Journal articles on the topic 'Heparin Therapeutic use'
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Banik, Nipa, Seong-Bin Yang, Tae-Bong Kang, Ji-Hong Lim, and Jooho Park. "Heparin and Its Derivatives: Challenges and Advances in Therapeutic Biomolecules." International Journal of Molecular Sciences 22, no. 19 (September 29, 2021): 10524. http://dx.doi.org/10.3390/ijms221910524.
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Heparin has been extensively studied as a safe medicine and biomolecule over the past few decades. Heparin derivatives, including low-molecular-weight heparins (LMWH) and heparin pentasaccharide, are effective anticoagulants currently used in clinical settings. They have also been studied as functional biomolecules or biomaterials for various therapeutic uses to treat diseases. Heparin, which has a similar molecular structure to heparan sulfate, can be used as a remarkable biomedicine due to its uniquely high safety and biocompatibility. In particular, it has recently drawn attention for use in drug-delivery systems, biomaterial-based tissue engineering, nanoformulations, and new drug-development systems through molecular formulas. A variety of new heparin-based biomolecules and conjugates have been developed in recent years and are currently being evaluated for use in clinical applications. This article reviews heparin derivatives recently studied in the field of drug development for the treatment of various diseases.
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Mycroft-West, Courtney J., Lynsay C. Cooper, Anthony J. Devlin, Patricia Procter, Scott E. Guimond, Marco Guerrini, David G. Fernig, Marcelo A. Lima, Edwin A. Yates, and Mark A. Skidmore. "A Glycosaminoglycan Extract from Portunus pelagicus Inhibits BACE1, the β Secretase Implicated in Alzheimer’s Disease." Marine Drugs 17, no. 5 (May 16, 2019): 293. http://dx.doi.org/10.3390/md17050293.
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Therapeutic options for Alzheimer’s disease, the most common form of dementia, are currently restricted to palliative treatments. The glycosaminoglycan heparin, widely used as a clinical anticoagulant, has previously been shown to inhibit the Alzheimer’s disease-relevant β-secretase 1 (BACE1). Despite this, the deployment of pharmaceutical heparin for the treatment of Alzheimer’s disease is largely precluded by its potent anticoagulant activity. Furthermore, ongoing concerns regarding the use of mammalian-sourced heparins, primarily due to prion diseases and religious beliefs hinder the deployment of alternative heparin-based therapeutics. A marine-derived, heparan sulphate-containing glycosaminoglycan extract, isolated from the crab Portunus pelagicus, was identified to inhibit human BACE1 with comparable bioactivity to that of mammalian heparin (IC50 = 1.85 μg mL−1 (R2 = 0.94) and 2.43 μg mL−1 (R2 = 0.93), respectively), while possessing highly attenuated anticoagulant activities. The results from several structural techniques suggest that the interactions between BACE1 and the extract from P. pelagicus are complex and distinct from those of heparin.
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Beurskens, Danielle M. H., Joram P. Huckriede, Roy Schrijver, H. Coenraad Hemker, Chris P. Reutelingsperger, and Gerry A. F. Nicolaes. "The Anticoagulant and Nonanticoagulant Properties of Heparin." Thrombosis and Haemostasis 120, no. 10 (August 20, 2020): 1371–83. http://dx.doi.org/10.1055/s-0040-1715460.
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AbstractHeparins represent one of the most frequently used pharmacotherapeutics. Discovered around 1926, routine clinical anticoagulant use of heparin was initiated only after the publication of several seminal papers in the early 1970s by the group of Kakkar. It was shown that heparin prevents venous thromboembolism and mortality from pulmonary embolism in patients after surgery. With the subsequent development of low-molecular-weight heparins and synthetic heparin derivatives, a family of related drugs was created that continues to prove its clinical value in thromboprophylaxis and in prevention of clotting in extracorporeal devices. Fundamental and applied research has revealed a complex pharmacodynamic profile of heparins that goes beyond its anticoagulant use. Recognition of the complex multifaceted beneficial effects of heparin underscores its therapeutic potential in various clinical situations. In this review we focus on the anticoagulant and nonanticoagulant activities of heparin and, where possible, discuss the underlying molecular mechanisms that explain the diversity of heparin's biological actions.
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Ludwig, Ralf. "Therapeutic Use of Heparin beyond Anticoagulation." Current Drug Discovery Technologies 6, no. 4 (December 1, 2009): 281–89. http://dx.doi.org/10.2174/157016309789869001.
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Kutzner, H., and G. Hesse. "Therapeutic use of lowmolecular weight heparin for capillaritis alba." Phlebologie 37, no. 05 (2008): 259–65. http://dx.doi.org/10.1055/s-0037-1622240.
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SummaryThe reason of the so called ulcerated capillaritis alba or idiopathic atrophie blanche is vasculopathy caused by severe venous hypertension. Thrombosed and rarificated vessels worsen the oxygenation, increase permanent inflammation and impede the necessary compression therapy. The anti-inflammatory effects of heparin alleviate pain and being independent from the antithrombotic ones it needs much lower doses for treatment. This anti-inflammatory effect is now becoming more important in clinical phlebology. Case studies of more than 50 patients and one prospective randomized study of 87 patients clearly demonstrate the ameliorated healing of ulcerated atrophie blanche. In our office we could document this positive effect with 22 patients. We present the pathophysiology of low molecular heparins for ulcerated capillaritis alba and our own experiences with it.
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Shaughnessy, SG, E. Young, P. Deschamps, and J. Hirsh. "The effects of low molecular weight and standard heparin on calcium loss from fetal rat calvaria." Blood 86, no. 4 (August 15, 1995): 1368–73. http://dx.doi.org/10.1182/blood.v86.4.1368.bloodjournal8641368.
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Osteoporosis is a well-recognized complication of long-term heparin use. However, the mechanisms by which heparin can influence bone metabolism are unclear. We report here that unfractionated heparin stimulates the process of bone resorption and that the low molecular weight heparins (LMWHs), enoxaparin, fragmin, logiparin, and ardeparin produce significantly less calcium loss than unfractionated heparin. To assess calcium loss from bone, we quantified the release of 45Ca into the culture medium of fetal rat calvaria. 45Ca release was increased in a dose-dependent manner by the addition of either unfractionated heparin or the LMWHs; but more than 50-fold higher LMWH concentrations were required to obtain an equivalent effect to unfractionated heparin. Thus, at concentration > or = 2 micrograms/mL (0.35 anti-Xa units/mL), unfractionated heparin stimulated 45Ca release 1.53 +/- 0.06 fold. 45Ca release was increased to a similar extent by the addition of either 10(- 7) mol/L parathyroid hormone (PTH) or 10(-6) mol/L 1,25 dihydroxyvitamin D3 (1,25 Vit D3). In contrast to unfractionated heparin, LMWH concentrations > or = 100 micrograms/mL (> or = 14.0 anti- Xa units/mL) were required before maximum isotope release was observed. At concentrations well above therapeutic levels, the LMWHs stimulated 45Ca release by only 1.25 /+- 0.01-fold. Heparins with high and low antithrombin III affinities stimulated 45Ca release equally well. Both size and sulfation were found to be major determinants of heparin's ability to promote isotope release. Thus, the ability of defined heparin fragments to stimulate 45Ca release correlated with their molecular weight, and after N-desulfation the ability of heparin to induce isotope release was greatly diminished. Dermatan sulfate had no effect on 45Ca release. We conclude that size and sulfation are major determinants of heparin's ability to promote bone resorption and that the risk of heparin-induced osteoporosis may be reduced by the use of LMWH preparations.
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Hoffman, Nannette B., and David J. Frohnapple. "Heparin Dosing Order Form Use in an Academic-Affiliated Veterans Affairs Medical Center." Journal of Pharmacy Technology 12, no. 6 (November 1996): 276–79. http://dx.doi.org/10.1177/875512259601200609.
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Objective: Because a drug utilization evaluation (DUE) showed poor intravenous heparin prescribing practice in our medical center, we developed a preprinted intravenous heparin order form for use by physicians to improve heparin administration. Methods: Two DUEs were performed, one prior to use of a weight-based heparin dosing order form and another after the introduction of the form. Indicators that were evaluated included dosing, laboratory monitoring, and intramuscular injections. DUE results before and after introduction of the order form were statistically compared using Fisher's exact text. Results: The initial DUE showed that only 3% of patients who were administered intravenous heparin received appropriate dosing, and only 60% had a therapeutic activated partial thromboplastin time (aPTT) ratio within the first 24 hours. Blood samples for the aPTTs were drawn at incorrect × in 27% of patients, and 9% of patients received intramuscular injections of other drugs. After implementation of the preprinted intravenous heparin order form, 73% of the patients received appropriate heparin dosing (p < 0.00001), and 79% of the patients had a therapeutic aPTT ratio within the first 24 hours (p = 0.08). The aPTTs were drawn at incorrect × in 12% of patients, and 3% of patients received intramuscular injections (NS for both). All patients receiving appropriate heparin dosing achieved a therapeutic aPTT ratio within the first 24 hours, whereas only 29% of patients on the acute wards and 50% of those in the intensive care units achieved a therapeutic ratio when dosing was inappropriate (p < 0.0001). Conclusions: We improved the intravenous heparin prescribing practice in an academic-affiliated tertiary Veteran's Affairs Medical Center using a preprinted intravenous heparin order form for physician use. The form was also effective in achieving the desired aPTT ratio within 24 hours.
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Bitsadze, V. O., E. V. Slukhanchuk, J. Kh Khizroeva, M. V. Tretyakova, N. V. Pyatigorskaya, S. V. Akinshina, N. A. Makatsariya, et al. "Anticoagulant, anti-inflammatory, antiviral and antitumor properties of heparins." Obstetrics, Gynecology and Reproduction 15, no. 3 (July 9, 2021): 295–312. http://dx.doi.org/10.17749/2313-7347/ob.gyn.rep.2021.216.
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Our knowledge regarding chemical structure and properties of heparin and its derivatives, including biological properties in blood plasma, on the cell surface and while interacting with receptors, has been progressively growing. New insights are followed by the expansion of therapeutic opportunities and indications for the use of heparins. There are prerequisites for the creation of new generation drugs with modified properties that reduce a bleeding risk while applied for a non-anticoagulant goal. The non-anticoagulant heparin properties allow to consider it as a candidate for pathogenetic treatment of patients with COVID-19. This review focuses on the anticoagulant and non-anticoagulant heparin properties as well as the underlying molecular mechanisms.
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Sung, Michelle, Jeanine Walenga, Walter Jeske, Omer Iqbal, and Mamdouh Bakhos. "Comparing a New Bovine Source Heparin to the Clinically Used Porcine Heparin for Platelet Function Effects and Heparin-Induced Thrombocytopenia Potential." Blood 132, Supplement 1 (November 29, 2018): 2540. http://dx.doi.org/10.1182/blood-2018-99-118781.
