Seminars In Thrombosis And Hemostasis[JOURNAL]
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200 papers
Bridging the Gap in Laboratory Monitoring of Extended Half-Life Factor VIII and IX: Can Thrombin Generation Assays Overcome Assay Discrepancies?
Sacco M, De Cristofaro R, Lancellotti S
Semin Thromb Hemost · 2026 Jul · PMID 42398958 · Publisher ↗
The management of hemophilia A has been transformed by the introduction of extended half-life factor VIII (EHL-FVIII) products. Similarly, the development of extended half-life factor IX (EHL-FIX) products has also impac...
The management of hemophilia A has been transformed by the introduction of extended half-life factor VIII (EHL-FVIII) products. Similarly, the development of extended half-life factor IX (EHL-FIX) products has also impacted the treatment of hemophilia B, improving treatment adherence and reducing bleeding episodes. These bioengineered molecules, created through Fc-fusion, PEGylation, single-chain technologies, or albumin conjugation (particularly for FIX), offer patients reduced infusion frequency while maintaining effective bleed protection. However, the structural modifications of both EHL-FVIII and EHL-FIX pose significant challenges for accurate laboratory monitoring. Traditional one-stage and chromogenic substrate assays often yield discrepant results, varying by reagent, analytical platforms, and product type, complicating clinical decision-making and pharmacokinetic assessments. The thrombin generation assay (TGA) has emerged as a powerful global hemostasis tool that provides a functional readout of a patient's overall coagulation potential. By measuring the enzymatic capacity to generate thrombin over time, TGA offers a more integrated view of hemostatic efficacy than conventional factor activity tests. Although promising, TGA remains limited by lack of standardization, interplatform variability, and absence of validated clinical thresholds. Current data support its use as a complementary tool rather than a replacement for conventional assays. Future prospective studies integrating laboratory and clinical endpoints are required to define its role in precision hemophilia care and to determine whether TGA can better reflect bleeding phenotype and guide individualized therapy. Ultimately, the integration of functional assays into clinical practice will depend on harmonization efforts and demonstration of added clinical value in real-world settings and trials.
External Quality Assessment for Low Molecular Weight Heparin Monitoring in the Australasia/Asia-Pacific Region.
Favaloro EJ, Arunachalam S, Pasalic L
Semin Thromb Hemost · 2026 Jul · PMID 42398957 · Publisher ↗
Low molecular weight heparin (LMWH) remains a widely utilized parenteral anticoagulant in hospital and outpatient settings for thromboprophylaxis and treatment of venous thromboembolism. While LMWH typically does not req...
Low molecular weight heparin (LMWH) remains a widely utilized parenteral anticoagulant in hospital and outpatient settings for thromboprophylaxis and treatment of venous thromboembolism. While LMWH typically does not require routine monitoring due to predictable pharmacokinetics, anti-factor Xa (anti-Xa) monitoring is indicated in specific populations, including those with renal impairment, extremes of body weight, pregnancy, or unexplained treatment failure. LMWH monitoring relies exclusively on chromogenic anti-Xa assays, as LMWH's predominant anti-Xa activity with minimal anti-IIa effect renders activated partial thromboplastin time insensitive. Therapeutic targets are context-dependent: peak anti-Xa levels of 0.5 to 1.2 U/mL for twice-daily therapeutic dosing or 1.0 to 2.0 U/mL for once-daily dosing, measured 3- to 5-hour postdose. We report external quality assessment findings for anti-Xa testing of LMWH from the past 6 years (2020-2025 inclusive) using RCPAQAP (Royal College of Pathologists of Australasia Quality Assurance Program) data, an international program with approximately 150 laboratory enrolments. Four samples are assessed annually at varied LMWH concentrations (0, 0.2-0.3, 0.5-0.6, 0.8-1.0 U/mL). Good reproducibility was demonstrated for duplicate samples across surveys. Coefficient of variation data revealed moderate variability (10-25%) for detectable LMWH levels, lower than unfractionated heparin (UFH) monitoring variability. Method-related differences were observed, with Siemens Innovance anti-Xa assays yielding slightly higher values than Werfen HemosIL or Stago STA assays. Participant interpretations of LMWH levels (below/within/above therapeutic range) showed greater variability than UFH due to multiple valid therapeutic ranges for LMWH depending on dosing context. Overall, laboratories demonstrated acceptable analytical and interpretative performance for LMWH monitoring, which should provide some reassurance to both patients and their clinical carers.
