Peripheral blood stem cells collection on spectra optia apheresis system using the continuous mononuclear cell collection protocol: A single center report of 39 procedures.

BACKGROUND: The aim of the study was to assess the performance of the new Continuous Mononuclear Cell Collection (CMNC) protocol on the Spectra Optia Apheresis System for collecting autologous Peripheral Blood Stem Cells (PBSC) in adult patients with respect to collection variables, CD34+ cells harvest prediction and engraftment data. In this retrospective study, 39 CMNC procedures on 23 mobilized patients with multiple myeloma and lymphoma were analyzed. CD34+ cells and blood cells yields, collection efficiencies (CE1 and CE2), cell losses were calculated. Engraftment data of 17 autologous transplantations were collected. RESULTS: Apheresis duration was 239 min for a product volume of 220 mL. Cell product haematocrit, MNC and platelets counts were acceptable (respectively 2.4%, 65%, 834 x 109/L). Median platelet loss was 27.3%. Median CD34+ CE1 and CE2 were 64.6% and 48.5% respectively. We harvested 2.92 × 106 CD34+ cells/kg, with a CD34 dose ≥ 2 × 106 /kg for 67% of the procedures. Linear correlation between preapheresis CD34 count and the CP CD34 dose/kg allowed a prediction model with a decrease trend for high WBC precount. Procedures were well tolerated. For 17 autologous transplantations, median time to neutrophils and platelets reconstitutions were 12 and 13 days respectively. CONCLUSIONS: Spectra Optia CMNC protocol successfully collected CD34+ cells with yields permitting the harvest of sufficient enriched grafts for autologous transplantation. The CD34+ cell yield prediction was excellent. PBSC collection with CMNC protocol had advantages of high processing rate, low product volume, and acceptable contamination by platelets. J. Clin. Apheresis 32:182-190, 2017. © 2016 Wiley Periodicals, Inc.

[Treatment of immune-mediated thrombotic thrombocytopenic purpura: A decisive turning point]. / Traitement du purpura thrombotique thrombocytopénique auto-immun : un tournant décisif.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening thrombotic microangiopathy characterized by severe deficiency of ADAMTS13, the enzyme that cleaves von Willebrand factor multimers. Recent insights into iTTP pathophysiology have led to the development of new therapies targeting ADAMTS13 replacement, anti-ADAMTS13 antibodies, and von Willebrand factor-platelet interactions. New maximalist therapeutic strategies are emerging based on triple therapy. While plasma exchange remains the cornerstone therapy of the acute phase, the introduction of front-line immunosuppressive treatments, corticosteroids and rituximab, has led to a reduction in exacerbations and relapses but without any significant improvement in survival. Caplacizumab, a bivalent humanized anti-von Willebrand factor nanobody, is poised to revolutionize the treatment of the acute phase. By inhibiting the interaction between von Willebrand factor multimers and platelets, caplacizumab prevents platelets adhesion, prevents the formation of new microthrombi and protects organs from ischemia. Its early combination with plasma exchange and immunosuppressive therapy prevents unfavorable outcomes and reduces the burden of care. Supported by repeated ADAMTS13 assays, rituximab prevents relapse in patients with persistent or recurrent ADAMTS13 deficiency in clinical remission. This review examines how advances in diagnostics and targeted therapies are changing the current treatment paradigm in both the acute and remission phases and are contributing to dramatically improve the iTTP prognosis.

Caplacizumab to treat immune-mediated thrombotic thrombocytopenic purpura.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and multiorgan failure, resulting from autoantibody-mediated severe A disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) deficiency. In spite of treatment with plasma exchange and immunosuppression, patients remain at risk of exacerbations, refractoriness and death. Caplacizumab (Cablivi; Ablynx, a Sanofi company), a nanobody targeting von Willebrand factor (vWF), has been recently approved in the E.U. and the U.S. as the first therapeutic specifically indicated for the treatment of adults experiencing an episode of iTTP. Caplacizumab blocks the interaction of all multimers with platelets and, therefore, has an immediate effect on platelet aggregation and the ensuing formation and accumulation of platelet-rich microthrombi. This immediate effect of caplacizumab has the potential to protect the patient from tissue ischemia and organ dysfunction while the underlying disease process resolves. We detail here the preclinical and clinical data on caplacizumab for iTTP, including the recent studies that led to approval by the U.S. Food and Drug Administration (FDA) in 2019.

