The role of the hemostatic system in host defense underscores the significant connection among coagulation, platelets, and inflammation. Both the hemostatic and the immune systems share a common ancestral origin. During infections, blood coagulation and platelet activation work in tandem with the immune system to combat bacterial and viral threats. Together, they help limit the spread of these pathogens by forming a fibrin clot network that not only kills pathogens but also promotes tissue repair. However, an excessive response is dangerous, as it can lead to both thrombosis and bleeding. The aim of this narrative review is to present the link between inflammation and the hemostatic system across different pathological conditions, such as infectious diseases (sepsis, plague, COVID-19 infection, Ebola, and Dengue virus infection, and malaria) and autoimmune diseases (antiphospholipid syndrome, systemic sclerosis, and rheumatoid arthritis). Although infectious diseases are characterized by a direct attack on the innate immune system, which in turn activates blood coagulation and platelets, Autoimmune diseases, through antibody production, can induce a coagulative reaction that can generate both thrombosis and fibrosis.

Atrial fibrillation is the most common cardiac arrhythmia in adults, affecting approximately 59.7 million people worldwide as of 2019-a 111% increase since 1990. Over the past 20 years, the prevalence of AF has risen by 33%, and it is projected to increase by more than 60% by 2050. Age plays a critical role in the factors that contribute to AF. Its prevalence is low (0.1%) in adults under 55 years old but rises to 5.9% in individuals aged 65 and older and 9.0% in those aged 80 and older. In this chapter, we provide a brief history of vitamin K antagonists and direct oral anticoagulants, both of which play a paramount role in atrial fibrillation. We also review the main differences between these two classes of anticoagulants. Furthermore, we aim to address the most common issues associated with DOACs use, particularly concerning patients with renal failure, obesity, and elderly or frail individuals. Lastly, we will discuss some remarks on randomized controlled trials and their limitations. The pivotal role of anticoagulation clinics is also highlighted here, underscoring the need for regular follow-up of both VKAs and DOACs.

center dot Context.-Clot waveform analysis (CWA) is a method that provides a detailed view of the clotting process for simple clotting tests such as prothrombin time (PT) or activated partial thromboplastin time (aPTT). Coagulometers with optical clot detection systems capture detailed information during each analysis, which can be used for CWA at no additional reagent expense. Objective.-To investigate (1) whether CWA can detect a hypercoagulable state in different clinical conditions similar to the thrombin generation (TG) assay, and (2) whether there are differences in the texture of in vitro clots by scanning electron microscopy (SEM). Design.-PT INR (international normalized ratio), aPTT ratio, CWA, D-dimer, fibrinogen, von Willebrand factor antigen (vWF:Ag), von Willebrand factor ristocetin cofactor (vWF:RiCo) activity, TG assays, and clot scans by SEM were obtained for 191 patients (65 with COVID-19, 51 with systemic sclerosis, 51 with liver cirrhosis, 13 with high Padua Prediction Score [PPS] without antithrombotic prophylaxis, and 11 with low PPS). A texture analysis for images acquired by SEM was performed with MATLAB software. Data are described as median and range. Results.-Compared to healthy controls, patients with COVID-19, systemic sclerosis, high PPS, and low PPS had higher levels of CWA, fibrinogen, D-dimer, and TG, as well as thicker clots by SEM. The highest values of both vWF:Ag and vWF:RiCo were found in patients with COVID-19. Conclusions.-We have shown that similar to the TG assay, CWA can detect a hypercoagulable state in patients at increased risk of clotting. Furthermore, we identified differences of in vitro clot texture by SEM that may provide further insight into the underlying pathology. Even though CWA is currently considered a research tool, it might one day become a clinically accepted test and provide value-added information to PT or aPTT testing at minimal computational costs. (Arch Pathol Lab Med. 2026;150:146-154; doi: 10.5858/ arpa.2024-0298-OA)

