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Journal of Critical Care Dec 2020The aim of this study was to investigate potential markers of coagulopathy and the effects of thromboprophylaxis with low-molecular-weight heparin (LMWH) on... (Observational Study)
Observational Study
PURPOSE
The aim of this study was to investigate potential markers of coagulopathy and the effects of thromboprophylaxis with low-molecular-weight heparin (LMWH) on thromboelastography (TEG) and anti-factor Xa in critically ill COVID-19 patients.
MATERIAL AND METHODS
We conducted a prospective study in 31 consecutive adult intensive care unit (ICU) patients. TEG with and without heparinase and anti-factor Xa analysis were performed. Standard thromboprophylaxis was given with dalteparin (75-100 IU/kg subcutaneously).
RESULTS
Five patients (16%) had symptomatic thromboembolic events. All patients had a maximum amplitude (MA) > 65 mm and 13 (42%) had MA > 72 mm at some point during ICU stay. Anti-factor Xa activity were below the target range in 23% of the patients and above target range in 46% of patients. There was no significant correlation between dalteparin dose and anti-factor Xa activity.
CONCLUSIONS
Patients with COVID-19 have hypercoagulability with high MA on TEG. The effect of LMWH on thromboembolic disease, anti-factor Xa activity and TEG was variable and could not be reliably predicted. This indicates that standard prophylactic doses of LMWH may be insufficient. Monitoring coagulation and the LMWH effect is important in patients with COVID-19 but interpreting the results in relation to risk of thromboembolic disease poses difficulties.
Topics: Adult; Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Critical Illness; Dalteparin; Factor Xa Inhibitors; Female; Heparin, Low-Molecular-Weight; Humans; Intensive Care Units; Male; Middle Aged; Prospective Studies; Risk; Thrombelastography; Venous Thromboembolism; COVID-19 Drug Treatment
PubMed: 32920503
DOI: 10.1016/j.jcrc.2020.08.026 -
BMC Medicine Nov 2022The Accelerating Innovation for Mothers (AIM) project established a database of candidate medicines in research and development (R&D) between 2000 and 2021 for five...
BACKGROUND
The Accelerating Innovation for Mothers (AIM) project established a database of candidate medicines in research and development (R&D) between 2000 and 2021 for five pregnancy-related conditions, including pre-eclampsia. In parallel, we published target product profiles (TPPs) that describe optimal characteristics of medicines for use in preventing/treating pre-eclampsia. The study objective was to use systematic double screening and extraction to identify all candidate medicines being investigated for pre-eclampsia prevention/treatment and rank their potential based on the TPPs.
METHODS
Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched (Jan-May 2021). The AIM database was screened for all candidates being investigated for pre-eclampsia. Candidates in clinical development were evaluated against nine prespecified criteria from TPPs identified as key for wide-scale implementation, and classified as high, medium or low potential based on matching to the TPPs. Preclinical candidates were categorised by product type, archetype and medicine subclass.
RESULTS
The AIM database identified 153 candidates for pre-eclampsia. Of the 87 candidates in clinical development, seven were classified as high potential (prevention: esomeprazole, L-arginine, chloroquine, vitamin D and metformin; treatment: sulfasalazine and metformin) and eight as medium potential (prevention: probiotic lactobacilli, dalteparin, selenium and omega-3 fatty acid; treatment: sulforaphane, pravastatin, rosuvastatin and vitamin B3). Sixty-six candidates were in preclinical development, the most common being amino acid/peptides, siRNA-based medicines and polyphenols.
CONCLUSIONS
This is a novel, evidence-informed approach to identifying promising candidates for pre-eclampsia prevention and treatment - a vital step in stimulating R&D of new medicines for pre-eclampsia suitable for real-world implementation.
Topics: Humans; Pregnancy; Female; Pre-Eclampsia; Biological Products; Dietary Supplements; Vitamin D; Metformin
PubMed: 36329468
DOI: 10.1186/s12916-022-02582-z -
Journal of Thrombosis and Haemostasis :... Dec 2021In the Hokusai VTE Cancer study, the risk of major bleeding was 2.9% higher in the edoxaban group compared with the dalteparin group, mainly due to more gastrointestinal... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the Hokusai VTE Cancer study, the risk of major bleeding was 2.9% higher in the edoxaban group compared with the dalteparin group, mainly due to more gastrointestinal bleedings in patients with gastrointestinal cancer. The identification of risk factors for gastrointestinal bleeding may help to guide the use of DOACs in these patients.
OBJECTIVES
To evaluate risk factors for gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban.
PATIENTS/METHODS
In this nested case-control study in patients with gastrointestinal cancer randomized to edoxaban in the Hokusai VTE Cancer study, cases (patients with clinically relevant gastrointestinal bleeding during treatment) were randomly matched to three controls (patients who had no gastrointestinal bleeding). Data for the 4-week period prior to bleeding were retrospectively collected. Odds ratios (ORs) were calculated in a crude conditional logistic regression model and a multivariable model adjusted for age, sex, and cancer type.
