Follicular lymphoma (FL) is a generally incurable malignancy that originates from developmentally blocked germinal center B cells residing, primarily, within lymph nodes (LNs). During the long natural history of FL, malignant B cells often disseminate to multiple LNs and can affect virtually any organ. Nonmalignant LNs are highly organized structures distributed throughout the body, in which they perform functions critical for host defense. In FL, the malignant B cells "re-educate" the lymphoid environment by altering the phenotype, distribution, and abundance of other cells such as T cells, macrophages, and subsets of stromal cells. Consequently, dramatic anatomical changes occur and include alterations in the number, shape, and size of neoplastic follicles with an accompanying attenuation of the T-cell zone. Ongoing and dynamic interactions between FL B cells and the tumor microenvironment (TME) result in significant clinical heterogeneity observed both within and across patients. Over time, FL evolves into pathological variants associated with distinct outcomes, ranging from an indolent disease to more aggressive clinical courses with early death. Given the importance of both cell-intrinsic and -extrinsic factors in shaping disease progression and patient survival, comprehensive examination of FL tumors is critical. Here, we describe the cellular composition and architecture of normal and malignant human LNs and provide a broad overview of emerging technologies for deconstructing the FL TME at single-cell and spatial resolution. We additionally discuss the importance of capturing samples at landmark time points as well as longitudinally for clinical decision-making.

Factor XI (FXI) deficiency is a rare bleeding disorder that presents complex challenges in patient assessment and bleeding risk management. Despite generally causing mild to moderate bleeding symptoms, clinical manifestations can vary, and bleeding tendency does not always correlate with FXI plasma levels or genotype. Our manuscript delves into the age-related nuances of FXI deficiency across an individual's lifespan. We emphasize issues faced by specific groups, including neonates and females of reproductive age experiencing abnormal uterine bleeding and postpartum hemorrhage. Older patients present unique challenges and concerns related to the management of bleeding as well as thrombotic complications. The current assortment of diagnostic laboratory assays shows limited success in predicting bleeding risk in the perisurgical setting of patients with FXI deficiency. This review explores the intricate interplay between individual bleeding profiles, surgical sites, and FXI activity levels. We also evaluate the accuracy of existing laboratory assays in predicting bleeding and discuss the potential role of investigational global assays in perioperative assessment. Furthermore, we outline our suggested diagnostic approach to refine treatment strategies and decision making. Available treatment options are presented, including antifibrinolytics, replacement products, and recombinant activated FVII. Finally, we discuss promising nonreplacement therapies for the treatment of rare bleeding disorders that can potentially address the challenges faced when managing FXI deficiency-related bleeding complications.

Targeted protein degradation (TPD) is a revolutionary approach to targeted therapy in hematological malignancies that potentially circumvents many constraints of existing small-molecule inhibitors. Heterobifunctional proteolysis-targeting chimeras (PROTACs) are the leading TPD drug class, with numerous agents now in clinical trials for a range of blood cancers. PROTACs harness the cell-intrinsic protein recycling infrastructure, the ubiquitin-proteasome system, to completely degrade target proteins. Distinct from targeted small-molecule inhibitor therapies, PROTACs can eliminate critical but conventionally "undruggable" targets, overcome resistance mechanisms to small-molecule therapies, and can improve tissue specificity and off-target toxicity. Orally bioavailable, PROTACs are not dependent on the occupancy-driven pharmacology inherent to inhibitory therapeutics, facilitating substoichiometric dosing that does not require an active or allosteric target binding site. Preliminary clinical data demonstrate promising therapeutic activity in heavily pretreated populations and novel technology platforms are poised to exploit a myriad of permutations of PROTAC molecular design to enhance efficacy and targeting specificity. As the field rapidly progresses and various non-PROTAC TPD drug candidates emerge, this review explores the scientific and preclinical foundations of PROTACs and presents them within common clinical contexts. Additionally, we examine the latest findings from ongoing active PROTAC clinical trials.

