Markers Of Thrombosis Research Articles

CHANGES IN NEUROHUMORAL STATUS OF PATIENTS WITH COMMUNITY-ACQUIRED PNEUMONIA IN ASSOCIATION WITH CORONAVIRUS INFECTION COVID-19

The aim of this study was to analyze and summarize the available data on changes in neurohumoral status in patients with community-acquired pneumonia associated with COVID-19, as well as to identify the main mechanisms explaining these changes. Materials and methods. For a systematic review of the literature, scientific articles published in leading scientific databases, including PubMed, Scopus, Google Scholar and Web of Science, which provide access to peer-reviewed articles and other scientific publications, were selected. Results. Among patients with community-acquired pneumonia caused by COVID-19, the most common forms of involvement were bilateral multisegmental and right-sided lower lobe pneumonia. The localization of pneumonia varies significantly by gender and age group, with right-sided lower lobe pneumonia more common in men aged 20-30 and 51-60 years, and right-sided upper lobe pneumonia in women aged 20-30 years and left-sided lower lobe pneumonia in women aged 31-50 years. The most common forms in mild disease are left-sided and right-sided lower lobe pneumonia, while in severe disease, bilateral multisegmental pneumonia is the most common. Changes in the levels of immunoinflammatory markers (CRP, IL-6), the stress hormone cortisol, and the thrombosis marker D-dimer were important prognostic markers of disease severity. In patients with severe pneumonia, a significant increase in these parameters was observed, which is associated with a high risk of developing thromboembolic complications and required intensive care. Elevated levels of CRP, IL-6, D-dimer and cortisol in patients with severe COVID-19 are prognostic markers for assessing the severity of the disease and the development of complications such as thromboembolism. Conclusion. Thus, early detection of changes in the levels of inflammatory and stress markers allows predicting the severity of the disease, assessing the risk of complications, and timely applying treatment strategies to reduce mortality and improve treatment outcomes.

Transplant-associated TMA: the conundrum of diagnosis and treatment.

Transplant-associated thrombotic microangiopathy (TA-TMA) after hematopoietic cell transplantation is characterized by microangiopathic hemolytic anemia (MAHA) with persistent schistocytosis, elevated markers of hemolysis, thrombocytopenia, and microvascular thrombosis leading to ischemic injuries in the kidneys and other organs. The initial evaluation of the disease requires confirmation of non-immune MAHA and careful examination of known secondary causes of TMA. Due to increased likelihood of long-term renal failure and overall mortality, a rapid diagnosis and treatment of the underlying trigger is needed. However, the diagnostic criteria proposed to define TA-TMA remain insufficient. sC5b9, the soluble form of the membrane attack complex of the terminal complement pathway, is the most studied prognostic biomarker for the disease, though its sensitivity and specificity remain suboptimal for clinical use. Current evidence does not support the cessation of calcineurin inhibitors without cause or the use of therapeutic plasma exchange. Many recent single-arm studies targeting the complement pathway inhibition have been reported, and larger randomized controlled trials are ongoing. This review aims to provide an evidence-based discussion from both adult and pediatric perspectives on the advances and conundrums in TA-TMA diagnosis and treatment.

Role of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio As Diagnostic and Prognostic Markers in Cerebral Venous Sinus Thrombosis: A Systematic Review and Meta-Analysis

Role of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio As Diagnostic and Prognostic Markers in Cerebral Venous Sinus Thrombosis: A Systematic Review and Meta-Analysis

Oxidised low-density lipoprotein and antibodies against oxidised low-density lipoprotein in patients with antiphospholipid syndrome.

