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1
Gallistl, Siegfried, Gerhard Cvirn, Birgit Roschitz, Martina Petritsch, Bettina Leschnik, Wolfgang Muntean, and Martin Koestenberger. "Combined Effects of Eptifibatide and Anticoagulants: Differences between LMWH and UH or rH in Thrombin Generation Inhibition but not in Platelet Aggregation Inhibition." Thrombosis and Haemostasis 88, no. 12 (2002): 1012–19. http://dx.doi.org/10.1055/s-0037-1613348.
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SummaryAim of our study was to investigate effects of eptifibatide and anticoagulants on platelet aggregation and thrombin generation under low and high coagulant challenge in tissue factor-activated platelet rich plasma using a model allowing simultaneous determination of the time course of platelet aggregation and thrombin generation. Eptifibatide exerted a dose-dependent anti-aggregating effect under both high and significantly stronger under low coagulant challenge. Combination of eptifibatide and anticoagulants resulted in significant additive prolongation of the lag phase until the onset of platelet aggregation, more pronounced under low coagulant challenge. Under high, but not under low coagulant challenge combination of eptifibatide and anticoagulants had a significant synergistic inhibitory effect on platelet aggregation. Under low coagulant challenge combination of eptifibatide with LMWH, but not with UH, or rH, resulted in significantly reduced thrombin potential, F 1+2 generation, and FXa formation compared to measurements in the absence of eptifibatide.We demonstrate a synergistic effect of eptifibatide and anticoagulants on platelet aggregation inhibition and an additional inhibitory effect of LMWH and eptifibatide on thrombin generation. Our results support the notion that combination of eptifibatide and anticoagulants might be beneficial in atherosclerotic disease to palliate the thrombogenic potency of ruptured atherosclerotic plaques.
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Cimminiello, C., M. Milani, T. Uberti, G. Arpaia, and G. Bonfardeci. "Effects of Ticlopidine and Indobufen on Platelet Aggregation Induced by A23187 and Adrenaline in the Presence of Different Anticoagulants." Journal of International Medical Research 17, no. 6 (November 1989): 514–20. http://dx.doi.org/10.1177/030006058901700603.
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As Ca2+ is known to play a fundamental role in platelet function, the effect of combining two platelet aggregating agents (adrenaline and the ionophore A23187) with different effects on Ca2+ was studied at levels subthreshold for aggregation using platelet-rich plasma from eight atherosclerotic patients. Adrenaline lowered the A23187 threshold required to induce aggregation. The effects of treating patients with the antiplatelet agents, indobufen and ticlopidine, on A23187 and adrenaline induced aggregation of platelets prepared in hirudin or sodium citrate was also evaluated. Aggregation was also studied using platelets resuspended in Ca2+-free and Ca2+-enriched Tyrode solution. Before treatment hirudin treated platelet-rich plasma, which has physiological extraplatelet Ca2+ levels, was more sensitive to A23187 and adrenaline than was citrated platelet-rich plasma, which has suppressed Ca2+ levels. Ticlopidine significantly raised the concentration of A23187 required to induce aggregation in citrated but not hirudin treated platelet-rich plasma. Indobufen did not significantly affect A23187 induced aggregation. Ticlopidine acts by inhibiting the glycoprotein IIb – IIIa complex on the platelet membranes. Low levels of extracellular Ca2+ and ticlopidine may act synergistically to reduce the aggregatory response of stimulated platelets.
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Wallén, N. Håkan, Claes Held, Nina Rehnqvist, and Paul Hjemdahl. "Impact of Treatment with Acetylsalicylic Acid on the Proaggregatory Effects of Adrenaline in vitro in Patients with Stable Angina Pectoris: Influence of the Anticoagulant." Clinical Science 85, no. 5 (November 1, 1993): 577–83. http://dx.doi.org/10.1042/cs0850577.
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1. The impact of oral acetylsalicylic acid treatment on the enhancing effect of adrenaline on platelet aggregation in vitro was investigated in patients with stable angina pectoris. In addition, the influence of different anticoagulants (i.e. hirudin and citrate) on platelet aggregation in vitro was compared. 2. Eighty-four patients with stable angina pectoris were studied. Sixteen patients were on acetylsalicylic acid treatment (150-250 mg daily), whereas 68 patients were free from acetylsalicylic acid. Platelet-rich-plasma was prepared from citrate- or hirudin-antkoagulated blood. The EC50 (i.e. the concentration of agonist required to produce half-maximal aggregation) for the ADP-induced extent of aggregation was determined. Thereafter the enhancing effect of adrenaline (10 and 50 nmol/l) on ADP-induced aggregation (at EC50) was investigated. 3. In the patients with angina, acetylsalicylic acid caused the expected effects on ADP-induced platelet responses. Adrenaline significantly enhanced both the extent of aggregation and the initial rate of aggregation (primary aggregation), irrespective of the anticoagulant used. In acetylsalicylic acid-treated patients (citrated platelet-rich plasma) the extent of aggregation was partly inhibited, but no significant effect on the rate of aggregation could be observed. 4. A comparative substudy of the anticoagulants in healthy subjects (n = 8) showed that both the aggregating effect of ADP per se and the enhancing effect of adrenaline on ADP-induced aggregation (at EC50) were less influenced by acetylsalicylic acid when evaluated in hirudinized platelet-rich plasma (i.e. with physiological levels of extracellular calcium) as compared with citrated platelet-rich plasma. 5. It is concluded that acetylsalicylic acid treatment slightly attenuates the proaggregatory effect of high physiological concentrations of adrenaline in vitro. The impact of acetylsalicylic acid in vitro is, however, strongly dependent on the anticoagulant used, and is significantly weaker when evaluated in a medium with normal extracellular calcium levels (i.e. hirudin) than in a medium with low levels of extracellular calcium (citrate). Thus, acetylsalicylic acid may be a weak antagonist of catecholamine-induced platelet activation in vivo.
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Białecka, Monika, Anna Machoy-Mokrzyńska, and Anna Pierzchlińska. "Lumbar puncture in patients on anticoagulants." Aktualności Neurologiczne 20, no. 2 (October 30, 2020): 51–58. http://dx.doi.org/10.15557/an.2020.0007.
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Lumbar puncture is an important invasive procedure often used in the diagnosis of neurological disorders. Generally, lumbar puncture is a safe procedure, with a very low incidence of serious complications, the risk of which, however, may increase in the group of patients on anticoagulant therapy (anticoagulants and platelet anti-aggregation agents). This applies to both the risk of haemorrhagic complications and the risk of thrombotic events during temporary discontinuation of anticoagulants. This paper presents the current knowledge on the management in patients receiving anticoagulants (vitamin K antagonists, new anticoagulants, heparins, fondaparinux) and platelet anti-aggregation agents (P2Y12 platelet receptor antagonists, glycoprotein IIb/IIIa inhibitors, acetylsalicylic acid) who require lumbar puncture. Furthermore, we present the issue of bridging therapy in patients at a high risk of thrombotic complications. In the case of neurological indications for a lumbar puncture in a patient on anticoagulants or anti-aggregation therapy, the urgency of the procedure and the risk of adverse effects should be assessed and other diagnostic methods should be considered in the first place. If there is a need for an urgent lumbar puncture, treatment modification or the use of drugs to reverse the anticoagulant or anti-aggregation effect may be necessary. Each case must be treated individually, considering medical and family history, comorbidities and other medications taken by the patient. Most of the available recommendations related to the presented problem have been developed by anaesthetic associations. There is a need to popularise the principles of management in patients on anticoagulants who require lumbar puncture due to neurological disorders.
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Lewis, Bruce E., Christopher Aranda, Mary Lewis, Debra Hoppensteadt, Jeanine M. Walenga, and Jawed Fareed. "Unlike Heparins Newer Oral Anticoagulants Do Not Interact with HIT Antibodies and Maybe Useful in the Longterm Anticoagulant Management of Heparin Compromised Patients." Blood 118, no. 21 (November 18, 2011): 2317. http://dx.doi.org/10.1182/blood.v118.21.2317.2317.
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Abstract Abstract 2317 Introduction: Heparin and low molecular weight heparins such as enoxaparin and dlateparin are widely used in the management of thrombosis and cardiovascular disorders. However these anticoagulants are capable of producing the generation of HIT antibodies and their use is not recommended in patients with previous history of HIT. More recently several new oral anticoagulants have been approved around the world. These include the oral anti-Xa agents namely, Apixaban (Bristol-Myers Squibb), Rivaroxaban(Bayer Healthcare) and anti-IIa agents, dabigatran (Boehringer-Ingelheim). All of these represent synthetic low molecular weight compounds. Apixaban and Rivaroxaban are active agents where as Dabigatran requires endogenous activation. The purpose of this investigation was to determine the relative effects of the newer anticoagulants and enoxaparin on HIT antibody mediated platelet aggregation and other interactions with platelets. Materials: Rivaroxaban was obtained in powdered form from Bayer Healthcare (Wuppertal, Germany) Apixaban and Dabigatran were of synthetic origin. Enoxaparin was obtained from Sanofi-Aventis (paris, France). All drugs were dissolved in appropriate solutions and a working solution of 100 ug/ml was prepared in buffered saline. Pooled HIT sera was prepared by pooling clinically symptomatic HIT patients with high titers of anti-heparin platelet factor 4 antibodies. Method: Whole blood samples drawn from normal healthy volunteers were supplemented with each of these agents at a graded concentration of 0–100 ug/ml for 60 minutes to determine the relative release of platelet factor 4. To test the interaction of HIT antibody with each of these agents 50 ul of PRP samples were mixed with 150 ul HIT positive heat inactivated sera/plasma or plasmapheresis fliud (collected from symptomatic HIT patients). Graded amounts of each of these new anticoagulants at 0.1, 1.0 and 10 ug/ml were added to test the platelet aggregation response at a period of 60 minutes. Results: In contrast to enoxaparin which produced an increase in the platelet factor 4 release upon 60 minute incubation 25.6+3.1 ng/ml), none of the new oral anticoagulants produced an increase in the PF4 <15.0 ng/ml. Enoxaparin also produced a strong HIT antibody mediated response, whereas none of these newer oral agents produced any aggregation responses. Conclusion: These studies demonstrate that –enoxaparin the newer oral anticoagulant drugs do not interact with HIT antibody to mediate plarelet aggregation responses. Moreover, these newer agents do not promote platelet factor 4 release. Thus, these agents can be used in the long term anticoagulant management of heparin compromised patients. Disclosures: No relevant conflicts of interest to declare.
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Sokolova, N. A., M. I. Savina, and O. S. Shokhina. "EDTA‑dependent pseudothrombocytopenia in child (clinical case report)." Medical alphabet, no. 13 (June 29, 2021): 51–54. http://dx.doi.org/10.33667/2078-5631-2021-13-51-54.
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Ethylenediaminetetraacetic acid (EDTA)-dependent pseudothrombocytopenia is the phenomenon of a spurious low platelet count due to antiplatelet antibodies that cause platelet clumping in blood anticoagulated with EDTA. The aggregation of platelets in EDTA-dependent pseudothrombocytopenia is usually prevented by other anticoagulants, such as sodium citrate. EDTA-dependent pseudothrombocytopenia has never been associated with hemorrhagic diathesis or platelet dysfunction. In this article, a 2,5-year-old boy with EDTA-dependent pseudothrombocytopenia is presented because of rare presentation. We report that EDTA can induce platelet clumping, and thus spuriously low platelet counts. However, aggregation of platelets was not detected in blood samples with sodium citrate, and platelet count was normal.
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Wysokinski, Waldemar, Robert McBane, James H. Chesebro, and Whyte G. Owen. "Reversibility of Platelet Thrombosis In Vivo." Thrombosis and Haemostasis 76, no. 06 (1996): 1108–13. http://dx.doi.org/10.1055/s-0038-1650714.
