Artificial intelligence (AI), most often in the form of machine learning (ML), attracts high expectations across medicine and is often discussed as a transformative, rapidly evolving topic. In thrombosis and hemostasis, these expectations are reinforced by the nature of clinical decision-making, which rarely hinges on a single definitive test. Instead, clinicians integrate clinical context with laboratory results, imaging, and treatment information. Despite a rapidly expanding literature, translation into routine decision support remains scarce. Most published models are early-stage prototypes and provide limited evidence for transportability, clinical utility, and safe deployment. In this review, we argue that the most practical way to achieve and assess clinical usefulness is to treat ML tools as diagnostic instruments. This framing also clarifies what "useful" means at the bedside: improving a specific decision, at a specific moment, for a specific patient. Building on this concept, we provide a roadmap for diagnostic translation, starting with intended use and population definition, then addressing real-world data and reference standards, fit-for-purpose model behavior, phased validation as evidence generation, and the requirements for implementation and lifecycle governance. Two figures summarize the translation roadmap and map ML to laboratory thinking from preanalytics to quality management. A clinically deployable checklist supports structured reading of published studies and helps identify what evidence is missing for implementation. The goal is to help clinicians and laboratory specialists distinguish promising prototypes from tools that are ready for clinical translation and sustainable use. This article is a narrative review. It does not aim to provide a systematic synthesis of all machine learning (ML) studies in the field. Our aim is to provide a practical roadmap for diagnostic translation and two pragmatic tools that help readers assess published studies and plan evidence generation toward clinically deployable ML tools. To do so, we formulated a concept-driven translation framework by combining (1) established principles from diagnostic research and test evaluation, (2) targeted searches for guidance and reporting frameworks relevant to clinical ML and diagnostic translation, and (3) selective review of systematic reviews and meta-research on common sources of bias, external validation, and implementation barriers. Case examples were chosen to illustrate how the framework applies to real tools and to highlight where translation succeeds or stalls.
Sepsis disrupts the physiological balance between coagulation and fibrinolysis, resulting in a state in which fibrin formation exceeds fibrin removal and drives microvascular thrombosis, organ failure, and mortality. Although an early burst of endothelial tissue-type plasminogen activator (t-PA) may transiently increase plasmin generation, this phase is rapidly eclipsed by sustained upregulation of plasminogen activator inhibitor-1 (PAI-1), dysregulated activation of thrombin-activatable fibrinolysis inhibitor, depletion of endogenous anticoagulants, and progressive endotheliopathy. Beyond inhibitor excess, emerging evidence indicates that a quantitative defect in plasminogen is a central contributor to fibrinolytic insufficiency. Neutrophil extracellular traps (NETs) contain elastase, which cleaves plasminogen into inactive fragments, reducing functional plasminogen availability and impairing fibrin-bound plasmin generation. When functional plasminogen falls below rate-limiting levels, fibrin surfaces cannot efficiently support plasmin formation, resulting in persistent microvascular fibrin deposition despite elevated D-dimer concentrations. This NET-plasminogen axis links immunothrombosis to the "fibrinolytic insufficiency phenotype observed in sepsis-induced coagulopathy and overt disseminated intravascular coagulation (DIC)." Clinically, hypofibrinolysis is characterized by high D-dimers, elevated PAI-1, reduced plasmin generation, and low fibrinolytic activity on viscoelastic testing. Multimodal assessment integrating biomarker panels and viscoelastic assays, including t-PA- or urokinase-challenged protocols, may improve risk stratification. Therapeutic strategies largely targeted coagulation; however, persistent hypofibrinolysis limits their effectiveness. Translational data demonstrate that plasminogen supplementation restores functional plasminogen levels and normalizes plasmin generation in septic patients and in experimental DIC, providing proof of concept for fibrinolysis-directed therapy. Future progress requires standardized definitions, functional fibrinolytic phenotyping, and phenotype-guided clinical trials to restore the coagulo-fibrinolytic balance in sepsis.
