Role of HIF-1α in hypercoagulable state of COPD in rats.

OBJECTIVE: To explore the role of HIF-1α in hypercoagulable state of COPD induced by lipopolysaccharide plus smoking in rats. It also has to explore the regulatory mechanism of HIF-1α-EPO/EDN-1/VEGF pathway by using its activator and inhibitor. METHODS: 60 Sprague-Dawley rats (SD rats) were randomly divided into healthy control group, COPD hypercoagulable control group, activator group, and inhibitor group with 15 rats in each group. The healthy control group was fed freely. The other groups were given smoke and lipopolysaccharide by tracheal instillation to establish the experimental animal model of COPD hypercoagulability. After successful modeling, each experimental group was given 0.9 % sodium chloride solution and corresponding drugs by intraperitoneal injection for 7 days. Lung function was detected after drug administration. Hematoxylin-eosin staining was used to observe the pathological changes of lung tissue. Enzyme-linked immunosorbent assay was used to detect serum D-D,F (1 + 2),IL-6,TNF-α. The mRNA expressions of HIF-1α, EPO, EDN-1, and VEGF were detected by RT-PCR. Western-Blot and IHC were used to detect the expression of HIF-1α, EPO, EDN-1, and VEGF in lung tissue of rats. RESULTS: Compared with the healthy control group, rats in COPD hypercoagulable control group had COPD symptoms/signs, decreased lung function, increased the expression of serum D-D and F (1 + 2), increased the expression of inflammatory factors IL-6,TNF-α, and increased the expression of proteins HIF-1α, EPO, EDN-1 and VEGF. Compared with COPD hypercoagulable control group, lung function in activator group and inhibitor group had no obvious changes. The expressions of serum D-D,F (1 + 2),IL-6,TNF-α in activator group have increased noticeably. The expressions of proteins HIF-1α, EPO, EDN-1, and VEGF have further increased. Compared with COPD hypercoagulable control group, the expression of serum D-D, F (1 + 2), HIF-1α, EPO, EDN-1, and VEGF in the inhibitor group decreased. CONCLUSION: HIF-1α-EPO/EDN-1/VEGF pathway plays an important role in the hypercoagulable state of COPD. HIF-1α inhibitor can improve airway inflammation and reduce hypercoagulability in COPD model rats.

Persistent hypofibrinolysis in severe COVID-19 associated with elevated fibrinolysis inhibitors activity.

Hypercoagulability and reduced fibrinolysis are well-established complications associated with COVID-19. However, the timelines for the onset and resolution of these complications remain unclear. The aim of this study was to evaluate, in a cohort of COVID-19 patients, changes in coagulation and fibrinolytic activity through ROTEM assay at different time points during the initial 30 days following the onset of symptoms in both mild and severe cases. Blood samples were collected at five intervals after symptoms onset: 6-10 days, 11-15 days, 16-20 days, 21-25 days, and 26-30 days. In addition, fibrinogen, plasminogen, PAI-1, and alpha 2-antiplasmin activities were determined. Out of 85 participants, 71% had mild COVID-19. Twenty uninfected individuals were evaluated as controls. ROTEM parameters showed a hypercoagulable state among mild COVID-19 patients beginning in the second week of symptoms onset, with a trend towards reversal after the third week of symptoms. In severe COVID-19 cases, hypercoagulability was observed since the first few days of symptoms, with a tendency towards reversal after the fourth week of symptoms onset. A hypofibrinolytic state was identified in severe COVID-19 patients from early stages and persisted even after 30 days of symptoms. Elevated activity of PAI-1 and alpha 2-antiplasmin was also detected in severe COVID-19 patients. In conclusion, both mild and severe cases of COVID-19 exhibited transient hypercoagulability, reverted by the end of the first month. However, severe COVID-19 cases sustain hypofibrinolysis throughout the course of the disease, which is associated with elevated activity of fibrinolysis inhibitors. Persistent hypofibrinolysis could contribute to long COVID-19 manifestations.

The coagulation status in women of endometriosis with stage IV.