Human evolution: between hemorrhage and thrombosis.
Franchini M, Zani M, Focosi D
Semin Thromb Hemost · 2026 Jul · PMID 42398954 · Publisher ↗
The human coagulation system has resulted from thousands of years of evolutionary pressure, finely balancing the competing risks of lethal hemorrhage and catastrophic thrombosis. There are several examples of the close i...
The human coagulation system has resulted from thousands of years of evolutionary pressure, finely balancing the competing risks of lethal hemorrhage and catastrophic thrombosis. There are several examples of the close interaction between the two opposing sides of hemostasis. A paradigmatic case is offered by the factor V Leiden mutation. Emerging approximately 22,000 years ago, this gain-of-function variant is now expressed in about 5% of Caucasians. While it now significantly elevates the risk of venous thromboembolism, it historically provided crucial evolutionary advantages, including reduced peripartum blood loss, enhanced iron stores, improved fertility, and increased embryo implantation rates. Conversely, congenital hypocoagulable states, such as hemophilia, demonstrate the other side of the coin. With modern therapeutic advances now extend the life expectancy of individuals with hemophilia, clinicians are increasingly managing age-related comorbidities. While experimental models suggest a chronic hypocoagulable state might mitigate the risk of occlusive cardiovascular events or suppress cancer metastasis, clinical and epidemiological data remain conflicting. Mild factor deficiencies may offer some protection against ischemic heart disease, but overall cardiovascular and oncological risk profiles in patients with hemophilia increasingly mirror those of the aging general population. This review explores the genetic and environmental forces that shape this homeostatic equilibrium, illustrating how historical survival mechanisms influence modern disease patterns.
Full- vs Reduced-Dose Direct Oral Anticoagulants for Extended Treatment of Cancer-Associated Thrombosis: A Multicenter Retrospective Cohort Study.
Santini P, Santagata D, Mosoni C … +11 more , Mancinetti F, Porfidia A, Bertù L, Zurlo C, Scandiuzzi Piovesan T, Menichelli D, Pignatelli P, Visonà A, Donadini MP, Ageno W, Pola R
Semin Thromb Hemost · 2026 Jun · PMID 42379243 · Publisher ↗
Extended anticoagulation is recommended in subjects with cancer-associated thrombosis (CAT). The API-CAT trial showed that reduced-dose apixaban is noninferior to full-dose for preventing recurrent venous thromboembolism...
Extended anticoagulation is recommended in subjects with cancer-associated thrombosis (CAT). The API-CAT trial showed that reduced-dose apixaban is noninferior to full-dose for preventing recurrent venous thromboembolism (VTE), but the generalizability of these findings to real-world populations remains to be determined. We conducted a multicenter retrospective cohort study including patients with CAT receiving extended direct oral anticoagulants (DOACs) at full or reduced dose, after at least 6 months of anticoagulation. The primary efficacy outcome was recurrent VTE. The primary safety outcome was major bleeding (MB) and clinically relevant non-major bleeding (CRNMB). A total of 603 patients were included, of whom 381 (63.2%) received reduced-dose and 222 (36.8%) full-dose DOACs. During a median follow-up of 335 days, recurrent VTE occurred in 3.9% of patients in the reduced-dose and 2.7% in the full-dose group (p=0.4). MB occurred in 1.0% and 0.9% (p=0.9), and CRNMB in 4.7% and 5.4% (p=0.7), respectively. In adjusted analyses, reduced-dose DOACs were associated with a non-significant increase in VTE recurrence (hazard ratio 1.4, 95% CI 0.5-3.7), with no differences in bleeding outcomes. In this multicenter real-world cohort, reduced-dose DOACs were associated with low rates of recurrent VTE and bleeding, comparable to those observed with full-dose regimens. These findings suggest that reduced-dose anticoagulation may be a feasible option in selected patients with CAT requiring extended treatment, supporting individualized decision-making. Further studies are needed to better define optimal dose selection in this setting.