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SummaryReversibility in vivo of acute platelet thrombosis in response to specific anticoagulants is analyzed with thrombi that develop in segments (1 cm) of porcine carotid arteries externally crushed with a hemostat. Most thrombi fill the lumens of the injured segments (ca. 1 cm × 3 mm, 1 × w) within 30 min and comprise masses of platelets interpenetrated with neutrophil-lined seepage channels of blood. Continuous quantitative assay of thrombus mass is provided by a gamma detector placed over the injured segments to collect counts from 111In-labeled platelets. Thrombi established 30 min after injury, otherwise stable for 6 h, clear during 30-60 min of continuous infusion of either hirudin, tick anticoagulant or activated porcine protein C, or intermittent activation of endogenous protein C with a latent thrombin reagent. Anticoagulant dose-dependence of thrombus clearance is established for hirudin between 0.01 and 1.0 mg/kg/min. Thrombi become progressively refractory to hirudin between 0.5 and 6 h after injury. Neither heparin nor low-molecular-weight heparin in full (clinical) anticoagulant doses yield significant dethrombosis. It is concluded that, within time limits, controlled thrombin generation in platelet thrombi maintains platelet cohesion without catalyzing irreversible platelet aggregation or clotting of fibrinogen.
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Sunardi, Agus, Nadjwa Zamalek Dalimoenthe, Coriejati Rita, and Adhi Kristianto Sugianli. "THE CORRELATION BETWEEN THE MEAN PLATELET VOLUME VALUES WITH THROMBOCYTE AGGREGATION IN NEPHROPATHY DIABETIC PATIENTS." INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 25, no. 1 (April 10, 2019): 79. http://dx.doi.org/10.24293/ijcpml.v25i1.1510.
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Diabetic nephropathy is the most important cause of end-stage renal failure. Chronic hyperglycemia will cause glomerular endothelial damage, and this damage will stimulate hemostasis activation including platelets so that platelet aggregation will increase. The increase of platelet aggregation will increase platelet consumption, which further stimulates thrombopoiesis which will lead to immature platelets of large size to be released into the circulation. This research aimed to determine the positive correlation between MPV with platelet aggregation in patients with diabetic nephropathy. This study was an analytic observational study with a cross-sectional study design. The research was conducted in the Dr. Hasan Sadikin Hospital Bandung from July 2016 to October 2017. A total of 52 subjects who met the inclusion criteria were included in the study. Mean platelet volume and platelet aggregation were performed with venous examination with EDTA and sodium citrate 3.2% anticoagulants. The result of platelet aggregation examination showing platelet hyper-aggregation was found in 44.2% of subjects, 50% normal-aggregation, 5.8% hypo-aggregation. While the median value of MPV in this study was 9.2 fL with the range of 8.00 – 11.80 fL. A positive correlation was found between MPV value with platelet aggregation with r= 0.067, p= 0.634. The conclusion was that there was no correlation between MPV values with platelet aggregation in diabetic nephropathy patients. This small and insignificant r-value might be due to several factors that also affect platelet aggregation in diabetic nephropathy patients, requiring further investigation.
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Eslam, Roza Badr, Nina Reiter, Alexandra Kaider, Irene Lang, and Simon Panzer. "High-shear- and-thrombin-inducible platelet adhesion and aggregation in patients undergoing percutaneous coronary intervention." Thrombosis and Haemostasis 105, no. 03 (2011): 496–500. http://dx.doi.org/10.1160/th10-06-0384.
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SummaryThrombin-generation and activation of platelets during percutaneous coronary intervention (PCI) play a key role for early thrombotic events. Heparin and bivalirudin are approved anticoagulants for PCI. We examined the specific effects of these anticoagulants on platelet adhesion and aggregation under high shear conditions, and the presence of excess thrombin. To simulate in vivo conditions that may precipitate a bleeding/thrombotic event, we added thrombin in vitro to blood samples from 89 stable patients who had been randomly assigned to receive heparin or bivalirudin for elective PCI and examined thrombininducible platelet adhesion and aggregation under high shear conditions. Platelet adhesion increased by 10% of baseline with heparin, but decreased by 20% with bivalirudin (p=0.0047). Thrombin-inducible platelet adhesion and size of aggregates was equally inhibited by heparin and bivalirudin. Thus, under high shear conditions and excessive thrombin generation as they occur in atherosclerotic vascular compartments and acute vascular syndromes, heparin and bivalirudin inhibit thrombin-induced platelet adhesion and aggregation to a similar extent, while they have opposite effects on platelet adhesion in the absence of thrombin.This study was part of the doctorial thesis of NR at the Department of Blood Group Serology and Transfusion Medicine.
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Fareed, Jawed, Debra Hoppensteadt, Omer Iqbal, Josephine Cunanan, Vinod Bansal, Schuharazad Abro, and Rakesh Wahi. "Defibrotide Interactions with Newer Oral Anticoagulants and Antithrombotic Agents." Blood 120, no. 21 (November 16, 2012): 3411. http://dx.doi.org/10.1182/blood.v120.21.3411.3411.
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Abstract Abstract 3411 Defibrotide is a polydisperse mixture of porcine-derived single-stranded oligonucleotides which has been used for multiple clinical indications. Recent clinical trials of defibrotide indicate that this drug may provide benefits both for the treatment and prophylaxis of hepatic veno-occlusive disease (VOD) in hematopoietic stem cell therapy. In VOD it is believed that defibrotide exerts two distinct effects; 1. Endothelial cell protection and 2. Restoration of the thrombotic-fibrinolytic balance. Although antithrombotic in nature, defibrotide does not produce any systemic anticoagulant effects atthe selected dose of 25 mg/kg/day Conventional oral anticoagulants are routinely not used in veno-occlusive disease however heparin is often used in the management of these patients. More recently, newer oral anticoagulant drugs such as dabigatran, apixiban and rivaroxiban have been approved for the management of post orthopaedic surgical venous thrombosis and stroke prevention in atrial fibrillation. The current study was undertaken to investigate the effect of defibrotide on the anticoagulant and antiprotease effects of the newer oral anticoagulant drugs in the whole blood, plasma and platelet rich plasma based systems. Materials and Methods Native whole blood was drawn from 25 normal healthy individuals and supplemented with 100 μg/mL defibrotide and 250 ng/mL of each of the individual oral anticoagulant drugs alone and with defibrotide. Activated clotting time (ACT) measurements were made on a Hemachron instrument using celite ACT tubes. For the plasma based anticoagulant studies, a fixed concentration of defibrotide of 100 μg/mL was supplemented with defibrotide to pool plasma alone and with each of the individual oral anticoagulantagents in a concentration range of 0–1000 ng/mL. To investigate the effect of defibrotide on agonist induced platelet aggregation platelet rich plasma was prepared with varying amounts of defibrotide (0–100ug/ml). Such agonsits as ADP, epinephrine, collagen and arachodonic acid were used. To test the effects of newer oral anticoagulants, each agent was supplemented at 250–500ng/ml to the defibrotide enriched PRP (100ug/ml) and agonist induced aggregation studies were carried out in comparison to saline and defibrotide control. To test the effect of defibrotide on the conventional oral anticoagulant agents, plasma samples from patients with INR range of 1.5–3.0 were supplemented with 100ug/ml and the PT/INR was re-determined using Innovin® reagent. Results In the whole blood studies apixaban and rivaroxaban did not produce any prolongation of the whole blood ACT. However, dabigatran produced a modest increase in the ACT at 250 ng/mL. In the anticoagulant assays, supplementation of these agents did not result in any prolongation of the PT with defibrotide and newer oral anticoagulants. In the aPTT assay, the apixaban and rivaroxaban did not have any interaction, at a concentration greater than 500 ng/mL. Dabigatran shows a slight interaction in the aPTT assay. Defibrotide, did not produce any alterations of the effect on the agonist (ADP, epinephrine, collagen, arachidonic acid) induced aggregation of platelets in concentrations up to 100 μg/mL. Studies carried out where defibrotide at 100 μg/mL is combined with 250 ng/mL of each of the new anticoagulants does not show any modification of the aggregation responses. Defibrotide supplementation to anti-platelet therapy treated patient's blood collected did not result in any augmentation of the observed inhibitory responses. Defibrotide did not produce any changes in the PT/INR values of plasma samples collected from warfarin treated patients at concentrations of up to 100 μg/ml. Conclusions These studies indicate that in a concentration range of 0–1000 ng/mL the new anticoagulants do not exhibit any significant interactions with defibrotide. Since dabigatran exhibits some anticoagulant effect of its own, minor interactions with defibrotide may be observed. Based on the indications for the new oral anticoagulant drugs, their circulating levels and rapid clearance, it is unlikely that defibrotide will produce any interactions with these drugs. Disclosures: No relevant conflicts of interest to declare.
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Perdomo, Jose, Jaa Yien New, Zohra Ahmadi, Xing-Mai Jiang, and Beng H. Chong. "A Humanized Anti FcγRIIa Scfv Inhibits Platelet Activation, Aggregation and Thrombus Formation in Heparin-Induced Thrombocytopenia (HIT)." Blood 126, no. 23 (December 3, 2015): 10. http://dx.doi.org/10.1182/blood.v126.23.10.10.
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Abstract Introduction. Heparin is widely used as an anticoagulant to prevent thrombosis and to treat venous thromboembolism and myocardial infarction. A complication of heparin use is the development of heparin-induced thrombocytopenia (HIT), which is a limb- and life-threatening disorder due to associated thrombotic events. HIT arises through the formation of immune complexes between heparin, platelet factor 4 and HIT autoantibodies. These immune complexes engage with FcγRIIa receptors on platelets, leading to platelet activation and aggregation and subsequent initiation of the coagulation pathway. Current HIT treatment consists of cessation of heparin administration and substitution with parenteral anticoagulants such as argatroban and danaparoid. While these anticoagulants are generally beneficial in reducing thrombocytopenia, they are only partially effective since the risk of thrombosis continues due to the underlying FcγRIIa-mediated platelet activation. Thus, alternative anticoagulants do not reduce morbidity and mortality rates, highlighting the need for more effective HIT interventions. Methods. IV.3 is a monoclonal antibody that recognizes and blocks the FcγRIIa receptor and is used in assays to confirm the presence of HIT antibodies. We derived the VH and VL sequences of IV.3 and constructed a single-chain variable fragment (scFv) antibody in the form of VH-linker-VL. Using a complementarity determining region grafting and point mutation approach the scFv was humanized with the aim of reducing potential immunogenicity for future clinical applications. The molecule was expressed in E. coli and purified by FPLC. We reconstituted the HIT condition in a micro-fluidics device on a Vena8 Fluoro+ biochip coated with vWf using whole blood flowing at 20 dyne/cm2 at 37oC. Whole blood was stained with DiOC6 and the formation of platelet aggregates was monitored by fluorescence microscopy. Video images were acquired at 1 frame every 2 sec for 460 sec. Results. The purified scFv interacts with FcγRIIa on platelets. Platelet aggregation and serotonin release assays show that the scFv effectively prevents aggregation and activation induced by HIT immune complexes. We demonstrate that in the HIT condition reconstituted in a micro-fluidics system the scFv precludes thrombus deposition in a dose-dependent manner as determined by thrombus coverage area and mean thrombus diameter (Figure 1). Conclusions. These data provide evidence that a humanized scFv binds and neutralizes FcγRIIa on platelets. This interaction prevents HIT immune complex-induced platelet aggregation and activation in vitro and stops thrombus deposition ex vivo. This molecule, therefore, inhibits a critical initiating event in HIT and may serve as a potential treatment for this condition. Disclosures No relevant conflicts of interest to declare.
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Steigerwald, U., U. Walter, and J. Kössler. "Anticoagulants of primary haemostasis." Hämostaseologie 29, no. 03 (2009): 274–78. http://dx.doi.org/10.1055/s-0037-1617031.
