AT-III Levels Research Articles

Effects of Dexmedetomidine on Oxidative Stress, Inflammatory Response, Coagulation Function and Hemodynamics in Patients Undergoing Hysterectomy

<i>Objective</i> To investigate the effects of dexmedetomidine on oxidative stress, inflammatory response, coagulation function and hemodynamics in patients undergoing hysterectomy. <i>Methods</i> 92 patients who underwent hysterectomy in our hospital from January to September 2023 were selected as subjects. According to the difference in anesthesia, 46 patients were in the control group and 46 in the dexmedetomidine group. Patients in the control group received midazolam anesthesia, and patients in the dexmedetomidine group received dexmedetomidine anesthesia. The changes of oxidative stress, inflammatory response, coagulation function and hemodynamics were compared between T0 (before anesthesia), T1 (10 min after anesthesia), T2 (after extubation) and T3 (24 h after surgery). <i>Results</i> At T0, there was no significant difference in T-AOC, GSH-Px, MBP, MCP-1, AT III, FDP, MAP and SpO<sub>2</sub> between the two groups (<I>P</I>>0.05). At the time of T1, T2 and T3, the two groups of patients T-AOC, GSH-Px were all lower than T0 (<I>P</I><0.05), MBP and MCP-1 were all higher than T0 (<I>P</I><0.05). The levels of T-AOC and GSH-Px in the dexmedetomidine group were significantly higher than those in the control group (<I>P</I><0.05). The levels of MCP-1 was significantly lower than that of the control group (<I>P</I><0.05). At the T1 and T2, ATIII levels was lower than T0 (<I>P</I><0.05), and FDP levels was higher than T0 (<I>P</I><0.05). At the time of T3, the levels of ATIII and FDP in the dexmedetomidine group recovered to the normal level of T0. There was no significant change in MAP and SpO<sub>2</sub> at each time in the dexmedetomidine group (<I>P</I>>0.05). <i>Conclusion</i> Dexmedetomidine can more effectively alleviate the oxidative stress response in patients with hysterectomy, reduce the symptoms of inflammation in patients, improve the coagulation status of patients and have less influence on hemodynamics, and have high clinical value.

Risk factors analysis and the establishment of nomogram prediction model for PICC-related venous thrombosis in patients with lymphoma: a double-center cohort-based case-control study.

The objective of this study is to examine the risk factors associated with the occurrence of PICC-Related Venous Thrombosis (PICC-RVTE) in individuals diagnosed with lymphoma, as well as to develop a predictive risk nomogram model. A total of 215 patients with lymphoma treated at Yunnan Provincial Tumor Hospital from January 2017 to December 2020 were retrospectively evaluated as the training cohort; 90 patients with lymphoma treated at the Department of Oncology of the First People's Hospital of Anning, Affiliated to Kunming University of Science and Technology during the January 2021 to September 2023 were evaluated as the validation cohort. Independent influencing factors were analyzed by logistic regression, a nomogram was developed and validated, and the model was evaluated using internal and external data cohorts for validation. A total of 305 lymphoma patients were selected and 35 (11.48%) PICC-RVTE occurred, the median time was 13 days. The incidence within 1-2week was 65.71%. Multivariate analysis suggested that the activity amount, thrombosis history(within the last 12 months), ATIII, Total cholesterol and D-dimer levels were independently associated with PICC-RVTE, and a nomogram was constructed based on the multivariate analysis. ROC analysis indicated good discrimination in the training set (area under the curve [AUC] = 0.907, 95%CI:0.850-0.964) and the testing set (AUC = 0.896, 95%CI: 0.782-1.000) for the PICC-RVTE nomogram. The calibration curves showed good calibration abilities, and the decision curves indicated the clinical usefulness of the prediction nomograms. Patients should be advised to undergo color Doppler ultrasound system testing within two week after the implantation of a PICC catheter to detect PICC-RVTE at an early stage. The validated nomogram can be used to predict the risk of catheter-related thrombosis (CRT) in patients with lymphoma who received at least one chemotherapy after PICC catheterization, no bleeding tendency, no recent history of anticoagulant exposure and no severe heart, lung, renal insufficiency. This model has the potential to assist clinicians in formulating individualized treatment strategies for each patient.