Too Old for PESI?: Risk Stratification of Octogenarians with Pulmonary Embolism in the Emergency Department.
Lipa AJ, Janata-Schwatczek K, Sterz M … +6 more , Brock R, Kornfehl A, Herkner H, Schoergenhofer C, Schwameis M, Grafeneder J
Semin Thromb Hemost · 2026 Jun · PMID 42361814 · Publisher ↗
Pulmonary embolism (PE) in octogenarians (i.e., patients > 80 years) is associated with substantial morbidity and mortality, yet this population remains underrepresented in major studies. We compared the predictive perfo...
Pulmonary embolism (PE) in octogenarians (i.e., patients > 80 years) is associated with substantial morbidity and mortality, yet this population remains underrepresented in major studies. We compared the predictive performance of the Pulmonary Embolism Severity Index (PESI), simplified PESI (sPESI), European Society of Cardiology (ESC) risk classes, and National Early Warning Score (NEWS) for mortality prediction in octogenarians versus younger emergency department (ED) patients. In this single-center retrospective cohort study, adults with confirmed PE presenting to an ED in Vienna, Austria, between January 2017 and December 2024 were included. Patients were categorized as octogenarians or ≤80 years. Clinical characteristics, treatment, and outcomes were compared. Predictive performance for 30-day mortality was assessed using receiver operating characteristic analyses and diagnostic accuracy measures. Sensitivity analyses and evaluation of 7-day mortality were also performed. Among 773 patients, 114 were octogenarians. Compared with younger patients, octogenarians had more cardiovascular comorbidities, higher cardiac biomarker levels, more right ventricular strain, and significantly higher 30-day mortality. PESI showed the most consistent overall prognostic performance but was less accurate in octogenarians. sPESI demonstrated limited specificity because most octogenarians were classified as high risk. ESC risk classes provided moderate discrimination. NEWS ≥ 7 showed prognostic value for short-term mortality among octogenarians, although the differences from PESI were not statistically significant. Established PE prognostic tools perform less well in octogenarians. PESI showed the most consistent overall performance, while NEWS demonstrated promising short-term prognostic value that warrants further investigation.
Acute Management and Bleeding Outcomes in Pediatric Pulmonary Embolism: A Large Single-Center Retrospective Cohort Study.
Wagner KM, Raffini L, Whitworth H
Semin Thromb Hemost · 2026 Jun · PMID 42349848 · Publisher ↗
Pediatric pulmonary embolism (PE) is a relatively rare but high-risk disease. There is minimal evidence to guide clinical management, particularly with respect to reperfusion therapies. Few studies capture bleeding outco...
Pediatric pulmonary embolism (PE) is a relatively rare but high-risk disease. There is minimal evidence to guide clinical management, particularly with respect to reperfusion therapies. Few studies capture bleeding outcomes to inform risk-benefit management decisions. In this single-center, retrospective cohort study, we aimed to describe pediatric patients <21 years of age who received acute PE care at our institution, excluding those with comorbid cardiac disease. We described the PE risk factors, in-hospital management, and acute outcomes, including bleeding and mortality. Between 2003 and 2022, 175 patients met eligibility: 120 low-risk (69%), 44 intermediate-risk (25%), and 11 high-risk (6%) PE. Most (N=142) received anticoagulation alone; 29 patients received reperfusion therapy for PE, the most common reperfusion therapy was systemic thrombolysis. There were 34 clinically relevant bleeding events in 27 patients, including major bleeding in 9 (5%) and clinically relevant non-major bleeding events in 18 (10%) patients. Sixty-two percent (21/34) of bleeding events occurred in patients receiving anticoagulation alone, while 10/34 (29%) occurred in patients receiving systemic thrombolysis. In the high-risk PE cohort, clinically relevant bleeding occurred in 73% and 45% died. Most patients with major bleeding had other bleeding risk factors independent of their PE-directed therapy. All-cause mortality was 4%, with 2% PE-related mortality. This cohort study highlights that reperfusion therapy is well-tolerated in select pediatric patients and rates of bleeding and death are high in high-risk PE. Future research should validate these findings with prospective, standardized bleeding outcome collection to inform management decisions in pediatric PE.
