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.

With increasing survival, cumulative complications of sickle cell disease (SCD), which develop insidiously over time, are becoming more apparent and common in older patients, particularly those in their fifth decade and beyond. The older patient is also more likely to develop other age-related nonsickle conditions that interact and add to the disease morbidity. A common misconception is that any symptom in a SCD patient is attributable to their SCD and this may lead to delays in diagnosis and appropriate intervention. We recommend regular comprehensive reviews and monitoring for early signs of organ damage and a low threshold for the use of hydroxyurea and blood transfusions as preventative measures for end-organ disease. Treatable comorbidities and acute deterioration should be managed aggressively. Although the primary goal in management of the older adult with SCD is improving anemia and minimizing organ damage, the time has come for us to be more proactive in considering curative therapies previously offered to the younger patient. Curative or experimental interventions should be discussed early, before complications render the patients ineligible for these treatments.

Hemoglobinopathies are caused by genetic mutations that result in abnormal hemoglobin molecules, resulting in hemolytic anemia. Chronic complications involving the lung parenchyma, vasculature, and cardiac function in hemoglobinopathies result in impaired gas exchange, resulting in tissue hypoxia. Hypoxia is defined as the deficiency in the amount of oxygen reaching the tissues of the body and is prevalent in patients with hemoglobinopathies, and its cause is often multifactorial. Chronic hypoxia in hemoglobinopathies is often a sign of disease severity and is associated with increased morbidity and mortality. Therefore, a thorough understanding of the pathophysiology of hypoxia in these disease processes is important in order to appropriately treat the underlying cause and prevent complications. In this article, we discuss management of hypoxia based on three different cases: sickle cell disease, β-thalassemia, and hereditary spherocytosis. These cases are used to review the current understanding of the disease pathophysiology, demonstrate the importance of a thorough clinical history and physical examination, explore diagnostic pathways, and review the current management.

Direct oral anticoagulants (DOACs) have significantly improved the care of patients requiring anticoagulation. With similar or better efficacy and safety outcomes and easier use in the outpatient setting compared with the standard-of-care vitamin K antagonists and low molecular weight heparin, DOACs are now endorsed as first-line treatment of indications including prevention of stroke and systemic embolism in nonvalvular atrial fibrillation and treatment of venous thromboembolism. DOACs are easy-to-use oral agents that offer simple dosing and short half-lives, with no need to test levels because of the wide therapeutic window and limited drug-drug interactions. After almost a decade of DOAC use, the question of testing DOAC levels in certain clinical situations has become the focus of debate. Although guidance for using routine coagulation tests is available, these tests are inadequate for optimal care. DOAC-specific tests have been developed but have limited availability in Europe and less availability in the United States. None are licensed. DOAC testing may be useful in the setting of critical clinical situations such as life-threatening bleeding or need for emergent surgery, especially with the availability of DOAC reversal agents. Patients with characteristics that fall outside the normal range may benefit from the guidance that DOAC testing could offer. Obstacles to adopting DOAC testing have been raised, such as test reliability and staffing costs; however, these problems are rapidly being resolved. Further investigation of the role of DOAC testing is needed to explore its full potential and role in clinical practice.

To further our understanding of inherited susceptibility to Hodgkin lymphoma (HL), we performed a meta-analysis of 7 genome-wide association studies totaling 5325 HL cases and 22 423 control patients. We identify 5 new HL risk loci at 6p21.31 (rs649775; P = 2.11 × 10-10), 6q23.3 (rs1002658; P = 2.97 × 10-8), 11q23.1 (rs7111520; P = 1.44 × 10-11), 16p11.2 (rs6565176; P = 4.00 × 10-8), and 20q13.12 (rs2425752; P = 2.01 × 10-8). Integration of gene expression, histone modification, and in situ promoter capture Hi-C data at the 5 new and 13 known risk loci implicates dysfunction of the germinal center reaction, disrupted T-cell differentiation and function, and constitutive NF-κB activation as mechanisms of predisposition. These data provide further insights into the genetic susceptibility and biology of HL.