Recurrent thrombosis is one of the main clinical features of antiphospholipid syndrome (APS), and recent studies revealed that APS shares similar pathophysiological mechanisms with atherosclerosis. Oxidised low-density lipoprotein (OxLDL) and antibodies against OxLDL (anti-OxLDL) are involved in the development of atherosclerosis. This study aims to investigate the clinical significance of OxLDL and anti-OxLDL in APS patients. One hundred and seventy APS patients and 39 healthy controls (HC) were enrolled. Clinical and laboratory data were collected from Clinical Data Center of Peking University People's Hospital. OxLDL and anti-OxLDL were detected using enzyme-linked immunosorbent assay. Among the 170 APS patients, 106 had isolated thrombotic APS. Compared with HC, APS patients exhibited higher titres of OxLDL [413.86 (220.11-853.67) ng/mL vs. 45.54 (0-105.98) ng/mL, p<0.001] and anti-OxLDL [107.62 (75.68-174.18) U/L vs. 44.13 (18.44-79.76) U/L, p<0.001]. Also, APS patients exhibited a higher positivity rate for OxLDL (88.2% vs. 5.1%, p<0.001) and anti-OxLDL (84.1% vs. 36.5%, p<0.001) compared to HC. APS patients with elevated levels of OxLDL had a higher rate of LAC positivity (68.0% vs. 45.0%, p=0.042). Furthermore, APS patients with positive anti-OxLDL demonstrated a higher occurrence of venous thrombosis (46.2% vs. 18.5%, p=0.008) and a lower rate of Coomb's test positivity (52.6% vs. 76.2%, p=0.049). Multivariate logistic regression revealed that anti-OxLDL positivity (OR 12.424, 95%CI 1.108-139.330, p=0.041) were risk factors for venous thrombotic APS. This study indicates that the presence of anti-OxLDL may serve as potential markers for venous thrombosis in APS patients. OxLDL and anti-OxLDL may function as valuable biomarkers for monitoring APS.

Successfully intravenous thrombolytic therapy in systemic lupus erythematosus-related ischemic stroke: A case report.

Stroke is a relatively frequent complication occurring in patients with systemic lupus erythematosus (SLE). The increasing number of patients with Ischemic Stroke secondary to SLE aroused the clinician's concern. SLE thrombosis markers, diagnostic high-resolution magnetic resonance image (HR-MRI), and therapeutic interventions for acute ischemic stroke were recently coming into focus perspectives from the field. A 42-year-old female with slurred speech and numbness in her left limb was admitted to our hospital. Magnetic resonance imaging (MRI) revealed right thalamic infarction with diffusion-weighted lesions. Prior to admission, the patient had a National Institute of Health Stroke Scale (NIHSS) score of 3. In light of the clinical manifestation, the American Heart Association/American Stroke Association (AHA/ASA) Guidelines for Intravenous Thrombolysis in Acute Ischemic Stroke (2019) should be referred to. The patient was treated with thrombolytic alteplase (rt-PA). The patient was hospitalized for 2 weeks and discharged after his symptoms improved. After thrombolysis, the NIHSS score of the patient decreased to zero. The computed tomography scan was reexamined 24 hours later, and no acute changes or hemorrhage were identified in the infarcted area. Subsequent imaging and serological analyses indicated that HR-MRI of the responsible vessel was negative, but the infarction in this patient was still regarded as being caused by vasculitis of the right posterior cerebral artery in the region supplying the thalamus. This is the first case of successful intravenous thrombolytic therapy with rt-PA in a patient with SLE secondary to stroke with an NIHSS score of 3. This provides further evidence for expanding the reference of indications with rt-PA intravenous thrombolysis.

D-dimer as a Predictor of ICU Admission and Mortality in COVID-19 Patients: Insights From a Two-Year Retrospective Study From a Tertiary Care Center in South India.

Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced pneumonitis results in a prothrombotic and hypercoagulable state. Prognostic indicators are crucial for identifying patients at risk of complications. D-dimer, a degradation product of cross-linked fibrin, is a specific marker for thrombosis. Elevated D-dimer levels have been strongly correlated with poor prognosis and increased severity of illness in COVID-19 patients. Given D-dimer's eight-hour half-life, periodic measurement is necessary to track disease progression. This study aimed to analyze and derive threshold and peak D-dimer values to predict outcomes in COVID-19 patients, comparing those treated in isolation wards to those requiring intensive care. Methods This two-year retrospective observational study included patients above 18 years with confirmed COVID-19. Patients were categorized into those treated in isolation wards and those admitted to the intensive care unit (ICU). Based on the outcome, they were further divided into survivors and non-survivors. Demographic and outcome-related data were collected from the hospital's laboratory information system. Serial D-dimer measurements were taken at eight time points. Statistical analysis was performed using the Mann-Whitney test for laboratory values and the chi-square test for demographic data. Receiver operating characteristic (ROC) curve analysis was utilized to derive critical D-dimer values. The area under the curve (AUC) was calculated for initial and peak D-dimer values. Results Of 2.149 patients with confirmed COVID-19, 811 (38%) presented with elevated D-dimer levels. ICU admission was required for 239 patients, either due to direct admission or worsening conditions. An initial D-dimer value of ≥0.93 mg/L FEU indicated the need for ICU admission, while a peak D-dimer value of 5.65 mg/L FEU predicted mortality. The AUC for the initial D-dimer was 0.60 (95% CI: 0.55-0.64), indicating moderate discriminatory power. The AUC for the peak D-dimer was 0.58 (95% CI: 0.54-0.62), suggesting lower predictive accuracy for peak values. Sensitivity was high for both initial (0.925) and peak (0.960) D-dimer values, although specificity was lower, especially for the peak D-dimer (0.486), resulting in a higher rate of false positives. Among the ICU patients, the age range was 27-97 years, with a mean of 53.5 years. Males were more affected than females (71% vs. 29%), with a male-to-female ratio of 1.4:1. Of the ICU patients, 64.8% recovered, while 35.2% succumbed to the disease. Younger patients (mean age: 50.5 ± 12 years) recovered faster than older patients (mean age: 64 ± 16 years), with a significant difference in recovery time (p < 0.001). Gender did not significantly impact outcomes (p = 0.743). Survivors spent less time in the ICU (3-7 days) compared to non-survivors (4-14 days) (p = 0.041). Conclusion Serial D-dimer monitoring is essential for predicting outcomes and guiding treatment in COVID-19 patients. Initial and peak D-dimer values can help identify patients requiring intensive care and those at risk of mortality, allowing for timely interventions. D-dimer levels should be integrated into routine clinical assessments for managing COVID-19 patients.

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio as novel prognostic biomarkers in BCR-ABL negative myeloproliferative neoplasms.

Higher neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been associated with increased risk of thrombosis, cardiovascular mortality, but their role in myeloproliferative neoplasms (MPN) remains unclear. We analyzed NLR and PLR as prognostic markers for thrombosis and overall survival (OS) in the study that included 461 consecutive MPN patients who were diagnosed from 2018 to 2022 at University center. Twenty age-matched patients without hematological disorder were used as controls. NLR and PLR were significantly increased in whole MPN group compared to controls. NLR was highest in PV > PMF > ET (p < 0.001) while PLR was highest in ET > PMF > PV (p < 0.001). Thrombosis occurrence during follow-up correlated with NLR, NLR ≥ 4.5, presence of ≥ 2 CV factors and previous thrombosis. Arterial thrombosis was associated with previous thrombosis, NLR and NLR ≥ 4.5. Similarly in venous thrombosis previous thrombosis was risk factor, together with NLR, NLR ≥ 4.5, PLR, but also secondary malignancy and female gender. In multivariate Cox model, most important factors for thrombosis development during follow-up were previous thrombosis, NLR ≥ 4.5 and PLR ≥ 500; for arterial thrombosis, NLR ≥ 4.5 and previous thrombosis; for venous thrombosis PLR ≥ 500 and previous thrombosis. Patients with pre-PMF had significantly higher NLR than ET patients. In multivariate Cox regression model, most important factors associated with survival were NLR ≥ 4.5 and PLR ≥ 500. This study highlights strong prognostic correlation of NLR ≥ 4.5 and PLR ≥ 500 with development of thrombosis and OS in MPN. Besides previous thrombosis, most important factor associated with development of arterial thrombosis is NLR ≥ 4.5 and for venous PLR ≥ 500. Our results revealed that NLR ≥ 4.5 could be used as additional marker to distinguish ET from prePMF.

SARS-CoV-2 spike aggravates lupus nephritis and lung fibrosis in systemic lupus erythematosus

ObjectiveCOVID-19 induces the development of autoimmune diseases, including SLE, which are characterised by inflammation, autoantibodies and thrombosis. However, the effects of COVID-19 on SLE remain unclear.MethodsWe investigated the effects of...

IgA Anti-β2-Glycoprotein I Antibodies as Markers of Thrombosis and Severity in COVID-19 Patients.