Red Blood Cells in Hemostasis and Thrombosis: Mechanisms, Interactions, and Clinical Implications.
Bucciol R, Othman M
Semin Thromb Hemost · 2026 Jul · PMID 42335963 · Publisher ↗
Abstract loading — click title to view on PubMed.
Pediatric Pulmonary Infarction and Infarction-Like Pulmonary Injury: An Etiology-Oriented Narrative Review.
Li S, Zhang Y, Tian X … +2 more , Zhao W, Xu Y
Semin Thromb Hemost · 2026 Jun · PMID 42309148 · Publisher ↗
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...
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.
Comparison of the Coagulation Profile Following Treatment of Major Surgical Haemorrhage with Fresh Frozen Plasma or Fibrinogen Concentrate.
Young IJB, Aitken N, Dickson A … +4 more , Anderson J, Morrison G, Dargaud Y, Nimmo A
Semin Thromb Hemost · 2026 Jun · PMID 42302861 · Publisher ↗
In a parallel-assignment, single-blinded study, we measured the detailed coagulation profile of 20 patients randomized to receive infusions of fresh frozen plasma (FFP) or fibrinogen concentrate during surgery associated...
In a parallel-assignment, single-blinded study, we measured the detailed coagulation profile of 20 patients randomized to receive infusions of fresh frozen plasma (FFP) or fibrinogen concentrate during surgery associated with major surgical hemorrhage-Extent 4 Thoraco-abdominal Aortic Aneurysm repair. Ten patients received FFP; 10 fibrinogen concentrate, infused to achieve plasma fibrinogen concentration around 1.5 g/L. There were predefined hemoglobin and ROTEM cut-offs for red cell and platelet administration. Blood samples were taken at up to 12 predefined time points before, during, and after surgery. Measurements included coagulation and anticoagulant factor concentrations, thrombin generation, activated protein C (aPC) concentrations, and thromboelastography. Intraoperative blood loss was between 2,750 and 16,500 mL. During surgery, plasma fibrinogen concentration was slightly lower in the FFP group but maintained or restored to approximately 1.5 g/L. When blood loss exceeded approximately 4,000 mL, most factor concentrations and conventional tests were superior in the FFP group. Mean (standard deviation) 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; < 0.001. Protein C and aPC concentrations trended higher in the FFP group: protein C = 59.7 (18.4) versus 30.0 (10.6)% normal; < 0.001, aPC = 6.9 (5.5) versus 3.1 (2.3) g/L; = 0.001. Differences in peak thrombin generation 2 hours postoperatively in the FFP group did not meet statistical significance: (224.3 [54.8] vs. 133.0 [66.0]) nM; = 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 4,000 mL, this was not associated with worse surgical hemostasis or observed bleeding complications. · Question: in patients undergoing major surgical hemorrhage during thoracoabdominal aortic aneurysm repair, how does treatment with FFP compare with fibrinogen concentrate in maintaining coagulation profiles?. · Findings: both treatments maintained plasma fibrinogen concentrations, but patients receiving FFP had higher levels of coagulation factors, thrombin generation, and aPC when blood loss exceeded 4,000 mL.. · Meaning: although FFP led to superior laboratory coagulation parameters at high blood loss, in this exploratory cohort with blood losses of up to 16,500 mL, observed hemostasis remained clinically satisfactory when managed by either fibrinogen concentrate or FFP..
Is Vaginal Estrogen Treatment Associated with Risk of Thrombosis in Postmenopausal Women? A Scoping Review.
Juul SL, Glavind-Kristensen M, Bor P … +1 more , Bor MV
Semin Thromb Hemost · 2026 Jun · PMID 42285171 · Publisher ↗
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...
