Search Results (143)

Background and Clinical Significance: Left ventricular hypoplasia is often repaired surgically in sequence to a Fontan circulation, which is a physiologic state that presents unique challenges during pregnancy. Although women with Fontan physiology can achieve successful pregnancy outcomes, they remain at elevated risk for cardiac, thrombotic, and obstetric complications. Case Presentation: We describe a 38-year-old woman with Fontan physiology and acquired von Willebrand syndrome (AVWS) who was admitted at 23 weeks gestation for preterm premature rupture of membranes. The patient had history of prior classical cesarean delivery and two previous miscarriages. Her pregnancy was further complicated by abnormal placental vasculature and uterine arteriovenous malformation. Given her bleeding diathesis, hematology advised against anticoagulation or antiplatelet therapy, and she ultimately underwent a successful low transverse cesarean delivery under general anesthesia at 24 weeks. Postpartum hemorrhage was managed with clotting factor replacement and supportive care. Conclusions: This case illustrates how AVWS may mitigate thrombotic risk in Fontan physiology and how early activation of a cardio-obstetrics team can enable tailored planning. As more patients with complex congenital heart disease reach reproductive age, multidisciplinary coordination, shared infrastructure, and individualized birth plans will be essential to achieving optimal maternal–fetal outcomes. Full article

As a synthetic analogue of vasopressin, desmopressin or DDAVP has well established hemostatic properties. We present a review of DDAVP and summarize the clinical and laboratory evidence for its use in hemophilia A, von Willebrand disease (VWD), platelet function disorders, uremia, liver cirrhosis, and pregnancy, followed by illustrative examples of its broad efficacy from our local practice. In brief, DDAVP acts to release von Willebrand factor (VWF) and factor VIII from endogenously stored reserves, thereby correcting plasma deficiencies present in mild to moderately affected patients with hemophilia A and VWD. Thus, DDAVP represents a non-transfusional therapy for these disorders. Typically, a trial of DDAVP is arranged to assess individual responsiveness before employing DDAVP clinically, since there is individual variation in responsiveness. Thereafter, DDAVP can be utilized in responsive patients for clinical use and provides a factor replacement sparing strategy in these patients for some clinical situations. Nevertheless, DDAVP is best applied as a factor replacement sparing strategy, especially for minor procedures or short-term use. Full article

Haemostasis is a critical physiological process that ensures blood loss is minimised following vascular injury. Understanding the mechanisms of normal haemostasis is essential for managing patients with inherited bleeding disorders, particularly in the surgical setting. Inherited bleeding disorders, such as haemophilia and von Willebrand disease (vWD), pose unique challenges for anaesthesiologists and surgeons due to the increased risk of excessive bleeding during and after surgery. This state-of-the-art review outlines the essential knowledge for anaesthesiologists regarding normal haemostasis, the pathophysiology of inherited bleeding disorders, and the perioperative management strategies required for these patients. It draws on existing literature and current clinical guidelines to offer practical approaches for assessing and managing bleeding risks in surgical settings. Full article

Severe COVID-19 is often associated with coagulopathy and thrombotic complications. The underlying mechanisms are complex and multifactorial, involving platelet activation, dysregulation of the complement cascade, fibrinolytic imbalance, release of pro-inflammatory cytokines, immunothrombosis, antiphospholipid antibodies, and alterations in the von Willebrand factor (vWF)/ADAMTS13 axis. These pathways are also implicated in thrombotic microangiopathies (TMAs), characterized by endothelial injury and widespread microvascular thrombosis. In this prospective monocentric observational study, we investigated whether COVID-19-associated coagulopathy meets the criteria for TMA and evaluated the roles of complement activation and vWF/ADAMTS13 imbalance in disease severity. Forty-three hospitalized COVID-19 patients were enrolled and stratified by disease severity. Blood samples collected at admission were analyzed for hematologic, coagulation, inflammatory, and complement parameters. A 30-day follow-up recorded survival and thrombotic events. All patients showed elevated vWF and factor VIII levels; however, only vWF collagen-binding activity (vWF-CBA) significantly correlated with disease severity. ADAMTS13 activity remained above 60% in all cases, and no schistocytes were detected, arguing against a diagnosis of classical TMA. Nevertheless, the vWF-CBA/ADAMTS13 ratio was significantly higher in severe cases, particularly in unvaccinated individuals, suggesting endothelial dysregulation. Complement analysis revealed increased C5a levels and decreased C3b/iC3b ratios in severe disease, consistent with complement activation and consumption. C2 levels were also lower in these patients. Although complement activation and vWF/ADAMTS13 imbalance did not directly correlate, both pathways showed a similar trend according to disease severity. Overall, our findings indicate that COVID-19-related coagulopathy does not fulfill the criteria for classical TMA but shows features of complement-mediated endothelial injury and vWF dysregulation. The vWF-CBA may serve as a rapid, standardized tool for assessing endothelial dysfunction. Activation of the complement system, particularly via the lectin and alternative pathways, appears central to the prothrombotic state in severe COVID-19. Full article