BACKGROUND: Endometriosis is considered as a systemic disease with the presence of proinflammatory cytokines in the circulation, which drives hypercoagulable state of endometriosis. Currently, endometriosis is classified into four stages: I (minimal), II (mild), III (moderate) and IV (severe). The aim of this study is to investigate the correlations between inflammatory markers and coagulation factors in patients diagnosed of endometriosis with stage IV. METHODS: This retrospective case-control study included 171 endometriosis patients with stage IV and 184 controls. Continuous data were expressed by mean ± standard deviation. Mann-Whitney U and χ2 tests were used to compare the medians and frequencies among the groups. Spearman analysis was conducted to determine the correlation among the measured parameters. The diagnostic values of the parameters differentiating endometriomas were tested by receiver operating characteristic (ROC) curve. RESULTS: The time of activated partial thromboplastin time (APTT) was decreased and the concentration of fibrinogen (FIB) and neutrophil-to-lymphocyte ratio (NLR) were increased in women of endometriosis with stage IV. The APTT were negatively correlated with NLR while the concentrations of FIB were positively correlated with NLR. The ROC analysis showed that the Area under the curve (AUC) of FIB was 0.766 (95% confidence interval:0.717-0.814) with sensitivity and specificity reaching 86.5 and 60.9%, respectively. The AUC of CA125 and CA199 was 0.638 (95% confidence interval: 0.578-0.697), 0.71 (95% confidence interval: 0.656-0.763) with sensitivity and specificity reaching 40.9 and 91.8%, 80.7 and 56.5% respectively. The combination of these factors showed the highest AUC of 0.895 (0.862-0.927) with sensitivity of 88.9% and specificity of 77.7%. CONCLUSION: In the present study, we found that inflammatory factors showed significant correlation with APTT or FIB in endometriosis with stage IV. Moreover, the coagulation factors combined with CA125 and CA199 were more reliable for identifying the endometriosis with stage IV.

Ventricular mural thrombi - An occult occurrence?

Background: Ventricular mural thrombi are rare occurrences and form one of the common mechanical complications of myocardial infarctions. They also occur in patients with nonischemic myocardial disorders and even in those devoid of cardiac diseases. Clinical detection often depends on the size of the thrombi. Aim: This study was aimed at ascertaining the etiopathogenesis of mural thrombi with a clinicopathologic correlation. Materials and Methods: This was a 12-year retrospective observational study reviewing the autopsy records of all cases showing ventricular mural thrombi. The location, size, morphology, and histologic appearances of the thrombi were noted. The cases, depending on the etiology, were categorized into myocardial ischemic (Group 1), myocardial nonischemic (Group 2), and non-myocardial (Group 3) causes. These features were correlated with the clinical settings. Results: There were 93 cases of mural thrombi with an almost equal sex distribution and a mean age of 45.9 years. The cause was ischemic heart disease in most of the patients (Group 1, 46.2%), while 21.5% and 32.3% of patients belonged to Group 2 and Group 3, respectively. Unlike the large and dominantly left ventricular thrombi seen in Group 1, the other two groups frequently had biventricular involvement, location in the intertrabecular spaces, and a high microscopic detection. Clinical diagnosis had been made in only 3.2% of patients. Thromboembolism was noted in other organs in 34.4% of the total cases. Conclusion: Ventricular thrombi should be ruled out in patients with evidence of systemic and/or pulmonary thromboembolism, even in those without any cardiac disorders.

Prognostic impact of hypercoagulability and impaired fibrinolysis in acute myocardial infarction.

AIMS: Atherothrombotic events are influenced by systemic hypercoagulability and fibrinolytic activity. The present study evaluated thrombogenicity indices and their prognostic implications according to disease acuity. METHODS AND RESULTS: From the consecutive patients undergoing percutaneous coronary intervention (PCI), those with thrombogenicity indices (n = 2705) were grouped according to disease acuity [acute myocardial infarction (AMI) vs. non-AMI]. Thrombogenicity indices were measured by thromboelastography (TEG). Blood samples for TEG were obtained immediately after insertion of the PCI sheath, and TEG tracing was performed within 4 h post-sampling. Major adverse cardiovascular events (MACE, a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) were evaluated for up to 4 years. Compared with non-AMI patients, AMI patients had higher platelet-fibrin clot strength [maximal amplitude (MA): 66.5 ± 7.8 vs. 65.3 ± 7.2 mm, P < 0.001] and lower fibrinolytic activity [clot lysis at 30 min (LY30): 0.9 ± 1.8% vs. 1.1 ± 1.9%, P < 0.001]. Index AMI presentation was associated with MA [per one-mm increase: odds ratio (OR): 1.024; 95% confidence interval (CI): 1.013-1.036; P < 0.001] and LY30 (per one% increase: OR: 0.934; 95% CI: 0.893-0.978; P = 0.004). The presence of high platelet-fibrin clot strength (MA ≥68 mm) and low fibrinolytic activity (LY30 < 0.2%) was synergistically associated with MACE occurrence. In the multivariable analysis, the combined phenotype of 'MA ≥ 68 mm' and 'LY30 < 0.2%' was a major predictor of post-PCI MACE in the AMI group [adjusted hazard ratio (HR): 1.744; 95% CI: 1.135-2.679; P = 0.011], but not in the non-AMI group (adjusted HR: 1.031; 95% CI: 0.499-2.129; P = 0.935). CONCLUSION: AMI occurrence is significantly associated with hypercoagulability and impaired fibrinolysis. Their combined phenotype increases the risk of post-PCI atherothrombotic event only in AMI patients. These observations may support individualized therapy that targets thrombogenicity for better outcomes in patients with AMI. CLINICAL TRIAL REGISTRATION: Gyeongsang National University Hospital (G-NUH) Registry, NCT04650529.

