PURPOSE OF REVIEW:Acute graft-versus-host disease (aGVHD) remains a principal driver of nonrelapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Fifty percent of patients fail to achieve durable responses to first-line corticosteroids, defining steroid-refractory aGVHD (SR-aGVHD) and limited long-term survival. The Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib became the standard second-line therapy. Nevertheless, primary resistance and secondary loss of response continue to leave a substantial proportion of patients without effective treatment. RECENT FINDINGS:This review synthesizes evidence available up to June 2026 on second-line and salvage options that complement or follow ruxolitinib, including mesenchymal stromal cells, extracorporeal photopheresis administered alone or in combination with ruxolitinib, mammalian target of rapamycin (mTOR) inhibitors with or without interleukin-2 receptor antagonists (IL-2RAs), the humanized anti-CD25 monoclonal antibody xenopax, antithymocyte globulin as salvage, and investigational agents. We examine 2025 four-RCT meta-analysis supporting mesencymal stem cells (MSCs), the 2025 conditional approval by the Chinese NMPA of umbilical cord-derived MSC product for SR-aGVHD, the REACH2 long-term data, and biomarker-guided risk stratification using suppression of tumorigenicity 2 and regenerating islet-derived 3-alpha (REG3α). SUMMARY:We propose an evidence-based clinical sequencing algorithm that integrates ruxolitinib, MSCs, extracorporeal photopheresis (ECP), mTOR-targeted salvage, ATG, and clinical trial enrollment and supportive-care priorities, including infectious prophylaxis and organ-specific management.
PURPOSE OF REVIEW:Allogeneic hematopoietic cell transplantation (allo-HCT) is complicated by life-threatening conditions whose prompt diagnosis is essential yet frequently delayed. This review examines proteomic approaches to biomarker discovery for the most common posttransplant complications, emphasizing methodological reliability and translational status. RECENT FINDINGS:Proximity extension assay (PEA) and aptamer-based platforms now permit simultaneous quantification of thousands of proteins from microliter plasma volumes. For acute graft-versus-host disease (GVHD), validated plasma panels incorporating ST2 and REG3α have been established as prognostic tools, and a PEA discovery study in patients with acute myeloid leukemia identified a four-marker panel (SLAMF7, IL-1ra, BTN3A2, and DAB2) with an area under the curve of 0.90. For sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), a PEA study of very severe cases identified multiple candidate proteins at diagnosis and four proteins whose serum levels declined during defibrotide treatment. Proteomic evidence for other complications remains sparse and early in development. SUMMARY:Most proteomic biomarker studies in allo-HCT derive from small single-center discovery cohorts. Multicenter validation, harmonized biobanking, and integration with clinical risk models are required before these biomarkers can enter transplant practice.
PURPOSE OF REVIEW:TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remain among the most challenging myeloid malignancies, with poor long-term outcomes despite allogeneic stem cell transplantation (HCT). Venetoclax-based regimens produce encouraging response rates, but their role as optimal pre-transplant therapy for TP53 mutated MDS/AML remains unconfirmed. This review evaluates the rationale and clinical evidence supporting venetoclax as a bridging strategy to HCT. RECENT FINDINGS:Recent studies have refined risk stratification through TP53 allelic-state characterization, demonstrating poor transplant outcomes. Studies show venetoclax-based therapy may induce deeper and faster remissions. A higher proportion of patients who receive venetoclax successfully transition to transplantation. However, higher response rates do not consistently translate into a survival advantage post-transplant. Efforts to study venetoclax regimens in the pre-transplant setting lack stratification by TP53 allelic state or design focus for this subgroup. SUMMARY:Current evidence supports venetoclax as an acceptable bridging strategy to accelerate response and cytoreduction for TP53-mutated MDS/AML. There is a limited number of studies of venetoclax-containing regimens specific for transplant eligible patients with TP53 mutated MDS/AML. It is important for future studies to incorporate a standardized TP53 allelic-state assessment, molecular measurable residual disease evaluation, and transplant-specific endpoints.