[Therapeutic erythrocytapheresis: technical aspects and clinical applications]. / L'érythraphérèse thérapeutique : technique et applications cliniques.

PURPOSE: Therapeutic erythrocytapheresis is a selective red cell-depletion aphaeresis technique. CURRENT KNOWLEDGE AND KEY POINT: Using a discontinuous or continuous flow blood cell separator, the technique safely allows quickly and automatically collecting a large volume of red cells. The main obstacle of implementation is a poor peripheral venous access. The procedure is well-tolerated. Polycythemia vera, hereditary hemochromatosis, complicated sickle-cell-disease and retinal venous occlusion are the main clinical applications. PROSPECT AND PROJECT: Therapeutic erythrocytapheresis is a more modern and more effective method than the classic patient-bleeding. It has to be preferred in the early treatment of patients with polycythemia vera and hereditary hemochromatosis.

[Update on thrombotic thrombocytopenic purpura]. / Le purpura thrombotique thrombocytopénique acquis de l'adulte : actualités.

PURPOSE: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder and early treatment is vital. Here, we review the recent advances in the understanding of the pathophysiology of TTP and its treatment. CURRENT KNOWLEDGE AND KEY POINTS: Recent advances have shown that TTP is caused by deficiency of the (ADAMTS-13) metalloprotease that cleaves von Willebrand factor multimers. Acquired TTP is associated to inhibitory antibodies directed against ADAMTS-13. This has led to assess new therapeutic approaches in refractory and relapsing forms of TTP and the use of rituximab has shown very encouraging results. FUTURE PROSPECTS AND PROJECTS: A better characterization of TTP amongst the other thrombotic microangiopathies has allowed the use of new therapeutic approaches with the use of rituximab. The encouraging results reported with rituximab in some forms of TTP challenge the classic treatment based on plasma exchanges.

[Paediatric case report of an acquired autoimmune thrombotic thrombocytopenic purpura]. / Purpura thrombotique thrombocytopénique acquis auto-immun chez l'enfant: à propos d'1 cas.

UNLABELLED: Thrombotic thrombocytopenic purpura (TTP), when accompanied by regenerative anaemia with schizocytosis, thrombopenia and neurological manifestations, is a disease whose main characteristic is the absence of the von Willebrand factor (vWF) cleaving protease. The two types of TTP are distinguishable by the presence or absence of antiprotease inhibitors, which are, respectively, either acquired or constitutional. The acquired autoimmune form is most frequently observed in adults. OBSERVATION: An adolescent with a previous history of moderate, isolated thrombopenia first showed symptoms of TTP at the age of 14. Positive antiprotease inhibitors in combination with a degeneration of protease activity confirmed the diagnosis of acquired autoimmune TTP. A treatment consisting of daily plasma exchange led to rapid improvement; however, a failed attempt to space out plasma exchanges necessitated the introduction of 4 weekly injections of Rituximab beginning on day 40, which was successful. Indeed, since the second injection of Rituximab on day 51, the number of platelets stabilized at a normal level, thereby allowing for the complete cessation of plasma exchange. At this writing - day 89 - the patient remains in persistent remission. CONCLUSION: Given the different therapeutic and prognostic implications of the 2 types of TTP in child patients, it is mandatory to end at an accurate biological diagnosis: whereas the constitutional form is effectively treated with plasma injections, the acquired form, while initially requiring plasma exchange, often necessitates the use of immunosuppressors during acute or relapse phase. The present study concerns a paediatric case of acquired TTP treated successfully with Rituximab during an acute dependant phase.