Myelodysplastic syndromes (MDS) can be difficult to diagnose, especially when morphological changes in blood and marrow cells are minimal, myeloblast proportion is not increased, and the karyotype is normal. The discovery of >40 genes that are recurrently somatically mutated in MDS patients raised hope that molecular genetic testing for these mutations might help clarify the diagnosis in ambiguous cases where patients present with cytopenias and nondiagnostic marrow morphological findings. However, many older healthy individuals also harbor somatic mutations in leukemia-associated driver genes, especially in DNMT3A, TET2, and ASXL1, and detection of common aging-associated mutations in a cytopenic patient can cause diagnostic uncertainty. Despite this potential confounding factor, certain somatic mutation patterns when observed in cytopenic patients confer a high likelihood of disease progression and may allow a provisional diagnosis of MDS even if morphologic dysplasia and other diagnostic criteria are absent. A subset of acquired mutations also influences risk stratification of patients with an established MDS diagnosis and can inform treatment selection. Many unanswered questions remain about the implications of specific mutations, and clinicians also vary widely in their comfort with interpreting sequencing results. Here, I review the use of molecular genetic assays in patients with possible MDS or diagnosed MDS.

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma that is most commonly treated with combination chemo-immunotherapy at diagnosis because of the poor prognosis. More indolent presentations have been described including patients who can defer initial therapy without adverse impact on survival. The 2016 World Health Organization updated classification describes 2 major subtypes, classical and leukemic nonnodal MCL, each with unique molecular features and clinical presentations. Although there is no standard of care for MCL, aggressive chemo-immunotherapy regimens containing rituximab and cytarabine, followed by consolidation with autologous stem cell transplantation and maintenance rituximab, are the most used approach in young fit patients, and chemo-immunotherapy, followed by rituximab maintenance, is most commonly used in older patients. Despite the improvement in response durations with currently available therapies, patients will inevitably relapse. A number of targeted therapies are approved in the relapsed setting and are now under evaluation in combination with standard frontline therapy. Although the approval of ibrutinib changed the landscape of therapy for relapsed MCL, prognosis remains poor after progression on ibrutinib supporting the development of ibrutinib combinations to prolong response duration as well as the development of other novel agents for ibrutinib refractory disease. With ibrutinib being incorporated into initial therapy regimens, new options will be needed at relapse. Prognostic markers, such as minimal residual disease, have been shown to correlate independently with outcomes along with predicting relapse, with the potential to guide therapeutic decisions. The future treatment of MCL therapy will need to incorporate therapy based on risk-stratification and nonchemotherapeutic approaches.

Primary effusion lymphoma (PEL) is a rare B-cell malignancy that most often occurs in immunocompromised patients, such as HIV-infected individuals and patients receiving organ transplantation. The main characteristic of PEL is neoplastic effusions in body cavities without detectable tumor masses. The onset of the disease is associated with latent infection of human herpes virus 8/Kaposi sarcoma-associated herpes virus, and the normal counterpart of tumor cells is B cells with plasmablastic differentiation. A condition of immunodeficiency and a usual absence of CD20 expression lead to the expectation of the lack of efficacy of anti-CD20 monoclonal antibody; clinical outcomes of the disease remain extremely poor, with an overall survival at 1 year of ∼30%. Although recent progress in antiretroviral therapy has improved outcomes of HIV-infected patients, its benefit is still limited in patients with PEL. Furthermore, the usual high expression of programmed death ligand 1 in tumor cells, one of the most important immune-checkpoint molecules, results in the immune escape of tumor cells from the host immune defense, which could be the underlying mechanism of poor treatment efficacy. Molecular-targeted therapies for the activating pathways in PEL, including NF-κB, JAK/STAT, and phosphatidylinositol 3-kinase/AKT, have emerged to treat this intractable disease. A combination of immunological recovery from immune deficiency, overcoming the immune escape, and the development of more effective drugs will be vital for improving the outcomes of PEL patients in the future.

Intravascular large B-cell lymphoma (IVLBCL) is a rare, clinically aggressive lymphoma entity characterized by an almost exclusive growth of large cells within the lumen of all sized blood vessels. The reasons for this peculiar localization of neoplastic cells are only partially understood. Clinically, in its classical variant, IVLBCL presents with many nonspecific signs and symptoms such as fever of unknown origin and involvement of the central nervous system and skin. Cases, which show disease limited to the skin, following extensive staging workup, are called cutaneous variants and show a better prognosis. In addition, a hemophagocytic variant associated with hemophagocytic syndrome and often with hepatosplenic involvement and cytopenia has been described. The classical and hemophagocytic variants are present mainly in western or Asian countries, respectively, although exceptions have been increasingly reported in both geographical areas. The cutaneous variant is mostly observed in western countries. Staging of IVLBCL is difficult and still not satisfactory. The often poor prognosis of this type of lymphoma has been substantially improved by immunochemotherapy, in particular with rituximab. Despite improved outcome, a significant proportion of patients relapse, in particular those with central nervous system manifestations. This review focuses on histopathological features, pathogenetic elements, presenting symptoms, clinical variants, disease progression, prognostic factors, therapeutic management, and the outcome of IVLBCL.

