Potential Role of CTNNA3 and FRMPD4 in Vascular Thrombosis of Colon Adenocarcinoma

Background: Vascular tumor thrombus is an important pathological feature of malignant tumors, closely related to lymph node metastasis, and considered to be tumor micrometastasis. Two down-regulated genes, Catenin Alpha 3 (CTNNA3) and FERM And PDZ Domain Containing 4 (FRMPD4) were selected via analyzing the differential expression of vascular tumor thrombus in colon adenocarcinoma and paracancerous tissues. Furthermore, we observed the potential role of them in vascular thrombosis of colon adenocarcinoma.Method: Candidate genes for vascular thrombosis of colon adenocarcinoma were screened by GSE127069, and then pan-cancer verification and immune infiltration analysis were performed. The relationship between gene and vascular thrombosis was analyzed from the level of gene mutation by cBioPortal. Finally, the clinical samples collected were used for expression verification.Results: CTNNA3 and FRMPD4 were low-expressed in vascular tumor thrombus of colon adenocarcinoma, which were positively correlated with microsatellite instability (MSI). They were also closely related to immune microenvironment and immune cell subtype infiltration. According to the analysis of gene mutation, their gene deletion was related to the vascular invasion indicator. Finally, the protein and mRNA expression of CTNNA3 and FRMPD4 were down-regulated in the samples of vascular thrombosis of colon adenocarcinoma, compared with the normal glands which from paracancerous tissues.Conclusion: Our study demonstrates that CTNNA3 and FRMPD4 may be potential biomarkers of vascular thrombosis in colon adenocarcinoma. These results may provide a new strategy to identify the micrometastasis in colon adenocarcinoma.

Antiphospholipid Antibodies From Women With Pregnancy Morbidity and Vascular Thrombosis Induce Endothelial Mitochondrial Dysfunction, mTOR Activation, and Autophagy

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by thrombosis and pregnancy morbidity (PM) obstetric events together with persistent high titers of circulating antiphospholipid antibodies (aPL). Several mechanisms that explain the development of thrombosis and PM in APS include the association of aPL with alterations in the coagulation cascade and inflammatory events. Other mechanisms disturbing cellular homeostases, such as mitochondrial dysfunction, autophagy, and cell proliferation, have been described in other autoimmune diseases. Therefore, the objective of this study was to investigate the impact of aPL from different patient populations on endothelial cell mitochondrial function, activation of the mammalian target of rapamycin (mTOR) and autophagy pathways, and cellular growth. Using an in vitro model, human umbilical vein endothelial cells (HUVECs) were treated with polyclonal immunoglobulin G (IgG) purified from the serum of women with both PM and vascular thrombosis (PM/VT), with VT only (VT), or with PM and non-criteria aPL (seronegative-obstetric APS, SN-OAPS). We included IgG from women with PM without aPL (PM/aPL-) and healthy women with previous uncomplicated pregnancies (normal human serum, NHS) as control groups. Mitochondrial function, mTOR activation, autophagy, and cell proliferation were evaluated by Western blotting, flow cytometry, and functional assays. IgG from women with PM/VT increased HUVEC mitochondrial hyperpolarization and activation of the mTOR and autophagic pathways, while IgG from patients with VT induced endothelial autophagy and cell proliferation in the absence of elevated mTOR activity or mitochondrial dysfunction. IgG from the SN-OAPS patient group had no effect on any of these HUVEC responses. In conclusion, aPL from women with PM and vascular events induce cellular stress evidenced by mitochondrial hyperpolarization and increased activation of the mTOR and autophagic pathways which may play a role in the pathogenesis of obstetric APS.

Thrombosis and Bleeding After Implementation of an Intermediate-Dose Prophylactic Anticoagulation Protocol in ICU Patients With COVID-19: A Multicenter Screening Study

Thrombosis and bleeding after implementation of an intermediate-dose prophylactic anticoagulation protocol in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19): a multicenter screening study Background: Venous thromboembolism (VTE) is common among critically ill patients with COVID-19. Information regarding VTE prevalence and bleeding complications after implementation of intermediate-dose prophylactic anticoagulation in such patients is, however, limited. Methods: We performed a prospective, observational study in 6 ICUs in 2 university-affiliated teaching hospitals in Sweden. After implementation of an intermediate-dose prophylactic anticoagulation protocol, we performed ultrasound screening for proximal lower-extremity deep vein thrombosis (DVT) and collected routine computed tomography pulmonary angiography exam results. Results: A total of 100 COVID-19 patients were included from June 21, 2020, through February 18, 2021. During a median follow-up of 120 (IQR, 89-134) days, we found VTE in 37 patients with the majority (78.4%) being diagnosed after ICU arrival. Overall, 20 patients had proximal lower-extremity DVT with 95% being detected on ultrasound screening; 22 patients had pulmonary vascular thrombosis; and 4 patients had venous thrombosis at other sites. A total of 6 patients had both proximal lower-extremity DVT and pulmonary vascular thrombosis. On univariate logistic regression analysis of 14 baseline characteristics, only pre-existing heart failure was associated with VTE (OR 4.67, 95% CI 1.13-19.34). Major and non-major bleeding occurred in 10 and 18 patients, respectively. Conclusions: In our cohort of ICU patients with COVID-19, we observed a high prevalence of VTE and bleeding complications after implementation of intermediate-dose anticoagulation. In approximately half of patients, VTE was identified on screening ultrasound.