Aldehyde dehydrogenases inhibition eradicates leukemia stem cells while sparing normal progenitors.

The vast majority of patients with acute myeloid leukemia (AML) achieve complete remission (CR) after standard induction chemotherapy. However, the majority subsequently relapse and die of the disease. A leukemia stem cell (LSC) paradigm has been invoked to explain this failure of CR to reliably translate into cure. Indeed, LSCs are highly enriched in CD34+CD38- leukemic cells that exhibit positive aldehyde dehydrogenase activity (ALDH+) on flow cytometry, these LSCs are resistant to currently existing treatments in AML such as cytarabine and anthracycline that, at the cost of great toxicity on normal cells, are highly active against the leukemic bulk, but spare the LSCs responsible for relapse. To try to combat the LSC population selectively, a well-characterized ALDH inhibitor by the trivial name of dimethyl ampal thiolester (DIMATE) was assessed on sorted CD34+CD38- subpopulations from AML patients and healthy patients. ALDH activity and cell viability were monitored by flow cytometry. From enzyme kinetic studies DIMATE is an active enzyme-dependent, competitive, irreversible inhibitor of ALDH1. On cells in culture, DIMATE is a powerful inhibitor of ALDHs 1 and 3, has a major cytotoxic activity on human AML cell lines. Moreover, DIMATE is highly active against leukemic populations enriched in LSCs, but, unlike conventional chemotherapy, DIMATE is not toxic for healthy hematopoietic stem cells which retained, after treatment, their self-renewing and multi-lineage differentiation capacity in immunodeficient mice, xenografted with human leukemic cells. DIMATE eradicates specifically human AML cells and spares healthy mouse hematologic cells.

Cardiac troponin-I on diagnosis predicts early death and refractoriness in acquired thrombotic thrombocytopenic purpura. Experience of the French Thrombotic Microangiopathies Reference Center.

BACKGROUND: Cardiac involvement is a major cause of mortality in patients with thrombotic thrombocytopenic purpura (TTP). However, diagnosis remains underestimated and delayed, owing to subclinical injuries. Cardiac troponin-I measurement (cTnI) on admission could improve the early diagnosis of cardiac involvement and have prognostic value. OBJECTIVES: To assess the predictive value of cTnI in patients with TTP for death or refractoriness. PATIENTS/METHODS: The study involved a prospective cohort of adult TTP patients with acquired severe ADAMTS-13 deficiency (< 10%) and included in the registry of the French Reference Center for Thrombotic Microangiopathies. Centralized cTnI measurements were performed on frozen serum on admission. RESULTS: Between January 2003 and December 2011, 133 patients with TTP (mean age, 48 ± 17 years) had available cTnI measurements on admission. Thirty-two patients (24%) had clinical and/or electrocardiogram features. Nineteen (14.3%) had cardiac symptoms, mainly congestive heart failure and myocardial infarction. Electrocardiogram changes, mainly repolarization disorders, were present in 13 cases. An increased cTnI level (> 0.1 µg L(-1) ) was present in 78 patients (59%), of whom 46 (59%) had no clinical cardiac involvement. The main outcomes were death (25%) and refractoriness (17%). Age (P = 0.02) and cTnI level (P = 0.002) showed the greatest impact on survival. A cTnI level of > 0.25 µg L(-1) was the only independent factor in predicting death (odds ratio [OR] 2.87; 95% confidence interval [CI] 1.13-7.22; P = 0.024) and/or refractoriness (OR 3.03; 95% CI 1.27-7.3; P = 0.01). CONCLUSIONS: A CTnI level of > 0.25 µg L(-1) at presentation in patients with TTP appears to be an independent factor associated with a three-fold increase in the risk of death or refractoriness. Therefore, cTnI level should be considered as a prognostic indicator in patients diagnosed with TTP.

