Effects Of Dabigatran Research Articles

Dabigatran: its protective effect against endothelial cell damage by oxysterol

Recent data showed that dabigatran can reduce not only procoagulatory effects but also block proinflammatory stimuli by inhibiting the expression of cytokines and chemokines and reducing thrombin-induced endothelial permeability. The aim of our study was to assess the effect of dabigatran on the integrity and inflammatory properties of endothelial cells stimulated by 25-hydroxycholesterol (25-OHC, oxysterol). HUVECs (Human Umbilical Vein Endothelial Cells) were stimulated with 25-hydroxycholesterol 10 µg/ml, dabigatran 100 ng/ml or 500 ng/ml and 25-hydroxycholesterol + dabigatran (100 ng/ml, 500 ng/ml). HUVEC integrity and permeability was measured in the RTCA-DP xCELLigence system and by the paracellular flux system. The mRNA expression of ICAM-1, VEGF, IL-33, MCP-1 and TNF-α was analyzed by Real-time PCR. Cell apoptosis and viability was measured by flow cytometry. VEGF protein concentration was assessed in supernatants by ELISA. VE-cadherin expression in endothelial cells was evaluated by confocal microscopy. Pre-stimulation of HUVECs with 25-OHC decreased endothelial cell integrity (p < 0.001) and increased the expression of IL-33, ICAM-1, MCP-1, VEGF, TNF-α mRNA (p < 0.01) compared to unstimulated controls. Following stimulation of HUVECs with dabigatran 100 ng/ml or 500 ng/ml restored HUVEC integrity interrupted by 25-OHC (p < 0.001). In HUVECs pre-stimulated with oxysterol, dabigatran stimulation decreased mRNA expression of the proinflammatory cytokines IL-33 and TNF-α, chemokines MCP-1 ICAM-1 and VEGF (p < 0.01). Dabigatran 500 mg/ml+ 25-OHC increased the endothelial expression of VE-cadherin as compared to 25-OHC (p < 0.01).Our findings suggest that dabigatran stabilizes the endothelial barrier and inhibits the inflammation caused by oxysterol.

Prothrombin complex concentrate in the management of major bleeding induced by oral anticoagulant therapy.

Objectives:To share clinical data on the efficacy of 4F-PCC in the treatment of major bleeding caused by warfarin, dabigatran, and rivaroxaban.Methods:This is a retrospective study of patients admitted to King Fahad Medical City, Riyadh, Saudi Arabia with major bleeding caused by oral anticoagulants and treated with 4-factor prothrombin complex concentrate (4F-PCC). The International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria were used to evaluate the effectiveness of PCCs.Results:A total of 22 patients were included in the study. Ten of the events were caused by gastrointestinal bleeding (46%). In the majority of patients, anticoagulation was prescribed for stroke prevention, atrial fibrillation, and venous thromboembolism. The median international normalized ratio was significantly lower before and after PCC administration (p<0.001). In patients treated with 4-factor PCC, the rate of thromboembolic events was 0%. The hemostatic effectiveness of PCC was effective in 19 patients. During treatment, no clinically significant bleeding complications occurred.Conclusion:Prothrombin complex concentrate can effectively reverse the effects of warfarin and rivaroxaban in patients with major bleeding, but only partially reverses the effect of dabigatran.

Effects of direct oral anticoagulants dabigatran and rivaroxaban on the blood coagulation function in rabbits.

The aim of this study was to explore the effects of dabigatran and rivaroxaban on the activities of various coagulation factors. To achieve that, 60 rabbits were randomly divided into experimental groups that received different doses of dabigatran or rivaroxaban. The effects of dabigatran and rivaroxaban on the activities of FII, FV, FVIII, FX, and activated protein C (APC) were analyzed. In the dabigatran groups, activated partial thromboplastin time and thromboplastin time (TT) were prolonged after drug administration, and the activities of FII, FV, FVIII, and FX were inhibited as the drug concentration increased. Low doses of dabigatran inhibited APC activity. In the rivaroxaban groups, APTT and TT were not significantly prolonged after drug administration. In contrast, the high-dose rivaroxaban group exhibited prolonged PT, and the degree of inhibition of the activities of FII, FV, FVIII, and FX increased as the drug concentration increased. Rivaroxaban had no significant effect on APC activity regardless of dosage. As the drug concentration increased, both NOACs had more significant inhibitory effects on the activities of FII, FV, FVIII, and FX. Low concentrations of dabigatran generated an inhibitory effect on APC activity, while high concentrations of dabigatran had no significant effect. Rivaroxaban had no significant effect on APC activity.

