Hypomethylating agents (HMA) azacitidine and decitabine are standard of care for myelodysplastic syndrome (MDS). Response to these agents occurs in ∼50% of treated patients, and duration of response, although variable, is transient. Prediction of response to HMAs is possible with clinical and molecular parameters, but alternative approved treatments are not available, and in the case of HMA failure, there are no standard therapeutic opportunities. It is important to develop a reasoned choice of therapy after HMA failure. This choice should be based on evaluation of type of resistance (primary vs secondary, progression of disease [acute leukemia or higher risk MDS] vs absence of hematological improvement) as well as on molecular and cytogenetic characteristics reassessed at the moment of HMA failure. Rescue strategies may include stem-cell transplantation, which remains the only curative option, and chemotherapy, both of which are feasible in only a minority of cases, and experimental agents. Patients experiencing HMA failure should be recruited to clinical experimental trials as often as possible. Several novel agents with different mechanisms of action are currently being tested in this setting. Drugs targeting molecular alterations (IDH2 mutations, spliceosome gene mutations) or altered signaling pathways (BCL2 inhibitors) seem to be the most promising.

The canonical role of the hemostatic and fibrinolytic systems is to maintain vascular integrity. Perturbations in either system can prompt primary pathological end points of hemorrhage or thrombosis with vessel occlusion. However, fibrin(ogen) and proteases controlling its deposition and clearance, including (pro)thrombin and plasmin(ogen), have powerful roles in driving acute and reparative inflammatory pathways that affect the spectrum of tissue injury, remodeling, and repair. Indeed, fibrin(ogen) deposits are a near-universal feature of tissue injury, regardless of the nature of the inciting event, including injuries driven by mechanical insult, infection, or immunological derangements. Fibrin can modify multiple aspects of inflammatory cell function by engaging leukocytes through a variety of cellular receptors and mechanisms. Studies on the role of coagulation system activation and fibrin(ogen) deposition in models of inflammatory disease and tissue injury have revealed points of commonality, as well as context-dependent contributions of coagulation and fibrinolytic factors. However, there remains a critical need to define the precise temporal and spatial mechanisms by which fibrinogen-directed inflammatory events may dictate the severity of tissue injury and coordinate the remodeling and repair events essential to restore normal organ function. Current research trends suggest that future studies will give way to the identification of novel hemostatic factor-targeted therapies for a range of tissue injuries and disease.

Sickle cell trait (SCT) is unique among the carrier states that are identified during newborn screening. Unlike other heterozygous states for rare recessive diseases, SCT is exceedingly prevalent throughout regions of the world, making sickle cell disease one of the most common monogenetic diseases worldwide. Because of this high frequency, reproductive counseling is of paramount importance. In addition, unlike other carrier states, SCT seems to be a risk factor for several clinical complications, such as extreme exertional injury, chronic kidney disease, and venous thromboembolism. Increasing knowledge about these clinical outcomes can help inform genetic counseling recommendations. Expanding research and clinical efforts are needed to ensure that the promises of modern and precision medicine can be delivered to the millions of SCT carriers and their children.

Castleman disease (CD) describes a heterogeneous group of hematologic disorders that share characteristic lymph node histopathology. Patients of all ages present with either a solitary enlarged lymph node (unicentric CD) or multicentric lymphadenopathy (MCD) with systemic inflammation, cytopenias, and life-threatening multiple organ dysfunction resulting from a cytokine storm often driven by interleukin 6 (IL-6). Uncontrolled human herpesvirus-8 (HHV-8) infection causes approximately 50% of MCD cases, whereas the etiology is unknown in the remaining HHV-8-negative/idiopathic MCD cases (iMCD). The limited understanding of etiology, cell types, and signaling pathways involved in iMCD has slowed development of treatments and contributed to historically poor patient outcomes. Here, recent progress for diagnosing iMCD, characterizing etio-pathogenesis, and advancing treatments are reviewed. Several clinicopathological analyses provided the evidence base for the first-ever diagnostic criteria and revealed distinct clinical subtypes: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly (iMCD-TAFRO) or iMCD-not otherwise specified (iMCD-NOS), which are both observed all over the world. In 2014, the anti-IL-6 therapy siltuximab became the first iMCD treatment approved by the US Food and Drug Administration, on the basis of a 34% durable response rate; consensus guidelines recommend it as front-line therapy. Recent cytokine and proteomic profiling has revealed normal IL-6 levels in many patients with iMCD and potential alternative driver cytokines. Candidate novel genomic alterations, dysregulated cell types, and signaling pathways have also been identified as candidate therapeutic targets. RNA sequencing for viral transcripts did not reveal novel viruses, HHV-8, or other viruses pathologically associated with iMCD. Despite progress, iMCD remains poorly understood. Further efforts to elucidate etiology, pathogenesis, and treatment approaches, particularly for siltuximab-refractory patients, are needed.

