Thrombin plays a central role in hemostasis, serving as both the primary enzyme driving fibrin formation and 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 (TGA) provide a global view of coagulation, measuring both formation and inhibition of thrombin over time. We conducted a narrative literature review using PubMed and Embase up to January 2025, focusing on publications evaluating TGA methodology, clinical applications, and translational potential. Additional references were identified through citation review. TGA 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. TGA can also evaluate the efficacy of bypassing agents and novel hemostatic drugs in ex vivo settings. Barriers include technical complexity, pre-analytical variability, and lack of standardization across laboratories. TGA 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 multicentre studies, and integration into clinical decision-making pathways.

Coagulopathies are common in hematological malignancies and can cause life-threatening bleeding or thrombosis. Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, carry cargo that reflects their cellular origin. They frequently express tissue factor (TF) and expose phosphatidylserine (PS), which initiate and amplify coagulation and can also transport fibrinolytic mediators that modulate plasmin generation. Procoagulant EVs are commonly assessed using TF- and PS-dependent functional assays, global hemostasis tests such av overall hemostatic potential, and flow cytometric phenotyping. Clinical and experimental data show elevated EV numbers and activity at diagnosis in several hematological malignancies. In acute leukemias, EV-associated procoagulant activity often declines with treatment yet may remain above control levels, consistent with residual risk. In plasma cell disorders and myeloproliferative neoplasms, platelet-derived and TF/PS-positive EVs are frequently increased and have been linked to enhanced thrombin generation. EVs appear to play key roles across leukemias, multiple myeloma, lymphoid and myeloproliferative neoplasms. However, considerable methodological heterogeneity, including differences in pre-analytical handling, EV isolation, characterization, and activity measurement limits comparability and clinical translation. Disease-specific mechanistic studies are needed to clarify how EVs modulate hemostasis in different hematologic malignancies. In parallel, standardized protocols and adequately powered clinical studies are required to validate EVs as biomarkers.

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 non-standardized reporting. To understand D-dimer reporting practices, the College of American Pathologists (CAP) Hemostasis and Thrombosis Committee (HaTC) 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 quantify the proportion of laboratories reporting units that may be considered incorrect. To accomplish this, we harmonized all D-dimer results to ng/mL fibrinogen equivalent units (FEU) for all results 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 DDU commonly exhibited significant deviations from the dominant population. For one instrument/reagent combination, most reported values differed by approximately twice the COA 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.

Guidelines recommend placement of inferior vena cava filters (IVCF) in patients with acute proximal lower extremity deep vein thrombosis (DVT) and a contraindication to anticoagulation. IVCF placement during pregnancy or immediately postpartum presents technical challenges and is not extensively described in the existing literature. To describe the use of IVCF in the obstetric population along with outcomes related to filter placement. Retrospective chart review of all patients at Mayo Clinic from 2001-2020 with an IVCF at the time of conception or who underwent placement during pregnancy/postpartum. 24 pregnancies in 23 women (mean age 26.3 years, range 18-41) were included: 5 (21%) with IVCF placement prior to pregnancy, 7 (29%) during pregnancy, and 12 (50%) during postpartum. IVCF placed during pregnancy were frequently in the suprarenal position, in 5 (71%) cases. Meanwhile, 16 (94%) were deployed in an infrarenal position prior to pregnancy and postpartum. Complications included multiple attempts to remove the IVCF (n=2), severe angulation (n=4), embedded struts (n=3), fracture (n=1), and one case of cardiac tamponade (n=1). Complications were more common when placement was performed prior to pregnancy or during pregnancy (2, 40% and 4, 57% respectively) versus postpartum (2, 17%). IVCF placement prior or during pregnancy/ postpartum is uncommon and is associated with a high incidence of complications, although most did not fundamentally impact clinical outcomes. While IVCF remain an option for clinicians treating pregnant and postpartum patients, these should be considered as a last resource.