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Abstract Background Heparin is a sulfated polysaccharide obtained from intestinal mucosa with anticoagulant properties that is widely used as a standard clinical therapeutic agent to treat and prevent thrombosis. Heparin is known to affect platelet function, and among its side effects is heparin-induced thrombocytopenia (HIT) that can occur in about 1% of patients exposed to heparin. Presently, only porcine source heparin is approved for use in the United States. The aims of this study were to determine if platelet activation by physiological agonists and platelet aggregation induced by HIT antibodies would be equivalent in the presence of bovine source heparin and porcine source heparin. Materials and Methods Seven lots of bovine heparin from Eurofarma and 3 lots of commercial clinical grade porcine heparin (Pfizer/Hospira) were evaluated. The USP Reference Standard for porcine heparin was used to determine anti-Xa and anti-IIa potencies of the bovine heparins. For each study, blood was collected from healthy volunteers (n=5 per test group), anticoagulated with sodium citrate, and centrifuged to obtain platelet rich plasma (PRP). Platelet aggregation responses were assessed using the BioData PAP-8 platelet aggregometer. For the first aim to evaluate platelet function, PRP was combined with heparin at final concentrations of 10.0, 1.0, and 0.1 µg/mL, covering both therapeutic and prophylactic ranges. Platelet agonists included adenosine diphosphate (ADP), collagen, epinephrine, arachidonic acid, and thrombin receptor agonist peptide (TRAP). The aggregation response was quantitated in terms of primary slope (PS), area under the curve (AUC), maximum aggregation (MA), and final aggregation (FA). For the second aim to evaluate the HIT potential, antibodies to the complex of heparin-platelet factor 4 (H-PF4) from banked HIT patient apheresis fluid were combined with donor PRP and heparin. Heparins were tested at final concentrations of 0.1, 0.4, 0.8, 1, and 100 U/mL. PS and FA results were recorded. For all data, comparisons were analyzed with 2-Way ANOVA using SigmaPlot software. Results In the presence of either bovine (BMH) or porcine heparin (PMH), the normal platelet aggregation response of all donors was not altered from that obtained with saline (see representative aggregation tracing in the image below). All heparin concentrations produced the same response. There were no significant differences between the bovine and porcine heparins for each of the 4 platelet aggregation parameters for ADP, arachidonic acid, collagen, epinephrine, and TRAP. Variation in the PS for arachidonic acid and collagen need to be assessed in a larger pool of donors to assure the lack of significant difference. Platelet activation to H-PF4 antibodies was strong at 0.1 to 1 U/mL concentrations with the expected inhibition observed when using 100 U/mL heparin. The HIT potential between bovine heparin and porcine heparin demonstrated no significant difference between the heparins (see MA responses in the image below). There were no lot to lot differences for the bovine heparins or the porcine heparins in either the platelet aggregation studies or the assessment for HIT. Conclusion In these studies of platelet function, the bovine and porcine source heparins were comparable with regards to their effects on platelet aggregation induced by multiple different agonists and their HIT potential. Figure. Figure. Disclosures Walenga: Eurofarma: Research Funding.
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Oliynyk, Oleksandr, Wojciech Barg, Anna Slifirczyk, Yanina Oliynyk, Serhij Dubrov, Vitaliy Gurianov, and Marta Rorat. "Comparison of the Effect of Unfractionated Heparin and Enoxaparin Sodium at Different Doses on the Course of COVID-19-Associated Coagulopathy." Life 11, no. 10 (September 30, 2021): 1032. http://dx.doi.org/10.3390/life11101032.
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Background: COVID-19-associated coagulopathy (CAC) exacerbates the course of coronavirus infection and contributes to increased mortality. Current recommendations for CAC treatment include the use of low-molecular weight heparins (LMWH) at prophylactic or therapeutic doses, as well as the use of unfractionated heparin (UFH). Methods: A randomised, controlled trial enrolled 126 patients hospitalised in the intensive care unit with severe COVID-19 complicated by CAC. The effects of LMWH at preventive and therapeutic doses and UFH at therapeutic doses on mortality and intubation rates were compared. Results: The number of intubations and deaths showed no significant difference depending on the anticoagulant therapy used. However, multivariate logistic regression models revealed an increased risk of intubation (p = 0.026, odds ratio (OR) = 3.33, 95% confidence interval (CI) 1.15–9.59), and an increased risk of death (p = 0.046, OR = 3.01, 95% CI 1.02–8.90), for patients treated with LMWH at a prophylactic dose but not at a therapeutic dose as compared to patients treated with UFH when controlling for other risk factors. Conclusions: The use of unfractionated heparin in the treatment of COVID-19-associated coagulopathy seems to be more effective at reducing the risk of intubation and death than enoxaparin at prophylactic doses.
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Sullivan, Louisa, Asia N. Quan, Karen J. Richey, and Kevin N. Foster. "513 Continuous Heparin Infusion in Burn Patients on Continuous Renal Replacement Therapy." Journal of Burn Care & Research 42, Supplement_1 (April 1, 2021): S103—S104. http://dx.doi.org/10.1093/jbcr/irab032.164.
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Abstract Introduction Hyper-coagulopathy has been widely described in patients following burn injury. In burn patients with renal dysfunction requiring continuous renal replacement therapy (CRRT), citrate is commonly used to anticoagulate the circuit. However, if venous thromboembolism develops, or if the patient requires treatment-dose anticoagulation for acute coronary syndrome or atrial fibrillation, an unfractionated heparin (UFH) infusion can be used for anticoagulation. This study reviewed the use of heparin infusion in burned patients on concomitant continuous renal replacement therapy. Methods This study was a retrospective review of patients in a single burn center over six years. Patients were included if they were 18 years or older and receiving UFH as a continuous infusion for VTE, acute coronary syndrome (ACS), or new onset atrial fibrillation while on concomitant CRRT. Results Eight patients were included. Seven of eight patients reached a therapeutic aPTT level. The maximum rate of heparin infusion which was required to produce a therapeutic aPTT was 34 units/kg/hr while the minimum was 9 units/kg/hr. The patient requiring the highest heparin infusion rate met criteria for heparin resistance. Four of eight patients developed clinically significant bleeding while on heparin infusion. All four patients had some duration of concomitant citrate infusion during heparin infusion and all four were receiving heparin for VTE. Each of these patients required a heparin infusion rate of 24 units/kg/hr or greater to obtain therapeutic aPTT levels. Patients who did not have clinically significant bleeding had a maximum therapeutic heparin infusion rate of 22 units/kg/hr or less. Conclusions Heparin infusion can be used successfully in burn patients who are receiving concomitant CRRT, with the majority (7 of 8) of the patients in this study able to achieve a therapeutic aPTT level. Clinically significant bleeding occurred in 50% of patients and was associated with higher rates of heparin infusion (> 24 units/kg/hr) and the use of concomitant citrate infusion to anticoagulate the CRRT circuit. Heparin resistance appeared to be present in at least one patient in the study, with high doses of heparin required to achieve a therapeutic aPTT level.
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Malloy, Katherine M., Tara A. McCabe, and Robert J. Kuhn. "Bivalirudin Use in an Infant With Persistent Clotting on Unfractionated Heparin." Journal of Pediatric Pharmacology and Therapeutics 16, no. 2 (April 1, 2011): 108–12. http://dx.doi.org/10.5863/1551-6776-16.2.108.
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ABSTRACT Bivalirudin is a direct thrombin inhibitor approved for use in adult patients with heparin-induced thrombocytopenia (HIT) undergoing percutaneous coronary intervention. Recently, its use in the pediatric population has increased due to its anti-thrombin-independent mechanism of action. As heparin products produce great inter- and intraindividual variability in pediatric patients, often due to decreased anti-thrombin concentrations in the first year of life, some practitioners have turned to direct thrombin inhibitors, such as bivalirudin, for more predictable pharmacokinetics and effects on bound and circulating thrombin. We report our experience using bivalirudin in a 2-month-old female with recurrent systemic thrombi despite continuous unfractionated heparin infusion. Due to the patient's inability to maintain therapeutic activated partial thromboplastin time (aPTT) values during heparin infusion, bivalirudin was initiated at 0.1 mg/kg/h and increased due to subtherapeutic aPTTs to a maximum of 0.58 mg/kg/h. Therapeutic aPTTs were achieved at the increased dose; however, the patient's worsening renal impairment with resultant drug accumulation and overwhelming sepsis on day 5 of therapy led to discontinuation of the infusion and the initiation of comfort measures.
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Bosco, Michael, and Troy Kish. "Hepatotoxicity With Elevated Bilirubin Secondary to Prophylactic Doses of Unfractionated Heparin: A Case Report and Review of Heparin-Induced Hepatotoxicity." Journal of Pharmacy Technology 35, no. 1 (September 28, 2018): 36–40. http://dx.doi.org/10.1177/8755122518803363.
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Objective: To report a case of heparin-induced hepatotoxicity in a patient without prior liver dysfunction who received prophylactic doses of unfractionated heparin (UFH). Case Summary: A 70-year-old man with no prior liver dysfunction was admitted to the hospital for presyncope, secondary to dehydration, and new-onset congestive heart failure. Prophylactic UFH was initiated for deep vein thrombosis prophylaxis. Within 2 days, he developed increases in aspartate aminotransferase and alanine aminotransferase. By day 4, aspartate aminotransferase and alanine aminotransferase were greater than 5 and 9 times the upper limit of normal, respectively. Alkaline phosphatase and bilirubin were markedly elevated as well. UFH was discontinued on day 4, and liver enzymes subsequently normalized. Discussion: Hepatotoxicity, defined as increases in transaminases greater than 3 times the upper limit of normal, is relatively rare—estimated to occur in only 5% of those receiving therapy with UFH. Concurrent elevations in bilirubin have rarely been reported. Enzymes typically begin to rise after 4 to 5 days of UFH use and return to normal within 2 weeks of discontinuation. Previously published case reports of heparin-induced hepatotoxicity have occurred with therapeutic doses of either UFH or low-molecular-weight heparins. Conclusions: Heparin-induced hepatotoxicity may occur more rapidly than previously described, and even with the use of prophylactic doses of UFH. Given their widespread use, it is important for clinicians to consider heparins in their differential as a potential cause of hepatotoxicity especially in patients without underlying hepatic disease.
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Husted, Steen, Lars Wallentin, Felicita Andreotti, Harald Arnesen, Fedor Bachmann, Colin Baigent, Kurt Huber, et al. "Parenteral anticoagulants in heart disease: Current status and perspectives (Section II)." Thrombosis and Haemostasis 109, no. 05 (2013): 769–86. http://dx.doi.org/10.1160/th12-06-0403.
