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Sickle cell anemia is the world's most common monogenic disease, with a steady rise in the number of cases also in Switzerland. It presents as regenerative anemia and recurrent vaso-occlusive episodes, which can impact all organs. Acute and chronic complications increase morbidity and mortality, significantly reducing life expectancy compared to the general population. Optimal and multidisciplinary management of acute events is essential to improve patients' quality of life and overall prognosis. Vaso-occlusive crises and acute chest syndrome are the two most frequent acute complications. Their treatment, described here, is threefold: analgesia, treatment of causative factors and prevention of further complications., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêt en relation avec cet article.

Elderly with multimorbidity are at higher risk of accumulating direct oral anticoagulants (DOAC). The presence of renal insufficiency, an extreme age or weight, a limited functional reserve, and a polypharmacy that may interact with DOAC, lead to an increased risk of bleeding. A medication review and an evaluation of DOAC exposure in this population could help identify this risk and better manage it. This evaluation is conducted in collaboration with coagulation experts through calibrated measurement of anti-Xa (rivarobaxan, apixaban and edoxaban), along with D-dimers measurement as a potential tool to assess thrombo-hemorrhagic risk. In the event of DOAC accumulation, experts could then propose personalized intervention, such as a dose reduction or a switch to another DOAC., Competing Interests: les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

The organic compounds 2-chloro- N -(aryl)acetamide (Ps13-Ps18) and 2-azido- N -(aryl)acetamide (148-153) were synthesized and analyzed using 1 H, 13 C NMR. The acute oral toxicity study was carried out according to OECD guidelines, which approve that the compounds (Ps18 and 153) were nontoxic. In addition, the compounds were evaluated for its antidiabetic and antihyperglycemic properties ( in vitro and in vivo ) and for antioxidant activity by utilizing several tests as 1,1-diphenyl2-picrylhydrazyl DPPH , (2,2'-azino-bis(3-ethyl benzthiazoline-6-sulfonicacid) ABTS , reducing power test FRAP and hydrogen peroxide activity H 2 O 2 . The molecular docking studies were performed to investigate the antidiabetic activity of Ps18 and 153 and compared with the experimental results. These compounds are a potent antidiabetic from both the experimental and molecular docking results. Finally, the physicochemical, pharmacokinetic and toxicological properties of Ps18 and 153 have been evaluated by using in silico absorption, distribution, metabolism, excretion and toxicity analysis prediction.Communicated by Ramaswamy H. Sarma.

