Abstract 1718: Combination of Direct Acting FXa Inhibitor and P2Y 12 Antagonist at Non-Effective doses Provides Significant Inhibition of Arterial Thrombosis

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Patrick Andre ◽  
Pamela B Conley ◽  
Francis Deguzman ◽  
Yvonne Pak ◽  
Mayuko Inagaki ◽  
...  
Keyword(s):  
Arterial Thrombosis ◽  
Plasma Concentrations ◽  
Chronic Phase ◽  
Vascular Occlusion ◽  
Mesenteric Arteries ◽  
Late Time ◽  
Thrombotic Risk ◽  
Antithrombotic Activity ◽  
Effective Doses ◽  
Fxa Inhibitor

Previous studies have shown that inhibition of FXa and P2Y 12 used individually inhibit arterial thrombosis. The present study was designed to determine the antithrombotic activity achieved by the combination of non-effective doses of PRT054021 (FXa inhibitor) and PRT060128 (P2Y 12 antagonist). Arterial thrombosis was achieved by FeCl 3 injury of mesenteric arteries of the mouse and monitored in real time using intravital microscopy. Antagonism of either FXa or P2Y 12 dose-dependently inhibited early (time for appearance of first thrombus, TFFT) and late (time to vascular occlusion, TTO) phases of thrombosis (see Table ). Maximal effects were achieved at plasma concentrations superior or equal to 1 μg/ml for the two antagonists. Interestingly, the co-administration of non-effective doses of PRT054021 and PRT060128 significantly delayed time for appearance of first thrombus and vascular occlusion, demonstrating potent synergistic antithrombotic activity. PRT054021 and PRT060128 demonstrated a strong synergistic effect when administered in combination at non-effective doses. This combination is of particular relevance in acute settings, when thrombotic risk is at its paroxysm and maximal protection is sought as early as possible. These data also indicate that combined inhibition of FXa and P2Y 12 by reversible antagonists could provide substantial benefits to ACS patients throughout the chronic phase of the disease.

Thrombosis in IBD in the Era of JAK Inhibition

2020 ◽  
Vol 22 (1) ◽  
pp. 126-136
Author(s):  
Virginia Solitano ◽  
Gionata Fiorino ◽  
Ferdinando D’Amico ◽  
Laurent Peyrin-Biroulet ◽  
Silvio Danese
Keyword(s):  
Small Molecules ◽  
Arterial Thrombosis ◽  
Protective Role ◽  
Jak Inhibitors ◽  
Thrombotic Risk ◽  
Increased Risk ◽  
Bowel Diseases ◽  
Thrombotic Complications ◽  
Inflammatory Bowel ◽  
Inflammatory Effect

: Patients with inflammatory bowel diseases (IBD) have an increased risk of thrombosis. The interaction between inflammation and coagulation has been extensively studied. It is well-known that some drugs can influence the haemostatic system, but several concerns on the association between therapies and increased risk of thrombosis remain open. While biologics seem to have a protective role against thrombosis via their anti-inflammatory effect, some concerns about an increased risk of thrombosis with JAK inhibitors have been raised. We conducted a literature review to assess the association between biologics/small molecules and venous/arterial thrombotic complications. An increased risk of venous and arterial thrombosis was found in patients treated with corticosteroids, whereas anti-TNF were considered protective agents. No thromboembolic adverse event was reported with vedolizumab and ustekinumab. In addition, thromboembolic events rarely occurred in patients with ulcerative colitis (UC) after therapy with tofacitinib. The overall risk of both venous and arterial thrombosis was not increased based on the available evidence. Finally, in the era of JAK inhibitors, treatment should be individualized by evaluating the pre-existing potential thrombotic risk balanced with the intrinsic risk of the medication used.

RPR120844, a Novel, Specific Inhibitor of Coagulation Factor Xa Inhibits Venous Thrombosis in the Rabbit

1999 ◽  
Vol 81 (01) ◽  
pp. 157-160 ◽  
Author(s):  
Ross Bentley ◽  
Suzanne Morgan ◽  
Karen Brown ◽  
Valeria Chu ◽  
Richard Ewing ◽  
...  
Keyword(s):  
Jugular Vein ◽  
Drug Effect ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Specific Inhibitor ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Antithrombotic Activity ◽  
Fxa Inhibitor