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SummaryAnticoagulants are a mainstay of cardiovascular therapy, and parenteral anticoagulants have widespread use in cardiology, especially in acute situations. Parenteral anticoagulants include unfractionated heparin, low-molecular-weight heparins, the synthetic pentasaccharides fondaparinux, idraparinux and idrabiotaparinux, and parenteral direct thrombin inhibitors. The several shortcomings of unfractionated heparin and of low-molecular-weight heparins have prompted the development of the other newer agents. Here we review the mechanisms of action, pharmacological properties and side effects of parenteral anticoagulants used in the management of coronary heart disease treated with or without percutaneous coronary interventions, cardioversion for atrial fibrillation, and prosthetic heart valves and valve repair. Using an evidence-based approach, we describe the results of completed clinical trials, highlight ongoing research with currently available agents, and recommend therapeutic options for specific heart diseases.
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Melissari, Euthemia, Christopher J. Parker, Noel V. Wilson, Giovanni Monte, Chryso Kanthou, Kieran D. Pemberton, Kypros H. Nicolaides, John J. Barrett, and Vijay V. Kakkar. "Use of Low Molecular Weight Heparin in Pregnancy." Thrombosis and Haemostasis 68, no. 06 (1992): 652–56. http://dx.doi.org/10.1055/s-0038-1646338.
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SummaryIn a controlled study of 15 pregnant patients undergoing therapeutic termination of pregnancy, seven received subcutaneously 5,000 anti-FXa units of low molecular weight (LMW) heparin 15 and 3 h prior to the termination, and eight patients acted as controls. Paired maternal and fetal blood samples were taken (before or immediately after the termination) for assay of heparin activity by a chromogenic anti-FXa method sensitive to levels of 0.02 anti-FXa U/ml. LMW heparin was detected in all maternal samples of the test patients but was not detected in any of the fetal samples.The use of LMW heparin as a thromboprophylactic agent was then evaluated in 11 patients who were known to have a severe thromboembolic tendency, had suffered recurrent miscarriages and had responded poorly to conventional anticoagulation (oral anticoagulant, conventional heparin). All patients receiving LMW heparin in thromboprophylactic doses completed uneventful pregnancies and gave birth to healthy babies (three for the first time) without complication. Bone density scans performed in all patients shortly after the delivery showed normal mineral mass. We conclude that LMW heparin does not cross the placental barrier, and in addition offers satisfactory antithrombotic protection for both maternal and placental circulation. In addition, this study provides preliminary data from 11 patients suggesting LMWH may not give rise to maternal osteoporosis, a finding that now needs further investigation.
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Moore, Bonnie Rush, and Kenneth W. Hinchcliff. "Heparin: A Review of its Pharmacology and Therapeutic Use in Horses." Journal of Veterinary Internal Medicine 8, no. 1 (January 1994): 26–35. http://dx.doi.org/10.1111/j.1939-1676.1994.tb03192.x.
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North, Angela M., Helen L. Barrett, Karin M. Lust, and Karen M. Whitfield. "Therapeutic heparin during the peripartum period - challenges associated with safe use." Journal of Pharmacy Practice and Research 48, no. 4 (June 21, 2018): 314–19. http://dx.doi.org/10.1002/jppr.1399.
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Jones, Allison J., Keliana L. O'Mara, Brian J. Kelly, and Ravi S. Samraj. "The Impact of Antithrombin III Use in Achieving Anticoagulant Goals in Pediatric Patients." Journal of Pediatric Pharmacology and Therapeutics 22, no. 5 (September 1, 2017): 320–25. http://dx.doi.org/10.5863/1551-6776-22.5.320.
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OBJECTIVES To determine the percentage of patients with >10% reduction in heparin infusion rate within 48 hours of antithrombin III (ATIII) administration. Secondary objectives include the achievement of therapeutic anticoagulation and determining the days of subtherapeutic infusion prior to supplementation. METHODS Retrospective chart review of 12 patients younger than 18 years of age who received ATIII concentrate supplementation while on continuous heparin infusion. Specific indications for heparin infusion therapy included extracorporeal membrane oxygenation (ECMO), treatment of thrombus, and post implantation of ventricular assist device(s). RESULTS From time of heparin initiation to ATIII supplementation, patients spent a mean 4.9 ± 2.6 days of subtherapeutic infusion and required uptitration from a mean of 15.3 ± 4.4 units/kg/hr to a mean rate of 40.7 ± 9.5 units/kg/hr. 58.3% of the patients (n = 7) had a ≥10% reduction from the baseline heparin infusion rate within 48 hours of ATIII administration. Those patients considered responders (≥10% reduction from baseline rate) had a slightly higher mean baseline antithrombin level (76.3% ± 22.0% vs. 58.6% ± 2.7% in non-responders, p = 0.1) and were administered comparable doses of ATIII. ATIII supplementation did appear to increase the time of therapeutic anticoagulation within the 48 hours. CONCLUSIONS Administration of ATIII is associated with >10% decrease in heparin requirements in more than half of the patients identified. In those patients deemed non-responders, there was a trend towards lower baseline antithrombin serum levels. Further studies are warranted to determine if the lack of response in some patients is due to inadequate dosing of ATIII or any patient-related factors.
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Jain, Amit, Kristen Smit, and Naveen Manchanda. "Increased Use of Direct Thrombin Inhibitor Argatroban In Hospitalized Patients." Blood 116, no. 21 (November 19, 2010): 4398. http://dx.doi.org/10.1182/blood.v116.21.4398.4398.
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Abstract Abstract 4398 Heparin Associated Thrombocytopenia (HAT) is associated with profound thrombo-embolic complications and Heparin substitutes are widely used as prophylactic and sometimes as therapeutic anticoagulants. Argatroban is one of several Direct Thrombin Inhibitors (DTI) used in these patients. We observed over the past several years that there was increasing use of Argatroban in hospitalized patients without a suspicion or diagnosis of HAT. In order to determine the extent and indications for use of Argatroban at our university hospital we analyzed medical records of all patients who had received this drug over a three-year period. Of the 60 individual patients who received Argatroban over a one year period, most of them received this drug once during their hospitalization and few received it multiple times over several hospitalizations. Seven of these patients (11.6%) received this drug for non-HAT related diagnoses. The following indications were provided for use of this agent: 1. Recurrent VTE on therapeutic Enoxaparin/Fondaparinux in patients with cancer: 3 2. Recurrent VTE on therapeutic Enoxaparin/Fondaparinux: 1 3. Anti-thrombin deficiency: 2 4. Heparin allergy: 1 Outcomes: 1. Cancer associated DVT: One survived, one died of progressive thrombosis; one lost to follow-up 2. Recurrent VTE on Enoxaparin/Fondaparinux: currently off Argatroban 3. Patients with AT deficiency and Heparin allergy are off anticoagulants. Argatroban, a DTI, is a drug with a narrow therapeutic index and is licensed for use in patients known or suspected to have HAT. Recently, it has found increasing use as an anticoagulant considered to have increased efficacy as compared to Enoxaparin and Fondaparinux. While accepted as an alternate to UFH in several instances, it is considered less effective in situation involving Cardiopulmonary bypass. However, whether it is a better agent to treat patients with or without cancer who have recurrent or progressive VTE and have failed conventional anticoagulants needs to be investigated further. Disclosures: No relevant conflicts of interest to declare.
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Schlicht, John R., Lisa Sunyecz, Robert J. Weber, Gary H. Tabas, and Roy E. Smith. "Reevaluation of a Weight-Based Heparin Dosing Nomogram: Is Institution-Specific Modification Necessary?" Annals of Pharmacotherapy 31, no. 12 (December 1997): 1454–59. http://dx.doi.org/10.1177/106002809703101202.
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OBJECTIVE: To compare a heparin dosing nomogram using an initial infusion rate of 18 units/kg/h with physician-directed heparin prescribing and with a modified version of the nomogram adjusted for institution-specific data. METHODS: During consecutive phases of this cohort study, patients' intravenous heparin therapies were initiated and adjusted by using one of the following three methods: (1) physician-directed dosing, (2) a body weight—based dosing nomogram with an initial infusion rate of 18 units/kg/h, and (3) a body weight—based dosing nomogram with an initial infusion rate determined by the median dose of heparin (in units/kg/h) required to achieve therapeutic activated partial thromboplastin times (aPTTs) during the first two phases. The time required to achieve therapeutic aPTTs as well as the percentage of initial aPTTs in the therapeutic range were compared for the three phases. RESULTS: The heparin dosing nomogram in which the initial infusion rate was adjusted for our individual institution resulted in a statistically shorter median time until aPTTs were in the therapeutic range than did either the physician-directed dosing or unmodified nomogram groups (6.1 h in the modified nomogram group, 10.5 h in the physician-directed group, 21.5 h in the unmodified nomogram group; p < 0.05 for all differences). Use of the institution-specific nomogram resulted in the greatest percentage of initial aPTTs in the therapeutic range (84% in the 13 units/kg/h nomogram group vs. 47% in the physician-directed group and 18% in the 18 units/kg/h nomogram group; p < 0.05 for all differences). CONCLUSIONS: Use of a heparin dosing nomogram with an initial infusion rate of 18 units/kg/h resulted in prolongation of the time to reach therapeutic aPTTs. By modifying the nomogram for use at an individual institution, we reduced the time to achieve therapeutic range of aPTTs while still reducing the likelihood of excessive anticoagulation of patients.
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Lambert, J. R., S. K. Austin, D. Peebles, and H. Cohen. "Audit of the peri-delivery use of unfractionated heparin in women on therapeutic low-molecular weight heparin." British Journal of Haematology 142, no. 3 (August 2008): 453–56. http://dx.doi.org/10.1111/j.1365-2141.2008.07198.x.
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Lai, K. N., K. Ho, M. Li, and C. C. Szeto. "Use of Single Dose Low-Molecular-Weight Heparin in Long Hemodialysis." International Journal of Artificial Organs 21, no. 4 (April 1998): 196–200. http://dx.doi.org/10.1177/039139889802100404.
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Low-molecular-weight (LMW) heparin has recently been used for anti-coagulation in maintenance hemodialysis. The LMW heparin was administered as a single bolus in hemodialysis that usually lasted for four hours or less. The regimen for administering LMW heparin in hemodialysis of longer duration (5 hours or more) is not well documented and manufacturers recommend a supplementary dose equivalent to one-quarter of the initial dose to be given at 4 hours after the commencement of hemodialysis. In this study, we explored whether administering a single dose of LMW heparin is feasible in hemodialysis of longer duration. Maintenance five-hour hemodialysis sessions were performed in nine uremic patients with two different heparin regimens: single dose of LMW heparin (nadroparin) 12,500 ICU AXa at the beginning of dialysis or a priming dose of nadroparin 10,000 ICU AXa at the beginning of dialysis followed by a supplementary dose of nadroparin 2,500 ICU AXa at the beginning of the fifth hour of dialysis. Clots in the airtraps or clotting of the dialyser were not observed in hemodialysis with the single dose heparin regimen. The anti-Xa activities at different time intervals during dialysis were above the therapeutic range of 0.5 U/ml except towards the end of the hemodialysis treatment. There was no difference between anti-Xa activities determined in dialysis sessions using two different regimens of LMW heparin at any individual time interval. The anti-throm-botic effect determined by the area under the time response curve for anti-Xa activity was comparable in the two LMW heparin regimens. Hence, our findings suggest a single bolus dose of LMW heparin (nadroparin) at 12,500 ICU AXa provides adequate, safe, and effective anti-coagulation for five-hour hemodialysis. This practice is convenient and avoids the necessity of administering a double dose of LMW heparin.
