Search Results (17)

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

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

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

Heyde’s syndrome (HS) represents an association between aortic stenosis and intestinal angiodysplasias, and it has been demonstrated that acquired von Willebrand disease plays a pivotal role in the pathophysiology of this syndrome. In patients with HS, von Willebrand factor deficiency represents an additional risk factor, further contributing to the risk of bleeding and anemia. We present the case of an 86-year-old patient diagnosed with HS and von Willebrand deficiency in 2018. Four years prior, the patient underwent surgical aortic valve replacement. Since then, she has been receiving chronic oral anticoagulation therapy with a vitamin K antagonist. The patient was admitted to the Internal Medicine Clinic due to semi-solid dark stools, diffuse abdominal pain, and asthenia. Upon examination, the patient presented with an altered general status and clinical signs suggestive of anemia. Laboratory findings revealed anemia with elevated INR and aPTT values. Colonic angiodysplasias were identified during a colonoscopy, although no sources of active bleeding were detected. On the 9th day of hospitalization, the patient experienced an episode of lower gastrointestinal bleeding. The pharmacological management was adjusted, and argon plasma coagulation was recommended. Following treatment of the angiodysplastic lesions, the patient’s clinical evolution was favorable, with the correction of the anemia. Full article

Under different pathophysiological conditions, endothelial cells lose endothelial phenotype and gain mesenchymal cell-like phenotype via a process known as endothelial-to-mesenchymal transition (EndMT). At the molecular level, endothelial cells lose the expression of endothelial cell-specific markers such as CD31/platelet-endothelial cell adhesion molecule, von Willebrand factor, and vascular-endothelial cadherin and gain the expression of mesenchymal cell markers such as α-smooth muscle actin, N-cadherin, vimentin, fibroblast specific protein-1, and collagens. EndMT is induced by numerous different pathways triggered and modulated by multiple different and often redundant mechanisms in a context-dependent manner depending on the pathophysiological status of the cell. EndMT plays an essential role in embryonic development, particularly in atrioventricular valve development; however, EndMT is also implicated in the pathogenesis of several genetically determined and acquired diseases, including malignant, cardiovascular, inflammatory, and fibrotic disorders. Among cardiovascular diseases, aberrant EndMT is reported in atherosclerosis, pulmonary hypertension, valvular disease, fibroelastosis, and cardiac fibrosis. Accordingly, understanding the mechanisms behind the cause and/or effect of EndMT to eventually target EndMT appears to be a promising strategy for treating aberrant EndMT-associated diseases. However, this approach is limited by a lack of precise functional and molecular pathways, causes and/or effects, and a lack of robust animal models and human data about EndMT in different diseases. Here, we review different mechanisms in EndMT and the role of EndMT in various cardiovascular diseases. Full article

Thrombotic microangiopathies (TMAs) comprise a distinct group of diseases with different manifestations that can occur in both pediatric and adult patients. They can be hereditary or acquired, with subtle onset or a rapidly progressive course, and they are particularly known for their morbidity and mortality. Pregnancy is a high-risk time for the development of several types of thrombotic microangiopathies. The three major syndromes are hemolysis, elevated liver function tests, and low platelets (HELLP); hemolytic uremic syndrome (HUS); and thrombotic thrombocytopenic purpura (TTP). Because of their rarity, clinical information and therapeutic results related to these conditions are often obtained from case reports, small series, registries, and reviews. The collection of individual observations, the evolution of diagnostic laboratories that have identified autoimmune and/or genetic abnormalities using von Willebrand factor post-secretion processing or genetic–functional alterations in the regulation of alternative complement pathways in some of these TMAs, and, most importantly, the introduction of advanced treatments, have enabled the preservation of affected organs and improved survival rates. Although TMAs may show different etiopathogenesis routes, they all show the presence of pathological lesions, which are characterized by endothelial damage and the formation of thrombi rich in platelets at the microvascular level, as a common denominator, and thrombotic damage to microcirculation pathways induces “mechanical” (microangiopathic) hemolytic anemia, the consumption of platelets, and ischemic organ damage. In this review, we highlight the current knowledge about the diagnosis and management of these complications during pregnancy. Full article

