During first-line therapy, thalidomide and dexamethasone were administered for 75 days (200 mg/day) and 3 months, respectively. The monthly dose of dexamethasone was 20 mg/m2/day for 4 days, with cycles repeated on days 9 to 12 and 17 to 20 on the first and the third month of therapy. After first-line therapy, a collection of peripheral blood stem cells (PBSC) was performed. Between May 2003 and September 2004, 60 patients were included. On an intent-to-treat basis, the overall response (> or =partial response) rate was 74%, including 24% of patients who obtained a complete remission. Grade 3-4 toxicities consisted of infections (12%), deep-vein thrombosis (3%), constipation (5%), and neuropathy (5%). A total of 58 patients (96%) proceeded to PBSC mobilisation and yielded a median number of 8 x 10(6) CD34+ cells/kg. First-line thalidomide-dexamethasone therapy is effective and relatively well tolerated in young patients with symptomatic multiple myeloma. This combination does not affect PBSC mobilisation.

[Solitary bone plasmocytoma: treatment and outcome features].

PURPOSE: - To describe natural history of solitary bone plasmocytomas (SBO) after treatment. PATIENTS AND METHODS: - Between 1975 and 1998, we retrospectively identified 13 patients with SBO treated in the department of radiotherapy at Salah-Azaïz institute of Tunis. To be included in this study, three criteria were needed: histologic confirmation and only one bone lesion without medullary infiltration (or less than 10%). Mean age was 43 years (22-64) with sex-ratio of 3,3. Tumor sites were vertebra (6), flat bones (6) and tibia (1). Megavoltage radiotherapy was given to all patients, associated to surgery in eight cases (5 excisions and 3 laminectomies) and to chemotherapy in three. RESULTS: - With a mean follow-up of 63 months, two local failures were noted at 24 and 48 months. Two patients developed multifocal lesions and one patient had an extramedullary lesion. Multiple myeloma occurred in four patients (30%) after a median follow-up 3,5 years. Unfavorable outcome could not be predicted by age, gender or site of disease but by myeloma protein. CONCLUSION: - Radiotherapy is an effective local treatment for solitary bone plasmocytoma. Prospective studies are needed to better define predictive parameters of unfavourable outcome and indications of combined chemotherapy.

[Costal hydatid cyst (report of 2 cases)]. / Kyste hydatique costal (a propos de 2 cas).

Hydatidosis is an endemic affection in our country. Hepatic and pulmonary localisation is the most frequent. The other localisation especially in the bone, are exceptional. We report 2 cases of costal hydatid diagnosed on 17 and 33 years old male patients admitted for parietal tumor respectively localized in cervix and thorax. The diagnosis, suspected on chest tomography is confirmed by histologic patterns of resected rib.