Patients with COVID-19 may develop a hypercoagulable state due to tissue and endothelial injury, produced by an unbalanced immune response. Therefore, an increased number of thromboembolic events has been reported in these patients. The aim of this study is to investigate the presence of antiphospholipid antibodies (aPL) in COVID-19 patients, their role in the development of thrombosis and their relationship with the severity of the disease. In this retrospective study, serum samples from 159 COVID-19 patients and 80 healthy donors were analysed for the presence of aPL. A total of 29 patients (18.2%) and 14 healthy donors (17.5%) were positive for aPL. Nineteen COVID-19 patients (12%) but no healthy donor presented a positive percentage of the IgA isotype aPL. IgA anti-β2-glycoprotein I antibodies (anti-β2GPI) were the most frequent type (6.3%) in patients but was not detected in any healthy donor. The positivity of this antibody was found to be significantly elevated in patients with thromboembolic events (25% vs. 5%, p = 0.029); in fact, patients with positive IgA anti-β2GPI had an incidence of thrombosis over six times higher than those who had normal antibody concentrations [OR (CI 95%) of 6.67 (1.5-30.2), p = 0.014]. Additionally, patients with moderate-severe disease presented a higher aPL positivity than patients with mild disease according to the Brescia (p = 0.029) and CURB-65 (p = 0.011) severity scales. A multivariate analysis showed that positivity for IgA anti-β2GPI is significantly associated with disease severity measured by CURB-65 [OR (CI 95%) 17.8 (1.7-187), p = 0.0016]. In conclusion, COVID-19 patients have a significantly higher positive percentage of the IgA isotype aPL than healthy donors. IgA anti-β2GPI antibodies were the most frequently detected aPL in COVID-19 patients and were associated with thrombosis and severe COVID-19 and are thus proposed as a possible marker to identify high-risk patients.

Thrombosis marker levels at various levels of chronic obstructive pulmonary disease: degree of obstruction and severity

Thrombosis marker levels at various levels of chronic obstructive pulmonary disease: degree of obstruction and severity

Computer based visualization of clot structures in extracorporeal membrane oxygenation and histological clot investigations for understanding thrombosis in membrane lungs.

Extracorporeal membrane oxygenation (ECMO) was established as a treatment for severe cardiac or respiratory disease. Intra-device clot formation is a common risk. This is based on complex coagulation phenomena which are not yet sufficiently understood. The objective was the development and validation of a methodology to capture the key properties of clots deposed in membrane lungs (MLs), such as clot size, distribution, burden, and composition. One end-of-therapy PLS ML was examined. Clot detection was performed using multidetector computed tomography (MDCT), microcomputed tomography (μCT), and photography of fiber mats (fiber mat imaging, FMI). Histological staining was conducted for von Willebrand factor (vWF), platelets (CD42b, CD62P), fibrin, and nucleated cells (4', 6-diamidino-2-phenylindole, DAPI). The three imaging methods showed similar clot distribution inside the ML. Independent of the imaging method, clot loading was detected predominantly in the inlet chamber of the ML. The μCT had the highest accuracy. However, it was more expensive and time consuming than MDCT or FMI. The MDCT detected the clots with low scanning time. Due to its lower resolution, it only showed clotted areas but not the exact shape of clot structures. FMI represented the simplest variant, requiring little effort and resources. FMI allowed clot localization and calculation of clot volume. Histological evaluation indicated omnipresent immunological deposits throughout the ML. Visually clot-free areas were covered with leukocytes and platelets forming platelet-leukocyte aggregates (PLAs). Cells were embedded in vWF cobwebs, while vWF fibers were negligible. In conclusion, the presented methodology allowed adequate clot identification and histological classification of possible thrombosis markers such as PLAs.

Influence of Covid-19 disease on hemostasis dynamics during extracorporeal membrane oxygenation (ECMO)1.