Aortic valve stenosis (AS) is a common heart valve disease in the elderly population, and its pathogenesis remains an interesting area of research. The degeneration of the aortic valve leaflets gradually progresses to valve sclerosis. The advanced phase is marked by the presence of extracellular fibrosis and calcification. Turbulent, accelerated blood flow generated by the stenotic valve causes excessive damage to the aortic wall. Elevated shear stress due to AS leads to the degradation of high-molecular weight multimers of von Willebrand factor, which may involve bleeding in the mucosal tissues. Conversely, elevated shear stress has been associated with the release of thrombin and the activation of platelets, even in individuals with acquired von Willebrand syndrome. Moreover, turbulent blood flow in the aorta may activate the endothelium and promote platelet adhesion and activation on the aortic valve surface. Platelets release a wide range of mediators, including lysophosphatidic acid, which have pro-osteogenic effects in AS. All of these interactions result in blood coagulation, fibrinolysis, and the hemostatic process. This review summarizes the current knowledge on high shear stress-induced hemostatic disorders, the influence of AS on platelets and antiplatelet therapy. Full article

Acute or intense exercise can result in metabolic imbalances, muscle injuries, or reveal hidden disorders. Laboratory medicine in sports is playing an increasingly crucial role in monitoring athletes’ health conditions. In this study, we designed an integrated approach to explore the causes of a deep venous thrombosis event in an elite basketball player. Since the complete blood count revealed a marked platelet count (838 × 10³ µL), and thrombophilia screening tests did not reveal any significant alteration, we evaluated the thrombin generation, which highlights a state of hypercoagulability. First-level haemostasis exams showed only a slight prolongation of the activated Partial Thromboplastin Time (aPTT). Thus, screening tests for von Willebrand Disease showed a reduction in vWF parameters. Therefore, we directed our hypothesis towards a diagnosis of acquired von Willebrand disease secondary to Essential Thrombocythemia (ET). To confirm this hypothesis and highlight the molecular mechanism underlying the observed phenotype, molecular tests were performed to evaluate the presence of the most common mutations associated with ET, revealing a 52-bp deletion in the coding region of CALR exon 9. This case report highlights the importance of an integrated approach to monitoring the athletes’ health status to personalise training and treatments, thus avoiding the appearance of diseases and injuries that, if underestimated, can undermine the athlete’s life. Full article

Background: Hemodynamic alterations in Fontan patients (FP) are associated with hemostatic dysbalance and Fontan-associated liver disease. Studies of other hepatopathologies indicate an interplay between cholestasis, tissue factor (TF), and von Willebrand factor (VWF). Hence, we hypothesized a relationship between the accumulation of bile acids (BA) and these hemostatic factors in FP. Methods: We included 34 FP (Phenprocoumon n = 15, acetylsalicylic acid (ASA) n = 16). BA were assessed by mass spectrometry. TF activity and VWF antigen (VWF:Ag) were determined by chromogenic assays. VWF collagen-binding activity (VWF:CB) was assessed via ELISA. Results: Cholestasis was observed in 6/34 FP (total BA ≥ 10 µM). BA levels and TF activity did not correlate (p = 0.724). Cholestatic FP had lower platelet counts (p = 0.013) from which 5/6 FP were not treated with ASA. VWF:Ag levels were increased in 9/34 FP and significantly lower in FP receiving ASA (p = 0.044). Acquired von Willebrand syndrome (AVWS) was observed in 10/34-FP, with a higher incidence in cholestatic FP (4/6) (p = 0.048). Conclusions: Cholestasis is unexpectedly infrequent in FP and seems to be less frequent under ASA therapy. Therefore, ASA may reduce the risk of advanced liver fibrosis. FP should be screened for AVWS to avoid bleeding events, especially in cholestatic states. Full article