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 ( = 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 ( = 5; aHRs: 0.52 [0.31-0.85] to 0.83 [0.77-0.89]) and stroke ( = 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.
Association between Sex and Platelet Function in Patients with Diabetes Mellitus Type II: A Systematic Review.
Mikkelsen R, Larsen JB, Smidt K
Semin Thromb Hemost · 2026 Jun · PMID 42263761 · Publisher ↗
Type 2 diabetes mellitus (T2DM) is associated with a significant risk for development of cardiovascular diseases (CVD), in which platelets play a pivotal role. Sex-related differences in CVD exist in terms of prevalence,...
Type 2 diabetes mellitus (T2DM) is associated with a significant risk for development of cardiovascular diseases (CVD), in which platelets play a pivotal role. Sex-related differences in CVD exist in terms of prevalence, risk factors, clinical presentation, treatment, outcomes, and prognosis. Platelet activation may contribute to these sex-related differences. The aim of this systematic review was to investigate whether platelet function differs between men and women with T2DM. The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Literature searches in PubMed and Embase were performed. We included studies that investigated differences in platelet function parameters, platelet indices, or platelet transcriptomics in patients with T2DM. The risk of bias was assessed according to the National Heart, Lung and Blood Institute. Twenty-six studies were included. No significant differences in platelet activation between men and women with T2DM were consistently reported in the literature, although 7 of the 26 studies found significantly altered platelet indices, higher platelet aggregation, higher P-selectin expression, or higher prevalence of acetylsalicylic acid resistance in women. Two studies reported a significantly higher platelet aggregation in men. None of the included studies investigated the association between sex and platelet function as a primary outcome. A wide range of platelet function methods were employed, which caused considerable heterogeneity and challenged the comparison across the studies. Due to the limited amount of evidence on this topic, further studies are needed to provide insight into sex differences in platelet function in patients with T2DM.
Peripartum Vascular Calamities: Placental Abruption and Amniotic Fluid Emboli.
Wolfovitz A, Brenner B, Solt I
Semin Thromb Hemost · 2026 Jun · PMID 42259376 · Publisher ↗
Amniotic fluid embolism (AFE) and placental abruption represent two of the most catastrophic obstetric emergencies, sharing a common pathway of severe coagulopathy while differing fundamentally in their underlying pathop...
Amniotic fluid embolism (AFE) and placental abruption represent two of the most catastrophic obstetric emergencies, sharing a common pathway of severe coagulopathy while differing fundamentally in their underlying pathophysiology. AFE is characterized by sudden cardiovascular collapse, respiratory distress, and disseminated intravascular coagulation (DIC), likely triggered by an anaphylactoid-like reaction to fetal antigens entering maternal circulation. The condition manifests with both consumptive coagulopathy and hyperfibrinolysis, with platelet counts frequently falling below 50,000/μL and precipitous drops in fibrinogen levels. Management requires immediate advanced cardiac life support and aggressive hemodynamic support, mechanical ventilation, and massive transfusion protocols guided by viscoelastic testing. Emerging therapies include extracorporeal membrane oxygenation for refractory cardiopulmonary collapse and recombinant factor VIIa for intractable hemorrhage. Placental abruption results from premature placental separation and presents vaginal bleeding, abdominal pain, and fetal compromise. The condition arises from chronic uteroplacental ischemia and decidual arteriopathy, with retroplacental hematomas serving as massive sources of tissue factors that trigger the coagulation cascade. Abruption-related DIC primarily manifests consumption coagulopathy. Unlike AFE, urgent delivery of the fetus and placenta can eliminate the source of thromboplastic material, often resolving the coagulopathy. Both conditions demand, among others, institutional preparedness with established massive transfusion protocols and multidisciplinary teams trained in obstetric critical care. While advances in viscoelastic testing, targeted factor concentrates, and life support technologies have improved outcomes, AFE and placental abruption continue to challenge even experienced obstetric teams.
Diagnosis and Management of Recurrent Thrombosis and Pregnancy Loss in a Patient with Multilevel Thrombophilia.