Abstract 246: Consumptive Coagulopathy is Associated With Poor Neurological Outcome in Patients With Refractory VT/VF Cardiac Arrest Requiring Extracorporeal Cardiopulmonary Resuscitation

Introduction: Post cardiac arrest syndrome is associated with altered hemostasis. This is aggravated further by the foreign surface in the extracorporeal circuit leading to a coagulofibrinolytic imbalance. Aim: We examined the serial changes of consumptive coagulopathy markers and their association with neurologic outcomes. Methods: A single-center, retrospective cohort study of consecutive patients with VT/VF cardiac arrest meeting criteria for ECMO-facilitated resuscitation (ECPR) between December 2015 and January 2023 were included. Consumptive coagulopathy markers (INR, D-dimer, platelet count, antithrombin III and fibrinogen) were obtained after VA ECMO cannulation and serially on day 1, 2 and 3. We compared the coagulation profiles of patients who had a neurologically favorable outcome (defined as Cerebral Performance Categories (CPC) 1-2) and those with a neurologically unfavorable outcome (CPC 3-5). Results: Of 258 patients, 82 (32%) survived to hospital discharge. Of these, 87% (71/82) survived with favorable neurological outcome. Prolonged INR, elevated D-dimer levels and decreased ATIII levels were associated (p<0.05) with neurologically unfavorable survival and decreased over time (p<0.05)(Figure1). Platelet count and fibrinogen levels were not associated with neurological outcomes. In adjusted analysis (including age, lactate, CPR time and use of dual antiplatelet therapy), each point increase in the INR on day 1, 2 and 3 was associated with neurologically unfavorable survival (OR 4.4, p=0.01; OR 7.14, p=0.04; OR 8.5, p=0.03 respectively). Conclusion: Markers of consumptive coagulopathy with a prolonged INR are associated with unfavorable neurological outcome.

Venous Thromboembolism Risk Assessment among Beta-thalassemia Patients

BACKGROUND: Thromboembolic (TE) disorders are among the most common complications of beta-thalassemia. We designed this cross-sectional study to investigate the state of hypercoagulability and platelet activation in patients with beta-thalassemia. PATIENTS AND METHODS: Seventy-five patients diagnosed with beta-thalassemia by hemoglobin electrophoresis were divided into three groups of 25 patients each: Group I (thalassemia trait), Group II (thalassemia intermedia [TI]), and Group III (thalassemia major). In addition, 50 healthy individuals were included as controls. Both patients and control groups were subjected to clinical and laboratory assessment, which included measurement of protein C, anti-thrombin III, D-dimer, CD41, CD42, CD61, and CD62P, and detection of beta-chain mutations. RESULTS: Levels of the platelet activation marker CD62P were significantly higher in beta-thalassemia patients (26.28 ± 18.01%) than in controls (4.78 ± 2.27%) (P < 0.001). The D-dimer level was significantly higher in beta-thalassemia patients (348.41 ± 571.01 ng/mL) than in controls (71.6 ± 39.61 ng/mL) (P < 0.001). Protein-C and AT-III levels were significantly lower in beta-thalassemia patients (71.45 ± 13.26%, 78.38 ± 15.32%) in comparison with controls (94.9 ± 13.03%, 96.52 ± 11.01%) (P < 0.001 and P < 0.001, respectively). TE disorders were found in 7/25 (9%) beta-thalassemia patients, especially in older and postsplenectomy patients. TE was most commonly found in beta-TI. Beta-chain mutations were found in all patients with TE disorders, especially compound heterozygous intervening sequence (IVS) (IVS1.6 [T > C]/IVS1.110 [G > A]). CONCLUSION: Postsplenectomy teenagers and adults with beta-thalassemia with lower levels of natural anticoagulant in the blood, an increased level of D-dimer, and platelet activator factor had a significantly higher risk for TE than those with childhood beta-thalassemia and the control group. In comparison with other beta-thalassemia patients, TI with beta-chain mutations is more likely to develop TE.

Antithrombin III levels in critically ill surgical patients: do they correlate with VTE?

ObjectiveAntithrombin III (ATIII) deficiency may result from hereditary or acquired reduction in ATIII levels and is associated with an increase in venous thromboembolism (VTE) in the general population. VTE is...

Plasma Antithrombin III Levels Can Be a Prognostic Factor in Liver Cirrhosis Patients with Portal Vein Thrombosis.

Liver function influences the plasma antithrombin (AT)-III levels. AT-III is beneficial for patients with portal vein thrombosis (PVT) and low plasma AT-III levels. However, whether these levels affect prognosis in patients with cirrhosis-associated PVT remains unknown. This retrospective study involved 75 patients with cirrhosis and PVT treated with danaparoid sodium with or without AT-III. The plasma AT-III level was significantly lower in patients with liver failure-related death than in those with hepatocellular carcinoma (HCC)-related death (p = 0.005), although the Child-Pugh and albumin-bilirubin (ALBI) scores were not significantly different between these two groups. Receiver operating characteristic curve analysis of the plasma AT-III levels showed cutoff values of 54.0% at 5-year survival. Low plasma AT-III levels (<54.0%) were associated with significantly worse prognosis than high levels in both overall survival (p = 0.0013) and survival excluding HCC-related death (p < 0.0001). Low plasma AT-III (<54.0%) was also associated with a significantly worse prognosis among patients with Child-Pugh A/B or ALBI grade 1/2 (p < 0.0001). Multivariate analyses indicated that low plasma AT-III levels (<54.0%) were an independent prognostic factor for poor survival outcome. Low plasma AT-III levels may be associated with mortality, particularly liver failure-related death, independent of liver function.