Aplastic anemia is a rare disease with a large differential diagnosis, including neoplastic origin as well as congenital bone marrow failure syndromes. Investigations must be quick and precise. Treatment depends on the patient's age and consists of immunosuppression treatment or allogeneic bone marrow transplantation. Because of the risk of progression to other hematological diseases, a close specialized follow-up is recommended., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Purpose of Review: The discovery that patients suffering from chronic myeloid leukemia who obtain deep and long-lasting molecular responses upon treatment with tyrosine kinase inhibitors may maintain their disease silent for many years after therapy discontinuation launched the era of treatment-free remission as a key management goal in clinical practice. The purpose of this review on treatment-free remission is to discuss clinical advances, highlight knowledge gaps, and describe areas of research., Recent Findings: Patients in treatment-free remission are a minority, and it is believed that some may still retain a reservoir of leukemic stem cells; thus, whether they can be considered as truly cured is uncertain. Strengthening BCR::ABL1 inhibition increases deep molecular responses but is not sufficient to improve treatment-free remission, and we lack biomarkers to identify and specifically target residual cells with aggressive potential. Another level of complexity resides in the intra- and inter-patient clonal heterogeneity of minimal residual disease and characteristics of the bone marrow environment. Finding determinants of deep molecular responses achievement and elucidating varying biological mechanisms enabling either post-tyrosine kinase inhibitor chronic myeloid leukemia control or relapse may help develop innovative and safe therapies. In the light of the increasing prevalence of CML, targeting the residual leukemic stem cell pool is thought to be the key., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Tyrosine kinase inhibitors (TKI) have emerged as a paradigm-shifting therapeutic approach for the treatment of chronic myeloid leukemia (CML) following their regulatory approval in 2001. These agents have revolutionized the management of CML by significantly improving patient outcomes and enabling them to achieve near-normal life expectancies. Consequently, the utilization of TKI has become increasingly prevalent, accompanied by the recognition and management of their associated adverse effects. Given the expanding patient population receiving TKI therapy, it is imperative that hematologists, as well as general practitioners, assume the responsibility of closely and meticulously monitoring patients' treatment progress while effectively addressing the occurrence of any untoward effects., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Recurrent miscarriages have a major psychological and somatic impact, as well as a significant economic burden. An etiological work-up should be offered after two or three miscarriages, the threshold varying from one scientific society to another. However, the proposed biological work-up must be justified by scientific evidence. A simple blood count, basic coagulation tests including fibrinogen assay and anti-phospholipid antibodies testing should be performed initially. Hereditary thrombophilia testing should only be carried out if there is a history of maternal thrombosis. In the event of an abnormality, management should be multidisciplinary, and the prescription of medication should follow recommended guidelines. Prophylactic treatment is not justified in the absence of a known etiology., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Objective: The objective of this study was to describe the clinical and laboratory manifestations, triggers factors, treatment, and outcome of MAS complicating SLE., Methods: We retrospectively analyzed the medical records of adult patients with SLE for a period of 8 years (2009-2016) and identified patients who had developed MAS. We conducted statistical analysis to identify factors associated with MAS., Results: Among 208 consecutive lupus patients, 20 patients (19 women) were identified having MAS. The mean age of patients was 35.4 ± 10 years. MAS revealed lupus in 7 patients. In the others, the delay between diagnosis of SLE and MAS was 33,3 months. All cases required hospital admission, and 2 patients were admitted to the intensive care unit. An anemia (hemoglobin < 10 g/dL) was found in all patients. A thrombopenia was observed in 19 (95%) cases. Hypertriglyceridemia and hyperferritinemia were present in all patients. All patients had anti-nuclear antibodies and anti-double-stranded DNA antibodies. Bone marrow aspiration showed hemophagocytosis in 15 (94%) cases. The mean SLEDAI was 20.95 corresponding to an SLE of a very high activity. The mean H-Score was 233.85. MAS was associated with a lupus flare in 13 patients. Documented bacterial infections, viral infections, and a breast cancer were respectively diagnosed in 4, 3, and 1 cases respectively. The corticosteroids were administered in all patients. Intravenous cyclophosphamide was used together with corticosteroids in 6 patients, mycophenolate mofetil in 2 cases and azathioprine in 2 cases. Intravenous immunoglobulin was given in 4 cases, etoposide in one case and rituximab was used as the third line treatment in one patient. All infectious episodes were also treated by broad spectrum antibiotics. All patients had a good outcome without any mortality at the management, with a mean follow-up of 24 months. The clinical parameters significantly associated with MAS were fever (p = 0,001), splenomegaly (p < 0.0001), lymphadenopathy (p < 0.0001), oral and/or nasopharyngeal ulceration (p = 0.04), arthritis (p = 0.017), and pulmonary signs (p = 0.003). Laboratory parameters associated with MAS were anemia (p < 0.0001), thrombopenia (p < 0.0001), hyperferritinemia (p < 0.0001), hypertriglyceridemia (p < 0.0001), SLEDAI (p < 0.0001), and H-Score (p < 0.0001). Receiver operating characteristic (ROC) analysis identified optimal cutoff values of ferritin (> 695 ng/mL) and SLEDAI (> 13.5) to predict the occurrence of MAS in SLE., Conclusion: MAS was observed in 9.62% Moroccan adult patients with SLE. SLE flare and infection were the common triggers of MAS in our study. Our study indicates that the occurrence of unexplained fever, splenomegaly, lymphadenopathy, profound cytopenia, hyperferritinemia, hypertriglyceridemia, high SLEDAI, and H-Score should raises the possibility of the diagnosis of MAS in SLE patients. Early diagnosis and urgent therapeutic management improves the overall prognosis. Key Points • Macrophage activation syndrome (MAS) is an underdiagnosed complication of systemic lupus erythematosus (SLE). The prevalence of this complication in this study is nearly 10%. • The diagnosis of MAS represents a major challenge for clinicians, as it could mimic a SLE flare up or be confused with infections. Validated diagnostic criteria for MAS in adults secondary to SLE are urgently needed. • In this study, the H-score calculate the individual risk of adult patients having reactive MAS. The cut-off value for the H-score was 190.5 (sensitivity 96.7%, specificity 97.6%). • The prognosis of MAS with SLE is good in our study. However, in the literature MAS may be a fatal condition in SLE patients. Prospective studies are necessary to confirm these results., (© 2022. International League of Associations for Rheumatology (ILAR).)