Hormone replacement therapy (HRT) effectively alleviates vasomotor symptoms related to menopause, but it can also raise the risk of cardiovascular disease. Several factors influence the likelihood of developing coronary artery disease or ischemic stroke, including a woman's age, the time since menopause, the type, dose, and route of hormone therapy administration, as well as woman’s personal risk factors and existing or past health conditions. Starting HRT at an older age or more than 10 years after menopause increases the risk of ischemic stroke by 21% (RR=1.21, 95% CI 1.07-1.38), without any benefit in reducing mortality (RR=1.06, 95% CI 0.95-1.18) or cardiovascular events (RR=1.03, 95% CI 0.92-1.15). In contrast, beginning HRT at a younger age and within 10 years of menopause lowers all-cause mortality by 28% (RR=0.72, 95% CI 0.54-0.97), reduces cardiovascular events by 40% (RR=0.60, 95% CI 0.41-0.86), and does not significantly increase the risk of ischemic stroke (RR=1.37, 95% CI 0.91-2.05). Oral estrogen-progestin combinations are linked to a higher risk of ischemic heart disease (HR=1.21, 95% CI 1.00-1.46), and this effect depends on the dose. Therefore, it is advised to use the lowest effective estrogen dose. Progesterone, dydrogesterone, and levonorgestrel should be selected because they do not elevate cardiovascular risk. Transdermal estrogens or estrogen-progestins do not increase the risk of cardiovascular events and are recommended for women at moderate to high risk of stroke and coronary heart disease. A multidisciplinary approach may be beneficial for the safe and effective management of both menopausal symptoms and related conditions. Graphical Abstract

Background: The progressive aging of the global population has been accompanied by a parallel increase in both dementia and atrial fibrillation (AF), two conditions that frequently coexist and are linked through complex cerebrovascular and systemic mechanisms. Beyond overt ischemic stroke, AF has been increasingly associated with subclinical brain injury and cognitive decline. Objective: This review examines the relationship between AF, oral anticoagulation, and cognitive outcomes, with a particular focus on elderly patients and those with cognitive impairment. Methods: Study Design and Literature Search Strategy: This article is a narrative review based on a structured literature search conducted in PubMed/MEDLINE, Scopus, and relevant guideline databases. The search focused on studies addressing atrial fibrillation, oral anticoagulation, cognitive decline, dementia, silent cerebral infarction, cerebral microbleeds, and neurovascular injury. Priority was given to systematic reviews, meta-analyses, randomized controlled trials, observational cohort studies, and current international guidelines. Relevant English-language articles published up to 2025 were considered. We performed a narrative synthesis of the current evidence addressing the biological pathways connecting AF and neurodegeneration, as well as clinical studies evaluating the impact of oral anticoagulant therapy on cognitive trajectories. Results: Oral anticoagulation remains central to stroke prevention in AF, yet its role in modulating cognitive decline remains incompletely defined. Observational data suggest that direct oral anticoagulants (DOACs) may be associated with a lower incidence of dementia, potentially through the reduction of microembolism and silent cerebral ischemia. However, these findings are not conclusive and should be interpreted with caution. Concerns regarding bleeding risk, particularly intracerebral hemorrhage, continue to influence treatment decisions, especially in frail and cognitively impaired populations. Conclusion: Managing anticoagulation in patients with AF and cognitive impairment requires a careful balance between preventing blood clots and minimizing bleeding risk. A comprehensive, patientfocused approach, supported by multidisciplinary collaboration, may improve clinical decisionmaking. More research is needed to understand the long-term cognitive effects of anticoagulant treatments in this vulnerable group.

BACKGROUND:Direct oral anticoagulants (DOACs) are widely used in patients with atrial fibrillation and venous thromboembolism. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently coprescribed in this population due to comorbid musculoskeletal or inflammatory conditions. However, the combined use of DOACs and NSAIDs is associated with an increased risk of bleeding due to additive pharmacodynamic effects and potential pharmacokinetic interactions. AREA OF UNCERTAINTY:Although the bleeding risk of this drug combination is well-recognized, evidence-based strategies to mitigate such risk remain limited. Current clinical guidelines do not offer detailed, stratified recommendations based on specific NSAID classes, individual DOAC agents, or particular high-risk populations such as elderly patients, individuals with cancer, those with chronic kidney disease, or patients with autoimmune disorders requiring prolonged NSAID therapy. In addition, the clinical relevance of pharmacokinetic interactions involving CYP3A4 and P-glycoprotein (P-gp), which may influence both DOAC and NSAID metabolism, remains insufficiently explored in real-world settings. DATA SOURCES:We conducted a structured literature search across PubMed/MEDLINE, Scopus, and Web of Science from January 2005 to December 2024 using the terms "direct oral anticoagulants," "NSAIDs," "bleeding," "drug interactions," and related MeSH headings. We included pharmacological studies, randomized trials, real-world cohort analyses, narrative reviews, and meta-analyses. Articles were screened by title and abstract, with full-text assessment for eligibility. THERAPEUTIC ADVANCES:The concomitant use of NSAIDs and direct oral anticoagulants (DOACs) presents a well-recognized bleeding risk due to their synergistic effects on platelet function and gastrointestinal mucosa integrity. However, the clinical message should not be a blanket prohibition of NSAID use in anticoagulated patients. However, careful and judicious use, at the lowest effective dose and for the shortest necessary duration, should be considered in select clinical situations.