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SummaryInhibition of platelet function plays an important role in the treatment and secondary prevention of cardiovascular or cerebrovascular ischemic diseases. Established antiplatelet agents use different pharmacological targets for this role. Acetylic salicylic acid achieves a reduction of thromboxane A2 formation by inhibition of COX-1. Ticlopidin or clopidogrel are ADP-P2Y12 receptor antagonists. Tirofiban, abciximab or eptifibatid are used for the inhibition of the glycoprotein IIb/IIIa receptor which is activated at the surface of platelets preceding the final step of their aggregation. The mechanism of dipyridamole is based on the inhibition of adenosine uptake and of phosphodiesterase-5.Efforts are made to improve antiplatetelet therapy with the aim to find agents with favorable clinical outcome and lower bleeding risk. Current clinical studies focus on a new generation of ADP receptor antagonists (prasugrel, cangrelor and ticagrelor) as successors of ticlopidin and clopidogrel after coronary arterial interventions. Developments using platelet targets different from established drugs are thrombin receptor antagonists (like SCH530348) or thromboxane receptor antagonists (like S18886/terutroban) in patients with cerebrovascular events. Results from recent experimental studies could lead to new strategies for antiplatetelet therapy (like inhibition of GP Ib receptor, GP VI receptor, platelet-leukocyte interaction, factor XII and others) in the future.
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Jarek-Martynowa, Iwona R., Mikhail Y. Martynov, Karina G. Sarkisova, Ekaterina O. Koksharova, Ekaterina E. Mishina, Albina N. Yasamanova, and Marina V. Shestakova. "Influence of hyperinsulinemic – hypoglycemic clamp on induced platelet aggregation, activity of physiological anticoagulants and von Willebrand factor in patients with type I diabetes." Diabetes mellitus 21, no. 2 (May 21, 2018): 84–91. http://dx.doi.org/10.14341/dm9533.
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Background. Intensive glycaemic control in patients with type 1 diabetes may lead to hypoglycaemia and thus increase the risk of cardiovascular and cerebrovascular events. Platelet activation and/or decreased activity of physiological anticoagulants during hypoglycaemia may play a role in the development of cardiovascular or cerebrovascular complications.
Aims. To investigate induced platelet activity, the activity of physiological anticoagulants, and the von Wil-lebrand factor in patients with type 1 diabetes with the hyperinsulinaemichypoglycaemic clamp.
Materials and methods. We examined 11 patients with type 1 diabetes without macro- and micro-vascular complications (6 males, 5 females, mean age 23.7 5.6 years, A1C 9.7 2.3%). Induced platelet aggregation, physiological anticoagulants (Protein S, Protein C, AT III) and the von Willebrand factor were studied at hyperglycaemic, euglycaemic, and hypoglycaemic stages during use of a hyperinsulinaemic (1 mU/kg/min) hypoglycaemic clamp.
Results. Platelet aggregation to all agonists increased significantly during the hypoglycaemic stage, compared with the euglycaemic or hyperglycaemic stages. There was no difference in platelet aggregation between the euglycaemic and hyperglycaemic stages. Platelet aggregation to all agonists increased during the hypoglycaemic stage compared with the hyperglycaemic period: thrombin23.9%, ADP30.6%, arachidonic acid30.9%, collagen69.4% and ristocetin70.8%. During hypoglycaemia aggregation to ADP, arachidonic acid and collagen remained within normal limits (upper quartile); aggregation to thrombin was significantly above normal limits and aggregation to ristocetin remained significantly below lower limits. Protein S activity was significantly increased during hypoglycaemia compared with euglycaemia (p = 0.046) and hyperglycaemia (p = 0.046). Antithrombin-III activity decreased significantly at the euglycaemic and hypoglycaemic stages, compared with the hyperglycaemic period, but still remained significantly elevated above the upper threshold. Protein C and vWf activity did not change significantly.
Conclusions. In patients with type 1 diabetes platelet aggregation and protein S activity increases significantly at the hypoglycaemic stage of the hyperinsulinaemichypoglycaemic clamp. Platelet activation is directly caused by hypoglycaemia and not by decreasing glucose levels. Increased protein S activity is a compensatory response to platelet activation.
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Suciu, Oana, Bogdan Deleanu, Horia Haragus, Teodora Hoinoiu, Cristina Tudoran, Adrian Todor, Andrei Ghiorghitoiu, Nevena Velimirovici, and Roxana Ramona Onofrei. "Platelet Aggregation Inhibitors and Anticoagulants Delay Surgery for Hip Fractures." Applied Sciences 10, no. 23 (December 2, 2020): 8617. http://dx.doi.org/10.3390/app10238617.
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Background: we aimed to analyze the influence of antithrombotic medication in delaying surgery for fragility hip fractures; Method: a total of 312 consecutive hip fracture cases over 55 years who underwent surgery in our Orthopedic Clinic; Results: of these, 90 patients received chronic antithrombotic medication. There were no differences between the medicated group and controls (n = 222) regarding age, gender, type of fracture and haemoglobin at admittance. However, median time to surgery was significantly longer in the medicated group: 4(3–6) days compared to 2(1–4) (p < 0.0001). By type of medication, time to surgery was: 3(1–4) days for acetylsalicylic acid (n = 44), 6(5.25–7.75) days for clopidogrel (n = 15), 4.5(4–7) days for acenocoumarin (n = 18) and 5(4–7.25) days for novel direct oral anticoagulants (n = 13). The Charlson comorbidity index was significantly higher in the medicated group: 5 [4–5] versus 4 [3–5]. There were no differences in transfusions except for fresh frozen plasma, which was administered more in the medicated patients; Conclusions: the prevalence of platelet aggregation inhibitors and anticoagulant use among fragility hip fracture patients is high, with almost a third using some form of antithrombotic medication. This may significantly lengthen time to surgery.
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Nehaj, Frantisek, Juraj Sokol, Jela Ivankova, Michal Mokan, Frantisek Kovar, Jan Stasko, and Marian Mokan. "First Evidence: TRAP-Induced Platelet Aggregation Is Reduced in Patients Receiving Xabans." Clinical and Applied Thrombosis/Hemostasis 24, no. 6 (October 19, 2017): 914–19. http://dx.doi.org/10.1177/1076029617734310.
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The availability of direct oral anticoagulants has caused a paradigm shift in the management of thrombosis. Rivaroxaban and apixaban are 2 direct oral anticoagulants whose target specificity is activated factor X (FXa). However, it is still not fully understood if and how xabans impact platelet function. This observational study aimed to assess the in vitro platelet function in patients with atrial fibrillation receiving xabans. This was a single-center study quantifying platelet aggregation in 41 patients treated with apixaban or rivaroxaban by light transmission aggregometry. The thrombin receptor activating peptide (TRAP)-induced platelet aggregation was significantly lower 2 hours after taking rivaroxaban or apixaban compared to baseline value (56.15% [8.53%] vs 29.51% [12.9%]; P = .000). Moreover, concomitant use of angiotensin-converting enzyme blockers, proton pump inhibitors, and statins reduces the efficiency of xabans. The TRAP-induced platelet aggregation was reduced in patients with cardiovascular disease 2 hours after receiving xabans.
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Farias, Wladimir, Rômulo Nazareth, and Paulo Mourão. "Dual Effects of Sulfated D-galactans from the Red Algae Botryocladia occidentalis Preventing Thrombosis and Inducing Platelet Aggregation." Thrombosis and Haemostasis 86, no. 12 (2001): 1540–46. http://dx.doi.org/10.1055/s-0037-1616760.
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SummarySulfated D-galactans occur on the red algae Botryocladia occidentalis as three fractions that differ in their sulfate content. Fractions F2 and F3 are potent anticoagulants. Like heparin, they enhance thrombin and factor Xa inhibition by antithrombin and/or heparin cofactor II. The inhibition potency increases simultaneously with the sulfate content of the fractions. The antithrombotic activity of these sulfated D-galactans was investigated on an experimental thrombosis model in which thrombus formation was induced by a combination of stasis and hypercoagulability. In contrast with heparin, the sulfated D-galactans showed a dual dose-response curve preventing thrombosis at doses up to0.5 mg/ kg body weight but losing the effect at higher doses. This unexpected behavior is probably due to a combined action of the sulfated D-galactan as anticoagulant and also as a strong inducer of platelet aggregation. In platelet-depleted animals the antithrombotic activity at higher dose of sulfated D-galactan is restored and almost total inhibition of thrombus formation is achieved. The sulfated D-galactan has no hemorrhagic effect even at high doses, possibly as a consequence of its effect on platelet aggregation. At comparable dose heparin has an intense bleeding effect. These results indicate that new polysaccharides, with well-defined structures, can help to distinguish events, such as antithrombotic and anticoagulant activities, bleeding and platelet-aggregating effects, which are obscure when induced simultaneously by a single compound.
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Salzet, Michel. "Anticoagulants and inhibitors of platelet aggregation derived from leeches." FEBS Letters 492, no. 3 (March 12, 2001): 187–92. http://dx.doi.org/10.1016/s0014-5793(01)02212-8.
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Bowry, S. K., and G. Müller-Berghaus. "Aggregation of Washed Platelets from Non-Anticoagulated Human Blood Is Not Reversible." Thrombosis and Haemostasis 56, no. 02 (1986): 172–77. http://dx.doi.org/10.1055/s-0038-1661634.
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SummaryMost of the knowledge acquired on platelet function and biochemistry has been obtained from platelets prepared from blood anticoagulated with sodium citrate. Using washed platelets from human blood (PNB) to which no anticoagulants were added, we report on responses not observed with platelets prepared from citrate-anticoagulated blood. Native blood was passed rapidly (within 5 min of venepuncture) through a Sephadex G-25/G-50 column to remove divalent ions and thus prevent coagulation. Platelets were separated from the gel-filtered blood by differential centrifugation. Responses of PNB to thrombin, collagen, calcium ionophore, ristocetin, release of 14C-5hydroxytryptamine and p-thromboglobulin, and generation of thromboxane A2 were similar to those observed for citrated platelets. Comparison of PNB with thrombin-treated platelets, which demonstrate an increase of platelet factor 3 activity, a reduction of the adenylate energy charge and an impairment of clot retraction, indicated the absence of platelet activation. Unlike citrated platelets, however, aggregation of PNB in response to ADP was irreversible in the presence of Ca2+ and fibrinogen, even at concentrations as low as 0.2 μM ADP, with aggregation taking up to 25 times longer to reach the same extent of aggregation as for citrated platelets. PNB did not aggregate to epinephrine even in the presence of Ca2+ and fibrinogen. Sodium citrate impaired ADP-induced aggregation and clot retraction of PNB. Thus citrate affects platelet function and may cause changes resulting in the unphy-siological behaviour and responses of platelets.
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Markwardt, Fritz. "State-of-the-Art Review : Antithrombotic Agents from Hematophagous Animals." Clinical and Applied Thrombosis/Hemostasis 2, no. 2 (April 1996): 75–82. http://dx.doi.org/10.1177/107602969600200201.
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Bloodsucking animals produce anticoagu lantly effective substances that are a challenge to coagu lation studies. In the past 40 years efforts have been fo cused on the isolation and chemical characterization of such agents as well as on the clarification of their modes of action. Following the success in the development of the anticoagulant agent hirudin from medicinal leeches, these naturally occurring anticoagulants were recently in vestigated as a source of antithrombotics for pharmaceu tical use. These polypeptides or miniproteins were shown to be specific inhibitors of certain coagulation factors that block either the formation or the effect of thrombin or are supported by substances that inhibit the aggregation and adhesion of blood platelets and by proteolytic enzymes with fibrinolytic activity. By advances in biotechnology of protein-like substances, especially gene technology, these antithrombotics have been obtained in amounts suf ficient for preclinical and clinical studies. Thus, the in vestigation of the anticoagulant agents from hematopha gous animals offers a new line of research in antithrom botic drugs. Key Words: Bloodsucking animals— Naturally occurring anticoagulants—Fibrinolytics and platelet inhibitors.
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Goldman, I. L., and B. R. Schwartz. "277 ANTICOAGULANT ACTIVITY OF ALLIUM ACCESSIONS." HortScience 29, no. 5 (May 1994): 469f—469. http://dx.doi.org/10.21273/hortsci.29.5.469f.