COVID-19 causes a considerable degradation of pulmonary function to the point of an acute respiratory distress syndrome (ARDS). Over the course of the disease the gas exchange capability of the lung can get impaired to such an extent that extracorporeal membrane oxygenation (ECMO) is needed as a life-saving intervention. In patients COVID-19 as well as ECMO may cause severe coagulopathies which manifest themselves in micro and macro thrombosis. Previous studies established D-dimers as a marker for critical thrombosis of the ECMO system while on admission increased D-dimers are associated with a higher mortality in COIVD-19 patients. It is therefore crucial to determine if COVID-19 poses an increased risk of early thrombosis of the vital ECMO system. 40 patients who required ECMO support were enrolled in a retrospective analysis and assigned into 2 groups. The COVID group consist of 20 COVID-19 patients who required ECMO support (n = 20), whereas 20 ECMO patients without COVID-19 were assigned to the control group. D-dimers, fibrinogen, antithrombin III (AT III), lactate dehydrogenase (LDH) and platelet count were analysed using locally weighted scatterplot smoothing and MANOVAs. The analysis of both groups shows highly significant differences in the dynamics of hemostasis. The increase in D-dimers that is associated with thrombosis of the ECMO systems occurs in COVID-19 patients around 2 days earlier (p = 2,8115 10-11) while fibrinogen is consumed steadily. In the control group fibrinogen levels increase rapidly after ten days with a plateau phase of around five days (p = 1,407 10-3). Both groups experience a rapid increase in AT III after start of support by ECMO (p = 5,96 10-15). In the COVID group platelet count decreased from 210 giga/l to 130 giga/l within eight days, while in the same time span in the control group platelets decreased from 180 giga/l to 105 giga/l (p = 1,1 10-15). In both groups a marked increase in LDH beyond 5000 U/l occurs (p = 3,0865 10-15). The early increase in D-dimers and decrease in fibrinogen suggests that COVID-19 patients bear an increased risk of early thrombosis of the ECMO system compared to other diseases treated with ECMO. Additionally, the control group shows signs of severe inflammation 10 days after the start of ECMO which were absent in COVID-19 patients.

The proteasome inhibitor carfilzomib exerts anti-inflammatory and antithrombotic effects on the endothelium

BackgroundCarfilzomib (CFZ) is a second-generation proteasome inhibitor used to treat multiple myeloma. Potent inhibition of the proteasome results in chronic proteotoxic endoplasmic reticulum (ER) stress, leading to apoptosis. While CFZ has improved survival rates in multiple myeloma, it is associated with an increased risk of cardiovascular adverse effects. While this has been putatively linked to cardiotoxicity, CFZ could potentially also exhibit adverse effects on the endothelium. ObjectivesTo investigate the effects of CFZ on the endothelium. MethodsHuman umbilical vein endothelial cells (HUVECs) were treated with CFZ, and expression of relevant markers of ER stress, inflammation, and thrombosis was measured and functionally assessed. ResultsCFZ failed to induce ER stress in HUVECs but induced the expression of Kruppel-like factor 4, endothelial nitric oxide synthase, tissue plasminogen activator, and thrombomodulin and reduced tumor necrosis factor alpha (TNFα)-mediated intercellular adhesion molecule 1 and tissue factor expression, suggesting a potential protective effect on the endothelium. Consistent with these observations, CFZ reduced leukocyte adhesion under shear stress and reduced factor Xa generation and fibrin clot formation on the endothelium following TNFα treatment and inhibited von Willebrand factor (VWF) and angiopoietin-2 exocytosis from Weibel–Palade bodies. Subsequently, CFZ inhibited the formation of VWF-platelet strings, and moreover, media derived from myeloma cell lines induced VWF release, a process also inhibited by CFZ. ConclusionThese data demonstrate that CFZ is unable to induce ER stress in confluent resting endothelial cells and can conversely attenuate the prothrombotic effects of TNFα on the endothelium. This study suggests that CFZ does not negatively alter HUVECs, and proteasome inhibition of the endothelium may offer a potential way to prevent thrombosis.

Idiopathic multicentric Castleman disease - TAFRO results in high levels of mTOR activator SVEP1, tissue factor, and endotheliopathy

AbstractIdiopathic multicentric Castleman disease (iMCD) is an inflammatory disease associated with a cytokine storm, activation of the PI3K/AKT/mTOR pathway, coagulopathy, and increased risk of thrombosis. The mechanisms underlying these pathologic processes remain elusive. We studied novel markers of mTOR activation and thrombosis in 1 patient with typical features of iMCD with TAFRO (thrombocytopenia, anasarca, fevers, reticulin myelofibrosis, and organomegaly) syndrome (iMCD-TAFRO). Plasma levels of SVEP1 (Sushi, von Willebrand factor type A, epidermal growth factor, and pentraxin domain–containing 1 protein), a newly identified mTOR activator associated with cardiovascular diseases and dementia, in addition to cytokines, chemokines and components of the coagulation cascade and complement system were evaluated by enzyme-linked immunosorbent assay (ELISA) and arrays. Compared with healthy controls, a 15-fold increase in SVEP1 was observed. High levels of factor VIIa/antithrombin and microparticles expressing functional tissue factor (TF) were detected. The anticoagulants thrombomodulin and soluble endothelial protein C receptor were elevated, indicating shedding from endothelial cells. Plasminogen activator inhibitor 1 was increased, consistent with hypofibrinolysis, whereas high levels of C3b and C5a are in keeping with complement activation. Furthermore, markers of endothelial cell activation (e.g. von Willebrand factor, angiopoietin-2), cell adhesion molecules, and angiogenesis mediators were upregulated. SVEP1 emerges as a potential mechanism of mTOR activation in iMCD-TAFRO, while multiple pathways influence coagulopathy. Immunothrombosis emerges as a potential therapeutic target for iMCD.

