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Evaluation of heparinized syringes for measuring newborn metabolites in neonates with a central arterial line.
Ryckman, KK, Ramesh, A, Cho, H, Oltman, SP, Rogers, EE, Dagle, JM, Jelliffe-Pawlowski, LL
Clinical biochemistry. 2022;:78-81
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Abstract
Newborn metabolic screening is emerging as a novel method for predicting neonatal morbidity and mortality in neonates born very preterm (<32 weeks gestation). The purpose of our study was to determine if blood collected by an electrolyte-balanced dry lithium heparin syringe, as is routine for blood gas measurements, affects targeted metabolite and biomarker levels. Two blood samples (one collected with a heparinized syringe and the other with a non-heparinized syringe) were obtained at the same time from 20 infants with a central arterial line and tested for 49 metabolites and biomarkers using standard procedures for newborn screening. Overall, the median metabolite levels did not significantly differ by syringe type. However, there was wide variability, particularly for amino acids and immunoreactive trypsinogen, for individual paired samples and therefore, consideration should be given to sample collection when using these metabolites in prediction models of neonatal morbidity and mortality.
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Rationale for the Role of Heparin and Related GAG Antithrombotics in COVID-19 Infection.
Magnani, HN
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2021;:1076029620977702
Abstract
The SARS-CoV-2 pandemic has focused attention on prevention, restriction and treatment methods that are acceptable worldwide. This means that they should be simple and inexpensive. This review examines the possible role of glycosaminoglycan (GAG) antithrombotics in the treatment of COVID-19. The pathophysiology of this disease reveals a complex interplay between the hemostatic and immune systems that can be readily disrupted by SARS-CoV-2. Some of the GAG antithrombotics also possess immune-modulatory actions and since they are relatively inexpensive they could play an important role in the management of COVID-19 and its complications.
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A Scoping Review of Alternative Anticoagulation Strategies for Hemodialysis Patients with a Mechanical Heart Valve.
Thomson, BKA, Pilkey, NG, Monteith, B, Holden, RM
American journal of nephrology. 2021;(10-11):861-870
Abstract
INTRODUCTION Patients with end-stage renal disease (ESRD) have high rates of cardiac valvulopathy but can develop contraindications for vitamin K antagonist (VKA) therapy. We explored the evidence for alternative anticoagulation strategies in patients with ESRD with a contraindication for VKA therapy. METHODS A scoping review was completed, searching MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Conference abstracts from inception to March 30, 2021. The study population was patients with ESRD who were on VKA therapy and developed a contraindication to VKA therapy use. All data regarding studies, patient characteristics, anticoagulation strategy, and clinical outcomes were summarized. RESULTS Twenty-three articles met inclusion criteria. These articles included 57 patients. Contraindications to VKA therapy included calcific uremic arteriolopathy (CUA) (n = 55) and warfarin-induced skin necrosis (n = 2). All studies were either case reports or case series. There were 10 anticoagulation strategies identified. Continuation of VKA therapy was associated with increased death and decreased rates of CUA resolution (80.0% and 10.0%, respectively), compared to apixaban (24.0% and 70.8%), subcutaneous (SC) low-molecular-weight heparin (LMWH) (14.3%, 85.7%), and SC unfractionated heparin (0.0%, 100.0%). While only 5 patient cases were reported with mechanical heart valves, SC LMWH use has been reported in this context with good outcomes. CONCLUSIONS In patients with ESRD who develop a contraindication to VKA therapy, several alternative anticoagulation strategies have been reported with superior outcomes to VKA continuation. While outcomes appear superior to continuation of VKA therapy, more data are required before definitive recommendations can be made for the patient with ESRD and a mechanical heart valve.
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Design and Rationale of a Randomized, Double-Blind, Placebo-Controlled, Phase 2/3 Study Evaluating Dociparstat in Acute Lung Injury Associated with Severe COVID-19.