Von Willebrand disease (VWD) is the most common inherited bleeding disorder, caused by quantitative or qualitative defects in von Willebrand factor (VWF). Diagnosis is challenging and requires integrating bleeding history, VWF antigen and activity measurements, FVIII assays, and specialized phenotyping. Genetic testing is increasingly recognized as a key component. Here, we review current concepts in VWD diagnostics and highlight the Spanish Clinical and Molecular Profile of von Willebrand Disease (PCM-EVW-ES) project as a model for genomics-enabled precision medicine. PCM-EVW-ES is a multicenter initiative involving 48 hospitals, centralized phenotypic testing, and next-generation sequencing of the VWF coding region, enabling definitive classification in 730 individuals with VWD to date. Harmonized recruitment criteria and standardized workflows improve subtype assignment, uncover complex genotypes, refine genotype-phenotype correlations, and facilitate the identification of asymptomatic carriers. The PCM-EVW-ES variant spectrum highlights recurrent disease-causing variants in Spain and underscores the value of coordinated national registries for variant curation. Building on these data, we propose a diagnostic algorithm in which bleeding assessment and first-line VWF/FVIII assays, combined with, early VWF molecular testing increases diagnostic accuracy and guides targeted second-line investigations to confirm and refine VWD subtype classification. We also outline persisting challenges, including the interpretation of variants of uncertain significance and patients without identifiable pathogenic VWF variants, and future directions integrating third-generation sequencing, expanded gene panels, functional studies, and artificial-intelligence-driven multiomic approaches. Together, these advances illustrate how robust multicenter studies can bridge the gap between complex diagnostics and clinical practice in VWD.
Patients with liver disease exhibit complex changes in the hemostatic system that are often presumed to drive bleeding and thrombosis. Historically, liver disease was considered a bleeding disorder based on thrombocytopenia, prolonged routine coagulation tests, and reports of fulminant bleeding. Present evidence, however, indicates that antihemostatic changes are compensated for by simultaneous prohemostatic changes, resulting in a rebalanced hemostatic system. Further hemostatic changes may be induced by liver disease progression and extrahepatic factors, such as systemic inflammation, acute kidney injury and cardiometabolic diseases. Despite extensive hemostatic changes in liver disease, current evidence does not consistently show that they increase bleeding risk, although this has been suggested repeatedly in published literature. Indeed, hemostatic changes appear largely unrelated to most bleeding complications, and specific thrombotic complications also appear unrelated to hemostatic changes. Major bleeding is common but predominantly reflects portal hypertension-related acute variceal bleeding and mechanical injury-related procedural bleeding. A proportion of bleedings, however, may be hemostasis-related, but the vast majority of such events do not require prohemostatic intervention. In contrast, a large proportion of thrombotic complications, including venous thromboembolism, portal vein thrombosis, and intrahepatic thrombosis, may in part be related to prohemostatic changes, although the role of hypercoagulability in portal vein thrombosis is increasingly questioned. Despite greater attention for thrombotic complications in liver disease, robust studies on optimal anticoagulant strategies are currently lacking. Studies evaluating the pharmacokinetics, pharmacodynamics, and efficacy for prevention of thrombosis and liver decompensation, of direct oral anticoagulants and factor XIa inhibitors are therefore urgently needed.
Thrombin plays a central role in hemostasis, serving as both the primary enzyme driving fibrin formation and the central regulator of anticoagulant pathways. Routine coagulation assays, such as prothrombin time and activated partial thromboplastin time, capture only a limited fraction of thrombin's role, overlooking inhibitory pathways and downstream regulation. Thrombin generation assays (TGAs) provide a global view of coagulation, measuring both formation and inhibition of thrombin over time. TGAs generate thrombin activity curves, from which parameters such as lag time, peak thrombin, time to peak, velocity index, and endogenous thrombin potential are derived. These parameters reflect hyper- or hypocoagulability and have been linked to clinical outcomes. Applications include monitoring anticoagulant therapy and reversal strategies, predicting venous thromboembolism recurrence, assessing thrombotic risk in cardiovascular disease and antiphospholipid syndrome, and stratifying bleeding risk in bleeding disorders. TGAs can also evaluate the efficacy of bypassing agents and novel hemostatic drugs in ex vivo settings. Barriers include technical complexity, preanalytical variability, and lack of standardization across laboratories. TGAs provide a global assessment of coagulation, demonstrating added value in both hyper- and hypocoagulable states. While most data remain research-based, growing evidence supports their utility in thrombotic risk prediction and bleeding risk assessment. Wider adoption in clinical practice will depend on assay standardization, validation in multicenter studies, and integration into clinical decision-making pathways.
