Paul Coppo

Thrombotic thrombocytopenic purpura related to severe ADAMTS13 deficiency in children.

Thrombotic thrombocytopenic purpura (TTP) related to a severely deficient activity of the von Willebrand factor cleaving protease, ADAMTS (A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats) 13, is a life-threatening event, the onset of which may occur as early as childhood. TTP is either inherited (Upshaw-Schulman syndrome) via ADAMTS13 gene mutations (neonatal onset) or acquired via anti-ADAMTS13 autoantibodies (childhood onset). TTP is due to platelet- and von-Willebrand-factor-rich thrombi of the microvasculature, inducing mechanical hemolytic anemia, consumption thrombocytopenia, and multivisceral ischemia. Clinical course consists of relapsing acute events triggered mostly by infections, associated icterus and hyperbilirubinemia, severe hemolytic anemia with schistocytosis and a negative Coombs test, severe thrombocytopenia, and sometimes symptoms related to visceral ischemia (renal failure, central nervous system vascular events, other organ failure). The recently available ADAMTS13 laboratory investigation combining measurement of ADAMTS13 activity in plasma, search for an ADAMTS13 circulating inhibitor, and anti-ADAMTS13 IgG and ADAMTS13 gene sequencing is a crucial addition to TTP diagnosis. Plasma exchanges are first-line treatment of acquired TTP, combined with steroids and immunosuppressive drugs. Curative treatment of acute events in Upshaw-Schulman syndrome relies on plasma infusions (provider of active ADAMTS13). Guidelines for preventive treatment of relapses are not clearly established but should associate plasmatherapy and caution to triggers of relapses. Therapeutic perspectives are focused on the development of concentrated plasma-derived ADAMTS13 or recombinant ADAMTS13.

Partial Fanconi Syndrome Induced by Imatinib Therapy: A Novel Cause of Urinary Phosphate Loss

Imatinib mesylate (Gleevec, Glivec; Novartis, Basel, Switzerland) is a specific tyrosine kinase inhibitor that has become the gold-standard treatment for patients with chronic myeloid leukemia. Several tyrosine kinases inhibited by imatinib are expressed in the kidney, and although the drug is usually well tolerated, several cases of acute renal failure were reported. We describe for the first time a case of a patient treated by imatinib for chronic myeloid leukemia who developed partial Fanconi syndrome with mild renal failure, which leads to a discussion of the pathophysiological characteristics of imatinib-induced renal toxicity. Patients on long-term imatinib treatment should be monitored for renal failure, as well as proximal tubule dysfunction, including hypophosphatemia.

Current management and therapeutical perspectives in thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a particular form of thrombotic microangiopathy typically characterized by microangiopathic hemolytic anemia, profound peripheral thrombocytopenia, and a severe deficiency of the von Willebrand factor-cleaving protease ADAMTS13 (acronym for A Disintegrin And Metalloproteinase with ThromboSpondin-1 motifs [13th member of the family]). ADAMTS13 deficiency is usually severe (<10% of normal activity) and results from autoantibodies directed to ADAMTS13 (acquired TTP) or from biallelic mutations of the encoding gene. In some cases, acquired TTP occurs in association with specific conditions that must be identified for appropriate management: a HIV infection, a connective tissue disease, a pregnancy, a cancer or a treatment with antiplatelet agents. TTP requires a rapid diagnosis and an adapted management in emergency, which allows current remission rates of 80 to 90%. Maximal measures of resuscitation may be required. Daily sessions of therapeutical plasma exchange (TPE) until durable platelet count recovery remain the basis of management of acquired TTP. In the last few years, the anti-CD20 monoclonal antibody rituximab has been increasingly used in patients with a suboptimal response to standard treatment, such as those with refractory disease (∼10% of cases) or an exacerbation of the disease despite intensive TPE (∼50% of cases). Rituximab prevents 1-year but not long-term relapses. Further studies should specify the optimal schedule of rituximab administration and its role as a prophylactic treatment in asymptomatic patients with severe acquired ADAMTS13 deficiency that persists even in disease remission. In hereditary TTP, also known as Upshaw-Schulman syndrome (USS), a diagnosis early in life is mandatory. Prophylactic infusions of plasma should be performed in chronic relapsing forms to prevent long-term organ complications, which have to be assessed accurately and regularly. In the upcoming years, new targeted therapies evaluated through international trials should further improve the management of these diseases. Consensual guidelines for the treatment of very specific and rare situations (such as management during pregnancy in USS patients and prevention of relapses in chronic relapsing acquired TTP) should arise from the shared experience of national groups.

