Cerebral complications are among the most devastating manifestations of sickle cell disease (SCD), affecting children and adults with a spectrum that includes overt ischemic and hemorrhagic stroke, silent cerebral infarcts, vasculopathy, and long-term neurocognitive impairment. Advances in screening, primary and secondary stroke prevention, and acute stroke care have reduced risk for some patients, yet cerebrovascular injury remains common and likely underdiagnosed. The pathophysiology of cerebral injury in SCD is multifactorial, resulting from chronic hemolytic anemia, vaso-occlusion, large- and small-vessel vasculopathy, endothelial dysfunction, inflammation, and altered cerebral hemodynamics. Emerging data suggest stabilization or reduced incidence of new infarcts and preservation of neurocognitive function after successful hematopoietic cell transplantation (HCT), although some neurodevelopmental deficits may persist. This review synthesizes contemporary epidemiology, pathophysiology, diagnostic strategies, prevention and treatment, in the context of HCT. Key gaps for future research include optimizing screening strategies, quantifying neurocognitive benefit of curative therapy, and improving access to prevention in resource-limited settings.
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by dysregulated myeloid proliferation and hyperactive JAK-STAT signaling pathway. While JAK inhibitors have become standard therapies for the management of these conditions, significant challenges remain due to resistance to these medications and adverse effects such as cytopenias and infectious complications. This review explores novel therapeutic strategies that target pathways beyond JAK-STAT signaling.We discuss BET inhibitors (pelabresib), PIM kinase inhibitors (TP-3654), telomerase inhibition (imetelstat), nuclear export inhibition (selinexor), LSD1 inhibition (bomedemstat), MDM2 antagonism (navtemadlin), mutant CALR-directed immunotherapies, and activin receptor ligand traps (elritercept). Emerging data suggest that pairing JAK inhibitors with agents that target transcriptional regulation, clonal persistence, anemia, or fibrosis can demonstrate improved responses and enhance safety profiles. Strategies such as high-molecular-risk mutation profiling and variant allele frequency monitoring to assess disease progression and clonal burden will also be discussed. As the focus of MPN management shifts towards curative non-transplant options, a combination of improved access to clinical trials and accounting for patient-reported outcomes will be vital if we are to realize the promise of these next-generation therapies.
Transfusion therapy remains a cornerstone in the management of sickle cell disease (SCD). Yet, repeated exposure to donor red blood cells poses a substantial risk for alloimmunization against red blood cell antigens. Patients with SCD exhibit a disproportionately high incidence of alloimmunization and often experience more severe clinical consequences than other transfusion-dependent populations. This review explores the multifactorial mechanisms underlying this heightened immunogenicity, the clinical and immunologic sequelae that result, and the factors contributing to the under-recognition of alloimmunization's impact in SCD. It will also highlight current and emerging strategies to prevent alloimmunization and advances in the management of its complications, including delayed hemolytic transfusion reactions.
The Philadelphia chromosome negative myeloproliferative neoplasms (MPNs), essential thrombocythemia, polycythemia vera, and primary myelofibrosis, are clonal hematopoietic stem cell disorders unified by constitutive thrombopoietin receptor (MPL) signaling. All 3 MPN driver mutations, JAK2, CALR, and MPL, converge on enhanced MPL signaling, establishing the thrombopoietin (TPO)/MPL axis as the central molecular hub linking clonal hematopoiesis to the cardinal manifestations of MPN, including thrombosis, hemorrhage, and fibrotic progression. As the principal regulator of hematopoietic stem cell maintenance and megakaryopoiesis and a key mediator of platelet priming, the TPO/MPL axis links stem cell biology to thromboinflammation and disease progression. This review summarizes the physiologic functions of the TPO/MPL axis, its dysregulation in MPN, and the downstream mechanisms linking aberrant MPL signaling to thrombosis, hemorrhage, and fibrotic progression. We further highlight recent advances in our understanding of TPO/MPL signaling in platelet biology, including its roles in platelet activation, metabolism, and thromboinflammation, and discuss emerging therapeutic strategies targeting the TPO/MPL pathway with the goal of simultaneously reducing thrombohemorrhagic complications, limiting fibrotic progression, and diminishing the malignant stem cell clone.