Venous thromboembolism is a leading cause of maternal morbidity and mortality with an overall incidence of 1-2 cases per 1000 pregnancies. The purpose of this article is to summarize more recent recommendations for the management of venous thromboembolism during pregnancy and post-partum period., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Vitamin B12 deficiency is common in outpatients and inpatient populations, with potentially severe neuropsychiatric and hematological impact, which requires timely diagnosis and treatment. The different diagnostic tests all have their limitations but can be combined, sequentially. We propose to review the treatment options according to the different etiologies of the deficiency, highlighting the costs of the therapies and their coverage by the health insurance., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Competing Interests: Les auteurs déclarent n'avoir aucun lien d'intérêts.

Antibodies against factor VIII (FVIII) can be detected based on their ability to neutralize the procoagulant activity of FVIII (neutralizing antibodies, inhibitors), or based on their specific binding capacity to FVIII protein. This article reviews the available assays and their clinical interpretation in patients with congenital and acquired hemophilia., Competing Interests: The authors declare, that they have no conflict of interest., (Thieme. All rights reserved.)

The COVID-19 pandemic impacts the hematology practice. Intensive chemotherapies for high-grade lymphomas and acute leukemias, multiple myeloma treatments and most hematopoietic stem cell transplantations should be performed as usual. Low-grade lymphomas should only be treated when strictly indicated, maintenance can be postponed. Other myeloid neoplasia and their therapies cause imunosupression; dose adjustment is recommended but no brisk stopping. Sickle cell anemia patients are highly succeptible to severe COVID-19 course. Thrombocytopenia and procoagulant state are associated with severe courses of COVID-19, requiring an individualized therapy. No data indicate a risk of SARS-CoV-2 transmission through blood product transfusion., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Immune-checkpoint inhibitors (ICIs), including anti-cytotoxic T lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1) and anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are arguably the most important development in cancer therapy over the past decade. The indications for these agents continue to expand across malignancies and disease settings, thus reshaping many of the previous standard-of-care approaches and bringing new hope to patients. One of the costs of these advances is the emergence of a new spectrum of immune-related adverse events (irAEs), which are often distinctly different from the classical chemotherapy-related toxicities. Owing to the growing use of ICIs in oncology, clinicians will increasingly be confronted with common but also rare irAEs; hence, awareness needs to be raised regarding the clinical presentation, diagnosis and management of these toxicities. In this Review, we provide an overview of the various types of irAEs that have emerged to date. We discuss the epidemiology of these events and their kinetics, risk factors, subtypes and pathophysiology, as well as new insights regarding screening and surveillance strategies. We also highlight the most important aspects of the management of irAEs.

Background: Epithelial cytokines, including IL-33 and Thymic stromal lymphopoietin (TSLP), have attracted interest because of their roles in chronic allergic inflammation-related conditions such as asthma. Mast cells are one of the major targets of IL-33, to which they respond by secreting cytokines. Most studies performed thus far have investigated the acute effects of IL-33 on mast cells. In the current study, we investigated how acute vs. prolonged exposure of mast cells to IL-33 and TSLP affects mediator synthesis and IgE-mediated activation. Methods: Human lung mast cells (HLMCs), cord blood-derived mast cells (CBMCs), and the ROSA mast cell line were used for this study. Receptor expression and the levels of mediators were measured after treatment with IL-33 and/or TSLP. Results: IL-33 induced the release of cytokines. Prolonged exposure to IL-33 increased while TSLP reduced intracellular levels of tryptase. Acute IL-33 treatment strongly potentiated IgE-mediated activation. In contrast, 4 days of exposure to IL-33 decreased IgE-mediated activation, an effect that was accompanied by a reduction in FcεRI expression. Conclusion: We show that IL-33 plays dual roles in mast cells, in which its acute effects include cytokine release and the potentiation of IgE-mediated degranulation, whereas prolonged exposure to IL-33 reduces IgE-mediated activation. We conclude that mast cells act quickly in response to the alarmin IL-33 to initiate an acute inflammatory response, whereas extended exposure to IL-33 during prolonged inflammation reduces IgE-mediated responses. This negative feedback effect suggests the presence of a novel regulatory pathway that modulates IgE-mediated human mast cell responses.

