Anticoagulant therapies, including heparins, vitamin K antagonists, and direct oral anticoagulants (DOACs) such as rivaroxaban, apixaban and dabigatran, are crucial for the treatment and the prevention of venous thromboembolism (VTE). While DOACs offer improved safety profiles, their use, espe-cially in women of reproductive age, increases the risk of abnormal uterine bleeding (AUB), partic-ularly heavy menstrual bleeding (HMB). HMB, defined as blood loss exceeding 80 mL per cycle or causing significant life disruption, is associated with reduced quality of life and substantial economic costs. Women on anticoagulants report higher incidences of HMB, often requiring adjustments in therapy or additional interventions. Management strategies include the referral for a gynecological consultation, the adjustment of hormonal therapy and anticoagulant treatment, the administration of tranexamic acid, and the treatment of iron deficiency. The review underscores the importance of a comprehensive, personalized approach to managing AUB in women on anticoagulants to optimize both anticoagulation effectiveness and patient quality of life.
Background: A recent U.S. study of initial anticoagulation in adults with acute pulmonary embolism (PE) requiring hospitalization found intravenous unfractionated heparin (UFH) use exceeded 50%. Guidelines, however, recommend low molecular weight heparin (LMWH) over UFH for most patients requiring parenteral anticoagulation. Use patterns in other geographic regions are unclear. Methods: We analyzed data from RIETE, a prospective multinational registry of consecutive patients with venous thromboembolism. We included adults hospitalized for acute PE from 2013 through 2024 in 273 hospitals across 31 countries. We assessed temporal trend and regional variation in initial anticoagulation. Using multivariable regression, we identified variables independently associated with UFH. Results: Among 36,210 adults, 83.2% received subcutaneous LMWH, 7.1% UFH, and 6.8% direct oral anticoagulants. LMWH use decreased slightly from 2013 to 2024 (85.8% to 79.2%; unadjusted), while UFH increased (8.9% to 10.4%). Wide geographic variation was observed in overall use of LMWH (37%--95%) and UFH (2%--39%). When adjusted for demographic and clinical covariates, increased weight, recent surgery, recent major bleeding, severe anemia, thrombocytopenia, severe renal dysfunction, abnormal vital signs, and early reperfusion therapy were positively associated, whereas age >80 years, active cancer, chronic lung disease, prior ischemic stroke, and year were negatively associated with UFH. Compared with Spanish hospitals, hospitals in other European countries, the United States, and Asia were independently associated with UFH use. Conclusions: Results highlight opportunities for some geographic regions to align anticoagulation practices more closely with evidence-based guidelines recommending LMWH as the preferred parenteral agent in most patients with PE requiring hospitalization.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) was characterized as a hepatic regulator of low-density lipoprotein receptor (LDLR) degradation. Monoclonal antibodies directed at PCSK9 lower low-density lipoprotein cholesterol (LDL-C) and reduce major adverse cardiovascular events; small interfering RNA directed at PCSK9 lowers LDL-C, and cardiovascular outcome testing is ongoing. A parallel body of work has since linked PCSK9 to thrombo-inflammatory processes. Experimental studies indicate that extracellular PCSK9 activates platelets through CD36, induces monocyte tissue factor expression via Toll-like receptor 4 and nuclear factor-κB, promotes release of procoagulant extracellular vesicles, and impairs endothelial homeostasis; PCSK9 may also raise factor VIII by accelerating turnover of LDLR family members. Clinical biomarker studies report lower platelet-activation markers, and fibrinogen and plasminogen activator inhibitor-1 during treatment. However, randomized placebo-controlled studies using direct platelet-function assays, as well as their pooled analysis, have not demonstrated a consistent reduction in platelet reactivity with PCSK9 monoclonal antibodies. This review synthesizes and evaluates the evidence by cellular compartment, separating circulating, locally released and intracellular PCSK9, and by evidentiary level, separating preclinical mechanism, observational association, circulating biomarker, randomized pharmacodynamic endpoint, clinical outcome, and human genetics. It also examines why experimental findings may not translate into measurable platelet inhibition in treated patients, and how concomitant antithrombotic and statin therapy conditions any such measurement. Preclinical plausibility is substantial. A clinically measurable, LDL-independent antiplatelet effect of PCSK9 inhibition has not been established, and the randomized evidence is more precise against a large platelet effect than against a modest one.