Pain is the most common complication experienced by individuals living with sickle cell disease (SCD). While episodes of acute pain, also known as vaso-occlusive crises, are the hallmark of the disease, chronic pain is prevalent in SCD and is associated with many comorbidities. We review current understanding of pain in SCD across the lifespan, integrating definitions, mechanistic categories, and management within biologic, psychosocial, and environmental contexts. Acute vaso-occlusive pain, which emerges as early as infancy, evolves from intermittent nociceptive events driven by multicellular vaso-occlusion, hemolysis, inflammation, and ischemia-reperfusion injury. Chronic pain, which commonly emerges in adolescence and increases with age, reflects heterogeneous nociceptive, neuropathic, and nociplastic mechanisms shaped by SCD-related complications, psychological comorbidities, and social stressors. Chronic pain also contributes to the pathogenesis of acute pain through sensitization processes. Evaluation of mechanisms using tools such as quantitative sensory testing and functional neuroimaging supports hyperexcitability within the peripheral and central nervous system, which is likely important in the development and maintenance of chronic pain. Therapeutically, most guidelines to manage SCD pain are limited by low-certainty evidence; nonetheless, multimodal strategies emphasize timely individualized opioids with nonopioid and nonpharmacologic adjuncts, which are most effective when delivered within multidisciplinary, patient-centered care models. We propose that an individualized whole-person care approach guided by patient-report and biomarker-based framework is key in delineating mechanisms and advancing mechanistic interventions to address pain and related morbidities in SCD.
Treatment for the classical Philadelphia-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV) and essential thrombocythemia (ET), has long relied on reducing thrombotic risk without a focus on underlying disease modification. The simplified framework of age and thrombosis history inadequately captures the biological complexity of these diseases with emerging data identifying leukocytosis, elevated neutrophil-to-lymphocyte ratio, and high JAK2 V617F variant allele frequency as independent predictors of thrombotic risk. Furthermore, prognostic models such as MIPSS-PV and MIPSS-ET incorporate somatic mutations to better predict survival. Despite these advances, real-world practice remains anchored to traditional risk categories, with over 30% of high-risk patients receiving no cytoreductive therapy. In this evidence-based review, we trace the evolution of risk stratification in PV and ET and examine the clinical evidence supporting current cytoreductive options, specifically hydroxyurea, interferons, ruxolitinib, and anagrelide. We argue for a paradigm shift away from binarily driven thrombosis-centric risk stratification toward a personalized, proactive approach that integrates molecular and inflammatory biomarkers, expands the population offered cytoreduction, and prioritizes disease-modifying therapies. Prospective studies are needed to validate the incorporation of these markers into risk-adapted algorithms and to define the long-term impact of early disease modification on transformation, survival, and quality of life.
Sickle cell disease (SCD) is a systemic vasculopathy, which progressively remodels the heart and pulmonary circulation through chronic anemia, hemolysis, and endothelial dysfunction. This review integrates current evidence on the mechanisms, clinical spectrum, and management of SCD-related cardiopulmonary complications. Chronic anemia drives a high-output state characterized by cardiac chamber dilation leading to eccentric remodeling that, over time, may evolve toward diastolic dysfunction, heart failure with preserved ejection fraction (HFpEF), and postcapillary pulmonary hypertension (PH). Concomitant hemolysis, oxidative stress, and microvascular injury promote diffuse myocardial fibrosis that acts as an arrhythmogenic substrate underlying both atrial and ventricular arrhythmias (VAs). Beyond left-sided cardiac disease, SCD also contributes to pulmonary vascular injury and "relative systemic hypertension", both reflecting a vasculopathy process that amplifies target organs damage. Transthoracic echocardiography (TTE) remains the cornerstone of diagnosis and prognosis of SCD-related cardiomyopathy, enabling longitudinal assessment of ventricular performance, chamber remodeling and hemodynamics including pulmonary pressures, while cardiac magnetic resonance (CMR) adds information on tissue characterization and quantification of diffuse fibrosis. Emerging data suggests that curative therapies. Such as hematopoietic stem cell transplantation and gene therapy can reverse cardiac remodeling and fibrosis yet necessitate structured long-term follow-up. Recognizing SCD-related cardiomyopathy as a dynamic and potentially reversible cardiopulmonary continuum is essential for establishing disease-specific diagnostic criteria and guiding physiological grounded therapeutic strategies.
Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by chronic hemolytic anemia, painful vaso-occlusive episodes, and end-organ damage. Population-level studies indicate individuals with SCD are at an increased risk for myeloid neoplasia (MN). While the absolute risk of MN remains low, fatal cases of myelodysplastic syndrome and acute myeloid leukemia suggest MN risk is enhanced in the setting of curative cellular therapies for SCD, including allogeneic hematopoietic cell transplantation and autologous gene therapy. Clonal hematopoiesis (CH), the expansion of a genetically related population of hematopoietic stem or progenitor cells, is commonly caused by mutations in myeloid leukemia driver genes and is a recognized precursor state for MNs, including myelodysplastic syndrome and acute myeloid leukemia. This review synthesizes current data on MN incidence in SCD populations, prevalence of adverse-risk CH in SCD, and clustering of high-risk subtypes of MN among cases involving SCD patients. CH emerges as a potential biological mechanism linking SCD to increased susceptibility to MN with implications for clinical research and counseling of patients with SCD.
Patients with myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera, and myelofibrosis, are at increased risk of cardiovascular disease and complications. The most recognized cardiovascular complications among patients with MPN are arterial and venous thrombotic events. However, mounting evidence suggest that nonthrombotic cardiovascular complications, including heart failure and pulmonary hypertension, are also common and are associated with adverse outcomes and overall prognosis. Therefore, it is important that hematologists become aware of such complications and are able to identify them as they arise. Additionally, cardiovascular disease treatment, including antithrombotic therapy and guideline-directed medical therapy for heart failure, may impact MPN-specific outcomes. Therefore, we review current literature of cardiovascular disease and complications among patients with MPNs and their impact on patient outcomes and prognosis.
With the growing interest in precision medicine and personalized treatments for sickle cell disease (SCD) comes a realization that our approach to individuals living with the hemoglobin SC (HbSC) genotype is inadequate. For many decades HbSC was viewed as a milder form of SCD that does not demand aggressive management. Consequently, when resources, funding, and treatments for SCD were limited, clinical and research efforts were largely directed towards the more prevalent homozygous HbSS genotype. This has left many individuals with HbSC disease facing substantial morbidity and limited therapeutic options. Recent evidence demonstrating the efficacy of hydroxyurea in HbSC disease together with the development of a novel murine model, has renewed interest in this understudied genotype. This review highlights the main similarities and differences between HbSS and HbSC disease, addresses common misconceptions regarding HbSC disease, and discusses emerging biomarkers and therapeutic strategies for this patient population.
Recent advances in understanding sickle cell disease (SCD) pathophysiology have revealed the critical role of abnormal mitochondrial retention in mature erythrocytes. This comprehensive review examines how disrupted mitochondrial clearance contributes to disease progression through multiple mechanisms, including oxidative stress, metabolic dysfunction, and immune activation. We will review evidence from both human studies and animal models demonstrating that retained mitochondria remain functionally active and contribute to cellular damage. Furthermore, we will highlight emerging findings that active mitochondria in reticulocytes are also detrimental in SCD, exacerbating oxidative stress, and promoting premature cellular damage. This review examines therapeutic approaches targeting mitochondrial dysfunction, including pyruvate kinase activation and mitophagy enhancement strategies. Understanding these mechanisms provides new opportunities for therapeutic intervention in SCD and related disorders.
Patient advocacy has emerged as a transformative force within the rare disease landscape. Few rare diseases illustrate this dynamic as clearly as Telomere Biology Disorders (TBDs). Once regarded primarily as rare pediatric bone marrow failure syndromes, TBDs are now understood as multisystem, lifelong conditions affecting individuals across the age spectrum. In this review, we examine TBDs as a case study in rare disease advocacy, highlighting how advocacy has functioned not only as a support mechanism but as an organizing architecture underpinning progress across diagnosis, management, research, and community engagement. We describe how advocacy efforts have advanced diagnostic awareness and access to validated testing, informed the development and dissemination of clinical management guidelines, enabled multidisciplinary models of care, and fostered robust research ecosystems through funding, registries, and collaborative convenings. We further explore the essential role of advocacy in addressing psychosocial needs, sustaining patient engagement, and confronting persistent inequities in access, representation, and care delivery. The TBD experience demonstrates that advocacy is not ancillary to science, but integral to its progress and impact. As the field enters a new era characterized by expanding diagnoses and emerging therapies, the TBD community offers a scalable framework for integrating advocacy as a core component of rare disease ecosystems.