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In the past twenty years, the presence of blood anticoagulants in plants has been confirmed by a range of clinical and in vitro investigations. The presence of anti-clotting factors in plants presents a unique opportunity for dietary enhancement of circularion and fibrinolysis. Experiments were conducted to assess variability in anticoagulant activity of a range of Allium wild species and cultivated accessions. Anticoagulant activity was determined via a platelet aggregation assay with human plasma. Extracts were prepared from 19 Allium species accessions and 24 cultivated accessions of Allium cepa, including standard inbred lines and open-pollinated popularions. Relative inhibition of platelet aggregation was measured for each accession and inhibition constants (IC50) were calculated. Data from this investigation dcmonstrate large IC50 variability among accessions. Larger IC50 differences (up to 45-fold) were measured among A. cepa accessions than among Allium species accessions (up to 16-fold). Yellow storagc-type A. cepa accessions exhibited the strongest inhibitory activity. Implications of these findings to onion breeding and platelet function will be presented.
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Nilsson, Benjamin, Valentina Back, Ran Wei, Frances Plane, Paul Jurasz, and Tammy J. Bungard. "Potential Antimigraine Effects of Warfarin: An Exploration of Biological Mechanism with Survey of Patients." TH Open 03, no. 02 (April 2019): e180-e189. http://dx.doi.org/10.1055/s-0039-1692989.
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AbstractCase reports suggest a link between anticoagulant use and improved migraine symptoms, and a role for platelet-induced cerebral vasoconstriction in migraine pathobiology. Hence, we investigated the mechanism by which warfarin may affect migraine symptoms and whether there is a change in migraine symptomology in patients initiating oral anticoagulants, most commonly warfarin. The effects of warfarin on human platelet aggregation and secretion as well as platelet-induced rat cerebral artery vasoconstriction were studied. A survey of migraine and symptom change after starting or stopping oral anticoagulants was also conducted. Warfarin inhibited platelet aggregation and 5-hydroxytryptamine (5-HT) secretion in a concentration-dependent manner. Warfarin-inhibited platelet secretion products constricted middle cerebral arteries from male but not from female rats. For the survey, patient demographic information, migraine and medical history, and Migraine Disability Assessment Score (MIDAS) changes were collected. Out of 175 consenting, 40 respondents met the criteria for migraine and completed the survey. A total of 11 patients reported migraine symptom change, all coinciding with starting warfarin. Of those having symptom and MIDAS improvement, most were female with migraines with aura, whereas those worsening were male with fewer having migraine with aura. Of those reporting migraine symptom change with warfarin, female sex may be associated with improved MIDAS, and those experiencing an aura component are more likely to report a symptom change. Warfarin-mediated symptom improvement in females may occur due to inhibition of platelet 5-HT secretion and a lower sensitivity of female cerebral blood vessels to platelet-derived 5-HT-induced vasoconstriction.
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Kalinin, E. P., N. N. Buslaeva, and D. I. Boyarintsev. "Biological effects and assessment of acute toxicity of anticoagulants extracted from plants." Medical Science And Education Of Ural 21, no. 4 (December 30, 2020): 27–29. http://dx.doi.org/10.36361/1814-8999-2020-21-4-27-29.
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The aim of the study – was to study the biological effects and assess acute toxicity in an in vivo experimental study when injecting plant-derived effectors with an anticoagulant effect to laboratory animals. Materials and methods. As the studied effectors, plant anticoagulants obtained from the leaves of blueberry (Vaccinium myrtillus) and peloid, which were obtained in the previous studies, were used. The biological effect of effectors was evaluated by indicators characterizing coagulation and platelet hemostasis when administered to laboratory animals. Acute toxicity was assessed by the survival rate of animals after administration of effectors. Results. Blueberry leaf extract demonstrated an inhibitory effect on the development of reactions of the internal pathway of plasma coagulation and ADP – induced platelet aggregation. The effector obtained from sapropel significantly inhibits both plasma coagulation and platelet reactions. None of the effectors showed acute toxicity. Conclusion. As a result of this study, we consider the most promising peptide for further study, derived from peloid, as a promising direct-acting anticoagulant that affects the final pathway of plasma coagulation. The anticoagulant from blueberry leaves did not demonstrate the expected activity in the in vivo experiment, presumably due to the presence of impurities that neutralize its anticoagulant effect, and needs additional purification and evaluation.
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Kuijpers, Marijke, Cécile Nieuwenhuys, Marion Feijge, Willem Kloots, Peter Giesen, Johann Jerling, Mirjam oude Egbrink, and Johan Heemskerk. "Regulation of tissue factor-induced coagulation and platelet aggregation in flowing whole blood." Thrombosis and Haemostasis 93, no. 01 (2005): 97–105. http://dx.doi.org/10.1160/th04-02-0091.
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SummaryPhotochemically induced thrombosis (a thrombin-dependent process) was measured in rats treated with moderate doses of anticoagulants, but which appeared to be unchanged. We considered the possibility that platelet-inhibiting agents, which also indirectly inhibit coagulation, would act as more potent antithrombotic agents.Inhibitors used as such were prostaglandin E1 (PGE1), which elevates cyclic AMP levels, and the P2Y12 ADP-receptor antagonist,AR-C69931MX. Effects of these agents were investigated in an ex vivo model system, in which whole blood under coagulant conditions was perfused over fibrinogen at defined wall shear rate. Perfusion of blood (rat or human) in the presence of tissue factor resulted in deposition of activated platelets and subsequent aggregate formation, along with exposure of procoagulant phosphatidylserine (PS) on the platelet surface and formation of fibrin fibers. In the presence of PGE1 aggregation was completely inhibited,but platelet adhesion and PS exposure were only party reduced, while fibrin formation was hardly affected. Treatment with AR-C69931MX caused similar, but less complete effects.These results indicate that in tissue factor- triggered blood under conditions of flow:(i) the platelet procoagulant response is independent of aggregate formation; (ii) the platelet-inhibiting effect of PGE1 and AR-C69931MX is sufficient to suppress aggregation, but not platelet adhesion and coagulation. These platelet inhibitors thus maintain their aggregation- inhibiting effect at sites of thrombin formation.
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Kalb, Madeleine L., Lukasz Potura, Gisela Scharbert, and Sibylle A. Kozek-Langenecker. "The effect of ex vivo anticoagulants on whole blood platelet aggregation." Platelets 20, no. 1 (January 2009): 7–11. http://dx.doi.org/10.1080/09537100802364076.
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Dzhumaeva, M. J., A. I. Tabarov, and Kh T. Fayzulloev. "Combination of the therapy of the anticoagulants and Tivortin in patients with cardiac ishemia at COVID-19." Infusion & Chemotherapy, no. 3.1 (October 11, 2020): 91. http://dx.doi.org/10.32902/2663-0338-2020-3.1-76.
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Background. Аn L-arginine is a conditionally essential amino acid. The daily average requirement is 4.2 mg. The L-arginine exhibits angioprotective properties, regulates proliferation and apoptosis, oxidative processes, blocks platelet aggregation and has a fibrinolytic effect ‒ antithrombotic (prevents the adhesion of circulating platelets and leukocytes) for anti-inflammatory effects. The likelihood of developing thrombotic complications in all patients with COVID-19 is very high, such patients are recommended to double dosage of anticoagulants.
Objective. To study the combination of the anticoagulant therapy and the drug Tivortin in patients with coronary artery disease with COVID-19.
Materials and methods. 28 patients with the cardiac ischemia of the exertion stenocardia functional class II-III with COVID-19 were examined. The patients were divided into the main and control groups. One of the groups, in addition to the anticoagulant therapy Clexan 2 times 0.6 mg, have taken the drug Tivortin, manufactured by “Yuria-Pharm” (Ukraine), containing L-arginine (4.2 mg).
Results. The therapy with the use of the nitrate oxide donors in combination with the anticoagulants in the main group showed an increase in exercise tolerance, in the SpO2 level, i.e., a decrease in hypoxia in the main group compared with the control group.
Conclusions. The addition of Tivortin to the therapy of anticoagulants that inhibit the activity of the blood coagulation system may increase the chances of survival of patients hospitalized with COVID-19.
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Fareed, Jawed, Michael J. Moorman, Walter Jeske, and Debra Hoppensteadt. "Defibrotide Interaction With Newer Oral Anticoagulant and Antiplatelet Drugs." Blood 122, no. 21 (November 15, 2013): 4804. http://dx.doi.org/10.1182/blood.v122.21.4804.4804.
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Introduction Defibrotide represents a single stranded mammalian DNA derived agent originally developed for anti-thrombotic and anti-ischemic indications. Defibrotide is currently used to treat or prevent failure of normal blood flow (Veno-occlusive disease, VOD) in the liver of patients who had bone marrow transplants or received drugs such as oral estrogens and mercatopurine. Defibrotide is a polypharmocologic agent with multiple sites of actions, which include anti-inflammatory and vaso-facilitatory effects. The purpose of this investigation is to determine potential interactions of defibrotide and some of the newer oral anticoagulant drugs, such as dabigatran, apixaban and rivaroxaban and antiplatelet drugs such as ticagrelor. Materials & Methods Defibrotide (lot no. DV0601) was obtained in powder form from Gentium s.p.A (Villa Guardia, Italy). The active form of dabigatran was purchased from Selleckcham (Houston, TX). Apixaban and rivaroxaban were obtained commercially and were of synthetic origin. The effect of defibrotide on dabigatran, apixaban, rivaroxaban and ticagrelor, on agonists (epinephrine, ADP, collagen, arachidonic acid and 2.5U thrombin) was measured using platelet aggregation techniques. The platelet rich plasma collected from normal healthy donors (n=15) were also supplemented with each of the individual anticoagulant drugs, alone in a range of 0-1000 ng/ml and in combination with defibrotide at 50-250ug/ml. Such clotting times as the PT, aPTT and Heptest and thrombin generation studies were carried out. In addition, whole blood activated clotting time (celite) studies were carried out by supplementing each of the individual oral anticoagulant agents at 1ug/ml, alone and with defibrotide at 100ug/ml. Results Neither defibrotide nor the newer anticoagulants and ticagrelor produced any effects on the epinephrine, ADP, collagen and arachidonic acid induced aggregation of PRP (p>0.05). However, dabigatran at concentrations of >62.5ng/ml produced inhibition of thrombin induced aggregation, all of the other agents did not have any effect on thrombin. Defibrotide at a concentration 100 ug/ml did not alter the aggregation profile in anticoagulant supplemented PRP. In both the plasma and whole blood anticoagulant assays, dabigatran produced stronger anticoagulant effects (306+30sec) than both apixaban (145+12sec) and rivaroxaban(160+15sec). Defibrotide exhibited minimal effects (135+10sec). Ticagrelor did not have any anticoagulant effect. Defibrotide in combination with dabigatran produced modest augmentation of the anticoagulant responses (360+42sec), however, it had much weaker effects on rivaroxaban (168+18sec) and apixaban(152+14sec). All of the anticoagulants in the TGA produced varying degrees of inhibition of thrombin generation in the following order; dabigatran > rivaroxaban > apixaban. Ticagrelor did not produce any inhibition of thrombin generation. Defibrotide did not produce any effects on TGA at concentrations up to 100ug/ml. When combined with oral anticoagulants, it did not show any augmentation of rivaroxaban and apixaban; however, it enhanced dabigatrans inhibitory effects. Conclusions These results suggest that defibrotide itself has weak or negligible anticoagulant effects in the plasma and whole blood assays. All of the new oral anticoagulants produced varying degrees of assay dependent anticoagulant effects in plasma and whole blood systems. However defibrotide did not show any interactions with apixaban and rivaroxaban, it showed some augmentation of the anticoagulant responses of dabigatran. Ticagrelor did not exhibit any interactions with defibrotide. These studies demonstrate that unlike heparins, defibrotide exhibits minimal interactions with newer oral anticoagulant and antiplatelet drugs. Disclosures: No relevant conflicts of interest to declare.