Lasky, JA, Fuloria, J, Morrison, ME, Lanier, R, Naderer, O, Brundage, T, Melemed, A
Advances in therapy. 2021;(1):782-791
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Abstract
INTRODUCTION The COVID-19 global pandemic caused by the novel coronavirus, SARS-CoV-2, and the consequent morbidity and mortality attributable to progressive hypoxemia and subsequent respiratory failure threaten to overrun hospital critical care units globally. New agents that address the hyperinflammatory "cytokine storm" and hypercoagulable pathology seen in these patients may be a promising approach to treat patients, minimize hospital stays, and ensure hospital wards and critical care units are able to operate effectively. Dociparstat sodium (DSTAT) is a glycosaminoglycan derivative of heparin with robust anti-inflammatory properties, with the potential to address underlying causes of coagulation disorders with substantially reduced risk of bleeding compared to commercially available heparin. METHODS This study is a randomized, double-blind, placebo-controlled, phase 2/3 trial to determine the safety and efficacy of DSTAT added to standard of care in hospitalized adults with COVID-19 who require supplemental oxygen. Phase 2 will enroll 12 participants in each of two dose-escalating cohorts to confirm the safety of DSTAT in this population. Following review of the data, an additional 50 participants will be enrolled. Contingent upon positive results, phase 3 will enroll approximately 450 participants randomized to DSTAT or placebo. The primary endpoint is the proportion of participants who survive and do not require mechanical ventilation through day 28. DISCUSSION Advances in standard of care, recent emergency use authorizations, and positive data with dexamethasone have likely contributed to an increasing proportion of patients who are surviving without the need for mechanical ventilation. Therefore, examining the time to improvement in the NIAID score will be essential to provide a measure of drug effect on recovery. Analysis of additional endpoints, including supportive biomarkers (e.g., IL-6, HMGB1, soluble-RAGE, D-dimer), will be performed to further define the effect of DSTAT in patients with COVID-19 infection. TRIAL REGISTRATION ClinicalTrials.gov identifier; NCT04389840, Registered 13 May 2020.
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Combination of dociparstat sodium (DSTAT), a CXCL12/CXCR4 inhibitor, with azacitidine for the treatment of hypomethylating agent refractory AML and MDS.
Huselton, E, Rettig, MP, Campbell, K, Cashen, AF, DiPersio, JF, Gao, F, Jacoby, MA, Pusic, I, Romee, R, Schroeder, MA, et al
Leukemia research. 2021;:106713
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Abstract
Leukemia stem cells utilize cell adhesion molecules like CXCR4/CXCL12 to home to bone marrow stromal niches where they are maintained in a dormant, protected state. Dociparstat sodium (DSTAT, CX-01) is a low anticoagulant heparin with multiple mechanisms of action, including inhibition of the CXCR4/CXCL12 axis, blocking HMGB1, and binding platelet factor 4 (PF-4). We conducted a pilot study adding DSTAT to azacitidine for patients with AML or MDS unresponsive to or relapsed after prior hypomethylating agent therapy, hypothesizing that DSTAT may improve response rates. Twenty patients were enrolled, with a median of 2 prior lines of therapy and 6 cycles of prior hypomethylating agents. Among fifteen patients evaluable for response, there was 1 complete remission, and 3 marrow complete remissions, for a response rate of 27 % among evaluable patients (20 % overall). Hematologic improvement was observed in 5 additional patients. The median overall survival for all enrolled patients was 205 days (95 % CI 119-302). While cytopenias and infections were common, these were not out of proportion to what would be expected in this population of patients undergoing treatment with azacitidine alone. In summary, this trial demonstrated the feasibility of combining DSTAT with azacitidine, with several responses observed, suggesting this combination warrants further study.
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Comment on "Emissive H-Aggregates of an Ultrafast Molecular Rotor: A Promising Platform for Sensing Heparin".
Zsila, F
ACS applied materials & interfaces. 2021;(43):50585-50588
Abstract
For heparin sensing, Mudliar and Singh developed fluorescence and absorption spectroscopic approaches by utilizing emissive H-aggregates of thioflavin T (ThT) formed upon heparin binding. It has been proposed that the methods work not only in pure aqueous solution but also in complex biological media such as human serum. However, the optical features used to detect and quantify heparin are very sensitive to the ionic strength of the solution and completely vanish at 1.45 mM NaCl. Curiously, the authors were able to determine the heparin content of 1% serum samples containing the same level of electrolyte. In addition, the experimental conditions employed for heparin detection in serum samples were substantially modified, reducing the optical path length from 1 to 0.1 cm and increasing the dye concentration by an unknown measure. ThT shows a concentration-dependent tendency for aqueous aggregation, which markedly modifies its absorption and fluorescence properties. The authors have failed to verify that spectral characteristics of the ThT-heparin system observed in pure aqueous medium remain unchanged at higher dye concentrations and in the presence of serum components. Taking these issues into consideration, the heparin detection scheme offered for serum samples cannot be reproduced.
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Venous Thromboembolism in Children: From Diagnosis to Management.