People with hemophilia (PwH) face persistent joint damage risk despite prophylactic factor replacement therapies. Although muscles are recognized as biomechanical stabilizers, their broader protective mechanisms remain poorly understood. This review provides an integrative theoretical framework that examines how muscles protect joints in PwH through three interconnected dimensions: (1) mechanical-via joint stabilization and force absorption; (2) neuromuscular control; and (3) biochemical regulation through exercise-induced myokines (exerkines). Muscle contractions provide joint stabilization and attenuate mechanical impacts via eccentric actions and muscle-tendon buffering, thereby reducing joint loading during daily activities. Neuromuscular control maintains joint stability through coordinated muscle activation, though excessive co-contraction in arthropathy can paradoxically increase joint stress. Critically, the endocrine function of skeletal muscle, producing anti-inflammatory and cartilage-protective exerkines including interleukin-6, irisin, and lubricin (among others), represents an underexplored yet crucial protective mechanism. Physical inactivity and intramuscular fat accumulation impair these protective functions, accelerating joint degeneration. This integrative theoretical perspective offers a comprehensive framework for understanding how muscles protect joints in hemophilia. Understanding these integrated mechanisms is essential for developing targeted rehabilitation strategies and guiding future research to optimize joint health in PwH.
Bleeding disorders arising from dysfunctional platelet-protein interactions pose a significant clinical challenge due to their heterogeneity and complexity. Primary hemostasis is mediated by von Willebrand factor (VWF) and platelet surface receptors GPIbα and αIIbβ3. This protein triad is central to clot formation, and interfering with their associated activity can cause several primary hemostasis-related disorders. While traditional therapies, including factor replacement and monoclonal antibodies, have improved outcomes, they are often limited by availability, cost, immunogenicity, and inadequate precision. Recent advances in computational biology and peptide engineering now offer potential for improved hematologic therapeutics. This review outlines two major strategies in peptide drug design: Structure-based modeling and small motif-based design. These approaches enable the creation of short, stable peptides capable of targeting disease-specific protein-protein interactions (PPIs) with high specificity. We highlight the recent development of G14-an artificial intelligence (AI)-designed peptide that selectively disrupts the aberrant GPIbα-VWF interaction in platelet-type von Willebrand disease. The peptide demonstrated selective inhibition of the enhanced patient-derived platelet aggregation and VWF binding. By combining systems biology, structural modeling, and AI, peptide design can now yield rapid, scalable, and personalized therapies for bleeding disorders. Thus, the growing adoption and integration of intelligently designed peptides offer a new perspective on precision medicine for thrombosis and hemostasis.
Although the thromboembolic risk associated with oral estrogen is recognized, the risk profile of vaginal estrogen treatment remains inconclusive. This scoping review aims to explore available evidence on the association between vaginal estrogen treatment in postmenopausal women and the risk of thrombosis. We conducted a systematic search of PubMed and Embase, investigating vaginal estrogen treatment and thrombosis, for all records up to May 21, 2025. The process was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews (PRISMA-ScR) and a preregistered protocol (osf.io/hgecd). We excluded systemic estrogen treatments, contraception, fertility treatments, gender-affirming therapies, and hormone treatments other than estrogen. Eligible study designs included clinical trials, randomized controlled trials, observational, case-control, and cohort studies. The search identified 866 articles, whereof 8 were eligible. Manual searching through citations and references yielded 3 additional studies, resulting in 11 included articles, all observational. One study reported a reduced risk of recurrent myocardial infarction (MI) following discontinuation of vaginal estrogen treatment (adjusted hazard ratio [aHR]: 0.54; 95% confidence interval [CI]: [0.34-0.86]). Remaining studies found no thrombosis risk in vaginal estrogen users. For venous thromboembolism (n = 6), effect estimates ranged from null to reduced risk (aHRs: 0.68 [0.36-1.28], to 1.06 [0.58-1.93]), similar for MI (n = 5; aHRs: 0.52 [0.31-0.85] to 0.83 [0.77-0.89]) and stroke (n = 6, aHRs: 0.68 [0.62-0.70] to 0.96 [0.93-0.99]). This scoping review, including studies of generally moderate to high methodological quality, indicates no increased risk of thrombosis associated with vaginal estrogen use in postmenopausal women. Further prospective, high-quality clinical trials, including high-risk populations and women with prior thrombosis, are warranted.