The severe outbreak of SARS-CoV-2, the etiological agent of COVID-19, has precipitated the development of vaccines and antiviral therapeutics. However, it remains a significant public health concern. This study investigated the association between disease severity, biomarkers of coagulation, and endothelial damage, including P-selectin, thrombomodulin, PAI, von Willebrand antigen (VWF: Ag) and von Willebrand factor ristocetin cofactor (VWF: RCo). A cross-sectional, observational study was conducted in a cohort of 90 adult COVID-19 patients (≥18 years), categorized into three groups: ICU-hospitalized, non-ICU hospitalized, and asymptomatic non-hospitalized (outpatient). In these groups, biomarkers, including PAI-1, TM, and P-selectin, were assessed using enzyme-linked immunosorbent assay (ELISA), and immunological assays for VWF: Ag and VWF: RCo. Across all groups, we observed significantly elevated levels of P-selectin, VWF: Ag, and VWF: RCo. Elevated levels of PAI-1 and TM were observed in ICU patients compared to non-ICU and asymptomatic patients, indicating increased endothelial injury and activation. Furthermore, COVID-19 mutations significantly affect the P-selectin biomarker. This finding supports the hypothesis that P-selectin is a more reliable biomarker for assessing the severity of the disease than other endothelial damage and coagulation markers, especially in heterogeneous clinical presentations. Our study also highlights the requirement of comprehensive examination for its broader implications in viral strains, infection severity, and genetic variants. Full article

Thrombotic thrombocytopenia purpura is a serious disease that can involve complex symptomatology, prolonged hospitalization, and a high risk of mortality if treatment is delayed. This disease is rare, but it is even rarer among pediatric patients. Even though it was first described 100 years ago, the earliest documented case was a pediatric patient. The last three decades have seen the discovery of the pathological mechanisms responsible for its clinical presentation. Symptoms/signs characteristic of microangiopathic hemolytic anemia with significant thrombocytopenia characterize the vast majority of patients. Its pathology centers on the accumulation of ultra-large von Willebrand factor multimers due to an enzyme deficiency that prevents their breakdown. Currently, in pediatric patients, two forms of the disease are known: congenital due to a mutation in the enzyme’s gene and immune-mediated due to enzyme depletion or neutralization secondary to autoantibody formation. With the advent of therapeutic plasma exchanges, immunosuppression, and, more recently, a TTP-specific nanobody, there is reason for optimism that the disease does not necessarily equate to a bad outcome. Thus, the aim of this review is to contrast the congenital and immune-mediated forms of the disease in pediatric patients while presenting them in the context of their pathologic mechanisms, diagnosis, and treatment. Full article