SummaryThe in vivo antithrombotic activity of RPR120844, a novel synthetic coagulation factor Xa (fXa) inhibitor (Ki = 7 nM), was assessed by its ability to inhibit thrombus formation in a damaged segment of the rabbit jugular vein. Intravenous dose-response studies were performed and thrombus mass (TM), activated partial thromboplastin time (APTT), prothrombin time (PT), inhibition of ex vivo fXa activity and plasma drug levels (PDL) were determined. TM, measured at the end of a 50 min infusion, was significantly reduced (p <0.05 vs saline-treated animals) by RPR120844 at 30 and 100 μg/kg/min. At doses of 10, 30 and 100 μg/kg/min, APTT was prolonged by 2.1, 4.2 and 6.1-fold, and PT was prolonged by 1.4, 2.2 and 3.5-fold, respectively. PDL were determined by measuring anti-fXa activity using an amidolytic assay. Peak PDL were 0.8 ± 0.3, 1.5 ± 0.9 and 2.4 ± 0.6 μM, respectively. The drug effect was reversible with APTT, PT and PDL returning toward pretreatment values 30 min after termination of treatment. The results suggest that RPR120844, or similar compounds, may provide an efficacious, yet easily reversible, means of inhibiting thrombus formation.

Comparative Studies of an Orally-active Factor Xa Inhibitor, YM-60828, with other Antithrombotic Agents in a Rat Model of Arterial Thrombosis

1998 ◽  
Vol 79 (02) ◽  
pp. 410-416 ◽  
Author(s):  
Kazuo Sato ◽  
Yumiko Sakai ◽  
Fukushi Hirayama ◽  
Hiroyuki Koshio ◽  
Yuta Taniuchi ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Arterial Thrombosis ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Test Drug ◽  
Antithrombotic Agent ◽  
Antithrombotic Activity ◽  
Thrombosis Model ◽  
Treatment And Prevention ◽  
Orally Active

SummaryWe examined the antithrombotic activity of a novel synthetic inhibitor of factor Xa, YM-60828, in an electrically-induced carotid artery thrombosis model in rats. In the first experiment, the antithrombotic activity of YM-60828 after i.v. infusion was compared with those of heparin, darteparin and argatroban. Test drug was administered by i.v. infusion from 30 min before electrical stimulation to the end of the experiment. YM-60828 at 1 mg/kg/h significantly improved patency status, prolonged the time to occlusive thrombus formation and duration of patency. Heparin at 300 U/kg/h also improved these parameters, but were accompanied by a marked increase in systemic coagulation time. In the second experiment, the antithrombotic activity of YM-60828 after oral administration was compared with those of ticlopidine, cilostazol, aspirin, beraprost, ethyl icosapentate and warfarin. Test drug was orally administered to fasted rats 60 min before electrical stimulation. YM-60828 at 30 mg/kg p.o., but not ticlopidine, cilostazol, aspirin, beraprost, ethyl icosapentate or warfarin, significantly reduced the incidence of occlusion and improved carotid arterial patency. These results suggest that YM-60828 may be a promising antithrombotic agent for the treatment and prevention of arterial thrombosis which can be given by oral as well as intravenous administration.

scholarly journals A Diagnostic Solution for Lupus Anticoagulant Testing in Patients Taking Direct Oral FXa Inhibitors Using DOAC Filter

2021 ◽  
Vol 8 ◽  
Author(s):  
Carine Farkh ◽  
Syrine Ellouze ◽  
Louis Gounelle ◽  
Mama Sad Houari ◽  
Jérôme Duchemin ◽  
...  
Keyword(s):  
Lupus Anticoagulant ◽  
Solid Phase ◽  
Covalent Binding ◽  
Plasma Concentrations ◽  
Factor Xa ◽  
New Device ◽  
Before And After ◽  
Single Use ◽  
Fxa Inhibitor ◽  
Inhibitor Compounds