Cancer-associated thrombosis (CAT) remains a leading cause of morbidity and mortality in oncology, reflecting the convergence of tumor-driven hypercoagulability, endothelial dysfunction, and venous stasis. While current models of CAT pathogenesis emphasize tumor-derived procoagulant factors, platelets, and leukocytes, the contribution of red blood cell (RBC) biomechanics has received comparatively limited attention. Emerging evidence indicates that both malignancy and cancer-related therapies impair RBC deformability and increase RBC aggregation; alterations that are known to influence blood viscosity, platelet margination, microvascular flow, and clot contraction. Hence, these alterations have been hypothesized to promote thrombosis, supported by evidence of increased thrombosis risk in diseases that primarily affect RBC biomechanics. While cancer-induced alterations in RBC biomechanics and their role in thrombosis are well-described in non-cancerous conditions, the relationship between altered RBC biomechanics and thrombosis in the setting of cancer has not been thoroughly investigated. Accordingly, this review synthesizes the mechanistic and clinical data linking altered RBC biomechanics to thrombus initiation, propagation, and stability, with particular emphasis on their relationship with established cancer-related prothrombotic pathways such as extracellular vesicle release, neutrophil extracellular trap formation, stasis, and oxidative stress. Finally, we critically assess current CAT risk assessment models (RAMs) and discuss the potential role of RBC biomechanical parameters as dynamic, integrative biomarkers to improve thrombosis risk stratification in cancer patients. Advances in automated and standardized rheological technologies may facilitate the clinical translation of RBC biomechanics, offering new opportunities to refine risk prediction and deepen mechanistic understanding of CAT.
There is growing recognition that red blood cells (RBCs) play a role in thrombosis beyond their traditional role as passive cellular components. This systematic review synthesizes contemporary evidence on RBC-platelet interactions in the mechanistic, structural, and clinical domains. A comprehensive search of PubMed, Scopus, Web of Science, and ScienceDirect from January 2014 to March 2026 identified 45 eligible studies, predominantly experimental and in vitro studies, with fewer animal, computational, and clinical/translational studies. Available evidence suggests that RBCs may contribute to thrombosis through several partially overlapping pathways, including shear-dependent platelet margination, phosphatidylserine-associated thrombin generation, direct RBC-platelet adhesion, and EV-associated procoagulant activity. In addition, the biophysical properties of RBCs influence thrombus architecture, density, and stability. Clinical studies have suggested an association between altered RBC function and thrombotic risk in conditions such as polycythemia, diabetes mellitus, and sickle cell disease. However, despite consistent mechanistic evidence, clinical validation remains limited, particularly in large-scale human studies. Overall, these findings support a more integrated cellular framework of thrombosis, in which RBCs may modulate platelet behavior, coagulation dynamics, and thrombus architecture. However, because most of the included studies were experimental or mechanistic, clinical translation remains limited. Future research should prioritize standardized experimental platforms, harmonized outcome measures, and prospective multicenter clinical studies before RBC-related parameters can be considered for biomarker development and therapeutic targeting.
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host immune response to an infection. Sepsis is often associated with significant hemostatic disorders that may lead to extensive intravascular thrombosis, disseminated intravascular coagulation (DIC), multi-organ dysfunction syndrome (MODS), and increased mortality. Sepsis-induced coagulopathy (SIC) is currently recognized as an early distinct phase of hemostatic derangement caused by sepsis, and a prodrome of overt DIC. SIC is characterized by endovascular clotting activation, hypercoagulability, and consumption of clotting factors and platelets. DIC, traditionally considered the final stage of this process, is now recognized as a part of a continuum of pathophysiological dysregulation with a distinct clinical significance. Despite being extensively studied in the adult population, SIC remains poorly defined in neonates. The distinct characteristics of neonatal hemostasis, coupled with immunological immaturity, pose significant challenges to the direct application of adult diagnostic approaches of SIC in this population. This review focuses on the pathophysiological mechanisms of SIC and the unique characteristics of neonatal hemostasis, summarizes current knowledge regarding the underlying mechanisms of neonatal SIC, and explores the developmental interplay between inflammation and hemostasis. By integrating current evidence, the review aims to establish a conceptual framework that will guide future experimental and clinical studies directed toward improving the management and outcomes of neonates who develop coagulopathy during sepsis.
