Dabigatran reduces endothelial permeability through inhibition of thrombin-induced cytoskeleton reorganization

Choi, Hyun-Jung,Kim, Na-Eun,Kim, Jayoung,An, Sunho,Yang, Seung-Hee,Ha, Jimin,Cho, Sunghee,Kwon, Il,Kim, Young Dae,Nam, Hyo Suk,Heo, Ji Hoe Pergamon Press 2018 Thrombosis research Vol.167 No.-

<P><B>Abstract</B></P> <P>Dabigatran etexilate (DE), a new oral anti-coagulant, is a direct thrombin inhibitor. Clinical trials showed the favorable benefit-to-risk profile of DE compared to warfarin for the prevention of ischemic stroke in patients with atrial fibrillation. Remarkably, patients treated with dabigatran showed reduced rates of intracerebral hemorrhage compared to warfarin. As the breakdown of endothelial barrier integrity is associated with hemorrhagic events and as thrombin increases endothelial permeability, we hypothesized that dabigatran preserves the endothelial barrier by inhibiting thrombin-induced permeability. We assessed leakage of fluorescein isothiocyanate (FITC)-dextran through the endothelial monolayer and measured trans-endothelial electrical resistance of the endothelial monolayer after treatment of thrombin or thrombin pre-incubated with dabigatran. Thrombin increased the permeability of endothelial cells. Dabigatran effectively blocked the ability of thrombin to increase permeability. Dabigatran inhibited the formation of actin stress fibers induced by thrombin and inhibited consequent destabilization of junctional protein complexes and intercellular gap formation. The interaction of thrombin with protease activated receptor-1 activates the Rho A guanosine triphosphate (GTP)ase-myosin light chain (MLC) phosphorylation signaling axis, leading to actin cytoskeleton changes. This signaling pathway was effectively inhibited by dabigatran in endothelial cells. Consistently, the number of phosphorylated MLC-positive cells was significantly decreased in ischemic tissue of rat brains. These results indicate dabigatran blocks the ability of thrombin to induce vascular permeability and the resulting underlying signaling cascade in endothelial cells. Our findings provide evidence that dabigatran may confer a lower risk of intracerebral hemorrhage by preserving endothelial barrier integrity.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Dabigatran inhibits the effect of thrombin to increase endothelial permeability and to change endothelial actin cytoskeleton. </LI> <LI> Dabigatran inhibits thrombin-induced phosphorylation of a regulatory myosin light chain and activation of Rho A. </LI> <LI> Dabigatran may contribute to a lower risk of intracerebral hemorrhage by preserving endothelial barrier integrity. </LI> </UL> </P>

Alimentary Tract ; Gastrointestinal Bleeding with Dabigatran, a Comparative Study with Warfarin: A Multicenter Experience

( Muhammed Sherid ),( Humberto Sifuentes ),( Samian Sulaiman ),( Salih Samo ),( Husein Husein ),( Ruth Tupper ),( Charles Spurr ),( Subbaramiah Sridhar ) 대한소화기학회 2015 대한소화기학회지 Vol.65 No.4

Background/Aims: The risk of gastrointestinal (GI) bleeding with dabigatran when compared to warfarin has been controversial in the literature. The aim of our study was to assess this risk with the use of dabigatran. Methods: We examined the medical records of patients who were started on dabigatran or warfarin from October 2010 to October 2012. The study was conducted in two hospitals. Results: A total of 417 patients were included (208 dabigatran vs. 209 warfarin). GI bleeding occurred in 10 patients (4.8%) in the dabigatran group compared to 21 patients (10.1%) in the warfarin group (p=0.0375). Multivariate analysis showed that patients who were on dabigatran for ≤100 days had a higher incidence of GI bleeding than those who were on it for >100 days (p=0.0007). The odds of GI bleeding in patients who were on dabigatran for ≤100 days was 8.2 times higher compared to those who were on the drug for >100 days. The incidence of GI bleeding in patients >65 years old was higher than in those <65 years old (p=0.0453, OR=3). History of previous GI bleeding was another risk factor for GI bleeding in the dabigatran group (p=0.036, OR=6.3). The lower GI tract was the most common site for GI bleeding in the dabigatran group (80.0% vs. 38.1%, p=0.014). Conclusions: The risk of GI bleeding was lower with dabigatran. The risk factors for GI bleeding with dabigtran were the first 100 days, age >65 years, and a history of previous GI bleeding. (Korean J Gastroenterol 2015;65:205-214)