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Sandoval, Elena, Miquel Lozano, Daniel Pereda, Eduard Quintana, Joan Cid, Ana García-Álvarez, Alejandro Fernández-Cisneros, and Manuel Castellá. "A combined approach to treat heparin-induced thrombocytopaenia before heart transplant." Interactive CardioVascular and Thoracic Surgery 31, no. 6 (November 6, 2020): 881–83. http://dx.doi.org/10.1093/icvts/ivaa196.
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Abstract Heparin-induced thrombocytopaenia (HIT) complicates the management of patients in need for mechanical circulatory support awaiting heart transplantation. The limited available treatment options are fraught with complications and limitations in their applicability. We report on the combined use of therapeutic plasma exchange therapy and intravenous immunoglobulin, used in 3 consecutive heparin-induced thrombocytopaenia-positive patients on temporary mechanical circulatory support awaiting urgent heart transplant. This combined approach allowed us to use heparin safely.
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Schwiesow, Sarah J., Andrea M. Wessell, and Terrence E. Steyer. "Use of a Modified Dosing Weight for Heparin Therapy in a Morbidly Obese Patient." Annals of Pharmacotherapy 39, no. 4 (April 2005): 753–56. http://dx.doi.org/10.1345/aph.1e300.
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OBJECTIVE: To report a case of successful anticoagulation using a modified dosing weight (DW) for unfractionated heparin (UFH) therapy in a morbidly obese female. CASE SUMMARY: A 54-year-old morbidly obese (182.4 kg, 155 cm) white female presented to the emergency department with tachycardia, shortness of breath, and chest pain, and was diagnosed with a pulmonary embolism. Anticoagulation with UFH was initiated. A modified DW of 120 kg was obtained from the average of the actual body weight (ABW) and ideal body weight (~50 kg). We selected this modified DW to account for heparin's altered volume of distribution in an obese patient and avoid potentially supratherapeutic activated partial thromboplastin times (aPTTs) using ABW and subtherapeutic aPTTs using DW. Therapy was initiated with a bolus dose of 9600 units (80 units/kg x 120 kg) and continuous infusion rate of 2160 units/h (18 units/kg/h x 120 kg). This infusion rate was maintained throughout the course of heparin therapy and was successful in maintaining therapeutic aPTTs. DISCUSSION: Proper diagnosis and rapid initiation of therapy prevent mortality in patients with PE. Although weight-based heparin nomograms provide standardization through initial bolus and continuous infusion recommendations, many do not address dosing in morbidly obese patients. Several retrospective studies have evaluated actual, dosing, and ideal body weights for heparin therapy in obese patients; however, none has evaluated modified DW. In our patient, successful anticoagulation was objectively confirmed. CONCLUSIONS: Further investigation is necessary to determine the optimal DW for UFH in morbidly obese patients presenting with acute thrombosis.
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Poli, Maura, Domenico Girelli, Annamaria Naggi, Natascia Campostrini, Dario Finazzi, Federica Maccarinelli, Annalisa Castagna, and Paolo Arosio. "Hepcidin Inhibition by Modified Heparins without Anticoagulant Activity." Blood 120, no. 21 (November 16, 2012): 483. http://dx.doi.org/10.1182/blood.v120.21.483.483.
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Abstract Abstract 483 Background. There is an increasing interest in the development of pharmacological agents able to modulate hepcidin, the peptide hormone that critically regulates iron metabolism. In particular, hepcidin antagonist may have a therapeutic role in the anemia of chronic diseases, where hepcidin levels are often increased by pro-inflammatory cytokines. We previously demonstrated that heparin is a potent inhibitor of hepcidin expression in hepatic cell lines, probably by interfering with BMP/HJV/SMAD signalling, and that it was also effective in reducing hepcidin expression in mice (Poli M, Blood 2011; 117:997–1004). Since the therapeutic use of heparin for hepcidin modulation is hampered by its strong anticoagulant activity, we were interested in evaluating modified heparins without such activity. Methods. Heparins modified to inactivate the antithrombin binding site, with different molecular weight and degree of sulfation, were supplied to hepatic cell lines and mice to evaluate their potential modulation of hepcidin expression. We analysed their interference with the BMP/SMAD signalling, as well as serum hepcidin levels in mice by mass spectrometry. Results. Over 20 modified heparins were initially screened by evaluating their dose-dependent suppression of hepcidin expression before and after BMP induction. All of them showed a certain degree of anti-hepcidin activity, with two glycol-split molecules being as potent as classical unfractionated heparin. These two molecules suppressed BMP/SMAD signalling in HepG2 cells at pharmacological concentrations with maximum inhibition after 6 hours. In mice, treatments with 20 or 60 mg/Kg did not affect coagulation but strongly reduced liver pSMAD, hepcidin mRNA and serum hepcidin. Again, the maximum effect on liver hepcidin expression was observed 6 hours after the injection. This effect was observed also in conditions of high hepcidin caused by experimental inflammation or iron overload. Conclusions. Some non-anticoagulant heparins have strong anti-hepcidin activity both in vitro and in vivo, and may represent promising hepcidin antagonist with potential therapeutic applications. Disclosures: No relevant conflicts of interest to declare.
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Walenga, Jeanine, Walter Jeske, Sabrina Bertini, Giulia Risi, Michelle Sung, Ambar Farooqui, Cassie Bacher, et al. "Bovine Heparin Demonstrates the Same Interaction with HIT Antibodies As Porcine Heparin." Blood 134, Supplement_1 (November 13, 2019): 2351. http://dx.doi.org/10.1182/blood-2019-127304.
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Heparin, an anticoagulant widely used in numerous medical applications, is considered an essential medicine by the WHO. Due to its high volume use and that it is the parent material for low molecular weight heparins, there is potential for the raw material to be in short supply. The African swine fever epidemic in China, ongoing since August 2018, has added further restraints on heparin source material supply. At present medical grade heparin in the US is only derived from porcine intestinal mucosa; however, there are explorations into using bovine, ovine, and other sources. Bovine heparin, once common place in the US pharmaceutical sector, is again under consideration by the US FDA. This study focused on the primary immunogenic activity associated with heparin, that is heparin-induced thrombocytopenia (HIT), and how the interaction of bovine heparin with functional HIT antibodies compares to that of porcine heparin. Materials and Methods Bovine unfractionated heparin from multiple manufacturers was compared to commercial medical grade porcine heparin obtained from US pharmacies. The US Pharmacopeia porcine heparin standard was used to determine potency equivalence. Antibodies to the complex of platelet factor 4/heparin (PF4/heparin) from banked clinically confirmed HIT patient apheresis fluids were combined with heparin and donor platelet rich plasma (PRP; blood collected in citrate from volunteers after signing a consent document). Heparins were tested at final concentrations of 0.1, 0.4, 0.8, 1, and 100 U/mL. The platelet activation response was determined on the BioData PAP-8 Platelet Aggregometer and quantitated in terms of primary slope (PS), area under the curve (AUC), maximum aggregation (MA), and final aggregation (FA). Characterization of the biophysical interaction between varying molar ratios of human PF4 and heparin was performed using photon correlation spectroscopy (PCS) and zeta potential (Zp) measurements of PF4/heparin complexes using Zetasizer Nano ZS instrumentation and software. Differences between bovine and porcine heparin were assessed by t-test or Mann-Whitney test. Concentration-response curves were analyzed by two-way ANOVA followed by the Holm-Sidak multiple comparison test using SigmaPlot software. Results Platelet activation to PF4/heparin antibodies at bovine and porcine heparin concentrations of 0.1 U/mL (56 ± 9 % vs. 54 ± 11 % MA) and 0.4 U/mL (59 ± 10 % vs. 65 ± 8 % MA) were the same with the expected inhibition (9 ± 4% MA) at the supra-therapeutic concentration of 100 U/mL. Consistent responses were obtained across 21 lots of bovine heparin, 30 lots of porcine heparin, and 38 platelet-HIT antibody combinations. The HIT potential of bovine heparin and porcine heparin was not statistically different (p>0.05). At higher medical use doses, the platelet aggregation response in the presence of HIT antibodies was actually lower for bovine heparin than porcine heparin (0.8 U/mL, 49 ± 10 % vs. 64 ± 9 % MA, p<0.05; and 1.0 U/mL, 45 ± 11 % vs. 62 ± 9 % MA, p<0.05). By PCS, it was observed that the maximal aggregation between PF4 and either porcine or bovine heparin occurred at comparable molar ratios (7.3 ± 1.5 vs. 6.4 ± 0). Although the porcine and bovine heparins exhibited comparable molecular weights (16,333 ± 153 vs. 16,790 ± 230 Da) and polydispersities (1.19 ± 0.02 vs. 1.15 ± 0.01), porcine heparin formed somewhat larger complexes with PF4 (1113 ± 65 nm) than did bovine heparin (863 ± 68 nm). The molar ratios of PF4 to heparin at which the charge of the complex was fully neutralized (Zp = 0) was comparable for porcine and bovine heparin (9.04 ± 0.19 vs. 9.97 ± 0.65). Consistent responses were obtained across 4 lots of bovine heparin and 3 lots of porcine heparin. Conclusions Bovine heparin and porcine heparin had the same in vitro functional platelet activation response in the presence of HIT antibodies, the same potential to form complexes with human PF4, and the same associated features that make PF4 immunogenic. This investigation demonstrates that bovine heparins should have a similar immunogenic response as porcine heparin at equi-unit dosing. Current refinements in the manufacturing process for bovine and porcine heparins have led to well-characterized and purified products which is reflected in their comparable biological behavior. Disclosures No relevant conflicts of interest to declare.
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Hodgman, Tudy. "A Review of Common Approaches to Heparin Dosing." Journal of Pharmacy Practice 8, no. 1 (February 1995): 39–46. http://dx.doi.org/10.1177/089719009500800105.
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The use of heparin has remained steady for the last 20 years. Significant advances have been made in the understanding of the pathogenesis of clotting disorders and their prevention. Despite these gains, our understanding of the most safe and effective approach to optimizing the dosing of heparin has lagged. With new insight into improvements in outcome related to rapid achievement of the therapeutic range, it has become apparent that the standard approach to heparin dosing is out of date. Individualized heparin dosing based on weight and computer-assisted dosing methods is superior for bringing patients into the desired therapeutic range more quickly, with less cost and better short- and long-term outcomes. Copyright © 1995 by W.B. Saunders Company
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Phillips, David E., D. Keith Payne, and Glenn M. Mills. "Heparin-Induced Thrombotic Thrombocytopenia." Annals of Pharmacotherapy 28, no. 1 (January 1994): 43–46. http://dx.doi.org/10.1177/106002809402800108.