Antiphospholipid syndrome (APS), heparin-induced thrombocytopenia, and paroxysmal nocturnal hemoglobinuria are 3 acquired thrombophilias that carry a high risk of venous and arterial thromboembolism. Management of these conditions has largely included anticoagulation with a vitamin K antagonist after an initial period of a parenteral anticoagulant, for as long as the thrombotic risk is still present. The available evidence for the use of direct oral anticoagulants (DOACs) is limited and primarily consists of case series and cohort studies, which are summarized in this chapter. Randomized trials evaluating DOACs in patients with APS are reviewed. Further research is needed prior to widely adopting DOACs for use in these high-risk acquired thrombophilias; however, there may be selected low-risk subgroups where DOAC use is possible after careful consideration and patient discussion.

Oral anticoagulants are commonly prescribed but high risk to cause adverse events. Skilled drug interaction management is essential to ensure safe and effective use of these therapies. Clinically relevant interactions with warfarin include drugs that modify cytochrome 2C9, 3A4, or both. Drugs that modify p-glycoprotein may interact with all direct oral anticoagulants, and modifiers of cytochrome 3A4 may interact with rivaroxaban and apixaban. Antiplatelet agents, nonsteroidal anti-inflammatory drugs, and serotonergic agents, such as selective serotonin reuptake inhibitors, can increase risk of bleeding when combined with any oral anticoagulant, and concomitant use should be routinely assessed. New data on anticoagulant drug interactions are available almost daily, and therefore, it is vital that clinicians regularly search interaction databases and the literature for updated management strategies. Skilled drug interaction management will improve outcomes and prevent adverse events in patients taking oral anticoagulants.

Heavy menstrual bleeding (HMB) is frequently reported by adolescents. The role of the hematologist is threefold in the evaluation of such patients: 1) perform a clinical and laboratory evaluation for an underlying bleeding disorder based on the degree of clinical suspicion, 2) identify and manage any concomitant iron deficiency, and 3) provide input to the referring provider regarding the management of HMB, particulary for patients with identified hemostatic defects. Several clues in the menstrual history should raise suspicion for an underlying bleeding disorder, such as menses lasting >7 days, menstrual flow which soaks >5 products daily or requires product change during the night, passage of large blood clots, or failure to respond to conventional therapies. A detailed personal and family history of other bleeding symptoms should also be obtained. Iron deficiency with and without anemia is commonly found in young women with HMB. Therefore, it is important to obtain not only a hemoglobin, but also a ferritin level, when evaluating these patients. Iron supplementation is often a key component of management in the adolescent with heavy menses, and is still needed even in those who have received packed red cell transfusions due to severe anemia. Strategies for decreasing menstrual blood flow are similar between adults and adolescents with heavy menses, with combined hormonal contraceptives recommended as first-line therapy. However, adolescent-specific considerations exist for many of these agents, and must be incorporated into shared decision making when selecting the most appropriate treatment.

With the advent of tyrosine kinase inhibitors (TKIs), the goals of therapy in chronic myeloid leukemia (CML) are steadily shifting. Long-term disease control on TKI therapy has been the goal and expectation for most patients. More recently, treatment-free remission (TFR) has entered mainstream practice and is increasingly being adopted as the main goal of therapy. This therapeutic shift not only influences TKI selection but also, has necessitated the refinement and dissemination of highly sensitive and accurate molecular monitoring techniques. Measurement of BCR-ABL1 messenger RNA expression through reverse transcription quantitative polymerase chain reaction, reported according to the International Scale, has become the primary tool for response assessment in CML. Achieving specific time-dependent molecular milestones, as defined by global therapeutic guidelines, has been established as critical in maximizing optimal outcomes while identifying patients at risk of therapy failure. Depth and duration of a deep molecular response have become the new therapeutic targets in patients considered for TFR. Consequently, molecular monitoring in CML has become even more critical to ongoing response assessment, identifying patients with TKI resistance and poor drug adherence, and enabling TFR to be attempted safely and effectively.