The French Working Group on Perioperative Haemostasis (GIHP) and the French Study Group on Haemostasis and Thrombosis (GFHT) in collaboration with the French Society of Anaesthesia and Intensive Care Medicine (SFAR) drafted up-to-date proposals on the management of antiplatelet therapy for non-elective invasive procedures or bleeding complications. The proposals were discussed and validated by a vote; all proposals could be assigned with a high strength. Emergency management of oral antiplatelet agents (APA) requires knowledge on their pharmacokinetic/pharmacodynamics parameters, evaluation of the degree of the alteration of haemostatic competence and the associated bleeding risk. Platelet function testing may be considered. When APA-induced bleeding risk may worsen the prognosis, measures should be taken to neutralise antiplatelet therapy by considering not only the efficacy of available means (which can be limited for prasugrel and even more for ticagrelor) but also the risks that these means expose the patient to. The measures include platelet transfusion at the appropriate dose and haemostatic agents (tranexamic acid; rFVIIa for ticagrelor). When possible, postponing non-elective invasive procedures at least for a few hours until the elimination of the active compound (which could compromise the effect of transfused platelets) or if possible a few days (reduction of the effect of APA) should be considered., (Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Clonal chromosome abnormalities in Philadelphia-negative cells could concern chronic myeloid leukemia patients treated by tyrosine kinase inhibitors. The European LeukemiaNet distinguishes -7/del(7q) abnormalities as a "warning". However, the impact of clonal chromosome abnormalities, and specifically those of -7/del(7q), in Philadelphia-negative cells on clinical outcomes is unclear and based on case-reports showing morphological dysplasia and increased risk of acute myeloid leukemia, suggesting the coexistence of chronic myeloid leukemia and high-risk myelodysplastic syndrome. The aim of this study was to determine whether the impact of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells on the clinical outcome is different from that of other types of abnormalities, and we argue for an underlying associated high-risk myelodysplastic syndrome. Among 102 chronic myeloid leukemia patients with clonal chromosome abnormalities in Philadelphia-negative cells with more than a median of 6 years of follow up, patients with -7/del(7q) more frequently had signs of dysplasia, a lower cumulative incidence of deep molecular response and often needed further treatment lines, with the consequent impact on event-free and progression-free survival. Morphological features of dysplasia are associated with myelodysplastic syndrome/acute myeloid leukemia mutations and compromise the optimal response to tyrosine kinase inhibitors, irrespectively of the type of clonal chromosome abnormalities in Philadelphia-negative cells. However, mutation patterns determined by next-generation sequencing could not clearly explain the underlying high-risk disease. We hereby confirm the pejorative prognostic value of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells and suggest that myelodysplastic features constitute a warning signal that response to tyrosine kinase inhibitors may be less than optimal., (Copyright© 2019 Ferrata Storti Foundation.)