Bilateral neurorethinovasculitis associated with COVID-19 infection in a girl 17 years old

Despite dominant lung lesions, new coronavirus infection (COVID-19) can influence almost any organ, including eyes. According to modern data, frequency of eye damage by COVID-19 reaches 32%, and spectrum of clinical manifestations is diverse. Changes are observed both in the anterior (mainly conjunctivitis) and posterior (mostly retinal vascular thrombosis, optic neuritis, neuroretinitis) segments of the eye, and the timing of their occurrence varies from the first (sometimes the only) clinical symptoms of the disease to the development at the peak or during the period of convalescence from COVID-19. In children symptomatic COVID-19 infection is diagnosed less frequently than in adults, and ophthalmic manifestations are less investigated. This article describes a case of bilateral neuroretinovasculitis in a 17-year-old girl with a mild course of COVID-19, that arose 3 weeks after the onset of the disease, which broadens the understanding of ocular manifestations of COVID-19 in children. We emphasize that an ophthalmologist should know ocular manifestations of COVID-19, which can help in the diagnosis and further study of the frequency and spectrum of ophthalmic symptoms, especially in children

Comparative Analysis of Direct Oral Anticoagulants and Vitamin K Antagonists in Antiphospholipid Syndrome Patients

Introduction Antiphospholipid syndrome (APS) is a major acquired thrombophilia in which vascular thrombosis (venous or arterial) and/or pregnancy losses occur. Despite the use of vitamin K antagonists (VKAs), the annual risk for recurrent thrombosis among APS patients ranges between 2-5% (Crowther et al. NEJM 2003). The evidence for direct oral anticoagulants (DOAC) use in APS patients is still lacking. Therefore, we conducted a retrospective cohort study to explore the efficacy and safety of DOACs vs. VKAs in this patient population. Methods The electronic medical records at Emory University Hospitals were queried for patients ≥18 years old with APS diagnosis, according to the Sydney international census criteria (Miyakis et al. JTH 2006). Included patients must have experienced acute thrombosis between 01/01/2012 and 12/31/2018 and started anticoagulation therapy with DOACs or VKAs. We reviewed patient charts from the index thrombosis date till the end of the study period (12/31/2019). Clinical endpoints were: recurrent vascular thrombosis, clinically relevant bleeding (CRB), which included major and non-major bleeding events as defined by the ISTH society, and composite outcome of thrombosis and bleeding (Kaatz et al. JTH 2015). Patients presenting with pregnancy complications only during the identification period were excluded. Results A total of 153 patients with confirmed APS diagnosis were included in the study. Mean age was 51 (range, 18-79 y.o.). 94 patients (61.4%) were females and 80 patients (52.3%) were white. The most common sites of index thrombosis were pulmonary embolism (N=62, 40.5%), proximal lower extremity deep venous thrombosis (N=49, 32%), and stroke/TIA (N=29, 19%). The majority of patients had a single positive antiphospholipid antibody (aPL) (N=83, 54.2%). 35 (22.9%) had double positive and 24 (15.7%) had triple positive disease. Following index thrombosis, 75 patients started DOAC, whereas 72 started warfarin. Six patients started subcutaneous heparin for a short duration before starting an oral form of anticoagulation. Of those on DOAC, 50 started rivaroxaban while 22 started apixaban. After a mean of 19.8 months (range, 0.68 - 69.8) from the index thrombosis, 62 patients (40.5%) switched to a different class of anticoagulation. The most common reasons for switching therapy were recurrent thrombosis (N=16, 25.8%), followed by patient preference (N=13, 20.9%), side effects including bleeding (N=9, 14.5%), and other reasons, such as confirmed APS diagnosis or renal insufficiency (N=12, 19.3%). We found no statistically significant differences in risk of recurrent thrombosis or CRB events among patients who were started on DOAC vs. VKAs (Figure). The number of arterial thrombosis events was minimal and similar in both treatment groups: N=3 in DOAC group vs. N=5 in the VKA group. Patients treated with rivaroxaban had a similar risk of recurrent thrombosis (log rank, p-value=0.629) and CRB events (log rank, p-value=0.631) compared to those treated with apixaban. The risk of recurrent thrombosis was not affected by degree of aPL positivity or previous history of arterial thrombosis in multivariate models (HR 0.791, 95% CI 0.357 - 1.751) (Table). Discussion and Conclusion Our experience suggests that DOACs -particularly rivaroxaban / apixaban- could be an effective and safe alternative to warfarin in APS patients. We realize that patients with triple aPL positivity constitute a special population with a substantial risk of arterial and venous thrombosis. Given the retrospective nature of our data and that triple aPL positive patients compromised only 15% of our patient population, we conclude that the use of DOACs in these high risk patients remains uncertain. Prospective and large-scale multicenter studies are highly encouraged to explore DOAC use in APS patients with various background profiles. We build on our current experience by starting a multicenter collaboration that will facilitate meaningful subgroup comparisons in APS patients. Figure 1 Figure 1. Disclosures Gaddh: Agios: Consultancy, Other: Advisory board.