Evaluation of a chromogenic commercial assay using VWF-73 peptide for ADAMTS13 activity measurement.

INTRODUCTION Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy (TMA), related to a severe functional deficiency of ADAMTS13 activity (<10% of normal). ADAMTS13 activity is thus crucial to confirm the clinical suspicion of TTP, to distinguish it from other TMAs, and to perform the follow-up of TTP patients. MATERIAL AND METHODS We compared the performance of the commercial chromogenic assay Technozym ADAMTS13 Activity ELISA (chromogenic VWF73 substrate, Chr-VWF73, Technoclone, Vienna, Austria), to that of our in-house FRETS-VWF73 used as reference method. A large group of 247 subjects (30 healthy volunteers and 217 patients with miscellaneaous TMAs) was studied. RESULTS The lower limit of detection of the Chr-VWF73 was 3%, which is well adapted to the clinically relevant threshold for TTP diagnosis (10%). Our results showed a reasonable agreement between FRETS-VWF73 and Chr-VWF73 assays to distinguish samples with an ADAMTS13 activity <10% from those with an ADAMTS13 activity >10%. However, Chr-VWF73 assay provided false negative results in ~12% of acute TTP patients. Inversely, the Chr-VWF73 assay globally underestimated ADAMTS13 activity in detectable values ranging from 11 to 100% (with a great variability compared to FRETS-VWF73), which may be a concern for the follow-up of TTP patients in remission. CONCLUSION In-house assays developed and performed by expert laboratories remain the reference methods that should be used without limitation to control values provided by commercial assays when needed. Also, the development of an international reference preparation will be crucial to improve standardization.

Diversity and combinations of infectious agents in 38 adults with an infection-triggered reactive haemophagocytic syndrome: a multicenter study

Reactive haemophagocytic syndrome (HS) is a rare condition that occurs in patients with infections, haematological malignancies or autoimmune diseases. Although various microorganisms are thought to trigger HS, most of the literature data on this topic have been gathered in single-centre case series. Here, we sought to characterize infectious triggers in a large, multicentre cohort of patients with HS. Patients were included in the present study if HS was solely due to one or more infections. Detailed microbiological data were recorded. Of the 162 patients with HS in the cohort, 40 (25%) had at least one infection and 38 of the latter (including 14 women, 36.8%) were included. The median age was 46 years. Seven patients were presumed to be immunocompetent (18.4%), whereas 19 patients (50%) were infected with human immunodeficiency virus and 12 patients (31.6%) were immunocompromised for other reasons. Twenty-seven patients (71.1%) had a single infection, whereas six (15.8%) and five (13.1%) patients had, respectively, two and three concomitant infections. We observed pyogenic bacterial infections (n = 7), tuberculosis (n = 10), non-tuberculous mycobacteriosis (n = 3), viral infections (n = 17: 11 cytomegalovirus, three Epstein-Barr virus, two human herpesvirus 8, one herpes simplex virus 2), parasitic infections (n = 8: four disseminated toxoplasmosis, one leishmaniasis, three malaria), fungal infections (n = 5: four pulmonary pneumocystosis and one candidaemia). Eighteen patients (47.4%) received corticosteroids and/or etoposide. Twelve patients died (31.6%). All multiple infections and all deaths occurred in immunocompromised patients. When compared with patients suffering from malignancy-associated HS, patients with infection-triggered HS were younger and more likely to be immunocompromised, and had a better outcome.

Thrombotic microangiopathies: from empiricism to targeted therapies.

Thrombotic microangiopathies: from empiricism to targeted therapies P. Coppo, Paris, France Genetics of hemolytic uremic syndromes M. Malina et al., Prague, Czech Republic Management of hemolytic uremic syndrome C. Loirat et al., Paris, France Paradigm shift of childhood thrombotic thrombocytopenic purpura with severe ADAMTS13 deficiency H. Yagi et al., Nara, Japan Advantages and limits of Adamts13 testing in the prognostic assessment of thrombotic thrombocytopenic purpura P.M. Mannucci, Milan, Italy and M. Franchini, Parma, Italy Current management and therapeutical perspectives in thrombotic thrombocytopenic purpura P. Coppo, Paris, France and A. Veyradier, Clamart, France Thrombotic microangiopathic syndromes associated with drugs, HIV infection, hematopoietic stem cell transplantation and cancer J.N. George et al., Oklahoma City, USA