Background: Direct oral factor Xa (FXa) inhibitors interfere with lupus anticoagulant (LA) assays challenging antiphospholipid syndrome diagnosis in treated patients. We evaluated a new device, called DOAC Filter, and its usefulness in this setting. It is a single-use filtration cartridge in which FXa inhibitor compounds are trapped by non-covalent binding while plasma is filtered through a solid phase. Patient samples were analyzed before and after filtration: 38 rivaroxaban, 41 apixaban, and 68 none. Anticoagulant plasma concentrations were measured using specific anti-Xa assays and HPLC-MS/MS. LA testing was performed using dilute Russell Viper Venom Time (dRVVT) and Silica Clotting Time (SCT). Baseline median [min–max] concentrations were 64.8 [17.6; 311.4] for rivaroxaban and 92.1 ng/mL [37.1; 390.7] for apixaban (HPLC-MS/MS). They were significantly correlated with anti-Xa assay results (r = 0.98 and r = 0.94, respectively). dRVVT was positive in 92% rivaroxaban and 72% apixaban and SCT in 28 and 41% of samples, respectively. Post-filtration, median % of neutralization was 100% with rivaroxaban and apixaban concentrations of, respectively, &lt;2 [&lt;2–2.4] and &lt;2 ng/mL [&lt;2–9.6] using HPLC-MS/MS. No significant effect of DOAC Filter was observed on LA testing in controls (n = 31) and LA-positive (n = 37) non-anticoagulated samples. dRVVT and SCT remained positive in, respectively, 16 and 8% of rivaroxaban and 41 and 18% of apixaban samples. DOAC Filter would be an easy-to-use device allowing FXa inhibitor removal from plasma samples, limiting their interference with LA testing in treated patients.

scholarly journals Occlusive arterial thrombosis in cynomolgus monkeys with varying plasma concentrations of lipoprotein(a).

1993 ◽  
Vol 13 (4) ◽  
pp. 548-554 ◽  
Author(s):  
J K Williams ◽  
D A Bellinger ◽  
T C Nichols ◽  
T R Griggs ◽  
T F Bumol ◽  
...  
Keyword(s):  
Arterial Thrombosis ◽  
Plasma Concentrations ◽  
Cynomolgus Monkeys ◽  
Lipoprotein A

288Thrombotic events in bleeding patients treated with andexanet alpha: an ANNEXA-4 sub-study

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Beyer-Westendorf ◽  
P Yue ◽  
M Crowther ◽  
J W Eikelboom ◽  
C M Gibson ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Median Time ◽  
Major Bleeding ◽  
Oral Anticoagulation ◽  
Thrombotic Event ◽  
Thrombotic Risk ◽  
Number Of Patients ◽  
Fxa Inhibitor ◽  
Deep Vein ◽  
Deep Vein Thromboses

Abstract Background/Introduction Andexanet alfa (“andexanet”) was developed as a specific reversal agent for patients with major bleeding while using factor Xa (FXa) inhibitors. While thrombotic events (TEs) have been reported in patients receiving andexanet, the scope, nature, and timing of these events have not been fully characterized. Purpose The ANNEXA-4 study was a prospective, single-arm, open-label clinical trial that evaluated the safety and efficacy of andexanet in patients with acute major bleeding. In this secondary analysis, the occurrence of TEs was investigated. Methods Patients presenting with acute major bleeding within 18 hours after their last dose of FXa inhibitor were treated with andexanet. Safety outcomes, including TEs (reviewed by an adjudication committee), were evaluated at 30 days. Results Among 352 patients treated with andexanet, 34 (9.7%) experienced one or more TEs (Table). Strokes and deep vein thromboses were the most frequent TE types. Compared to patients with arterial TEs, patients with venous TEs were more likely to have been originally anticoagulated for venous thromboembolism. Median time to first TE was 10.5 days (Figure); time to event was shorter for arterial TEs than for venous TEs. TEs were nonfatal for most patients. Subgroups by age, bleed type, baseline anti-fXa activity, FXa inhibitor dose, and andexanet dose were not associated with the occurrence of TEs. Of the 34 TE patients, 26 (76.4%) had TEs before restart of any (full or prophylactic) anticoagulation; all first TEs occurred in patients not receiving oral anticoagulation. No TEs occurred after resumption of oral anticoagulation (N=100). Table 1. Thrombotic event characteristics Characteristic Result (n/N [%]) TE type   Strokes 14/352 (4.0%)   Deep vein thromboses 13/352 (3.7%)   Myocardial infarctions 7/352 (2.0%)   Pulmonary embolisms 5/352 (1.4%)   Transient ischemic attacks 1/352 (0.3%) Bleed type   Intracranial 23/227 (10.1%)   Gastrointestinal 7/90 (7.8%)   Other 4/35 (11.4%) Arterial TEs   Anticoagulated for AF 17/22 (77.3%)   Anticoagulated for VTE 6/22 (27.3%) Venous TEs   Anticoagulated for AF 11/18 (61.1%)   Anticoagulated for VTE 8/18 (44.4%)   Median time to first TE 10.5 days   Arterial 6 days   Venous 15 days Outcome   Fatal 7/34 (20.6%)   Nonfatal 27/34 (79.4%) AF = atrial fibrillation; n = number of patients with TEs; N = total number of patients for each characteristic; TE = thrombotic event; VTE = venous thromboembolism. Figure 1. Thrombotic Events Over Time Conclusions In patients with FXa inhibitor-associated acute major bleeding treated with andexanet, TEs occurred a rate not unexpected given the high thrombotic risk of the population. No factors predictive of TEs were identified. Resumption of anticoagulation was associated with fewer TEs. Acknowledgement/Funding Study funded by Portola Pharmaceuticals, Inc.