Adrenal coma hormone therapy case

When diagnosing various coma, one should bear in mind the possibility of coma due to acute adrenal insufficiency, which develops as a result of partial or complete destruction of the adrenal glands in infectious diseases, adrenal hemorrhages, adrenal vascular thrombosis or surgery on the adrenal glands.

The state of the peripheral circulatory system in infectious diseases

The state of blood circulation and the causes of its disorder, both in chronic and, in particular, in acute infectious diseases, have always been of great interest to both clinicians and pathologists. Since the time of Laennec, who first drew attention to the weakness of the heart muscles in those who died from febrile diseases and emphasized, like Louis, weakness and fragility of the heart muscle, they began to look for the causes of these disorders in the state of the heart muscles. A significant success in the study of diseases of the heart muscle in infectious diseases was the teaching of Virchow about parenchymal inflammation, confirmed by Bttcher for typhoid and Mosler for diphtheria. While these authors spoke only about parenchymal inflammation of the heart muscle, Hayem was able to establish under the same conditions also interstitial myocarditis, and later productive endoarteritis of the coronary vessels, which, causing vascular thrombosis, could be the cause of sudden death during typhoid.

Laboratory Analysis of Antiphospholipid Antibodies with Clinical Correlation: A Hospital-Based 10 Year Study

Introduction/Objective Antiphospholipid syndrome (APS) is an autoimmune disorder and its diagnosis requires both laboratory evaluation of antiphospholipid antibodies (APAs) and clinical correlation. This study focused on the laboratory analysis of APS with clinical correlation in a hospital-based patient population. Methods/Case Report From 2010-2020, immunological studies for APAs were performed at Department of Pathology, William Beaumont Hospital – Troy, Michigan and patients with positive results were selected for further analysis. Four APAs were included: IgG and IgM beta-2 glycoprotein I antibodies (IgG B2GA and IgM B2GA), and IgG and IgM anticardiolipin antibodies (IgG ACA and IgM ACA). Clinical information was collected from hospital electronic medical chart with focus on thromboembolism and abortion history, autoimmune disorders, antithrombotic therapies and other studies. Results (if a Case Study enter NA) There were 167 patients, 136 females and 31 males (F/M=4.4). The median age for females was 50 and for males, 57. Overall, B2GA was present more than ACA (102/81) in females, and ACA was present slightly more than B2GA (20/17) in males. IgM APAs were much more common than IgG APAs; IgM B2GA/IgG B2GA: 87/32 (p<0.01) and IgM ACA/IgG ACA: 81/20 (p<0.01). Most APAs were at the low-intermediate titer range and increased APAs titer correlated with decreased positive rate: APAs titer at 20-40, 41-80 and >80 with positive results at 115, 61 and 44 respectively. In addition to documented autoimmune disorders, pregnancy miscarriage was a common clinical condition (24/66) in females at age <45. But for females at age >45, vascular thrombosis became more common (18/70). Vascular thrombosis was a common clinical disease in males (16/31) followed by autoimmune disorders (10/31). Most patients with vascular thrombosis received antithrombotic therapies. Conclusion Female patients positive for APAs was significantly more and younger than males in this study. IgM B2GA was the most common type of APAs followed by IgM ACA. IgG B2GA and IgG ACA were much less common. In younger female patients autoimmune disorders and abortion were the most common clinical conditions. In older female and male patients, autoimmune disorders and vascular thrombosis were the most common clinical conditions. The titer of APAs detected was at low-intermediate range in most patients. The relationship between the titer of APAs and clinical conditions needs further study.