Circulating Naturally-Occurring Anticoagulants before Treatment and after Recovery from SARS-CoV-2 Infection in Ghana

Background: Disturbance in naturally-occurring anticoagulants may contribute to the hypercoagulable state in COVID-19. This study determined the plasma antigen levels of protein C (PC), protein S (PS), antithrombin-III (AT-III), and thrombomodulin (TM) before treatment and after recovery from COVID-19. Materials and Methods: This cross-sectional study, conducted from February to August 2022 at Kumasi South Hospital, recruited sixty-five RT-PCR-confirmed COVID-19 participants. A venous blood sample was taken for full blood count (FBC) analysis using a 3-part fully automated haematology analyzer, and PC, PS, AT-III, and TM antigen levels measured using ELISA. The data were analyzed using SPSS version 26.0. P&lt;0.05 was considered statistically significant. Results: Severe COVID-19 participants had relatively lower haemoglobin (p&lt;0.001), RBC (p&lt;0.001), HCT% (p&lt;0.001) and platelets (p&lt;0.001), but higher RDW-CV% (p=0.013), WBC (p&lt;0.001), and absolute lymphocyte counts (p&lt;0.001) compared to those with the non-severe form of the disease. The overall prevalence of anaemia among the participants was 58.5%, and 32 (84.2%) and 6 (15.8%) of the anaemic participants had mild and moderate anaemia respectively. Protein C (p&lt;0.001), PS (p&lt;0.001) and ATIII (p&lt;0.001) levels were lower among the severe COVID-19 participants than in the non-severe group. But severe COVID-19 group had higher TM levels (p&lt;0.001) than the non-severe group. Again, participants had higher haemoglobin (p&lt;0.001), RBC (p&lt;0.001), HCT% (p=0.049), absolute neutrophil count (p&lt;0.001) and platelets (p&lt;0.001) after recovery from COVID-19 than the values on admission. Additionally, after recovery, participants had higher levels of PC (p&lt;0.001), PS (p&lt;0.001), and ATIII (p&lt;0.001), but reduced TM (p&lt;0.001). Conclusion: Severe COVID-19 patients had higher PC, PS, and AT-III, but lower TM levels. The changes in circulating anticoagulants may contribute to the hypercoagulable state of COVID-19. Blood cell indices are negatively affected during COVID-19. Complete recovery from the SARS-CoV-2 infection normalised the haematological indices. Assessment of naturally-occurring anticoagulants and the provision of anticoagulants are recommended in the management of COVID-19. Doi: 10.28991/SciMedJ-2022-04-04-01 Full Text: PDF

MiR-3064-5p and miR-4745-5p affect heparin sensitivity in patients undergoing cardiac surgery by regulating AT-III and factor X mRNA levels.

Subject: Perioperative regulation of coagulation function through heparin in patients undergoing cardiac surgery with cardiopulmonary bypass is an important part of performing cardiac surgery, and postoperative bleeding due to abnormal coagulation function caused by differences in heparin sensitivity in different individuals is an independent risk factor for postoperative complications and death. Method: Using an online database, 10 miRNAs interacting with AT-III and FX genes were predicted. Patients were divided into three groups according to the difference in activated clotting time (ACT) after the first dose of heparin (2.5 mg kg−1): group A: hyposensitive group (ACT < 480 s); group B: sensitive group (480 s ≤ ACT ≤ 760 s); and group C: hypersensitive group (ACT > 760 s). Perioperative and 24 h postoperative blood loss and other clinical data of patients in the three groups were recorded. Blood samples were collected before surgery, and RT-PCR was used to detect the levels of AT-III and FX gene mRNA and the levels of predicted 10 miRNAs. Result: Heparin sensitivity was positively correlated with AT-III mRNA levels and negatively correlated with FX gene mRNA levels in the three groups, and the blood loss in group B was significantly lower than that in groups A and C, which was statistically significant (p < 0.05). miR-3064-5p and miR-4745-5p expression levels were significantly different among group A, group B, and group C (p < 0.05) and were closely correlated with AT-III and FX gene mRNA expression levels, respectively. Conclusion: Differences in heparin sensitivity in patients undergoing cardiac surgery were associated with the mRNA expression of AT-III and FX genes, and the expression levels of miR-3064-5p and miR-4745-5p were found to be closely related to the AT-III and FX gene mRNA, respectively, indicating that miR-3064-5p and miR-4745-5p affect the differences in heparin sensitivity among different individuals by regulating the mRNA expression levels of AT-III and FX genes. Clinical Trial Registration: http://www.chictr.org.cn/abouten.aspx, identifier registration number: ChiCTR-2100047348

Implications of Ezetimibe in Combination with Low- to Moderate-Intensity Atorvastatin Adjuvant Aspirin Therapy for Cerebrovascular Disease.

