The deregulation of polycomb repressive complexes (PRCs) has been reported in a number of hematological malignancies. These complexes exert oncogenic or tumor-suppressive functions depending on tumor type. These findings have revolutionized our understanding of the pathophysiology of hematological malignancies and the impact of deregulated epigenomes in tumor development and progression. The therapeutic targeting of PRCs is currently attracting increasing attention and being extensively examined in clinical studies, leading to new therapeutic strategies that may improve the outcomes of patients with hematological malignancies.

Since their discovery, immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptors have been shown to inhibit signaling from immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors in almost all hematopoietic cells, including platelets. However, a growing body of evidence has emerged demonstrating that this is an oversimplification, and that ITIM-containing receptors are versatile regulators of platelet signal transduction, with functions beyond inhibiting ITAM-mediated platelet activation. PECAM-1 was the first ITIM-containing receptor identified in platelets and appeared to conform to the established model of ITIM-mediated attenuation of ITAM-driven activation. PECAM-1 was therefore widely accepted as a major negative regulator of platelet activation and thrombosis for many years, but more recent findings suggest a more complex role for this receptor, including the facilitation of αIIbβ3-mediated platelet functions. Since the identification of PECAM-1, several other ITIM-containing platelet receptors have been discovered. These include G6b-B, a critical regulator of platelet reactivity and production, and the noncanonical ITIM-containing receptor TREM-like transcript-1, which is localized to α-granules in resting platelets, binds fibrinogen, and acts as a positive regulator of platelet activation. Despite structural similarities and shared binding partners, including the Src homology 2 domain-containing protein-tyrosine phosphatases Shp1 and Shp2, knockout and transgenic mouse models have revealed distinct phenotypes and nonredundant functions for each ITIM-containing receptor in the context of platelet homeostasis. These roles are likely influenced by receptor density, compartmentalization, and as-yet unknown binding partners. In this review, we discuss the diverse repertoire of ITIM-containing receptors in platelets, highlighting intriguing new functions, controversies, and future areas of investigation.

In hemophilia A, the most severe complication of factor VIII (FVIII) replacement therapy involves the formation of FVIII neutralizing antibodies, also known as inhibitors, in 25% to 30% of patients. This adverse event is associated with a significant increase in morbidity and economic burden, thus highlighting the need to identify methods to limit FVIII immunogenicity. Inhibitor development is regulated by a complex balance of genetic factors, such as FVIII genotype, and environmental variables, such as coexistent inflammation. One of the hypothesized risk factors of inhibitor development is the source of the FVIII concentrate, which could be either recombinant or plasma derived. Differential immunogenicity of these concentrates has been documented in several recent epidemiologic studies, thus generating significant debate within the hemophilia treatment community. To date, these discussions have been unable to reach a consensus regarding how these outcomes might be integrated into enhancing clinical care. Moreover, the biological mechanistic explanations for the observed differences are poorly understood. In this article, we complement the existing epidemiologic investigations with an overview of the range of possible biochemical and immunologic mechanisms that may contribute to the different immune outcomes observed with plasma-derived and recombinant FVIII products.

Heparin-induced thrombocytopenia (HIT) is an immune complication of heparin therapy caused by antibodies to complexes of platelet factor 4 (PF4) and heparin. Pathogenic antibodies to PF4/heparin bind and activate cellular FcγRIIA on platelets and monocytes to propagate a hypercoagulable state culminating in life-threatening thrombosis. It is now recognized that anti-PF4/heparin antibodies develop commonly after heparin exposure, but only a subset of sensitized patients progress to life-threatening complications of thrombocytopenia and thrombosis. Recent scientific developments have clarified mechanisms underlying PF4/heparin immunogenicity, disease susceptibility, and clinical manifestations of disease. Insights from clinical and laboratory findings have also been recently harnessed for disease prevention. This review will summarize our current understanding of HIT by reviewing pathogenesis, essential clinical and laboratory features, and management.