[Apropos of 2 cases of severe malaria contracted in the port of Marseille]. / A propos de deux cas de paludisme grave contractés sur le port de Marseille.

Acute Plasmodium falciparum malaria occurred during summer 1993 in two inhabitants living close to Marseille harbour. History of blood transfusion and travel outside France were excluded as was also discarded airport malaria. Entomological investigations confirmed the absence of Anopheles breeding sites in the port area. An hypothesis is a vectorial transmission following introduction of one or several anopheles arrived on a ship coming from tropical Africa. During this season, the weather conditions were favourable to the survival of anopheles and the completion of P. falciparum sporogonic cycle. Physicians were advised to take into consideration malaria in the differential diagnosis of fever from unknown origin in any patient working or living inside or around the harbour area regardless history of previous travel in malaria endemic region.

[Heparin-induced thrombopenia: rapid regression of thrombopenia and thrombosis after plasma exchange. Case report]. / Thrombopénie induite par l'héparine: régression rapide de la thrombopénie et de la thrombose après échange plasmatique. A propos d'un cas.

INTRODUCTION: Heparin-induced thrombocytopenia with thrombosis is a rare but severe adverse reaction to heparin therapy, whose management is difficult. After heparin withdrawal, the initiation of an alternative anticoagulant therapy, such as recombinant hirudin or danaparoid, is strongly recommended before vitamin K antagonists are effective. Several reports of the efficacity of plasma exchanges in patients with life-threatening thrombosis have been made. EXEGESIS: We report on a patient with severe aortic thrombosis related to heparin therapy in whom a unique plasma exchange resulted in both dramatic improvement in the platelet count and marked reduction of the thrombosis. CONCLUSION: This case provides further evidence that plasma exchanges can be useful in the management of heparin-induced thrombocytopenia with thrombosis. They are rapidly efficient and can be used before heparin alternative treatment is effective.

[Diabetes insipidus disclosing metastasis of breast adenocarcinoma]. / Diabète insipide révélant une métastase d'un adénocarcinome mammaire.

We are reporting on a case of diabetes insipidus (DI) and anterior pituitary failure revealing a breast cancer metastasis. Ten years after being diagnosed with a unilateral breast cancer, the patient presented with asthenia, thirst, polyuria and nocturia improved by subcutaneous DDAVP. MRI revealed a thickened pituitary stalk. DI is uncommon, late and usually asymptomatic in breast cancer. The association with an anterior pituitary failure is even more rare. In our patient the metastasis is in the pituitary stalk and seems to be due to meningeal deposits. MRI appears to be the best procedure to perform, showing a thickening stalk. Extension to the pituitary gland is related to direct tumor invasion from adjacent structures rather than haematogenous spread.

[Idiopathic thrombotic thrombocytopenic purpura or Moschowitz syndrome: current physiopathologic and therapeutic perspectives]. / Le purpura thrombotique thrombocytopénique idiopathique ou syndrome de Moschowitz: actualités physiopathologiques et perspectives thérapeutiques.

INTRODUCTION: The objective of this work was to review current data about the physiopathology, clinical features, and treatment of thrombotic thrombocytopenic purpura (Moschowitz's syndrome). CURRENT KNOWLEDGE AND KEY POINTS: Thrombotic thrombocytopenic purpura is a rare disorder characterized by widespread thrombotic injuries of platelets in the microcirculation. Its physiopathology has been elucidated recently. Evidence of a deficiency of Von Willebrand's factor-cleaving protease would be due to either IgG antibodies in the acute form of the disease or constitutional deficiency in the chronic form of the disease. FUTURE PROSPECTS AND PROJECTS: Plasma exchange is the current reference treatment. However, in the light of recent publications, either infusions of concentrates of purified enzyme or more intensive immunosuppressive therapy would be more specific.