The French Working Group on Perioperative Haemostasis (GIHP) and the French Study Group on Haemostasis and Thrombosis (GFHT), in collaboration with the French Society for Anaesthesia and Intensive Care (SFAR), drafted up-to-date proposals on the management of antiplatelet therapy for non-elective invasive procedures or bleeding complications. The proposals were discussed and validated by a vote; all proposals could be assigned with a high strength. Management of oral antiplatelet agents in emergency settings requires knowledge of their pharmacokinetic and pharmacodynamic parameters, evaluation of the degree of alteration of haemostatic competence and the associated bleeding risk. Platelet function testing may be considered. When antiplatelet agent-induced bleeding risk may worsen the prognosis, measures should be taken to neutralize antiplatelet therapy, by considering not only the efficacy of available means (which can be limited for prasugrel and even more for ticagrelor), but also the risks that these means expose the patient to. The measures include platelet transfusion at the appropriate dose and haemostatic agents (tranexamic acid; recombinant activated factor VII for ticagrelor). When possible, postponing non-elective invasive procedures at least for a few hours until the elimination of the active compound (which could compromise the effect of transfused platelets) or, if possible, for a few days (reduction of the effect of antiplatelet agents) should be considered., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Clinical trials have formally demonstrated that in chronic myeloid leukemia (CML), patients treated with tyrosine kinase inhibitors (TKI) who achieved and maintained deep molecular responses could discontinue their treatment after several years without facing overt signs of disease relapse in approximately 50% of the cases. In patients with a molecular relapse, prompt re-introduction of TKI therapy was able to rapidly restore deep molecular responses. The concept of a lifelong therapy with TKI has thus been challenged and treatment-free remission (TFR) strategies will soon integrate clinical practice, providing that safe recommendations will be established. In this article, we give an update on TKI discontinuation studies in CML and we also provide an overview of upcoming TFR clinical and biological challenges.

Severe postpartum hemorrhage (sPPH) is an obstetric emergency that needs prompt and effective therapy to reduce the risk of complications. In this study, women who developed sPPH (study cohort, n = 27) were treated according to a standardized management protocol prescribing sequential administration of uterotonic drugs, crystalloids, tranexamic acid, labile blood products, low-dose fibrinogen, and recombinant activated factor VII (rFVIIa). This group was compared to patients treated with different strategies during 2 preceding periods: an in-house guideline regulating the administration of rFVIIa (historical cohort 1, n = 20) and no specific guideline (historical cohort 2, n = 27). The management protocol was used over 33 months. The study cohort had a lower estimated blood loss ( P = .004) and required less red blood cell concentrates ( P = .007), fresh frozen plasma units ( P = .004), and platelet concentrates ( P = .020) compared to historical cohort 1 and historical cohort 2, respectively. The necessity of emergency postpartum hysterectomy was lower in the study group ( P = .012). In conclusion, in patients with sPPH treated with this standardized management protocol, we observed a decreased requirement of labile blood products and lower need to proceed to emergency postpartum hysterectomy.

Hemophagocytic Lymphohistiocytosis Abstract. Hemophagocytic lymphohistiocytosis (HLH) is a group of rare diseases characterized by over-activation of the immune system. They form two groups: primary and secondary HLH. Primary HLH are linked to mutations impairing lymphocyte cytotoxicity. Secondary HLH are triggered by infections, autoimmune diseases or neoplasia, the remaining cases being labeled idiopathic. HLH manifest as febrile states, cytopenias and hepatosplenomegaly. In the absence of treatment, they quickly lead to multiple organ failure. The diagnosis is currently based on the presence of several clinical and biological markers. Treatment consists of suppression of the triggering factor, organ support and immunosuppression. Primary forms, affecting a pediatric population, have been the subject of intense research, and are nowadays treated with established therapeutic protocols. Several recent retrospective studies have improved our knowledge of secondary HLH, which affects mostly adults and whose incidence seems to be increasing. Thus, new diagnostic criteria are currently being studied for secondary HLH, and several treatment protocols have just been published or are being evaluated.

Point of care testing (POCT) must comply with regulatory requirements according to standard EN ISO 22870, which identify biologists as responsible for POCT. INR for vitamin K antagonists (VKAs) monitoring is a test frequently performed in haemostasis laboratories. Bedside INR is useful in emergency room, in particular in case of VKAs overdosage but also for specific populations of patients like paediatrics or geriatrics. INR POCT devices are widely used at home by the patients for self-testing, but their use in the hospital by the clinical staff for bedside measurement is growing, with devices which now comply with standard for POCT accreditation for hospital use. The majority of point of care devices for INR monitoring has shown a good precision and accuracy with results similar to those obtained in laboratory. With the aim to help the multidisciplinary groups for POCT supervision, the medical departments and the biologists to be in accordance with the standard, we present the guidelines of the GFHT (Groupe français d'étude sur l'hémostase et la thrombose, subcommittee "CEC et biologie délocalisée") for the certification of POCT INR. These guidelines are based on the SFBC guidelines for the certification of POCT and on the analysis of the literature to ascertain the justification of clinical need and assess the analytical performance of main analysers used in France, as well as on a survey conducted with biologists.