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OBJECTIVE: To report a case of heparin-induced thrombotic thrombocytopenia (HITTS) and discuss the incidence, possible mechanisms, complications, and treatment for this syndrome. DATA SOURCES: Case reports and review articles identified by MEDLINE from 1980 through 1991. Older articles located by manual searches. DATA EXTRACTION: Data were extracted and reviewed from published sources. Cases were selected on the basis of case presentation, time of disease onset, pathophysiology of disease, and therapeutic options. SETTING: A 600-bed university teaching hospital and an affiliated community hospital. PATIENT: A 36-year-old woman with insulin-dependent diabetes mellitus, sepsis, adult respiratory distress syndrome, diabetic ketoacidosis, oliguric renal failure developed HITTS and subsequent gangrene of her right arm. INTERVENTION: Immediate cessation of all heparin use and amputation of the patient's right arm. RESULTS: The patient's condition improved progressively over the following 60 days and she was discharged to outpatient care. CONCLUSIONS: Heparin has been associated with thrombocytopenia and thrombotic events. Laboratory tests for HITTS are unreliable and the diagnosis is usually suspected by the clinical presentation of the patient. Platelet counts should be monitored closely during heparin use. In the event of a marked decrease in platelet count associated with venous or arterial thrombosis, heparin therapy should be stopped immediately. If further anticoagulation is necessary, oral anticoagulants such as warfarin may be used instead. As the onset of warfarin may take several days to become therapeutic, aspirin, dipyridamole, or both may be used effectively. Healthcare workers should be aware that in these patients, the use of even small amounts of heparin can produce catastrophic results.
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Cacciapuoti, Federico. "Thrombophilias: therapeutic employment of direct oral anticoagulants in venous hypercoagulable states." Italian Journal of Medicine 14, no. 3 (September 17, 2020): 136–42. http://dx.doi.org/10.4081/itjm.2020.1296.
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Thrombophilia or hypercoagulable state is a predisposition to form clots. Thrombophilia can be inherited or acquired, and prevalently involves venous vessels. Inherited thrombophilia consists of congenital conditions, as methylenetetrahydrofolate reductase polymorphism, Factor V Leiden and prothrombin gene mutations, natural anticoagulant deficiencies, high level of factor VIII, or dysfibrinogenemia. These congenital disorders can be responsible for venous thromboembolism, particularly deep venous thrombosis, pulmonary embolism, and, less frequently, mesenteric veins thrombosis, kidneys’ veins thrombosis or retinal vein occlusion. Acquired thrombophilia can be associated both with venous and arterial thrombosis and may be caused by antiphospholipid syndrome, aging, some malignancies, oral contraceptive use, heparin-induced thrombocytopenia, and human immunodeficiency virus. Antiplatelets’ drugs are employed in arterial thrombosis, while, heparins/oral vitamin K antagonists are indicated for acute and long-term anticoagulation. However, new oral anticoagulants can be usefully used for venous thromboembolic events. Recent experiences demonstrated that their employment is useful in some thrombophilias only, whereas other investigations are requested to evaluate their use in all hypercoagulable disorders.
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Simko, Robert J., Faye FW Tsung, and Eric J. Stanek. "Activated Clotting Time Versus Activated Partial Thromboplastin Time for Therapeutic Monitoring of Heparin." Annals of Pharmacotherapy 29, no. 10 (October 1995): 1015–21. http://dx.doi.org/10.1177/106002809502901012.
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Objective: To compare and contrast the activated partial thromboplastin time (aPTT) and the activated clotting time (ACT) for the therapeutic monitoring of heparin therapy. Data Sources: Relevant articles were identified through an English-language MEDLINE search from 1966 to 1995. Additional sources were identified from the reference lists of these articles. Study Selection: Studies that investigated the use and limitations of the individual assays and those offering direct comparisons were chosen for review. Data Extraction: Features demonstrating clinical applications and limitations of the aPTT and the ACT were extracted. Where possible, data suggesting preferential application of either assay also were extracted. Data Synthesis: Both the aPTT and ACT are clinically useful for the monitoring of heparin therapy. The aPTT is used more frequently for routine monitoring; the ACT is used in specialized situations requiring large heparin doses. The ACT is typically performed at bedside and is capable of yielding results rapidly and perhaps at a lower cost than an aPTT performed by a central laboratory. Most practitioners are familiar with the central laboratory aPTT. A bedside aPTT device is available, but is not yet in widespread clinical use. Both assay techniques are subject to various limitations. Conclusions: The ACT is theoretically equally as useful as the aPTT for the routine monitoring of heparin therapy, but has not been well-studied. The ACT appears more useful in situations in which high serum concentrations of heparin are required. Further cost-effectiveness and clinical outcome studies directly comparing the ACT and the aPTT in specific clinical situations are needed.
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Lukinova, Nina, Mano Venkatesan, and Jill White. "Novel Point-Of-Use FXa Assay For Monitoring Anticoagulant Therapy By Oral Factor Xa Inhibitors and Heparin." Blood 122, no. 21 (November 15, 2013): 4816. http://dx.doi.org/10.1182/blood.v122.21.4816.4816.
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Introduction A highly specific, rapid, robust and sensitive assay for Factor Xa (FXa) activity will greatly improve monitoring and optimization of anticoagulant therapy by direct FXa inhibitors and by low molecular weight (LMW) heparins. We have developed a new point-of-use diagnostic system that will provide results in less than 30 minutes, enabling rapid medical decisions based on quantitation of FXa activity and anticoagulant drugs in patients’ blood. Anticoagulant therapy with unfractionated or LMW heparins needs aggressive monitoring in pregnant women, patients with renal insufficiency, and neonates, in particular in cases of treatment-related side effects, including heparin-induced thrombocytopenia and bleeding tendency (Chest, 2008). New oral anticoagulants rivaroxaban (Xarelto®) and apixaban (Eliquis®) have been effective in reducing risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, and in preventing and treating deep vein thrombosis. Both drugs directly inhibit FXa and have significant therapeutic potential as an alternative to warfarin. Unlike warfarin, these drugs do not require constant monitoring and dose adjustment to maintain anticoagulation within the therapeutic interval. However, excessive anticoagulation and consequent hemorrhage risks have been sufficiently common problems to warrant clinical development of specific antidotes for FXa inhibitors. Currently available anti-Xa heparin assays may not be appropriate for rivaroxaban and apixaban measurements. Additionally, recently published data indicate that new oral anticoagulants interfere with the measurement of common test parameters, expanding the need for more specific diagnostic tests (Clinical Chemistry, February 2013). This novel rapid and specific FXa assay will allow monitoring LMW heparins and the new FXa inhibitors, identify heparin-refractory patients as well as those requiring antidotes to oral Factor Xa inhibitors, in addition to directly measuring FXa activity in patients with inherited deficiency of Factor X, congenital antithrombin deficiency, and acquired FXa deficiencies. Method A diagnostic assay to measure FXa activity in human plasma using electrochemiluminescence (ECL) technology was developed at Wellstat Diagnostics, LLC. The assay utilizes a synthetic peptide containing an FXa substrate sequence that is recognized by specific antibodies (labeled with an ECL-active ruthenium chelate) only after specific cleavage by FXa protease. The resulting ECL signal is directly proportional to FXa activity within the physiological range. The assay has been adapted to also provide quantitative measurement of activity of anticoagulant drugs that inhibit FXa. In the modified format the resulting ECL signal is inversely proportional to the concentration of rivaroxaban, apixaban or heparin in plasma. Results The ECL-based assay measures activity of anticoagulant drugs on FXa in human plasma with high intra- and inter-assay reproducibility, accuracy and specificity. Using FX-deficient plasma spiked with Factor X in the range 1-100 ng/mL, we have demonstrated linear increases of ECL signal directly proportional to the concentration of spiked Factor X activated by a specific Russell Viper Venom activator. Serial dilutions of anticoagulant drugs rivaroxaban, apixaban and enoxaparin (LMW heparin) in normal donor plasma showed exponential decreases of ECL signal in the range of concentrations relevant to the therapeutic doses of all three drugs. The dynamic range of the drug detection was 15 - 500 ng/mL for rivaroxaban and apixaban, and 0.2 - 2 IU/mL of enoxaparin. The assay was specific to activity of FXa, while insensitive to variable concentrations of other clotting factors in human plasma, as well as to the presence of other drugs in plasma that don’t directly inhibit FXa. Conclusions The point-of-use FXa assay is shown to be highly specific, robust, rapid and reproducible for measurements of anticoagulant activity of apixaban, rivaroxaban and enoxaparin in human plasma. Use of this point-of-use system for monitoring anticoagulant therapy may be further extended to measure other blood clotting factors (for example, Factor IXa, VIIa, FVIII), for monitoring activity of drugs acting on these factors and for rapid diagnosis of coagulation disorders. Disclosures: No relevant conflicts of interest to declare.
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Gonda, David D., Jared Fridley, Sheila L. Ryan, Valentina Briceño, Sandi K. Lam, MD MBA, Thomas G. Luerssen, and Andrew Jea. "The safety and efficacy of use of low-molecular-weight heparin in pediatric neurosurgical patients." Journal of Neurosurgery: Pediatrics 16, no. 3 (September 2015): 329–34. http://dx.doi.org/10.3171/2015.1.peds14489.
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OBJECT Low-molecular-weight heparins (LMWHs), mainly enoxaparin, offer several advantages over standard anticoagulation therapies such as unfractionated heparin and warfarin, including predictable pharmacokinetics, minimal monitoring, and subcutaneous administration. The purpose of this study was to determine the safety and efficacy of LMWHs in pediatric neurosurgical patients. METHODS A retrospective study was performed with patients 18 years old or younger who were admitted to the Pediatric Neurosurgery Service at Texas Children's Hospital and treated with LMWH for either therapeutic or prophylactic purposes between March 1, 2011, and December 30, 2013. Demographic and clinical features and outcomes were recorded. RESULTS LMWH was administered for treatment of venous thromboembolic events (VTEs) in 17 children and for prophylaxis in 24 children. Clinical resolution of VTEs occurred in 100% (17 of 17) of patients receiving therapeutic doses of LMWH. No patient receiving prophylactic doses of LMWH developed a new VTE. Major or minor bleeding complications occurred in 18% (3 of 17 children) and 4% (1 of 24 children) of those receiving therapeutic and prophylactic doses, respectively. All 4 patients who experienced hemorrhagic complications had other bleeding risk factors—i.e., coagulopathies and antiplatelet medications. CONCLUSIONS LMWH seems to be safe and efficacious for both management and prophylaxis of VTEs in pediatric neurosurgery. However, pediatric practitioners should be aware of higher risk for bleeding complications with increasing doses of LMWH, especially in patients with preexisting bleeding disorders or concurrent use of antiplatelet agents.
