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Biomedicine & Pharmacotherapy =... Sep 2022The objectives of this study were to investigate the antithrombotic effect and physiological mechanism of okanin, a flavonoid monomer in Coreopsis tinctoria Nutt. The...
The objectives of this study were to investigate the antithrombotic effect and physiological mechanism of okanin, a flavonoid monomer in Coreopsis tinctoria Nutt. The antithrombotic effects of okanin were determined by the anticoagulant activity test in vitro and in vivo, the venous thrombosis and arterial thrombosis test in rats. To study the antithrombotic physiological mechanisms of okanin, UV spectrophotometer and enzyme-linked immunosorbent assay (ELISA) were used to determine the effects of three concentrations of okanin on the contents of 6-keto-prostaglandin F1α (6-Keto-PGF), thromboxane B (TXB), endothelin-1 (ET-1), antithrombin III (AT-Ⅲ), protein C (PC) and von willebrand factor (vWF) in the plasma of rats with arterial thrombosis; ELISA was used to detect the effects of okanin on the contents of plasminogen (PLG), tissue plasminogen activator (t-PA) and type-1 plasminogen activator inhibitor (PAI-1) in the plasma of mice and Chinese white rabbits. The results showed that okanin could prolong the coagulation time in vitro and in vivo of animals (P < 0.01 in the high dose group) and the activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) of human venous blood (ATPP of medium dose group P < 0.01; PT, TT P < 0.05. P < 0.01 in the high dose group); inhibit the maximum platelet aggregation rate of rabbits (P < 0.05 in the low dose group; P < 0.01 in the medium and high dose groups), decrease the dry and wet weight of venous thrombosis and the wet weight of common carotid artery thrombosis in rats (low dose group, P < 0.05; medium and high dose groups, P < 0.01); increase the levels of 6-Keto-PGF, AT-Ⅲ, PLG and t-PA in animal plasma; decrease the levels of TXB, ET-1, vWF and PAI- in animal plasma. It is concluded that okanin can significantly inhibit thrombosis, and its physiological mechanisms were related to affecting the activation of related coagulation factors in endogenous and exogenous coagulation pathways, affecting the physiological characteristics of platelets, repairing damaged vascular endothelial cells and enhancing the activity of the fibrinolytic system.
Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anticoagulants; Chalcones; Endothelial Cells; Fibrinolytic Agents; Humans; Rabbits; Rats; Thrombosis; Tissue Plasminogen Activator; von Willebrand Factor
PubMed: 35785699
DOI: 10.1016/j.biopha.2022.113358 -
Blood Advances Nov 2022In the phase 2b/3 DIVERSITY trial, 3 months treatment with dabigatran was noninferior to standard of care (SOC) for acute venous thromboembolism (VTE) in children. In a...
In the phase 2b/3 DIVERSITY trial, 3 months treatment with dabigatran was noninferior to standard of care (SOC) for acute venous thromboembolism (VTE) in children. In a single-arm, phase 3, secondary VTE prevention study, up to 12 months dabigatran use was associated with favorable safety. Dabigatran is approved by the European Medicines Agency and US Food and Drug Administration for pediatric indications. We assessed primary composite efficacy (complete thrombus resolution and freedom from VTE recurrence/VTE-related death) in subgroups with thrombophilia vs those with negative/unknown thrombophilia status in the DIVERSITY trial and safety in both studies. Thrombophilia types were similar between the DIVERSITY trial (total population) and secondary prevention studies: factor V Leiden, 42% vs 33%; prothrombin mutation (G20210A), 19% vs 17%; antithrombin deficiency, 15% vs 20%; protein C/S deficiency, 23% vs 25%; and antiphospholipid antibodies, 18% vs 20% of patients, respectively. In DIVERSITY, 36% and 22% of thrombophilia subgroup patients treated with dabigatran and SOC, respectively, met the primary end point (Mantel-Haenszel-weighted rate difference, -0.135; 95% confidence interval, -0.36 to 0.08; noninferiority P = .0014); comparable to the total DIVERSITY trial population (46% vs 42%) showing dabigatran noninferiority to SOC. Within this subgroup, numerically fewer patients experienced VTE recurrence or progression of index thrombus in the dabigatran treatment group vs SOC. In the secondary prevention study, VTE recurrence at 12 months occurred in 2.8% of patients with thrombophilia vs 0% with negative/unknown thrombophilia. Safety profiles were consistent with those reported previously. Although they should be interpreted with caution, these exploratory findings suggest dabigatran could be an appropriate long-term anticoagulant for children with thrombophilia. These trials were registered at www.clinicaltrials.gov as #NCT01895777 and #NCT02197416.