Pharmacologic targeting of coagulation factors XII and XI by monoclonal antibodies reduces thrombosis in nitinol stents under flow

BackgroundCardiovascular implantable devices, such as vascular stents, are critical for the treatment of cardiovascular diseases. However, their success is dependent on robust and often long-term antithrombotic therapies. Yet, the current standard-of-care therapies often pose significant bleeding risks to patients. Coagulation factor (F)XI and FXII have emerged as potentially safe and efficacious targets to safely reduce pathologic thrombin generation in medical devices. ObjectivesTo study the efficacy of monoclonal antibody–targeting FXII and FXI of the contact pathway in preventing vascular device–related thrombosis. MethodsThe effects of inhibition of FXII and FXI using function-blocking monoclonal antibodies were examined in a nonhuman primate model of nitinol stent–related thrombosis under arterial and venous flow conditions. ResultsWe found that function-blocking antibodies of FXII and FXI reduced markers of stent-induced thrombosis in vitro and ex vivo. However, FXI inhibition resulted in more effective mitigation of thrombosis markers under varied flow conditions. ConclusionThis work provides further support for the translation of contact pathway of coagulation inhibitors for their adjunctive clinical use with cardiovascular devices.

The effects of dienogest and combined oral contraceptives on protein S-specific activity in endometriosis patients

ObjectiveOne serious side effect of combined oral contraceptives (COCs) is venous thromboembolism. Reduced activity in activated protein C-related coagulation pathways is attributable to low protein S activity in one-third of Japanese patients with deep vein thrombosis. Herer, we quantified the behavior of protein S-specific activity in response to dienogest (DNG) and COCs using the protein S-specific activity assay system to explore its potential utility as a thrombosis marker. Study DesignThis was a prospective cohort study. Female patients aged 20 – 49 years who were starting drug treatment for endometriosis using DNG or COCs were enrolled. Blood samples were taken before treatment and at the first, third, and sixth months of treatment. To analyze the primary endpoints, changes in total protein S antigen levels, total protein S activity, and protein S-specific activity from baseline to each time point were estimated using a linear mixed-effects model. All statistical analyses were performed in the SAS software version 9.4 (SAS Institute, Cary, NC). A two-sided P < 0.05 was considered statistically significant. Results64 patients took DNG and 34 patients took COCs. Protein S-specific activity did not change significantly from baseline in the six months after treatment started in either group. In the DNG group, total protein S activity and total protein S antigen levels increased slightly from baseline levels after the treatment. The means for total protein S activity and total protein S antigen levels in the COC group remained within reference limits, but they both decreased markedly in the first month and stayed low. Protein S-specific activity in four women remaind below the reference limit throughout the whole study period, suggesting they may have potential protein S deficiencies. ConclusionThe effects of DNG on protein S were negligible, though both total protein S activity and antigen levels decreased soon after COC treatment began and remained low. As there was no VTE event during the study, further studies with larger numbers of patients will be needed to confirm that protein S-specific activity can be a surrogate maker of VTE risk.

Omega-3 Fatty Acids and Markers of Thrombosis in Patients with Atrial Fibrillation.