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Walenga, Jeanine M., Margaret Prechel, Debra Hoppensteadt, Vicki Escalante, Talhah Chaudhry, Walter Jeske, and Mamdouh Bakhos. "Validation of the Use of Apixaban As an Alternate Anticoagulant for the Management of Patients with Heparin-Induced Thrombocytopenia." Blood 120, no. 21 (November 16, 2012): 2265. http://dx.doi.org/10.1182/blood.v120.21.2265.2265.
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Abstract Abstract 2265 Background: Heparin-induced thrombocytopenia (HIT), an immune mediated disorder due to antibodies generated against platelet factor 4 (PF4) complexed with heparin, is associated with a pronounced hypercoagulable state, thrombin generation, endothelial cell damage, and upregulation of an inflammatory state. Alternative anticoagulants that do not interact with HIT antibodies are needed for the anticoagulant management of these heparin compromised patients. Intravenous use direct thrombin inhibitors (DTIs) such as argatroban and lepirudin became the first effective non-heparin anticoagulant drug treatments for patients with HIT. Although DTIs are effective, their use is associated with a bleeding risk and drug-specific limitations. For the long-term anticoagulation, patients are switched from the intravenous DTI to oral warfarin. Aside from the unpredictable pharmacokinetics and need for routine monitoring, the slow onset of action and potential to precipitate venous limb gangrene/skin necrosis due to inhibition of protein C are concerning aspects of warfarin treatment of patients with HIT. Apixaban is a new small molecule, direct acting oral FXa inhibitor that may be considered for the anticoagulant management of patients with HIT. Methods: In order to determine if there is a lack of functional platelet activation and platelet aggregation for apixaban in the presence of HIT antibodies, the two traditional and widely used clinical laboratory tests for the diagnosis of HIT were utilized: the gold standard 14C-Serotonin Release Assay (14C-SRA; using washed platelets) and the heparin-induced platelet aggregation assay (PA-HIT; using platelet rich plasma). Based on different methodologies, these assays have different specificities and sensitivities to HIT antibodies and provide different yet complimentary information. This study employed HIT antibodies from multiple patients and platelets from different donors to assure the robustness of the data outcome. The response to apixaban concentrations covering the clinical dose range (0.05 to 50 mg/mL) was compared to the response obtained with clinically relevant concentrations of unfractionated heparin (UFH; 0.1 and 100 U/mL). Results: In the 14C-SRA (n=35) and in the PA-HIT (n=37), only baseline negative platelet activation and aggregation responses with all of the HIT specimens were observed at all apixaban concentrations (average across all concentrations: 11 ± 4 % serotonin release and 8 ± 3 % aggregation, respectively; mean ± SEM; positive responses are >20%). In comparison, UFH gave strong positive responses to each of the same HIT antibody specimen/platelet donor combinations (82 ± 3 % release and 78 ± 6 % aggregation at 0.1 U/mL; p<0.01 vs apixaban). Comparative studies demonstrated strong responses for enoxaparin (n=10; 73 ± 5 % release and 62 ± 7 % aggregation at 10 mg/mL) equal to UFH and no positive response for fondaparinux (n=20) in both test systems. Conclusions: This study confirms a consistent absence of platelet activation and platelet aggregation with apixaban in the presence of HIT antibodies across a wide range of concentrations. Based on the inert response of apixaban in these in vitro studies and because it is structurally unrelated to heparin, apixaban is not expected to contribute to the propagation of the HIT syndrome and could potentially be used for the anticoagulant management of patients with HIT. Since apixaban is a potent inhibitor of thrombin generation it is expected to have an additional benefit in blunting the hypercoagulable state which is observed in the HIT syndrome. Apixaban may provide an option for oral anticoagulation in patients with HIT both for in-hospital and out-patient settings, for the extended management of heparin compromised patients, and for the prevention of HIT. Clinical trials to determine dosing regimens that provide safe and effective anticoagulation during the various clinical phases of HIT are warranted. Disclosures: Walenga: Bristol-Myer Squibb: Research Funding. Prechel:Bristol-Myer Suibb: Research Funding. Hoppensteadt:Bristol-Myer Squibb: Research Funding. Escalante:Bristol-Myer Squibb: Research Funding. Chaudhry:Bristol-Myer Squibb: Research Funding. Jeske:Bristol-Myer Squibb: Research Funding. Bakhos:Bristol-Myer Squibb: Research Funding.
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Meissner, M. H. "Indications for platelet aggregation inhibitors after venous stents." Phlebology: The Journal of Venous Disease 28, no. 1_suppl (March 2013): 91–98. http://dx.doi.org/10.1177/0268355513476828.
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Iliofemoral venous obstruction may arise from either primary compressive lesions or may be secondary to an episode of deep venous thrombosis. Regardless of aetiology, these lesions, either alone or in association with more distal reflux, may be responsible for lower extremity pain, swelling, and ulceration. Conventional surgical procedures for the treatment of iliofemoral venous obstruction have largely been supplanted by endovascular approaches relying on the deployment of venous stents. Large series have reported good technical and clinical results from venous stenting, particularly for primary lesions. However, early stent occlusions and late re-stenosis do occur. Although most of these appear related to technical factors, there is likely a role for pharmacological adjuncts in maintaining stent patency. The use of anticoagulants and antiplatelet agents is largely based on the underlying pathophysiology and extrapolation from arterial interventions, which likely are significantly different with respect to their pathophysiology and natural history. Although lacking substantial evidence demonstrating efficacy, the use of adjunctive antiplatelet agents in stents placed for primary lesions and consideration of anticoagulation for high-risk post-thrombotic lesions appears to be reasonable.
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Dwyer, Scott D., and Kenneth M. Meyers. "Anesthetics and anticoagulants used in the preparation of rat platelet-rich-plasma alter rat platelet aggregation." Thrombosis Research 42, no. 2 (April 1986): 139–51. http://dx.doi.org/10.1016/0049-3848(86)90290-2.
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Kozek-Langenecker, S. "Modern anaesthetic techniques and anticoagulation." Hämostaseologie 26, S 02 (2006): S40—S49. http://dx.doi.org/10.1055/s-0037-1617081.
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SummaryThe many possibilities for anticoagulant pharmacotherapy are constantly increasing. Anaesthetists and pain therapists are confronted with patients being treated with highly effective anticoagulants and/or platelet aggregation inhibitors for coronary heart disease, stroke or peripheral arterial occlusive disease. These patients in particular benefit from neuraxial blockade when undergoing cardiac surgery, revascularisation procedures or amputation. The anaesthetist needs to be familiar with the pharmacology, indications, and adverse effects of the various anti- and procoagulant substances, and to integrate this knowledge into the management concept to prevent haemorrhagic complications.This review presents the basics of coagulation, sites of action of currently-used anticoagulants, and the Austrian standards for performing modern central and peripheral nerve blocks in patients on antithrombotic medication. Preoperative assessment of existing anticoagulant therapy is also very important in general anaesthesia, as this can be used to determine the appropriate procedures for perioperative coagulation management. In order to prevent bleeding complications in patients on antithrombotic therapy, the following questions are addressed and appropriate recommendations given: intervals between administering anticoagulant agents and puncture/removal of catheters or a general anaesthesia and surgery; the choice of local or regional anaesthetic method and of intraoperative coagulation analysis; reversal of anticoagulation in acute situations.
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Sahay, Tannu, Haroon Faraz, Andrea S. Haggood, Maggie Jones, and Judith C. Andersen. "“Sticky Platelet Syndrome”: In Vitro Response to Small Dose Aspirin Is Reflected in Clinical Benefit." Blood 110, no. 11 (November 16, 2007): 3212. http://dx.doi.org/10.1182/blood.v110.11.3212.3212.
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Abstract Introduction: “Sticky Platelet Syndrome” (SPS), a consistently demonstrable platelet aggregability to subthreshold concentrations of epinephrine and/or adenosine dinucleotide phosphate (ADP), is an autosomal dominant condition with thrombotic consequences (Mammen, 1984). Because published studies regarding SPS are few and platelet function testing unusual in thrombophilia evaluation, SPS may be an under-recognized contributor to arterial and venous thrombosis. The precise pathogenesis of SPS is undefined, but prior observations have suggested that small-dose aspirin may be useful in modulating increased aggregability and preventing recurrent thrombosis. Methods: Laboratory and clinical response to aspirin in patients with SPS was determined by retrospective review of a large university thrombophilia clinic database in which platelet function was a routine component of extensive thrombophilia testing. As previously reported, SPS was diagnosed by demonstration of aggregation amplitude of 50% or more with epinephrine and/or ADP concentrations 20-fold lower than routine activation thresholds on two separate occasions at least 2 weeks apart. Records of individuals exhibiting SPS prescribed antiplatelet therapy for whom follow-up laboratory and clinical data were available were analyzed for modulation of aggregation abnormality and clinical outcome. Laboratory response to anti-platelet therapy was defined as return of function to laboratory “normal” or “decreased” function on testing >2 weeks following initiation of therapy. Platelet function and clinical outcomes were followed for 6 months to 13 years. Results: Of 149 patients with treated SPS, 97 (65%) had one or more thrombotic events prior to presentation 42/149 (28%) despite warfarin or low molecular weight heparin therapy. Of 149, 53% had venous, 35% arterial, 5% both arterial and venous events; 7% had recurrent fetal loss. 52/149 (35%) were individuals evaluated for primary family relationship to an SPS patient. 25 (16.7%) patients had SPS as a solitary risk factor. 147/149 patients (98.6%) demonstrated reversal of hyperfunction, 108/147 (73%) with aspirin (81mg/day); all responders normalized with </= 325 mg aspirin daily and experienced no significant side-effects. Aspirin was used in 56% of patients as a sole anti-thrombotic agent, in 27% with anticoagulants (warfarin or a parenteral agent), in 10% with other anti-platelet agent(s), in 2% with anticoagulant and anti-platelet agent(s). 4% of patients received no aspirin because of allergy. Of those demonstrating response, 7 patients (4.8%) had a further thrombotic event. Of these, 2 patients received clopidogrel alone due to aspirin allergy and 5 patients received aspirin plus anticoagulants at “therapeutic” levels; all had multiple thrombotic risk factors. Conclusions: Aspirin, in minimal, inexpensive, well-tolerated doses, “normalized” in vitro platelet function in SPS patients and prevented thrombosis recurrence in most, many of whom had experienced rethrombosis on anticoagulants alone. Because undiagnosed platelet hyperfunction (identified in 1/3 of patients evaluated at a large urban university center: Faraz et al., 2007) may predispose to rethrombosis and classical anticoagulants alone do not abrogate thrombogenic potential in pateints with SPS, platelet function testing deserves a place in thrombophilia evaluation - and may be of greater utility than the currently performed “thrombophilia panels.”
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Husted, Steen, Lars Wallentin, Felicita Andreotti, Harald Arnesen, Fedor Bachmann, Colin Baigent, Kurt Huber, et al. "General mechanisms of coagulation and targets of anticoagulants (Section I)." Thrombosis and Haemostasis 109, no. 04 (2013): 569–79. http://dx.doi.org/10.1160/th12-10-0772.
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SummaryContrary to previous models based on plasma, coagulation processes are currently believed to be mostly cell surface-based, including three overlapping phases: initiation, when tissue factor-expressing cells and microparticles are exposed to plasma; amplification, whereby small amounts of thrombin induce platelet activation and aggregation, and promote activation of factors (F)V, FVIII and FXI on platelet surfaces; and propagation, in which the Xase (tenase) and prothrombinase complexes are formed, producing a burst of thrombin and the cleavage of fibrinogen to fibrin. Thrombin exerts a number of additional biological actions, including platelet activation, amplification and self-inhibition of coagulation, clot stabilisation and anti-fibrinolysis, in processes occurring in the proximity of vessel injury, tightly regulated by a series of inhibitory mechanisms. ″Classical″ anticoagulants, including heparin and vitamin K antagonists, typically target multiple coagulation steps. A number of new anticoagulants, already developed or under development, target specific steps in the process, inhibiting a single coagulation factor or mimicking natural coagulation inhibitors.