Purpose of review Relapse remains the leading cause of treatment failure after allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), and outcomes after relapse are poor. This review summarizes and critically appraises current evidence for post-HCT maintenance therapy aimed at relapse prevention. Recent findings Patient selection increasingly rests on disease risk and the presence of a targetable mutation. FLT3 inhibitors carry the strongest evidence: randomized trials support sorafenib and gilteritinib in FLT3 internal tandem duplication ( FLT3-ITD ) AML, and the MORPHO trial showed that measurable residual disease (MRD) status identifies patients most likely to benefit. Isocitrate dehydrogenase ( IDH ) inhibitors and menin inhibitors are promising but lack randomized data. For patients without actionable mutations, hypomethylating agent maintenance has produced inconsistent results, and the evidence more strongly supports MRD-triggered preemptive therapy. Summary Post-HCT maintenance has shifted from broadly applied, poorly tolerated regimens toward targeted, MRD-guided strategies. Important uncertainties remain regarding optimal patient selection, agent choice, timing, and duration. Adequately powered, HCT-specific randomized trials with standardized MRD endpoints are the principal unmet need.
Purpose of review During infectious and noninfectious inflammatory diseases, disruption of the immune-hemostatic balance increases both thrombotic and hemorrhagic risk. We propose that this bidirectional dysregulation reflects the integrated contribution of megakaryocyte reprogramming during thrombopoiesis and direct remodeling of circulating platelets by inflammatory mediators, two interconnected regulatory levels that together shape the prothrombotic and hemorrhagic platelet phenotypes observed across inflammatory conditions. Recent findings Current evidence supports a two-level framework through which inflammation remodels platelet responses. Upstream, recent studies demonstrate that inflammation remodels thrombopoiesis, megakaryocyte transcriptional programs, and immunometabolism, generating platelets with altered immunothrombotic, thromboinflammatory, and prothrombotic properties. Converging evidence from aging, sepsis, myeloproliferative neoplasms, and rheumatoid arthritis identifies autophagy as a central target of inflammatory signaling linking megakaryocyte and platelet reprogramming to mitochondrial dysfunction and impaired clot contraction. Downstream, inflammatory mediators directly remodel platelet receptor signaling and promote receptor transfer, generating context-dependent platelet functional states that contribute to both thrombotic and hemorrhagic complications. Summary The platelet phenotype observed across inflammatory diseases reflects the integrated contribution of megakaryocyte reprogramming during thrombopoiesis and direct remodeling of circulating platelets by inflammatory mediators. These two levels of regulation likely operate simultaneously and may amplify each other, yet how they interact to determine platelet functional outcomes in specific inflammatory contexts remains to be determined. Defining these interactions will inform the development of mechanism-based therapeutic strategies that target inflammation-driven platelet dysfunction to reduce thrombotic and hemorrhagic complications across inflammatory diseases.
Purpose of review Immune reconstitution after adult allogeneic haematopoietic stem cell transplantation (allo-HSCT) shapes infection risk, vaccine responsiveness, relapse and nonrelapse mortality. Advances in graft-vs.-host disease (GvHD) prophylaxis, serotherapy exposure management, cytomegalovirus (CMV) control, functional immune monitoring and adoptive cellular therapy have changed which aspects of recovery can be modified and which augmentors are realistic in current practice. This review sets out what has evolved in adult practice and where intervention can now improve it. Recent findings GvHD prophylaxis, serotherapy dosing and CMV prophylaxis can increasingly be tuned to individual risk rather than applied uniformly, and exposure-guided and function-based measures are beginning to supplement simple subset counts. Adoptive approaches such as virus-specific T-cells offer targeted immune replacement in refractory viral disease, while thymic regeneration and cytokine-based strategies remain investigational. Updated vaccination guidance and recent immunogenicity data are sharpening humoral monitoring. Summary Taken together, these developments point towards a move from numerical subset counts to function- and exposure-guided assessment of immune reconstitution. Several determinants, including serotherapy exposure, GvHD prophylaxis, CMV control, microbiome preservation and selective adoptive immune replacement, now support individualised decisions, although prospectively validated intervention thresholds remain few.