The correlation between anti-phospholipase A2 receptor antibodies and hypercoagulability in patients with idiopathic membranous nephropathy.

BACKGROUND: Patients with idiopathic membranous nephropathy (IMN) are more likely to be complicated by venous thromboembolism (VTE). The aim of the study was to investigate the potential association between anti-phospholipase A2 receptor (PLA2R) antibodies and hypercoagulability in patients with IMN. METHODS: A total of 168 patients with biopsy-proven IMN and 36 patients with biopsy-proven minimal change disease (MCD) were enrolled in this study. The clinical data, serum anti-PLA2R antibodies and coagulation-related indices of the patients were retrospectively analyzed. RESULTS: Patients with IMN were categorized into glomerular PLA2R staining-positive (GAg+) IMN group and glomerular PLA2R staining-negative (GAg-) IMN group in the study. Patients with IMN who were GAg + had lower PT, APTT and R time than patients with IMN who were GAg-, while the CI value was higher in patients with IMN who were GAg+. Patients with IMN who were GAg + were divided into the SAb+/GAg + group and the SAb-/GAg + group. Patients with IMN who were SAb+/GAg + had higher Fib and MA values than patients with IMN who were SAb-/GAg+. Correlation analysis showed that serum anti-PLA2R antibodies were positively correlated with fibrinogen, D-dimer, K time, CI value, α-angle, and MA value. Multiple linear regression analysis indicated that anti-PLA2R antibodies were independently correlated with fibrinogen and MA value. CONCLUSION: Our study provides a new perspective on the underlying mechanisms of hypercoagulability in patients with IMN. Anti-PLA2R antibodies are associated with hypercoagulability in patients with IMN and may affect coagulation in patients with IMN by affecting platelet aggregation function and fibrinogen counts.

[A case of COVID-19 associated ischemic colitis].

Ischemic colitis is a disease in which local tissue in the intestinal wall dies to varying degrees due to insufficient blood supply to the colon. Risk factors include cardiovascular disease, diabetes, chronic kidney disease, chronic obstructive pulmonary disease, etc. Typical clinical manifestations of the disease are abdominal pain and hematochezia. The most common locations are the watershed areas of splenic flexure and rectosigmoid junction. The lesions are segmental and clearly demarcated from normal mucosa under endoscopy. The digestive tract is a common extra-pulmonary organ affected by the novel coronavirus, which can be directly damaged by the virus or indirectly caused by virus-mediated inflammation and hypercoagulability. The corona virus disease 2019 (COVID-19) associated intestinal injury can be characterized by malabsorption, malnutrition, intestinal flora shift, etc. CT can show intestinal ischemia, intestinal wall thickening, intestinal wall cystoid gas, intestinal obstruction, ascites, intussusception and other signs. In this study, we reported a case of ischemic colitis in a moderate COVID-19 patient. The affected area was atypical and the endoscope showed diffuse lesions from the cecum to the rectosigmoid junction. No signs of intestinal ischemia were found on imaging and clear thrombosis in small interstitial vessels was found in pathological tissue. Combined with the fact that the patient had no special risk factors in his past history, the laboratory tests indicated elevated ferritin and D-dimer, while the autoantibodies and fecal etiology results were negative, we speculated that the hypercoagulability caused by novel coronavirus infection was involved in the occurrence and development of the disease in this patient. After prolonged infusion support and prophylactic anti-infection therapy, the patient slowly resumed diet and eventually went into remission. Finally, we hoped to attract clinical attention with the help of this case of moderate COVID-19 complicated with ischemic colitis which had a wide range of lesions and a slow reco-very. For patients with abdominal pain and blood in the stool after being diagnosed as COVID-19, even if they are not severe COVID-19, they should be alert to the possibility of ischemic colitis, so as not to be mistaken for gastrointestinal reactions related to COVID-19.

[Comparison of thrombodynamic methods and routine hemostasis tests in the evaluation of hypercoagulable syndrome in chronic glomerulonephritis].