비판막성 심방세동 환자의 뇌졸중 예방에서 dabigatran과 rivaroxaban의 임상적용의 현황

박유경,강지은,김승준,라현오,이정연 한국임상약학회 2016 한국임상약학회지 Vol.26 No.3

Objective: Prescription rate of dabigatran and rivaroxaban, which are the direct oral anticoagulants (DOAC), has increased. We have analyzed the prescription trend and medication use of dabigatran and rivaroxaban in patients with non-valvular atrial fibrillation (NVAF). Methods: It was retrospectively studied from September 2012 to April 2014 using the electronic medical records and the progress notes. Patients with NVAF (n=424) were evaluated on the medication use, prescribing preferences, adverse drug reactions (ADRs) and the availability of prescription reimbursement of dabigatran (n=210) and rivaroxaban (n=214). Results: Dabigatran was prescribed higher than rivaroxaban (23.3% versus 7.5%, p<0.001) in the neurology department, but rivaroxaban was prescribed higher compared to dabigatran in the cardiology department (87.4% versus 74.3%, p<0.001). Dabigatran was prescribed more than rivaroxaban in high risk patients with CHADS2 score ≥ 3 (44.3% versus 31.3%, p=0.006). Dabigatran patients seemed to have more ADRs than patients with rivaroxaban (25.2% versus 11.2%, p<0.001), but no serious thrombotic events and bleeding were found. Only 35.6% (n=151) were eligible for prescription reimbursement by the National Health Insurance (NHI). Bridging therapy (86, 31.5%) and direct-current cardioversion (57, 20.2%) were main reasons of ineligibility for reimbursement. Conclusion: Prescription preferences were present in choosing either dabigatran or rivaroxaban for patients with NVAF. Inpatient protocols and procedures considering patient-factors in NVAF need to be developed.

국내 비판막성 심방세동 환자의 뇌졸중 및 전신색전증 예방을 위한 Dabigatran의 비용-효과성 연구

김준수,오윤환,김정대 한국보건의료기술평가학회 2014 보건의료기술평가 Vol.2 No.2

Objectives: The aim of this economic evaluation is to estimate the cost-effectiveness of dabigatran etexilate, an orally active thrombin inhibitor that has predictable and stable pharmacokinetics and a wide therapeutic margin, as treatment for the prevention of stroke in non-valvular AF patients who are warfarin eligible according to their stroke risk. Methods: A Markov model estimated the cost-effectiveness of dabigatran etexilate versus warfarin. A Markov model simulated AF patients at moderate to high risk of stroke while tracking clinical events [primary and recurrent ischaemic strokes, systemic embolism, transient ischaemic attack, haemorrhage (intracranial, extracranial, and minor), acute myocardial infarction and death] and resulting functional disability. Acute event costs and resulting long-term follow-up costs incurred by disabled stroke survivors were based on published literature and national statistics. Modelled outcomes over a lifetime horizon included clinical events, quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratios. Results: Dabigatran is cost effective vs. warfarin in prescribed setting, which results in an ICER of 18,711,096 KRW/QALY. When compared to warfarin, dabigatran costs 6,574,192 KRW more per patient while increases QALY by 0.21 year per patient. Conclusion: This study demonstrates that dabigatran etexilate is a highly cost-effective alternative, using the ICER threshold (GDP per capita) as Health Insurance Review & Assessment Service(HIRA) recommended, to current care for the prevention of stroke and systemic embolism among Korean non-valvular AF patients.