Topics: Child; Humans; Dabigatran; Protein C Deficiency; Risk Factors; Secondary Prevention; Thrombophilia; United States; Venous Thromboembolism; Recurrence
PubMed: 36150047
DOI: 10.1182/bloodadvances.2021005681 -
Yonago Acta Medica May 2021As antithrombin III (AT-III) is produced in the hepatocytes, its serum activity decreases at the time of liver failure, in addition to ischemia reperfusion injury,...
BACKGROUND
As antithrombin III (AT-III) is produced in the hepatocytes, its serum activity decreases at the time of liver failure, in addition to ischemia reperfusion injury, vascular endothelial dysfunction, and disseminated intravascular coagulation (DIC). Here, we examined whether the serum AT-III value after hepatectomy could be a prognostic factor for hepatocellular carcinoma (HCC).
METHODS
Of 141 patients who underwent hepatectomy for HCC, data for 101 patients in whom serum AT-III activity was measured on the first postoperative day were extracted. Patients with serum AT-III activity > 50% and ≤ 50% were assigned to high value (72 cases) and low value (29 cases) groups, respectively. We examined the clinical and prognostic differences between these two groups.
RESULTS
The average age of enrolled patients (83 men and 18 women) was 68.0 years. The 5-year overall survival rate was 88% and 60% in the high and low value groups, respectively ( < 0.01). Furthermore, the 2-year relapse-free survival rate was 71% and 54% in the high and low value groups, respectively ( = 0.03).
CONCLUSION
This is the first study to demonstrate that serum AT-III levels on the first postoperative day may serve as a prognostic factor in HCC patients.
PubMed: 34025191
DOI: 10.33160/yam.2021.05.007 -
The Journal of Extra-corporeal... Jun 2022Pediatric patients undergoing cardiopulmonary bypass (CPB) require adequate anticoagulation to combat hemostatic activation. Heparin is used to bind and catalyze... (Review)
Review
Pediatric patients undergoing cardiopulmonary bypass (CPB) require adequate anticoagulation to combat hemostatic activation. Heparin is used to bind and catalyze antithrombin III (ATIII) that works to inhibit clot formation. To dose heparin, a weight-based (WB) or patient-specific concentration-based (PSCB) method can be used. The WB protocol calculates the dose based on the patients' weight and uses an activated clotting time (ACT) test to ensure anticoagulation. The ACT has limitations during CPB especially for pediatric patients who have immature hemostatic systems. The PSCB method predicts the patients' response to heparin by projecting a heparin dose-response (HDR) curve. Some investigators have found benefit to using the PSCB method but further investigation into how well the HDR predicts the heparin response is needed. A literature review was conducted for studies that looked at heparin management strategies in pediatric CPB patients between 1992 and 2020. Articles that focused on pediatric physiology, heparin management strategies, and anticoagulation were included. Articles older than 1990 were excluded. The literature review highlights that utilizing the PSCB approach more adequately anticoagulated patients. The WB protocol was found to have several flaws due to its reliance on the ACT, especially in infants. The results show that further investigation is needed to understand why there is benefit to using the PSCB approach. Observing the association between the HDR curve and subsequent heparin concentrations could determine how accurately it predicts the patients' response to heparin and why there is benefit to using this method.
Topics: Anticoagulants; Blood Coagulation; Cardiopulmonary Bypass; Child; Hemostatics; Heparin; Humans; Infant; Whole Blood Coagulation Time
PubMed: 35928334
DOI: 10.1182/ject-153-160 -
Anesthesiology and Pain Medicine Jun 2023After the COVID-19 pandemic, multiple reviews have documented the success of veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Patients who experience... (Review)
Review
CONTEXT
After the COVID-19 pandemic, multiple reviews have documented the success of veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Patients who experience hypoxemia but have normal contractility may be switched to veno-venous-ECMO (VV-ECMO).