[Renal complications from intravenous immunoglobulins. Role of renal hemodynamic factors]. / Complications rénales des immunoglobulines intraveineuses. Rôle des facteurs hémodynamiques rénaux.

In idiopathic thrombocytopenic purpura, intravenous immunoglobulin therapy is currently a treatment of choice. It is usually effective with little side-effects. Acute renal failure has been recently identified as a potential, though rare, complication of intravenous immunoglobulins. However, the mechanism remains unclear. A 53 year-old-woman with idiopathic thrombocytopenic purpura developed oliguric renal failure after high doses of intravenous immunoglobulins. Her renal function returned to normal after dialysis and plasmapheresis. This rapid normalization suggested that acute renal failure was functional. Since laboratory tests showed an increase in protidemia concomitant to the immunoglobulin therapy, acute renal failure was likely to be related to hyperosmolar renal damage.

[Extracorporeal photochemotherapy in therapy-refractory subacute lupus]. / Lupus subaigu multirésistant: traitement par photophérèse.

BACKGROUND: Extracorporeal photopheresis is a leukapheresis therapy that uses psoralen and ultraviolet A irradiation. We report the case of a woman with a refractory sub acute lupus which dramatically but transitionally responded to extracorporeal photopheresis. CASE REPORT: This women, born in 1960, developed erythematous and squamous patches located on face and neckline, associated with hyperpigmented and atrophic lesions on the arms and shoulders. Investigations confirmed the diagnosis of subacute lupus without systemic disease. All lesions progressed, despite all conventional therapies leading to major aesthetic prejudice. Extracorporeal photopheresis was initiated, and after two months, all lesions, including atrophic and healing lesions had regressed, but laboratory abnormalities did not change. Extracorporeal photopheresis was well tolerated. However, treatment was discontinued nine months later, since the cutaneous lesions relapsed. COMMENTS: Extracorporeal photopheresis could be efficient in the treatment of cutaneous autoimmune diseases through several immunomodulatory mechanisms. Extracorporeal photopheresis is a potent alternative agent in the therapy of refractory dermatological diseases

[Pemphigoid and acquired hemophilia]. / Pemphigoïde et hémophilie acquise.

INTRODUCTION: The association of bullous pemphigoid and acquired haemophilia is reported. CASE-REPORT: A 74 year-old man developed a bullous pemphigoid after decreasing corticotherapy, ecchymosis and haematomas revealing a high level of acquired anti-VIII antibodies (110 Bethesda UB units; TCA 98 s). Immunosuppressive treatment (cyclosporine, prednisone, azathioprine and bolus of cyclophosphamide) did not stop the disease. Perfusion of recombinant factor VIIa, human immunoglobulins and prednisone-azathioprine association permitted clinical and biological remission. DISCUSSION: Acquired haemophilia is idiopathic half the time. It can appear in autoimmmune diseases. Mortality is high. Only 4 cases of association with bullous pemphigoid have been reported in the literature. At the haemorrhagic phase, porcine factor VIII or more recombinant activated factor VII with human immunoglobulins are necessary. Immunosuppressive treatment is used to decrease production of anti-factor VIII antibodies.

[Camptocormia in the elderly patient: myopathy or muscular dystonia?]. / La camptocormie du sujet agé: myopathie ou dystonie musculaire?

Two cases of camptocormia in elderly patients are reported. Both patients presented with an anterior curvature of the trunk which disappeared in the decubitus position. Computed tomography demonstrated hypodensity of the muscles which preceded atrophy. Histological changes were of low specificity and diverse with irregular and a trophic muscle fibers and occasionally endomysial fat or mitochondrial abnormalities. These findings suggest that camptocormia may be the consequence of a disease of spinal muscles. Pathophysiological hypotheses include neurogenic atrophy of spinal muscles, spinal amyotrophy, and delayed primary myopathy. None of these hypotheses was consistent with findings in our two patients. The terms "muscular dystrophy" and "mitochondrial myopathy" occasionally used seem inappropriate in view of the lack of specificity of the lesions. A better term may be "muscular insufficiency", the mechanism of which is still unclear.