Abstract Factor XI (FXI) is a coagulation protease that contributes to thrombin amplification. FXI circulates as a disulfide-linked homodimer whose structure and function depend on a complex cysteine network comprising 17 intrachain disulfide bonds, free Cys29, and the interchain Cys339–Cys339 disulfide bond. This study aimed to characterize the structural and functional consequences of the previously undescribed FXI p.Phe295Cys variant identified in a hemizygous patient with a de novo 7-Mb deletion involving F11 and KLKB1. Clinical, biochemical, genetic, and functional studies were performed in the proband and relatives. Thrombin generation was triggered with tissue factor and silica. Recombinant wild-type (WT) and mutant FXI were expressed in HEK293 cells and evaluated by immunoblotting, functional assays, and mutagenesis, including liquid chromatography–electrospray ionization–tandem mass spectrometry (LC/ESI-MS/MS) under non-reducing thiol-alkylating conditions. The proband showed a mild prekallikrein deficiency and severe FXI deficiency with residual procoagulant FXI (FXI:C) activity (7%) and two disulfide-linked FXI species with different electrophoretic mobilities in plasma, which collapsed into a single entity under reducing conditions. Recombinant expression reproduced this heterogeneity in dimeric and apparent monomeric species. Mutagenesis did not support Cys295-mediated interchain disulfide formation or involvement of Cys29 in the aberrant dimer. Proteomic analysis discarded interaction with other proteins and identified Carbamidomethylation (CAM)-modified Cys317, Cys321, and Cys193 exclusively in mutant FXI, indicating altered thiol availability. Contact pathway-dependent FIX activation in the proband was associated with impaired thrombin generation, whereas tissue factor-triggered thrombin generation was preserved. The proband had no spontaneous bleeding and underwent two procedures uneventfully with prophylaxis. The p.Phe295Cys variant is associated with disulfide-dependent structural heterogeneity and impaired FXI function. The findings support perturbation of the native FXI disulfide network but do not establish the precise alternative disulfide connectivity.
Background Children with hemophilia A and F8 null mutations represent a refractory phenotype in immune tolerance induction (ITI). However, clinical heterogeneity remains poorly understood; thus, identifying driving factors is crucial for developing effective solutions. Objective To investigate the genetic factors underlying ITI outcome heterogeneity in pediatric F8 null mutations. Methods We retrospectively analyzed 109 patients with null mutations across three levels: (i) mutation type (nonsense, large deletions, frameshifts); (ii) mutation location (heavy- vs. light-chain); and (iii) specific domain and amino acid (aa) boundaries. Results The overall ITI success was 64.2%. Mutation location remained associated with ITI success after multivariable adjustment (odds ratio = 4.815, P = 0.013). Heavy-chain mutations demonstrated a significant advantage, with an estimated time to 50% success of 9.0 versus 27.4 months for light-chain mutations (P = 0.013). This location-dependent pattern was prominent in nonsense and large deletion but absent in frameshift mutations. Further refinement identified the A1-domain as the most favorable zone (highest success rate in nonsense subgroup: 100% [7/7]). In an exploratory analysis of nonsense mutations, mutations proximal to aa 446 showed higher observed success than those distal to it. Conversely, A3-C1 domains represented high-risk regions for failure. Conclusions Mutation location was associated with ITI outcome heterogeneity among patients with non-inversion F8 null variants. Heavy-chain mutations were associated with 4.8-fold higher odds of ITI success than light-chain mutations, mainly in nonsense mutations and large deletions. The A1-domain findings and exploratory aa 446 boundary may refine genetic risk stratification, but require external validation.