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Sayani, Shermin, Omer Iqbal, Debra Hoppensteadt, and Jawed Fareed. "Drug Interactions of Newer Oral Anticoagulants Dabigatran, Rivaroxaban, and Apixaban with Routinely Used Nonanticoagulant/Antiplatelet Drugs." Blood 124, no. 21 (December 6, 2014): 4267. http://dx.doi.org/10.1182/blood.v124.21.4267.4267.
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Abstract Introduction: The newer non-vitamin K antagonist oral anticoagulant drugs (NOACs) such as dabigatran, apixaban and rivaroxaban are now commonly used for various indications in a large group of patients who are simultaneously managed with several other routinely used drugs. Given the lack of available information on the interaction of newer oral anticoagulant drugs (NOACs) with commonly used non-anticoagulants / anti-platelet drugs, it is important to recognize the impact of these interactions on the safety and efficacy of these agents. We hypothesized that some of the commonly used drugs may modulate the anticoagulant effects of NOACs. This study aims to determine the antiplatelet, anticoagulant, and bleeding effects of the NOACs at varying concentrations with and without routinely used drugs both in the in vivo and in vitro systems. Materials and Methods:Dabigatran (Boehringer Ingelheim, Ridgefield, CT), rivaroxaban (Janssen Pharmaceuticals, Inc., Titusville, NJ), and apixaban (Bristol-Myers Squibb Company, Princeton, NJ and Pfizer Inc., New York, NY); and such routinely used drugs as alendronate sodium, chondroitin sulfate, hydrocodone-acetaminophen, klonopin, penicillin, tacrolimus, tramadol chlorhydrate, and tranexamic acid were commercially obtained and supplemented in citrated plasma at projected therapeutic ranges. Such tests as PT, APTT, dRVVT, TT, Heptest, and Anti- Xa and anti-IIa tests were performed. Agonist induced platelet aggregation studies using ADP, AA, Collagen, Epinephrine, and Thrombin agonists were performed on the Platelet Aggregation Profiler- 8 (PAP-8) (Biodata corporation, Horsham, PA) with dabigatran, apixaban and rivaroxaban alone and with the routinely used drugs. For the in-vivo bleeding studies a model of rat tail transection was used, following ketamine and xylazine anesthesia, 6-8 weeks old male Sprague-Dawley rats weighing 250-300g (n=15) were used to perform the rat tail transection bleeding time using dabigatran alone and dabigatran followed by tranexamic acid. Blood was drawn by cardiac puncture for ex vivo analysis. The collected data from the bleeding and ex vivo studies were tabulated and statistically analyzed using ANOVA. Results: In the in vitro studies, all of the NOACs produced assay dependant anticoagulant and antiprotease effects. Rivaroxaban and apixaban did not exhibit any interactions at the projected therapeutic dosage range when combined with any of the routinely used drugs. However dabigatran at a fixed concentration of 1 µg/ml combined with the commonly used drugs at a fixed concentration of 0.1 µg /ml or 1 µg/ml produced augmented assay-dependent anticoagulant and antiprotease activity. The most pronounced interaction was noticed with tacrolimus (111% difference in PT, 231% difference in APTT, and 46% difference in anti-IIa assay), followed by tramadol (57% difference in PT and 54% difference in Anti-IIa assay). Platelet Aggregation studies revealed no modulation of antiplatelet effects (<10%) with the addition of the commonly used drugs and the NOACs. In the rat tail transection bleeding model, there was a significant difference (p=0.03, α=0.05) between the bleeding time with dabigatran (100 µg/kg) alone (13.1 ±1.5 minutes) intravenously compared to dabigatran with tranexamic acid (10 mg/kg) (10.3 ±1.8 minutes) in each study. Ex-vivo analysis showed a reduction in PT and Heptest assay responses with dabigatran and tranexamic acid by 38% and 80%, respectively, and minimal change (5%) in APTT. Conclusion: In contrast to rivaroxban and apixaban in vitro, dabigatran exhibited stronger interactions with the commonly used drugs and variable assay dependent augmentation of anticoagulant and antiprotease responses. Tacrolimus and tramadol showed the strongest interactions. Agonist induced platelet aggregation studies did not show any interactions. Interestingly, tranexamic acid reduced the anticoagulant effect of dabigatran in the in vivo and ex vivo studies. These results warrant a review of post-marketing surveillance on the reported bleeding in patients concomitantly treated with NOACs and the reported routinely used drugs. Furthermore, these observations underscore the need to screen other commonly used drugs and supplements for their potential interactions with NOACs. Disclosures No relevant conflicts of interest to declare.
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Qi, Ruomei, Yutaka Yatomi, and Yukio Ozaki. "Effects of Incubation Time, Temperature, and Anticoagulants on Platelet Aggregation in Whole Blood." Thrombosis Research 101, no. 3 (February 2001): 139–44. http://dx.doi.org/10.1016/s0049-3848(00)00408-4.
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Vootukuri, Spandana, Jihong Li, Mark Nedelman, Craig Thomas, Jiang-Kang Jiang, Mariana Babayeva, and Barry S. Coller. "Preclinical studies of RUC-4, a novel platelet αIIbβ3 antagonist, in non-human primates and with human platelets." Journal of Clinical and Translational Science 3, no. 2-3 (June 2019): 65–74. http://dx.doi.org/10.1017/cts.2019.382.
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AbstractIntroduction:We are developing the novel αIIbβ3 antagonist, RUC-4, for subcutaneously (SC)-administered first-point-of-medical-contact treatment for ST segment elevation myocardial infarction (STEMI).Methods:We studied the (1) pharmacokinetics (PK) of RUC-4 at 1.0, 1.93, and 3.86 mg/kg intravenous (IV), intramuscular (IM), and SC in non-human primates (NHPs); (2) impact of aspirin on RUC-4 IC50in human platelet-rich plasma (PRP); (3) effect of different anticoagulants on the RUC-4 IC50in human PRP; and (4) relationship between αIIbβ3 receptor blockade by RUC-4 and inhibition of ADP-induced platelet aggregation.Results:(1) All doses of RUC-4 were well tolerated, but animals demonstrated variable temporary bruising. IM and SC RUC-4 reached dose-dependent peak levels within 5–15 minutes, with T1/2s between 0.28 and 0.56 hours. Platelet aggregation studies in NHPs receiving IM RUC-4 demonstrated >80% inhibition of the initial slope of ADP-induced aggregation with all three doses 30 minutes post-dosing, with subsequent dose-dependent loss of inhibition over 4–5 hours. (2) The RUC-4 IC50for ADP-induced platelet aggregation was unaffected by aspirin treatment (40±9 nM vs 37±5 nM;p= 0.39). (3) The RUC-4 IC50was significantly higher in PRP prepared from D-phenylalanyl-prolyl-arginyl chloromethyl ketone (PPACK)-anticoagulated blood compared to citrate-anticoagulated blood using either thrombin receptor activating peptide (TRAP) (122±17 vs 66±25 nM;p= 0.05;n= 4) or ADP (102±22 vs 54±13;p<0.001;n= 5). (4) There was a close correspondence between receptor blockade and inhibition of ADP-induced platelet aggregation, with aggregation inhibition beginning with ~40% receptor blockade and becoming nearly complete at >80% receptor blockade.Discussion:Based on these results and others, RUC-4 has now progressed to formal preclinical toxicology studies.
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Falcon, Cristina R., Marco Cattaneo, Alberto Ghidoni, and Pier Mannuccio Mannucci. "The In Vitro Production of Thromboxane B2 by Platelets of Diabetic Patients Is Normal at Physiological Concentrations of lonized Calcium." Thrombosis and Haemostasis 70, no. 03 (1993): 389–92. http://dx.doi.org/10.1055/s-0038-1649591.
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SummaryPlatelets of patients with diabetes and no evidence of macroangiopathy produce normal amounts of thromboxane (Tx) B2 in vivo, whereas they usually show increased production in vitro. Since in vitro studies have been usually performed in citrated PRP, we tested the hypothesis that the discrepancy between in vivo and in vitro studies is due to the low concentration of plasma ionized calcium ([Ca 2+ ]o) that is present in citrated PRP. In fact, low [Ca 2+ ]o artifactually potentiates the platelet TxB2 production in vitro. Forty patients with diabetes mellitus and 37 matched Controls were studied. Blood was anticoagulated with citrate, the thrombin inhibitor D-phenylalanyl-l-prolyl-l-chloromethylketone (PPACK) or both anticoagulants. Platelet aggregation, release of 14C-serotonin and TxB2 production were induced in platelet rieh plasma (PRP) by several agonists. The following results were obtained: i) Citrated PRP: Arachidonic acid induced aggregation (p <0.01) and TxB2 production (p <0.02) were significantly greater in patients than in Controls. No statistically significant differences were found with other agonists. ii) PPACK PRP: No statistically significant difference was found between diabetic platelets and Controls, iii) PPACK plus citrate PRP: The results were not different from those obtained with citrate alone. Therefore, our results show that diabetic platelets produce normal amounts of TxB2 in vitro when the [Ca2+]o is physiological.
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Iqbal, Omer, George Plamoottil, Nasir Sadeghi, Debra Hoppensteadt, and Jawed Fareed. "Oversulfated Chondroitin Sulfate Does Not Cause Augmentation in HIT Antibody Mediated Heparin-Induced Platelet Aggregation (HIPA)." Blood 114, no. 22 (November 20, 2009): 2417. http://dx.doi.org/10.1182/blood.v114.22.2417.2417.
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Abstract Abstract 2417 Poster Board II-394 Heparin is one of the widely used anticoagulants for the prophylaxis and treatment of thrombotic disorders. Heparin, a linear polysaccharide belonging to a family of glycosaminoglycans (GAGS) consists of repeating disaccharide units of 1-4 linked iduronic acid and glucosamine residues. Heparin is a mixture of low, medium and high molecular fractions and is heterogeneous not only in terms of molecular weight but also sites and degree of sulfation. Oversulfated chondroitin sulfate, one of the important toxic contaminants in certain batches of heparins manufactured during 2007 to 2008 resulted in deaths of some patients following intravenous administration that led to the recall of these heparins by the FDA. An increased incidence of heparin-induced thrombocytopenia (HIT) and thrombosis syndrome (HITTS) was reported as a result of contaminated heparins. It was hypothesized that OSCS interacts with heparins and other LMWHs increasing their HIT/HITTS potential. In order to validate this hypothesis blood was drawn from healthy volunteers (n=5) and mixed with 3.2% sodium citrate solution (9 parts of whole blood to 1 part of citrate). The citrated blood samples were centrifuged at 800 rpm to obtain platelet rich plasma (PRP) and further centrifuged at 3000 rpm to obtain platelet poor plasma (PPP). Apheresis fluid was collected from confirmed cases of HIT and pooled. The platelet aggregometers (Biodata) were blanked with individual PPP. The PRP (300ml) was mixed with HIT positive pooled apheresis fluid (200ml) and platelet aggregation was recorded using Gentium Heparin, Enoxaparin, and Bemiparin at a final concentration of 10mg/ml, either alone or in mixtures of 10%, 20% and 30% OSCS. The Heparin-induced platelet aggregations (HIPA) were run for a period of 30 minutes and the tracings obtained. While OSCS alone at a final concentration of 10 mg/ml caused an average of 29.5% platelet aggregation, it did not cause an augmentation of platelet aggregation in 10%, 20% and 30% mixtures with Heparin, Enoxaparin, Bemiparin and AVE 5026 (see table). This data suggests that drugs like heparin, and low molecular weight heparins such as Enoxaparin, and Bemiparin did not augment HIT/HITTS response when combined in various proportions with OSCS. Based on HIPA the reported increase in HIT response may therefore be due to in vivo interactions of the OSCS with platelets and endothelial cells. Corroborative evidence from clinical studies are warranted to validate these preliminary results. Disclosures: No relevant conflicts of interest to declare.
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Mongan, John P., Hanna Mieszczanska, Richard P. Phipps, and Charles W. Francis. "Pioglitazone Inhibits Platelet Function and Potentiates the Effects of Aspirin." Blood 118, no. 21 (November 18, 2011): 1228. http://dx.doi.org/10.1182/blood.v118.21.1228.1228.
