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Journal of Thrombosis and Haemostasis :... Dec 2020Inflammation with leukocyte activation is a hallmark of cancer-associated thrombosis (CAT), and elevated leukocytes predict venous thromboembolism in cancer outpatients....
BACKGROUND
Inflammation with leukocyte activation is a hallmark of cancer-associated thrombosis (CAT), and elevated leukocytes predict venous thromboembolism in cancer outpatients. In a recent trial, rivaroxaban was more efficacious than dalteparin in preventing CAT recurrence.
OBJECTIVES
In a proof-of-concept study, we aimed to provide a mechanistic basis for improved efficacy of rivaroxaban compared to low molecular weight heparin in CAT treatment.
METHODS
We studied the effects of rivaroxaban, dalteparin, and tinzaparin at peak and trough levels on tumor cell-induced procoagulant activity and platelet aggregation in the presence or absence of the cationic leukocyte-derived enzyme, myeloperoxidase (MPO). Furthermore, pro-inflammatory conditions were generated by stimulating whole blood with lipopolysaccharide (LPS) or phorbol-myristate-acetate (PMA), before measuring thrombin generation in plasma supernatants.
RESULTS
All three anticoagulants inhibited thrombin generation, fibrin clot formation, and platelet aggregation induced by the tissue factor-expressing prostate carcinoma cell line, 22Rv1. Pre-incubation with MPO partially attenuated the anticoagulant activity of dalteparin and tinzaparin, but not rivaroxaban, at trough levels. The effect of MPO did not involve the enzyme's catalytic properties, but required its structural integrity, as indicated by heat denaturation. In plasma obtained from LPS- or PMA-stimulated whole blood, elevated MPO antigen levels inversely correlated with the ability of tinzaparin to inhibit 22Rv1-induced thrombin generation.
CONCLUSIONS
Myeloperoxidase release may partially attenuate the anticoagulant activity of trough levels of dalteparin and tinzaparin in the context of paraneoplastic leukocyte activation. However, this effect is likely not sufficient to explain the improved efficacy of rivaroxaban, and possibly other oral factor Xa inhibitors, in CAT treatment.
Topics: Anticoagulants; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Male; Neoplasms; Peroxidase; Rivaroxaban
PubMed: 32865287
DOI: 10.1111/jth.15075 -
Population Pharmacokinetic Analysis of Dalteparin in Pediatric Patients With Venous Thromboembolism.Journal of Clinical Pharmacology Feb 2021This article describes the population pharmacokinetics (PK) of dalteparin in pediatric patients with venous thromboembolism (VTE). A prospective multicenter open-label...
This article describes the population pharmacokinetics (PK) of dalteparin in pediatric patients with venous thromboembolism (VTE). A prospective multicenter open-label study was conducted in children who required anticoagulation for the treatment of VTE. The study population included children with and without cancer. The goal was to describe the pharmacokinetics of dalteparin using anti-Xa as a surrogate marker and to determine the dose required to achieve therapeutic anti-Xa levels (0.5-1.0 IU/mL). The anti-Xa data were supplemented with 2 published studies and analyzed using population pharmacokinetic approaches. The pharmacokinetics of dalteparin following subcutaneous injection in pediatric patients was described by a 1-compartment model with linear absorption and elimination. Body weight was added as a covariate on both CL/F and Vd/F as a power function with fixed exponents of 0.75 and 1.0, respectively. The estimates of CL/F and Vd/F in the full model were 929 mL/h and 7180 mL, respectively, for a reference female patient aged 12 years with body weight of 43 kg. Body weight-normalized CL/F decreased with age. Cancer status and sex did not have significant effects on CL/F and Vd/F. Simulations were conducted to select starting doses of dalteparin that would rapidly achieve therapeutic anti-Xa levels. These simulations suggested that the recommended starting doses of dalteparin administered subcutaneously in pediatric patients of different age cohort groups for treatment of VTE were 150 IU/kg every 12 hours (1 month to <2 years), 125 IU/kg every 12 hours (≥2 to <8 years), and 100 IU/kg every 12 hours (≥8 to <19 years).