Pulmonary infarction (PI) has traditionally been regarded as a complication of pulmonary embolism (PE). However, increasing evidence suggests that pediatric PI represents a heterogeneous spectrum of ischemic lung injury extending beyond classic thromboembolic disease. This narrative review adopted an etiology-oriented framework to summarize the epidemiology, pathophysiology, imaging features, diagnostic strategies, treatment approaches, prognosis, and follow-up considerations of pediatric PI and infarction-like pulmonary injury. Published pediatric PI-related cases were also descriptively summarized. Pediatric PI remains underrecognized and lacks standardized diagnostic criteria. Compared with adults, children demonstrate greater etiologic heterogeneity, including thromboembolic PE, in situ pulmonary artery thrombosis, congenital pulmonary developmental anomalies, such as extralobar pulmonary sequestration, immune-mediated vascular injury, and infection-related microthrombosis. Imaging findings including Hampton hump, reverse halo sign, and cavitary transformation may suggest PI but have not been systematically validated in children. Imaging evaluation must also balance diagnostic performance with radiation exposure under the "as low as reasonably achievable" principle. Treatment strategies differ substantially according to underlying mechanisms: thromboembolic PI generally requires anticoagulation, congenital vascular anomalies are primarily managed surgically, whereas inflammatory and infection-related phenotypes often require immunomodulatory or multidisciplinary management. Evidence regarding long-term pulmonary outcomes and chronic thromboembolic pulmonary hypertension in children remains limited. Pediatric PI and infarction-like pulmonary injury should be considered a heterogeneous ischemic lung injury syndrome rather than a single disease entity. Etiology-oriented classification is critical for diagnosis, individualized treatment, and long-term management. Further multicenter studies are needed to establish standardized pediatric diagnostic and follow-up frameworks.
In a parallel-assignment, single-blinded study, we measured the detailed coagulation profile of 20 patients randomised to receive infusions of fresh frozen plasma (FFP) or fibrinogen concentrate during surgery associated with major surgical haemorrhage - Extent 4 Thoraco-abdominal Aortic Aneurysm repair.Ten patients received FFP; ten fibrinogen concentrate, infused to achieve plasma fibrinogen concentration around 1.5g.l-1. There were pre-defined haemoglobin and ROTEM cutoffs for red cell and platelet administration. Blood samples were taken at up to twelve pre-defined timepoints before, during, and after surgery. Measurements included coagulation and anticoagulant factor concentrations, thrombin generation, activated protein C concentrations and thromboelastography.Intraoperative blood loss was between 2750ml and 16,500ml. During surgery, plasma fibrinogen concentration was slightly lower in the FFP group but maintained or restored to ~1.5g.l-1. When blood loss exceeded ~4000ml, most factor concentrations and conventional tests were superior in the FFP group. Mean(SD) prothrombin time (15.8(2.3) vs. 26.3(5.1) and activated partial thromboplastin time (42.8(8.6) vs. 60.4(15.8) seconds; p<0.001. Protein C and activated protein C (aPC) concentrations trended higher in the FFP group: Protein C 59.7(18.4) vs. 30.0(10.6) % normal; p<0.001, aPC 6.9(5.5) vs. 3.1(2.3) ng.ml-1; p=0.001. Differences in peak thrombin generation two hours postoperatively in the FFP group did not meet statistical significance: (224.3(54.8) vs. 133.0(66.0) nM; p=0.004.In this exploratory cohort, both FFP and fibrinogen concentrate administration achieved low-normal plasma fibrinogen concentrations. Although coagulation factor concentrations and thrombin generation were lower in the fibrinogen concentrate group at blood losses above 4000ml, this was not associated with worse surgical haemostasis or observed bleeding complications.