Background: Blood donation in Morocco and more particularly in the northwest region is carried out without prior determination of the pre-donation hemoglobin. In addition, we note the lack of scientific research that reports data on the red blood cells, leukocytes and platelet lines in donated blood at the regional or even national level., Aims: To study hemogram profile in blood donors taken from the Northwest region of Morocco in order to provide decision makers of the National Center of Blood Transfusion and Hematology with valid scientific arguments to complete the criteria to donate whole blood, by the hemogram., Methods: Prospective study, conducted in 15797 volunteer blood donors (BD) aged between 18 and 60 years, collected during mobile or fixed collections carried out by the Regional Blood Transfusion Center of Tangier and Tetouan from November 2014 to May 2016. The hemogram was performed using a Sysmex KX21N ® and the analysis of the data was done by the software SPSS 20.0., Results: According to the World Health Organization, anemia corresponds to a hemoglobin level less than 12g/dL in women and less than 13g/dL in men. We found that 14.5 % of women (n=1054) and 3.0 % of men (n=245) were anemic and anemia was hypochromic microcytic in 58,66 % of these BD. Analysis of the white line showed leucopenia in 2.05 % of BD and 807 cases of leukocytosis (5.27 % of BD). Platelet study showed thrombocytopenia in 3.97 % of BD and thrombocytosis in 151BD (0.99 % of cases)., Conclusion: This study shows the interest of systematic pre-donation hemoglobin measurement and periodic realization of the hemogram among BD in the Northwest region of Morocco., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Introduction: Congenital hypofibrinogenaemia is a quantitative fibrinogen disorder characterized by proportionally decreased levels of functional and antigenic fibrinogen. Mutations accounting for quantitative fibrinogen disorders are relatively frequent in the conserved COOH-terminal globular domains of the γ and Bβ chains. The latter mutations are of particular interest since the Bβ-chain is considered the rate-limiting chain in the hepatic production of the fibrinogen hexamer., Aim: The aim of this study was to study the molecular pattern of four patients with congenital hypofibrinogenaemia., Methods: Four novel fibrinogen Bβ-chain mutations leading to congenital hypofibrinogenaemia were identified in four women with heterogeneous symptoms. The human fibrinogen beta chain precursor protein sequence (P02675) was obtained from the UniProt database. The resulting models were analysed using swisspdbviewer 4.1.0., Results: Three patients were heterozygous for different missense mutations located in the highly conserved β nodule: c.882G>C:Arg294Ser (Arg264Ser), c.1298G>T:Trp433Leu (Trp403Leu) and c.1329C>G:Asn443Lys (Asn413Lys). Modelling analyses predicted major structural modifications likely to result in impaired fibrinogen secretion. One patient was heterozygous for an intron 7 donor splice mutation (c.1244 + 1G>A), leading to the complete abolishment of the donor site., Conclusions: Protein modelling of new causative mutations and comparison of molecular, biochemical and clinical data continue to yield valuable information on the development and course of fibrinogen disorders as well as on the choice of the most appropriate treatments., (© 2017 John Wiley & Sons Ltd.)