The antiphospholipid syndrome (APS) is a complex autoimmune disease that causes a state of hypercoagulability that can result in recurrent venous and arterial thromboses. APS may lead to cardiac manifestations requiring cardiac surgery with cardiopulmonary bypass. Perioperative anticoagulation management in APS patients is complex. This complexity arises from both the prothrombotic nature of APS and interference of antiphospholipid antibodies (aPLs) with phospholipid-dependent coagulation assays like activated clotting time (ACT). Given that current literature on cardiopulmonary bypass (CPB) management in APS patients is largely limited to isolated case reports and lacks a comprehensive synthesis, this review summarizes the cardiac manifestations of APS, challenges posed by CPB, and current strategies for intraoperative anticoagulation management, including heaprin dosing, anticoagulation monitoring methods and protamine reversal practices. We further highlight gaps in evidence and propose a practical three-category framework for managing aPL-positive patients undergoing CPB.

Catastrophic antiphospholipid syndrome (CAPS) is a rare, potentially lethal, multiple-faceted, systemic disease, often triggered by a precipitating factor. Its tissue lesions are mainly the consequence of an antiphospholipid antibody (aPL Abs)-mediated thrombotic microangiopathy associated with a so-called cytokine storm. Bleeding may coexist, making it difficult to manage. In an emergency situation, the differential diagnosis is not always straightforward in patients not known to be aPL Abs carriers, or with no history of thrombotic or obstetric complications. What we have gradually learned about its clinical presentation and therapeutic management mainly comes from the CAPS registry. So far, there have been no randomized controlled trials to guide treatment. The current therapeutic recommendations insist on prescribing first-line triple therapy, combining early anticoagulation, immunosuppression, and the removal/neutralization of aPL Abs, as early as possible. The prognosis has improved but remains bleak. Future research to develop pathophysiological treatments blocking the activation of target cells by aPL Abs is warranted.

Clot waveform analysis (CWA) extends routine coagulation assays (activated partial thromboplastin time [aPTT] and prothrombin time [PT]) by incorporating continuous optical monitoring to generate kinetic profiles of clot formation. This method provides both qualitative and quantitative information on hemostasis, with increasing evidence for its clinical utility in detecting factor deficiencies and characterizing thrombotic and bleeding disorders. Despite the growing body of evidence, translation of CWA into routine clinical practice remains limited.This review identifies three principal barriers: (1) variability arising from differences in optical detection methods (absorbance vs. transmittance), (2) interreagent variation even within the same analyzer platform, and (3) lack of a clear distinction between standard CWA, performed with commercially available reagents, and modified CWA, incorporating in-house adjustments. To address these challenges, we encourage adopting distinct nomenclature for detection modalities (CWA-A; A for absorbance and CWA-T; T for transmittance), establishing standardized reporting requirements including reagent and platform details, and establishing quality assurance frameworks for CWA.Standardization of terminology and reporting will enhance reproducibility, enable cross-study comparisons, and accelerate the clinical translation of CWA from the laboratory bench to the bedside.

People with hemophilia (PwH) face persistent joint damage risk despite prophylactic factor replacement therapies. While 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.

Acquired hemophilia A (AHA) is a rare bleeding disorder caused by factor VIII inhibitors. Standard therapies are limited by thrombotic risk and prolonged hospitalization. Emicizumab, approved for congenital hemophilia A, has emerged as a potential alternative in AHA based on case reports and early clinical trial data. To evaluate the efficacy and safety of emicizumab in AHA through a retrospective real-world case series and a systematic literature review with patient-level data analysis. We retrospectively analysed five AHA cases treated with Emicizumab at two Italian centres and performed a PRISMA-compliant systematic review of published reports, extracting and analysing patient-level data using JBI tools. In the real-world cohort, early emicizumab use in five patients with high-titer inhibitors and severe bleeding led to rapid hemorrhagic control, early withdrawal of bypassing agents, and no thrombotic or adverse events. All the five patients received immunosuppression and inhibitor eradication was achieved in 60% of patients but for 40% follow up is still ongoin. The literature review identified 24 patients from 18 publications. Early emicizumab administration (at admission) was associated with reduced bleeding recurrence (0% vs. 56.3%), shorter in-hospital stay (median 23.5 vs. 39 days), and lower bleeding-related mortality (0% vs. 12.5%) compared to delayed administration. Early emicizumab initiation appears to be a safe and effective strategy for AHA management, particularly in fragile or high-risk populations. Its subcutaneous route, favourable safety profile, and ability to reduce hospitalization support its integration into first-line therapeutic algorithms. Further prospective studies are warranted to define.