Direct oral anticoagulants (DOACs) that inhibit the coagulation proteases thrombin or factor Xa (FXa) have replaced warfarin and other vitamin K antagonists (VKAs) for most indications requiring long-term anticoagulation. In many clinical situations, DOACs are as effective as VKAs, cause less bleeding, and do not require laboratory monitoring. However, because DOACs target proteases that are required for hemostasis, their use increases the risk of serious bleeding. Concerns over therapy-related bleeding undoubtedly contribute to undertreatment of many patients who would benefit from anticoagulation therapy. There is considerable interest in the plasma zymogen factor XI (FXI) and its protease form factor XIa (FXIa) as drug targets for treating and preventing thrombosis. Laboratory and epidemiologic studies support the conclusion that FXI contributes to venous and arterial thrombosis. Based on 70 years of clinical observations of patients lacking FXI, it is anticipated that drugs targeting this protein will cause less severe bleeding than warfarin or DOACs. In phase 2 studies, drugs that inhibit FXI or FXIa prevent venous thromboembolism after total knee arthroplasty as well as, or better than, low molecular weight heparin. Patients with heart disease on FXI or FXIa inhibitors experienced less bleeding than patients taking DOACs. Based on these early results, phase 3 trials have been initiated that compare drugs targeting FXI and FXIa to standard treatments or placebo. Here, we review the contributions of FXI to normal and abnormal coagulation and discuss results from preclinical, nonclinical, and clinical studies of FXI and FXIa inhibitors.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of mature T-cell neoplasms that represent ∼10% of all non-Hodgkin lymphoma. Outcomes for the majority of patients with PTCL are poor, and treatment approaches have been relatively uniform using cyclophosphamide, doxorubicin, vincristine, and prednisone-based therapy. For example, large registry studies consistently demonstrate 5-year overall survival of ∼30% to 40%. However, as our understanding of the biology underpinning the heterogeneity of PTCL improves and as treatments specifically for PTCL are developed, risk stratification has become a more relevant question. Tools including positron emission tomography-computed tomography and minimal residual disease (MRD) monitoring offer the potential for dynamic risk stratification. In this review, we first summarize registry data describing outcomes in the most common subtypes of PTCL: PTCL not otherwise specified, nodal T-follicular helper cell lymphoma including angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma. We describe current clinically based prognostic indices validated for PTCL and highlight emerging tools for prognostication including novel molecular biomarkers, imaging-based metrics, and MRD dynamics.

B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells are the most potent treatment against multiple myeloma (MM). Here, we review the increasing body of clinical and correlative preclinical data that support their inclusion into firstline therapy and sequencing before T-cell-engaging antibodies. The ambition to cure MM with (BCMA-)CAR T cells is informed by genomic and phenotypic analysis that assess BCMA expression for patient stratification and monitoring, steadily improving early diagnosis and management of side effects, and advances in rapid, scalable CAR T-cell manufacturing to improve access.

Thrombocytopenia is a common hematologic abnormality in pregnancy, encountered in ∼10% of pregnancies. There are many possible causes, ranging from benign conditions that do not require intervention to life-threatening disorders necessitating urgent recognition and treatment. Although thrombocytopenia may be an inherited condition or predate pregnancy, most commonly it is a new diagnosis. Identifying the responsible mechanism and predicting its course is made challenging by the tremendous overlap of clinical features and laboratory data between normal pregnancy and the many potential causes of thrombocytopenia. Multidisciplinary collaboration between hematology, obstetrics, and anesthesia and shared decision-making with the involved patient is encouraged to enhance diagnostic clarity and develop an optimized treatment regimen, with careful consideration of management of labor and delivery and the potential fetal impact of maternal thrombocytopenia and any proposed therapeutic intervention. In this review, we outline a diagnostic approach to pregnant patients with thrombocytopenia, highlighting the subtle differences in presentation, physical examination, clinical course, and laboratory abnormalities that can be applied to focus the differential. Four clinical scenarios are presented to highlight the pathophysiology and treatment of the most common causes of thrombocytopenia in pregnancy: gestational thrombocytopenia, preeclampsia, and immune thrombocytopenia.

