Background Emicizumab is a bispecific recombinant, humanized immunoglobulin that substitutes the cofactor function of activated factor VIII, used for prophylaxis in congenital hemophilia A. Our institution added emicizumab to formulary in 2019 for congenital hemophilia A. This study aims to characterize perioperative management for patients with hemophilia A before and after the addition of emicizumab into clinical practice. Methods This retrospective descriptive analysis included adult patients diagnosed with congenital hemophilia A who underwent inpatient procedures between July 2014 and September 2024, excluding procedures in 2019 (emicizumab introduction). Patients were identified if they had a surgery encounter during the study period. All patients with and without inhibitors were included.The major outcome variable was peri-operative clotting factor concentrate (CFC) usage (dose, dosing interval, and duration) pre- and post-introduction of emicizumab. Minor outcomes included the time to first CFC factor dose de-escalation, escalation due to bleed, and hospital length of stay (LOS). Results were analyzed using descriptive statistics. Results A total of 77 surgical procedures were included. In patients without inhibitors, 49 procedures were included, of which 28 were pre-2019 (15 patients, 5 unplanned, 14 minor, 14 major) and 21 were post-2019, 12 of which were in patients on emicizumab (13 patients, 7 unplanned, 12 minor, 9 major). The most common periprocedural CFC regimen was a one-time dose of recombinant FVIII (rFVIII) with octocog alfa 50 units/kg pre-procedure (82.1% pre-2019 vs. 66.7% post-2019), followed by 25 units/kg every 12 h post-procedure, de-escalated after 3 days. Bleeding-related dosing escalation occurred after 2 procedures (7.1%) pre-2019 and 2 procedures (9.5%) post-2019.In patients with inhibitors, 28 procedures were included, of which 3 were pre-2019 (2 patients, 1 unplanned, 2 minor, 1 major) and 25 post-2019; 16 occurred in patients on emicizumab (4 patients, 11 unplanned, 21 minor, 4 major). The most common CFC regimens in the pre-2019 group were recombinant activated factor VII (rVIIa) with eptacog alfa 90 mcg/kg every 2 h or activated prothrombin complex concentrate (aPCC) 50 units/kg every 12 h, de-escalated after 1 and 2 days, respectively. In the post-2019 group, the predominant regimen was rVIIa 90 mcg/kg every 2-3 h, de-escalated after 1 day.Hospital LOS for patients without inhibitors was 1.5 days pre-2019 and 3 days post-2019, whereas LOS was 11 days pre-2019 and 21 days post-2019 in those with inhibitors. Conclusions In this single-center analysis of CFC dosing practices before and after the introduction of emicizumab, inpatient periprocedural use of CFC during hospital admissions did not appear to be impacted. We observe that the preferred bypassing agent changed from aPCC to rFVIIa. Among patients undergoing major procedures, a shorter interval to first CFC dose de-escalation was observed in procedures performed after 2019. There were a greater number of procedures performed in patients with inhibitors post-2019. The length of stay was longer in post-2019 patients with inhibitors, however, this may be attributable to bleeding events unrelated to procedures and differences in patient comorbidities. Most patients receiving emicizumab outpatient did not require additional factor repletion following discharge.
Background Risk stratification tools for venous thromboembolic disease (VTE) oversimplify patient heterogeneity. This exploratory study aimed to identify distinct clinical profiles in deep vein thrombosis (DVT) using unsupervised machine learning and to describe their association with one-year outcomes. Methods Retrospective analysis of DVT patients at a quaternary hospital in Bogotá, Colombia (2019–2025). The K-modes algorithm was applied to 24 categorical clinical variables. Age was excluded from clustering because it is a continuous variable and the K-modes algorithm requires categorical inputs; age-related clinical burden was captured indirectly through age-associated comorbidities. K = 4 was selected based on the elbow method, clinical interpretability, and bootstrap stability analysis. One-year all-cause mortality and recurrent thrombosis were compared with chi-squared tests and Wilson 95% confidence intervals. Results 583 patients were included. Four clinical profiles were identified: Cluster 1 (n = 155), predominantly women without cardiovascular comorbidities; Cluster 2 (n = 182), patients with chronic comorbidities and hypertension as defining feature; Cluster 3 (n = 98), younger men without active cancer; Cluster 4 (n = 148), men with identifiable risk factors. One-year mortality differed across clusters: C1 2.6% (95% CI 1.0–6.4%), C2 7.1% (4.2–11.8%), C3 1.0% (0.2–5.6%), C4 6.8% (3.7–12.0%) (p = 0.04). Rethrombosis also differed: C1 1.9% (0.7–5.5%), C2 1.6% (0.6–4.7%), C3 6.1% (2.8–12.7%), C4 0.7% (0.1–3.7%) (p = 0.03). Bootstrap stability was low-to-moderate (mean Jaccard 0.486). Conclusion Unsupervised clustering identified four clinically distinct DVT profiles with different one-year outcome distributions. Because the clusters incorporate treatment patterns (anticoagulant choice), they represent clinico-therapeutic profiles rather than biological phenotypes, and the outcome differences should not be interpreted as causal. These exploratory, hypothesis-generating findings require external validation before any clinical application.