Objective To analyze the significance of ezetimibe in combination with low- to moderate-intensity atorvastatin adjuvant aspirin therapy for cerebrovascular disease. Methods 110 patients with cerebrovascular disease treated in our hospital from June 2020 to June 2021 were selected and divided into 55 patients in the control group and 55 patients in the study group according to the lottery method. After a comprehensive examination, patients in the two groups should be given aspirin for treatment; the control group was treated with conventional dose of atorvastatin on top of the above, and the study group was given ezetimibe and medium-low-dose atorvastatin on top of aspirin treatment, activities of daily living (ADL) score, carotid artery intima-media thickness, lipid level, coagulation level, clinical effect, and adverse rate of the two groups which were tested and compared. Results After treatment, ADL score, high-density leptin cholesterol (HDL-C), and ATIII levels increased, while carotid artery media thickness, triglyceride (TG), total cholesterol (TC), low-density leptin cholesterol (LDL-C), DD, PC, and hs-CRP levels decreased (P < 0.05). After treatment, ADL score, HDL-C, and ATIII levels were higher in the study group. The levels of carotid media thickness, TG, TC, LDL-C, DD, PC, and hs-CRP were significantly lower (P < 0.05). The clinical effect of the study group was outstanding (P < 0.05). The defect rate of the study group was lower than that of the control group, but there was no difference (P < 0.05). Conclusion Ezetimibe combined with medium- and low-intensity atorvastatin with aspirin in the treatment of cerebrovascular diseases can effectively improve the coagulation function of patients, reduce the level of inflammatory factors in patients, and improve the level of blood lipids in patients, with high safety and worthy of clinical application.

S2939 A Rare Case of Superior Mesenteric Vein Thrombosis With Antithrombin III Deficiency and Recent COVID-19 mRNA Vaccination

Introduction: Superior mesenteric vein (SMV) thrombosis is a condition with low incidence but high mortality. It is well-known to occur in the setting of prothrombotic states such as malignancy, local abdominal inflammation, inherited or acquired coagulopathies, and myeloproliferative conditions secondary to JAK-2 mutation. We present a rare case of SMV thrombosis in a patient found to have antithrombin III deficiency with recent COVID-19 mRNA vaccination. Case Description/Methods: A 67-year-old male with past medical history significant for hyperlipidemia and coronary artery disease presented to the emergency department with three days of intermittent lower abdominal pain radiating laterally in a band-like distribution with pressure and bloating sensation. On physical exam his abdomen was mildly distended but soft and non-tender with hypoactive bowel sounds. Computed tomography (CT) of the abdomen and pelvis with intravenous contrast revealed diffuse SMV thrombosis with extension of thrombus into the main and left hepatic portal veins. There was no clear intra-abdominal inflammatory process, no sign of infection or malignancy, and no history of inherited thrombophilia. Patient was started on therapeutic enoxaparin subcutaneously. Further history revealed that he received both doses of the Pfizer-BioNTech (BNT162b2) mRNA COVID-19 vaccine, with the second dose administered 75 days prior to admission. SARS CoV-2 IgG level was 69 AU/mL, which confirmed the presence of circulating IgG antibodies specific for SARS-CoV-2 at high levels. SARS-CoV-2 RNA was not detected on reverse-transcriptase–polymerase-chain-reaction assay of a nasopharyngeal swab. Lab work revealed low antithrombin III (AT III) at 69% and prolonged Russell’s Viper Venom test not corrected by phospholipid reagent. Discussion: It is unclear if this patient’s low ATIII levels were in the setting of acute thrombosis, or if they were low prior to thrombus formation and secondary to circulating Covid-19 antibodies. There have been a few case reports of individuals with vaccine-induced immune-thrombotic thrombocytopenia (ITTP), deep vein thrombosis (DVT), and acquired hemophilia. It is important to bring awareness to uncommon adverse events that may be linked to COVID-19 mRNA vaccine administration so that providers and patients can be aware of the possibility of these events and not delay diagnosis and treatment.Figure 1.: Computed tomography (CT) of the abdomen and pelvis revealing diffuse SMV thrombosis with adjacent fat stranding.

