Abstract Hereditary haemorrhagic telangiectasia, inherited as an autosomal dominant trait, affects approximately 1 in 5000 people. The abnormal vascular structures in HHT result from mutations in genes (most commonly endoglin or ACVRL1 ) whose protein products influence TGF-ß superfamily signalling in vascular endothelial cells. The cellular mechanisms underlying the generation of HHT telangiectasia and arteriovenous malformations are being unravelled, with recent data focussing on a defective response to angiogenic stimuli in particular settings. For affected individuals, there is often substantial morbidity due to sustained and repeated haemorrhages from telangiectasia in the nose and gut. Particular haematological clinical challenges include the management of severe iron deficiency anaemia; handling the intricate balance of antiplatelet or anticoagulants for HHT patients in whom there are often compelling clinical reasons to use such agents; and evaluation of apparently attractive experimental therapies promoted in high profile publications when guidelines and reviews are quickly superseded. There is also a need for sound screening programmes for silent arteriovenous malformations. These occur commonly in the pulmonary, cerebral, and hepatic circulations, may haemorrhage, but predominantly result in more complex pathophysiology due to consequences of defective endothelium, or shunts that bypass specific capillary beds. This review will focus on the new evidence and concepts in this complex and fascinating condition, placing these in context for both clinicians and scientists, with a particular emphasis on haematological settings.
Abstract The inherited marrow failure syndromes are a diverse set of genetic disorders characterized by hematopoietic aplasia and cancer predisposition. The clinical phenotypes are highly variable and much broader than previously recognized. The medical management of the inherited marrow failure syndromes differs from that of acquired aplastic anemia or malignancies arising in the general population. Diagnostic workup, molecular pathogenesis, and clinical treatment are reviewed.
Abstract Multiple myeloma (MM) is a clonal B-cell malignancy characterized by the aberrant expansion of plasma cells within the bone marrow, as well as at extramedullary sites. Decades of scientific research are now beginning to unravel the intricate biology that underlies the pathophysiology of MM. In particular, the roles of cellular differentiation, molecular pathogenesis, and oncogenes involved in the natural history of MM are becoming clearer. This has enabled the identification of specific cytokines, adhesion molecules, and stromal cells that affect MM cell development, disease progression, and treatment responses. This review describes our current understanding regarding the biology of MM, and how this has led to a robust pipeline of novel therapeutic agents with the potential to overcome resistance to existing MM therapies and, therefore, further improve outcomes in patients with MM.
Abstract Drug-induced immune hemolytic anemia (DIIHA) is rare; it can be mild or associated with acute severe hemolytic anemia (HA) and death. About 125 drugs have been implicated as the cause. The HA can be caused by drug-independent antibodies that are indistinguishable, in vitro and in vivo, from autoantibodies causing idiopathic warm type autoimmune hemolytic anemia (AIHA). More commonly, the antibodies are drug-dependent (i.e., will only react in vitro in the presence of the drug). The most common drugs to cause DIIHA are anti-microbials (e.g., cefotetan, ceftriaxone and piperacillin), which are associated with drug-dependent antibodies. The most common drug to cause AIHA is fludarabine. Finding out which drug is causing the problem and stopping that drug is the first approach to therapy. It is not easy to identify the drug interactions accurately in vitro; laboratories specializing in this area can be of great help.
Abstract The common autosomally inherited mucocutaneous bleeding disorder, von Willebrand disease (VWD) results from quantitative or qualitative defects in plasma von Willebrand factor (VWF). Mutation can affect VWF quantity or its functions mediating platelet adhesion and aggregation at sites of vascular damage and carrying pro-coagulant factor VIII (FVIII). Phenotype and genotype analysis in patients with the three VWD types has aided understanding of VWF structure and function. Investigation of patients with specific disease types has identified mutations in up to 70% of type 1 and 100% of type 3 VWD cases. Missense mutations predominate in type 1 VWD and act through mechanisms including rapid clearance and intracellular retention. Many mutations are incompletely penetrant and attributing pathogenicity is challenging. Other factors including blood group O contribute to low VWF level. Missense mutations affecting platelet- or FVIII-binding through a number of mechanisms are responsible for the four type 2 subtypes; 2A, 2B, 2M and 2N. In contrast, mutations resulting in a lack of VWF expression predominate in recessive type 3 VWD. This review explores the genetic basis of each VWD type, relating mutations identified to disease mechanism. Additionally, utility of genetic analysis within the different disease types is explored.