Acquired von Willebrand syndrome (AVWS) is caused by an acquired deficiency of von Willebrand factor (VWF), a multimeric protein required for primary hemostasis. For patients with heart valve diseases, high gradient across the malfunctioning valves could cause elevated shear stress and damage the most effective large VWF, eventually resulting in AVWS. However, AVWS has not been reported in association with normally functioning mechanical valves. Herein, we reported a 74-year-old female who suffered from recurrent gastrointestinal bleeding with a history of mechanical aortic and mitral valve replacement. This patient’s function/antigen ratio of VWF was decreased and gel electrophoresis revealed the loss of large VWF, which confirmed the diagnosis of AVWS. Echocardiogram showed that the function of the prostheses was normal. However, the gradient across aortic valve was increased due to a high cardiac state which is secondary to chronic anemia, resulting in the disruption of large VWF multimers and exacerbation of gastrointestinal (GI) bleeding. After managing the patient’s anemia with transfusion, the gradient across the aortic valve had improved, with the resolution of GI bleeding. This is the first case report of AVWS that is associated with a normally functioning mechanical valve. AVWS should be considered one of the differential diagnoses if patients present with unexplained GI bleeding on the background of having prosthetic heart valves. The management of the underlying condition is essential. Full article

Background: Vascular anomalies comprise a diverse group of rare diseases with altered blood flow and are often associated with coagulation disorders. The most common example is a localized intravascular coagulopathy in venous malformations leading to elevated D-dimers. In severe cases, this may progress to a disseminated intravascular coagulopathy with subsequent consumption of fibrinogen and thrombocytes predisposing to serious bleeding. A separate coagulopathy is the Kasabach–Merritt phenomenon in kaposiform hemangioendothelioma characterized by platelet trapping leading to thrombocytopenia and eventually consumptive coagulopathy. Our previous work showed impaired von Willebrand factor and platelet aggregometry due to abnormal blood flow, i.e., in ventricular assist devices or extracorporeal membrane oxygenation. With altered blood flow also present in vascular anomalies, we hypothesized that, in particular, the von Willebrand factor parameters and the platelet function may be similarly impacted. Methods: We prospectively recruited 73 patients with different vascular anomaly entities and analyzed their coagulation parameters. Results: Acquired von Willebrand syndrome was observed in both of our patients with Kasabach–Merritt phenomenon. In six out of nine patients with complex lymphatic anomalies, both the vWF antigen and activity were upregulated. Platelet aggregometry was impaired in both patients with Kasabach–Merritt phenomenon and in seven out of eight patients with an arteriovenous malformation. Conclusions: The analysis of coagulation parameters in our patients with vascular anomalies advanced our understanding of the underlying pathophysiologies of the observed coagulopathies. This may lead to new treatment options for the, in part, life-threatening bleeding risks in these patients in the future. Full article

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak in December 2019, causing millions of deaths all over the world, and the lack of specific treatment for severe forms of coronavirus disease 2019 (COVID-19) have led to the development of vaccines in record time, increasing the risk of vaccine safety issues. Recently, several cases of thrombotic thrombocytopenic purpura (TTP) have been reported following COVID-19 vaccination. TTP is a rare disease characterized by thrombocytopenia, microangiopathic hemolytic anemia and ischemic end-organ lesions. It can be either congenital or acquired. Various events such as viral infections, medication, pregnancy, malignancies, and vaccinations may cause TTP. Here, we report two cases of acquired TTP following Sinopharm COVID-19 vaccine (BBIBP-CorV) and Sinovac COVID-19 vaccine (CoronaVac). Diagnosis was based on clinical presentation and confirmed with a severe reduction in the activity of von Willebrand factor-cleaving protease ADAMTS-13 and the presence of inhibitory autoantibodies. The two patients were successfully treated with corticosteroids, plasma exchange therapy and rituximab in the acute phase. In the literature, the reported cases of TTP induced by COVID-19 vaccination occurred after Adenoviral Vector DNA- and SARS-CoV-2 mRNA-Based COVID-19 vaccines. To the best of our knowledge, this is the first report of acquired TTP after inactivated virus COVID-19 vaccination. Full article