PURPOSE OF REVIEW:Factor XI (FXI) and its activated form, factor XIa (FXIa), have emerged as a leading novel anticoagulant target of the past decade. This review summarizes mechanistic and clinical data from 2023 through 2026 and proposes an indication-specific framework for FXIa inhibitor positioning. RECENT FINDINGS:Three large randomized studies diverged by indication. Abelacimab reduced major and clinically relevant nonmajor bleeding by 62% versus rivaroxaban in atrial fibrillation (AZALEA-TIMI 71). Asundexian was inferior to apixaban for stroke prevention in atrial fibrillation (OCEANIC-AF) yet reduced recurrent stroke after noncardioembolic events (OCEANIC-STROKE). Milvexian entered a three-trial phase 3 program. FXIa has been found to drive platelet and endothelial activation in inflammation-associated thrombosis, whereas the FXI zymogen has noncoagulation roles that include activation of bone morphogenetic protein 7-SMAD1/5 cardioprotection. A fifth drug class of allosteric FXI activation inhibitors was further characterized. SUMMARY:FXIa contribution to thrombus formation varies by anatomic site, flow conditions, and inflammatory phenotype. The clinical data support indication-specific positioning for cancer-associated thrombosis, secondary stroke prevention, and patients at high bleeding risk, but provide weaker support for broad substitution for direct oral anticoagulants.
PURPOSE OF REVIEW:Myeloid-derived suppressor cells (MDSCs) are central mediators of immune dysregulation in cancer, infection, and inflammatory diseases. This review highlights recent advances redefining MDSCs' biology, with a focus on their developmental origin, functional plasticity, and the signaling and metabolic networks that regulate their expansion and activity within the bone marrow and peripheral tissues. RECENT FINDINGS:Single-cell and lineage-tracing studies demonstrate that MDSCs do not represent a discrete lineage but instead arise as dynamic functional states across the myeloid continuum during emergency myelopoiesis. These states encompass polymorphonuclear and monocytic subsets derived from both immature progenitors and reprogrammed mature myeloid cells under inflammatory conditions. Transcriptional regulators, including STAT3, C/EBPβ, and IRF8, coordinate their differentiation, while cytokine signaling, chemokine-mediated trafficking, and metabolic reprogramming sustain suppressive function within diseased tissues. Emerging evidence further implicates bone marrow niche-derived signals and microbial cues as critical modulators of MDSC expansion and recruitment. SUMMARY:MDSCs are best understood as context-dependent myeloid states shaped by inflammatory and metabolic cues. Defining the regulatory checkpoints governing these transitions has important implications in hematological malignancies and inflammatory disorders. Emerging therapeutic strategies aimed at limiting MDSC recruitment, reprogramming suppressive myeloid states, or targeting their metabolic and signaling dependencies hold significant potential to enhance immunotherapy efficacy and restore immune homeostasis across cancer and inflammatory diseases.
Purpose of review Brain-derived neurotrophic factor (BDNF), a neurotrophin associated with neuronal survival and plasticity, has emerged as a significant player in cardiovascular biology. This review examines the evidence for BDNF as a regulator of hemostasis and thrombosis, integrating experimental, clinical, and genetic data to clarify its role in platelet function and thrombotic disease. Recent findings Human platelets represent the largest peripheral reservoir of BDNF, releasing it upon activation by classical agonists. Once secreted, BDNF further amplifies platelet activation through a truncated isoform of the TrkB receptor via a kinase-independent signaling pathway. It also modulates clot architecture by promoting thinner, less stable fibrin networks and facilitating fibrinolysis. Paradoxically, lower circulating BDNF levels are consistently associated with greater severity of ischemic stroke and coronary artery disease, suggesting a systemic protective role. Genetic studies offer a more nuanced understanding linking BDNF to endothelial dysfunction and elevated cardiovascular risk. Summary: BDNF is a context-dependent modulator of thrombosis, amplifying platelet activation at sites of injury while exerting protective effects on vascular integrity systemically. Its potential as a cardiovascular biomarker and therapeutic target warrants further investigation.
Purpose of review The purpose of this review is to describe the activity and function megakaryocytes and platelets in the myeloproliferative neoplasms (MPNs.) Specific attention is paid to how megakaryocytes relate to disease progression and altered hemostasis and how current therapies are beginning to target them. Recent findings MPN megakaryocytes are hyperproliferative and induce further dysregulation within the niche via inflammatory cytokine secretion, while MPN platelets display a contradictory phenotype of baseline preactivation and functional exhaustion upon stimulation, due in part to mitochondrial dysregulation. Platelet transcriptomic profiling has further revealed disease subtype-specific gene expression and a shared thrombo-inflammatory profile. CALR -mutated MPNs have significantly advanced with the development of mutation-specific interventions in early clinical trials. Summary Thrombotic and hemorrhagic complications represent the most common cause of morbidity in MPNs, however the mechanisms underlying this pathology remain opaque. Cytoreduction and antithrombotic therapies, the mainstay for treatment of MPNs, inadequately address platelet dysfunction, though emerging therapies targeting the MPN clone are promising. Thus, a deeper understanding of megakaryocyte and platelet biology in MPNs is essential for the development of precise therapeutic strategies to reduce thrombotic complications and improve patient outcomes.