Plasma hyperviscosity is a rare complication of both monoclonal and polyclonal disorders associated with elevation of immunoglobulins. Asymptomatic patients with an elevation in the serum viscosity do not require plasma exchange, and the majority will have other indications for therapeutic intervention. For patients with hemorrhagic or central nervous system manifestations, plasma exchange is the therapy of choice and is relatively safe. Viscosity measurements are not required to initiate therapy if the index of suspicion is high and the clinical presentation is typical. However, patients should have a sample sent for confirmation of the diagnosis. Whole-blood hyperviscosity is seen in patients with extreme elevation of the red cell and white cell count. Phlebotomy of patients with primary and secondary elevation of the red cell count is a well-established therapy.

Chronic innate immune signaling in hematopoietic cells is widely described in myelodysplastic syndromes (MDS), and innate immune pathway activation, predominantly via pattern recognition receptors, increases the risk of developing MDS. An inflammatory component to MDS has been reported for many years, but only recently has evidence supported a more direct role of chronic innate immune signaling and associated inflammatory pathways in the pathogenesis of MDS. Here we review recent findings and discuss relevant questions related to chronic immune response dysregulation in MDS.

Generating a hematopoietic stem cell (HSC) in vitro from nonhematopoietic tissue has been a goal of experimental hematologists for decades. Until recently, no in vitro-derived cell has closely demonstrated the full lineage potential and self-renewal capacity of a true HSC. Studies revealing stem cell ontogeny from embryonic mesoderm to hemogenic endothelium to HSC provided the key to inducing HSC-like cells in vitro from a variety of cell types. Here we review the path to this discovery and discuss the future of autologous transplantation with in vitro-derived HSCs as a therapeutic modality.

Immunodeficiency-associated lymphoproliferative disorders (IA-LPDs) are pathologically and clinically heterogeneous. In many instances, similar features are shared by a spectrum of IA-LPDs in clinically diverse settings. However, the World Health Organization (WHO) classifies IA-LPDs by their immunodeficiency setting largely according to the paradigm of posttransplant lymphoproliferative disorders but with inconsistent terminology and disease definitions. The field currently lacks standardization and would greatly benefit from thinking across immunodeficiency categories by adopting a common working vocabulary to better understand these disorders and guide clinical management. We propose a 3-part unifying nomenclature that includes the name of the lesion, associated virus, and the specific immunodeficiency setting for all IA-LPDs. B-cell lymphoproliferative disorders (LPDs) are usually Epstein-Barr virus (EBV)+ and show a spectrum of lesions, including hyperplasias, polymorphic LPDs, aggressive lymphomas, and, rarely, indolent lymphomas. Human herpes virus 8-associated LPDs also include polyclonal and monoclonal proliferations. EBV- B-cell LPDs and T- and NK-cell LPDs are rare and less well characterized. Recognition of any immunodeficiency is important because it impacts the choice of treatment options. There is an urgent need for reappraisal of IA-LPDs because a common framework will facilitate meaningful biological insights and pave the way for future work in the field.

Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry-specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P = 6.6 × 10-5) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

Advances in genetic labeling and barcoding of hematopoietic stem cells (HSCs) in situ now allow direct measurements of physiological HSC output, both quantitatively and qualitatively. Turning on a heritable label in HSCs and measuring the kinetics of label emergence in downstream compartments reveal rates of differentiation and self-renewal of HSCs and progenitor cells, whereas endogenous HSC barcoding probes physiological precursor-product relationships. Labels have been inserted at different stages of the hematopoietic differentiation hierarchy. Recent genetic and functional evidence suggests a phenotype (Tie2+ ) for tip HSCs. Fate mapping shows that many tip HSCs regularly feed into downstream stages, with individual cells contributing infrequently. Stem and progenitor cells downstream of tip HSCs serve as a major, nearly self-renewing source of day-to-day hematopoiesis, rendering the blood and immune system HSC-independent for extended periods of time. HSCs realize multilineage output, yet, fates restricted to several lineages or even a single lineage have also been observed. Single HSCs within a clone in the bone marrow that develop from a fetal HSC precursor have been observed to express clone-specific fates. Thus, the new tools probing HSC differentiation in situ are progressing beyond assays for HSC activity based on proliferation measurements and fates of transplanted stem cells, and the data challenge lineage interpretations of single-cell gene expression snapshots. Linking in vivo fate analyses to gene expression and other molecular determinants of cell fate will aid in unraveling the mechanisms of lineage commitment and the architecture of physiological hematopoiesis.