PURPOSE
In this review, we present three protocols for anesthesiologists. Firstly, transesophageal echocardiography (TEE) aids in cannulation and weaning off inotropes and fluids. Our main objective is to assist in patient selection for the Avalon Elite single catheter, which is inserted into the right internal jugular vein and terminates in the right atrium. Secondly, we propose appropriate anticoagulant doses. We outline day-to-day monitoring protocols to prevent heparin-induced thrombocytopenia (HIT) or resistance. Once the effects of neuromuscular paralysis subside, sedation should be reduced. Therefore, we describe techniques that may prevent delirium from progressing into permanent cognitive decline.
METHODS
We conducted a PubMed search using the keywords VV-ECMO, TEE, Avalon Elite (Maquet, Germany), and quetiapine. We combined these findings with interviews conducted with nurses and anesthesiologists from two academic ECMO centers, focusing on anticoagulation and sedation.
RESULTS
Our qualitative evidence synthesis reveals how TEE confirms cannulation while avoiding right atrial rupture or low flows. Additionally, we discovered that typically, after initial heparinization, activated partial thromboplastin time (PTT) is drawn every 1 to 2 hours or every 6 to 8 hours once stable. Daily thromboelastograms, along with platelet counts and antithrombin III levels, may detect HIT or resistance, respectively. These side effects can be prevented by discontinuing heparin on day two and initiating argatroban at a dose of 1 μg/kg/min while maintaining PTT between 61 - 80 seconds. The argatroban dose is adjusted by 10 - 20% if PTT is between 40 - 60 or 80 - 90 seconds. Perfusionists assist in establishing protocols following manufacturer guidelines. Lastly, we describe the replacement of narcotics and benzodiazepines with dexmedetomidine at a dose of 0.5 to 1 μg/kg/hour, limited by bradycardia, and the use of quetiapine starting at 25 mg per day and gradually increasing up to 200 mg twice a day, limited by prolonged QT interval.
CONCLUSIONS
The limitation of this review is that it necessarily covers a broad range of ECMO decisions faced by an anesthesiologist. However, its main advantage lies in the identification of straightforward argatroban protocols through interviews, as well as the discovery, via PubMed, of the usefulness of TEE in determining cannula position and contractility estimates for transitioning from VA-ECMO to VV-ECMO. Additionally, we emphasize the benefits in terms of morbidity and mortality of a seldom-discussed sedation supplement, quetiapine, to dexmedetomidine.
PubMed: 38021335
DOI: 10.5812/aapm-136524 -
The Journal of Pediatric Pharmacology... 2022The purpose was to characterize antimicrobial and anticoagulation therapies used in health systems with children receiving extracorporeal membrane oxygenation (ECMO).
OBJECTIVE
The purpose was to characterize antimicrobial and anticoagulation therapies used in health systems with children receiving extracorporeal membrane oxygenation (ECMO).
METHODS
An anonymous electronic survey assessing health system demographics and antimicrobial and anticoagulation therapies during ECMO was distributed to the American College of Clinical Pharmacy Pediatric Practice and Research Network and the Pediatric Pharmacy Association Critical Care Special Interest Group. The primary objective was to identify the number of respondents using antimicrobial prophylaxis for ECMO cannulation and ECMO runs. Secondary objectives included the first- and second-line anticoagulants and anticoagulation laboratory parameters. Additionally, the antimicrobial regimens and the dosing and administration of antithrombin III (AT III) with systemic anticoagulation were collected. Descriptive statistics were employed.
RESULTS
The questionnaire was completed by 38 respondents from 33 health systems; respondents practiced in the pediatric ICU (n = 20; 52.6%), cardiovascular ICU (n = 14; 36.8%), and neonatal ICU (n = 4; 10.5%). Twenty-eight (73.6%) respondents use antimicrobial prophylaxis during ECMO cannulation or ECMO runs, with most units using cefazolin monotherapy. Thirty-five (92.1%) respondents use heparin as the first-line anticoagulant and used a variety of laboratory tests including anti-factor Xa, activated clotting time, and activated partial thromboplastin time. The most common second-line anticoagulant was bivalirudin (n = 24; 63.2%). Thirty-six (94.7%) respondents use AT III with heparin, with most patients receiving AT III dosing calculated based on a formula for the desired AT III concentration.