Omega-3 fatty acids (n-3 FAs) are associated with a lower risk of ischemic stroke in patients with atrial fibrillation (AF). Antithrombotic mechanisms may in part explain this observation. Therefore, we examined the association of n-3 FAs with D-dimer and beta-thromboglobulin (BTG), markers for activated coagulation and platelets, respectively. The n-3 FAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and alpha-linolenic acid (ALA) were determined via gas chromatography in the whole blood of 2373 patients with AF from the Swiss Atrial Fibrillation cohort study (ClinicalTrials.gov Identifier: NCT02105844). In a cross-sectional analysis, we examined the association of total n-3 FAs (EPA + DHA + DPA + ALA) and the association of individual fatty acids with D-dimer in patients with detectable D-dimer values (n = 1096) as well as with BTG (n = 2371) using multiple linear regression models adjusted for confounders. Median D-dimer and BTG levels were 0.340 ug/mL and 448 ng/mL, respectively. Higher total n-3 FAs correlated with lower D-dimer levels (coefficient 0.94, 95% confidence interval (Cl) 0.90-0.98, p = 0.004) and lower BTG levels (coefficient 0.97, Cl 0.95-0.99, p = 0.003). Likewise, the individual n-3 FAs EPA, DHA, DPA and ALA showed an inverse association with D-dimer. Higher levels of DHA, DPA and ALA correlated with lower BTG levels, whereas EPA showed a positive association with BTG. In patients with AF, higher levels of n-3 FAs were associated with lower levels of D-dimer and BTG, markers for activated coagulation and platelets, respectively. These findings suggest that n-3 FAs may exert antithrombotic properties in patients with AF.

PROGNOSTIC MARKERS FOR THROMBOTIC EVENTS IN PATIENTS WITH GASTRIC OR COLORECTAL ADENOCARCINOMAS.

The relationship between thrombosis and cancer is based on evidence that cancer promotes prothrombotic changes in the host hemostatic system. The activation of blood coagulation is closely linked to tumor growth and dissemination. To evaluate whether quantifications of plasma circulation tumor deoxyribonucleic acid (DNA) and thrombin-antithrombin complex could act as predictors for thrombotic events and death in patients with gastric or colorectal adenocarcinomas, while also evaluating the Karnofsky Performance Status. Eighty-two patients were included in the study and divided into three groups: controls (n=20), gastric adenocarcinomas (n=21), and colorectal adenocarcinomas (n=41). In order to calculate the Karnofsky index, information was collected to measure the patient's ability to perform common daily tasks. The following serum measurements were conducted: complete blood count, platelet count, extracellular deoxyribonucleic acid, and thrombin-antithrombin complex. Ten patients (16%) experienced thrombosis during treatment. Patients with thrombin-antithrombin complex levels greater than 0.53 had a five-times higher risk of thrombosis. Lower Karnofsky Performance Status was also a risk factor for the event in this population. Neither thrombin-antithrombin complex nor plasma circulation tumor DNA were predictors of death after multivariate adjustment. Thus, Karnofsky index signaled a better overall survival prognosis for colorectal and gastric adenocarcinoma patients. Thrombin-antithrombin complex acts as a marker for thrombosis in patients with colorectal and gastric adenocarcinomas. We recommend prophylactic anticoagulation when the Karnofsky value is low and/or the thrombin-antithrombin complex concentration is greater than 0.53 ng/ml.

Adhatoda vasica and Tinospora cordifolia extracts ameliorate clinical and molecular markers in mild COVID-19 patients: a randomized open-label three-armed study

BackgroundSARS-CoV-2 infections caused mild-to-moderate illness. However, a sizable portion of infected people experience a rapid progression of hyper-inflammatory and hypoxic respiratory illness that necessitates an effective and safer remedy to combat COVID-19.MethodsA total of 150 COVID-19-positive patients with no to mild symptoms, between the age groups 19–65 years were enrolled in this randomized, open-labeled three-armed clinical trial. Among them, 136 patients completed the study with RT-PCR negative reports. The patients received herbal drugs orally (Group A (Adhatoda vasica; AV; 500 mg; n = 50); Group B (Tinospora cordifolia; TC; 500 mg; n = 43), and Group C (AV + TC; 250 mg each; n = 43)) for 14 days. Clinical symptoms, vital parameters, and viral clearance were taken as primary outcomes, and biochemical, hematological parameters, cytokines, and biomarkers were evaluated at three time points as secondary outcomes.ResultsWe found that the mean viral clearance time was 13.92 days (95% confidence interval [CI] 12.85–14.99) in Group A, 13.44 days (95% confidence interval [CI] 12.14–14.74) in Group B, and 11.86 days (95% confidence interval [CI] 10.62–13.11) days in Group C. Over a period of 14 days, the mean temperature in Groups A, and B significantly decreased linearly. In Group A, during the trial period, eosinophils, and PT/INR increased significantly, while monocytes, SGOT, globulin, serum ferritin, and HIF-1α, a marker of hypoxia reduced significantly. On the other hand, in Group B hsCRP decreased at mid-treatment. Eosinophil levels increased in Group C during the treatment, while MCP-3 levels were significantly reduced.ConclusionsAll the patients of the three-armed interventions recovered from COVID-19 and none of them reported any adverse effects from the drugs. Group C patients (AV + TC) resulted in a quicker viral clearance as compared to the other two groups. We provide the first clinical report of AV herbal extract acting as a modifier of HIF-1α in COVID-19 patients along with a reduction in levels of ferritin, VEGF, and PT/INR as the markers of hypoxia, inflammation, and thrombosis highlighting the potential use in progression stages, whereas the TC group showed immunomodulatory effects.Trial registration Clinical Trials Database -India (ICMR-NIMS), CTRI/2020/09/028043. Registered 24th September 2020, https://www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=47443&EncHid=&modid=&compid=%27,%2747443det%27Graphical