Hemoglobinopathies are congenital disorders resultimg from hemoglobin abnormalities. Major forms are often severe, their management is difficult and associated with a great psychosocial impact on patients and their families. They are classified as rare diseases and are still insufficiently known by health professionals. This lack of knowledge is at the origin of diagnostic errors, delay in their management and therefore high morbidity and mortality rate for these patients. In 2008, the World Health Organization (WHO) has published data on hemoglobinopathies epidemiology: more than 330.000 cases of hemoglobinopathy occur each year (83% of cases of sickle cell anemia, 17 % of cases of thalassemia). Hemoglobin disorders are responsible for approximately 3.4% of deaths among people under the age of 5. At the global level, approximately 7% of pregnant women would be carriers of a form of thalassemia and 1% of couples are at risk. However, they are relatively frequent in some regions of the globe where consanguineous marriages are common. We conducted a descriptive cross-sectional study based on two surveys, the first in May 2015 and the second in June of the same year. It was performed in the immunization days to deliver pneumococcal vaccine to the index cases and it was aimed to describe the epidemiological features of families at risk of hemoglobinopathies (index case study), whose index cases were treated in the Department of Pediatrics at the Provincial Hospital El Idrisi, Kenitra, Morocco. After having collected the epidemiological data from patients, laboratory tests were performed including: blood count with red blood cells morphological assessment using the MGG assay and automatic numbering of reticulocytes; hemoglobin electrophoresis at alkaline pH (8.8) and then at acid pH (5.4) on agarose gel and densitometric integration. 275 patients had laboratory profiles compatible with hemoglobinopathy. The majority of these patients were born to consanguineous marriages (83.1%) and came from the north regions of Morocco. This family survey allowed to identify families at risk with a high frequency of sickle cell anemia. Our results confirm the existence of hemoglobinopathies variants among Moroccan population.

The combined action of collagen and thrombin induces the formation of COAT platelets, which are characterised by a coat of procoagulant and adhesive molecules on their surface. Although recent work has started to highlight their clinical relevance, the exact mechanisms regulating the formation of procoagulant COAT platelets remain unclear. Therefore, we employed flow cytometry in order to visualise in real time surface and intracellular events following simultaneous platelet activation with convulxin and thrombin. After a rapid initial response pattern characterised by the homogenous activation of the fibrinogen receptor glycoprotein IIb/IIIa in all platelets, starting with a delay of about 2 minutes an increasing fraction transforms to procoagulant COAT platelets. Their surface is characterised by progressive loss of PAC-1 binding, expression of negative phospholipids and retention of α-granule von Willebrand factor. Intracellular events in procoagulant COAT platelets are a marked increase of free calcium into the low micromolar range, concomitantly with early depolarisation of the mitochondrial membrane and activation of caspase-3, while non-COAT platelets keep the intracellular free calcium in the nanomolar range and maintain an intact mitochondrial membrane. We show for the first time that the flow-cytometrically distinct fractions of COAT and non-COAT platelets differentially phosphorylate two signalling proteins, PKCα and p38MAPK, which may be involved in the regulation of the different calcium fluxes observed in COAT versus non-COAT platelets. This study demonstrates the utility of concomitant cellular and signalling evaluation using flow cytometry in order to further dissect the mechanisms underlying the dichotomous platelet response observed after collagen/thrombin stimulation.

Systemic mastocytosis (SM) is a clonal bone marrow disorder, where therapeutical options are limited. Over 90% of the patients carry the D816V point mutation in the KIT receptor that renders this receptor constitutively active. We assessed the sensitivity of primary mast cells (MC) and mast cell lines HMC1.2 (D816V mutated), ROSA (KIT WT) and ROSA (KIT D816V) cells to histone deacetylase inhibitor (HDACi) treatment. We found that of four HDACi, suberoyl anilide hydroxamic acid (SAHA) was the most effective in killing mutated MC. SAHA downregulated KIT, followed by major MC apoptosis. Primary SM patient MC cultured ex vivo were even more sensitive to SAHA than HMC1.2 cells, whereas primary MC from healthy subjects were less affected. There was a correlation between cell death and SM disease severity, where cell death was more pronounced in the case of aggressive SM, with almost 100% cell death among MC from the mast cell leukemia patient. Additionally, ROSA (KIT D816V) was more affected by HDACi than ROSA (KIT WT) cells. Using ChIP qPCR, we found that the level of active chromatin mark H3K18ac/H3 decreased significantly in the KIT region. This epigenetic silencing was seen only in the KIT region and not in control genes upstream and downstream of KIT, indicating that the downregulation of KIT is exerted by specific epigenetic silencing. In conclusion, KIT D816V mutation sensitized MC to HDACi mediated killing, and SAHA may be of value as specific treatment for SM, although the specific mechanism of action requires further investigation.