Healthcare Resource Utilization for Oral Anticoagulant Reversal Therapies in Non-Valvular Atrial Fibrillation/Venous Thromboembolism Patients.

BackgroundThe objective of the study was to describe the healthcare resource utilization (HCRU) and associated costs with hospitalized patients receiving specific versus non-specific oral anticoagulation reversal therapy for life-threatening bleeds and emergency surgeries or urgent procedures.MethodsThis retrospective observational study using the Premier Healthcare Database included adult patients aged ≥ 18 years treated with idarucizumab (IDA) or 3- or 4-factor prothrombin complex concentrates (PCC) to reverse the effects of dabigatran or warfarin, respectively, between October 2015 and February 2018.ResultsMedian ages for IDA (n = 1,232) and PCC (n = 4,939) patients were 78 and 74 years (P < 0.001), respectively. IDA patients had lower bleeding and stroke risk assessment scores (HAS-BLED; P < 0.001 and CHA2DS2-VASc; P = 0.014) and lower prevalence of comorbidities compared with PCC patients. Median hospital length of stay was 6 and 7 days for patients who received IDA or PCC (P < 0.001), respectively. The percentage of patients with an intensive care unit (ICU) admission was lower for IDA patients compared with PCC patients (61.3% vs. 68.7%; P < 0.001). Median total costs per hospitalization were $19,357 for IDA patients and $26,920 for PCC patients (P < 0.001). Median costs per hospitalization for IDA and PCC treatment were $3,277 and $4,424, respectively. When HCRU and costs were examined by cause of reversal and type of bleed, similar trends in hospitalized costs emerged for IDA compared with PCC treatment.ConclusionsThis analysis revealed lower HCRU and total hospital costs in patients administered IDA compared with PCC for reversal of oral anticoagulation, though differences in population characteristics and bleeding events were observed that may have contributed to these findings.

Effects of uninterrupted dabigatran on the intensity of anticoagulation during atrial fibrillation ablation.

BackgroundUninterrupted dabigatran during atrial fibrillation (AF) ablation is now established as the standard therapy. However, there are few reports on the effects of uninterrupted dabigatran on the intensity of anticoagulation during AF ablation.MethodsWe retrospectively analyzed 247 consecutive patients who underwent AF ablation in our hospital from January 2017 to December 2018. Patients who took warfarin or uninterrupted direct oral anticoagulants (DOACs) except for dabigatran were excluded. 89 patients underwent ablation with uninterrupted dabigatran (uninterrupted group, male 71, mean age 59.6 ± 14.0) and 124 with interrupted DOACs (interrupted group, male 105, mean age 56.9 ± 12.9) during AF ablation. The initial ACT level, proportion of ACT levels of more than 300 s, and total amount of heparin were compared. Furthermore, the incidence of procedure complications was also evaluated.ResultsThe initial ACT levels were significantly higher in the uninterrupted group, and the total number of ACTs of more than 300 s was significantly higher in the uninterrupted group (uninterrupted vs. interrupted; initial ACT level, 315.6 ± 59.8 vs. 264.5 ± 48.6, p < .001; total number of ACTs ≧300, n [%], 304/ 484 [62.8 %] vs. 372/745 [49.9%], p < .001). The total amount of heparin during procedure was significantly lower in the uninterrupted group (uninterrupted group vs. interrupted group; 12966 ± 4773 vs. 16371 ± 5212, p < .001). There was no significant difference in the incidence of complications between the two groups.ConclusionsIn the catheter ablation of AF, uninterrupted dabigatran would be useful to obtain a stable anticoagulation status during the entire procedure.