Purpose of review Metabolic diseases, including obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), and diabetes, are associated with increased thrombotic risks. Conversely, components of the hemostatic system influence the development of metabolic pathologies, suggesting a bidirectional relationship between metabolic and thrombotic diseases. This review provides an update on recent advances in the mechanisms by which metabolic pathologies drive thrombosis and how hemostatic system components modulate metabolic diseases. Recent findings Novel insights into fibrinolytic changes as a driver of thrombosis, improved thrombotic risk prediction models, synergistic thrombotic effect with other prothrombotic conditions in metabolic pathologies as well as the impact of weight loss therapies on metabolic dysfunction-associated thrombosis are discussed. Furthermore, recent updates on the roles of urokinase plasminogen activator and factor XIIIA (FXIIIA) in metabolic pathology development are highlighted. Summary Metabolic pathologies suppress fibrinolytic activity and are largely driven by elevated plasminogen activator inhibitor 1 (PAI-1) levels. Development of novel strategies targeting PAI-1 to attenuate thrombotic risks are in progress. Weight loss following bariatric surgery is associated with reduced thrombotic risk, though the impact of glucagon-like peptide 1 receptor agonist on obesity-associated cardiovascular disease risk remains unclear. Conversely, new insights identify urokinase and FXIIIA as promoters of metabolic dysfunction, particularly MASLD.
Purpose of reviewPlatelet G protein-coupled receptor (GPCR) signaling plays a central role in platelet activation and thrombus formation; however, much of our current understanding of GPCR regulation is derived from isolated platelets and single-receptor knockout mouse models, and it does not fully capture vascular bed-specific regulation in vivo. This review highlights recent advances in GPCR regulatory mechanisms, including GPCR kinases (GRKs) and biased signaling, and discusses the challenges posed by interspecies differences in modeling and interpreting human thrombin/PAR signaling.Recent findingsRecent work reveals distinct roles of platelets in arterial thrombosis versus venous thromboembolism, platelet heterogeneity within developing thrombi, and the emergence of procoagulant platelets as a functional link between coagulation and thromboinflammation. Together, these findings indicate that platelet GPCR signaling should be reconsidered in the context of vascular bed-specific cues, platelet-immune cell crosstalk, and the spatial organization of growing thrombi, highlighting its dynamic and context-dependent nature.SummarySpatiotemporal regulation of platelet GPCR signaling provides a conceptual framework to better understand context-dependent platelet function in hemostasis and thrombosis and may inform the development of more selective antithrombotic strategies, including approaches that target specific GPCR downstream effectors or signaling bias while preserving physiological hemostasis.
PURPOSE OF REVIEW:Stress granules (SGs) are RNA and protein assemblies that form rapidly in the cytoplasm in response to cellular or environmental stress. SGs, traditionally recognized as transient repressors of translation, are now understood as versatile regulatory centers that shape RNA metabolism, signaling, proteostasis, and cell fate. In this review, we collate recent findings showing SGs' role in steady-state and regenerative stress in erythropoiesis. RECENT FINDINGS:Blood loss, anemia caused by ribosomal mutations, has been reported to alter the SG axis and protein translation. During regeneration stress, SGs selectively capture lineage-defining RNAs to regulate their translation during recovery phases. This process ensures that blood progenitors and differentiating cells retain essential transcripts, supporting proper fate decisions and regeneration. Pathological SG accumulation disrupts RNA metabolism and translational reprogramming, key to blood cell regeneration. SUMMARY:SGs regulate the transcriptome to endure stress via translational control mechanisms during erythropoiesis. SG deregulation can undermine these adaptive processes. Therapies modulating SG formation, dissolving pathological SGs, or influencing RNA sorting via genetics or targeted small molecules promise new directions to restore blood health, treat anemia, and regeneration in a range of blood disorders.