Antithrombin III as predictive indicator of survival in idiopathic pulmonary fibrosis (IPF) patients treated with nintedanib: a preliminary study.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease often managed with nintedanib, a tyrosine kinase inhibitor targeting several profibrotic pathways. Although clotting processes are involved in wound healing and repair in the lung, there are no data on the role of antithrombin III (ATIII) in IPF patients treated with nintedanib. A previous proteomic analysis of serum of IPF patients before and after 1 year of nintedanib treatment showed differential protein expression of ATIII. Here we used quantitative methods to evaluate differential ATIII concentrations in IPF patients before and after 1 year of nintedanib treatment and to assess the potential of ATIII as a prognostic biomarker in IPF patients. Serum levels of ATIII were measured by enzyme-linked immunosorbent assay in 14 IPF patients before and after 1 year of nintedanib treatment. A statistically significant inverse correlation was found between serum ATIII concentrations and pulmonary function test parameters in all patients at baseline and follow up. Baseline serum ATIII and bronchoalveolar lavage (BAL) neutrophils proved to be reliable predictors of poor prognosis. A baseline ATIII threshold of 126.5 μg/mL discriminated survivors from non-survivors. After 12 months of antifibrotic treatment, IPF patients with high serum ATIII concentrations and high BAL neutrophil percentages had a poor prognosis and increased survival risk. The results of this preliminary study suggest that ATIII has potential as a biomarker of IPF severity and in predicting response to nintedanib therapy. As a marker, ATIII showed several advantages over BAL neutrophil percentage.

COAGULATION ASSAYS AND AT-III ON LEVONORGESTREL IMPLANT ACCEPTORS

Background: Indonesia is the fourth most populous country in the world, so the government has focused Family Planning Program using contraception. Implants and IUDs are two most effective reversible contraceptive methods and often used in Indonesia. Implant releases progestin, with most common reported side effect of abnormal bleeding. Specically for levonorgestrel implants, changes in menstrual intervals, duration, volume of menstrual ow can occur. Progestins are believed to cause changes in platelet and blood vessel, leading to hypercoagulability state, which can be assessed through coagulation assays (PT, TT, aPTT) and level of AT-III. Objective: This aims to determine the differences in coagulation assays and AT-III levels between levonorgestrel implant versus IUD acceptors. Methods: This study was an observational analytic study with retrospective cross-sectional design. The population were case population (levonorgestrel implant acceptors) and control population (IUD). A total of 74 respondents were chosen by consecutive sampling. Characteristics data were obtained by interview, anthropometric measurements, and medical records; PT, TT, aPTT, and AT-III data were obtained from blood samples by ELISA method. An independent T-test was used to analyze the data. Results: Mean PT was the same for implant and IUD users, 13.11 seconds (SD=0.81 seconds) (p=0.1,000). Mean TT of implant users was 14.78 seconds (SD=1.18 seconds) and IUD 14.58 seconds. (SD=1.18 seconds) (p=0.75). Mean aPTT for implant users was 30.22 seconds (SD=4.65 seconds) and IUD 30.55 seconds (SD=2.79 seconds) (p=0.200). Mean of ATIII in implant users was 92.18% (SD=9.72%) and IUD 84.79% (SD=14.74%) (p=0.250). Conclusion: No signicant mean differences for PT, TT, aPTT, and AT-III between groups of levonorgestrel implant and IUD acceptors (p value&gt; 0.05).

Predictive Value of Platelet Aggregation Responses and Coagulation Parameters for Thromboembolic Risk in Children with Idiopathic Nephrotic Syndrome.

Introduction: Idiopathicnephrotic syndrome (INS) is the most common renal disease among children. INS present with proteinuria, hyperlipidemia, edema, hypoalbuminemia, and hypercoagulability. A serious consequence of INS is arterial and/or venous thromboembolism e.g., deep vein thrombosis (DVT), pulmonary emboli and renal vein thrombosis. This hypercoagulability may be due to urinary loss of small proteins, specifically antithrombin (AT) III, protein C and S. INS children have been observed to develop thrombocytosis and platelet hyper aggregation leading to increased thromboembolic risk. Aim of the Study: To evaluate the coagulation profile and results of platelet functions during active nephrosis in children with steroid sensitive and steroid resistant INS. Methods: Thirty-six children with INS were studied.Twenty-four steroid sensitive and 12 steroid resistant patients were evaluated for platelet function and coagulation parameters during active nephrosis (either at presentation or relapse). The study also included 15 healthy age and sex matched children as control.Doppler imaging was done to confirm thromboembolic events. Results: Thrombo-embolic complications were observed in 14/36 patients, diagnosed both clinically and/or by doppler.Prolonged PTT was observed during active nephrosis, compared to control. Hypoalbuminemia and hyperlipidemia contributed to hypercoagulability. Mean platelet aggregation to ADP and Ristocetin were significantly elevated among both groups (108.3±10.8% and 104.8±13.2% respectively). Levels of ATIII were significantly reduced, further adds to thrombotic risk. Conclusion: Thromboembolic complications are not uncommon in nephrotic children. Platelet hyperaggregability positively correlated with VTE in INS children and can be a beneficial predictor of thrombosis during active nephrosis especially those past history of VTE.