RESULTS
Twenty-four cases and 64 matched controls were included. In the multivariable analysis, advanced cancer, defined as regionally advanced or metastatic cancer (OR 3.6, 95% CI 1.01-12.6) and low hemoglobin levels (OR 4.8, 95% CI 1.5-16.0) were significantly associated with bleeding. There was no significant difference in patients with resected tumors (OR 0.4, 95% CI 0.1-1.4), or in patients on chemotherapy (OR 1.3, 95% CI 0.5-3.5).
CONCLUSION
Advanced cancer and low hemoglobin levels were associated with an increased risk of gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban. We were unable to identify other risk factors, mainly due to limited statistical power.
Topics: Anticoagulants; Case-Control Studies; Factor Xa Inhibitors; Gastrointestinal Hemorrhage; Gastrointestinal Neoplasms; Humans; Pyridines; Retrospective Studies; Risk Factors; Thiazoles; Venous Thromboembolism
PubMed: 34455706
DOI: 10.1111/jth.15516 -
Clinical and Applied... Apr 2015We aimed to investigate whether prolonged treatment with dalteparin could inhibit plaque progression. With C57BL/6J mice as the control, genetically deficient...
We aimed to investigate whether prolonged treatment with dalteparin could inhibit plaque progression. With C57BL/6J mice as the control, genetically deficient apolipoprotein E (apo E) male mice of C57BL/6J strain (apo E(-/-)) were randomly divided into 3 groups. The model group received no dalteparin, while the other 2 groups received dalteparin at 100 and 200 U/kg d, respectively. The aorta was harvested for hematoxylin and eosin staining to observe plaque formation and for immunohistochemical staining to detect the expression of oxidized low-density lipoprotein receptor 1 (LOX-1). The expression of LOX-1 messenger RNA was detected by reverse transcription polymerase chain reaction, while the expression of LOX-1 protein was detected by Western blotting. Dalteparin decreased aortic plaque volume and inhibited aortic LOX-1 protein expression in apo E(-/-) mice. The effect persisted 4 weeks after dalteparin treatment was discontinued. Dalteparin may inhibit atherosclerotic lesions by downregulating the expression of LOX-1 protein.
Topics: Animals; Apolipoproteins E; Atherosclerosis; Dalteparin; Down-Regulation; Mice; Mice, Knockout; Plaque, Atherosclerotic; Scavenger Receptors, Class E
PubMed: 23965336
DOI: 10.1177/1076029613499818 -
Case Reports in Cardiology 2023A 45-year-old woman was admitted with severe pain in the right leg and dyspnea. Her medical history included previous endocarditis, biological aortic valve replacement,...
A 45-year-old woman was admitted with severe pain in the right leg and dyspnea. Her medical history included previous endocarditis, biological aortic valve replacement, and intravenous drug abuse. She was febrile but did not have any focal signs of infection. Blood tests showed raised infectious markers and troponin levels. Electrocardiogram showed sinus rhythm without signs of ischemia. Ultrasound revealed thrombosis of the right popliteal artery. The leg was not critically ischemic, and therefore, treatment with dalteparin was chosen. Transesophageal echocardiography showed an excrescence on the biological aortic valve. Empiric treatment for endocarditis was started with intravenous vancomycin, gentamicin, and oral rifampicin. Blood cultures subsequently grew . On day 2, treatment was changed to intravenous cloxacillin. Due to the comorbidity, the patient was not a candidate for the surgical treatment. On day 10, the patient developed moderate expressive aphasia and weakness in the right upper limb. Magnetic resonance imaging showed micro-embolic lesions scattered across both hemispheres of the brain. Treatment was changed from cloxacillin to cefuroxime. On day 42, infectious markers were normal, and echocardiography showed regression of the excrescence. Antibiotic treatment was stopped. Follow-up on day 52 did not show any signs of active infection. However, on day 143, the patient was readmitted with cardiogenic shock due to aortic root fistulation to the left atrium. She quickly deteriorated and died.
PubMed: 37013024
DOI: 10.1155/2023/4624492 -
CMAJ : Canadian Medical Association... Jan 2022
Topics: Administration, Intravenous; Adult; Anterior Compartment Syndrome; Anticoagulants; Dalteparin; Drug Overdose; Fasciotomy; Hemorrhage; Heparin Antagonists; Humans; Male; Protamines; Suicide, Attempted
PubMed: 35101871
DOI: 10.1503/cmaj.211083 -
International Journal of Surgery... Jun 2018To systematically evaluate the prophylaxis efficacy of low-molecular-weight heparin (LMWH) in the prevention of deep venous thrombosis (DVT) after total knee... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
To systematically evaluate the prophylaxis efficacy of low-molecular-weight heparin (LMWH) in the prevention of deep venous thrombosis (DVT) after total knee arthroplasty (TKA).
METHOD
PubMed, Cochrane, Embase, Wanfang, CNKI, and VIP databases were searched by index words to identify the eligible RCTs; relevant literature sources were also searched. The latest research was conducted in March 2017. Relative risks (RR), mean difference (MD), and their corresponding 95% confidence intervals (95% CIs) were used to analyze the main outcomes.