Effects of Long-term Thrombin Inhibition (Dabigatran Etexilate) on Spontaneous Thrombolytic Activity during the Progression of Atherosclerosis in ApoE−/−–LDLR−/− Double-Knockout Mice

Tomohide Sanda,Manami Yoshimura,Kanae Hyodo,Hiromitu Ishii,Tsutomu Yamashita 대한심장학회 2020 Korean Circulation Journal Vol.50 No.9

Background and Objectives: Atherosclerosis is characterized by a hypercoagulable state, during which coagulation and fibrinolytic factors are activated simultaneously. However, details regarding the thrombolytic pathway in this context remain unknown. Here we investigated how direct long-term inhibition of thrombin influenced spontaneous thrombolytic activity during atherosclerotic progression in apolipoprotein E (ApoE)–/––low density lipoprotein receptor (LDLR)–/– double-knockout mice. Methods: All mice received either standard chow (placebo group) or dabigatran-containing chow for 22 weeks, after which we evaluated them. The amount of atherosclerosis was estimated as the ratio of the atherosclerotic area to the total aortic intimal area. In addition, we used immunohistochemistry to analyze the expression of tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), and endothelial nitric oxide synthase (eNOS) in atherosclerotic regions. To evaluate thrombolysis, we used a He–Ne laser to induce thrombosis in vessels of the cremaster muscle and then measured the thrombus volume over time. Results: The atherosclerotic area was smaller and thrombolytic activity greater in the dabigatran-treated group than in the placebo group. Furthermore, according to the thrombolysis model, spontaneous thrombolytic activity was increased in the dabigatran-treated mice compared with the placebo mice. In support of these results, immunohistochemistry demonstrated decreased expression of PAI-1 and TAFI but increased expression of eNOS in the dabigatran group compared with the placebo group. However, t-PA expression did not differ between groups. Conclusions: Direct long-term inhibition by dabigatran etexilate of thrombin led to an increase in spontaneous thrombolytic activity decreasing the expression of PAI-1 and TAFI.

Dabigatran approaching the realm of heparin-induced thrombocytopenia

Patricia J Ho,Juan A Siordia 대한혈액학회 2016 Blood Research Vol.51 No.2

Heparin-induced thrombocytopenia (HIT) is a serious, immune mediated complication of exposure to unfractionated or low-molecular-weight heparin. Though rare, it is a con-dition associated with high morbidity and mortality that requires immediate change to alternative anticoagulants for the prevention of life-threatening thrombosis. The direct thrombin inhibitors lepirudin and argatroban are currently licensed for the treatment of HIT. Dabigatran, a novel oral anticoagulant (NOAC) with a similar mechanism of action and effective use in other indications, has recently been proposed as another therapeutic option in cases of HIT. This review serves as an introduction to using dabigatran for this purpose, detailing the clinical aspects of its administration, evidence of its performance compared to other anticoagulants, and the preliminary reports of HIT successfully treated with dabigatran. As the literature on this develops, it will need to include clinical trials that directly evaluate dabigatran against the other NOACs and current treatment options.

Hemorrhagic Transformation After Large Cerebral Infarction in Rats Pretreated With Dabigatran or Warfarin

Kwon, Il,An, Sunho,Kim, Jayoung,Yang, Seung-Hee,Yoo, Joonsang,Baek, Jang-Hyun,Nam, Hyo Suk,Kim, Young Dae,Lee, Hye Sun,Choi, Hyun-Jung,Heo, Ji Hoe American Heart Association, Inc. 2017 Stroke Vol.48 No.10

<P>Conclusions-The risk of HT after a large cerebral infarction was significantly increased in rats pretreated with warfarin than those with dabigatran. However, the results here may not have an exact clinical translation.</P>

Non-Vitamin K Oral Anticoagulants Associated Bleeding and Its Antidotes

Thorsten Steiner,Martin Köhrmann,Peter D. Schellinger,Georgios Tsivgoulis 대한뇌졸중학회 2018 Journal of stroke Vol.20 No.3

Oral anticoagulant-associated intracerebral hemorrhage (OAC-ICH) accounts for nearly 20% of all ICH. The number of patients with an indication for oral anticoagulant therapy (OAT) increases with increasing age. OAT became less complicate with the introduction of non-vitamin K oral anticoagulants (NOAC) OAT because of easier handling, favorable risk-benefit profile, reduced rates of ICH compared to vitamin K antagonists and no need for routine coagulation testing. Consequently, despite a better safety profile of NOAC the number of patients with OAC-ICH will increase. The mortality and complication rates of OAC-ICH are high and therefore they are the most feared complication of OAT. Immediate normalization of coagulation is the main goal and therefore knowledge of pharmacodynamics and coagulation status is essential. Laboratory measurements of anticoagulant activity in NOAC patients is challenging as specific tests are not widely available. More accessible tests such as the prothrombin time and activated partial thromboplastin time have important limitations. In dabigatran-associated ICH 5 g Idarucizumab should be administered. In rivaroxaban and apixaban-associated ICHs administration of andexanet alpha should be considered. Prothrombin complex concentrate may be considered if andexanet alpha is not available or in case of an ICH associated with edoxaban.