Evaluation of coagulation parameters in patients with parathyroid adenoma

Parathyroid adenoma is responsible for 80–85% of cases of primary hyperparathyroidism. Increased fibrinogen levels in patients with adenoma may increase the risk of atherosclerosis and cardiovascular events. The aim of this study was to investigate the relationship between coagulation parameters and parathyroid adenoma. A prospective study included 28 female patients with parathyroid adenoma aged 40–88 years and 27 age-matched healthy controls. The coagulation parameters were assessed for each participant. The mean ages of the patient and control groups were 57.7 ± 10.9 and 53.3 ± 9.31 years, respectively. The mean level of protein S activity was 65.79 ± 13.78 in the patient group and 77.00 ± 15.72 in the control group, and the difference was statistically significant (p = 0.013). The mean fibrinogen levels of the patient and control groups were 338.78 ± 63.87 mg/dL and 304.30 ± 45.67 mg/dL, respectively, and a significant difference was found (p = 0.041). However, no significant difference was evident between the two groups with regard to the D-dimer (p = 0.238), aPTT (p = 0.645), INR (p = 0.406), protein C (p = 0.076), and AT-III (p = 0.180) levels. A positive correlation was observed between adenoma volume and fibrinogen in the patient group (r = 0.711, p = 0.001). The protein S levels were lower and the fibrinogen levels higher in the patients with parathyroid adenoma.

Reducing Antithrombin in Plasma to Levels Observed in Fitusiran-Treated Patients Does Not Interfere with Coagulation Assays

Introduction: Fitusiran is being evaluated in phase 3 clinical studies as a once monthly subcutaneously administered RNA interference therapy designed to decrease endogenous expression of the anticoagulant antithrombin (AT). Reducing the anticoagulant potential of AT in the plasma of Hemophilia A and B patients, with or without inhibitors, restores the hemostatic balance and improves thrombin generation potential. Fitusiran and other non-Factor replacement molecules, such as emicizumab, use novel mechanisms to restore hemostasis. Consequently, some standard coagulation assays typically used to measure factor levels, such as the chromogenic, one-stage, and APTT assays have been shown to be affected by emicizumab. In order to assess the potential impact of fitusiran treatment on our ability to measure clotting factor activity in individuals with hemophilia A (HemA), we investigated the effect of decreased AT levels on standard coagulation laboratory assays. The following four assays were evaluated: one stage (OSA) and chromogenic (CSA) factor VIII (FVIII) activity assays, activated partial thromboplastin time (aPTT), and the prothrombin clotting time assay (PT). These assays are relevant to determine the FVIII plasma levels in patients dosed with FVIII replacement factors while treating potential breakthrough bleeds or undergoing surgery. Method and Results: Pooled human HemA plasma was used directly or after AT depletion using an affinity-based method to remove 95% AT activity, resulting in HemA plasma with 5% AT activity. Additional batches of HemA/AT levels were created by AT reconstitution to 10 and 20% AT plasma activity. Subsequently, the 4 HemA plasma pools (one with normal -100 %- AT and three with reduced levels of AT-5, 10, 20%) were prepared with FVIII spiked to 0, 5, 10, 20, 30, 50, and 100% . FVIII plasma activity was measured by OSA and CSA against Siemens normal standard plasma. Compared to FVIII plasma activity for all FVIII spikes in normal HemA plasma containing 100% AT, respective FVIII spikes in HemA/AT depleted plasma samples (5, 10, and 20% AT) did not show therapeutic significant effects of AT levels on measured FVIII activity by OSA and chromogenic FVIII activity assay. Additionally, we evaluated the effect of the various AT levels and FVIII spikes on clotting assays, aPTT and PT, among the HemA plasma with varying (5-100%) AT levels. AT level did not affect the aPTT for respective FVIII spikes in HemA and Hem/AT depleted plasma. Furthermore, no therapeutic relevant effect of ATIII and FVIII level was observed in PT values between HemA and Hem/AT depleted plasma. Conclusions: Our results demonstrate that a reduction of AT levels in plasma does not affect standard coagulation assays, suggesting these assays can be utilized to assess hemostasis and factor levels in individuals treated with fitusiran. The ability to monitor FVIII levels in patients treated with non-replacement therapies is important as these patients require factor to treat breakthrough bleeds and during some surgeries. Disclosures Wang: sanofi: Current Employment, Current equity holder in publicly-traded company. Kattula:Sanofi: Current Employment, Current equity holder in publicly-traded company. Ismail:Sanofi: Current Employment, Current equity holder in publicly-traded company. Leksa:Sanofi: Current Employment, Current equity holder in publicly-traded company. van Der Flier:sanofi: Current Employment, Current equity holder in publicly-traded company. Salas:sanofi: Current Employment, Current equity holder in publicly-traded company.

A prediction model of sepsis-associated acute kidney injury based on antithrombin III.