Correa Lara MVM, García Chavez J, Martinez Hernandez E
Semin Thromb Hemost · 2026 Jun · PMID 42248608 · Publisher ↗
Abstract loading — click title to view on PubMed.
Making Machine Learning Clinically Useful in Thrombosis and Hemostasis: A Roadmap for Diagnostic Translation.
Nagler M, Nilius H, Hastings J … +1 more , Nakas C
Semin Thromb Hemost · 2026 Jun · PMID 42242234 · Publisher ↗
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,...
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.
Laboratory Monitoring of Complement Activation in Gene Therapy: Analytical Pitfalls and Clinical Interpretation.
Henry BM, Rincon MY, Lippi G … +2 more , Prohászka Z, Benoit S
Semin Thromb Hemost · 2026 Jun · PMID 42235591 · Publisher ↗
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 th...
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.
Designing the Future of Hemostasis.
Kazmirchuk TDD, Wang J, Corbette J … +3 more , Hammad ZAA, Othman M, Golshani A
Semin Thromb Hemost · 2026 Jun · PMID 42225137 · Publisher ↗
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) a...
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.
Platelet-Red Blood Cell Interactions in Thrombosis: Integrating Hemodynamic, Molecular, and Clinical Evidence-A Systematic Review.
Alamin AA, Yahia AIO, Ibrahim E … +1 more , Alnefaie GO
Semin Thromb Hemost · 2026 Jul · PMID 42190738 · Publisher ↗
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 in...
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.
100 Years of von Willebrand Disease: Celebrating a Significant Milestone in von Willebrand Disease Diagnostics and Management.
Favaloro EJ
Semin Thromb Hemost · 2026 May · PMID 42190737 · Publisher ↗
Abstract loading — click title to view on PubMed.
Erythrocyte Heterogeneity as a Driver of Thrombus Architecture and Treatment Response.
Bucciol R, Zandi A, Qian A … +2 more , Kearn I, Othman M
Semin Thromb Hemost · 2026 Jul · PMID 42190729 · Publisher ↗
Thrombi are not uniform structures, and neither are the red blood cells (RBCs) that populate them. Most models of thrombosis, however, implicitly treat erythrocytes as mechanically and biologically uniform, obscuring a k...
Thrombi are not uniform structures, and neither are the red blood cells (RBCs) that populate them. Most models of thrombosis, however, implicitly treat erythrocytes as mechanically and biologically uniform, obscuring a key determinant of clot architecture: RBC heterogeneity. Circulating RBCs vary widely in size, shape, deformability, membrane composition, and biochemical state, generating subpopulations that behave differently under flow and within forming thrombi. These differences actively govern how RBCs marginate, where they localize during thrombus growth, how they interact with fibrin and platelets, and how they resist or accommodate platelet-driven contraction. The outcome is not merely variable RBC content but spatially organized thrombi with region-specific mechanics, permeability, and fibrinolytic susceptibility. Experimental models and analyses of patient-derived thrombi demonstrate that RBCs are unevenly distributed within clots. This spatial variability shapes local fibrin architecture, platelet activity, and clot mechanics in ways that cannot be inferred from total RBC content or average erythrocyte properties, highlighting RBC heterogeneity as a critical, yet underrecognized, determinant of thrombus formation. In this review, we present a conceptual framework of thrombus heterogeneity along three coupled axes, namely, mechanical, structural, and biochemical, illustrating how erythrocyte subpopulations influence clot formation and function. We synthesize emerging evidence, discuss approaches for identifying RBC subpopulations, and explore implications for thrombosis modeling, thrombolysis, thrombectomy, and clinical outcomes.
The Novel C-Terminal Cystine Knot (Exon 52) VWF p.Cys2771Phe Variant Produces a Type 2A von Willebrand Factor Multimer Pattern with an Apparent Dimerization Defect.
Brown M, Booth GS, Walker SC … +6 more , Baxter PG, Cross V, Matafonov A, Tillman BF, Gailani D, Jacobs JW
Semin Thromb Hemost · 2026 May · PMID 42173123 · Publisher ↗
Abstract loading — click title to view on PubMed.
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