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Fortenberry, Yolanda. "Characterization of Antithrombin-Specific RNA Aptamers for Use in Anticoagulant Therapy." Blood 124, no. 21 (December 6, 2014): 4236. http://dx.doi.org/10.1182/blood.v124.21.4236.4236.
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Abstract Historically, unfractionated heparin (a complex polysaccharide classified as a glycosaminoglycan) has been used in the treatment and prevention of thromboembolic disorders. However, due to complications associated with heparin (such as bleeding and heparin-induced thrombocytopenia), low molecular weight heparins (LMWHs) have been developed and are being used in place of unfractionated heparin. LMWHs have proven effective as antithrombotic agents; however, the effects of LMWHs cannot be readily reversed, while unfractionated heparin can be reversed by protamine sulfate. The overall goal of this project was to characterize an antithrombin (AT)-specific RNA aptamer that will combine the safety and efficacy of LMWH with the reversibility of unfractionated heparin. I have developed an RNA molecule (aptamer) that binds to AT. Using Systematic Evolution of Ligands by EXponential enrichment (SELEX) we created a combinatorial library consisting of single stranded RNA molecules with 20-40 randomized positions resulting in approximately 1014 different sequences. The RNA libraries after round 12 consisted of several different aptamers, and there was a progressive decrease in library complexity. We isolated four individual RNA molecules that bind in the nanomolar range to AT. Each displayed the same general properties, they accelerated factor Xa inhibition by AT in a dose-dependent manner. It should be noted that as anticipated, the aptamers did not promote the enhanced inhibition of thrombin by AT. Overall, our results show that these molecules are able to enhance the inhibition of factor Xa by AT. We suspect that these aptamers mimic the action of LMWH by binding to the D-helix of AT. Our previous AT specific RNA aptamer, Aptamer 7-4.16 was shown to prolonged bleeding in vivo in a vascular injury model. These data showed that Aptamer 7-4.16 is as effective as heparin in preventing clotting after vascular injury. We suspect that these new aptamers will have a similar effect in vivo. Proof of the concept was established by the work of Rusconi et al. (Nature, 2002), who developed an RNA aptamer and RNA aptamer antidote directed against coagulation factor IXa. The factor IXa aptamer completely inhibits the activation of factor X. Its anticoagulant action is controlled by the antidote, which is able to reverse the effects of the factor IXa aptamer within seconds. This aptamer/antidote pair is currently being tested clinically. Our data suggesting that antidotes to our AT aptamers have the ability to reverse its activity. If successful, this aptamer/antidote pair will have advantages over LMWHs because not only will it be able to control thrombosis in a fashion similar to LMWHs, but the availability of an antidote will allow for better therapeutic regulation and intervention. Disclosures No relevant conflicts of interest to declare.
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Campbell, Christopher T., Lucas Diaz, and Brian Kelly. "Description of Bivalirudin Use for Anticoagulation in Pediatric Patients on Mechanical Circulatory Support." Annals of Pharmacotherapy 55, no. 1 (June 26, 2020): 59–64. http://dx.doi.org/10.1177/1060028020937819.
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Background: Although heparin has previously been the anticoagulant of choice during mechanical circulatory support (MCS), there is a lack of consistency in dose-response in pediatric patients. Bivalirudin offers more consistent dose-response in adults; however, there are limited data for pediatrics use. Objective: The purpose was to characterize the usage, dosage, and safety profile of bivalirudin when used for pediatric MCS in a tertiary care pediatric hospital. Methods: A retrospective review of pediatric patients receiving bivalirudin for extracorporeal membrane oxygenation/ventricular assist device (ECMO/VAD) anticoagulation was conducted. The primary outcome was the average dose of bivalirudin. Additional outcomes included initial and maximum bivalirudin dose, time to first therapeutic activated partial thromboplastin time (aPTT), time within goal aPTT range, bleeding and clotting complications, and cost. Data were compared between ECMO and VAD patients. Results: Thirty-four patients were included. The median dose of bivalirudin was 0.37 mg/kg/h (interquartile range [IQR] = 0.21-0.56), with a maximum dose of 0.62 mg/kg/h (IQR = 0.33-0.91). VAD patients had a higher median and maximum dose as compared with ECMO patients. Patients achieved their therapeutic goal in a median of 6.1 hours and averaged 61.9% time within therapeutic aPTT. One patient had significant hemorrhage, whereas 3 patients had clotting requiring a circuit change. Bivalirudin acquisition cost was higher than heparin. Conclusion and Relevance: Bivalirudin dosing in ECMO and VAD patients is consistent with dosing seen in previous reports but may be higher in VAD patients. Comparative studies between heparin and bivalirudin are necessary to compare cost-effective outcomes for pediatric patients.
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Soares Ferreira Júnior, Alexandre, Stephen H. Boyle, Maragatha Kuchibhatla, Tomi Akinyemiju, and Oluwatoyosi A. Onwuemene. "Use of therapeutic plasma exchange in heparin‐induced thrombocytopenia: A population‐based study." Journal of Clinical Apheresis 36, no. 3 (January 16, 2021): 398–407. http://dx.doi.org/10.1002/jca.21876.
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Al-Eidan, Fahad. "IS THE INCIDENCE TREND OF HEPARIN-INDUCED THROMBOCYTOPENIA DECREASED BY THE INCREASED USE OF LOW-MOLECULAR-WEIGHT-HEPARIN?" Mediterranean Journal of Hematology and Infectious Diseases 7 (April 19, 2015): e2015029. http://dx.doi.org/10.4084/mjhid.2015.029.
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Background: The increasing trend of using low-molecular-weight-heparin (LMWH) versus unfractionated heparin (UFH) in hospitalized adult patients is raising concerns about the incidence of heparin-induced thrombocytopenia (HIT). Method: A retrospective study analyzed the requests for heparin-induced antibodies by enzyme-linked immunosorbent assay (ELISA) among adult hospitalized patients during the period from January 2011 to December 2013. These patients received either UFH or LMWH for prevention or therapeutic indications. Those with positive immune-mediated HIT were identified and considered as case patients. Result: The usage of LMWH and UFH and development of HIT was determined during the study period. The incidence of HIT in patients receiving UFH and those receiving LMWH was 4.09 per thousand patients and 0.48 per thousand patients, respectively, (p<0.0001) with an overall incidence of 2.49 per thousand patients. Conclusion: The increased trend of using LMWH over UFH among hospitalized adult patients was observed and can be said to contribute to the diminished overall incidence of HIT.
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Agnelli, G., C. Pascucci, B. Cosmi, and GG Nenci. "Effects of therapeutic doses of heparin on thrombolysis with tissue- type plasminogen activator in rabbits." Blood 76, no. 10 (November 15, 1990): 2030–36. http://dx.doi.org/10.1182/blood.v76.10.2030.2030.
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Abstract The objective of the study was to evaluate the ability of heparin to enhance the thrombolytic effect of recombinant tissue type plasminogen activator (rt-PA) and to prevent thrombus growth during and after thrombolysis with rt-PA. In the thrombolysis studies, three groups of rabbits were infused with rt-PA at a dose of 0.5 mg, 1 mg, or 2.5 mg over 3 hours, respectively. Rabbits in each group were randomized to receive, in addition to rt-PA, heparin, 20 or 60 antifactor Xa U/kg/h, or saline over 6 hours. The three doses of rt-PA produced the same extent of thrombolysis both in the two groups treated with heparin (34% +/- 6%, 52% +/- 7%, and 79% +/- 8% in the lower dose group; 39% +/- 6%, 49% +/- 4%, and 81% +/- 6% in the higher dose group) and in the group treated with saline (37% +/- 4%, 47% +/- 5%, and 84% +/- 7%). In the thrombus growth inhibition studies 0.5 mg of rt-PA was infused over 3 hours in each rabbit. In addition, the rt-PA-treated rabbits were randomized to receive heparin, 20 or 60 antifactor Xa U/kg/h over 6 hours, or saline. At the end of infusion, no statistically significant differences in thrombus growth were found in three groups of rabbits (54.8 +/- 7.4 micrograms and 52.4 +/- 12.1 micrograms in the low and high dose of heparin groups, respectively, and 59.4 +/- 10.4 micrograms in the saline group). In different experiments rabbits were randomized to receive heparin, 60 antifactor Xa U/kg/h, or saline at the end of the rt-PA infusion. In these experiments heparin inhibited thrombus growth more efficiently than saline (41.1 +/- 6.5 micrograms and 58.7 +/- 12.9 micrograms, respectively, P less than .05). In vitro experiments confirmed that heparin is unable to prevent fibrin accretion on the clots during lysis with rt-PA while both D-Phe-Pro-Arg- CH2-Cl (PPACK) and hirudin are able to prevent the accretion of fibrin. We conclude that the data obtained in these animal models do not support the concomitant use of heparin and rt-PA. However, heparin could be used successfully after rt-PA to inhibit thrombus growth.
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Agnelli, G., C. Pascucci, B. Cosmi, and GG Nenci. "Effects of therapeutic doses of heparin on thrombolysis with tissue- type plasminogen activator in rabbits." Blood 76, no. 10 (November 15, 1990): 2030–36. http://dx.doi.org/10.1182/blood.v76.10.2030.bloodjournal76102030.
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The objective of the study was to evaluate the ability of heparin to enhance the thrombolytic effect of recombinant tissue type plasminogen activator (rt-PA) and to prevent thrombus growth during and after thrombolysis with rt-PA. In the thrombolysis studies, three groups of rabbits were infused with rt-PA at a dose of 0.5 mg, 1 mg, or 2.5 mg over 3 hours, respectively. Rabbits in each group were randomized to receive, in addition to rt-PA, heparin, 20 or 60 antifactor Xa U/kg/h, or saline over 6 hours. The three doses of rt-PA produced the same extent of thrombolysis both in the two groups treated with heparin (34% +/- 6%, 52% +/- 7%, and 79% +/- 8% in the lower dose group; 39% +/- 6%, 49% +/- 4%, and 81% +/- 6% in the higher dose group) and in the group treated with saline (37% +/- 4%, 47% +/- 5%, and 84% +/- 7%). In the thrombus growth inhibition studies 0.5 mg of rt-PA was infused over 3 hours in each rabbit. In addition, the rt-PA-treated rabbits were randomized to receive heparin, 20 or 60 antifactor Xa U/kg/h over 6 hours, or saline. At the end of infusion, no statistically significant differences in thrombus growth were found in three groups of rabbits (54.8 +/- 7.4 micrograms and 52.4 +/- 12.1 micrograms in the low and high dose of heparin groups, respectively, and 59.4 +/- 10.4 micrograms in the saline group). In different experiments rabbits were randomized to receive heparin, 60 antifactor Xa U/kg/h, or saline at the end of the rt-PA infusion. In these experiments heparin inhibited thrombus growth more efficiently than saline (41.1 +/- 6.5 micrograms and 58.7 +/- 12.9 micrograms, respectively, P less than .05). In vitro experiments confirmed that heparin is unable to prevent fibrin accretion on the clots during lysis with rt-PA while both D-Phe-Pro-Arg- CH2-Cl (PPACK) and hirudin are able to prevent the accretion of fibrin. We conclude that the data obtained in these animal models do not support the concomitant use of heparin and rt-PA. However, heparin could be used successfully after rt-PA to inhibit thrombus growth.