Background and Objectives: Elevated von Willebrand factor (vWF) levels have been reported in malaria, but their relationship with disease severity remains unclear. This study aimed to compare vWF levels between Plasmodium-infected and uninfected individuals and assess changes in severe infections. Materials and Methods: The systematic review was registered in PROSPERO (CRD42024558479). A comprehensive search across six databases identified studies reporting vWF levels in malaria. A meta-analysis was conducted using a random-effects model, with standardized mean difference (SMD) as the effect measure due to varying measurement units. Heterogeneity was assessed using the I² statistic. Results: Of 1647 identified records, 26 studies met the inclusion criteria. The meta-analysis showed significantly higher vWF levels in Plasmodium-infected individuals compared to uninfected controls (p < 0.001, SMD: 2.689 [95% CI 1.362; 4.017], I²: 98.1%, 12 studies, 3109 participants). However, no significant difference was found between severe and less severe cases (p = 0.051, SMD: 3.551 [95% CI −0.007; 7.109], I²: 99.3%, 8 studies, 1453 participants). Conclusions: vWF levels are significantly elevated in individuals with Plasmodium infections, indicating a potential role in malaria pathophysiology. Although levels tend to be higher in severe cases, current evidence is insufficient to support vWF as a reliable marker for disease severity. Further prospective and well-controlled studies are needed to validate its diagnostic and prognostic value in malaria management. Full article

Cardiovascular complications are a major concern in thalassemia patients, primarily driven by endothelial dysfunction. This systematic review and meta-analysis evaluated endothelial biomarkers as indicators of cardiovascular disease risk in thalassemia. A systematic search of PubMed, Scopus, and Embase identified 41 studies comparing biomarkers in thalassemia patients and healthy individuals. The biomarkers analyzed included ICAM-1, VCAM-1, E-selectin, P-selectin, von Willebrand factor (vWF), endothelial microparticles (EMPs), nitric oxide (NO), nitric oxide synthase (NOS), asymmetric dimethylarginine (ADMA), and endothelin-1 (ET-1). Using random effects modeling, pooled standardized mean differences (SMDs) and 95% confidence intervals (CIs) were calculated. The results showed significantly elevated levels of ICAM-1 (SMD 2.15, 95% CI: 1.09–3.22), VCAM-1 (SMD 2.50, 95% CI: 1.35–3.66), E-selectin (SMD 1.21, 95% CI: 0.92–1.50), P-selectin (SMD 1.62, 95% CI: 0.83–2.42), and ET-1 (SMD 1.23, 95% CI: 0.03–2.42) in thalassemia patients. However, NO, ADMA, and vWF showed no significant differences. No studies on NOS were identified, while only one study found significantly elevated EMPs in thalassemia patients. This review highlights ICAM-1, VCAM-1, E-selectin, P-selectin, and ET-1 as key biomarkers for cardiovascular complications in thalassemia. Further research on EMPs and NOS is essential to enhance the understanding of endothelial dysfunction in this population. Full article

Background: This case report investigates the effects of sotorasib treatment in a patient with acquired von Willebrand syndrome (AVWS) associated with monoclonal gammopathy of undetermined significance (MGUS), who subsequently developed non-small-cell lung carcinoma (NSCLC) with a KRAS G12C mutation. Case Presentation: The patient, a 79-year-old male, presented with a prolonged history of recurrent lower gastrointestinal bleeding attributed to digestive angiodysplasia, which had persisted for over 30 years. AVWS was suspected based on a qualitative deficiency in von Willebrand factor (VWF), with abnormal results for factor VIII activity (FVIII:C), VWF antigen (VWF:Ag), and VWF ristocetin cofactor activity (VWF:Rco) (40%, 20%, and <2.4%, respectively). Further evaluation revealed the presence of an IgM kappa monoclonal spike, suggesting MGUS. In 2022, the patient was diagnosed with NSCLC harboring the KRAS G12C mutation and initiated second-line treatment with sotorasib. Notably, one year after the initiation of sotorasib therapy, the patient’s hemostasis had normalized, accompanied by significant improvements in VWF levels. VWF multimer electrophoresis demonstrated the restoration of high-molecular-weight multimers (HMWMs), and serum protein electrophoresis no longer detected MGUS. Conclusion: These improvements were likely attributable to the indirect effects of sotorasib on the bone marrow microenvironment. By inhibiting KRAS in stromal cells and osteoclasts, sotorasib may have disrupted the supportive niche necessary for malignant plasma cell survival, resulting in a reduction in the monoclonal spike. Unfortunately, the patient eventually succumbed to carcinogenic pleurisy. Full article