CONCLUSIONS
The majority of respondents use antimicrobial prophylaxis, but variations in the regimens were noted. Heparin was the most common anticoagulant, but variations in laboratory monitoring and concomitant use of AT III were found.
PubMed: 35002562
DOI: 10.5863/1551-6776-27.1.72 -
British Journal of Haematology Sep 2022Individuals with sickle cell disease (SCD) have persistently elevated thrombin generation that results in a state of systemic hypercoagulability. Antithrombin-III...
Individuals with sickle cell disease (SCD) have persistently elevated thrombin generation that results in a state of systemic hypercoagulability. Antithrombin-III (ATIII), an endogenous serine protease inhibitor, inhibits several enzymes in the coagulation cascade, including thrombin. Here, we utilize a biomimetic microfluidic device to model the morphology and adhesive properties of endothelial cells (ECs) activated by thrombin and examine the efficacy of ATIII in mitigating the adhesion of SCD patient-derived red blood cells (RBCs) and EC retraction. Microfluidic devices were fabricated, seeded with ECs, and incubated under physiological shear stress. Cells were then activated with thrombin with or without an ATIII pretreatment. Blood samples from subjects with normal haemoglobin (HbAA) and subjects with homozygous SCD (HbSS) were used to examine RBC adhesion to ECs. Endothelial cell surface adhesion molecule expression and confluency in response to thrombin and ATIII treatments were also evaluated. We found that ATIII pretreatment of ECs reduced HbSS RBC adhesion to thrombin-activated endothelium. Furthermore, ATIII mitigated cellular contraction and reduced surface expression of von Willebrand factor and vascular cell adhesion molecule-1 (VCAM-1) mediated by thrombin. Our findings suggest that, by attenuating thrombin-mediated EC damage and RBC adhesion to endothelium, ATIII may alleviate the thromboinflammatory manifestations of SCD.
Topics: Anemia, Sickle Cell; Anticoagulants; Antithrombins; Cell Adhesion; Endothelial Cells; Endothelium, Vascular; Erythrocytes; Humans; Thrombin
PubMed: 35822297
DOI: 10.1111/bjh.18328 -
Journal of Thrombosis and Haemostasis :... Jun 2023Venous thromboembolism (VTE) is associated with excessive coagulation activity, which in part can be attributed to activation of contact system. However, the knowledge...
BACKGROUND
Venous thromboembolism (VTE) is associated with excessive coagulation activity, which in part can be attributed to activation of contact system. However, the knowledge regarding the impact of contact activation in acute VTE is limited.
OBJECTIVE
To unravel the involvement of contact activation in acute VTE.
METHODS
Contact activation was investigated in patients with acute VTE (n = 321) and population controls without a history of VTE (n = 300). For comparison, Factor XI(a) levels, activity, and plasma kallikrein (PKa) activity were determined in plasma samples with an activated partial thromboplastin time- or thrombin generation-based assay (free FXI concentration [FXI:c] and calibrated automated thrombogram:FXIa, respectively) and with enzyme-linked immunosorbent assays for enzyme-inhibitor complexes (FXIa:alpha-1-antitrypsin [α1AT], FXIa:antithrombin [AT], FXIa:C1-inhibitor [C1Inh], and PKa:C1-inh).
RESULTS
In patients with VTE, higher FXI:c levels (124 ± 37% vs 114 ± 28%), but lower calibrated automated thrombogram:FXIa levels were apparent. This was accompanied by increased FXIa:α1AT, FXIa:AT, and PKa:C1-inh levels in patients compared with controls (312pM [238-424] vs 203pM [144-288]; 29pM [23-38] vs 23pM [20-30]; 1.9nM [1.2-4.7] vs 1.4nM [0.7-3.5], respectively), whereas FXIa:C1-inh levels did not differ. Logistic regression models showed good discriminatory values for FXI:c and FXIa:α1AT (area under the curve = 0.64 [0.6/0.69] and 0.73 [0.69/0.77], respectively). After a 2-year follow-up, 81 recurrent VTE events or deaths occurred in the patient cohort, for which the baseline levels of FXIa:α1AT and FXIa:C1Inh had a significant prognostic value (Hazard ratios per SD [95% CI], 1.26 [1.10-1.45]; p =.0012 and 1.19 [1.05-1.36]; p =.0082, respectively).