Understanding how tumor cells fundamentally alter their identity is critical to identify specific vulnerabilities for use in precision medicine. In B-cell malignancy, knowledge of genetic changes has resulted in great gains in our understanding of the biology of tumor cells, impacting diagnosis, prognosis, and treatment. Despite this knowledge, much remains to be explained as genetic events do not completely explain clinical behavior and outcomes. Many patients lack recurrent driver mutations, and said drivers can persist in nonmalignant cells of healthy individuals remaining cancer-free for decades. Epigenetics has emerged as a valuable avenue to further explain tumor phenotypes. The epigenetic landscape is the software that powers and stabilizes cellular identity by abridging a broad genome into the essential information required per cell. A genome-level view of B-cell malignancies reveals complex but recurrent epigenetic patterns that define tumor types and subtypes, permitting high-resolution classification and novel insight into tumor-specific mechanisms. Epigenetic alterations are guided by distinct cellular processes, such as polycomb-based silencing, transcription, signaling pathways, and transcription factor activity, and involve B-cell-specific aspects, such as activation-induced cytidine deaminase activity and germinal center-specific events. Armed with a detailed knowledge of the epigenetic events that occur across the spectrum of B-cell differentiation, B-cell tumor-specific aberrations can be detected with improved accuracy and serve as a model for identification of tumor-specific events in cancer. Insight gained through recent efforts may prove valuable in guiding the use of both epigenetic- and nonepigenetic-based therapies.

B-cell lymphoma 2 (BCL-2) was discovered at the breakpoint of the t(14;18) in follicular lymphoma >30 years ago. Although inhibition of BCL-2 first proved valuable in lymphoid malignancies, clinical progress in myeloid malignancies lagged. Here, we summarize the basic biology and preclinical results that spurred clinical BCL-2 inhibition in acute myeloid leukemia (AML). Response rates and toxicity for venetoclax in combination with standard AML agents, such as azacitidine, decitabine, and low-dose cytarabine, compare favorably with conventional induction chemotherapy. Durability of response requires further study.

Monoclonal gammopathy is a common condition, particularly in the elderly. It can indicate symptomatic multiple myeloma or another overt malignant lymphoid disorder requiring immediate chemotherapy. More frequently, it results from a small and/or quiescent secreting B-cell clone, is completely asymptomatic, and requires regular monitoring only, defining a monoclonal gammopathy of unknown significance (MGUS). Sometimes, although quiescent and not requiring any treatment per se, the clone is associated with potentially severe organ damage due to the toxicity of the monoclonal immunoglobulin or to other mechanisms. The latter situation is increasingly observed but still poorly recognized and frequently undertreated, although it often requires rapid specific intervention to preserve involved organ function. To improve early recognition and management of these small B-cell clone-related disorders, we propose to introduce the concept of monoclonal gammopathy of clinical significance (MGCS). This report identifies the spectrum of MGCSs that are classified according to mechanisms of tissue injury. It highlights the diversity of these disorders for which diagnosis and treatment are often challenging in clinical practice and require a multidisciplinary approach. Principles of management, including main diagnostic and therapeutic procedures, are also described. Importantly, efficient control of the underlying B-cell clone usually results in organ improvement. Currently, it relies mainly on chemotherapy and other anti-B-cell/plasma cell agents, which should aim at rapidly producing the best hematological response.

Dysregulation of the B-cell leukemia/lymphoma-2 (BCL-2) family of proteins of the intrinsic apoptotic pathway is fundamental to the pathophysiology of many hematologic malignancies. The BCL-2 family consists of regulatory proteins that either induce apoptosis (proapoptotic) or inhibit it (prosurvival). BCL-2, myeloid cell leukemia-1, and B-cell lymphoma-extra large are prosurvival proteins that are prime targets for anticancer therapy, and molecules targeting each are in various stages of preclinical and clinical development. The US Food and Drug Administration (FDA)-approved BCL-2 inhibitor venetoclax was first proven to be highly effective in chronic lymphocytic leukemia and some B-cell non-Hodgkin lymphoma subtypes. Subsequently, venetoclax was found to be active clinically against a diverse array of hematologic malignancies including multiple myeloma, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, and others. Here, we give a brief introduction to BCL-2 family biology and the mechanism of action of BCL-2 Homology 3 (BH3) mimetics, and provide an overview of the clinical data for therapeutically targeting prosurvival proteins in hematologic malignancies, with a focus on BCL-2 inhibition. To prioritize novel agent combinations and predict responders, we discuss the utility of functional assays such as BH3 profiling. Finally, we provide a perspective on how therapies targeting BCL-2 family proteins may be optimally implemented into future therapeutic regimens for hematologic malignancies.