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders characterized by elevated thrombotic and bleeding risk, and optimal risk stratification and management remain challenging. This review summarizes current evidence on the thrombotic complications in MPNs, including venous events (i.e., deep vein thrombosis, pulmonary embolism, and unusual site thrombosis), and arterial events (ischemic stroke, myocardial infarction, and peripheral arterial thrombosis), and the increased bleeding risk in these diseases. Mechanistically, JAK2-driven clonal hematopoiesis, elevated hematocrit, leukocytosis, platelet activation, endothelial dysfunction, and chronic inflammation interact to promote a pro-thrombotic state; conversely, extreme thrombocytosis, acquired von Willebrand syndrome, and anticoagulant/antiplatelet therapy contribute to bleeding risk. Clinically, thrombosis may precede MPN diagnosis, especially in unusual sites, and treatment should balance the risk of recurrent thrombosis against the risk of hemorrhagic complications. Antithrombotic strategies include low-dose aspirin, vitamin K antagonists, and direct oral anticoagulants, while cytoreductive therapy (hydroxyurea, anagrelide, interferon, and JAK inhibitors) is central for disease control as well as vascular risk reduction. Despite therapy, recurrence of thrombotic events and major bleeding persists, highlighting the need for optimized risk models and alternative therapeutic targets. Future research may focus on integrating molecular biomarkers, inflammation metrics, and vascular-specific endpoints to direct personalized preventive strategies.
Measurement of D-dimer, a fibrin degradation product, is crucial for diagnosing thrombotic and fibrinolytic conditions. Despite its expanding utility, D-dimer testing faces challenges due to varying assay methodologies and nonstandardized reporting. To understand D-dimer reporting practices, the College of American Pathologists Hemostasis and Thrombosis Committee analyzed proficiency testing data from D-dimer surveys conducted between 2020 and 2023 across multiple laboratories. The data demonstrate that laboratories commonly report units that differ from the assay package insert when reporting their proficiency testing results. We sought to assess variability in reporting practices and opportunities for improvement in D-dimer reporting amongst participants. To accomplish this, we harmonized all D-dimer results to ng/mL fibrinogen equivalent units from one distributed sample and assessed distinct populations of entries per instrument/reagent combination. Notable trends emerged from this analysis. Data from laboratories using the same instrument/reagent combinations clustered around different means, suggesting issues with unit reporting and/or conversion. Entries reported in mg/L or ug/mL D-dimer units commonly exhibited significant deviations from the dominant population. For one instrument/reagent combination, most reported values differed by approximately twice the certificate of analysis value. This analysis highlights potential issues with D-dimer reporting in proficiency testing. Whether these issues translate into issues with clinical D-dimer reporting requires further study.
Low-load blood flow restriction (LLBFR) training has gained traction as a rehabilitation and performance tool, offering muscle strength and hypertrophy adaptations comparable to high-load resistance training while minimizing joint and tissue stress. However, its application in athletes at risk for venous thromboembolism, post-thrombotic syndrome (PTS), inherited thrombophilia, and special populations (pregnant competitive female athletes and paralympic athletes with spinal cord injury) raises safety concerns. This narrative review synthesizes evidence on LLBFR's hemodynamic and endothelial effects, highlighting pressure-dependent basal lamina thickening, impaired flow-mediated dilation, and transient elevations in peripheral venous pressure. It emphasizes the importance of pre-exercise risk stratification, genetic screening for factor V Leiden and prothrombin mutations, and assessment of cardiovascular and coagulation markers. For athletes with confirmed deep vein thrombosis, PTS, or multiple risk factors, LLBFR should be contraindicated. In paralympic athletes with spinal cord injury, stringent exclusion criteria (e.g., severe autonomic dysreflexia, pressure ulcers) are essential, whereas female athletes may require individualized monitoring of coagulation changes during oral contraceptive use and pregnancy. Although LLBFR shows promise for preserving muscle function when traditional loading is impractical, robust, large-scale studies measuring thrombogenesis and fibrinolysis markers are urgently needed. Tailored protocols that balance musculoskeletal benefits against thrombotic risks will ensure safe, effective implementation across diverse athlete populations.
Combined thrombosis and bleeding disorders pose significant challenges in neonates, critically ill children, and patients with inherited or acquired coagulopathies, such as disseminated intravascular coagulation or liver dysfunction. These coexisting conditions are common in neonatal intensive care units (NICUs), where critically ill infants face environmental and medical interventions that may exacerbate both the risk of arterial and venous thromboembolism (VTE) or promote hemorrhagic risks. VTE affects up to 2% to 3% of NICU patients, and is primarily linked to sepsis and catheter-related events, while intracranial hemorrhage remains one of the leading causes of mortality and morbidity in preterm neonates. In the context of developmental immaturity, neonatal hemostasis predisposes these patients to an intersection of bleeding and thrombosis risks. This narrative review aims to navigate pathophysiology, clinical presentations, diagnostic dilemmas, and treatment strategies in neonates with thrombosis and bleeding disorders. We further explore emerging research and potential advances to improve outcomes in this vulnerable population.