CONCLUSION
Our study revealed elevated FXIa levels and activity in acute VTE, which was also associated with recurrent VTE, suggesting an important risk contribution of FXI activation to VTE. The evidence provided by this study supports the utility of FXIa inhibition in the setting of acute VTE.
Topics: Humans; Factor XIa; Venous Thromboembolism; Factor XI; Venous Thrombosis; Blood Coagulation; Plasma Kallikrein; Anticoagulants; Antithrombin III
PubMed: 37003466
DOI: 10.1016/j.jtha.2023.02.031 -
Annals of Laboratory Medicine Jan 2024Rotational thromboelastometry (ROTEM; TEM International GmbH, Munich, Germany) is a global coagulation test that guides evidence-based platelet transfusion in trauma...
BACKGROUND
Rotational thromboelastometry (ROTEM; TEM International GmbH, Munich, Germany) is a global coagulation test that guides evidence-based platelet transfusion in trauma patients. We evaluated ROTEM parameters for predicting mid-term (five days) platelet transfusion in trauma patients.
METHODS
Maximum clot firmness and clot amplitudes after 5, 10, and 15 mins (A5, A10, and A15, respectively) of fibrin-specific ROTEM (FIBTEM) and extrinsically activated ROTEM (EXTEM) were retrospectively collected from 82 hospitalized, stable, non-bleeding trauma patients after successful initial resuscitation. Platelet-specific ROTEM (PLTEM) was calculated by subtracting FIBTEM from EXTEM. Platelet transfusions were reviewed for five days after ROTEM.
RESULTS
The areas under the curve for FIBTEM, EXTEM, and PLTEM predicting platelet concentrate transfusion of >12 U at mid-term were 0.915-0.923, 0.878-0.896, and 0.551-0.735, respectively. FIBTEM and EXTEM parameters were comparable to those of fibrinogen, fibrin/fibrinogen degradation products, D-dimer, and antithrombin III. Strong correlations (>0.7) were noted between platelet count and EXTEM (A5, A10, and A15) or PLTEM (A5), platelet function (per platelet count) and EXTEM (A10 and A15), and fibrinogen levels and all FIBTEM parameters.
CONCLUSIONS
FIBTEM and EXTEM can reliably predict mid-term platelet transfusion in trauma patients. FIBTEM, EXTEM, and PLTEM parameters correlate with conventional coagulation tests (platelets and fibrinogen).
Topics: Humans; Thrombelastography; Platelet Transfusion; Retrospective Studies; Fibrinogen; Fibrin
PubMed: 37665288
DOI: 10.3343/alm.2024.44.1.74 -
Journal of Clinical Medicine Sep 2023Knowledge of the natural history and management of hepatic hemangiomas is lacking. The aim of this study was to investigate the natural history of hemangiomas and to...
BACKGROUND
Knowledge of the natural history and management of hepatic hemangiomas is lacking. The aim of this study was to investigate the natural history of hemangiomas and to elucidate the factors that determine tumor growth and optimal management.
METHODS
A total of 211 adult patients were enrolled, with follow-up for more than three years. Follow-up was performed with repeated ultrasonography (US) and laboratory tests for liver function and coagulation factors (platelets, prothrombin time (PT), fibrinogen, thrombin-antithrombin III complex (TAT), D-dimer, and fibrin and fibrinogen degradation products (FDP)).
RESULTS
Tumor size decreased in 38.9% of patients, showed no change in 31.3%, and increased in 29.8%. The incidence of a size increase was very high in patients under 40 years of age and decreased gradually with age, whereas the incidence of a size decrease increased with age and increased markedly over 60 years of age. The incidence of an increase in size decreased gradually with size enlargement, whereas the incidence of a decrease in size increased markedly with tumor size and further increased rapidly when hemangiomas became larger than 60 mm. Values of TAT, D-dimer, FDP, and Mac-2 binding protein glycosylation isomer (M2BPGi) were closely related to the change in size of hemangiomas.
CONCLUSIONS
Hemangiomas in older patients (>60 years of age) and larger tumors (>60 mm in size) had a tendency to decrease in size, resulting from the reduction in coagulation disorders and the progression of liver fibrosis. Therefore, the majority of patients with hemangiomas can be safely managed by clinical observation.
PubMed: 37685768
DOI: 10.3390/jcm12175703