RESULT
A total of 22 articles were included in the meta-analysis with a total number of 11,320 patients (5543 in the LMWH group and 5777 in the control group). The results indicated that in the LMWH group, the incidence of DVT (OR: 0.57, 95% CI: 0.41-0.77) and wound complications (SMD: 0.96, 95% CI: 0.75-1.22) was significantly lower than that in the control group. Furthermore, LMWH also increased the occurrence of bleeding event (OR: 1.57, 95% CI: 1.31-1.88) and the total blood transfused (SMD: 0.12, 95% CI: 0.04-0.19). However, no statistical difference was found in blood loss (SMD: -0.26, 95% CI: -0.65-0.14) between the two group. In the subgroup analysis, the incidence of DVT was significantly decreased in the ardeparin sodium group (OR: 0.70, 95%CI: 0.53-0.94) and the dalteparin group (OR:0.40, 95%CI:0.32-0.50).
CONCLUSION
Our meta-analysis demonstrated that LMWH is obviously efficacious in the prophylaxis of DVT after TKA. However, it has some negative effects, such as the increase in the number of bleeding events and the total blood transfused.
Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Knee; Blood Transfusion; Dalteparin; Female; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Postoperative Complications; Postoperative Hemorrhage; Venous Thrombosis
PubMed: 29733996
DOI: 10.1016/j.ijsu.2018.04.059 -
Heparanase as an Additional Tool for Detecting Structural Peculiarities of Heparin Oligosaccharides.Molecules (Basel, Switzerland) Dec 2019Due to the biological properties of heparin and low-molecular-weight heparin (LMWH), continuous advances in elucidation of their microheterogeneous structure and...
Due to the biological properties of heparin and low-molecular-weight heparin (LMWH), continuous advances in elucidation of their microheterogeneous structure and discovery of novel structural peculiarities are crucial. Effective strategies for monitoring manufacturing processes and assessment of more restrictive specifications, as imposed by the current regulatory agencies, need to be developed. Hereby, we apply an efficient heparanase-based strategy to assert the structure of two major isomeric octasaccharides of dalteparin and investigate the tetrasaccharides arising from antithrombin binding region (ATBR) of bovine mucosal heparin. Heparanase, especially when combined with other sample preparation methods (e.g., size exclusion, affinity chromatography, heparinase depolymerization), was shown to be a powerful tool providing relevant information about heparin structural peculiarities. The applied approach provided direct evidence that oligomers bearing glucuronic acid-glucosamine-3--sulfate at their nonreducing end represent an important structural signature of dalteparin. When extended to ATBR-related tetramers of bovine heparin, the heparanase-based approach allowed for elucidation of the structure of minor sequences that have not been reported yet. The obtained results are of high importance in the view of the growing interest of regulatory agencies and manufacturers in the development of low-molecular-weight heparin generics as well as bovine heparin as alternative source.
Topics: Animals; Antithrombins; Binding Sites; Cattle; Chromatography, High Pressure Liquid; Glucuronidase; Heparin; Heparin, Low-Molecular-Weight; Molecular Structure; Oligosaccharides; Polymerization; Protein Binding; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry
PubMed: 31810297
DOI: 10.3390/molecules24234403 -
British Journal of Haematology Oct 2016Unfractionated heparin (UFH) has procoagulant activity in antithrombin/heparin cofactor II (HCII)-depleted plasma. UFH prevents tissue factor pathway inhibitor alpha...
Unfractionated heparin (UFH) has procoagulant activity in antithrombin/heparin cofactor II (HCII)-depleted plasma. UFH prevents tissue factor pathway inhibitor alpha (TFPIα) from inhibiting the procoagulant enzyme complex, prothrombinase, providing a possible mechanism for its procoagulant activity. The procoagulant potential of UFH and various low molecular weight heparins (LMWHs) were characterized for TFPIα dependence, using thrombin generation assays performed with antithrombin/HCII-depleted plasma. UFH, the LMWHs enoxaparin and dalteparin, and the low anticoagulant LMWH 2-O, 3-O desulphated heparin (ODSH) all promoted thrombin generation, but fondaparinux did not, and this activity was blocked by a TFPIα antibody. UFH, enoxaparin, and dalteparin were anticoagulant in reactions containing 1-2% normal plasma. In prothrombinase activity assays, UFH, enoxaparin, dalteparin and ODSH blocked prothrombinase inhibition by TFPIα, while again fondaparinux did not. In both the plasma and purified assays, LMWHs displayed greater procoagulant potential than UFH, even when normalized to saccharide concentration. These biochemical data reveal that UFH and LMWHs, but not fondaparinux, block prothrombinase inhibition by TFPIα, thereby producing their paradoxical procoagulant activity observed in the absence of antithrombin/HCII. The findings may help to understand the complex pathophysiology and treatment of patients that are simultaneously bleeding and clotting, such as those with disseminated intravascular coagulation.
Topics: Anticoagulants; Antithrombins; Blood Coagulation; Dalteparin; Enoxaparin; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Lipoproteins; Polysaccharides; Thromboplastin
PubMed: 27301751
DOI: 10.1111/bjh.14182