Acquired thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are appropriately at the top of a clinician's differential when a patient presents with a clinical picture consistent with an acute thrombotic microangiopathy (TMA). However, there are several additional diagnoses that should be considered in patients presenting with an acute TMA, especially in patients with nondeficient ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity (>10%). An increased awareness of drug-induced TMA is also essential because the key to their diagnosis more often is an appropriately detailed medical history to inquire about potential exposures. Widespread inflammation and endothelial damage are central in the pathogenesis of the TMA, with the treatment directed at the underlying disease if possible. TMA presentations in the critically ill, drug-induced TMA, cancer-associated TMA, and hematopoietic transplant-associated TMA (TA-TMA) and their specific treatment, where applicable, will be discussed in this manuscript. A complete assessment of all the potential etiologies for the TMA findings including acquired TTP will allow for a more accurate diagnosis and prevent prolonged or inappropriate treatment with plasma exchange therapy when it is less likely to be successful.

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by intravascular hemolysis, thrombocytopenia, and acute kidney failure. HUS is usually categorized as typical, caused by Shiga toxin-producing Escherichia coli (STEC) infection, as atypical HUS (aHUS), usually caused by uncontrolled complement activation, or as secondary HUS with a coexisting disease. In recent years, a general understanding of the pathogenetic mechanisms driving HUS has increased. Typical HUS (ie, STEC-HUS) follows a gastrointestinal infection with STEC, whereas aHUS is associated primarily with mutations or autoantibodies leading to dysregulated complement activation. Among the 30% to 50% of patients with HUS who have no detectable complement defect, some have either impaired diacylglycerol kinase ε (DGKε) activity, cobalamin C deficiency, or plasminogen deficiency. Some have secondary HUS with a coexisting disease or trigger such as autoimmunity, transplantation, cancer, infection, certain cytotoxic drugs, or pregnancy. The common pathogenetic features in STEC-HUS, aHUS, and secondary HUS are simultaneous damage to endothelial cells, intravascular hemolysis, and activation of platelets leading to a procoagulative state, formation of microthrombi, and tissue damage. In this review, the differences and similarities in the pathogenesis of STEC-HUS, aHUS, and secondary HUS are discussed. Common for the pathogenesis seems to be the vicious cycle of complement activation, endothelial cell damage, platelet activation, and thrombosis. This process can be stopped by therapeutic complement inhibition in most patients with aHUS, but usually not those with a DGKε mutation, and some patients with STEC-HUS or secondary HUS. Therefore, understanding the pathogenesis of the different forms of HUS may prove helpful in clinical practice.

Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia linked to disseminated microvascular platelet rich-thrombi. TTP is specifically related to a severe deficiency in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13), the specific von Willebrand factor-cleaving protease. ADAMTS13 deficiency is most frequently acquired via ADAMTS13 autoantibodies, but rarely, it is inherited via mutations of the ADAMTS13 gene. The first acute episode of TTP usually occurs during adulthood, with a predominant anti-ADAMTS13 autoimmune etiology. In rare cases, however, TTP begins as soon as childhood, with frequent inherited forms. TTP is ∼2-fold more frequent in women, and its outcome is characterized by a relapsing tendency. Rapid recognition of TTP is crucial to initiate appropriate treatment. The first-line therapy for acute TTP is based on daily therapeutic plasma exchange supplying deficient ADAMTS13, with or without steroids. Additional immune modulators targeting ADAMTS13 autoantibodies are mainly based on steroids and the humanized anti-CD20 monoclonal antibody rituximab. In refractory or unresponsive TTP, more intensive therapies including twice-daily plasma exchange; pulses of cyclophosphamide, vincristine, or cyclosporine A; or salvage splenectomy are considered. New drugs including N-acetylcysteine, bortezomib, recombinant ADAMTS13, and caplacizumab show promise in the management of TTP. Also, long-term follow-up of patients with TTP is crucial to identify the occurrence of other autoimmune diseases, to control relapses, and to evaluate psychophysical sequelae. Further development of both patients' registries worldwide and innovative drugs is still needed to improve TTP management.