Autoantibodies to ADAMTS13 are at the center of pathology of the immune-mediated thrombotic thrombocytopenic purpura. These autoantibodies can be either inhibitory (enzymatic function) or non-inhibitory, resulting in protein depletion. Under normal physiologic conditions, antibodies are generated in response to foreign antigens, which can include infectious agents; however, these antibodies may at times cross-react with self-epitopes. This is one of the possible mechanisms mediating formation of anti-ADAMTS13 autoantibodies. The process known as “antigenic mimicry” may be responsible for the development of these autoantibodies that recognize and bind cryptic epitopes in ADAMTS13, disrupting its enzymatic function over ultra large von Willebrand factor multimers, forming the seeds for platelet activation and microthrombi formation. In particular, specific amino acid sequences in ADAMTS13 may lead to conformational structures recognized by autoantibodies. Generation of these antibodies may occur more frequently among patients with a genetic predisposition. Conformational changes in ADAMTS13 between open and closed states can also constitute the critical change driving either interactions with autoantibodies or their generation. Nowadays, there is a growing understanding of the role that autoantibodies play in ADAMTS13 pathology. This knowledge, especially of functional qualitative differences among antibodies and the ADAMTS13 sequence specificity of such antibodies, may make possible the development of targeted therapeutic agents to treat the disease. This review aims to present what is known of autoantibodies against ADAMTS13 and how their structure and function result in disease. Full article

(1) Background: Toll-like receptor 2 (TLR2) on platelets is increasingly recognized as a pivotal mediator in infection-induced platelet activation and aggregation, contributing to both inflammatory and thrombotic diseases. Targeting TLR2 on platelets offers a promising therapeutic strategy for inflammatory and thrombotic-related disorders. However, inhibitors targeting platelet TLR2 have not yet been reported. (2) Methods: Platelet aggregation was assessed using a light transmission aggregometer. Platelet activation was evaluated by measuring the release of P-selectin and von Willebrand factor (vWF) via ELISA. Intracellular Ca²⁺ mobilization was quantified using Fluo 3-AM fluorescence, recorded by flow cytometry. Static platelet adhesion was visualized under a microscope, and the formation of platelet–granulocyte aggregates in human whole blood was analyzed by flow cytometry. (3) Results: Fucosylated glycosaminoglycan (FG) tetradecasaccharide HS14 inhibited the activation and aggregation of human platelets induced by the synthetic bacterial lipopeptide Pam3CSK4 in a concentration-dependent manner. This inhibitory effect gives rise to significant anti-inflammatory and anti-thrombotic activities, as evidenced by reduced platelet adhesion and decreased platelet–granulocyte aggregates formation in human whole blood. (4) Conclusions: This study is the first to identify FG oligosaccharide HS14 as a promising inhibitor of platelet TLR2/TLR1, demonstrating significant therapeutic potential for inflammatory and thrombotic-related diseases. Full article

Circadian misalignment, due to shiftwork and/or individual chronotype and/or social jetlag (SJL), quantified as the difference between internal and social timing, may contribute to cardiovascular disease. Markers of endothelial dysfunction and activation of the coagulation system may predict cardiovascular pathology. The present study aim was to investigate the effects of shift work, SJL, and chronotype on endothelial function and coagulation parameters. One hundred female nurses underwent endothelial function testing using the EndoPAT and blood sampling for coagulation markers, repeated at 06:00–9:00 and 18:00–21:00. We found that compared with day workers, endothelial function and fibrinogen levels were lower (p = 0.001, p = 0.005, respectively) and the procoagulant parameters of plasminogen activator inhibitor-1 (PAI-1) and heparanase level and activity were higher amongst shift workers (p = 0.009, p = 0.03, p = 0.029, respectively). High SJL was associated with lower endothelial function (p = 0.002) and higher PAI-1, heparanase procoagulant activity, heparanase level, and D-Dimer level (p = 0.004, p = 0.003, p = 0.021, p = 0.006, respectively). In the late chronotype, PAI-1 and heparanase procoagulant activity were higher than in the early chronotype (p = 0.009, p = 0.007, respectively). Diurnal variation was found for PAI-1, von-Willebrand factor (vWF), heparanase, and heparan-sulfate with higher levels in the mornings. The correlation between shift/day workers and SJL or chronotype was moderately strong, indicating that SJL and chronotype are independent factors. In conclusion, findings suggest endothelial impairment and increased thrombotic risk in nurses working in shifts or with high SJL or late chronotype. The thrombotic risk is increased in the morning independent of circadian misalignment cause. These findings strengthen the importance of the alliance to the biological daily rhythm in daily life. Further research is needed to evaluate inhibitors of heparanase to attenuate the thrombotic risk in individuals with circadian misalignment. Full article