Investigating Thrombosis Risk Factors in Sickle Cell Disease Utilizing Archetypal Analysis

Background: Thrombosis in sickle cell disease (SCD) affects both the arterial and venous vasculature with devastating consequences. Individuals with SCD have an increased risk of venous thromboembolism (VTE). The risks are multifactorial with prior studies identifying both VTE-specific and SCD-specific risk factors. Machine learning (ML) offers the potential to detect non-linear relationships in complex multifactorial diseases and has successfully predicted outcomes in deeply phenotyped patients. We investigated whether archetypal analysis (AA), a method of ML would identify clinical and laboratory factors associated with arteriovenous thrombosis in patients with SCD. Methods: We retrospectively analyzed a prospective longitudinal cohort of patients with SCD (NCT00011648) studied between 2000-2017. A prior history of VTE and/or stroke at the time of study entry as captured by the electronic medical record was used to define index “cases”. SCD patients without a history of thrombosis were “controls”. The demographic and clinical characteristics of cases and controls were compared using Wilcoxon rank-sum test for continuous and Fisher's exact test for categorical variables. Unsupervised AA was used to identify patterns of clinical and laboratory test characteristics within the entire cohort of patients including cases and controls. AA identifies patterns are on the convex hull that encloses all patients in the cohort in the high-dimensional feature space. Once specific archetypes were identified, the frequency of each archetype was determined within cases and controls. In addition, we describe the age and laboratory characteristics of the archetypes that were significantly more prevalent in cases as compared to controls. Results: The cohort consisted of 633 out of 862 patients that had their whole exome sequenced. A combined total of 160 arterial and venous thrombosis events was detected in 148/633 patients (24%) with half (n=79) attributable to arterial stroke and half (n=81) attributable to VTE [Table 1]. A small proportion of patients had both arterial and venous thrombosis (n=12). The median age (31 years, p=0.94) and sex were similar between the cases (n=148) and controls (n=485). The distribution of genotypes was similar between the two groups (p=0.09). A significantly higher proportion of patient with thrombosis had a prior history of blood transfusion (p&amp;lt;0.0001) and history of insertion of a central venous access device (p=&amp;lt;0.0001) [Table 1]. History of medical management with hydroxyurea was similar among the cases and controls (p=0.70). Compared to controls, the cases had elevated laboratory parameters including AST levels (p=0.02), and serum ferritin (p&amp;lt;0.0001), while HbS percentages were significantly lower (p&amp;lt;0.0001). Based on the minimum error in matrix factorization, a total of 15 archetypes were identified in the cohort [Figure 1]. Each patient was decomposed as a weighted combination of the 15 archetypes. The contributing archetypes for each patient were those archetypes that have non-zero weights. Among those 15 archetypes, archetypes 9, 14 and 15 were significantly more enriched among the cases compared to controls (p&amp;lt;0.02) [Figure 1]. We observed elevated serum ferritin levels and low levels of HbS across the three archetypes, which are consistent with the previously identified risk factors [Figure 1]. Conclusions: Machine-identified archetypes are objective and reproducible feature representations. Archetype analysis-based machine learning appears to hold promise to identify both traditional VTE and SCD-specific risks for clinical thrombosis. Future studies will utilize archetypal analysis to investigate associations between clinical, laboratory and genetic markers for thrombosis and assess their reproducibility using validation cohorts.