Immune thrombocytopenia (ITP) occurs in 2 to 4/100 000 adults and results in variable bleeding symptoms and thrombocytopenia. In the last decade, changes in our understanding of the pathophysiology of the disorder have led to the publication of new guidelines for the diagnosis and management of ITP and standards for terminology. Current evidence supports alternatives to splenectomy for second-line management of patients with persistently low platelet counts and bleeding. Long-term follow-up data suggest both efficacy and safety, in particular, for the thrombopoietin receptor agonists and the occurrence of late remissions. Follow-up of patients who have undergone splenectomy for ITP reveals significant potential risks that should be discussed with patients and may influence clinician and patient choice of second-line therapy. Novel therapeutics are in development to address ongoing treatment gaps.

Transcription factors (TFs) are proteins that bind to specific DNA sequences and regulate expression of genes. The molecular and genetic mechanisms in most patients with inherited platelet defects are unknown. There is now increasing evidence that mutations in hematopoietic TFs are an important underlying cause for defects in platelet production, morphology, and function. The hematopoietic TFs implicated in patients with impaired platelet function and number include runt-related transcription factor 1, Fli-1 proto-oncogene, E-twenty-six (ETS) transcription factor (friend leukemia integration 1), GATA-binding protein 1, growth factor independent 1B transcriptional repressor, ETS variant 6, ecotropic viral integration site 1, and homeobox A11. These TFs act in a combinatorial manner to bind sequence-specific DNA within promoter regions to regulate lineage-specific gene expression, either as activators or repressors. TF mutations induce rippling downstream effects by simultaneously altering the expression of multiple genes. Mutations involving these TFs affect diverse aspects of megakaryocyte biology, and platelet production and function, culminating in thrombocytopenia and platelet dysfunction. Some are associated with predisposition to hematologic malignancies. These TF variants may occur more frequently in patients with inherited platelet defects than generally appreciated. This review focuses on alterations in hematopoietic TFs in the pathobiology of inherited platelet defects.

18F-Fluorodeoxyglucose-positron emission tomography (FDG-PET) has become a central tool for both accurate initial staging and determination of prognosis after treatment of diffuse large B-cell lymphoma (DLBCL). However, the role of PET during treatment (iPET) in daily practice remains a matter of significant debate. This perspective reviews the published studies on iPET in DLBCL, including the methods used to analyze iPET, its timing, and studies of iPET-driven therapy to illuminate where daily practice may benefit from the use of iPET. When performed after 2 and/or 4 courses of immunochemotherapy, iPET has a very good negative predictive value, utilizing both visual (qualitative) and semiquantitative methods. The visual method accurately predicts outcome for patients with limited disease. The semiquantitative method, eg, the change of the difference of maximum standardized uptake value (ΔSUVmax), is for patients with advanced DLBCL, for whom iPET identifies patients with very good outcome with continuation of standard therapy. A low ΔSUVmax also helps identify patients with a risk for relapse averaging 50% and warrants review of their scheduled therapy. To date, no trial has demonstrated the superiority of an iPET-driven strategy in DLBCL. However, the very good negative and good positive predictive values of iPET support its use in daily practice as a better predictive tool than contrast-enhanced computed tomographic scan for therapeutic decision making.

Transformation to aggressive lymphoma is a critical event in the clinical course of follicular lymphoma (FL) patients. Yet, it is a challenge to reliably predict transformation at the time of diagnosis. Understanding the risk of transformation would be useful for guiding and monitoring patients, as well as for evaluating novel treatment strategies that could potentially prevent transformation. Herein, we review the contribution of clinical, pathological, and genetic risk factors to transformation. Patients with multiple clinical high-risk factors are at elevated risk of transformation but we are currently lacking a prognostic index that would specifically address transformation rather than disease progression or overall survival. From the biological standpoint, multiple studies have correlated individual biomarkers with transformation. However, accurate prediction of this event is currently hampered by our limited knowledge of the evolutionary pathways leading to transformation, as well as the scarcity of comprehensive, large-scale studies that assess both the genomic landscape of alterations within tumor cells and the composition of the microenvironment. Liquid biopsies hold great promise for achieving precision medicine. Indeed, mutations detected within circulating tumor DNA may be a better reflection of the inherent intratumoral heterogeneity than the biopsy of a single site. Last, we will assess whether evidence exists in the literature that transformation might be prevented altogether, based on the choice of therapy for FL.