Clinical experience with idarucizumab prior to thrombolytic therapy of cerebral infarction in the Sverdlovsk region

Introduction. In recent years, the use of oral anticoagulants for the prevention of ischemic strokes (IS) in patients with atrial fibrillation (AF), as well as the prevention of deep vein thrombosis and thromboembolism has been increasing in clinical practice. According to epidemiological studies, ischemic strokes account for about 85% of all AMI. Cardioembolic strokes (CES), which develop due to embolism to the cerebral vessels from the heart chambers, deserve special attention. The presence of AF is associated with a twofold increase in the risk of death from cardiovascular disease and death from any cause. Timely anticoagulant therapy can reduce the risk of thromboembolic complications and improve the prognosis. Materials and Methods. The authors present a clinical observation in which a 47-year-old female patient diagnosed with venous insufficiency, who took dabigatran 150 mg twice a day for a year, developed IS with left-sided pronounced hemiparesis. After 170 minutes from the development of the stroke, idarucizumab was administered to neutralize the anticoagulant effect of dabigatran and thrombolytic therapy (TLT) was performed. Results. Twenty-four hours after TLT, the National Institutes of Health Stroke Scale (NIHSS) score decreased from 16 to 6. A repeat CT scan of the brain revealed a focus of ischemia in the right frontal, parietal, and temporal lobes. On the 19th day of the AI, dabigatran 150 mg 2 times a day was resumed. Conclusion. The presented observation confirms that in patients with AI developed against the background of dabigatran, the administration of idarucizumab is safe and allows for TLT.

Safety of idarucizumab in the reversal of dabigatran at six tertiary care Ontario hospitals

BackgroundIdarucizumab, a monoclonal antibody fragment that reverses the anticoagulant effect of dabigatran, was approved for use in Canada in 2016. ObjectiveOur objective was to assess the safety of idarucizumab among patients who received the drug within the first 3 years of its use in Canada. Patients/MethodsWe performed a retrospective health records review of all idarucizumab use, excluding use in those <18 years of age, between May 16, 2016, and August 1, 2019, at six Ontario tertiary care hospitals. The primary outcome was mortality. The secondary outcomes were in‐hospital arterial thrombotic event (ATE), in‐hospital venous thromboembolism (VTE), length of hospital stay, and length of critical care stay. ResultsA total of 85 patients received idarucizumab during the study period for the following indications: 37 (43.5%) for spontaneous bleeding, 28 (32.9%) for traumatic bleeding, 11 (12.9%) for emergency surgeries/procedures, 5 (5.9%) for elective surgeries/procedures, and 4 (4.7%) for other indications. Nineteen patients (22.4%; 95% confidence interval [CI], 14.8%‐32.3%) did not survive their hospitalization. During hospitalization, two patients (2.4%; 95% CI, 0.7%‐8.2%) had ATE, and three patients (3.5%; 95% CI, 1.2%‐9.9%) had VTE. The median length of stay was 8 (interquartile range [IQR], 2.5‐13) days in hospital and 3 (IQR, 2‐5) days in critical care. ConclusionsCompared with clinical trial data, we found a numerically higher rate of mortality and similar rate of ATE and VTE among patients treated with idarucizumab in the real world.

Idarucizumab for Reversing Anticoagulation in Patients Treated with Dabigatran: Experience in Our Center

