Protein S is a vitamin K-dependent protein that acts as a break in secondary hemostasis by inactivating activated factor V and activated factor VIII. We report a case of a 40 years old male who had the first episode of deep vein thrombosis of the left lower limb 10 years back, which despite treatment, reoccurred 3 months later in the bilateral lower limb. Thrombophilic screening showed severe protein S deficiency. The patient then developed deep vein thrombosis of both upper limbs. The patient was advised to place an inferior vena cava filter, which he denied. The patient is now presenting with multiple episodes of post-thrombotic syndrome. Such attacks are treated with elastic compression stockings, rivaroxaban, and morphine. However, despite medication, the pain has not yet subsided. Hence, even though protein S deficiency is the rare cause of deep vein thrombosis when recurrent should be considered despite its rare occurrence.

The laboratory detection of factors that participate in coagulation mechanisms in patients with coronary heart disease may lead to important findings regarding the contribution of endothelial function to atherosclerotic lesions of coronary arteries. The main purpose of this study was to investigate the role of high-sensitivity C-reactive protein (hs-CRP), von Willebrand factor (vWF) activity, thrombomodulin (TM), ADAMTS13 activity and myeloperoxidase (MPO) in patients undergoing coronary angiography due to non-ST-elevation myocardial infarction (NSTEMI), unstable angina (UA) and stable angina pectoris with positive stress testing-induced myocardial ischemia (controls). Furthermore, the measured biomarkers were examined among patients with classical cardiovascular risk factors. 50 NSTEMI patients, 50 UA patients and 30 controls referred to coronary angiography were included in the study. The blood samples were collected before the catheter procedure. MPO, TM and ADAMTS13 activity were measured by enzyme-linked immunosorbent assay (ELISA), while vWF activity was calculated with INNOVANCE vWF Ac. When the laboratory results were compared between the three study groups, hs-CRP was found to be higher in NSTEMI patients compared to UA patients (p=0.0015) and controls (p<0.0001). ADAMTS13 activity was higher in NSTEMI (p=0.0035) and UA patients (p=0.0102) compared to controls and TM was lower in NSTEMI patients compared to UA patients (p=0.0307) and controls (p=0.0002). Moreover, MPO was higher in UA patients compared to the control group (p=0.0227). Finally, each of the aforementioned biomarkers was compared in the presence of the following cardiovascular risk factors: smoking, diabetes mellitus, arterial hypertension, dyslipidemia, chronic kidney disease (CKD) and peripheral artery disease (PAD). The results of this study add more data to the current medical literature concerning the role of coagulation disorders, endothelial damage and immunothrombosis in patients with coronary artery disease and their correlation with traditional risk factors for cardiovascular disease.

Although von Willebrand disease (VWD) is the most common inherited bleeding disorder, its diagnosis and management are often challenging. Clinical practice guidelines, developed through systematic review of the medical literature and considering the best available evidence, provide guidance for common clinical scenarios. However, in the clinical setting, patients often present with characteristics and nuances that may fall outside the realm of available evidence and guidelines, and hence, shared decision-making will be essential in the evaluation and management of these patients. The challenges in the diagnosis of VWD are mainly attributable to the heterogeneity of the disorder, limitations of laboratory assays, and the significant impact of various physiologic processes on von Willebrand factor. The impact of physiologic normalization of von Willebrand factor, which may occur in various settings such as pregnancy, inflammation, or aging, remains uncertain, as is the optimal management in these scenarios. Multidisciplinary and individualized care, based on evolving evidence supported by clinicians, patients, caregivers, and stakeholders, will be needed to ensure the highest quality care for those who live with VWD.

Hemophilia A (HA) cell therapy approaches in pediatric individuals require suitable factor (F)VIII-producing cells for stable engraftment. Liver sinusoidal endothelial cells (LSEC) and hematopoietic stem cells (HSC) have been demonstrated to be suitable for the treatment of adult HA-mice. However, after transplantation in busulfan (BU)-conditioned newborn mice, adult LSEC/HSC cannot efficiently engraft, while murine fetal liver (FL) hemato/vascular cells from embryonic day 11-13 of gestation (E11-E13), strongly engraft the hematopoietic and endothelial compartments while also secreting FVIII. Our aim was to investigate the engraftment of FL cells in newborn HA mice for obtaining a suitable "proof of concept" for the development of a new HA treatment in neonates. Hence, we transplanted FLE11 or E13 cells and adult bone marrow (BM) cells into newborn HA mice with or without BU preconditioning. The engraftment levels and FVIII activity was assessed starting from 6 weeks after transplantation. FLE11-E13+BU-transplanted newborns reached up to 95% engraftment with stable FVIII activity levels observed for 16 months. FLE13 cells showed engraftment ability even in absence of BU preconditioning, while FLE11 cells did not. BM+BU transplanted newborn HA mice showed high levels of engraftment; nevertheless, in contrast to FL cells, BM cells cannot engraft HA newborns in non-conditioning regimen. Finally, none of the transplanted mice developed anti-FVIII antibodies. Overall, this study sheds some light on the therapeutic potential of healthy FL cells in the cure of HA neonatal/pediatric patients.