Although the root cause of sickle cell disease is the polymerization of hemoglobin S (HbS) to form fibers that make red cells less flexible, most drugs currently being assessed in clinical trials are targeting the downstream sequelae of this primary event. Less attention has been devoted to investigation of the multiple ways in which fiber formation can be inhibited. In this article, we describe the molecular rationale for 5 distinct approaches to inhibiting polymerization and also discuss progress with the few antipolymerization drugs currently in clinical trials.

Central venous access device (CVAD)-related thrombosis (CRT) is a common complication among patients requiring central venous access as part of their medical care. Complications of CRT include pulmonary embolism, recurrent deep venous thrombosis, loss of central venous access, and postthrombotic syndrome. Patient-, device-, and treatment-related factors can influence the risk of CRT. Despite numerous randomized controlled trials, the clinical benefit of pharmacologic thromboprophylaxis for the prevention of CRT remains to be established. Therefore, minimizing patient exposure to known risk factors is the best available approach to prevent CRT. Venous duplex is recommended for the diagnosis of CRT. Anticoagulation for at least 3 months or the duration of the indwelling CVAD is recommended for treatment of CRT. Thrombolysis should be considered for patients at low risk for bleeding who have limb-threatening thrombosis or whose symptoms fail to resolve with adequate anticoagulation. CVAD removal should be consider for patients with bacteremia, persistent symptoms despite anticoagulation, and if the CVAD is no longer needed. Superior vena cava filters should be avoided. Prospective studies are needed to define the optimal management of patients with or at risk for CRT.

B12 deficiency is the leading cause of megaloblastic anemia, and although more common in the elderly, can occur at any age. Clinical disease caused by B12 deficiency usually connotes severe deficiency, resulting from a failure of the gastric or ileal phase of physiological B12 absorption, best exemplified by the autoimmune disease pernicious anemia. There are many other causes of B12 deficiency, which range from severe to mild. Mild deficiency usually results from failure to render food B12 bioavailable or from dietary inadequacy. Although rarely resulting in megaloblastic anemia, mild deficiency may be associated with neurocognitive and other consequences. B12 deficiency is best diagnosed using a combination of tests because none alone is completely reliable. The features of B12 deficiency are variable and may be atypical. Timely diagnosis is important, and treatment is gratifying. Failure to diagnose B12 deficiency can have dire consequences, usually neurological. This review is written from the perspective of a practicing hematologist.

Autoimmune hemolytic anemia (AIHA) is an uncommon entity that presents diagnostic, prognostic, and therapeutic dilemmas despite being a well-recognized entity for over 150 years. This is because of significant differences in the rates of hemolysis and associated diseases and because there is considerable clinical heterogeneity. In addition, there is a lack of clinical trials required to refine and update standardized and evidence-based therapeutic approaches. To aid the clinician in AIHA management, we present four vignettes that represent and highlight distinct clinical presentations with separate diagnostic and therapeutic pathways that we use in our clinical practice setting. We also review the parameters present in diagnostic testing that allow for prognostic insight and present algorithms for both diagnosis and treatment of the AIHA patient in diverse situations. This is done in the hope that this review may offer guidance in regard to personalized therapy recommendations. A section is included for the diagnosis of suspected AIHA with negative test results, a relatively infrequent but challenging situation, in order to assist in the overall evaluation spectrum for these patients.

Mutations in RNA splicing factors are the single most common class of genetic alterations in myelodysplastic syndrome (MDS) patients. Although much has been learned about how these mutations affect splicing at a global- and transcript-specific level, critical questions about the role of these mutations in MDS development and maintenance remain. Here we present the questions to be addressed in order to understand the unique enrichment of these mutations in MDS.