Despite advances in understanding the molecular and cellular pathophysiology of sickle cell disease (SCD), the development of effective pharmacologic therapies has been slow. Hydroxyurea, a small molecule repurposed decades ago, remains the cornerstone of disease-modifying therapy, and it is the benchmark against which new therapies are measured. Recent approvals of additional agents have expanded therapeutic options, yet their clinical benefits have been narrow, sometimes uncertain, or complicated by regulatory withdrawals, underscoring the persistent challenges of translating biologically plausible mechanisms into clinical benefits. The central pathogenic event in SCD, the polymerization of deoxygenated sickle hemoglobin (Hb), initiates a cascade of red blood cell (RBC) injury, hemolysis, vaso-occlusion, vasculopathy, inflammation, and progressive organ damage. Drugs that act proximally in this pathway are more likely to be broadly effective. Small molecules, in particular, are appealing because of oral bioavailability, ability to enter RBCs, and scalability in manufacturing. In parallel to development of new agents, drug repurposing can accelerate the process of drug development by using agents with known pharmacologic and safety profiles. This review highlights recent and emerging disease-modifying approaches for SCD, with emphasis on small molecules and repurposed drugs, including pyruvate kinase activators, epigenetic fetal hemoglobin inducers, Hb oxygen-affinity modulators, and iron restriction strategies. Each therapy addresses distinct yet interconnected aspects of SCD pathophysiology. No single therapy is likely to be completely protective across the lifespan. The future of SCD pharmacotherapy will likely include mechanism-based combination therapies concurrent with the advancements in genetic and cellular therapies.
Telomere biology disorders (TBDs) are inherited conditions characterized by premature telomere shortening, leading to multisystemic manifestations and a high predisposition to hematologic complications. These include mainly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) that may show a unique mutational spectrum and cytogenetic abnormalities. Management of MDS/AML in TBD is challenging due to heightened sensitivity to DNA-damaging agents and transplant-related toxicity, necessitating individualized approaches and multidisciplinary care. Emerging therapies such as thymidine supplementation, gene therapy, and treatment with antisense oligonucleotides, offer promising results for improving clinical outcomes. Continued research and collaborative efforts are essential to optimize screening, risk stratification, and treatment strategies for this vulnerable population.
Telomere biology disorders (TBDs) are characterized by numerous somatic features across multiple organ systems, which contribute significantly to the morbidity and mortality of these conditions. In many cases, rare somatic manifestations may represent the earliest symptoms of a TBD and the first presentation to subspecialty care, and thus a high index of suspicion is necessary for timely diagnosis. Hoyeraal-Hriedarsson Syndrome, Revesz Syndrome, and Coats Plus Syndrome represent severe phenotypes with characteristic somatic features often diagnosed in early childhood. However, all patients with TBDs may exhibit these varied symptoms throughout the lifespan. Of note, patients continue to experience disease-related complications across multiple organ systems even after hematopoietic stem cell transplant, reinforcing the need for lifelong multidisciplinary care for patients with TBDs. In this chapter, we describe neurological, immunologic, gastrointestinal, ophthalmic, and endocrinologic manifestations of TBDs, among others.
Telomere biology disorders (TBDs) are caused by pathogenic germline variants in genes essential for telomere maintenance and function, including at least 17 different genes with X-linked recessive (XLR), autosomal dominant (AD) and/or autosomal recessive (AR) inheritance as well as de novo occurrence. Individuals with TBDs have short and/or dysfunctional telomeres and high rates of bone marrow failure, pulmonary fibrosis, liver disease, certain immunodeficiencies, and many other problems. TBDs are cancer predisposition syndromes with an approximately 3-fold increased risk of any cancer and an overall cancer-free survival in the mid-40s. Head/neck squamous cell carcinoma (HNSCC), the most common TBD-associated solid malignancy, is notable for a 43-fold increased risk in AD TBDs and 276-fold in AR/XLR disease compared with the general population. The limited data on cancer treatment in TBDs suggests poor tolerance of standard chemotherapy and radiation regimens and dismal outcomes. Cancer surveillance modalities have not been prospectively studied in TBDs and are currently based on expert opinion. The mechanisms by which cancer develops in TBDs are proposed to include chromosomal instability and DNA damage accumulation due to abnormal telomere function and an underlying T cell immunodeficiency with suboptimal immune surveillance. Clonal hematopoiesis (CH) is relatively common in TBDs, including reversion or compensation of the germline variant and recurrent clonal hematopoiesis mutations modulating the TP53 pathway associated with cancer development. This review highlights recent advances in understanding solid malignancies in TBDs and underscores the urgent need for prospective studies to develop the evidence base for cancer surveillance and treatment in these complex disorders.