The liver orchestrates systemic iron balance by producing and secreting hepcidin. Known as the iron hormone, hepcidin induces degradation of the iron exporter ferroportin to control iron entry into the bloodstream from dietary sources, iron recycling macrophages, and body stores. Under physiologic conditions, hepcidin production is reduced by iron deficiency and erythropoietic drive to increase the iron supply when needed to support red blood cell production and other essential functions. Conversely, hepcidin production is induced by iron loading and inflammation to prevent the toxicity of iron excess and limit its availability to pathogens. The inability to appropriately regulate hepcidin production in response to these physiologic cues underlies genetic disorders of iron overload and deficiency, including hereditary hemochromatosis and iron-refractory iron deficiency anemia. Moreover, excess hepcidin suppression in the setting of ineffective erythropoiesis contributes to iron-loading anemias such as β-thalassemia, whereas excess hepcidin induction contributes to iron-restricted erythropoiesis and anemia in chronic inflammatory diseases. These diseases have provided key insights into understanding the mechanisms by which the liver senses plasma and tissue iron levels, the iron demand of erythrocyte precursors, and the presence of potential pathogens and, importantly, how these various signals are integrated to appropriately regulate hepcidin production. This review will focus on recent insights into how the liver senses body iron levels and coordinates this with other signals to regulate hepcidin production and systemic iron homeostasis.

β-Thalassemia (BT) is an inherited genetic disorder that is characterized by ineffective erythropoiesis (IE), leading to anemia and abnormal iron metabolism. IE is an abnormal expansion of the number of erythroid progenitor cells with unproductive synthesis of enucleated erythrocytes, leading to anemia and hypoxia. Anemic patients affected by BT suffer from iron overload, even in the absence of chronic blood transfusion, suggesting the presence of ≥1 erythroid factor with the ability to modulate iron metabolism and dietary iron absorption. Recent studies suggest that decreased erythroid cell differentiation and survival also contribute to IE, aggravating the anemia in BT. Furthermore, hypoxia can also affect and increase iron absorption. Understanding the relationship between iron metabolism and IE could provide important insights into the BT condition and help to develop novel treatments. In fact, genetic or pharmacological manipulations of iron metabolism or erythroid cell differentiation and survival have been shown to improve IE, iron overload, and anemia in animal models of BT. Based on those findings, new therapeutic approaches and drugs have been proposed; clinical trials are underway that have the potential to improve erythrocyte production, as well as to reduce the iron overload and organ toxicity in BT and in other disorders characterized by IE.

The sideroblastic anemias (SAs) are a group of inherited and acquired bone marrow disorders defined by pathological iron accumulation in the mitochondria of erythroid precursors. Like most hematological diseases, the molecular genetic basis of the SAs has ridden the wave of technology advancement. Within the last 30 years, with the advent of positional cloning, the human genome project, solid-state genotyping technologies, and next-generation sequencing have evolved to the point where more than two-thirds of congenital SA cases, and an even greater proportion of cases of acquired clonal disease, can be attributed to mutations in a specific gene or genes. This review focuses on an analysis of the genetics of these diseases and how understanding these defects may contribute to the design and implementation of rational therapies.

Anemia of inflammation (AI), also known as anemia of chronic disease (ACD), is regarded as the most frequent anemia in hospitalized and chronically ill patients. It is prevalent in patients with diseases that cause prolonged immune activation, including infection, autoimmune diseases, and cancer. More recently, the list has grown to include chronic kidney disease, congestive heart failure, chronic pulmonary diseases, and obesity. Inflammation-inducible cytokines and the master regulator of iron homeostasis, hepcidin, block intestinal iron absorption and cause iron retention in reticuloendothelial cells, resulting in iron-restricted erythropoiesis. In addition, shortened erythrocyte half-life, suppressed erythropoietin response to anemia, and inhibition of erythroid cell differentiation by inflammatory mediators further contribute to AI in a disease-specific pattern. Although the diagnosis of AI is a diagnosis of exclusion and is supported by characteristic alterations in iron homeostasis, hypoferremia, and hyperferritinemia, the diagnosis of AI patients with coexisting iron deficiency is more difficult. In addition to treatment of the disease underlying AI, the combination of iron therapy and erythropoiesis-stimulating agents can improve anemia in many patients. In the future, emerging therapeutics that antagonize hepcidin function and redistribute endogenous iron for erythropoiesis may offer additional options. However, based on experience with anemia treatment in chronic kidney disease, critical illness, and cancer, finding the appropriate indications for the specific treatment of AI will require improved understanding and a balanced consideration of the contribution of anemia to each patient's morbidity and the impact of anemia treatment on the patient's prognosis in a variety of disease settings.