Abstract In patients with disseminated intravascular coagulation (DIC) a variety of altered coagulation parameters may be detectable, such as thrombocytopenia, prolonged global coagulation times, reduced levels of coagulation inhibitors, or high levels of fibrin split products. In addition, more sophisticated tests for activation of individual factors or pathways of coagulation may point to specific involvement of these components in the pathogenesis of the disorder. There is not a single test, however, that is sufficiently accurate to establish or reject a diagnosis of DIC. Nevertheless, a combination of widely available tests may be helpful in making the diagnosis of DIC and can also be helpful to guide in the selection of DIC patients that require specific, often expensive, interventions in the coagulation system. More recently developed dynamic algorithms, assessing changes in coagulation parameters over sequential days, could further increase the diagnostic accuracy for DIC and may be helpful to detect early stages of coagulopathy potentially evolving into DIC.
Abstract New effective strategies are required that specifically address the challenges of multiple myeloma (MM) treatment, namely, disease recurrence, immunosuppression, and treatment-related toxicities. Recent preclinical and clinical findings suggest that the IMiDs® immunomodulatory compound lenalidomide has a dual mechanism of action, involving both a direct tumoricidal activity and immunomodulation, which may result in rapid and sustained control of MM, respectively. The tumoricidal effect of lenalidomide occurs through several mechanisms, including disruption of stromal support, induction of tumor suppressor genes, and activation of caspases. The immunomodulatory effects of lenalidomide, including T-cell and natural killer (NK)-cell activation, and increased expression of death effector molecules, lead to enhanced immune cell function and may explain the beneficial effects of this agent in the maintenance setting. Lenalidomide appears to be effective regardless of prior thalidomide treatment, which may reflect mechanistic differences – lenalidomide has greater immunomodulatory properties than thalidomide, whereas thalidomide has greater antiangiogenic activity. Recent studies also suggest that the concomitant use of dexamethasone may influence lenalidomide's direct and immunomodulatory effects. Lenalidomide in combination with dexamethasone synergistically inhibits proliferation and induces apoptosis; however, dexamethasone appears to antagonize the immune-enhancing effect of lenalidomide. A study has demonstrated that a regimen of lenalidomide in combination with an optimal dose and schedule of dexamethasone may increase survival by allowing synergistic antiproliferative effects, without affecting immunomodulatory activity. As preclinical and clinical research continue, additional insights into the dual mechanism of action of lenalidomide will help to further optimize the use of lenalidomide in MM.
Abstract Acute myeloid leukaemia (AML) is one of the most common haematological malignancies and is increasing in frequency due to an ageing population. Whilst remission will be achieved in up to 80% of those receiving intensive chemotherapy, the main variables precluding cure are the treatment-related mortality and relapse rates. Decisions on intensification, de-escalation and allografting rely on the ability to divide an apparently homogeneous group according to risk. A wide range of clinical, cytogenetic and molecular variables may be used to inform this task. Cytogenetic and molecular characterisation has already identified subgroups, such as acute promyelocytic leukaemia (APL) with t(15;17)/ PML-RARA and AML with FLT3 mutation for which targeted therapies are available, and further molecularly defined groups who may be potential candidates for this approach are likely to be identified in the future. This review examines the range of established clinical and diagnostic parameters that should be used in assessing prognosis for a patient with AML and looks ahead to an expanding repertoire of potential variables that are currently under evaluation.
Abstract Most infants with birth weight < 1.0 kg are given multiple red blood cell (RBC) transfusions within the first few weeks of life. The anaemia of prematurity is caused by untimely birth occurring before placental iron transport and fetal erythropoiesis are complete, by phlebotomy blood losses taken for laboratory testing, by low plasma levels of erythropoietin due to both diminished production and accelerated catabolism, by rapid body growth and need for commensurate increase in red cell volume/mass, and by disorders causing RBC losses due to bleeding and/or hemolysis. RBC transfusions are the mainstay of therapy with recombinant human erythropoietin largely unused because it fails to substantially diminish RBC transfusion needs — despite exerting substantial erythropoietic effects on neonatal marrow.