Thrombotic risk according to SERPINC1 genotype in a large cohort of subjects with antithrombin inherited deficiency

2017 ◽  
Vol 117 (06) ◽  
pp. 1040-1051 ◽  
Author(s):  
Martine Alhenc-Gelas ◽  
Genevieve Plu-Bureau ◽  
Justine Hugon-Rodin ◽  
Veronique Picard ◽  
Marie-Helene Horellou ◽  
...  
Keyword(s):  
Arterial Thrombosis ◽  
Lower Risk ◽  
Thrombotic Event ◽  
Type I ◽  
Adjusted Relative Risk ◽  
Type Ii ◽  
Antithrombin Deficiency ◽  
Thrombotic Risk ◽  
Mutation Carriers ◽  
Increase Risk

SummaryInherited quantitative (type I) or qualitative (type II) antithrombin deficiency (ATD) due to mutations in the SERPINC1 gene is a well-known risk factor for venous thromboembolism. ATD may also increase risk for arterial thrombosis. Few studies have investigated risk for thrombosis according to mutations. We addressed this topic in a large retrospective cohort study of 540 heterozygous carriers of SERPINC1 mutations and compared risk for first venous or arterial thrombosis associated with carrying of different type II or type I mutations. No clear difference in risk for first venous thrombotic event was observed among type I (missense or null), type IIRS or type IIPE mutation carriers except for a few variants that displayed lower risk [all events, adjusted relative risk: Cambridge II: 0.42 (95%CI 0.25–0.70), Dublin: 0.35 (95%CI 0.13–0.99)]. IIHBS mutation carrying was associated with a clearly lower risk than type I mutation carrying [0.28 (95%CI 0.20–0.40)]. These differences in risk were observed for both all venous thrombotic events and pulmonary embolism associated with deep venous thrombosis. The HBS group was also heterogeneous, with AT Budapest 3 carriers displaying a non-significantly different risk [0.61 (95%CI 0.31–1.20)] compared to type I mutation carriers. We also studied risk for arterial thrombosis and found no significant influence of mutation type. Altogether, our findings suggest a place for SERPINC1 genotyping in the diagnosis of ATD.Supplementary Material to this article is available online at www.thrombosis-online.com.

Animal Models of Thrombosis Help Predict the Human Therapeutic Concentration of PRT54021, a Potent Oral Factor Xa Inhibitor.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 901-901 ◽  
Author(s):  
Keith Abe ◽  
Gail Siu ◽  
Susan Edwards ◽  
Pei Hua Lin ◽  
Bing Yan Zhu ◽  
...  
Keyword(s):  
Animal Models ◽  
Venous Thrombosis ◽  
Thrombin Generation ◽  
Ex Vivo ◽  
Vena Cava ◽  
Factor Xa ◽  
Fold Change ◽  
In Vivo Models ◽  
Antithrombotic Activity ◽  
Fxa Inhibitor