BACKGROUND:The clinical significance of persistently positive antiphospholipid antibodies (aPLs) remains incompletely defined. OBJECTIVES:To describe the clinical and laboratory characteristics of patients with confirmed aPL positivity enrolled in the nationwide START2 Antiphospholipid Registry. METHODS:Adult patients were included if all three laboratory tests-Lupus Anticoagulant (LA), anticardiolipin antibodies (aCL), and anti-β2-glycoprotein I antibodies (aβ2GPI)-were performed and confirmed after ≥12 weeks. Patients were categorized as Antiphospholipis Syndrome (APS) or aPL carriers. Clinical manifestations, non-criteria features, laboratory profiles, associated risk factors, and antithrombotic treatments were analyzed descriptively. RESULTS:Among 500 enrolled patients, 341 were classified as APS and 159 as carriers. Women were overrepresented among carriers (76% vs 62%, p = 0.002). APS patients displayed a higher prevalence of non-criteria manifestations, largely driven by renal involvement in those with SLE. Laboratory profiles were similarly distributed across APS and carriers: triple positivity (43% vs 44%), double positivity (13% vs 12%), and isolated LA positivity (23% vs 30%). Venous thromboembolism (VTE) occurred more frequently in APS patients LA-positive only (67%, p = 0.004), while arterial thrombosis was more evenly distributed across profiles. After a first VTE, most APS patients received warfarin (62%), whereas arterial APS was treated with either warfarin (51%) or aspirin (37%). Among carriers, aspirin was the preferred prophylactic strategy (45%). CONCLUSIONS:Triple, double, and LA positive only represent the most common laboratory patterns. LA positivity omly shows a disproportionately high rate of VTE. Non-criteria manifestations remain more common in APS. Substantial variability persists in antithrombotic management, underscoring the need for prospective treatment trials.

Abstract:Sex-related differences in outcomes after major orthopaedic surgery remain under-investigated, and the prognostic relevance of a history of venous thromboembolism (VTE) is unclear. The ORTHO-START registry is a prospective, multicenter study including 1,077 consecutive adults undergoing major orthopaedic surgery (elective hip/knee arthroplasty or urgent hip fracture repair) across six Italian centers between July 2018 and March 2022. Baseline characteristics, perioperative complications, and antithrombotic therapy were collected. The primary outcome was all-cause mortality at 24 months; secondary outcomes were thromboembolic and bleeding events. Multivariable logistic regression identified predictors of mortality. Women represented 72.3% (n = 775) of the cohort and were older than men (80.6 ± 10.0 vs. 76.2 ± 13.0 years, p < 0.001). Urgent procedures comprised 65.6% (n = 706) of surgeries, predominantly involving women (n = 542). At 24 months, mortality was higher in men (31 vs. 18%, p = 0.018). Independent predictors of mortality included male sex (odds ratio [OR] = 2.6, 95% confidence interval [CI]: 1.8-4.0), older age, lower body mass index, urgent surgery (OR = 7.2, 95% CI: 4.1-12.4), and prior VTE (OR = 5.7, 95% CI: 1.4-23.9). Causes of death were known for 160/210 (76.2%): neurological complications were most frequent (25%), followed by cardiovascular disease (21.3%) and immobility-related causes (14.4%); pulmonary embolism accounted for 1.3% of deaths. Thrombotic and hemorrhagic events occurred in both sexes without significant differences. Male sex and a history of VTE are independent predictors of long-term mortality following major orthopaedic surgery. Incorporating these factors into preoperative risk assessment may improve management and postoperative outcomes.

Patients with thrombotic antiphospholipid syndrome (APS) or subjects with persistent presence of antiphospholipid antibodies (aPLA), defined “carriers”, may develop thrombocytopenia. However, the prevalence and clinical characteristics associated with thrombocytopenia remain poorly understood. We aimed to describe the prevalence and the clinical characteristics associated with thrombocytopenia in APS patients and aPLA carriers included in the Survey on AnTicoAgulated Patients-RegisTry on antiphospholipid antibodies (START-APS), a multicentre prospective registry. Thrombocytopenia was defined as a platelet count < 150 × 109/L, while moderate-to-severe form was defined as < 100 × 109/L. Logistic regression analysis was performed, and results were expressed as Odds Ratio (OR) and 95