Telomere biology disorders (TBDs) are a heterogeneous group of inherited systemic diseases caused by pathogenic variants in genes encoding telomerase or proteins involved in telomere maintenance or protection. With very short and/or dysfunctional telomeres, patients with TBD have clinical manifestations clustered in tissues with high rates of cell proliferation. Bone marrow failure (BMF) is the most common hematologic complication of a TBD and can precede the development of more difficult-to-treat malignant transformation. However, not all patients with TBD develop BMF, and some genotype/phenotype correlations are emerging. While allogeneic hematopoietic cell transplant (HCT) is curative for BMF in TBD, toxicities of the conditioning regimen can be detrimental to other organs. Balancing the risk of malignant transformation with HCT toxicity is a core challenge for providers who care for patients with TBD-associated BMF. Herein, we review the clinical presentation, pathophysiology, surveillance, and non-HCT treatment of BMF in TBD, including supportive care, androgens, thrombopoietin receptor agonists, and investigational approaches.
Telomere biology disorders (TBDs) are inherited conditions characterized by defective telomere maintenance, leading to critically short telomeres and multisystem disease, with hematologic complications representing a major cause of morbidity and mortality. Bone marrow failure, myelodysplastic syndrome, and acute myeloid leukemia occur at markedly increased rates in affected individuals, and hematopoietic stem cell transplantation (HSCT) remains the only curative therapy for these hematologic manifestations. Historically, outcomes following HSCT in TBDs were poor, largely due to heightened sensitivity to myeloablative conditioning regimens, resulting in excessive early mortality, graft failure, graft-versus-host disease, and severe pulmonary and hepatic toxicity. Advances in disease recognition, donor selection, conditioning regimens, and supportive care have substantially improved transplant outcomes over the last several decades. Contemporary strategies emphasize reduced-intensity or reduced-toxicity approaches, with growing experience in the use of alkylator- and radiation-free platforms. Despite improved early survival, long-term outcomes remain limited by progressive non-hematologic organ dysfunction, vascular complications, and secondary malignancies inherent to telomere-mediated disease and potentially accelerated by transplantation. Optimal management of patients with TBDs undergoing HSCT requires careful patient selection, thorough pre-transplant evaluation, exclusion of occult TBDs in related donors, preference for bone marrow grafts, and aggressive strategies to prevent graft-versus-host disease. Lifelong, multidisciplinary posttransplant surveillance focused on multiorgan complications is essential. Emerging gene and cellular therapies, including autologous telomere-elongation approaches, offer promising alternatives for select patients and may further expand the therapeutic landscape. Continued progress will depend on disease-specific, multi-institutional prospective studies aimed at optimizing transplant strategies, minimizing long-term toxicity, and improving survival and quality of life for patients with TBDs.
Telomere biology disorders (TBDs) are a group of genetic conditions of varying severity caused by defects in telomere maintenance. Patients with TBDs can experience dysfunction in nearly all organ systems, including the bone marrow, with increased risk for bone marrow failure and myeloid neoplasms. Over the past decade, several groups have identified higher rates and earlier onset of clonal hematopoiesis (CH) in TBDs patients, with a distinct profile of somatic variants compared to the general population. While TBDs patients sometimes develop variants seen in age-related CH, these are proportionally much less prevalent in TBDs. Instead, TBDs patients develop recurrent gene variants that overcome cell growth constraints caused by telomere shortening or dysfunction. These variants include those that enhance telomere maintenance through reversion of the underlying TBD-causing germline variant or through compensatory mutations in other telomere maintenance machinery, mutations in spliceosome genes, and mutations that disrupt components of the DNA damage response. Early links between specific types of variants and subsequent progression to myeloid malignancies have been reported. In this manuscript, we critically review the existing literature, highlighting open questions in the field, and discuss clinical tools for detecting and monitoring CH in patients with TBDs.