Topics: Adolescent; Age Factors; Anticoagulants; Biomarkers; Body Weight; Child; Child, Preschool; Dalteparin; Factor Xa Inhibitors; Female; Humans; Infant; Infant, Newborn; Injections, Subcutaneous; Male; Metabolic Clearance Rate; Prospective Studies; Sex Factors; Venous Thromboembolism
PubMed: 32827160
DOI: 10.1002/jcph.1716 -
Anaesthesia Reports 2020We report the haematological management of a critically ill patient with coronavirus disease 2019 (COVID-19), with recurrent massive pulmonary emboli. A previous healthy...
We report the haematological management of a critically ill patient with coronavirus disease 2019 (COVID-19), with recurrent massive pulmonary emboli. A previous healthy 56-year-old man presented to the emergency department with severe hypoxaemic respiratory failure due to suspected COVID-19. He required invasive mechanical ventilation and transfer to the intensive care unit for increasing ventilatory requirements and cardiovascular instability. A computed tomography (CT) pulmonary angiogram demonstrated large bilateral pulmonary emboli with right heart strain, for which he received intravenous systemic thrombolysis followed by therapeutic weight-adjusted anticoagulation with low molecular weight heparin (dalteparin). Two weeks later, following an acute respiratory deterioration, a repeat CT pulmonary angiogram demonstrated a new saddle embolus with right heart strain requiring another regime of intravenous systemic thrombolysis. This occurred despite anti-Xa-guided therapeutic anticoagulation. The dose of therapeutic dalteparin was increased incrementally to an eventual dose of 12,500 units twice daily. A low threshold for radiological imaging should be considered in all COVID-19 patients with acute cardiorespiratory deterioration. Multidisciplinary team discussions highlighted aspects of balancing the risks of bleeding from anticoagulation vs. risk of death from pulmonary embolism. This report highlights the need for further research into the underlying mechanisms and optimal management of thrombotic complications in COVID-19.
PubMed: 32776010
DOI: 10.1002/anr3.12059 -
RSC Advances Jul 2020Oxytocin (OXT) is a small cyclic peptide that is administered to pregnant women to induce birth in cases where labour is prolonged. It has previously been observed that...
Oxytocin (OXT) is a small cyclic peptide that is administered to pregnant women to induce birth in cases where labour is prolonged. It has previously been observed that patients taking a low molecular weight heparin, dalteparin (DAL), and then prescribed, OXT experienced a swifter labour compared to women given OXT alone. Herein are described the interactions between OXT and a number of heparin-based oligosaccharides; DAL; fondaparinux (FP), which is a synthetic heparin oligosaccharide that represents the predominant antithrombin binding-site, and a family of chemically-derived heparin hexasaccharides. The latter oligosaccharides were chosen as they represent sequences found within the polysaccharide dalteparin. Furthermore, the carbohydrate chemical space was investigated by comparing the interaction between OXT and four chemically derivatived heparin hexasaccharides; I-A (DP6), I-A (DP6-2OH, de-2--sulfated hexasaccharide), I-A (DP6-6OH, de-6--sulfated hexasaccharide) and I-A (DP6-NAc, de--sulfated hexasaccharide). The interactions between the peptide and oligosaccharides were studied using a series of C-H and N-H HSQC NMR experiments, at a range of temperatures. This approach allowed the binding epitopes of the peptide and oligosaccharides to be identified, highlighting that 6-- and -sulfation substituent groups of heparin are important for the interaction between the peptide and carbohydrate. This is an important observation as de--sulfation is a traditional method for decreasing the anticoagulation properties of heparin. Furthermore, low temperature experiments of the OXT : FP complex indicate that hydrogen-bonding is very important for the interaction between the peptide and oligosaccharide.
PubMed: 35519099
DOI: 10.1039/d0ra04204h -
The Journal of Veterinary Medical... Sep 2020Two dogs with immune-mediated hemolytic anemia complicated with thromboembolism were presented. Both of the dogs were initially treated with immunosuppressive therapy in...