Lupus anticoagulant-hypoprothrombinemia syndrome (LAHS) is a rare hemorrhagic disorder that should be differentiated from classical antiphospholipid syndrome. Literature review shows that LAHS may affect people at any age but approximately 40% are children younger than 10 years. Autoimmune and infectious diseases are the most frequent triggering causes, and the laboratory profile is characterized by a prolongation of prothrombin time (PT) and activated partial thromboplastin time (aPTT) with a mild to severe reduction in factor II levels. In more than half the patients, the other coagulation factors are normal, while anti-cardiolipin and anti-β2-glycoprotein I antibodies show a high titer. Lupus anticoagulant (LA) is positive in 100% of cases, as this represents a defining feature. The majority of patients have mucocutaneous bleeding events (44%); cerebral bleeding can occur in 10% of patients and other common bleeding sites are the gastrointestinal and genitourinary tracts. There is no standard treatment for LAHS. Supportive measures, such as fresh frozen plasma, packed red blood, and platelet transfusion, are frequently administered in association with steroids alone or in combination with intravenous immunoglobulin or cyclophosphamide, azathioprine, and rituximab. Death, recurrent bleeding, and thrombosis can occur in approximately 3, 13, and 14% of patients, respectively. Our patient was an old man with a myocardial infarction and a systemic infection from Candida parapsilosis. Thrombin generation and clot waveform analysis were performed before and after treatment. Thrombin generation better reflected the role of prothrombin, revealing that a factor II value of below around 15% can represent a risk for major bleeding. Treatment with methylprednisolone and three-factor human prothrombin complex concentrate allowed the patient to reach a complete recovery 1 month after initial diagnosis.

Context.—:Clot waveform analysis (CWA) is a method that provides a detailed view of the clotting process for simple clotting tests such as prothrombin time (PT) or activated partial thromboplastin time (aPTT). Coagulometers with optical clot detection systems capture detailed information during each analysis, which can be used for CWA at no additional reagent expense. Objective.—:To investigate (1) whether CWA can detect a hypercoagulable state in different clinical conditions similar to the thrombin generation (TG) assay, and (2) whether there are differences in the texture of in vitro clots by scanning electron microscopy (SEM). Design.—:PT INR (international normalized ratio), aPTT ratio, CWA, D-dimer, fibrinogen, von Willebrand factor antigen (vWF:Ag), von Willebrand factor ristocetin cofactor (vWF:RiCo) activity, TG assays, and clot scans by SEM were obtained for 191 patients (65 with COVID-19, 51 with systemic sclerosis, 51 with liver cirrhosis, 13 with high Padua Prediction Score [PPS] without antithrombotic prophylaxis, and 11 with low PPS). A texture analysis for images acquired by SEM was performed with MATLAB software. Data are described as median and range. Results.—:Compared to healthy controls, patients with COVID-19, systemic sclerosis, high PPS, and low PPS had higher levels of CWA, fibrinogen, D-dimer, and TG, as well as thicker clots by SEM. The highest values of both vWF:Ag and vWF:RiCo were found in patients with COVID-19. Conclusions.—:We have shown that similar to the TG assay, CWA can detect a hypercoagulable state in patients at increased risk of clotting. Furthermore, we identified differences of in vitro clot texture by SEM that may provide further insight into the underlying pathology. Even though CWA is currently considered a research tool, it might one day become a clinically accepted test and provide value-added information to PT or aPTT testing at minimal computational costs.

Abstract:Evidence-based medicine (EBM) has created a revolutionary system for disseminating a scientific method. However, the scientific rigor of early EBM did not demonstrate any concern for ethics in the management of venous thromboembolism (VTE) and atrial fibrillation (AF). We critically reviewed whether EBM and ethical principles have always converged, focusing on the development and use of anticoagulants, by analyzing key trials in the treatment and prevention of those conditions. Moreover, we aimed to explore whether methodological rigor has sometimes overshadowed clinical ethics, particularly in the context of placebo-controlled trials. In our opinion, even if randomized clinical trials (RCTs) are considered the first step in the hierarchy of EBM, several of these appear unjustified, as observational studies had already indicated that anticoagulants (heparins and anti-vitamin K drugs [VKA]) were considered effective in the treatment and prevention of thrombotic diseases, such as VTE and AF. The use of a placebo was often unethical. This has caused unjustified mortality and morbidity to many people when a placebo has been used as a control. Even the methodology in favor of the non-inferiority margin is questionable, as it is considered satisfactory to maintain at least half of the efficacy of the current drug. In other words, a bonus for the new medicines seems to be always generous, and in the future, biocreep phenomenon is destined to be dangerous. The belief that only RCTs, even if of paramount importance, produce trustworthy results and that observational studies are misleading can lead to a disadvantage in patient care, clinical investigation, and the education of health care professionals (visual abstract).