Practice Preferences on Dabigatran and Rivaroxaban for Stroke Prevention in Patients with Non-valvular Atrial Fibrillation

박유경,이정연,강지은,김승준,라현오 한국임상약학회 2016 한국임상약학회지 Vol.26 No.3

Objective: Prescription rate of dabigatran and rivaroxaban, which are the direct oral anticoagulants (DOAC), has increased. We have analyzed the prescription trend and medication use of dabigatran and rivaroxaban in patients with non-valvular atrial fibrillation (NVAF). Methods: It was retrospectively studied from September 2012 to April 2014 using the electronic medical records and the progress notes. Patients with NVAF (n=424) were evaluated on the medication use, prescribing preferences, adverse drug reactions (ADRs) and the availability of prescription reimbursement of dabigatran (n=210) and rivaroxaban (n=214). Results: Dabigatran was prescribed higher than rivaroxaban (23.3% versus 7.5%, p<0.001) in the neurology department, but rivaroxaban was prescribed higher compared to dabigatran in the cardiology department (87.4% versus 74.3%, p<0.001). Dabigatran was prescribed more than rivaroxaban in high risk patients with CHADS2 score ≥ 3 (44.3% versus 31.3%, p=0.006). Dabigatran patients seemed to have more ADRs than patients with rivaroxaban (25.2% versus 11.2%, p<0.001), but no serious thrombotic events and bleeding were found. Only 35.6% (n=151) were eligible for prescription reimbursement by the National Health Insurance (NHI). Bridging therapy (86, 31.5%) and direct-current cardioversion (57, 20.2%) were main reasons of ineligibility for reimbursement. Conclusion: Prescription preferences were present in choosing either dabigatran or rivaroxaban for patients with NVAF. Inpatient protocols and procedures considering patient-factors in NVAF need to be developed.

급성신손상으로 인해 발생한 dabigatran 독성

문형호 ( Hyoung Ho Moon ),이승은 ( Seung Eun Lee ),오동준 ( Dong Jun Oh ),조희범 ( Hee Bum Jo ),권기환 ( Ki Hwan Kwon ),김윤진 ( Yoon Jin Kim ),김경수 ( Kyung Soo Kim ),신성준 ( Sung Joon Shin ) 대한임상독성학회 2014 대한임상독성학회지 Vol.12 No.2

Dabigatran is the first oral direct thrombin inhibitor approved by the US Food and Drug Administration (FDA) for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Because dabigatran is excreted mainly by the kidneys, serum levels of dabigatran can be elevated to a supratherapeutic range in patients with renal failure, predisposing to emergent bleeding. We describe the case of a 66-year-old man taking dabigatran 150 mg twice daily for atrial fibrillation and cerebral infarction who presented with hematochezia and disseminated intravascular coagulation. Laboratory evaluation showed a hemoglobin level of 6.3 g/dL, platelets of 138,000/mm3, activated partial thromboplastin time (aPTT) of 10?s, and an international normalized ratio (INR) of 8.17. Colonoscopy showed a bleeding anal fissure. Hemostasis was provided by hemoclips and packed red blood cells and fresh frozen plasma were transfused. Since then, there was no further hematochezia, however, bleeding including oral mucosal bleeding, hematuria, and intravenous site bleeding persisted. At presentation, his serum creatinine was 4.96 mg/dL (baseline creatinine, 0.9 mg/dL). Dabigatran toxicity secondary to acute kidney injury was presumed. Because acute kidney injury of unknown cause was progressing after admission, he was treated with hemodialysis. Fresh frozen plasma transfusion was provided with hemodialysis. At 15 days from admission, there was no further bleeding, and laboratory values, including hemoglobin, partial thromboplastin time, and prothrombin time were normalized. He was discharged without bleeding. After 2 months, he undergoes dialysis three times per week and no recurrence of bleeding has been observed.