Two dogs with immune-mediated hemolytic anemia complicated with thromboembolism were presented. Both of the dogs were initially treated with immunosuppressive therapy in conjunction with dalteparin and clopidogrel. Although the immunosuppressive therapy was effective, peritoneal effusion due to thromboembolism was observed during the course of the disease in these dogs. After initiation of rivaroxaban treatment, peritoneal effusion decreased immediately in parallel with the normalization of D-dimer, antithrombin (AT), and thrombin-antithrombin complex (TAT). Hematochezia, cutaneous hemorrhage, and hematuria were observed as adverse events after administration of rivaroxaban in one case. Rivaroxaban was effective for the control of thromboembolism secondary to immune-mediated hemolytic anemia, and D-dimer, AT, and TAT were useful to monitor the status of thromboembolic disease in dogs.
Topics: Animals; Anticoagulants; Dog Diseases; Dogs; Gastrointestinal Hemorrhage; Rivaroxaban; Venous Thromboembolism
PubMed: 32655095
DOI: 10.1292/jvms.19-0605 -
BILATERAL ADRENAL HEMORRHAGE WITH ADRENAL INSUFFICIENCY AFTER DALTEPARIN USE POST HIP ATHROPLASTIES.AACE Clinical Case Reports 2020Multiple case reports have implicated the use of heparin for deep vein thrombosis (DVT) prophylaxis with bilateral adrenal hemorrhage. Only 1 previous report has...
OBJECTIVE
Multiple case reports have implicated the use of heparin for deep vein thrombosis (DVT) prophylaxis with bilateral adrenal hemorrhage. Only 1 previous report has described this with the low molecular weight product, dalteparin. We report a case following bilateral hip arthroplasties.
METHODS
Clinical and laboratory data are presented.
RESULTS
A 69-year-old woman underwent bilateral total hip arthroplasties with dalteparin 5,000 international units subcutaneously daily for 30 days postoperatively. The patient's past medical history was unremarkable. She was discharged 5 days post-surgery and required readmission 1 day later for epigastric pain, nausea, and vomiting. Her platelet count was 91 × 10/L (normal, 150 to 400 × 10/L). She was discharged after 4 days with pain resolution. She presented 4 weeks later with nausea and vomiting for several days. Serum sodium was 123 mmol/L (normal, 133 to 145 mmol/L), potassium was 6.0 mmol/L (normal, 3.7 to 5.3 mmol/L), total calcium was 3.37 mmol/L (normal, 2.25 to 2.80 mmol/L), creatinine was 404 μmol/L (normal, 0 to 85 μmol/L), and her platelet count was normal. On short adrenocorticotropic hormone stimulation test, baseline plasma cortisol was 123 nmol/L and the peak was 129 nmol/L. She was treated with hydrocortisone, fludrocortisone, and 0.9% saline with resolution of symptoms and normalization of electrolytes, calcium, and renal function. Computed tomography showed bilateral adrenal masses. Core needle biopsy was consistent with necrosis. There were no bleeding disorders on hematologic work 3 months later. The most likely etiology of bilateral adrenal hemorrhage was heparin-induced thrombocytopenia from dalteparin.
CONCLUSION
This case highlights the importance of vigilance for the complication of bilateral adrenal hemorrhage with adrenal insufficiency in patients receiving dalteparin for DVT prophylaxis.
PubMed: 32524029
DOI: 10.4158/ACCR-2019-0434 -
Thrombosis Journal 2020Advanced pancreatic ductal adenocarcinoma (aPDAC) patients have a lifetime all type thromboembolic event (ATTE) rate of 25-35%. Efficacy and safety of increased dose...
BACKGROUND
Advanced pancreatic ductal adenocarcinoma (aPDAC) patients have a lifetime all type thromboembolic event (ATTE) rate of 25-35%. Efficacy and safety of increased dose primary thromboprophylaxis (IDPTP) with low molecular heparin (LMWH) given for 3 months has been shown in two prospective randomized trials.
OBJECTIVES
To report on efficacy -reduction of all type thromboembolic events (ATTE)-, safety -incidence of Major Bleeding (MB)- and compliance in a single-centre cohort of aPDAC patients receiving first line chemotherapy and LMWH-IDPTP.