The incidence of sepsis-associated acute kidney injury (AKI) is on the rise. Recent studies have found a correlation between antithrombin III and AKI. We established a predictive model for sepsis-associated AKI based on plasma ATIII levels. A prospective study (March 2018-January 2020) was conducted in sepsis patients admitted to the Critical Care Medicine Department at Shanghai General Hospital. ATIII levels were obtained within 48h after admission to the ICU and before the diagnosis of sepsis-associated AKI was recorded. Renal function was assessed by measuring serum creatinine levels and urine volume. Male sex, other cardiovascular disease, and low ATIII levels were identified as independent risk factors for AKI. Age, immune disease, and low ATIII levels were identified as independent risk factors for death. Plasma ATIII levels in the non-AKI group were higher than those in the AKI group, plasma ATIII levels were higher in the survival group than in the non-survival group, plasma ATIII levels in the non-CRRT group were higher than those in the CRRT group, and plasma ATIII levels in the non-CKD group were higher than those in the CKD group. ATIII was significantly higher in the group with pulmonary infection than in the group without pulmonary infection. ATIII was significantly lower in the celiac infection group than in the nonceliac infection group. There was no statistically significant difference between the ATIII in the gram-positive group and the gram-negative group. ATIII was significantly higher in medical patients than in surgical patients. The predictive model of sepsis-associated AKI established based on ATIII was ln[P/(1 - p)] = -1.211 × sex - 0.017 × ATIII + 0.022 × Cr + 0.004 × BUN - 2.8192. The model goodness-of-fit test (p = 0.000) and the area under the ROC curve of the model (0.9862) suggested that the model has a high degree of discrimination and calibration. ATIII reduction was closely related to the prognosis of patients with sepsis. ATIII reduction was an independent risk factor for sepsis-associated AKI and an independent risk factor for mortality in patients with sepsis. ATIII reduction could predict sepsis-associated AKI. Low ATIII predicted a poor prognosis.

Prominent coagulation disorder is closely related to inflammatory response and could be as a prognostic indicator for ICU patients with COVID-19

The new outbreak of Coronavirus Disease 2019 (COVID-19) has emerged as a serious global public health concern. A more in-depth study of blood coagulation abnormality is needed. We retrospectively analyzed 147 consecutive patients with COVID-19 who were admitted to three ICUs in Wuhan from February 9th, 2020 to March 20th, 2020. The baseline coagulation and other characteristics were studied. Our results showed that the prolonged PT, FDP, DD were positively correlated with the levels of neutrophils, ferritin, LDH, total bilirubin, multi-inflammation cytokines, and negatively correlated with the lymphocytes level (p < 0.01). The level of ATIII was significantly negatively correlated with the levels of neutrophils, ferritin, LDH, total bilirubin, IL2R, IL6 and IL8 (p < 0.05). The patients in the ARDS group had a more prominent abnormality in PT, FDP, DD and ATIII, while the patients in the AKI group had more prolonged PT, more severe FDP and DD level, more inferior ATIII and Fib level than those in the non-AKI group (p < 0.01). The value of PT, DD and FDP were positively correlated with the classical APACHE II, SOFA and qSOFA scores, while the ATIII was negatively correlated with them (p < 0.001). The high levels of PT, FDP and DD were correlated with in-hospital mortality (p < 0.001). In conclusion, blood coagulation disorder was prominent in ICU patients with COVID-19 and was correlated with multi-inflammation factors. The abnormality of blood coagulation parameters could be an adverse prognostic indicator for ICU patients with COVID-19.

Chronic intermittent hypoxia vs chronic continuous hypoxia: Effects on vascular endothelial function and myocardial contractility.

Both chronic intermittent hypoxia (CIH) and chronic continuous hypoxia (CCH) are risk factors for cardiovascular disease, which are associated with cardiac systolic function and associated with dysfunction of endothelia and coagulation-fibrinolysis system in the vasculature. However, the different effects of these two hypoxic models are not fully understood. In our study, we systemically compared the effects of CIH and CCH on cardiac function and related factor levels in serum using rat model. Forty-five male Sprague-Dawley rats were randomly divided into the normoxia control (NC), CIH and CCH groups. The rat CIH and CCH models were established, then the blood and tissue samples were collected to analyze the function of endothelium and the coagulation-fibrinolysis system. Also, the ultrasound cardiogram was performed to directly assess myocardial contractility. Both CIH and CCH significantly decreased the NO, eNOS, P-eNOS and AT-III levels in the rat serum but significantly increased the levels of ET-1, vWF, COX-2, NF-κB, FIB, FVIII and PAI-1 in the rat serum (P < 0.05). The expression of ET-1, VWF and ICAM-1 in CIH group were higher than CCH group (P < 0.05), however, the expression of CD62p was increased in CCH group but not in CIH group. The expression of t-PA in CIH group were lower than CCH group (P < 0.05), but there were no significant differences in CCH group and NC group (P > 0.05). Using transmission electron microscope, we found that the mitochondrial ultrastructure of thoracic aorta endothelial cells in CIH and CCH group were damaged. Moreover, the myocardial contractility in CIH and CCH group were significantly decreased compared with NC group. Our results suggested that CIH and CCH could cause endothelial dysfunction, dysfunction of the coagulation-fibrinolysis system and decreasing of myocardial contractility. Compared with CCH, CIH has greater effect on vasoconstriction and adhesion of vascular endothelial cells, and stronger procoagulant effect.