INTRODUCTIONPatients who are receiving oral anticoagulant therapy for the prevention of stroke or thrombosis may benefit from anticoagulant reversal if they present life-threatening bleeding or if they will be undergoing urgent surgery or intervention.Idarucizumab is a specific reversal agent for dabigatran. It is a humanized monoclonal antibody fragment (Fab) that binds dabigatran and its metabolites with a very high affinity, approximately 300 times more potent than the binding affinity of dabigatran to thrombin. It thus neutralizes its anticoagulant effect. It is indicated in adult patients treated with this direct oral anticoagulant when a rapid reversal of its anticoagulant effect is required, for surgical or urgent procedures and in the case of potentially fatal or uncontrolled bleeding.It is given intravenously. The recommended dose is 5 g administered in two intravenous infusions of 2.5 g every 5-10 minutes.OBJECTIVESThis is a descriptive study to determine whether darucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who are about to undergo an urgent procedure.METHODSThe two clinical cases of patients treated with idarucizumab in this year are described.CASE 1A 70-year-old woman receiving anticoagulant Dabigatran 150mg/12h for Non-valvular Atrial Fibrillation (NVAF), who comes to the emergency due to abdominal pain of several hours of evolution. In the previous 24 hours, surgical hysteroscopy had been performed, due to postmenopausal metrorrhagia, in order to rule out the endometrial process.Complementary tests showed a drop in hemoglobin levels from 14.8 mg/dL to 12.3 g/dL, prothrombin activity 8%,INR 10.58, Prothrombin time (PT) 8%, activated partial thromboplastin time (APTT) 55 seconds. Thus, it is administered 10 mgr Konakion and 1200 IU Human Prothrombin Complex. Two hours later: PT 23%, INR 3.15, PT 2.7 ratio. Renal function was normal.An abdominal/pelvic CT scan was performed, where pneumoperitoneum was observed in an important amount as well as abundant hemoperitoneum, suggesting uterine perforation.The patient was moved over specialized hospital.The last dosis of Dabigatran had been 6 hours ago. Due to the need of urgent surgery, idarazizumab was given in two intravenous boluses of 2.5 g.Hysterectomy with a double annexectomy was made.12 hours after surgery, anticoagulant treatment with low molecular weight heparin was introduced. She also presented hemorrhagic subhepatic abscess as a surgical complication (not related to dabigatran) that required percutaneous drainage, with good evolution. The patient was discharged continuing treatment with Bemiparin. 20 days later, Dabigatran 150mg/12h was reintroduced without further complications till the present date.CASE 2A 55-year-old male receiving anticoagulant Dabigatran 150mg/12h for NVAF, who came to the emergency for pain located in the right renal fossa for the previous 24h, along with dysuria and pollakiuria.On examination he had signs of severe pain; He was hemodynamically stable with fever (38ºC). Complementary tests: leukocytosis 12000x10e3/mm3, creatinine 1.5 mg/dL, and positive hematuria, Prothrombin activity 96%, APTT 37 seconds. Abdominal ultrasonography and CT scan were performed, showing complicated renal colic.It was decided to implant double J-catheter, for which we had to reverse the anticoagulant effect of Dabigatran, whose last dose had been taken in the previous 12 hours. For this, idarazizumab was given in two intravenous boluses of 2.5 g, and the intervention was carried out without incident.24 hours later, after a good clinical evolution of his renal pathology, and before no evidence of bleeding was evident, Dabigatran was restarted at its usual dose of 150mg/12h, with no new complications thus far.RESULTSThe use of idarucizumab permitted rapid and safe intervention of patients. Both had normal hemostasis during the procedure. 5 g dose of idarucizumab was sufficient and reversal was maintained for 24 hours. One patient presented hemorrhagic complication related to the surgical procedure.CONCLUSIONSIdarucizumab is integrated into protocol for the emergency management of patients on dabigatran. Idarucizumab is effective for dabigatran reversal among patients who have uncontrolled bleeding or will be undergoing urgent surgery. Idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. DisclosuresNo relevant conflicts of interest to declare.

Descriptive Analysis of Idarucizumab (Praxbind®) Use in a National Hospital Database