BACKGROUND: Nephrotic syndrome (NS) is associated with a high risk of thrombotic complications. In this group of patients, routine local tests for assessing hemostasis do not accurately reflect hypercoagulable state. Global functional tests for assessing hemostasis, including thrombodynamics (TD), are considered promising for assessing disorders in the blood coagulation system of these patients. AIM: To compare the rate of hypercoagulability according to routine hemostatic tests and TD and to evaluate the factors associated with increased risk of thrombotic complications in patients with chronic glomerulonephritis (CGN). MATERIALS AND METHODS: The study included 94 patients with active CGN who were not receiving anticoagulant therapy; 63 (80.3%) patients had NS, and 31 (19.7%) had active CGN without NS. Hemostasis parameters were assessed using local coagulation tests and TD test. Using logistic regression analysis, factors associated with the risk of thrombosis were assessed. RESULTS: Of the 94 patients with active CGN in 63 without preventive anticoagulant therapy, hypercoagulability according to routine tests was detected in 6 (9.5%) patients with NS and in 3 (9.7%) patients without NS (p<0.05). Hypercoagulability according to the TD test was detected in 24 (53.9%) patients with NS and in 5 (32.2%) without NS (p<0.05). The formation of spontaneous clots was observed in 29 (30.9%) of patients with CGN, most of them 24 (83%) with NS. 10.6% of patients in our cohort experienced thromboembolic events. The risk of thromboembolic events according to the univariate regression analysis was associated with older age, higher lipid levels, use of glucocorticosteroids and detection of spontaneous clots by the TD test. No association of thromboembolic events with abnormalities in routine hemostasis tests was obtained. CONCLUSION: In patients with CGN with nephrotic syndrome, hypercoagulability is detected in 9.5% of cases with routine coagulation tests and in 53.9% of cases with TD test. Detection of spontaneous clots by TD test is associated with a risk of thromboembolic events.

[Exploring the mechanism of IgA vasculitis pathogenesis through the interaction of thrombin and inflammatory factors using urinary proteomics]. / è¿ç”¨å°¿è›‹ç™½ç»„å­¦æŠ€æœ¯æŽ¢ç´¢å‡è¡€é ¶ä¸Žç‚Žç—‡å› å­ç›¸äº’ä½œç”¨å‚ä¸ŽIgAè¡€ç®¡ç‚Žå‘ç— çš„æœºåˆ¶.

OBJECTIVES: To explore the evidence, urinary biomarkers, and partial mechanisms of hypercoagulability in the pathogenesis of IgA vasculitis (IgAV). METHODS: Differential expression of proteins in the urine of 10 healthy children and 10 children with IgAV was screened using high-performance liquid chromatography-tandem mass spectrometry, followed by Reactome pathway analysis. Protein-protein interaction (PPI) network analysis was conducted using STRING and Cytoscape software. In the validation cohort, 15 healthy children and 25 children with IgAV were included, and the expression levels of differential urinary proteins were verified using enzyme-linked immunosorbent assay. RESULTS: A total of 772 differential proteins were identified between the IgAV group and the control group, with 768 upregulated and 4 downregulated. Reactome pathway enrichment results showed that neutrophil degranulation, platelet activation, and hemostasis pathways were involved in the pathogenesis of IgAV. Among the differential proteins, macrophage migration inhibitory factor (MIF) played a significant role in neutrophil degranulation and hemostasis, while thrombin was a key protein in platelet activation and hemostasis pathways. PPI analysis indicated that thrombin directly interacted with several proteins involved in inflammatory responses, and these interactions involved MIF. Validation results showed that compared to healthy children, children with IgAV had significantly higher urine thrombin/creatinine and urine MIF/creatinine levels (P<0.05). CONCLUSIONS: Thrombin contributes to the pathogenesis of IgAV through interactions with inflammatory factors. Urinary thrombin and MIF can serve as biomarkers reflecting the hypercoagulable and inflammatory states in children with IgAV.

[Urinary protein and renal pathological features in children with immunoglobulin A vasculitis with nephritis and hypercoagulability]. / 儿童IgAè¡€ç®¡ç‚Žè‚¾ç‚Žä¼´é«˜å‡çŠ¶æ€çš„å°¿è›‹ç™½å’Œè‚¾è„ç— ç†ç‰¹å¾åˆ†æž.