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Abstract Abstract 1228 BACKGROUND: Thiazolidinediones (TZDs) are agonists of PPARγ which favorably modify metabolic parameters and markers of atherosclerosis among type 2 diabetics. Enucleate platelets express PPARγ protein, and PPARγ agonists blunt release of CD40L and thromboxane B2 (TXB2) from thrombin-activated platelets. (Abbiyik, F et al, Human bone marrow megakaryocytes and platelets express PPARγ and PPARγ agonists blunt platelet release of CD40 ligand and thromboxanes. Blood, 2004 104(5):p.1361–8.) Diabetic subjects disproportionately experience arterial thromboses despite aspirin therapy. We assessed platelet function after pioglitazone in two risk groups in the presence and absence of aspirin to characterize its range of antiplatelet effect. SUBJECTS: 20 diabetic and 20 non-diabetic subjects were enrolled in a prospective study. Exclusion criteria among all subjects included current use of antiplatelet, anticoagulants, or pioglitazone, bleeding disorder, renal or liver disease, congestive heart failure, pregnancy or hypersensitivity to aspirin or pioglitazone. Non-diabetic subjects were excluded for BMI > 30 kg/m2, cardiovascular disease or risk factors. All subjects previously on aspirin underwent a 7 day minimum “wash-out” period. METHODS: Four separate blood samples from each subject were collected on 2 separate days separated by a 7 day interval. On day 1, a baseline blood sample was obtained followed by a second blood sample 3 hours after ingestion of 30 mg pioglitazone. Subjects returned 1 week later after having taken a single 81 mg aspirin 2–3 hours before arrival. Samples 3 and 4 were collected in the same manner as during week 1. Platelet rich plasma (PRP) was immediately prepared and platelet aggregation performed by the turbidometric method of Born with simultaneous measurement of ATP release. ADP (5M and 10M), arachidonic acid (0.5mM) and collagen (2g/mL) were used as agonists. PRP was activated with 0.8 unit/ mL thrombin for subsequent ELISA assays of TXB2 (Thromboxane B2), TGF-β (Transforming Growth Factor-Beta) and CD40L (CD 40 Ligand). RESULTS: By Diabetic Status: a.) Baseline platelet aggregations, ATP release and ELISAs were similar between diabetic and non-diabetic subjects, with the exception of platelet aggregation using 5 uM and 10uM as agonist. b.) Mean maximum platelet aggregation after aspirin alone was 20% higher among diabetic subjects. lp;&0.5qAmong all Subjects: a.) Mean TXB2 release among all subjects was reduced from a baseline of 42,075 ± 4,479 pg/ml to 32,719 ± 3,589pg/ml after pioglitazone alone (p = 0.0004). b.) Mean TXB2 release after aspirin alone was 20,829 ± 2,753 pg/ml which was reduced to 9,569 ± 1,653 pg/ml after the addition of pioglitazone (p = 0.0001). (Figure 1) c.) Twenty-five of 40 subjects (63%) had aggregation of greater than 20% using arachidonic acid as agonist despite ingestion of 81 mg aspirin. This decreased to 11 /40 (28%) after the administration of 30 mg of pioglitazone (p < 0.0001). (Figure 2) No significant effects were observed on release of CD40L or TGFβ. Conclusion: Pioglitazone has a direct platelet stabilizing effect and potentiates the effect of aspirin irrespective of underlying cardiovascular risk. Disclosures: Francis: Takeda Pharmaceuticals North America, Inc.: Research Funding.
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Vander, J. F. "Central and Hemicentral Retinal Vein Occlusion: Role of Anti–Platelet Aggregation Agents and Anticoagulants." Yearbook of Ophthalmology 2012 (January 2012): 130–31. http://dx.doi.org/10.1016/j.yoph.2011.12.006.
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L. Venkatraman, Kalkooru, Azeemullah A. Syed, Parimelazhagan Indumathi, and Alka Mehta. "VITPOR AI, A Coagulation Factor XIIa Inhibitor from Porphyra yezoensis: In Vivo Mode of Action and Assessment of Platelet Function Analysis." Protein & Peptide Letters 27, no. 3 (February 10, 2020): 243–50. http://dx.doi.org/10.2174/0929866526666191026111056.
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Background: Thrombosis represents as the prime contributor to the burden of diseases, worldwide. Conventional anticoagulants for thrombosis therapy have a common bleeding side effect. Bioactive peptides are studied to be an effective alternative for currently available therapeutic drugs. Objective: In this study, VITPOR AI peptide, a previously reported coagulation FXIIa inhibitor from Nori (Porphyra yezoensis), was assessed for its inhibitory activity against FXIIa and its in vivo mode of action. Methods: In vivo efficacy as well as the antithrombotic property of the peptide was evaluated in mice model by ex vivo activated Partial Thromboplastin Time assay, tail transection model and whole blood clotting time. The enzyme kinetics was studied using chromogenic substrate assay. Results: The kinetic behaviour of VITPOR AI showed that the peptide is a competitive inhibitor of FXIIa. Peptide showed significant inhibition of platelet adhesion and aggregation. VITPOR AI exhibited significant antithrombotic activity. Furthermore, ex vivo activated Partial Thromboplastin Time assay revealed that VITPOR AI exhibited potent anticoagulant activity in vivo. Tail bleeding assay revealed that the peptide did not prolong bleeding time in mice even at a higher dose of 5 mg/kg. Cytotoxicity studies of the peptide against human blood leukocytes indicated the safety of the peptide. Conclusion: VITPOR AI could be prospected as a potent anticoagulant with Factor XIIa inhibition, antiplatelet aggregation and antithrombotic activity. It was also studied to have no bleeding side effect.
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Piper, John T., and Jaroslav G. Vostal. "A Novel Animal Model for Detecting Damage to Human Platelet Transfusion Products: In Vivo Recovery and Survival in Severe Combined Immunodeficient Mice." Blood 106, no. 11 (November 16, 2005): 1891. http://dx.doi.org/10.1182/blood.v106.11.1891.1891.
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Abstract Clinical performance of platelet products processed or stored under novel conditions is difficult to predict based on in vitro studies alone. Evaluation of such products involves determination of recovery and survival of radiolabeled platelets in human volunteers as a surrogate endpoint for platelet efficacy. Such human studies pose some risk to volunteers, are a financial burden on the sponsor, and stifle innovation in the development of platelet products. The development of an animal model for evaluating human platelets has been limited by rapid, immunemediated clearance of human cells. In the current studies, severe combined immunodeficient (SCID) mice were used to circumvent the need to block the reticuloendothelial system and prolong circulation of human cells. Human platelets were infused via tail vein into normal and SCID mice, and the recoveries and survival times compared. Mouse whole blood was collected at various time points post-infusion, and human platelets were detected by flow cytometry using an anti-human CD41 monoclonal antibody. Recovery was defined as percent human platelets in circulation relative to time zero, and survival time in circulation as the t1/2 of the human platelets. Recoveries and survival times were different between normal and SCID mice, with a maximal difference in recovery of 60.3% at 4 hours post-infusion (normal recovery, 11.1 ± 9.1%; SCID recovery, 71.4 ± 8.8%), and survival times of 1.4 ± 0.4 hours and 10.7 ± 2.3 hours in normal and SCID mice, respectively (N=3). Chemically treated and aged platelets were used to evaluate the ability of the model to detect differences in control and damaged platelets. Chemical damage was induced by carbonyl cyanide 3-chlorophenylhydrazone (CCCP), a mitochondrial uncoupler which mimics the platelet storage lesion. Platelets were exposed to 10 μM CCCP in methanol, control platelets were exposed to an equal volume of methanol (N=3). CCCP treatment of platelets decreased agonist-induced aggregation (Control aggregation, 73.3 ± 6.8%; CCCP-treated platelet aggregation, 13.8 ± 5.3%). Recovery of control and CCCP-treated platelets were 31.5 ± 16.9% and 7.9 ± 5.1%, respectively, at 4-hours post-infusion. Survival times were 1.3 hours for control and 1.9 hours for CCCP-treated platelets. For storage studies, in vitro cell quality parameters were evaluated in three products, and each product was infused into 3 animals on Day 1 and 3 different animals on Day 7. In Day 7 platelets, in vitro platelet parameters were decreased compared to Day 1. Platelet counts decreased an average of 22.8% ± 2.2% between Day 1 and Day 7. pH decreased from 6.7 ± 0.1 at Day 1 to 5.8 ± 0.1 at Day 7. All platelet products had visible swirl on Day 1 and no swirl on Day 7. Platelets stored for 7 days showed decreased recovery over Day 1 platelets at 4 hours post-infusion (Day 1, 66.9 ± 12.8%; Day 7, 0.2 ± 0.08%). The SCID mouse may be a useful model for evaluating the impact of new technologies (apheresis devices, anticoagulants, storage containers, pathogen inactivation systems) on the in vivo efficacy of human platelets. In two different models of platelet damage (chemical and storage induced damage), this model can distinguish between normal and damaged platelets. Recovery of Infused Day 1 and Day 7 Human Platelets in SCID Mice Recovery of Infused Day 1 and Day 7 Human Platelets in SCID Mice
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Papadaki, S., and A. D. Tselepis. "The effect of direct oral anticoagulants on platelet aggregation induced by factor Xa and thrombin." Atherosclerosis 315 (December 2020): e84. http://dx.doi.org/10.1016/j.atherosclerosis.2020.10.256.
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Mullier, François, Severine Robert, Philippe Devel, Lutfiye Alpan, Nicolas Lufin, Bernard Chatelain, and Jean-Michel Dogné. "Pharmacological Study of Antimyeloma Agents on Hemostasis." Blood 116, no. 21 (November 19, 2010): 3175. http://dx.doi.org/10.1182/blood.v116.21.3175.3175.
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Abstract Abstract 3175 Introduction: Patients with multiple myeloma (MM) have an increasing risk of developing venous thromboembolism (VTE). The use of thalidomide or lenalidomide, two antimyeloma agents has been associated with an increased risk of VTE especially when associated with dexamethasone or melphalan-prednisone. This increased risk in less pronounced with the proteasome inhibitor bortezomib. The pharmacological effects of thalidomide, lenalidomide and bortezomib have never been studied on platelet aggregation or coagulation. These preliminary data are necessary to understand the differential effects of these drugs on thrombotic events. Aims: The aim of our study is to investigate the pharmacological effects of these drugs on primary hemostasis by light transmission agregometry (LTA) and on secondary hemostasis using thrombin generation test (TGT). Methods: LTA was performed with a Chrono-Log aggregometer (Kordia). Platelet-rich plasma (PRP) of healthy blood donors (n=3 to 10) was adjusted to 300,000 platelets/μl. Platelet-poor plasma (PPP) and PRP were used respectively to adjust the photometric measurement to the minimum and maximum optical density. The platelet reactivity of the healthy donors was previously checked by LTA. Thalidomide (racemic, enantiomer (+) and enantiomer (-)), lenalidomide and bortezomib were spiked at final concentration of 200 μM in PRP except for studying the influence of thalidomide on ADP-induced platelet aggregation where the maximal concentration usable was 100 μM. LTA was performed without (spontaneous aggregation) and with addition of 5μM ADP, 190μg/ml collagen, 600μM arachidonic acid (AA) and 10 μM PAR1-AP (final concentrations). Negative controls (physiological saline and DMSO at concentrations used to dissolve the drugs) were also included. TGT was performed both on PPP (from normal pool plasma (NPP)) and on PRP. We first validated the method on NPP and PRP with two anticoagulants: a thrombin direct inhibitor (i.e. argatroban) and a FXa direct inhibitor (i.e. ZK-807834). Thalidomide ((+/−), (+) and (-)), lenalidomide and bortezomid were tested at the final concentrations of 5, 10, 50, 100 and 200 μM. For the experiments on NPP, PPP reagent (5 pM TF + 4 μM PL in the final assays), PPP reagent low (1 pM TF + 4 μM PL in the final assays) and MP reagent (4 μM PL in the final assays) were used whereas for the experiments on PRP, PRP reagent (1 pM TF in the final assays) was used. Results: LTA Both three drugs did not induce spontaneous aggregation until 200 μM. Lenalidomide and bortezomib showed no effect on induced platelet aggregation until 200 μM, whatever the agonist used. On the contrary, for racemic thalidomide, platelet aggregation was reduced at 50 and 100 μM with 5 μM ADP and at 150 and 200 μM with 600 μM AA. These effects were more pronounced with thalidomide (+) than with thalidomide (-). So, the half maximal inhibitory concentrations (IC50) for platelet aggregation induced by 600 μM AA were 127, 143 and 221 μM for racemic, enantiomer (+) and enantiomer (-), respectively. When 190μg/ml collagen or 10 μM PAR1-AP were used as agonists, no effect was observed on platelet aggregation until 200 μM thalidomide. TGT. With argatroban and ZK-807834, we observed a concentration-dependent decrease and delay of the thrombin activity profiles in PRP and NPP, whatever the inducer used. No significant effect on thrombin activity in NPP or PRP has been observed for antimyeloma drugs at all concentrations tested, whatever the inducer used. Conclusions: Lenalidomide, thalidomide and bortezomid do not induce spontaneous platelet aggregation and do not affect platelet aggregation induced by collagen or PAR1-AP. Conversely to lenalidomide and bortezomib, thalidomide, and especially its enantiomer (+), moderately inhibits platelet aggregation induced by ADP and AA. Moreover, these antimyeloma agents have no effect on thrombin generation. The increased risk of VTE by thalidomide or lenalidomide in patients with multiple myeloma is thus not mediated by a direct impact on primary or secondary hemostasis at therapeutic concentrations. Disclosures: No relevant conflicts of interest to declare.