Iron deficiency anemia affects >1.2 billions individuals worldwide, and iron deficiency in the absence of anemia is even more frequent. Total-body (absolute) iron deficiency is caused by physiologically increased iron requirements in children, adolescents, young and pregnant women, by reduced iron intake, or by pathological defective absorption or chronic blood loss. Adaptation to iron deficiency at the tissue level is controlled by iron regulatory proteins to increase iron uptake and retention; at the systemic level, suppression of the iron hormone hepcidin increases iron release to plasma by absorptive enterocytes and recycling macrophages. The diagnosis of absolute iron deficiency is easy unless the condition is masked by inflammatory conditions. All cases of iron deficiency should be assessed for treatment and underlying cause. Special attention is needed in areas endemic for malaria and other infections to avoid worsening of infection by iron treatment. Ongoing efforts aim at optimizing iron salts-based therapy by protocols of administration based on the physiology of hepcidin control and reducing the common adverse effects of oral iron. IV iron, especially last-generation compounds administered at high doses in single infusions, is becoming an effective alternative in an increasing number of conditions because of a more rapid and persistent hematological response and acceptable safety profile. Risks/benefits of the different treatments should be weighed in a personalized therapeutic approach to iron deficiency.

Blastoid mantle cell lymphoma is characterized by highly aggressive features and a dismal clinical course. These blastoid and pleomorphic variants are defined by cytomorphological features, but the criteria are somewhat subjective. The diagnosis may be supported by a high cell proliferation based on the Ki-67 labeling index. Recent analyses have shown that the Ki-67 index overrules the prognostic information derived from the cytology subtypes. Nevertheless, genetic analysis suggests that blastoid and pleomorphic variants are distinct from classical mantle cell lymphoma. In clinical cohorts, the frequency of these subsets varies widely but probably represents ∼10% of all cases. Chemotherapy regimens commonly used in mantle cell lymphoma, such as bendamustine, rarely achieve prolonged remissions when given at the dosage developed for classical variants of the disease. Thus, high-dose cytarabine-containing regimens with high-dose consolidation may be generally recommended based on the more aggressive clinical course in these patients. However, even with these intensified regimens, the long-term outcome seems to be impaired. Thus, especially in this patient subset, allogeneic transplantation may be discussed at an early time point in disease management. Accordingly, targeted approaches are warranted in these patients, but clinical data are scarce. Ibrutinib treatment results in high rates of responses, but the median duration of remission is <6 months. Similarly, lenalidomide and temsirolimus result in only short-term remissions. Novel approaches, such as chimeric antigenic receptor T cells, may have the potential to finally improve the dismal long-term outcome of these patients.

The ability to upregulate and downregulate surface-exposed proteins and receptors is a powerful process that allows a cell to instantly respond to its microenvironment. In particular, mobile cells in the bloodstream must rapidly react to conditions where infection or inflammation are detected, and become proadhesive, phagocytic, and/or procoagulant. Platelets are one such blood cell that must rapidly acquire and manage proadhesive and procoagulant properties in order to execute their primary function in hemostasis. The regulation of platelet membrane properties is achieved via several mechanisms, one of which involves the controlled metalloproteolytic release of adhesion receptors and other proteins from the platelet surface. Proteolysis effectively lowers receptor density and reduces the reactivity of platelets, and is a mechanism to control robust platelet activation. Recent research has also established clear links between levels of platelet receptors and platelet lifespan. In this review, we will discuss the current knowledge of metalloproteolytic receptor regulation in the vasculature with emphasis on the platelet receptor system to highlight how receptor density can influence both platelet function and platelet survival.