METHODS
From May 2009 to October 2016, 82 patients received IDPTP -LMWH with dalteparin. Schedule: 55 kg and below: 7500 IU, between 55 and 80 kg: 10,000 IU, above 80 kg: 12,500 IU. MB is reported using the International Society of Thrombosis and Haemostasis (ISTH) criteria. ATTE was defined as any arterial or venous event, incidental or clinically symptomatic, including visceral VTE.
RESULTS
Mean and median time on dalteparin was 10.2 (95%CI 8.1, 12.4) and 8.0 (95%CI 6.2, 9.7) months respectively. ATTE was observed in 7 (8.5%) of patients, with a median time on IDPTP of 6.2 months (95% CI 10.0, 13.2). MB was seen in 10 (12.2%) patients with a median time on IDPTP of 4.5 months (95% CI 1.6, 7.4). Six major bleeds (60%) were the direct or indirect result of aPDAC. Eighty-one patients had died at the time of data collection with a median overall survival time of 8.7 months (95%CI 6.4, 11.0). Thromboembolism and bleeding were late events. No impact of thromboembolism or bleeding on overall survival was observed.
CONCLUSIONS
IDPTP-dalteparin was associated with lower ATTE occurrence rates than expected and comparable major bleeding rates. ATTE and MB were late events, the majority of MB was from direct or indirect result of locally progressing aPDAC. Since these conditions can frequently arise in aPDAC, IDPTP should be regularly reviewed beyond 3 months.
PubMed: 32514256
DOI: 10.1186/s12959-020-00222-1 -
Scandinavian Journal of Trauma,... Jun 2020Clinical research in severely ill or injured patients is required to improve healthcare but may be challenging to perform in practice. The aim of this study was to... (Observational Study)
Observational Study
BACKGROUND
Clinical research in severely ill or injured patients is required to improve healthcare but may be challenging to perform in practice. The aim of this study was to analyse barriers and challenges in the process of including critically ill patients in clinical studies.
METHODS
Data from critically ill patients considered for inclusion in an observational study of venous thromboembolism in Norway were analysed. This included quantitative and qualitative information from the screening log, consent forms and research notes.
RESULTS
Among 279 eligible critically ill patients, 204 (73%) were omitted from the study due to challenges and barriers in the inclusion process. Reasons for omission were categorised as practical in 133 (65%), medical in 31 (15%), and legal or ethical in 40 (20%) of the patients. Among 70 included patients, 29 (41%) consents were from patients and 41 (59%) from their next of kin. Several challenges were described herein; these included whether patients were competent to give consent, and which next of kin that should represent the patient. Furthermore, some included patients were unable to recall what they have consented, and some appeared unable to separate research from treatment.
CONCLUSIONS
Barriers and challenges in the inclusion process led to the omission of near three out of four eligible patients. This analysis provided information about where the problem resides and may be solved. The majority of challenges among included patients were related to issues of autonomy and validity of consent.
TRIAL REGISTRATION
ClinicalTrials.gov (NCT03405766).
Topics: Adult; Critical Illness; Dalteparin; Female; Fibrinolytic Agents; Humans; Informed Consent; Male; Norway; Patient Selection
PubMed: 32513204
DOI: 10.1186/s13049-020-00732-x -
Thrombosis Research Sep 2020• Venous thrombosis is common in patients with severe COVID-19 pneumonia. • Many of these thromboses may be immunothromboses due to local inflammation, rather than...
• Venous thrombosis is common in patients with severe COVID-19 pneumonia. • Many of these thromboses may be immunothromboses due to local inflammation, rather than thromboembolic disease. • Anticoagulated patients with COVID-19 pneumonia have a risk of major bleeding.
Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Betacoronavirus; COVID-19; Coronavirus Infections; Critical Care; Dalteparin; Extracorporeal Membrane Oxygenation; Female; Humans; Male; Middle Aged; Pandemics; Pneumonia, Viral; Retrospective Studies; SARS-CoV-2; Tertiary Healthcare; Thromboembolism; Ultrasonography, Doppler; United Kingdom; Young Adult
PubMed: 32485437
DOI: 10.1016/j.thromres.2020.05.049