Introduction: Intrahepatic cholangiocarcinoma (ICC) is one of the most highly heterogeneous malignant solid tumors; it is generally insensitive to clinical treatment and has a poor prognosis. Evidence suggests that abnormal neovascularization in the tumor microenvironment is an important cause of treatment resistance as well as recurrence and metastasis, but the key regulatory molecules are still largely unknown and should be identified. Method: We assessed the novel extracellular matrix protein (ECM) Sushi, von Willebrand factor type A, EGF and pentraxin containing 1 (SVEP1) expression pattern in the ICC by using immunohistochemistry. Multiplex immunofluorescence and Kaplan-Meier analysis were applied to explore the correlation between the low expression of SVEP1 and abnormal blood vessels and the clinical prognosis of ICC. Results: Our study showed that the expression of SVEP1 in most ICC samples was relatively lower than in the adjacent tissues. Statistical analysis suggested that patients with decreased SVEP1 expression always had shorter overall survival (OS) and disease-free survival (DFS). Moreover, the expression of SVEP1 was negatively correlated with the proportion of abnormal neovascularization in the tumor microenvironment of the ICC. Consistently, the key molecule of promoting vascular normalization, Ang-1, is positively correlated with the SVEP1 expression and prognosis in the ICC. In addition, the proportion of high Ki-67 expression was higher in the ICC samples with low SVEP1 expression, suggesting that the SVEP1 low expressed sample is in a malignant phenotype with high proliferation. Conclusion: This study reveals that SVEP1 is a promising prognostic biomarker for ICC and provides fresh insight into the role and potential new mechanism of abnormal neovascularization in ICC progression.

Acquired hemophilia A (AHA) is a rare disease caused by autoantibodies inhibiting factor VIII (FVIII) activity. Although the conditionis usually idiopathic, there may be other underlying diseases. Treatment consists of two steps: treatment of acute bleeding and immunosuppression. In this multicenter study, we aimed to demonstrate the clinical characteristics, management details, and survival of AHA patients in Turkey. Data was collected from eleven centers in Turkey. aPTT, FVIII, FVIII inhibitor, and hemoglobin (HB) levels, mixing test results, and demographics at diagnosis, treatment information, adverse events, bleeding episodes during follow-up, relapses, and outcome were analyzed. Twenty-nine patients were analyzed (58.6% female). No underlying disorder could be detected in 14 patients. The most prevalent etiologies were pregnancy, malignancy and infections. The median FVIII activity and FVIII inhibitor titer at diagnosis were 0.7% (0.0-29.4%) and 32.6 BU (0.6-135.6 BU) respectively. Bleeding was severe in 44.8% of patients. The HB value was significantly lower in patients with severe bleeding. Most of the patients (n = 25, 86.2%) had only one bleeding episode without relapse, three patients (10.3%) had two bleeding episodes, and one patient had more than three bleedings. 21 (75%) patients received hemostatic therapy. The use of recombinant FVIIa was slightly higher than activated prothrombin complex concentrate (15 versus 10 patients). Immunosuppressive treatment was initiated in 26 (93%) patients. Regimens containing steroid, cyclophosphamide, and rituximab in different combinations were the most preferred. The median follow-up period was 13 months (2-156 months). Median overall survival was 154.97 months. Four and six-year survival were 90.9 ± 0.8% and 77.9 ± 14.1% respectively. This is a unique study that investigated the demographic characteristics, treatment approaches, and patient survival of AHA in Turkey.

Disseminated intravascular coagulation (DIC) is not a disease criterion but a pathomechanistic process that accompanies various underlying diseases. According to the International Society on Thrombosis and Haemostasias definition, endothelial injury is an essential component in addition to systemic coagulation activation. Despite this definition, current diagnostic criteria for DIC do not include biomarkers for vascular endothelial injury. Endothelial cells are critical for hemostatic regulation because they produce various antithrombotic substances and express anticoagulant factors at the same time as facilitating coagulation, inflammatory reactions, platelet aggregation, and fibrinolysis with acute injury. Endothelial cells also exhibit various receptors, adhesion molecules, and the critical role of glycocalyx that regulates cellular interactions in thromboinflammation. For clinicians, biomarkers suitable for assessing endothelial injury are not readily available. Although we still do not have ideal biomarkers, antithrombin activity and von Willebrand factor can be candidates for the endothelium-related markers because those reflect the severity and are available in most clinical settings. Further, the dysfunction of endothelial cell in DIC arising from various underlying diseases is likely highly variable. For example, the involvement of endothelial dysfunction is significant in sepsis-induced coagulopathy, while moderate in trauma-induced coagulopathy, and variable in hematologic malignancy-associated coagulopathy. Because of the complexity of disease status associated with DIC, further research searching clinically available endothelium-related biomarkers is expected to establish individualized diagnostic criteria and potential therapeutic approaches.