Spontaneous intramuscular hematomas (SMHs) are rare but potentially serious complications of oral anticoagulation therapy. Although often attributed solely to anticoagulant use, such lesions may mask underlying soft tissue sarcomas or paraneoplastic conditions. We report the case of an 80-year-old man on warfarin who presented with a painful thigh mass initially interpreted as a hematoma but ultimately diagnosed as a malignant fibrous histiocytoma (MFH). In addition, we provide a narrative review of published cases, focusing on clinical presentation, diagnostic challenges, imaging strategies, and outcomes. Key pitfalls leading to delayed diagnosis include attribution bias, inadequate imaging, and premature management decisions. Epidemiological data show that while the incidence of SMHs is estimated at 0.5–1.5% among patients on vitamin K antagonists, clinically significant cases are increasingly reported with direct oral anticoagulants (DOACs). Suggested measures include clinical algorithms to prompt imaging and biopsy in persistent masses, validation of magnetic resonance imaging (MRI) criteria, and the establishment of prospective registries, aimed at facilitating earlier recognition of malignant lesions and improving patient outcomes. These strategies may improve early detection of malignancy and optimize care in anticoagulated patients presenting with soft tissue lesions.

Factor XI (FXI) deficiency, or hemophilia C, is a rare bleeding disorder resulting from reduced levels or dysfunctional FXI protein due to mutations in the F11 gene. This study investigated the correlation between FXI activity levels, F11 genotype, and bleeding phenotypes. Clinical and genetic characteristics of 93 individuals from southern Italy diagnosed with congenital FXI deficiency, including 39 index cases and their relatives, were evaluated. FXI:C plasma levels were measured. Sanger sequencing of F11 was performed, and the pathogenicity of variants identified was assessed using in silico tools. FXI activity levels ranged widely (1-69%), with most cases being heterozygous and showing moderate deficiency. Only 12 individuals had severe FXI deficiency, typically associated with homozygosity or compound heterozygosity. Bleeding symptoms varied from mild to severe and occurred in 31% of subjects, though only a minority of those with severe deficiency experienced spontaneous or surgery-related bleeding. Sanger sequencing revealed 24 distinct F11 gene variants, predominantly missense mutations, with three novel variants (p.Val89*, p.Leu306Pro, and p.Trp515Gly). Common mutations included p.Glu135* and p.Glu315Lys. Variants were distributed across the gene, with no domain-specific clustering. No clear genotype-phenotype correlation was observed. FXI levels alone did not reliably predict bleeding risk, highlighting the influence of additional factors such as age, gender, and clinical history. This study reinforces the allelic and clinical heterogeneity of FXI deficiency and the limited utility of FXI:C levels alone for predicting bleeding severity. Further research is needed to clarify the complex genotype-phenotype relationships in FXI deficiency.

Abstract:Puerperal sepsis (PPS) is a severe postpartum infection that remains a significant maternal health concern. Recent evidence suggests a potential link between PPS and ovarian vein thrombosis (OVT), a rare but life-threatening complication occurring in 0.01 to 0.18% of pregnancies. Despite the historical significance of PPS and its well-documented consequences, its association with thrombosis remains underrecognized in obstetric practice. This narrative review explores the historical context, clinical presentation, diagnosis, and management of PPS and OVT while emphasizing the need for increased awareness and preventive strategies. Sepsis triggers a hypercoagulable state through inflammatory cytokine release, endothelial injury, and coagulation activation, contributing to thrombotic complications such as OVT. The right ovarian vein is more commonly affected due to anatomical factors, including uterine dextrorotation during pregnancy. OVT typically presents with abdominal pain and fever, requiring imaging modalities such as Doppler ultrasound and magnetic resonance imaging for diagnosis. Although anticoagulation therapy is widely used for deep vein thrombosis, its application in OVT remains inconsistent, despite comparable recurrence rates between the two conditions. The review also highlights the lack of consensus on thromboprophylaxis in septic postpartum patients. Although guidelines from major obstetric organizations are inconsistent, emerging evidence suggests that low-molecular-weight heparins may reduce thrombotic risk in PPS. In the absence of large-scale randomized trials, observational studies remain essential for guiding clinical decisions.