PURPOSE OF REVIEW:It has been known that the cytokine TNF (tumor necrosis factor alpha) influences hematopoiesis for decades. We now know that increases in TNF in the aging microenvironment favor the persistence and expansion of myeloid progenitors, especially those that contain mutations associated with clonal hematopoiesis of indeterminate potential (CHIP). Herein, we will examine both seminal and recent studies that have advanced our understanding of how TNF shapes hematopoietic development during aging and influences clonal dynamics in CHIP. RECENT FINDINGS:Elevated levels of TNF contribute to engraftment and expansion of CHIP-mutant clones; however, there are subtle differences between the specific CHIP mutations. Sex differences in levels of TNF may contribute to differences in the frequency and types of CHIP mutations found in males and females. Anti-TNF inhibitors reduce the frequency of CHIP mutation containing clones in multiple inflammatory diseases. SUMMARY:The elevated levels of TNF that occur with both age and chronic inflammatory conditions contribute to both myeloid skewing and CHIP. Anti-TNF drugs reduce problematic changes in myeloid hematopoiesis. Anti-TNF drugs are not an effective strategy to treat CHIP and more research is needed as to whether other anti-inflammatory strategies, including diet and exercise, are also effective.
Purpose of ReviewYin Yang 1 (YY1) is a multifunctional transcription factor (TF) with established roles in lymphocyte development. More recently, its functions as a Polycomb group (PcG) protein and chromatin structural regulator in the hematopoietic system have gained increasing attention. This mini-review summarizes emerging insights into the epigenetic and architectural roles of YY1 in fetal and adult hematopoietic stem cells (HSCs), extending beyond its classical transcriptional activity. We also discuss how altered YY1 function contributes to HSC aging and hematopoietic decline.Recent FindingsRecent studies show that YY1 is essential for maintaining HSC quiescence, self-renewal, and engraftment during both fetal and adult hematopoiesis. Mechanistically, YY1 regulates hematopoiesis through PcG-dependent pathways and by shaping higher-order chromatin organization. It mediates long-range chromatin interactions, cooperates with cohesin and CTCF to organize three-dimensional genome architecture, and coordinates transcriptional and metabolic programs critical for stem cell maintenance. Notably, age-associated reductions in YY1 activity are linked to functional impairment of HSCs, implicating YY1 in hematopoietic aging.SummaryYY1 acts as a TF, chromatin organizer, and PcG protein in hematopoiesis. Defining its roles in normal and aging HSCs may reveal mechanisms of hematopoietic decline and inform strategies to preserve blood system function.
PURPOSE OF REVIEW:Recent studies have expanded the concept of the bone marrow niche beyond stromal cells to include differentiated hematopoietic progeny as direct regulators of hematopoietic stem cells (HSCs). Among these, megakaryocytes have emerged as key niche regulators of HSC function across homeostasis, stress responses, aging, and disease. This review summarizes recent advances defining how aging alters megakaryocyte-mediated regulation of hematopoiesis. RECENT FINDINGS:Megakaryocytes regulate HSC quiescence, lineage output, and stress responsiveness through spatial organization within the bone marrow microenvironment and the production of niche-derived factors. Recent studies revealed that aging is associated with changes in megakaryocyte abundance, maturation state, and transcriptional and secretory programs, resulting in altered niche functions and hematopoiesis. These findings establish megakaryocytes as dynamic niche components whose regulatory roles evolve across the lifespan. SUMMARY:Age-dependent remodeling of the megakaryocytic niche provides a conceptual framework for understanding how hematopoietic regulation is reprogrammed with aging. Targeting megakaryocyte-derived niche signals may offer new opportunities to rejuvenate hematopoiesis and improve outcomes in age-associated hematopoietic disorders.
Purpose of reviewHematopoietic stem and progenitor cells (HSPCs) ensure lifelong hematopoiesis through their unique ability to self-renew and differentiate into all blood cell lineages. Their localization within bone marrow niches and the ability to traffic between hematopoietic and peripheral tissues during development and adult life are governed by complex signaling networks involving adhesion molecules, chemokines, metabolic cues, and niche-derived factors.Recent findingsThis review explores the molecular and cellular mechanisms that regulate HSPC homing, retention, and mobilization during development, homeostasis, and therapeutic transplantation. In particular, we focus on intrinsic, dynamic properties of HSPCs that guide developmental transitions in trafficking behavior from fetal to adult niches, physiological egress under steady-state conditions, and dictate outcomes of forced mobilization and bone marrow homing during therapeutic collection and transplantation.SummaryThese findings highlight HSPC trafficking as a highly regulated and adaptable process integrating intrinsic stem cell states with extrinsic niche cues. Understanding these mechanisms provides a conceptual framework for improving strategies to enhance HSPC mobilization, homing, and engraftment toward optimizing hematopoietic stem cell therapies.