Heparin sensitivity and postoperative blood loss in patients undergoing cardiac surgery with cardiopulmonary bypass.

Heparin-associated coagulation disorder is an important factor related to postoperative bleeding in patients undergoing cardiac surgery with cardiopulmonary bypass. Currently, the relationship between heparin sensitivity and postoperative bleeding is unknown. To investigate the relationship between individual heparin sensitivity and postoperative blood loss in patients undergoing cardiac surgery. Prospective controlled study. Tertiary teaching hospital, Urumqi, Xinjiang, PR China. The study was conducted from January 2016 to August 2018. A total of 195 adult patients undergoing cardiac valve replacement surgery were included. After initial heparin dosing (2.5 mg kg), patients were divided into three groups according to the whole blood activated clotting time (ACT): group A, insensitive group (ACT < 480 s); group B, sensitive group (480 s < ACT < 750 s); group C, hypersensitive group (ACT > 750 s). First, intra-operative and 24-h postoperative blood loss. Second, antithrombin (AT) and factor X mRNA levels. Third, the plasma levels of AT-III and factor X. Fourth, heparin sensitivity index. Blood loss was approximately 20 to 25% lower in group B than in groups A and C, which was statistically significant (P < 0.01). The AT-III mRNA levels increased from groups A to C and was positively associated with heparin sensitivity; the factor X mRNA levels changed in the opposite direction; a significant difference was observed between groups A and C (P < 0.05). The factor X plasma level showed the same trend as its mRNA. The AT-III plasma level was significantly lower in group B than in groups A and C (P < 0.05). Postoperative blood loss is related to heparin sensitivity in patients undergoing cardiac surgery, and the moderately sensitive patients have the least postoperative bleeding. Individual variation in heparin sensitivity is related to the mRNA and plasma levels of AT-III and factor X. Registration number ChiCTR-RPC-17012259.

A Prediction Model of Sepsis-Associated Acute Kidney Injury Based on Antithrombin III

Background: The incidence of sepsis-associated acute kidney injury (AKI) is on the rise. Recent studies have found a correlation between antithrombin III and AKI. We established a predictive model for sepsis-associated AKI based on plasma ATIII levels. Methods: A prospective study (March 2018 to January 2020) was conducted in sepsis patients admitted to the Critical Care Medicine Department at Shanghai General Hospital. ATIII levels were obtained within 48 hours after admission to the ICU and before the diagnosis of sepsis-related AKI was recorded. Renal function was assessed by measuring serum creatinine levels and urine volume. Results: Male, cardiovascular disease, and low ATIII levels were identified as independent risk factors for AKI. Age, immune disease, and low ATIII levels were identified as independent risk factors for death. Plasma ATIII levels in the non-AKI group were higher than those in the AKI group, plasma ATIII levels were higher in the survival group than in the non-survival group, plasma ATIII levels in the non-CRRT group were higher than those in the CRRT group, and plasma ATIII levels in the non-CKD group were higher than those in the CKD group. ATIII was significantly higher in the group with pulmonary infection than in the group without pulmonary infection. ATIII was significantly lower in the celiac infection group than in the nonceliac infection group. The predictive model of sepsis-associated AKI established based on ATIII was ln[P/(1-p)]=-1.211×sex-0.017×ATIII+0.022×Cr+0.004×BUN-2.8192. The model goodness of fit test (P=0.000) and the area under the ROC curve of the model (0.9862) suggested that the model has a high degree of discrimination and calibration. Conclusions: ATIII reduction was an independent risk factor for sepsis-associated AKI and an independent risk factor for mortality in patients with sepsis. ATIII reduction could predict sepsis--associated AKI. Low ATIII predicted a poor prognosis. Funding Statement: The present study was supported by grants from Shanghai Science and Technology Committee Scientific and Technological Support Project (grant no. 18411950600 and 18411950602, respectively), Clinical Research Innovation Plan of Shanghai General Hospital (grant no. CTCCR2016B01) Wu Jieping Medical Foundation (grant no. 320.6750.18546) and Songjiang district science and technology project(19SJKJGG92). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Ethics approval was obtained from Shanghai General Hospital Institutional Review Board [approval no. (2018)KY004].