OBJECTIVES: To study the association of hypercoagulability with urinary protein and renal pathological damage in children with immunoglobulin A vasculitis with nephritis (IgAVN). METHODS: Based on the results of coagulation function, 349 children with IgAVN were divided into a hypercoagulability group consisting of 52 children and a non-hypercoagulability group consisting of 297 children. Urinary protein and renal pathological features were compared between the two groups, and the factors influencing the formation of hypercoagulability in children with IgAVN were analyzed. RESULTS: Compared with the non-hypercoagulability group, the hypercoagulability group had significantly higher levels of urinary erythrocyte count, 24-hour urinary protein, urinary protein/creatinine, urinary immunoglobulin G/creatinine, and urinary N-acetyl-ß-D-glucosaminidase (P<0.05). The hypercoagulability group also had a significantly higher proportion of children with a renal pathological grade of III-IV, diffuse mesangial proliferation, capillary endothelial cell proliferation, or >25% crescent formation (P<0.05). The multivariate logistic regression analysis showed that capillary endothelial cell proliferation and glomerular crescent formation >25% were associated with the formation of hypercoagulability in children with IgAVN (P<0.05). CONCLUSIONS: The renal injury in IgAVN children with hypercoagulability is more severe, with greater than 25% crescent formation and increased proliferation of glomerular endothelial cells being important contributing factors that exacerbate the hypercoagulable state in IgAVN.

Acute pancreatitis induces a transient hypercoagulable state in murine models.

BACKGROUND/OBJECTIVES: Although understudied, risk of venous thromboembolism (VTE) appears to be increased during acute pancreatitis (AP). We aimed to further characterize a hypercoagulable state associated with AP utilizing thromboelastography (TEG), a readily available, point of care test. METHODS: AP was induced in C57/Bl6 mice using l-arginine and caerulein. TEG was performed with citrated native samples. The maximum amplitude (MA) and coagulation index (CI), a composite marker of coagulability, were evaluated. Platelet aggregation was assessed using whole blood collagen-activated platelet impedance aggregometry. Circulating tissue factor (TF), the initiator of extrinsic coagulation, was measured with ELISA. A VTE model using IVC ligation followed by measurement of clot size and weight was evaluated. After IRB approval and consent, blood samples from patients hospitalized with a diagnosis of AP were evaluated by TEG. RESULTS: Mice with AP displayed a significant increase in MA and CI, consistent with hypercoagulability. Hypercoagulability peaked at 24 h after induction of pancreatitis, then returned to baseline by 72 h. AP resulted in significantly increased platelet aggregation and elevated circulating TF. Increased clot formation with AP was observed in an in vivo model of deep vein thrombosis. In a proof of concept, correlative study, over two thirds of patients with AP demonstrated an elevated MA and CI compared to the normal range, consistent with hypercoagulability. CONCLUSIONS: Murine acute pancreatitis results in a transient hypercoagulable state that can be assessed by TEG. Correlative evidence for hypercoagulability was also demonstrated in human pancreatitis. Further study to correlate coagulation measures to incidence of VTE in AP is warranted.

Adiposity and Coagulation: Predicting Postinjury Coagulation With Advanced Imaging Analysis.

INTRODUCTION: Anatomic distribution of adipose tissue has demonstrated variable associations with hypercoagulability. Utilizing a retrospective analysis of a previously enrolled prospective cohort, we assessed computed tomography (CT) scan-based anthropometric and volumetric measures of adiposity as predictors of postinjury hypercoagulability. METHODS: Segmentation analysis of arrival CT scans in significantly injured patients at a single level-I trauma center enrolled from December 2017 to August 2021 were analyzed for anthropometric indices of waist circumference (WC) and sagittal abdominal diameter (SAD), and volumetric parameters of visceral adipose tissue, superficial/deep subcutaneous adipose tissue, psoas/paravertebral muscle volume, and abdominal wall muscle volume. Associations with thromboelastography (TEG) were explored. RESULTS: Data from 91 patients showed strong correlations between body mass index and standard anthropometric measures of WC and SAD (P < 0.001); calculated volumes of subcutaneous adipose tissue and visceral adipose tissue (P < 0.001); and ratios of subcutaneous adipose:psoas muscle (SP ratio) and visceral adipose:psoas muscle ratio (both with P < 0.001, respectively). Correlation between TEG maximal amplitude (MA) and body mass index and SAD were not significant, with only weak correlation between TEG-MA and WC (r = 0.238, P = 0.041). Moderate but significant correlations existed between SP ratio and TEG-MA (r = 0.340, P = 0.005), but not visceral adipose:psoas muscle ratio (r = 0.159, P = 0.198). The relationship between TEG-MA and SP ratio remained significant when adjusted for injury severity score and lactate level (b = 0.302, P = 0.001). CONCLUSIONS: SP ratio is more strongly correlated with TEG-MA than standard obesity measures, and independently predicts increasing clot strength/stability after injury. Coagulation-relevant measures of sarcopenic obesity can be measured on CT scan, and may be used to optimize thromboprophylaxis strategies for obese injured patients.