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Martini, Nataly. "Potion or Poison? Cloves." Journal of Primary Health Care 7, no. 2 (2015): 163. http://dx.doi.org/10.1071/hc15163.
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SUMMARY MESSAGE: Eugenol contained in clove exhibits antimicrobial activity and has been shown to work synergistically with other conventional antimicrobials. There is evidence of clove's analgesic, anaesthetic, anti-inflammatory and antioxidant properties in low concentrations. High concentrations are toxic and can lead to tissue damage and hepatotoxicity. Avoid inhaling clove smoke, and avoid use in pregnancy and breastfeeding due to lack of safety and toxicity data. Eugenol has been shown to inhibit platelet aggregation and use should be avoided with anticoagulants and antiplatelet agents.
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Lin, Lisha, Sujuan Li, Na Gao, Weili Wang, Taocui Zhang, Lian Yang, Xingzhi Yang, Dan Luo, Xu Ji, and Jinhua Zhao. "The Toxicology of Native Fucosylated Glycosaminoglycans and the Safety of Their Depolymerized Products as Anticoagulants." Marine Drugs 19, no. 9 (August 27, 2021): 487. http://dx.doi.org/10.3390/md19090487.
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Fucosylated glycosaminoglycan (FG) from sea cucumber is a potent anticoagulant by inhibiting intrinsic coagulation tenase (iXase). However, high-molecular-weight FGs can activate platelets and plasma contact system, and induce hypotension in rats, which limits its application. Herein, we found that FG from T. ananas (TaFG) and FG from H. fuscopunctata (HfFG) at 4.0 mg/kg (i.v.) could cause significant cardiovascular and respiratory dysfunction in rats, even lethality, while their depolymerized products had no obvious side effects. After injection, native FG increased rat plasma kallikrein activity and levels of the vasoactive peptide bradykinin (BK), consistent with their contact activation activity, which was assumed to be the cause of hypotension in rats. However, the hemodynamic effects of native FG cannot be prevented by the BK receptor antagonist. Further study showed that native FG induced in vivo procoagulation, thrombocytopenia, and pulmonary embolism. Additionally, its lethal effect could be prevented by anticoagulant combined with antiplatelet drugs. In summary, the acute toxicity of native FG is mainly ascribed to pulmonary microvessel embolism due to platelet aggregation and contact activation-mediated coagulation, while depolymerized FG is a safe anticoagulant candidate by selectively targeting iXase.
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Kawahito, K., H. Adachi, and T. Ino. "Platelet aggregation in patients taking anticoagulants after valvular surgery: evaluation by a laser light-scattering method." Journal of Artificial Organs 5, no. 3 (September 1, 2002): 188–92. http://dx.doi.org/10.1007/s100470200035.
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Lu, Rui-Yi, Xin Zhou, Wen-Jie Ji, Rui Shi, Shan Zeng, Tie-Min Jiang, Yu-Ming Li, and Zhao-Zeng Guo. "PM168 Influence of Different Anticoagulants and Time Delay on Monocyte Subsets and Monocyte-Platelet Aggregation Analysis." Global Heart 9, no. 1 (March 2014): e96. http://dx.doi.org/10.1016/j.gheart.2014.03.1558.
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Weitz, Jeffrey. "Insights into the role of thrombin in the pathogenesis of recurrent ischaemia after acute coronary syndrome." Thrombosis and Haemostasis 112, no. 11 (2014): 924–31. http://dx.doi.org/10.1160/th14-03-0265.
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SummaryAcute coronary syndrome (ACS) is a medical emergency. Patients who survive the initial event remain at risk of recurrent cardiovascular events. In most cases, ACS is triggered by thrombosis after rupture of an atherosclerotic plaque. Key to thrombus formation at this site is the generation of thrombin, which not only converts fibrinogen to fibrin but also serves as a potent platelet agonist and induces platelet aggregation at the site of vascular injury. Although dual antiplatelet therapy is more effective for the prevention of recurrent events than aspirin alone after ACS, there remains an approximately 10 % risk of recurrent ischaemic events at one year. Recent studies have evaluated whether the addition of an anticoagulant to antiplatelet therapy reduces the risk of recurrent ischaemia after an ACS event. Rivaroxaban, an oral factor Xa inhibitor, attenuates thrombin generation. When used in conjunction with dual antiplatelet therapy in patients with stabilised ACS, rivaroxaban 2.5 mg twice daily significantly reduced the risk of the composite endpoint of cardiovascular death, myocardial infarction and stroke compared with placebo. Although it increased the risk of bleeding, rivaroxaban was associated with a reduction in mortality; a finding that supports the use of a dual-pathway approach that combines anticoagulant and antiplatelet therapy. This review explores the pathophysiology of ACS to provide perspective on the results of recent clinical trials with novel oral anticoagulants for ACS and to identify their potential role in this setting.
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Mendolicchio, Grazia Loredana, Corrado Lodigiani, Monica Bacci, Marco Scardino, Carlo Ferrari Matteo, Grappiolo Guido, Lidia Rota, and Zaverio M. Ruggeri. "Effect of New Direct Oral Anticoagulants on Ex Vivo Platelet and Fibrin Thrombus Formation in Blood Flowing Over Fibrillar Type I Collagen." Blood 118, no. 21 (November 18, 2011): 2318. http://dx.doi.org/10.1182/blood.v118.21.2318.2318.
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Abstract Abstract 2318 Background. Studies have shown that 40–85% of patients undergoing total knee replacement develop venographically confirmed deep vein thrombosis (DVT) if not given post-operative thromboprophylaxis; approximately 0.1 to 1.7% of these patients will suffer fatal pulmonary embolism (PE). Oral anti-vitamin K anticoagulants are effective for the prevention and treatment of venous thrombosis, but have limitations. In particular, they have multiple food and drug interactions as well as variable pharmacokinetics and pharmacodynamics, such that regular laboratory monitoring and dose adjustments are required to maintain an optimal therapeutic range as defined with the International Normalized Ratio (INR). New oral agents that inhibit coagulation factor Xa or thrombin have been developed and shown to be effective and safe without requiring laboratory monitoring. In view of the relevance of the latter point, we have studied patients treated with an oral anti factor Xa agent (Rivaroxaban) or Coumadin, and evaluated the antithrombotic efficacy of the respective drugs by measuring platelet aggregation and fibrin deposition in patient blood perfused over fibrillar collagen type I. Material and Methods. Blood drawn from an antecubital vein and containing 0.011 M trisodium citrate as anticoagulant was recalcified with 5 mM calcium chloride and immediately perfused through a rectangular chamber mounted on the stage of a confocal microscope and presenting a surface coated with fibrillar collagen type I under laminar flow conditions at the wall shear rate of 300 1/s. Platelets and fibrin were specifically detected in situ through distinct fluorochromes. We tested 8 normal controls, 8 patients treated with Coumadin and a stable INR value between 1.94 and 2.90 (mean 2.34; standard deviation 0.34), and 7 patients treated with Rivaroxaban at between 8 and 16 days (mean 12.14; standard deviation 2.48 days) from the initiation of therapy. The volume of platelet aggregates and fibrin deposited onto the collagen fibrils was measured distinctly from stacks of confocal sections by integrating surface coverage of each thrombus component in consecutive optical planes separated by 2 micrometers in height. Results and Discussion. There was no significant difference in the volume of platelet and fibrin aggregates formed in blood of normal control and patients treated with either Coumadin or Rivaroxaban. This result was surprising because the patients treated with Coumadin had a laboratory demonstration of significantly retarded coagulation. We reasoned, however, that coagulation tests are typically performed in platelet-poor plasma, while in the perfusion assay coagulation occurs in whole blood and on a surface onto which flowing platelets are fully activated, thus increasing the local procoagulant potential. For this reason, we performed a series of experiments in which a variable amount of a highly specific thrombin inhibitor, lepirudin, was titrated into the recalcified blood before perfusion. We thus determined that with 50 nM lepirudin added to blood there was no decrease in the volume of platelet aggregates and fibrin deposited onto collagen in blood of normal individuals, while the volume of fibrin was decreased in patients receiving either Coumadin or Rivaroxaban. The corresponding values for normal controls, Coumadin-treated and Rivaroxaban-treated patients, in the order, were (mean volume ± standard error of the mean in cubic micrometers): Platelet aggregates = 28,592±3,354; 36,959±4,973; 44,448±7,110; Fibrin = 84,190±9,740; 47,298±7,308; 35,780±5,091. The differences in platelet aggregate volumes were not significant, while fibrin volume was significantly smaller in the anticoagulant-treated patients as compared to normal (p<0.01 for Coumadin and p<0.001 for Rivaroxaban); the difference between patients treated with one or the other anticoagulant was not significant. These results show that Rivaroxaban and Coumadin at therapeutically effective dosage have comparable effect in reducing thrombin generation, as evidenced by the reduced volume of fibrin formed in flowing blood exposed to collagen. This, however, is accompanied by an increased volume of platelet aggregates on the highly thrombogenic collagen surface. The relevance of these experimental results with respect to prevention of arterial as opposed to venous thrombosis deserves further investigation. Disclosures: No relevant conflicts of interest to declare.
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James, Stacy H. "Hematology Pharmacology." AACN Advanced Critical Care 20, no. 2 (April 1, 2009): 177–92. http://dx.doi.org/10.4037/15597768-2009-2009.
Full textAbstract:
Alterations in hemostasis and coagulation are common problems during critical illness. For that reason, it is essential that advanced practice and critical care nurses have an understanding of the medications used to treat these potentially deadly disorders. The antithrombotic drugs, including anticoagulants, antiplatelet agents, and fibrinolytics, are among the most frequently used drug therapies in the United States. These agents prevent and treat the thrombotic diseases, a leading cause of morbidity and mortality. Anticoagulants, the indirect and direct thrombin inhibitors as well as the vitamin K antagonists, are critical in treating venous thrombosis and preventing serious thrombotic complications with atrial fibrillation. The antiplatelet drugs work to decrease platelet aggregation and are especially effective in preventing and managing arterial thrombus. On the other end of the spectrum, the procoagulants are used to help prevent and control blood loss. These agents include human blood stimulators, human factor concentrates, including recombinant activated factor VIIa, and desmopressin.