The discovery of ADAMTS13 in 2001 resolved a long-standing mystery in the pathogenesis of thrombotic thrombocytopenic purpura (TTP) and established the ADAMTS13-von Willebrand factor (VWF) axis as the central regulator of microvascular thrombosis. Severe ADAMTS13 deficiency, whether congenital or immune-mediated, permits the accumulation of ultra-large VWF (UL-VWF) multimers that drive platelet-rich microvascular thrombi and underlie the clinical manifestations of TTP. Over the past 25 years, ADAMTS13 has evolved from an elusive VWF-cleaving protease into a paradigm for understanding mechanoregulated proteolysis, force-dependent substrate recognition, and allosteric enzyme regulation. In this review, we commemorate the 25th anniversary of ADAMTS13 by tracing the discoveries that led to its identification and transformed our understanding of TTP. We highlight advances in the molecular and structural biology of the ADAMTS13-VWF axis, including shear-dependent VWF unfolding, multisite exosite-mediated substrate recognition, conformational latency, intramolecular autoinhibition, and VWF-induced allosteric activation. Biochemical, structural, and computational studies support a unified model in which dynamic interdomain interactions and force-dependent VWF engagement govern ADAMTS13 activity. This model integrates substrate recognition, activation, and proteolysis into a tightly regulated biological system. We discuss the clinical translation of these discoveries, including ADAMTS13 activity assays, diagnostic testing strategies, conformational biomarkers, recombinant ADAMTS13 replacement therapy, and targeted treatments that have transformed TTP from a frequently fatal disorder into a highly manageable disease. Finally, we outline emerging challenges and opportunities, including structural visualization of the intact ADAMTS13-VWF complex, development of next-generation ADAMTS13 therapeutics, precision medicine approaches, and exploration of the ADAMTS13-VWF axis in thrombotic and inflammatory diseases beyond TTP. Collectively, these advances establish the ADAMTS13-VWF axis as a model system for understanding mechanoregulated proteolysis with broad implications for thrombosis, hemostasis, and vascular biology.
Immunothrombosis describes the coordinated engagement of innate immunity and the coagulation system as a host-defense response. Microthrombi assembled at sites of pathogen exposure compartmentalize infection, restrict microbial dissemination, and support clearance without compromising the broader vasculature. When the spatial and temporal boundaries of this response fail, the same effector machinery propagates systemically and gives rise to the thromboinflammatory disorders that dominate modern critical care: sepsis-induced coagulopathy (SIC) and its progression to disseminated intravascular coagulation (DIC), the pulmonary microthrombosis of severe COVID-19, and the prothrombotic state of advanced malignancy.Here we synthesize the molecular drivers and regulatory checkpoints that govern the transition from protective to pathologic immunothrombosis. We first clarify the conceptual distinction between immunothrombosis and thromboinflammation and frame SIC and DIC as sequential stages of a single continuum. We then dissect the activation of tissue factor (TF) across its cellular, Nuclear Extracellular Trap (NET)-associated, and extracellular-vesicle compartments, with particular attention to pyroptotic decryption mediated by the caspase-11/caspase-4 axis. The endothelium is positioned as the principal gatekeeper, with phenotypic state transitions, Weibel–Palade body exocytosis, and glycocalyx kinetics determining whether activation remains compartmentalized. Amplification is examined through platelet–neutrophil crosstalk, NET heterogeneity, complement–coagulation interplay, and the inflammasome–pyroptosis axis. Resolution biology is treated in equal depth, with emphasis on DNase-mediated NET clearance, macrophage efferocytosis, and contact-system engagement on residual NET scaffolds. Finally, we map these mechanisms onto three disease modules (sepsis, COVID-19, and cancer-associated thrombosis), discuss the limits of conventional anticoagulation, and outline emerging therapeutic strategies aimed at TF decryption, NET formation and clearance, complement amplification loops, and contact-pathway activation.
Background Patients with advanced non-small cell lung cancer are at increased risk of venous thromboembolism (VTE) and often receive direct oral anticoagulants (DOACs) for thromboprophylaxis. Using oral anticancer small-molecule inhibitors (SMIs) concurrently may affect bleeding or thrombotic risk by altering DOAC pharmacokinetics. However, data on safety of concomitant use and the relevance of therapeutic drug monitoring (TDM) in this setting are limited. Methods Using pooled data from a prospective study and routine care, we evaluated DOAC pharmacokinetics and incidence of thromboembolic and clinically relevant bleeding (CRB) events during TDM-guided DOAC management in patients receiving SMIs. Patients were included if they had at least one steady-state DOAC peak or trough concentration measured during SMI treatment. DOAC concentrations were reported to the treating physician, who could adjust anticoagulant therapy at their discretion. Results DOAC concentrations outside the expected on-therapy range occurred in 17/48 patients; none were observed with osimertinib (0/13), whereas elevated exposure occurred more frequently with alectinib (5/9). During median follow-up of 11.9 (range: 0.3-48.8) months, no VTEs were observed, two strokes, and seven CRB events (of which three trauma-related) were recorded. Two CRB events occurred during elevated DOAC exposure prior to DOAC adjustment. No bleeding or thromboembolic events were observed following DOAC dose adjustment or switching. Conclusions While underpowered for subgroup analyses, our findings suggest that specific SMIs predispose to deviant DOAC exposure. TDM-guided management effectively restored DOAC exposure to within expected on-therapy ranges. Prospective validation is needed to assess whether this strategy can reduce bleeding and thromboembolic risk.