Clonal hematopoiesis (CH) is described as the outsized contribution of expanded clones of hematopoietic stem and progenitor cells (HSPCs) to blood cell production. The prevalence of CH increases dramatically with age. CH can be caused by somatic mutations in individual genes or by gains and/or losses of larger chromosomal segments. CH is a premalignant state; the somatic mutations detected in CH are the initiating mutations for hematologic malignancies, and CH is a strong predictor of the development of blood cancers. Moreover, CH is associated with nonmalignant disorders and increased overall mortality. The somatic mutations that drive clonal expansion of HSPCs can alter the function of terminally differentiated blood cells, including the release of elevated levels of inflammatory cytokines. These cytokines may then contribute to a broad range of inflammatory disorders that increase in prevalence with age. Specific somatic mutations in the peripheral blood in coordination with blood count parameters can powerfully predict the development of hematologic malignancies and overall mortality in CH. In this review, we summarize the current understanding of CH nosology and origins. We provide an overview of available tools for risk stratification and discuss management strategies for patients with CH presenting to hematology clinics.

Diffuse large B-cell lymphoma (DLBCL), not otherwise specified, is the most common subtype of large B-cell lymphoma, with differences in prognosis reflecting heterogeneity in the pathological, molecular, and clinical features. Current treatment standard is based on multiagent chemotherapy, including anthracycline and monoclonal anti-CD20 antibody, which leads to cure in 60% of patients. Recent years have brought new insights into lymphoma biology and have helped refine the risk groups. The results of these studies inspired the design of new clinical trials with targeted therapies and response-adapted strategies and allowed to identify groups of patients potentially benefiting from new agents. This review summarizes recent progress in identifying high-risk patients with DLBCL using clinical and biological prognostic factors assessed at diagnosis and during treatment in the front-line setting, as well as new treatment strategies with the application of targeted agents and immunotherapy, including response-adapted strategies.

Advancements in the conceptual thinking of hemostasis and thrombosis have been catalyzed by major developments within health research over several decades. The cascade model of coagulation was first described in the 1960s, when biochemistry gained prominence through innovative experimentation and technical developments. This was followed by the cell-based model, which integrated cellular coordination to the enzymology of clot formation and was conceptualized during the growth period in cell biology at the turn of the millennium. Each step forward has heralded a revolution in clinical therapeutics, both in procoagulant and anticoagulant treatments to improve patient care. In current times, the COVID-19 pandemic may also prove to be a catalyst: thrombotic challenges including the mixed responses to anticoagulant treatment and the vaccine-induced immune thrombotic thrombocytopenia have exposed limitations in our preexisting concepts while simultaneously demanding novel therapeutic approaches. It is increasingly clear that innate immune activation as part of the host response to injury is not separate but integrated into adaptive clot formation. Our review summarizes current understanding of the major molecules facilitating such a cross talk between immunity, inflammation and coagulation. We demonstrate how such effects can be layered upon the cascade and cell-based models to evolve conceptual understanding of the physiology of immunohemostasis and the pathology of immunothrombosis.

Over the past 2 decades, there has been a significant increase in the utilization of long-term mechanical circulatory support (MCS) for the treatment of cardiac failure. Left ventricular assist devices (LVADs) and total artificial hearts (TAHs) have been developed in parallel to serve as bridge-to-transplant and destination therapy solutions. Despite the distinct hemodynamic characteristics introduced by LVADs and TAHs, a comparative evaluation of these devices regarding potential complications in supported patients, has not been undertaken. Such a study could provide valuable insights into the complications associated with these devices. Although MCS has shown substantial clinical benefits, significant complications related to hemocompatibility persist, including thrombosis, recurrent bleeding, and cerebrovascular accidents. This review focuses on the current understanding of hemostasis, specifically thrombotic and bleeding complications, and explores the influence of different shear stress regimens in long-term MCS. Furthermore, the role of endothelial cells in protecting against hemocompatibility-related complications of MCS is discussed. We also compared the diverse mechanisms contributing to the occurrence of hemocompatibility-related complications in currently used LVADs and TAHs. By applying the existing knowledge, we present, for the first time, a comprehensive comparison between long-term MCS options.