Advances in Management of the Stroke Etiology One-Percenters.

PURPOSE OF REVIEW: Uncommon causes of stroke merit specific attention; when clinicians have less common etiologies of stoke in mind, the diagnosis may come more easily. This is key, as optimal management will in many cases differs significantly from "standard" care. RECENT FINDINGS: Randomized controlled trials (RCT) on the best medical therapy in the treatment of cervical artery dissection (CeAD) have demonstrated low rates of ischemia with both antiplatelet and vitamin K antagonism. RCT evidence supports the use of anticoagulation with vitamin K antagonism in "high-risk" patients with antiphospholipid antibody syndrome (APLAS), and there is new evidence supporting the utilization of direct oral anticoagulation in malignancy-associated thrombosis. Migraine with aura has been more conclusively linked not only with increased risk of ischemic and hemorrhagic stroke, but also with cardiovascular mortality. Recent literature has surprisingly not provided support the utilization of L-arginine in the treatment of patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); however, there is evidence at this time that support use of enzyme replacement in patients with Fabry disease. Additional triggers for reversible cerebral vasoconstriction syndrome (RCVS) have been identified, such as capsaicin. Imaging of cerebral blood vessel walls utilizing contrast-enhanced MRA is an emerging modality that may ultimately prove to be very useful in the evaluation of patients with uncommon causes of stroke. A plethora of associations between cerebrovascular disease and COVID-19 have been described. Where pertinent, authors provide additional tips and guidance. Less commonly encountered conditions with updates in diagnosis, and management along with clinical tips are reviewed.

Antithrombin Activity Is Associated with Persistent Thromboinflammation and Mortality in Patients with Severe COVID-19 Illness.

INTRODUCTION: Severe COVID-19 illness can lead to thrombotic complications, organ failure, and death. Antithrombin (AT) regulates thromboinflammation and is a key component of chemical thromboprophylaxis. Our goal was to examine the link between AT activity and responsiveness to thromboprophylaxis, markers of hypercoagulability, and inflammation among severe COVID-19 patients. METHODS: This was a single-center, prospective observational study enrolling SARS-CoV-2-positive patients admitted to the intensive care unit on prophylactic enoxaparin. Blood was collected daily for 7 days to assess AT activity and anti-factor Xa levels. Patient demographics, outcomes, and hospital laboratory results were collected. Continuous variables were compared using Mann-Whitney tests, and categorical variables were compared using χ2 tests. Multivariable logistic regression was used to determine the association between AT activity and mortality. RESULTS: In 36 patients, 3 thromboembolic events occurred, and 18 (50%) patients died. Patients who died had higher fibrinogen, D-dimer, and C-reactive protein (CRP) levels and lower AT activity. Reduced AT activity was independently associated with mortality and correlated with both markers of hypercoagulability (D-dimer) and inflammation (CRP). CONCLUSION: Low AT activity is associated with mortality and persistent hypercoagulable and proinflammatory states in severe COVID-19 patients. The anti-thromboinflammatory properties of AT make it an appealing therapeutic target for future studies.

Left atrial Thrombus formation after discontinuation of anticoagulation in patient with severe bioprosthetic mitral stenosis.

BACKGROUND: Mitral valve stenosis can be a highly symptomatic condition with significant complications if left untreated. In such cases, mitral valve replacement with a bioprosthetic or mechanical valve may be a viable solution to prevent progressive disease. Current guidelines do not recommend continued anticoagulation beyond 6 months for patients who have undergone bioprosthetic valve replacement without a separate indication for anticoagulation. With this case discussion we aim to 1) Review the current indications for anticoagulation for bioprosthetic mitral valves in patients without atrial fibrillation and 2) Discuss the constellation of comorbidities that may affect the decision to begin anticoagulation therapy. CASE PRESENTATION: We present a case describing a 55-year-old male with end-stage renal disease, coronary artery disease with coronary artery bypass graft surgery, and bioprosthetic mitral valve replacement 2 years prior with rapid degeneration of the replaced valve and on warfarin without a clear indication for anticoagulation. The patient was admitted for symptomatic, severe mitral stenosis and consideration of transcatheter mitral valve-in-valve replacement. During hospital admission, warfarin was discontinued and replaced with prophylactic anticoagulation. However, 8 days after warfarin cessation an intraoperative transesophageal echocardiography revealed a newly developed large left atrial thrombus leading to cancellation of the planned operation. CONCLUSIONS: This patient developed a left atrial thrombus after discontinuing warfarin in the setting of rapidly deteriorating bioprosthetic valve stenosis and vascular comorbidities. The decision to discontinue warfarin was made in concordance with current guidelines, which do not indicate systemic anticoagulation post 3-6 months after bioprosthetic valve replacement without separate indication for anticoagulation. This case identifies the need to investigate rebound hypercoagulability and further risk stratify comorbidities which may independently increase the risk of clot formation in the setting of severe mitral valve stenosis.