Cerebrovascular accident (CVA) is one of the leading causes of death in the United States. Von Willebrand factor plays an important role in platelet activation and adhesion. It remains unclear whether Von Willebrand disease (vWD) is associated with a decreased risk of developing CVA. The study aimed to compare the relative risk (RR) of CVA in patients with and without vWD. We queried the National Inpatient Sample from 2009 to 2014 for discharge data and records for vWD and CVA using International Classification of Diseases, Ninth-Revision codes. The unadjusted and adjusted RR of CVA in patients with and without vWD were estimated using log-binomial model. Descriptive measures including means, medians, standard deviations, and range were presented based on normality test of continuous data. The prevalence of CVA was lower in patients with vWD than in those without vWD (1.31% vs 2.04%), with a RR of 0.64 (95% confidence interval (CI): 0.60-0.68). After adjusting for common CVA risk factors, the RR remained lower in vWD patients: 0.81 (95% CI: 0.76-0.86). vWD is associated with a lower RR of developing CVA. This suggests that deficiency of Von Willebrand factor is potentially protective against the development of CVA. To the best of our knowledge, this is the first study in humans to compare the RR of CVA in patients with and without vWD. Future studies are needed to explore causal relationships and therapeutic benefits.

Background Heart transplantation with a donation after circulatory death (DCD) heart is complicated by substantial organ ischemia and ischemia-reperfusion injury. Exenatide, a glucagon-like peptide-1 receptor agonist, manifests protection against cardiac ischemia-reperfusion injury in other settings. Here we evaluate the effects of exenatide on DCD hearts in juvenile pigs. Methods and Results DCD hearts with 15-minutes of global warm ischemia after circulatory arrest were reperfused ex vivo and switched to working mode. Treatment with concentration 5-nmol exenatide was given during reperfusion. DCD hearts treated with exenatide showed higher myocardial oxygen consumption (exenatide [n=7] versus controls [n=7], over 60-120 minutes of reperfusion, P<0.001) and lower cardiac troponin-I release (27.94±11.17 versus 42.25±11.80 mmol/L, P=0.04) during reperfusion compared with controls. In working mode, exenatide-treated hearts showed better diastolic function (dp/dt min: -3644±620 versus -2193±610 mm Hg/s, P<0.001; Tau: 15.62±1.78 versus 24.59±7.35 milliseconds, P=0.02; lateral e' velocity: 11.27 ± 1.46 versus 7.19±2.96, P=0.01), as well as lower venous lactate levels (3.17±0.75 versus 5.17±1.44 mmol/L, P=0.01) compared with controls. Higher levels of activated endothelial nitric oxide synthase (phosphorylated to total endothelial nitric oxide synthase levels: 2.71±1.16 versus 1.37±0.35, P=0.02) with less histological evidence of endothelial damage (von Willebrand factor expression: 0.024±0.007 versus 0.331±0.302, pixel/μm, P=0.04) was also observed with exenatide treatment versus controls. Conclusions Acute treatment of DCD hearts with exenatide limits myocardial and endothelial injury and improves donor cardiac function.

Coronavirus disease 2019 (COVID-19) is often accompanied by pneumonia and can be fatal. We report a case of COVID-19-associated myocardial injury mimicking fulminant myocarditis. Endomyocardial biopsy revealed numerous von Willebrand factor-rich microthrombi with small myocardial necrotic areas, complement deposits in small vessels/microthrombi, and macrophage-predominant interstitial infiltration. These findings, distinct from those of typical lymphocytic myocarditis, show diffuse endothelial injury, complement activation, and activated macrophages as characteristic features of COVID-19-associated pathogenesis. Dysregulated serum cytokine profiles predicting severe/critical COVID-19-associated myocardial injury were also determined. This case emphasizes the occurrence of fatal cardiac manifestation with microthrombotic injury in the early stage of COVID-19.

Hemophilia A (factor VIII [FVIII] deficiency) and hemophilia B (factor IX [FIX] deficiency) are the X-linked recessive bleeding disorders that clinically manifest with recurrent bleeding, predominantly into muscles and joints. In its severe presentation, when factor activity is less than 1% of normal, hemophilia presents with spontaneous musculoskeletal bleeds and may progress to debilitating chronic arthropathy. Management of hemophilia has changed profoundly in the past decades. From on-demand to prophylactic factor concentrate replacement, the treatment goal shifted from controlling bleeds to preventing bleeds and improving quality of life. In this new scenario, gene therapy has arisen as a paradigm-changing therapeutic option, a one-time treatment with the potential to achieve sustained coagulation FVIII or FIX expression even within the normal range. This review discusses the critical impact of adeno-associated virus (AAV) gene transfer in hemophilia care, including the recent clinical outcomes, changes in disease perceptions, and its treatment burden. We also discuss the challenging scenario of the AAV-directed immune response in the clinical setting and potential strategies to improve the long-lasting efficacy of hemophilia gene therapy efficacy.