Cancer-associated thrombosis (CAT) remains a major cause of morbidity and mortality in patients with malignancy. Direct oral anticoagulants (DOACs) have expanded the therapeutic armamentarium for CAT and are now widely used as alternatives to low molecular weight heparins (LMWHs). However, the increasing complexity of contemporary oncologic care has heightened concerns regarding clinically relevant drug-drug interactions (DDIs). All DOACs are substrates of P-glycoprotein, and some undergo partial metabolism via cytochrome P4503A4, rendering them more susceptible to pharmacokinetic (PK) modulation by anticancer agents. Moreover, several antineoplastic drugs exert intrinsic prothrombotic or hemorrhagic effects, thereby introducing pharmacodynamic interactions that may further destabilize the already dysregulated hemostatic system in cancer. Despite these theoretical concerns, evidence from randomized trials and real-world studies remains limited and largely derived from subgroup analyses, PK investigations in healthy volunteers, or retrospective registries. Consequently, the true clinical magnitude of DDIs in CAT remains incompletely defined. This review critically appraises the pharmacological basis, clinical evidence, and translational implications of DDIs between DOACs and anticancer therapies. We propose that DDIs in CAT should not be viewed solely as PK phenomena, but also as potential biological amplifiers of cancer-associated coagulopathy. Until prospective, dedicated studies become available, a structured/individualized approach-integrating thrombotic/bleeding risk, interacting medications, and patient-specific factors-is warranted.
Antiphospholipid syndrome (APS) is an autoimmune disease defined by thrombotic or obstetrical clinical manifestations and the persistent presence of antiphospholipid antibodies, including lupus anticoagulant, anticardiolipin antibodies, and anti-β2-glycoprotein I antibodies. Obstetric APS (OAPS) is associated with pregnancy morbidity, including early recurrent pregnancy loss (RPL), preeclampsia, premature birth, and stillbirth. Treatment regimens for women with OAPS are designed to optimize pregnancy outcomes. It is still debated which intervention results in the most optimal pregnancy outcome. This scoping review examines treatment options for women with OAPS presenting with RPL based solely on randomized controlled trials (RCTs) reporting pregnancy outcomes. A systematic search identified 1,234 studies published up to January 2026, from which 14 RCTs met the inclusion criteria: pregnant women with APS defined as persistent aPL positivity and RPL (≥2) receiving therapeutic intervention with live birth as the primary outcome. These RCTs, published between 1992 and 2017, included 1,878 participants. Secondary outcomes, including birth weight, preeclampsia, preterm delivery, and bleeding, were also analyzed. Different treatment options such as low-dose aspirin (LDA), unfractionated heparin, low molecular weight heparin (LMWH), corticosteroids, and intravenous immunoglobulin were used in the clinical trials. Antithrombotic therapy (LDA + LMWH) was associated with higher live birth rates compared with the other evaluated strategies. However, this finding is based on a small number of heterogeneous RCTs and is disproportionately driven by a single large trial. Consequently, substantial uncertainty remains. High-quality, adequately powered RCTs are urgently needed to provide robust evidence for optimal OAPS management.
Complement activation is a consistent and predictable biological response to adeno-associated virus gene therapy, particularly after high-dose systemic administration. Early postdose laboratory changes, including mild thrombocytopenia, modest reductions in C3 and C4, and low-level elevations in complement activation markers, are commonly observed and generally reflect expected pharmacodynamic effects rather than toxicity in isolation. However, a subset of individuals progresses to complement-mediated endothelial injury and thrombotic microangiopathy, a rare but potentially severe complication. Despite increasing recognition of complement biology in gene therapy safety, laboratory monitoring practices remain inconsistent, and interpretation of complement biomarkers is often fragmented. Reliance on isolated measurements may obscure early pathologic trajectories, while functional assays are sensitive to preanalytical variability. Emerging data suggest that alternative pathway amplification governs severity across diverse initiating mechanisms and distinguishes self-limited complement activation from sustained endothelial injury. This article proposes a laboratory-centered framework that integrates complement biomarkers with hematologic and renal indices, emphasizing serial trends over isolated values. Standardized interpretation of complement testing is essential for early recognition of pathologic escalation and for maintaining patient safety as gene therapy expands across clinical settings.