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Norkin, Igor K., Kristina A. Yurova, Olga G. Khaziakhmatova, Vladimir V. Malashchenko, Denis D. Ligatyuk, Igor A. Khlusov, and Larisa S. Litvinova. "Effects of therapeutic doses of heparin on MSC functional activity in modeling the mechanisms of osteointegration under in vitro cultivation." Journal of Ural Medical Academic Science 19, no. 3 (2022): 231–40. http://dx.doi.org/10.22138/2500-0918-2022-19-3-231-240.
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The use of artificial materials in regenerative medicine is accompanied by the development of an inflammatory response and the initiation of blood clotting due to the contact of the implant with the soft tissues of the body. All this leads to the formation of thrombosis of the major and main arteries and the development of serious complications. To prevent the development of postoperative pathological conditions caused by hypercoagulable syndrome, classical therapeutic strategies with anticoagulants (mainly heparin) are used. However, the described treatment tactics lead to an interruption of the migration and adhesion processes of mesenchymal stem cells (MSC), which negatively affects the callus formation and the processes of osseointegration of the implant. The aim of this study was to investigate the effect of a suspension of HA nanoparticles in the presence of heparin in a gradient of therapeutic concentrations on migratory and proliferative activity of MSCs in human adipose tissue under in vitro cultivation conditions. Methods. To evaluate the migration and proliferation potential of MSC in the presence of HA nanosuspension and/or heparin, an electrode system for continuous observation — xCELLigence ® RTCA DP was used. Results. A significant decrease in the migratory activity and proliferative potential of MSC was observed under the conditions of their co-cultivation with HA nanosuspension in the presence/absence of heparin (0.5–1 IU/ml). onclusion. The results of the study may serve as a prerequisite for the development of new therapeutic approaches for the use of heparin in surgical patients at high risk of postoperative thrombosis after osteosynthesis.
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Nonaka, Taketoshi, Makoto Harada, Masahiko Sumi, Wataru Ishii, Tohru Ichikawa, and Mamoru Kobayashi. "A Case of Heparin-Induced Thrombocytopenia That Developed in the Therapeutic Course of Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis." Case Reports in Rheumatology 2019 (July 22, 2019): 1–4. http://dx.doi.org/10.1155/2019/2724304.
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Background. Heparin-induced thrombocytopenia (HIT) causes thrombocytopenia via an immunological mechanism, resulting in severe organ injury due to arterial-venous thrombosis. HIT often develops in hemodialysis patients owing to heparin use. Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic vasculitis, and cases of AAV complicated with HIT are rare. In addition, it mostly occurs in patients undergoing hemodialysis. Case Presentation. An 87-year-old woman presented with rapidly progressive renal failure and severe leg edema. She was diagnosed with AAV and treated with glucocorticoid and heparin calcium to prevent deep vein thrombosis. Eight days after the start of heparin calcium, her platelet count decreased and the anti-platelet factor 4-heparin complex antibody was strongly positive (>5.0 U/mL; the cutoff point of the anti-platelet factor 4-heparin complex antibody evaluated by the latex turbidity assay is 1.0 U/mL). She was diagnosed with HIT and treated with argatroban. Subsequently, her platelet counts increased gradually. Conclusion. We encountered a case of HIT that developed prior to the induction of hemodialysis in the clinical course of AAV. When AAV clinical course presents thrombocytopenia, the possibility of HIT should be considered.
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Kameneva, M. V., A. S. Parfenov, E. L. Klimanova, S. Khalil, G. I. Nikonov, and I. P. Baskova. "Effects of Heparin and Piyavit on blood rheological properties and platelet aggregation." Kazan medical journal 69, no. 5 (October 15, 1988): 331–34. http://dx.doi.org/10.17816/kazmj98424.
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Heparin in clinical practice is used either to prevent thrombosis or during extracorporeal hemoperfusion (hemo- and plasmabsorption, operation of artificial circulation devices and blood fractionators). Currently, indications for administration of heparin for therapeutic purposes tend to be limited. This is due to the fact that the vast experience of heparin therapy has revealed not only the favorable effects of heparin, consisting in its hypocoagulation action, but also the possibility of the development of various complications of its use. These adverse effects of heparin include primarily thrombocytopenia associated with intravascular platelet aggregation. In addition, in certain situations, heparin is able to block the action of antithrombin III in case of severe thrombinemia and antithrombin deficiency. Recently, data have appeared about the increase of platelet factor 4 concentration in plasma of patients with peripheral atherosclerosis during intravenous injection of heparin. Consequently, the search for compounds capable of replacing heparin is highly relevant.
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Su, Longxiang, Chun Liu, Dongkai Li, Jie He, Fanglan Zheng, Huizhen Jiang, Hao Wang, et al. "Toward Optimal Heparin Dosing by Comparing Multiple Machine Learning Methods: Retrospective Study." JMIR Medical Informatics 8, no. 6 (June 22, 2020): e17648. http://dx.doi.org/10.2196/17648.
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Background Heparin is one of the most commonly used medications in intensive care units. In clinical practice, the use of a weight-based heparin dosing nomogram is standard practice for the treatment of thrombosis. Recently, machine learning techniques have dramatically improved the ability of computers to provide clinical decision support and have allowed for the possibility of computer generated, algorithm-based heparin dosing recommendations. Objective The objective of this study was to predict the effects of heparin treatment using machine learning methods to optimize heparin dosing in intensive care units based on the predictions. Patient state predictions were based upon activated partial thromboplastin time in 3 different ranges: subtherapeutic, normal therapeutic, and supratherapeutic, respectively. Methods Retrospective data from 2 intensive care unit research databases (Multiparameter Intelligent Monitoring in Intensive Care III, MIMIC-III; e–Intensive Care Unit Collaborative Research Database, eICU) were used for the analysis. Candidate machine learning models (random forest, support vector machine, adaptive boosting, extreme gradient boosting, and shallow neural network) were compared in 3 patient groups to evaluate the classification performance for predicting the subtherapeutic, normal therapeutic, and supratherapeutic patient states. The model results were evaluated using precision, recall, F1 score, and accuracy. Results Data from the MIMIC-III database (n=2789 patients) and from the eICU database (n=575 patients) were used. In 3-class classification, the shallow neural network algorithm performed the best (F1 scores of 87.26%, 85.98%, and 87.55% for data set 1, 2, and 3, respectively). The shallow neural network algorithm achieved the highest F1 scores within the patient therapeutic state groups: subtherapeutic (data set 1: 79.35%; data set 2: 83.67%; data set 3: 83.33%), normal therapeutic (data set 1: 93.15%; data set 2: 87.76%; data set 3: 84.62%), and supratherapeutic (data set 1: 88.00%; data set 2: 86.54%; data set 3: 95.45%) therapeutic ranges, respectively. Conclusions The most appropriate model for predicting the effects of heparin treatment was found by comparing multiple machine learning models and can be used to further guide optimal heparin dosing. Using multicenter intensive care unit data, our study demonstrates the feasibility of predicting the outcomes of heparin treatment using data-driven methods, and thus, how machine learning–based models can be used to optimize and personalize heparin dosing to improve patient safety. Manual analysis and validation suggested that the model outperformed standard practice heparin treatment dosing.
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Manco-Johnson, Marilyn J., Neil Goldenberg, Lesley G. Mitchell, and Linda J. Jacobson. "Can Heparin-Based Therapy in Children Be Monitored on Samples Drawn Through Ports? An Analysis From Clinical Trials Data,." Blood 118, no. 21 (November 18, 2011): 3365. http://dx.doi.org/10.1182/blood.v118.21.3365.3365.
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Abstract Abstract 3365 Background: Based on preliminary data, children clear heparins more rapidly than adults, and thus most pediatric hematologists monitor heparin therapy. Many pediatric deep vein thrombosis patients have indwelling central venous lines (CVLs) due to co-morbid conditions and patients and clinicians desire to use these CVLs for blood sampling. Standard protocols are used to flush and clear CVLs prior to sample collection, but validated approaches to exclude contamination of heparin in dwell-volume (i.e., hep-lock) from systemic anticoagulant have not been established. Aims: This study was conducted to determine the accuracy of heparin monitoring in samples collected from CVLs. Methods: Anticoagulant effects of unfractionated heparin (UH) and dalteparin low molecular weight heparin (D) were determined by assay of anti-IIa activity, anti-Xa activity and the ratio of the two using chromogenic assays (Biophen). Normal pooled plasma was spiked with 2 U/mL of either drug and dilutions were made to 1.5, 1, 0.75, 0.5, 0.25 and 0.1 U/mL in normal pooled plasma. The assays and ratios were applied to plasma samples obtained by standard protocol from CVLs or peripheral venipuncture in two separate clinical trials. Results: Intra-assay CV for anti-IIa was 14.2 and 13.3% for UH and D, respectively; intra-assay CV for anti-Xa was 8.3 and 2.8% for UH and D, respectively. The ratio of anti-IIa to anti-Xa activity for UH was > 0.75 at all concentrations, while the ratio of anti-IIa to anti-Xa for D was < 0.5 when anti-Xa was within the therapeutic range of 0.5–1.0 U/mL, but overlapped with UH at concentrations ≥ 1.5 U/mL and ≤ 0.25 U/mL. In trial 1, DAVINCI, 4/26 (15.4% of) samples drawn from CVLs with therapeutic anti-Xa activity had ratios > 0.5 suggestive of UH contamination, while 0/8 peripherally drawn samples had ratios in that range. In trial 2, 5/26 (19.2% of) patient samples drawn from CVLs had ratios > 0.5. Conclusions: An anti-IIa/anti-Xa ratio < 0.5 is specific for uncontaminated D effect when anti-Xa is within the therapeutic range. However, without measuring ratios 15–20% of CVL samples used to monitor D will overestimate therapeutic response. Therefore, we favor peripherally drawn samples in order to reliably monitor anticoagulation in children. Disclosures: Manco-Johnson: Easai: Research Funding. Goldenberg:Easai: Research Funding.
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Garcia Ruiz, Maria Almudena, Francisco Jose Romero Martinez, Estefania Morente Constantin, Margarita Gomez Morales, and Manuel Jurado. "Continued Use of Tinzaparin at Therapeutic Doses for Prophylaxis of Venous Thromboembolism in Patients with Intolerance to Antivitamins K." Blood 126, no. 23 (December 3, 2015): 4735. http://dx.doi.org/10.1182/blood.v126.23.4735.4735.