Abstract Physicians treating patients with the classic Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs) (polycythemia vera [PV], essential thrombocythemia [ET] and primary myelofibrosis [PMF]) traditionally had few therapeutic drugs available. Spurred by the discovery of activating mutation of the JAK2 tyrosine kinase (JAK2 V617F mutation) in patients with Ph-negative MPNs several years ago, several JAK2 inhibitors were synthesized and are currently undergoing clinical trials in patients with PMF, PV and ET. Initial results from these studies have shown that these drugs can markedly reduce spleen size and alleviate constitutional symptoms, increase weight and improve exercise capacity in MF patients, thus improve quality of their life, which is significant clinical benefit. In ET and PV JAK2 inhibitor therapy may efficiently control blood cell count, as well as improve splenomegaly and control disease related symptoms. JAK2 inhibitors are a novel class of agents with promising results for treating patients with MF, PV and ET. In this article we will review the current evidence regarding the role of JAK2 mutations in the pathogenesis of Ph-negative MPNs and summarize results from the most recent clinical trials with JAK2 inhibitors in these disorders. JAK2 inhibitors are a novel class of agents with promising results for treating patients with MF, PV and ET.
Summary Developmental Hemostasis refers to the age-related changes in the coagulation system that are most marked during neonatal life and childhood. An understanding of these changes is crucial to the accurate diagnosis of hemostatic abnormalities in neonates and children. This paper explains the current understanding of developmental hemostasis and describes the common pitfalls observed in clinical practice through failure to implement the principles into routine diagnostic work. Finally, there is a brief discussion as to a potential physiological rationale for developmental hemostasis and the implications of this for hemostatic interventions in neonates and children. There remains a need for further study to improve our understanding of the implications of developmental hemostasis in normal growth and development.
Abstract Myeloid leukemias are clonal disorders originating in a primitive multipotential hematopoietic cell and characterized by aberrant proliferation, differentiation and maturation of leukemic progenitors and precursor cells. These diseases are the result of multiple genetic and epigenetic events, although the nature and number of events vary widely among patients. For over four decades, studies have identified sub-populations of leukemic cells possessing different functional capabilities. Investigators have struggled to understand the origin and significance of this heterogeneity. The stem cell model for myeloid malignancies has offered one potential explanation. Since 1994, experimental data supporting the presence of leukemia stem cells has been reported and validated in numerous studies. We will review the history of the model, data from the past decade supporting the stem cell model for myeloid malignancies, more recent data regarding patient specific variability in leukemic stem cell surface antigen phenotype and the impact the stem cell model has on the care of patients with myeloid malignancies.
Abstract The management of chronic lymphocytic leukaemia is currently undergoing profound changes. Several drugs like bendamustine, alemtuzumab and rituximab have recently been approved for CLL treatment by regulatory agencies. New and very promising compounds like lenalidomide, ofatumumab, GA101, flavopiridol, or ABT-263 are currently investigated in clinical trials and are likely to further enlarge the therapeutic armamentarium in the next years. Latest results show that chemoimmunotherapies like FCR (fludarabine, cyclophosphamide and rituximab) may improve the life expectancy of CLL patients. This new paradigm will modify the way of CLL management in a radical manner. Finally, the development of new biological markers that describe distinct forms of CLL allows to enter the era of personalized therapy similar to other malignancies.
Abstract Increased survival in patients with β thalassaemia major (TM) allowed for several morbidities to manifest. Renal manifestations of the disease and its treatment have been poorly evaluated. There is evidence, mainly from studies in the paediatric population, of tubular dysfunction and glomerular filtration rate abnormalities in this patient population. Long-term outcomes of these changes, however, have not been prospectively investigated. The pathogenesis of these abnormalities could be attributed to iron overload, too aggressive iron removal, and/or the underlying anaemia. These changes seem to be nonprogressive, resolve spontaneously in most part, or may require iron chelator dose modifications. Relative iron depletion may explain renal function changes attributed to chelation therapy; thus, sudden removal of iron or overchelation should be avoided. Future studies should aim to evaluate the natural history of kidney function in TM patients to help understand the mechanisms and long-term sequelae of the observed renal changes.