Enhanced thrombin generation detected with ST-Genesia analyzer in patients with newly diagnosed multiple myeloma.

The issue of how to identify newly diagnosed multiple myeloma (NDMM) patients requiring thromboprophylaxis remains unsolved. Several changes in thrombin generation (TG)-derived parameters have been described in multiple myeloma (MM) patients recently. Assessment of prothrombotic risk with a fully automated TG analyzer could reduce interlaboratory variability. Our objective was to determine whether ST-Genesia® could reveal a hypercoagulable state in NDMM compared to healthy controls. We conducted a multicenter observational study of NDMM requiring initial treatment to compare TG parameters obtained with ST-Genesia® analyzer and ST-ThromboScreen® reagent with a control group. Clinical data were obtained from medical records and blood samples were collected before initial anti-myeloma therapy. A thrombophilia panel was performed in all patients. Compared to age- and sex-matched controls (n = 83), NDMM patients (n = 83) had significantly higher peak height, higher velocity index, shorter time-to-peak and lower percentage of endogenous thrombin potential (ETP) inhibition after adding thrombomodulin (TM) (ETP%inh). NDMM on prophylactic low molecular weight heparin (LMWH) showed reduced both peak height and velocity index compared to NDMM who had not yet started VTE prophylaxis, similar to that of controls. Moreover, partial correction of ETP%inh was observed in MM patients on LMWH. The presence of a thrombophilia did not modify the TG phenotype. Untreated NDMM patients showed an enhanced TG, regardless of their thrombophilia status. They generate a higher peak of thrombin, take less time to produce it, and exhibit resistance to TM inhibition. Our findings suggest that standard prophylactic dose of LMWH may reduce TG at levels of healthy controls.

Association between the platelet/high-density lipoprotein cholesterol ratio and nonalcoholic fatty liver disease: results from NHANES 2017-2020.

The platelet/high-density lipoprotein cholesterol ratio (PHR) is a novel inflammatory and hypercoagulability marker that represents the severity of metabolic syndrome. Liver metabolic syndrome is manifested by nonalcoholic fatty liver disease (NAFLD), which is associated with inflammation and hypercoagulability. This cross-sectional investigation aimed to identify the relationship between PHR and NAFLD. Participants in the National Health and Nutrition Examination Survey (NHANES) 2017-2020 were evaluated for hepatic steatosis and fibrosis using vibration-controlled transient elastography. The PHR was calculated as the ratio of platelets to high-density lipoprotein cholesterol. Increased PHR was associated with an increased incidence of NAFLD and hepatic fibrosis. Compared with patients in the first PHR quartile, after adjustment for clinical variables, the corresponding odds ratio (OR) for NAFLD in the fourth quartile was 2.36 (95% CI, 1.76 to 3.18) (p < 0.05); however, the OR for hepatic fibrosis was not statistically significant (p > 0.05). Furthermore, restricted cubic spline analyses showed an S-shaped association between PHR and NAFLD and an L-shaped relationship between PHR and hepatic fibrosis. The results support the effectiveness of PHR as a marker for NAFLD and hepatic fibrosis. Therefore, interventions to improve the PHR may be of benefit in reducing the incidence of both hepatic steatosis and fibrosis.

Thromboelastography (TEG) parameters as potential predictors of malignancy and tumor progression in colorectal cancer.