Background: Gastrointestinal angiodysplasia is a significant vascular anomaly characterized by dilated, tortuous blood vessels in the gastrointestinal tract. The current literature extensively documents the association between angiodysplasia and aortic stenosis, known as Heyde syndrome, characterized by the triad of aortic stenosis, GIB, and acquired von Willebrand syndrome. However, other valvular diseases, including mitral and tricuspid regurgitation, have also been implicated. This comprehensive systematic review aims to investigate the spectrum of valvular abnormalities, exploring the intricate mechanisms by which they contribute to gastrointestinal bleeding. Furthermore, it will evaluate the available surgical and nonsurgical treatment modalities, assessing their efficacy in mitigating the incidence of such bleeding. Methods: A comprehensive search of the Pubmed/MEDLINE database was conducted to identify relevant studies to retrieve relevant articles from August 2014 to August 2024. A combination of Medical Subject Heading (MeSH) terms and text words related to cardiac valvular diseases and GIB were used. MeSH terms included “gastrointestinal bleeding”, “heart valve diseases”, “hematochezia”, “heart valve prosthesis”, “bioprosthesis”, “native valve diseases”, and “mechanical valve”. Results: Forty-five papers met the inclusion criteria. Twenty-seven studies covered GIB in aortic valve disease, ten on mitral valve disease, two on tricuspid valve disease, and six on multiple valves. Conclusions: This systematic review demonstrates the association between angiodysplasia and aortic stenosis and highlights mitral regurgitation and tricuspid regurgitation as potential etiologies. Definitive management with valvuloplasty or valve replacement is vital to preventing the onset or recurrence of GIB in patients with valvular disease. Full article

Background: Dental implants are commonly employed to address edentulism, while orthodontic treatments often incorporate mini-screws to enhance tooth movement and provide stable anchorage. Both procedures are integral to modern dental practice and frequently interact in comprehensive care scenarios. While oral health professionals routinely assess patients’ medical histories before procedures, undiagnosed coagulopathies, such as Von Willebrand Disease (VWD), can present significant challenges when invasive procedures are carried out, such as the insertion of implants or mini-implants. Case description: This case report discusses the surgical placement of dental implants and orthodontic mini-screws in a patient with previously undiagnosed VWD, underscoring the potential complications and the importance of recognizing bleeding disorders in clinical practice, and provides some advice on the management of patients with previously undiagnosed VWD after/during surgical procedures. Conclusions: To prevent the risk of excessive bleeding, before surgery, all patients should be screened through precise questions on bleeding history. Full article

COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is associated with hypercoagulability and increased incidence of thrombotic events. In this study, we investigated the levels of neutrophil extracellular trap biomarkers and von Willebrand factor to assess if these could predict the occurrence of a thrombotic event in COVID-19 patients. We enrolled 202 patients hospitalized with symptomatic COVID-19 infection. Of those, 104 patients did not experience any type of thrombotic events before or during their hospitalization. These patients were compared to the other cohort of 98, who experienced thrombotic events before or during their hospitalization. In total, 61 patients who experienced thrombotic events had the event after initial blood collection, so the predictive capacity of biomarkers in these patients was evaluated. Citrullinated histone H3 was the best predictive biomarker for thrombotic events in COVID-19 regardless of age, sex, and race; disease severity was also a significant predictor in most thrombotic event groups. These results may better inform treatment and prophylaxis of thrombotic events in COVID-19 and similar viral illnesses in the future to improve outcomes and reduce mortality. Full article