Unique among coagulation factors, the coagulation factor XI (FXI) arose through a duplication of the gene KLKB1, which encodes plasma prekallikrein. This evolutionary origin sets FXI apart structurally because it is a homodimer with 2 identical subunits composed of 4 apple and 1 catalytic domain. Each domain exhibits unique affinities for binding partners within the coagulation cascade, regulating the conversion of FXI to a serine protease as well as the selectivity of substrates cleaved by the active form of FXI. Beyond serving as the molecular nexus for the extrinsic and contact pathways to propagate thrombin generation by way of activating FIX, the function of FXI extends to contribute to barrier function, platelet activation, inflammation, and the immune response. Herein, we critically review the current understanding of the molecular biology of FXI, touching on some functional consequences at the cell, tissue, and organ level. We conclude each section by highlighting the DNA mutations within each domain that present as FXI deficiency. Together, a narrative review of the structure-function of the domains of FXI is imperative to understand the etiology of hemophilia C as well as to identify regions of FXI to safely inhibit the pathological function of activation or activity of FXI without compromising the physiologic role of FXI.

Platelets are key vascular effectors in hemostasis, with activation signals leading to fast recruitment, aggregation, and clot formation. The canonical process of hemostasis is well-characterized and shares many similarities with pathological thrombus formation. However, platelets are also crucially involved in the maintenance of vascular integrity under both steady-state and inflammatory conditions by ensuring blood vessel homeostasis and preventing microbleeds. In these settings, platelets use distinct receptors, signaling pathways, and ensuing effector functions to carry out their deeds. Instead of simply forming clots, they mainly act as individual sentinels that swiftly adapt their behavior to the local microenvironment. In this review, we summarize previously recognized and more recent studies that have elucidated how anucleate, small platelets manage to maintain vascular integrity when faced with challenges of infection, sterile inflammation, and even malignancy. We dissect how platelets are recruited to the vascular wall, how they identify sites of injury, and how they prevent hemorrhage as single cells. Furthermore, we discuss mechanisms and consequences of platelets' interaction with leukocytes and endothelial cells, the relevance of adhesion as well as signaling receptors, in particular immunoreceptor tyrosine-based activation motif receptors, and cross talk with the coagulation system. Finally, we outline how recent insights into inflammatory hemostasis and vascular integrity may aid in the development of novel therapeutic strategies to prevent hemorrhagic events and vascular dysfunction in patients who are critically ill.

Understanding the genetic alterations, disrupted signaling pathways, and hijacked mechanisms in oncogene-transformed hematologic cells is critical for the development of effective and durable treatment strategies against liquid tumors. In this review, we focus on the specific involvement of the Hedgehog (HH)/GLI pathway in the manifestation and initiation of various cancer features in hematologic malignancies, including multiple myeloma, T- and B-cell lymphomas, and lymphoid and myeloid leukemias. By reviewing canonical and noncanonical, Smoothened-independent HH/GLI signaling and summarizing preclinical in vitro and in vivo studies in hematologic malignancies, we elucidate common molecular mechanisms by which HH/GLI signaling controls key oncogenic processes and cancer hallmarks such as cell proliferation, cancer stem cell fate, genomic instability, microenvironment remodeling, and cell survival. We also summarize current clinical trials with HH inhibitors and discuss successes and challenges, as well as opportunities for future combined therapeutic approaches. By providing a bird's eye view of the role of HH/GLI signaling in liquid tumors, we suggest that a comprehensive understanding of the general oncogenic effects of HH/GLI signaling on the formation of cancer hallmarks is essential to identify critical vulnerabilities within tumor cells and their supporting remodeled microenvironment, paving the way for the development of novel and efficient personalized combination therapies for hematologic malignancies.

In this spotlight, we review technical issues that compromise single-cell analysis of tissue macrophages, including limited and unrepresentative yields, fragmentation and generation of remnants, and activation during tissue disaggregation. These issues may lead to a misleading definition of subpopulations of macrophages and the expression of macrophage-specific transcripts by unrelated cells. Recognition of the technical limitations of single-cell approaches is required in order to map the full spectrum of tissue-resident macrophage heterogeneity and assess its biological significance.