Abstract Thrombopoietin (TPO) is the key cytokine involved in thrombopoiesis, and is the endogenous ligand for the thrombopoietin receptor that is expressed on the surface of platelets, megakaryocytes, and megakaryocytic precursors. First-generation thrombopoietic agents were recombinant forms of human TPO, and their development was discontinued after prolonged thrombocytopenia due to neutralizing auto-antibodies cross-reacting with endogenous TPO was observed. Second-generation thrombopoiesis-stimulating molecules are now available, which have unique pharmacological properties and no sequence homology to endogenous TPO. Two of these new agents, romiplostim and eltrombopag, have already completed phase III trials in primary immune thrombocytopenia and have been granted marketing authorization for use in this disease. Phase II and III trials with these novel drugs are ongoing in other conditions characterized by thrombocytopenia, such as chemotherapy, chronic liver disease, and the myelodysplastic syndromes. Most of the other second-generation thrombopoietic growth factors are in early phase clinical development.
Summary Chronic kidney disease (CKD) is a widespread health problem in the world and anemia is a common complication. Anemia conveys significant risk for cardiovascular disease, faster progression of renal failure and decreased quality of life. Patients with CKD can have anemia for many reasons, including but not invariably their renal insufficiency. These patients require a thorough evaluation to identify and correct causes of anemia other than erythropoietin deficiency. The mainstay of treatment of anemia secondary to CKD has become erythropoiesis-stimulating agents (ESAs). The use of ESAs does carry risks and these agents need to be used judiciously. Iron deficiency often co-exists in this population and must be evaluated and treated. Correction of iron deficiency can improve anemia and reduce ESA requirements. Partial, but not complete, correction of anemia is associated with improved outcomes in patients with CKD.
Summary Invasive fungal infections are significant causes of morbidity and mortality in patients with hematological malignancies. Patients with acute myeloid leukemia and those who have undergone allogeneic hematopoietic stem cell transplantation are at especially high risk. Various fungal agents are responsible for this complication, but Aspergillus spp. and Candida spp. are the most frequently isolated micro-organisms; less commonly, infections could be caused by Zygomycetes or other rare molds or yeasts. Several new systemically-administered antifungal agents have been approved for clinical use since 2001; these agents include liposomal amphotericin B, voriconazole, caspofungin, and posaconazole, and they represent a major advance in antifungal therapy and have improved the prognosis of patients with hematological malignancies. This review focuses on therapeutic aspects of the management of fungal infections in hematological patients.
Abstract The diagnosis of antiphospholipid syndrome is predominantly made in the laboratory and depends on the persistent presence of antiphospholipid antibodies in individuals with thrombosis or pregnancy morbidity. Correct diagnosis of the syndrome is imperative to prevent unnecessary long secondary thromboprophylaxis. Three antiphospholipid antibody subtypes are included in the classification criteria of the antiphospholipid syndrome: lupus anticoagulants, anticardiolipin antibodies and anti-β2-glycoprotein I antibodies. Only lupus anticoagulants are undisputedly associated with thrombosis, which is why the serological criteria of the antiphospholipid syndrome are under debate. All of the assays used to detect antiphospholipid antibodies are in need of better standardization, although progress has been made in the detection of lupus anticoagulants. The inconsistent association between both anticardiolipin and anti-β2-glycoprotein I antibodies and thrombosis is a cause for alarm. We are in need of better assays to detect those individuals at risk for thrombosis and population-based prospective studies to provide us with accurate risk assessments.
Summary The discovery of human embryonic stem cells (hESCs) raised promises for a universal resource for cell based therapies in regenerative medicine. Recently, fast-paced progress has been made towards the generation of pluripotent stem cells (PSCs) amenable for clinical applications, culminating in reprogramming of adult somatic cells to autologous PSCs that can be indefinitely expanded in vitro . However, besides the efficient generation of bona fide, clinically safe PSCs (e.g., without the use of oncoproteins and gene transfer based on viruses inserting randomly into the genome), a major challenge in the field remains how to efficiently differentiate PSCs to specific lineages and how to select cells that will function normally upon transplantation in adults. In this review, we analyse the in vitro differentiation potential of PSCs to the hematopoietic lineage by discussing blood cell types that can be currently obtained, limitations in derivation of adult-type HSCs and prospects for clinical application of PSCs-derived blood cells.
Abstract Myeloproliferative disorders are commonly associated with thrombohemorrhagic manifestations. The current review highlights recent advances in understanding the epidemiology and pathogenetic mechanisms of thrombotic and bleeding complications. Therapeutic modalities and prophylactic interventions corresponding to the specific disease states are also discussed.