Lassandro, G, Palmieri, VV, Palladino, V, Amoruso, A, Faienza, MF, Giordano, P
International journal of environmental research and public health. 2020;(14)
Abstract
Venous thromboembolism (VTE) in children is a rare occurrence, although in recent decades we have seen an increase due to several factors, such as the rise in survival of subjects with chronic conditions, the use of catheters, and the increased sensitivity of diagnostic tools. Besides inherited thrombophilia, acquired conditions such as cardiovascular diseases, infections, chronic disorders, obesity and malignancy are also common risk factors for paediatric VTE. The treatment of paediatric VTE consists of the use of heparins and/or vitamin K antagonists to prevent dissemination, embolization, and secondary VTE. Randomized clinical trials of direct oral anticoagulants in paediatric VTE are ongoing, with the aim to improve the compliance and the care of patients. We reviewed the physiological and pathological mechanisms underlying paediatric thrombosis and updated the current diagnosis and treatment options.
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Primary prophylaxis for venous thromboembolism in people undergoing major amputation of the lower extremity.
Herlihy, DR, Thomas, M, Tran, QH, Puttaswamy, V
The Cochrane database of systematic reviews. 2020;(7):CD010525
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Abstract
BACKGROUND People undergoing major amputation of the lower limb are at increased risk of venous thromboembolism (VTE). Risk factors for VTE in amputees include advanced age, sedentary lifestyle, longstanding arterial disease and an identifiable hypercoagulable condition. Evidence suggests that pharmacological prophylaxis (e.g. heparin, factor Xa inhibitors, vitamin K antagonists, direct thrombin inhibitors, antiplatelets) is effective in preventing deep vein thrombosis (DVT), but is associated with an increased risk of bleeding. Mechanical prophylaxis (e.g. antiembolism stockings, intermittent pneumatic compression and foot impulse devices), on the other hand, is non-invasive and has minimal side effects. However, mechanical prophylaxis is not always appropriate for people with contraindications such as peripheral arterial disease (PAD), arteriosclerosis or bilateral lower limb amputations. It is important to determine the most effective thromboprophylaxis for people undergoing major amputation and whether this is one treatment alone or in combination with another. This is an update of the review first published in 2013. OBJECTIVES To determine the effectiveness of thromboprophylaxis in preventing VTE in people undergoing major amputation of the lower extremity. SEARCH METHODS The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase and Cumulative Index to Nursing and Allied Health Literature databases, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 5 November 2019. We planned to undertake reference checking of identified trials to identify additional studies. We did not apply any language restrictions. SELECTION CRITERIA We included randomised controlled trials and quasi-randomised controlled trials which allocated people undergoing a major unilateral or bilateral amputation (e.g. hip disarticulation, transfemoral, knee disarticulation and transtibial) of the lower extremity to different types or regimens of thromboprophylaxis (including pharmacological or mechanical prophylaxis) or placebo. DATA COLLECTION AND ANALYSIS Two review authors independently selected studies, extracted data and assessed risk of bias. We resolved any disagreements by discussion. Outcomes of interest were VTE (DVT and pulmonary embolism (PE)), mortality, adverse events and bleeding. We used GRADE criteria to assess the certainty of the evidence. The two included studies compared different treatments, so we could not pool the data in a meta-analysis. MAIN RESULTS We did not identify any eligible new studies for this update. Two studies with a combined total of 288 participants met the inclusion criteria for this review. Unfractionated heparin compared to low molecular weight heparin One study compared unfractionated heparin with low molecular weight heparin and found no evidence of a difference between the treatments in the prevention of DVT (odds ratio (OR) 1.23, 95% confidence interval (CI) 0.28 to 5.35; 75 participants; very low-certainty evidence). No bleeding events occurred in either group. Deaths and adverse events were not reported. This study was open-label and therefore at a high risk of performance bias. Additionally, the study did not report the method of randomisation, so the risk of selection bias was unclear. Heparin compared to placebo In the second study, there was no evidence of a benefit from heparin use in preventing PE when compared to placebo (OR 0.84, 95% CI 0.35 to 2.01; 134 participants; low-certainty evidence). Similarly, no evidence of improvement was detected when the level of amputation was considered, with a similar incidence of PE between the two treatment groups: above knee amputation (OR 0.79, 95% CI 0.31 to 1.97; 94 participants; low-certainty evidence); and below knee amputation (OR 1.53, 95% CI 0.09 to 26.43; 40 participants; low-certainty evidence). Ten participants died during the study; five underwent a post-mortem and three were found to have had a recent PE, all of whom had been on placebo (low-certainty evidence). Bleeding events were reported in less than 10% of participants in both treatment groups, but the study did not present specific data (low-certainty evidence). There were no reports of other adverse events. This study did not report the methods used to conceal allocation of treatment, so it was unclear whether selection bias occurred. However, this study appeared to be free from all other sources of bias. No study looked at mechanical prophylaxis. AUTHORS' CONCLUSIONS We did not identify any eligible new studies for this update. As we only included two studies in this review, each comparing different interventions, there is insufficient evidence to make any conclusions regarding the most effective thromboprophylaxis regimen in people undergoing lower limb amputation. Further large-scale studies of good quality are required.