Autoimmune manifestations associated with lymphoma: characteristics and outcome in a multicenter retrospective cohort study

Abstract This French multicenter retrospective cohort study aimed to describe the autoimmune manifestations (AIMs) associated with lymphoma among patients hospitalized between 2005 and 2016 in three French University Hospitals. Among 2503 patients with lymphoma, 108 (4.3%) had AIMs, mostly autoimmune cytopenias (71.3%), neurological diseases (10.2%), kidney diseases (6.5%), systemic vasculitis (5.6%) and others. As compared with the 2395 lymphoma patients without AIMs, those with AIMs were older (p = .01), more frequently had B-cell chronic lymphocytic leukemia (p < .01) and less frequently diffuse large B-cell lymphomas (p = .01) and Hodgkin lymphoma (p = .01). The 5-year overall survival with lymphoma was 65% and 79% (p = .03) with and without AIMs. This large cohort study shows that various types of AIMs, mostly cytopenias, could be associated with lymphoma and affect the overall outcome with lymphoma, in particular for B-cell non-Hodgkin lymphoma (p = .01) and T-cell non-Hodgkin lymphoma (p = .01), with no survival difference noted for other types of lymphoma (p = .2).

Manifestations auto-immunes et inflammatoires des hémopathies lymphoïdes

In this literature review, we reported autoimmune and inflammatory disorders associated with lymphoid hematological malignancies, including non-Hodgkins lymphoma, Hodgkins lymphoma and chronic lymphocytic leukemia. The different types of systemic involvement are classified by affected organ. We listed in this review the joint diseases, skin, neurologic, hematologic, renal, and vasculitis. We tried to determine whether there is a correlation between each autoimmune manifestation and a specific type of lymphoma or a particular feature that may support a paraneoplastic origin, if there is an impact on the prognosis of the hematological malignancy, and finally, we identified the different therapeutic strategies used in the literature.

Autoimmune and inflammatory disorders associated with lymphoid hematological malignancies

In this literature review, we reported autoimmune and inflammatory disorders associated with lymphoid hematological malignancies, including non-Hodgkins lymphoma, Hodgkins lymphoma and chronic lymphocytic leukemia. The different types of systemic involvement are classified by affected organ. We listed in this review the joint diseases, skin, neurologic, hematologic, renal, and vasculitis. We tried to determine whether there is a correlation between each autoimmune manifestation and a specific type of lymphoma or a particular feature that may support a paraneoplastic origin, if there is an impact on the prognosis of the hematological malignancy, and finally, we identified the different therapeutic strategies used in the literature.

Dissecting the pathophysiology of immune thrombotic thrombocytopenic purpura: interplay between genes and environmental triggers

Although outstanding progress has been made in understanding the pathophysiology of thrombotic thrombocytopenic purpura (TTP), knowledge of the immunopathogenesis of the disease is only at an early stage. Anti-ADAMTS13 auto-antibodies were shown to block proteolysis of von Willebrand factor and/or induce ADAMTS13 clearance from the circulation. However, it still remains to identify which immune cells are involved in the production of anti-ADAMTS13 autoantibodies, and therefore account for the remarkable efficacy of the B-cell depleting agents in this disease. The mechanisms leading to the loss of tolerance of the immune system towards ADAMTS13 involve the predisposing genetic factors of the human leukocyte antigen class II locus DRB1*11 and DQB1*03 alleles as well as the protective allele DRB1*04, and modifying factors such as ethnicity, sex and obesity. Future studies have to identify why these identified genetic risk factors are also frequently to be found in the healthy population although the incidence of immune-mediated thrombotic thrombocytopenic purpura (iTTP) is extremely low. Moreover, the development of recombinant ADAMTS13 opens a new therapeutic era in the field. Interactions of recombinant ADAMTS13 with the immune system of iTTP patients will require intensive investigation, especially for its potential immunogenicity. Better understanding of iTTP immunopathogenesis should, therefore, provide a basis for the development of novel therapeutic approaches to restore immune tolerance towards ADAMTS13 and thereby better prevent refractoriness and relapses in patients with iTTP. In this review, we address these issues and the related challenges in this field.