Homozygous sickle cell disease is one of the most frequent haemoglobinopathies in Morocco. Sickle cell disease is characterized by a large clinical and biological expression variability which depends on modulating genetic and environmental factors. Clinical manifestation includes regenerative anemia whose severity may vary among individuals. In the absence of treatment, it results in premature death. Sickle cell disease is characterized by a large clinical and biological expression variability which depends on genetic and environmental factors. A severe clinical picture marked by high early transfusion frequency, severe infectious complications and early mortality. A constant inflammatory condition characterized by elevated inflammatory proteins and compromised nutritional status. The objective of this study is to determine the hematological parameters profile in moroccan patients with homozygous sickle cell (SS) disease during stationary phases. We conducted a cross-sectional descriptive study of 87 patients with sickle cell (SS) disease. We performed a biological study based on: Hemogram with morphological assessment of red blood cells stained with MGG and automated reticulocyte counting; Hemoglobin electrophoresis test performed on alkaline agarose gel (pH 8.8) and densitometric integration. The average age is 13.22 years ± 16.36, ranging betrween 0.6 and 36 years, with a sex ratio (M/F) of 1.175. Biological effects of anemia were intense in 88.5% of patients; 67.8% of patients had normocytic anemia compared with 29.9% with microcytosis, and 2.3% with macrocytosis. The degree of anisocytosis was related to the degree of anemia, very evocative in patients with homozygous S/S (95.4%). Reticulocytosis was observed in 81.6% of patients; 52.9% of patients had thrombocytosis. Leukocytosis was observed in 64.4% of patients; 80.5% of patients had neutropenia. The parameters of the hemogram will serve as a basis for comparison during crises and will make it possible to evaluate the effectiveness of patient management. High white blood cell count, platelets and MCHC seem to be determinant of sickle cell anemia severity in Morocco. The haematological profile of moroccan patients with sickle cell disease exhibits data similar to those reported in literature relating to patients with leucocytosis from Central Africa. The results of our study suggest that sickle cell anemia is the most common health problem in Morocco and they are similar to those for major sickle cell syndrome., Competing Interests: Les auteurs ne déclarent aucun conflit d'intérêt.

Systemic mastocytosis are rare neoplasms characterized by accumulation of mast cells in at least one internal organ. The majority of systemic mastocytosis patients carry KIT D816V mutation, which activates constitutively the KIT receptor. Patient with advanced forms of systemic mastocytosis, such as aggressive systemic mastocytosis or mast cell leukemia, are poorly treated to date. Unfortunately, the lack of in vivo models reflecting KIT D816V+ advanced disease hampers pathophysiological studies and preclinical development of new therapies for such patients. Here, we describe a new in vivo model of KIT D816V+ advanced systemic mastocytosis developed by transplantation of the human ROSAKIT D816V-Gluc mast cell line in NOD-SCID IL-2R γ-/- mice, using Gaussia princeps luciferase as a reporter. Intravenous injection of ROSAKIT D816V-Gluc cells led, in 4 weeks, to engraftment in all injected primary recipient mice. Engrafted cells were found at high levels in bone marrow, and at lower levels in spleen, liver and peripheral blood. Disease progression was easily monitored by repeated quantification of Gaussia princeps luciferase activity in peripheral blood. This quantification evidenced a linear relationship between the number of cells injected and the neoplastic mast cell burden in mice. Interestingly, the secondary transplantation of ROSAKIT D816V-Gluc cells increased their engraftment capability. To conclude, this new in vivo model mimics at the best the features of human KIT D816V+ advanced systemic mastocytosis. In addition, it is a unique and convenient tool to study the kinetics of the disease and the potential in vivo activity of new drugs targeting neoplastic mast cells.

Cytogenetic analyses (karyotype and, if necessary, appropriate complementary FISH analyses) are mandatory at diagnosis in acute lymphoblastic leukemia (ALL) as their results are taken into account in therapeutic protocols due to their diagnostic and prognostic values. In some cases, karyotype can be completed by other techniques (RT-PCR, RQ-PCR, DNA content, SNP-array, MLPA…) that can be equally or more informative than FISH. Here, we have tempted to establish guidelines concerning karyotype and FISH analyses according to the most recent data of the litterature which is reviewed here, completing the 2008 WHO classification with the recent new cytogenomic entities such as Ph-like ALL and indicating possible therapeutic implications.