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Heparin for prophylaxis of venous thromboembolism in intracerebral haemorrhage.
Sprügel, MI, Sembill, JA, Kuramatsu, JB, Gerner, ST, Hagen, M, Roeder, SS, Endres, M, Haeusler, KG, Sobesky, J, Schurig, J, et al
Journal of neurology, neurosurgery, and psychiatry. 2019;(7):783-791
Abstract
OBJECTIVE To determine the occurrence of intracranial haemorrhagic complications (IHC) on heparin prophylaxis (low-dose subcutaneous heparin, LDSH) in primary spontaneous intracerebral haemorrhage (ICH) (not oral anticoagulation-associated ICH, non-OAC-ICH), vitamin K antagonist (VKA)-associated ICH and non-vitamin K antagonist oral anticoagulant (NOAC)-associated ICH. METHODS Retrospective cohort study (RETRACE) of 22 participating centres and prospective single-centre study with 1702 patients with VKA-associated or NOAC-associated ICH and 1022 patients with non-OAC-ICH with heparin prophylaxis between 2006 and 2015. Outcomes were defined as rates of IHC during hospital stay among patients with non-OAC-ICH, VKA-ICH and NOAC-ICH, mortality and functional outcome at 3 months between patients with ICH with and without IHC. RESULTS IHC occurred in 1.7% (42/2416) of patients with ICH. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (log-rank p=0.645; VKA-ICH: 27/1406 (1.9%), NOAC-ICH 1/130 (0.8%), non-OAC-ICH 14/880 (1.6%); p=0.577). Detailed analysis according to treatment exposure (days with and without LDSH) revealed no differences in incidence rates of IHC per 1000 patient-days (LDSH: 1.43 (1.04-1.93) vs non-LDSH: 1.32 (0.33-3.58), conditional maximum likelihood incidence rate ratio: 1.09 (0.38-4.43); p=0.953). Secondary outcomes showed differences in functional outcome (modified Rankin Scale=4-6: IHC: 29/37 (78.4%) vs non-IHC: 1213/2048 (59.2%); p=0.019) and mortality (IHC: 14/37 (37.8%) vs non-IHC: 485/2048 (23.7%); p=0.045) in disfavour of patients with IHC. Small ICH volume (OR: volume <4.4 mL: 0.18 (0.04-0.78); p=0.022) and low National Institutes of Health Stroke Scale (NIHSS) score on admission (OR: NIHSS <4: 0.29 (0.11-0.78); p=0.014) were significantly associated with fewer IHC. CONCLUSIONS Heparin administration for venous thromboembolism (VTE) prophylaxis in patients with ICH appears to be safe regarding IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH in this observational cohort analysis. Randomised controlled trials are needed to verify the safety and efficacy of heparin compared with other methods for VTE prevention.
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Safety and efficacy of heparin during dialysis in the context of systemic anticoagulant and antiplatelet medications.
Brunelli, SM, Cohen, DE, Marlowe, G, Liu, D, Njord, L, Van Wyck, D, Aronoff, G
Journal of nephrology. 2019;(3):453-460
Abstract
Heparin is widely used to prevent coagulation during hemodialysis. Although systemic anticoagulants and antiplatelet agents are commonly prescribed in the hemodialysis population, the safety and efficacy of heparin in the presence of these medications is unclear. This retrospective cohort study considered adult hemodialysis patients treated in the United States (August 2015-July 2017). For each month, patients were ascribed a three-part exposure status (heparin use, anticoagulant use, antiplatelet agent use) based on electronic health records. Outcomes included anemia measures, peri-treatment bleeding and clotting, and hospitalization for gastrointestinal (GI) bleeding. Within systemic medication exposure categories, associations of heparin use were examined using adjusted generalized linear, negative binomial, or Poisson models. Across all systemic medication exposures, heparin use was associated with lower erythropoiesis stimulating agent (ESA) dose, higher hemoglobin levels, and lower monthly intravenous (IV) iron dose; lower rates of clotting during treatment and hospitalization for GI bleeding; and similar rates of peri-treatment bleeding. Associations with respect to ESA, IV iron, hemoglobin, and clotting were approximately twofold more potent in the absence of a systemic anticoagulant; the presence of an antiplatelet agent had little impact. Neither medication type influenced associations between heparin use and peri-treatment or GI bleeding. These results suggest that heparin use is safe and effective in the presence and absence of systemic anticoagulants and antiplatelet agents. Clinical judgment must be applied to assess bleeding risk in individual patients; however, the decision to withhold heparin should not solely be based upon the concurrent use of anticoagulant or antiplatet agents.