PURPOSE: The purpose of this study was to investigate the use of thromboelastography (TEG) in patients with colorectal cancer and to examine whether the TEG parameters can be used as potential markers for disease screening and prediction of disease severity. METHODS: One-hundred fifteen healthy controls (HC), 43 patients with benign adenoma (BA), and 387 patients with colorectal cancers (CRC) were included in the study. TEG parameters (reaction time, R; clot kinetics, K; alpha angle, α-angle; maximum amplitude, MA), conventional laboratory parameters, and clinical information were collected and analyzed among the HC, BA, and CRC groups. Receiver operating characteristics (ROC) were used for differential analysis. The correlation between TEG parameters and pathological information of CRC (differentiation degree, vaso-nerve infiltration, TNM stage) was analyzed. The differences in TEG parameters at different stages of disease and pre-/post operation were compared. RESULTS: Shorter K and higher α-angle/MA were found in patients with CRC compared with HC and BA (P < 0.001). TEG parameters demonstrated moderate diagnostic value (distinguish CRC from HC + BA: K-AUC = 0.693, α-angle-AUC = 0.687, MA-AUC = 0.700) in CRC but did not outperform traditional laboratory parameters. TEG hypercoagulability was closely associated with tumor markers (carcinoma embryonic antigen and carbohydrate antigen 19-9) and pathological information (differentiation degree, vaso-nerve infiltration, and TNM stage) (P < 0.05). Trend analysis showed that K decreased, but α-angle/MA increased gradually as the tumor progressed (P < 0.001). K- and α-angle showed slightly better sensitivity in predicting advanced tumors compared to traditional laboratory parameters. In CRC patients, 3-6 months after tumor resection, K [from 1.8 (1.5, 2.3) to 1.9 (1.6, 2.6)], α-angle [from 65.3 (59.0, 68.6) to 63.7 (56.6, 68.5)], and MA [from 61.0 (58.2, 66.0) to 58.9 (55.8, 61.3)] exhibited modest improvements compared to their preoperative values (P < 0.05). CONCLUSION: TEG parameters possess moderate diagnostic value in CRC diagnosis and predicting advanced tumors, and they are closely linked to surgical interventions. Although TEG parameters do not significantly outperform traditional laboratory parameters, they still hold promise as potential alternative indicators in CRC patients.

Association of circulating proprotein convertase subtilisin/kexin type 9 concentration with coagulation abnormalities in patients with primary membranous nephropathy.

OBJECTIVES: The aims of the study were to explore the potential associations between plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) and coagulation indexes in patients with primary membranous nephropathy (PMN). METHODS: A total of 87 patients diagnosed with PMN were enrolled in our study. 30 healthy participants were recruited to match PMN participants. Plasma PCSK9 concentrations were tested by enzyme-linked immunosorbent assay (ELISA). Correlations between PCSK9 and coagulation abnormalities in patients with PMN were analyzed using univariate and multiple linear regression analysis. RESULTS: Plasma PCSK9 levels in patients with PMN were significantly higher than that in healthy controls [232.0 (143.5, 359.5) ng/mL vs. 166.8 (129.7, 199.7) ng/mL; p = 0.001]. Plasma levels of PCSK9 were positively correlated with factor VIII, factor IX, factor XI, log-transformed tissue factor, protein C and protein S (r = 0.267, p = 0.013; r = 0.496, p < 0.001; r = 0.217, p = 0.045; r = 0.584, p < 0.001; r = 0.372, p = 0.001; r = 0.282, p = 0.011). In multiple linear regression analysis, PCSK9 concentration was independently and positively correlated with factor VIII, factor IX, and tissue factor (ß = 0.186, p = 0.047; ß = 0.325, p = 0.001; ß = 0.531, p < 0.001; respectively). PCSK9 concentration was independently and negatively correlated with PT (ß= -0.343, p = 0.011). CONCLUSION: Plasma PCSK9 levels had good positive correlations with procoagulant clotting factors and negative correlations with PT in PMN, which might provide novel information with regard to PCSK9 and hypercoagulability in PMN.

Therapeutic effects and mechanism of human amnion-derived mesenchymal stem cells on hypercoagulability in a uremic calciphylaxis patient.

Calciphylaxis is a rare cutaneous vascular disease that manifests with intolerable pains, non-healing skin wounds, histologically characterized by calcification, fibrointimal hyperplasia, and microvessel thrombosis. Currently, there are no standardized guidelines for this disease. Recent studies have recognized a high prevalence of thrombophilias and hypercoagulable conditions in calciphylaxis patients. Here, we report a case of uremic calciphylaxis patient whom was refractory to conventional treatments and then received a salvage strategy with intravenous and local hAMSC application. In order to investigate the therapeutic mechanism of hAMSCs from the novel perspective of hypercoagulability, coagulation-related indicators, wound status, quality of life and skin biopsy were followed up. Polymerase chain reaction (PCR) was performed to determine the distribution of hAMSCs in multiple tissues including lung, kidney and muscle after infusion of hAMSCs for 24 h, 1 week and 1 month in mice aiming to investigate whether hAMSCs retain locally active roles after intravenous administration. Improvement of hypercoagulable condition involving correction of platelet, D-dimer and plasminogen levels, skin regeneration and pain alleviation were revealed after hAMSC administration over one-year period. Skin biopsy pathology suggested regenerative tissues after 1 month hAMSC application and full epidermal regeneration after 20 months hAMSC treatment. PCR analysis indicated that hAMSCs were homing in lung, kidney and muscle tissues of mice even until tail vein injection of hAMSCs for 1 month. We propose that hypercoagulability is a promising therapeutic target of calciphylaxis patients, which can be effectively improved by hAMSC treatment.