The treatment of multiple myeloma is considered a continuously evolving paradigm as a result of the growing availability of new and highly effective drugs, including first- and second-generation proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies. Clinical trials advocate long-term rather than short-term treatment schedules with combinations of these new anti-myeloma drug classes. Although the overall toxicity profile of the recommended regimens can be considered favorable, their increasing complexity and prolonged use warrant a heightened vigilance for early and late side effects, a priori because real-life patients can be more frail or present with 1 or more comorbidities. The treatment decision process, at diagnosis and at relapse, therefore requires myeloma physicians to carefully balance efficacy and toxicity profiles for each individual patient. Early and/or unnecessary tapering or treatment discontinuation for drug-related adverse events may not only reduce patients' quality of life, but also negatively impact their outcome. Accurate knowledge in recognizing and managing the potential side effects of present-day treatment regimens is therefore a cornerstone in myeloma care. Using 5 case vignettes, we discuss how to prevent and manage the most common nonhematological adverse events of anti-myeloma treatment regimens containing proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies.

The discovery of the GATA binding protein (GATA factor) transcription factor family revolutionized hematology. Studies of GATA proteins have yielded vital contributions to our understanding of how hematopoietic stem and progenitor cells develop from precursors, how progenitors generate red blood cells, how hemoglobin synthesis is regulated, and the molecular underpinnings of nonmalignant and malignant hematologic disorders. This thrilling journey began with mechanistic studies on a β-globin enhancer- and promoter-binding factor, GATA-1, the founding member of the GATA family. This work ushered in the cloning of related proteins, GATA-2-6, with distinct and/or overlapping expression patterns. Herein, we discuss how the hematopoietic GATA factors (GATA-1-3) function via a battery of mechanistic permutations, which can be GATA factor subtype, cell type, and locus specific. Understanding this intriguing protein family requires consideration of how the mechanistic permutations are amalgamated into circuits to orchestrate processes of interest to the hematologist and more broadly.

SCL/TAL1 (stem cell leukemia/T-cell acute lymphoblastic leukemia [T-ALL] 1) is an essential transcription factor in normal and malignant hematopoiesis. It is required for specification of the blood program during development, adult hematopoietic stem cell survival and quiescence, and terminal maturation of select blood lineages. Following ectopic expression, SCL contributes to oncogenesis in T-ALL. Remarkably, SCL's activities are all mediated through nucleation of a core quaternary protein complex (SCL:E-protein:LMO1/2 [LIM domain only 1 or 2]:LDB1 [LIM domain-binding protein 1]) and dynamic recruitment of conserved combinatorial associations of additional regulators in a lineage- and stage-specific context. The finely tuned control of SCL's regulatory functions (lineage priming, activation, and repression of gene expression programs) provides insight into fundamental developmental and transcriptional mechanisms, and highlights mechanistic parallels between normal and oncogenic processes. Importantly, recent discoveries are paving the way to the development of innovative therapeutic opportunities in SCL+ T-ALL.

GATA family proteins play essential roles in development of many cell types, including hematopoietic, cardiac, and endodermal lineages. The first three factors, GATAs 1, 2, and 3, are essential for normal hematopoiesis, and their mutations are responsible for a variety of blood disorders. Acquired and inherited GATA1 mutations contribute to Diamond-Blackfan anemia, acute megakaryoblastic leukemia, transient myeloproliferative disorder, and a group of related congenital dyserythropoietic anemias with thrombocytopenia. Conversely, germ line mutations in GATA2 are associated with GATA2 deficiency syndrome, whereas acquired mutations are seen in myelodysplastic syndrome, acute myeloid leukemia, and in blast crisis transformation of chronic myeloid leukemia. The fact that mutations in these genes are commonly seen in blood disorders underscores their critical roles and highlights the need to develop targeted therapies for transcription factors. This review focuses on hematopoietic disorders that are associated with mutations in two prominent GATA family members, GATA1 and GATA2.