The classic Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) are a heterogeneous group of hematopoietic stem-cell diseases, characterized by activated JAK/STAT signaling and significant phenotypic mimicry, including a propensity for evolution to myeloid blast phase disease. Effective therapeutic options are limited for patients with Ph- MPNs in the blast phase (MPN-BP), and allogeneic stem-cell transplantation is the only known cure. Our increasing understanding of the molecular pathogenesis of this group of diseases, coupled with the increasing availability of targeted agents, has the potential to inform new subset-specific therapeutic approaches. Ultimately, progress in MPN-BP will hinge on prospective clinical and translational investigations with the goal of generating more effective treatment interventions. This case-based review highlights the molecular and clinical heterogeneities of MPN-BP and incorporates a treatment algorithm that underscores the importance of a personalized approach to this challenging group of diseases.

Andexanet alfa, a reversing agent for anticoagulants that inhibit factor Xa, has recently been licensed in the United States. We discuss the impact of this licensure on current practice and review in detail the problems of a neglected and growing clinical area: reversing the anticoagulation effect of factor Xa inhibitors in bleeding trauma patients. We identify areas of practice that need research so that care of bleeding trauma patients receiving direct factor Xa inhibitors can be improved.

Antithrombotic therapies reduce cardiovascular diseases by preventing arterial thrombosis and thromboembolism, but at expense of increased bleeding risks. Arterial thrombosis studies using genetically modified mice have been invaluable for identification of new molecular targets. Because of low sample sizes and heterogeneity in approaches or methodologies, a formal meta-analysis to compare studies of mice with single-gene defects encountered major limitations. To overcome these, we developed a novel synthesis approach to quantitatively scale 1514 published studies of arterial thrombus formation (in vivo and in vitro), thromboembolism, and tail-bleeding of genetically modified mice. Using a newly defined consistency parameter (CP), indicating the strength of published data, comparisons were made of 431 mouse genes, of which 17 consistently contributed to thrombus formation without affecting hemostasis. Ranking analysis indicated high correlations between collagen-dependent thrombosis models in vivo (FeCl3 injury or ligation/compression) and in vitro. Integration of scores and CP values resulted in a network of protein interactions in thrombosis and hemostasis (PITH), which was combined with databases of genetically linked human bleeding and thrombotic disorders. The network contained 2946 nodes linked to modifying genes of thrombus formation, mostly with expression in megakaryocytes. Reactome pathway analysis and network characteristics revealed multiple novel genes with potential contribution to thrombosis/hemostasis. Studies with additional knockout mice revealed that 4 of 8 (Apoe, Fpr2, Ifnar1, Vps13a) new genes were modifying in thrombus formation. The PITH network further: (i) revealed a high similarity of murine and human hemostatic and thrombotic processes and (ii) identified multiple new candidate proteins regulating these processes.

Abdominal aortic aneurysm (AAA) is a degenerative vascular pathology resulting in significant morbidity and mortality in older adults due to rupture and sudden death. Despite 150 000 new cases and nearly 15 000 deaths annually, the only approved treatment of AAA is surgical or endovascular intervention when the risk for aortic rupture is increased. The goal of the scientific community is to develop novel pharmaceutical treatment strategies to reduce the need for surgical intervention. Because most clinically relevant AAAs contain a complex structure of fibrin, inflammatory cells, platelets, and red blood cells in the aneurysmal sac known as an intraluminal thrombus (ILT), antithrombotic therapies have emerged as potential pharmaceutical agents for the treatment of AAA progression. However, the efficacy of these treatments has not been shown, and the effects of shrinking the ILT may be as detrimental as they are beneficial. This review discusses the prospect of anticoagulant and antiplatelet (termed collectively as antithrombotic) therapies in AAA. Herein, we discuss the role of the coagulation cascade and platelet activation in human and animal models of AAA, the composition of ILT in AAA, a possible role of the ILT in aneurysm stabilization, and the implications of antithrombotic drugs in AAA treatment.

The complex pathophysiology in β-thalassemia can translate to multiple morbidities that affect every organ system. Improved survival due to advances in management means that patients are exposed to the harmful effects of ineffective erythropoiesis, anemia, and iron overload for a longer duration, and we started seeing new or more frequent complications in adult compared with younger patients. In this article, we highlight particular aspects of managing adult patients with β-thalassemia, using our own experience in treating such patients. We cover both transfusion-dependent and nontransfusion-dependent forms of the disease and tackle specific morbidities of highest interest.