Risk stratification and prognostication are crucial for the appropriate management of patients with myelodysplastic syndromes (MDSs) or myelodysplastic neoplasms, for whom the expected survival can vary from a few months to >10 years. For the past 5 decades, patients with MDS have been classified into higher-risk vs lower-risk disease phenotypes using sequentially developed clinical prognostic scoring systems. Factors such as morphologic dysplasia, clinical hematologic parameters, cytogenetics, and, more recently, mutational information have been captured in prognostic scoring systems that refine risk stratification and guide therapeutic management in patients with MDS. This review describes the progressive evolution and improvement of these systems which has led to the current Molecular International Prognostic Scoring System.

Given the shortcomings of current factor-, nonfactor-, and adeno-associated virus gene-based therapies, the recent advent of RNA-based therapeutics for hemophilia is changing the fundamental approach to hemophilia management. From small interfering RNA therapeutics that knockdown clot regulators antithrombin, protein S, and heparin cofactor II, to CRISPR/Cas9 gene editing that may personalize treatment, improved technologies have the potential to reduce bleeds and factor use and avoid inhibitor formation. These novel agents, some in preclinical studies and others in early phase trials, have the potential to simplify treatment and improve hemostasis and quality of life. Furthermore, because these therapies arise from manipulation of the coagulation cascade and thrombin generation and its regulation, they will enhance our understanding of hemostasis and thrombosis and ultimately lead to better therapies for children and adults with inherited bleeding disorders. What does the future hold? With the development of novel preclinical technologies at the bench, there will be fewer joint bleeds, debilitating joint disease, orthopedic surgery, and improved physical and mental health, which were not previously possible. In this review, we identify current limitations of treatment and progress in the development of novel RNA therapeutics, including messenger RNA nanoparticle delivery and gene editing for the treatment of hemophilia.

Mechanistic studies of immune bone marrow failure are difficult because of the scarcity of residual cells, the involvement of multiple cell types, and the inherent complexities of hematopoiesis and immunity. Single-cell genomic technologies and bioinformatics allow extensive, multidimensional analysis of a very limited number of cells. We review emerging applications of single-cell techniques, and early results related to disease pathogenesis: effector and target cell populations and relationships, cell-autonomous and nonautonomous phenotypes in clonal hematopoiesis, transcript splicing, chromosomal abnormalities, and T-cell receptor usage and clonality. Dense and complex data from single-cell techniques provide insights into pathophysiology, natural history, and therapeutic drug effects.

Multiple myeloma remains an incurable disease plagued by high relapse rates. Deeper and more sustainable responses, however, have been consistently shown to improve outcomes and could eventually pave the way to achieving a cure. Our understanding of disease response has surpassed complete response (CR), because the current definitions are suboptimal, and the treatment goal should aim even beyond stringent CR, toward molecular and flow CR, that is, measurable residual disease (MRD) negativity. It has been more than 20 years since the discrepancy in the outcome between patients in CR with and without MRD has been demonstrated, and the field has come a long way from multiparameter flow cytometry to next-generation flow and next-generation sequencing, able to detect up to a limit of detection of a single myeloma cell from 1 million healthy counterparts. This review aims to summarize the current available data regarding MRD but also its potential future use as a coprimary outcome both in clinical and trial settings as a survival surrogate as well as its use to evaluate treatment efficacy and for adaptive response-based and early-rescue therapy. Furthermore, we discuss whether these concepts are applicable in different settings (eg, newly diagnosed and relapsed/refractory myeloma, patients who are eligible and ineligible for tansplant, and standard- and high-risk disease).

Acute graft-versus-host disease (aGVHD) is a major life-threatening complication after allogeneic hematopoietic cell transplant. Traditional standard prophylaxis for aGVHD has included a calcineurin inhibitor plus an antimetabolite, whereas treatment has relied mainly on corticosteroids, followed by multiple nonstandard second-line options. In the past decade, this basic framework has been reshaped by approval of antithymocyte globulin products, the emergence of posttransplant cyclophosphamide, and recent pivotal trials studying abatacept and vedolizumab for GVHD prophylaxis, whereas ruxolitinib was approved for corticosteroid-refractory aGVHD treatment. Because of this progress, routine acute GVHD prophylaxis and treatment practices are starting to shift, and results of ongoing trials are eagerly awaited. Here, we review recent developments in aGVHD prevention and therapy, along with ongoing and future planned clinical trials in this space, outlining what future goals should be and the limitations of current clinical trial designs and end points.