von Willebrand factor (VWF) is a complex and large protein that is cleaved by ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13), and together they serve important roles in normal hemostasis. Malignancy can result in both a deficiency or excess of VWF, leading to aberrant hemostasis with either increased bleeding or thrombotic complications, as respectively seen with acquired von Willebrand syndrome and cancer-associated venous thromboembolism. There is emerging evidence to suggest VWF also plays a role in inflammation, angiogenesis and tumor biology, and it is likely that VWF promotes tumor metastasis. High VWF levels have been documented in a number of malignancies and in some cases correlate with more advanced disease and poor prognosis. Tumor cells can induce endothelial cells to release VWF and certain tumor cells have the capacity for de novo expression of VWF, leading to a proinflammatory microenvironment that is likely conducive to tumor progression, metastasis and micro-thrombosis. VWF can facilitate tumor cell adhesion to endothelial cells and aids with the recruitment of platelets into the tumor microenvironment, where tumor/platelet aggregates are able to form and facilitate hematogenous spread of cancer. As ADAMTS13 moderates VWF level and activity, it too is potentially involved in the pathophysiology of these events. VWF and ADAMTS13 have been explored as tumor biomarkers for the detection and prognostication of certain malignancies; however, the results are underdeveloped and so currently not utilized for clinical use. Further studies addressing the basic science mechanisms and real word epidemiology are required to better appreciate the intriguing connections between VWF, ADAMTS13 and malignancy. A better understanding of the role VWF and ADAMTS13 play in the promotion and inhibition of cancer and its metastasis will help direct further translational studies to aid with the development of novel cancer prognostic tools and treatment modalities. Full article

Myxomatous mitral valve degeneration (MMVD) is the most common acquired cardiac disease in canine species, and valvular interstitial cells (VICs) are considered the main responsible for the development of this pathology. The scientific interest is focused on isolating and characterizing these cells. The aims of the present study were to verify a novel VICs mechanical isolation method and to characterize isolated cells using immunocytochemistry and immunofluorescence, with parallel histological and immunohistochemistry assays on bovine and canine healthy and MMVD mitral valves. Antibodies against vimentin (VIM), smooth muscle actin (SMA), von Willebrand (vW) factor, Transforming Growth Factor (TGF) β1, and Transient Receptor Potential Vanilloid 1 (TRPV1) were used. The isolation method was considered reliable and able to isolate only VICs. The different assays demonstrated a different expression of SMA in healthy and MMVD mitral valves, and TRPV1 was isolated for the first time from bovine and canine VICs and the correspondent mitral valve leaflets. The novelties of the present study are the new isolation method, that may allow correlations between laboratory and clinical conditions, and the identification of TRPV1, which will lead to further investigations to understand its function and possible role in the etiology of MMVD and to the design of new therapeutic strategies. Full article

Von Willebrand factor (VWF) is a large multimeric hemostatic protein. VWF is critical in arresting platelets in regions of high shear stress found in blood circulation. Excessive cleavage of VWF that leads to reduced VWF multimer size in plasma can cause acquired von Willebrand syndrome, which is a bleeding disorder found in some heart valve diseases and in patients receiving mechanical circulatory support. It has been proposed that hemodynamics (blood flow) found in these environments ultimately leads to VWF cleavage. In the context of experiments reported in the literature, scission theory, developed for polymers, is applied here to provide insight into flow that can produce strong extensional forces on VWF that leads to domain unfolding and exposure of a cryptic site for cleavage through a metalloproteinase. Based on theoretical tensile forces, laminar flow only enables VWF cleavage when shear rate is large enough (>2800 s⁻¹) or when VWF is exposed to constant shear stress for nonphysiological exposure times (>20 min). Predicted forces increase in turbulence, increasing the chance for VWF cleavage. These findings can be used when designing blood-contacting medical devices by providing hemodynamic limits to these devices that can otherwise lead to acquired von Willebrand syndrome. Full article