Circulating endothelial cells and progenitors as prognostic factors during autoimmune thrombotic thrombocytopenic purpura: results of a prospective multicenter French study.

BACKGROUND: Autoimmune thrombotic thrombocytopenic purpura (AI-TTP) is characterized by an excess of circulating ultralarge von Willebrand factor (VWF) caused by anti-ADAMTS-13 autoantibodies. Animal studies, however, have shown that endothelial cell activation may also be an important trigger of AI-TTP. OBJECTIVES: To prospectively study circulating biomarkers of endothelial lesion and activation, such as circulating endothelial cells (CECs), soluble P-selectin (sP-selectin), or VWF, and of endothelial repair, such as circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs), in AI-TTP, in relation to disease severity and prognosis. RESULTS: Twenty-two patients were included in this study. CEC (P < 0.01), VWF (P < 0.05) and sP-selectin (P < 0.01) levels were significantly increased during crisis, and returned to baseline levels during remission. Both CEC (P < 0.05) and sP-selectin (P < 0.05) levels were significantly higher in patients who died or developed neurologic sequelae. CPC levels were substantially increased during the acute phase of the disease (P < 0.001), and returned to baseline levels during remission. Among CPCs, EPC levels were also increased during crisis (P < 0.05) and significantly decreased during remission. Patients who received < 16 plasma exchanges (PEs) had significantly higher EPC counts (P < 0.05) than those who needed more numerous PEs to obtain remission, suggesting that initial EPC counts may be associated with faster endothelial repair. CONCLUSION: The profile of circulating endothelial markers shows massive endothelial activation and repair/remodeling during AI-TTP, and suggests that CECs and EPCs may be promising prognostic biomarkers of the disease.

[Effectiveness of therapeutic erythrocytapheresis to achieve iron depletion in hereditary type 1 hemochromatosis: report of 30 cases]. / Intérêt des érythraphérèses à la phase initiale du traitement des hémochromatoses génétiques de type 1: expérience à propos de 30 cas.

PURPOSE OF THE STUDY: Weekly phlebotomy schedule is commonly recommended to achieve iron depletion in hereditary hemochromatosis (HH). However, in patients with severe iron overload, more than 2 years may be required, leading to fatigue and lack of compliance. For more than 10 years, we have used erythrocytapheresis (EA) as an alternative treatment. PATIENTS AND METHODS: To assess the number of EA to achieve iron depletion and the duration of the iron depletion therapy as well of the tolerance, we retrospectively analysed the data of newly diagnosed hemochromatosis patients, homozygote for the C282Y mutation, followed in our department between 2001 and 2007. EA were performed using a discontinuous or a continuous flow cell separators. The protocol consisted in a bimonthly EA until normalisation of the serum ferritin, with the aim of reducing the patient's hematocrit between 32-35% at the end of each session. Then we performed monthly EA until complete desaturation, defined as serum ferritin concentration below 50 µg/L and transferrin saturation below 40%. RESULTS: Thirty patients were included (23 male, mean age 52 years, range 25-78) and 625 procedures analyzed. The mean volume of removed erythrocytes in each procedure was 416.4 mL (range 150-948), which equals to 374 mg of removed iron. Iron depletion (ferritin < 50 µg/L) was achieved after 11 months with 20 sessions (range 14-78). No serious adverse reactions or citrate toxicity were observed during and after the apheresis procedures. No specific fatigue was reported during the iron depletion therapy. Patient compliance was 100%. Clinical improvement was noted in 12 out of 18 of symptomatic patients. CONCLUSION: We conclude that HH patients treated with bimonthly EA achieved iron depletion in less than 1 year under good condition of tolerance. These data support the use of EA in patients with a severe iron overload, since it may reduce the number of the procedures as well as the duration of the iron depletion therapy.