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 nontransplant 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.

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.

Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs) are clonal malignancies, with a complex interaction of the malignant clone, extramedullary haematopoiesis, and chronic inflammation. In high-risk disease, transformation to blast phase remains a constant risk and outcomes are usually dismal. Allogeneic blood or marrow transplantation (BMT) remains the only potentially curative treatment to date. In this narrative review, we summarize the evidence available to date on the role of BMT in MPNs and the ongoing investigations exploring the use of mutant CALR-targeted immune-based therapies, including engineered cellular therapeutics. BMT aims at the eradication of the malignant clone, although not without risks. To balance the risk vs benefit, BMT is usually considered in patients with higher risk features of disease. Historically, matched related or unrelated donors were preferred, but with the emergence of post-transplantation cyclophosphamide (PTCy), mismatched, family or unrelated, donors are increasingly used. Reduced-intensity conditioning regimens and peripheral blood graft sources are commonly employed but can vary by individual patient and institutional practice. Post-transplantation monitoring remains critical because engraftment is often delayed, contributing to nonrelapse mortality. Molecular evidence of disease post-transplantation increases the risk of relapse, but optimal timing of monitoring and interventions thereafter remain elusive. We also review the BMT landscape in MDS/MPN overlap neoplasms. Prevention and effective management of relapse remains an unmet need in both MPN and MDS/MPN. The role of cellular therapies in MPN is investigational. Progress in target identification in CALR-mutated MPN has resulted in the development of Fc-silent antibodies, T cell redirecting antibodies, and engineered cellular therapies which are advancing in clinical development.

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.

Pregnancy in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) is uncommon but clinically challenging. Essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) are clonal hematopoietic stem cell disorders characterized by myeloid proliferation, JAK-STAT pathway activation, and an increased risk of thrombotic and hemorrhagic complications. Pregnancy itself is a hypercoagulable state, and when it occurs in patients with MPNs, maternal and fetal complications are more frequent than in the general population. The most common fetal complications are first trimester pregnancy loss, placental insufficiency, fetal growth restriction, preeclampsia, preterm delivery, and stillbirth. Maternal complications include venous and arterial thrombosis, bleeding, acquired von Willebrand syndrome, and postpartum thromboembolism. ET is the most frequently encountered MPN in pregnancy and generally carries the most favorable prognosis. PV is associated with higher thrombotic and placental risk, largely related to erythrocytosis and hyperviscosity. Pregnancy in PMF is rare, and available data are limited to small series and case reports, making management particularly dependent on expert opinion. The mainstay of treatment is risk-adapted therapy with low-dose aspirin, low-molecular-weight heparin, phlebotomy for PV, and interferon-based cytoreduction when needed. Hydroxyurea, anagrelide, and JAK inhibitors are generally avoided due to limited fetal safety data. Given the paucity of prospective evidence, management should be individualized and coordinated by hematology and maternal-fetal medicine specialists. This review summarizes current data on MPN pregnancy outcomes and provides a practical approach to preconception counseling, antepartum management, delivery planning, postpartum care, and future research priorities.

Myeloproliferative neoplasms (MPNs) were previously thought to result solely from somatic mutations; however, familial clustering and germline genetic testing have revealed hereditary MPNs. These hereditary MPNs are one type of hereditary hematopoietic malignancy (HHM) syndrome, or hereditary blood cancer, and generally display an autosomal-dominant inheritance pattern within families. Point estimates of the prevalence of hereditary MPNs vary with testing methodology and the patient population sampled, but diagnostic yields for pathogenic/likely pathogenic variants in patients with MPNs range from 8% to 27% across all seemingly sporadic MPN cases. We discuss the history and current state of emerging knowledge regarding the genetic basis of hereditary MPNs. We use the broader HHM framework as a lens to identify and manage patients at risk for, and those who have developed, an MPN. This review discusses the selection of rigorous diagnostic assays, the need for personalized stem cell transplant care, and the lack of "precision" therapies for hereditary MPNs. Finally, we appraise hereditary MPNs in the context of existing criteria for genetic testing and discuss evidence pertaining to the potential benefits of universal germline genetic testing for patients with MPNs more broadly.

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.

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.

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.

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.

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.

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.