PURPOSE OF REVIEW:BEACH-domain-containing proteins (BDCPs) are large scaffolding proteins that regulate vesicle trafficking, autophagy, and granule biogenesis. This review synthesizes recent mechanistic and clinical advances defining BDCP functions in hematopoietic stem and progenitor cell (HSPC) biology, immune regulation, and platelet function, highlighting relevance to human disease. RECENT FINDINGS:Although BDCPs were initially linked to lineage-restricted hematopoietic disorders such as Chediak-Higashi syndrome and Gray platelet syndrome (GPS), emerging evidence demonstrates broader roles for BDCPs including NBEA, LRBA, LYST, and NBEAL2 in HSPC maintenance, receptor trafficking, and lineage specification. NBEA regulates NOTCH receptor turnover in HSPCs, linking vesicle dynamics to stem cell fate decisions. Recent studies provide mechanistic insights on how LRBA controls autophagy and CTLA-4 recycling, informing abatacept therapy; how NBEAL2 governs platelet α-granule biogenesis and immune homeostasis in GPS; and how LYST regulates lysosomal size and granule maturation in myeloid cells. Additionally, WDFY3, WDFY4, and WDR81 emerge as regulators of autophagy, antigen presentation, and inflammatory signaling. SUMMARY:Collectively, BDCPs integrate vesicle trafficking, autophagy, and receptor homeostasis to coordinate hematopoietic development and immune function. Their dysfunction underlies immunological, hematologic, and inflammatory disorders, positioning BDCPs as promising translational targets.
Purpose of reviewAging is associated with impaired B lymphopoiesis and T lymphopoiesis, contributing to immunosenescence and poor immune recovery. Although this decline can be attributed to intrinsic hematopoietic stem cell aging, growing evidence indicates that lymphoid failure reflects constraints operating across multiple levels of the hematopoietic system. This review frames age-associated lymphopoiesis decline as a systems-level problem and outlines conceptual avenues for therapeutic intervention.Recent findingsAge-associated lymphoid failure is increasingly attributed to inflammatory suppression, dominance of dysfunctional stem and progenitor states, and compromised extramedullary support. These insights provide a framework for interventions that restore immune competence by rebalancing hematopoiesis or selectively replacing compromised stem cell function.SummaryAge-associated lymphoid decline arises from coordinated constraints across the bone marrow niche, stem and progenitor composition, and extramedullary lymphoid support, rather than intrinsic stem cell exhaustion alone. Targeting these bottlenecks in a context-dependent manner offers multiple routes to improve lymphopoiesis and restore immune competence in aging.
Purpose of reviewThis review summarizes current understanding of platelet-endothelial contributions to thrombosis, emphasizing molecular crosstalk [von Willebrand factor (VWF)/ADAMTS13 balance, P-selectin, platelet glycoprotein VI (GPVI), integrins, extracellular vesicles, neutrophil extracellular traps (NETs)], high-risk clinical settings, and translational advances. Highlighting GPVI-directed therapeutics, the VWF/ADAMTS13 axis in COVID-19, and opportunities and challenges for targeting the platelet-endothelial interface.Recent findingsClinical and translational studies support the safety and potential efficacy of targeting platelet-endothelial interfaces. GPVI inhibitors (Glenzocimab, Revacept) have advanced through phase I/II studies with reassuring bleeding profiles and suggest benefit in ischemic stroke and lesion-directed settings. Direct interruption of platelet-VWF interactions (Caplacizumab) is established in immune thrombotic thrombocytopenic purpura (TTP), while studies show a persistent VWF/ADAMTS13 imbalance in severe COVID-19 and inflammatory states linked to microthrombosis and worse outcomes. Antiadhesion strategies (P-selectin blockade) and modulators of immunothrombosis (NET inhibitors, targeting extracellular vesicle) are also in evaluation.SummaryTargeting platelet-endothelial crosstalk has potential to reduce pathologic thrombosis while preserving hemostasis. Clinical proof of principle exists for focused approaches (anti-VWF in TTP; P-selectin blockade in vaso-occlusion; emerging GPVI inhibitors). Priorities are: defining disease contexts and timing where interface targeting is effective; validating biomarkers (VWF/ADAMTS13 ratio, soluble P-selectin, platelet activation signatures) for patient selection; and conducting adequately powered trials with rigorous bleeding endpoints.
