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.

[Orbital complications of sinusitis]. / Les complications orbitaires des sinusites.

PURPOSE: Orbital complications of sinusitis are rare but serious, with potential functional and even fatal consequences. The purpose of this work is to study the epidemiological, clinical and paraclinical features of the orbital complications of sinusitis, as well as the various treatment modalities and clinical course. PATIENTS AND METHODS: We report the results of a retrospective study of 34 cases of orbital complications of sinusitis, collected between 1998 and 2009. RESULTS: Mean age was 19 years 3 months, with a clear male predominance. No predisposing factors were found. All patients presented with periorbital edema. In addition to periorbital edema, ophthalmological examination also revealed: proptosis in 19 patients, decreased visual acuity in eight patients and ocular motility disturbances in 10 patients. All patients underwent emergent facial CT, two patients underwent orbital ultrasound, and one underwent magnetic resonance imaging. Initial treatment was based on empiric intravenous antibiotic therapy. Orbital drainage was performed in 20 patients. Sinus drainage was performed in 16 patients (14 cases during the acute phase) with a middle meatotomy in all cases. The initial response was favorable in 97.5% of cases. One patient had a recurrence. Mean follow-up was 11 months. CONCLUSION: Orbital complications of sinusitis are a diagnostic and therapeutic emergency. Imaging helps guide management. Directed treatment and early management can improve mortality and morbidity.

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.

[Pediatric mucoceles: clinical aspects and therapeutic approaches]. / Mucocèles de l'enfant : présentations cliniques et modalités thérapeutiques.

INTRODUCTION: Paranasal sinuses mucoceles are extremely rare in children and adolescents. The objective of this study was to assess their clinical presentations and the contribution of endoscopic surgery in their management. MATERIAL AND METHODS: we retrospectively reviewed 11 children with paranasal sinus mucoceles who were managed during a period of 15 years (1995-2009). RESULTS: The mean age was 11.8 years with a sex ratio of 2.66. One patient had a history of nasal polyposis surgery. The symptomatology was dominated by ophthalmological complains. The ethmoïd sinus was the main localization. Orbital extension was found in eight cases, pyomucocele in one case. The surgical management was endoscopic (nine cases), and by an external approach (two cases). Two cases of recurrence were assessed. The mean follow-up was 22.3 months. DISCUSSION: Paranasal sinuses mucocele is exceptional in children. Cystic fibrosis is the main etiologic factor. The symptoms depend on the location and size of the mucocele. The treatment is surgical and most authors prefer the endoscopic approach.

Evaluation of serum VEGF levels in untreated erythrocytosis patients.

The aim of this prospective study was to investigate the involvement of angiogenesis in the etiopathogenesis of the different classes of erythrocytosis (polycythemia vera PV, idiopathic erythrocytosis and secondary erythrocytosis). The angiogenic activity was evaluated by the assessment of the serum VEGF levels in 78 untreated erythrocytosis patients and 21 healthy subjects. The results indicated that VEGF was overproduced in advanced and untreated PV patients and at less degree, in early PV, a subgroup of idiopathic erythrocytosis, thus confirming an increased angiogenic activity. However, VEGF does not play an angiogenic role in secondary erythrocytosis.

[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).