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Abstract OBJECTIVES The low molecular weight heparins (LMWH) are typically administered at fixed doses like thromboprophylaxis or at doses adjusted to the weight of the patient in order to obtain a therapeutic effect. Generally they do not require laboratory monitoring, although it could be considered in special situations (renal failure, extreme weights, pregnant women). The LMWH do not affect the APTT, so it has been proposed to determine the anti-factor Xa activity when it is necessary to monitor its effect. The anti-factor Xa activity should be determined approximately 4 hours after sc administration of the LMWH that it is employed, concurring with the peak of activity. The therapeutic range of the anti-factor Xa activity is between 0.6 and 1 IU / mL when LMWH is administered every 12 hours. At single daily dose is less clear, although it seems that lies above 1 IU / mL. Nowadays, LMWH are the anticoagulant of choice during pregnancy. Numerous in vitro and in vivo studies have shown the existence of an antineoplastic effect of heparin. LMWH is commonly used for prolonged treatment of thrombosis associated with cancer. METHODS The main aim of our study is to evaluate the efficacy of tinzaparin sodium at therapeutic doses in preventing VTE in renal failure, active cancer and/or patients with contraindications to oral anticoagulation. The dose has been therapeutic and adjusting it has been made in terms of anti-factor Xa levels obtained monthly. Hemorrhagic or thrombotic complications and other possible side effects have been assessed. Until now, a total of 70 patients, 42 men and 28 women aged between 30 and 95 years old, have received tinzaparin sodium treatment. The main reason of anticoagulation are: atrial fibrillation and atrial flutter (with or without valve disease), VTE (with or without thrombophilia), stroke and transient ischemic attacks and mechanical prosthetic aortic and mitral valves (some of the patients carrying a double metal prosthesis). There was 1 resistance and 1 allergic reaction to anti-vitamin K. 4 of the patients were pregnant and 14 had renal failure. Prior to initiation of therapy, analytical determinations were performed, including: blood count, blood coagulation and biochemistry to assess renal function (urea and creatinine). 20 patients (14 were anticoagulated by atrial fibrillation, 2 for bearing a mechanical aortic prosthesis and 4 because of DVT, 1 of which had also a TEP) had active cancer or were in remission from their neoplasia (3 multiple myeloma, 1 LAM, 1 CMML, 4 renal tumors, 1 lung cancer, 5 prostate cancers, 1 hepatocellular carcinoma, 2 colon cancer, 1 endometrial adenocarcinoma and 1 retroperitoneal leiomyosarcoma). 1 with MDS was treated with LMWH because he had intra- and extrahepatic portal vein thrombosis. RESULTS Some of the patients had received prior treatment with anti-vitamin K (INR objective depending on pathology) but, in other cases, the low molecular weight heparin was the only treatment since the beginning of their anticoagulation. All the patients had received 175 IU / Kg of Tinzaparin Sodium once a day as initial dose, then the dose was adjusted according to the anti-factor Xa levels. They were controlled until 31/07/2015. In terms of side effects, 8 patients presented complications: 3 mucosal bleeding, 2 episodes of stroke in a patient, hemoptysis, deep vein thrombosis and 2 bleeding at the puncture site of heparin, which have not required discontinuation of therapy. When these complications occurred, we proceeded to the corresponding heparin dose adjustment based on new determinations of anti-factor Xa. CONCLUSIONS Although only in 70 cases, the results obtained confirm the efficacy, safety and cost-effectiveness of the continuous use of LMWH. Determination of anti-factor Xa levels are considered very useful for dose adjustment parameter. In our study, tinzaparin sodium has proved to be very useful in preventing venous thromboembolism associated or not with cancer, in patients with conditions requiring anticoagulation and presenting contraindications to the use of anti-vitamin K. The results obtained have demonstrated that tinzaparin is safe and, most likely, further studies will provide valuable confirmation data to support the use of low molecular weight heparins in the prolonged treatment of patients who require oral anticoagulation and can not receive it. Disclosures No relevant conflicts of interest to declare.
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Koenig, A., K. Norgard-Sumnicht, R. Linhardt, and A. Varki. "Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents." Journal of Clinical Investigation 101, no. 4 (February 15, 1998): 877–89. http://dx.doi.org/10.1172/jci1509.
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Hippensteel, Joseph A., Wells B. LaRiviere, James F. Colbert, Christophe J. Langouët-Astrié, and Eric P. Schmidt. "Heparin as a therapy for COVID-19: current evidence and future possibilities." American Journal of Physiology-Lung Cellular and Molecular Physiology 319, no. 2 (August 1, 2020): L211—L217. http://dx.doi.org/10.1152/ajplung.00199.2020.
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Coronavirus disease 2019 (COVID-19), the clinical syndrome associated with infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has impacted nearly every country in the world. Despite an unprecedented focus of scientific investigation, there is a paucity of evidence-based pharmacotherapies against this disease. Because of this lack of data-driven treatment strategies, broad variations in practice patterns have emerged. Observed hypercoagulability in patients with COVID-19 has created debate within the critical care community on the therapeutic utility of heparin. We seek to provide an overview of the data supporting the therapeutic use of heparin, both unfractionated and low molecular weight, as an anticoagulant for the treatment of SARS-CoV-2 infection. Additionally, we review preclinical evidence establishing biological plausibility for heparin and synthetic heparin-like drugs as therapies for COVID-19 through antiviral and anti-inflammatory effects. Finally, we discuss known adverse effects and theoretical off-target effects that may temper enthusiasm for the adoption of heparin as a therapy in COVID-19 without confirmatory prospective randomized controlled trials. Despite previous failures of anticoagulants in critical illness, plausibility of heparin for COVID-19 is sufficiently robust to justify urgent randomized controlled trials to determine the safety and effectiveness of this therapy.
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Nguyen, Thuy N., Peter Gal, J. Laurence Ransom, and Rita Carlos. "Lepirudin Use in a Neonate with Heparin-Induced Thrombocytopenia." Annals of Pharmacotherapy 37, no. 2 (February 2003): 229–33. http://dx.doi.org/10.1177/106002800303700214.
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OBJECTIVE: To describe a case of heparin-induced thrombocytopenia (HIT) in a premature infant and the doses of danaparoid and lepirudin needed to achieve appropriate therapeutic endpoints. CASE SUMMARY: A 30-week gestational age infant was diagnosed with HIT with heparin antibodies. Danaparoid 2.0–2.4 units/kg/h achieved anti-Xa levels of 0.2–0.4 U/mL, but thrombocytopenia failed to resolve. Lepirudin was started in place of danaparoid. Lepirudin doses of 0.03–0.05 mg/kg/h achieved target activated partial thromboplastin time values of 1.5–2.0 times baseline. DISCUSSION: Dosing information for danaparoid in neonates is limited, and information for lepirudin appears only in German literature at this time. HIT is well documented in newborns, and lepirudin use in these situations is likely to increase. This report provides some guidance for optimal dosing. It also provides some guidance for HIT evaluation in preterm infants, in whom blood volume for laboratory tests is a major issue. CONCLUSIONS: HIT is an important and potentially fatal problem in neonates. Lepirudin may be the drug of choice, especially since danaparoid is now unavailable. Initial lepirudin dosing should not exceed 0.05 mg/kg/h.
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Monagle, Paul, and Fiona Newall. "Management of thrombosis in children and neonates: practical use of anticoagulants in children." Hematology 2018, no. 1 (November 30, 2018): 399–404. http://dx.doi.org/10.1182/asheducation-2018.1.399.
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Abstract Venous thrombosis (VTE) in children and neonates presents numerous management challenges. Although increasing in frequency, VTE in children and neonates is still uncommon compared with adults. The epidemiology of VTE is vastly different in neonates vs children vs adolescents vs adults. In reality, pediatric thrombosis should be viewed as a multitude of rare diseases (eg, renal vein thrombosis, spontaneous thrombosis, catheter-related thrombosis, cerebral sinovenous thrombosis), all requiring different approaches to diagnosis and with different short- and long-term consequences, but linked by the use of common therapeutic agents. Further, children have fundamentally different physiology in terms of blood flow, developmental hemostasis, and, likely, endothelial function. The American Society ofHematology 2017 Guidelines for Management of Venous Thromboembolism: Treatment of Pediatric VTE provides up-to-date evidence-based guidelines related to treatment. Therefore, this article will focus on the practical use of therapeutic agents in the management of pediatric VTE, especially unfractionated heparin, low-molecular-weight heparin, and oral vitamin K antagonists, as the most common anticoagulants used in children. Direct oral anticoagulants (DOACs) remain in clinical trials in children and should not be used outside of formal trials for the foreseeable future.
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Ghiselli, Giancarlo. "Heparin Binding Proteins as Therapeutic Target: An Historical Account and Current Trends." Medicines 6, no. 3 (July 29, 2019): 80. http://dx.doi.org/10.3390/medicines6030080.
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The polyanionic nature and the ability to interact with proteins with different affinities are properties of sulfated glycosaminoglycans (GAGs) that determine their biological function. In designing drugs affecting the interaction of proteins with GAGs the challenge has been to generate agents with high binding specificity. The example to emulated has been a heparin-derived pentasaccharide that binds to antithrombin-III with high affinity. However, the portability of this model to other biological situations is questioned on several accounts. Because of their structural flexibility, oligosaccharides with different sulfation and uronic acid conformation can display the same binding proficiency to different proteins and produce comparable biological effects. This circumstance represents a formidable obstacle to the design of drugs based on the heparin scaffold. The conceptual framework discussed in this article is that through a direct intervention on the heparin-binding functionality of proteins is possible to achieve a high degree of action specificity. This objective is currently pursued through two strategies. The first makes use of small molecules for which in the text we provide examples from past and present literature concerning angiogenic factors and enzymes. The second approach entails the mutagenesis of the GAG-binding site of proteins as a means to generate a new class of biologics of therapeutic interest.
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Chao, Bo H., Lisa Lepeak, Ticiana Leal, and H. Ian Robins. "Clinical Use of the Low-Molecular-Weight Heparins in Cancer Patients: Focus on the Improved Patient Outcomes." Thrombosis 2011 (April 12, 2011): 1–10. http://dx.doi.org/10.1155/2011/530183.
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Patients with malignant neoplastic diseases represent a high-risk population relative to thromboembolic disease. With the advent of improved and accessible diagnostic technology, for example, ultrasound and/or spiral CT scans, timely diagnosis of venous thromboembolic events (VTE) is readily accomplished. The introduction of low-molecular-weight heparin (LMWH) approximately two decades ago (in contrast to unfractionated heparin and vitamin K antagonists) has provided a class of agents with a favorable therapeutic index. In the review to follow, the literature regarding the use of LMWH in oncologic patient populations is summarized. Topics addressed include prophylaxis, and treatment as well as consideration of the potential anti-neoplastic properties of this class of drugs.