Abstract Factor Xa (fXa) inhibition has resulted in the emergence of a new class of antithrombotics. Pharmacodynamic monitoring of these agents has proven problematic. The present study was designed to determine the target concentration of an oral fXa inhibitor required for clinical trials using both thrombin generation assays and three in vivo models and determine whether clotting assays such as activated partial thromboplastin time (aPTT) and prothrombin time (PT) would be suitable for monitoring human dosing. PRT54021 (PRT021) is a potent inhibitor of human fXa (Ki=117pM). PRT021 and fondaparinux, an indirect fXa inhibitor, both significantly inhibited TAT and F1.2 generation in human whole blood. Compared to a therapeutic level of fondaparinux (200nM), PRT021 (200nM) was more potent in suppressing both markers. Multiple doses of PRT021 were evaluated in three animal models. The first model, which measured clot accretion on cotton threads placed in rabbit abdominal vena cava, compared inhibition of thrombus mass by PRT021 to that of supratherapeutic doses of enoxaparin (a LMW heparin). The second model compared the ability of PRT021 to maintain vessel patency under arterial flow conditions in FeCl3 induced thrombosis in rat carotid artery to that achieved by enoxaparin or clopidogrel (an antiplatelet agent). The third model investigated inhibition of 111In labeled platelet deposition on dacron grafts and expansion chambers placed in femoral arteriovenous shunts in baboons. PRT021 and enoxaparin were administered as IV infusions and clopidogrel was dosed orally for three days. Ex vivo PT and aPTT were measured in all models. The models encompass stringent criteria of arterial and venous thrombosis and PRT021 produced dose-responsive antithrombotic activity in each of the three models. The efficacy of PRT021 compared favorably to supratherapeutic levels of enoxaparin and clopidogrel. Unlike in the rodent models, efficacy in primates was attained at a much lower dose with minimal prolongation of PT. Species specificity was also demonstrated by in vitro extensions of PT and aPTT in rat, rabbit, baboon and human plasma. A 2X change of PT was attained at concentrations of 8.9, 1.6, 1 and 0.4μM respectively. The data indicate that doses of PRT021 that inhibit thrombin generation in human blood and that provide anticoagulation similar to baboon dosed at 0.49mg/kg may be sufficient to prevent venous thrombosis in humans. Comparative modeling of extents of change in PT to levels of antithrombotic efficacy also leads us to predict that human therapeutic activity for PRT021 may be attained without concurrent changes in ex vivo clotting parameters. The targeted concentration is currently being tested in Phase II trials for its ability to prevent venous thromboembolism in orthopedic surgery patients. Model of Thrombosis Agent, Dose Antithrombotic Activity aPTT fold change PT fold change Rabbit vena cava PRT021,3mg/kg 76% inhibition 2.22 2.34 Rabbit vena cava Enoxaparin, 1.6mg/kg 96% inhibition 2.06 2.01 Rat carotid PRT021,19.1mg/kg 90% patency 1.69 2.20 Rat carotid Enoxaparin, 7.6mg/kg 70% patency 3.49 1.19 Rat carotid Clopidogrel, 3mg/kg/day 80% patency 1.03 1.01 Baboon arteriovenous PRT021,0.49mg/kg 90% inhibition (venous), 32% inhibition (arterial) 1.29 1.17

Imatinib Plasma Levels and Its Correlation with Response in Chronic-Phase Chronic Myeloid Leukemia: Experience of One Centre.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4284-4284
Author(s):  
J. Valentin Garcia. Gutierrez ◽  
Jesús Odriozola ◽  
Pilar Herrera ◽  
Javier Lopez ◽  
Maria Calbacho ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Plasma Levels ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Plasma Concentrations ◽  
Chronic Phase ◽  
Control Group ◽  
Treatment Optimisation ◽  
Number Of Patients

Abstract Abstract 4284 Introduction Imatinib (IM), 400 mg/d. induces durable responses in chronic myeloid leukaemia (CML) in chronic phase (CP). However, although IM-biodisponibility is fairly good, its plasma levels are variable and can not be predicted. Recently, these plasma concentrations have been related both to the dose being administrated and to the cytogenetic and molecular responses. Thus, Imatinib pharmacokinetics could be an issue towards treatment optimisation in CML patients. Recent studies suggest that therapeutic IM plasma levels should be above 1040 ng/dl. Aims To evaluate the association between IM dose and throughout plasma levels with different clinical outcomes. Results In this study, we looked for an association between plasma concentrations and clinical outcomes in 16/86 CML chronic phase patients who did not achieve optimal responses following the European Leukemia Net guidelines (ELN) (table 1). Patients with optimal responses and treated with the same standard doses were also analysed as a control group. Patients receiving doses above 400 mg showed throughout plasma levels considered as appropriate. In 7 of 16 patients (47.5%) not achieving optimal responses (ELN criteria), plasma levels were below the supposed therapeutic ranges. We have found no evidence for a correlation between clinical risk factors at diagnosis and the measurement of optimal plasma levels. Conclusions IM plasma levels are well correlated with IM dose administrated in the patients studied. In almost 50% of patients who did not achieve optimal responses, IM plasma levels were under the ranges considered therapeutic. Probably these are the patients who may benefit of a dose increase. Obviously, to learn more about the practical value of these measurements a longer follow up with a larger number of patients is needed. Disclosures: No relevant conflicts of interest to declare.

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