Study Objectives:Based on clinical data including the REVERSE AD study, idarucizumab (Praxbind®), the first reversal agent specific for dabigatran (Pradaxa®) users, received approval for indications of life threatening bleeding and emergency surgery/urgent procedures in patients treated with dabigatran when reversal of the anticoagulant effects of dabigatran is needed. The objectives of this analysis were to identify the number of idarucizumab encounters in a large national hospital database; describe indications and patient characteristics of those encounters; and, extrapolate the number of national uses.Methods:This is a retrospective analysis of the Premier Healthcare Database (PHD) among adult patients (age >18 years) with a hospital encounter between October 16, 2015 and September 30, 2016 and a billing charge for idarucizumab. For this analysis, idarucizumab indication was defined using ICD 9 and 10 diagnosis and procedures codes and Admission Type from the CMS UB04 Billing Form. Life threatening bleed was defined as intracranial hemorrhage or gastrointestinal bleed with admission type of emergent, urgent, or trauma; Emergency Surgery/Urgent Procedure was defined as procedure on the day of or day after admission with admission type of emergent, urgent, or trauma. Categorical variables were presented as counts and percentages (N, %) and continuous variables were summarized as means (standard deviations), medians and interquartiles. National volume projections were estimated using Premier's proprietary methodology that includes weighting according to hospital characteristics.Results:During the identification period, there were 558 encounters requiring idarucizumab. The mean patient age at encounter was 76 years (± 12), 53% were male, 88% were white, and the mean Charlson Comorbidity Index score was 2.4 (± 2.2). Among 494 patients, 60% were admitted with a life threatening bleed, 36% with an emergency surgery/urgent procedure and 4% fit both indication definitions; 64 (12%) could not be categorized. Among those admitted with life threatening bleeds, 61% were gastrointestinal and 36% were intracranial. The most common emergency surgery/urgent procedures were gastrointestinal surgeries for inspection, resection, excision, and/or repair (21%), bone repositioning (8%), drainage/repair of anatomical site (7%), joint replacement (7%) and hepatobiliary system/pancreas resection (6%). Overall, ninety-six percent of the initial dose administered was according to the label (5g/100mL). The estimated number of idarucizumab administrations nationally over the 1-year period was 2,225.Conclusion:This is the first real world descriptive analysis to characterize the utilization of idarucizumab in U.S. hospitals. From this analysis, withstanding the limitation of a retrospective analysis, the pattern of use for idarucizumb is consistent with what was observed in the REVERSE AD clinical trial. Further study is required to understand the implications of use on clinical and economic outcomes in a real-world setting. DisclosuresNo relevant conflicts of interest to declare.

Effects of Apixaban, Rivaroxaban, Dabigatran and Enoxaparin on Histopathology and Laboratory Parameters in Achilles Tendon Injury: An in vivo Study.

Objectives: To compare the effects of apixaban, rivaroxaban, dabigatran and enoxaparin on histopathology and blood parameters in rats with Achilles tendon injury.Materials and Methods: Thirty adult, male Wistar albino rats weighting 220–240 g were randomly divided into five (one control and four treatment) groups and placed in a controlled environment. The Achilles tendon was incised and re-sutured in each rat, after which each group was provided the following treatment for 28 days: a) 2 ml saline to the control group, b) apixaban in 1 ml of saline (10 mg/kg/day) +1 ml of saline, c) rivaroxaban in 1 ml of saline (2 mg/kg/day) +1 ml saline, d) dabigatran in 1 ml of saline (30 mg/kg/day) +1 ml of saline, e) enoxaparin (80 μg/kg/day) + 2 ml of saline.Results: Hemogram, biochemical and coagulation parameters differed significantly between the control and treatment groups (P < 0.05). Compared with the control group, in the apixaban group, type I and type III collagen immunoreactivity were severe and moderate, respectively. In the rivaroxaban and dabigatran groups, both type I and type III collagen immunoreactivity were medium and severe, respectively. In the enoxaparin group, type I and type III collagen immunoreactivity were mild and severe, respectively.Conclusion: The higher concentration of type I collagen in the apixaban and dabigatran indicates faster tendon healing in these groups, and the higher concentration of the type III collagen in the enoxaparin group indicates slower healing in this group.

Off‐target effects of oral anticoagulants – vascular effects of vitamin K antagonist and non‐vitamin K antagonist oral anticoagulant dabigatran etexilate

IntroductionVitamin K antagonists (VKA) and non‐vitamin K oral antagonist anticoagulants (NOAC) are used in the clinic to reduce risk of thrombosis. However, they also exhibit vascular off‐target effects. The aim of this study is to compare VKA and NOAC on atherosclerosis progression and calcification in an experimental setup. Material and methodsFemale Apoe−/− mice (age 12 weeks) were fed Western‐type diet as control or supplemented with dabigatran etexilate or warfarin for 6 or 18 weeks. Vascular calcification was measured in whole aortic arches using µCT and [18F]‐NaF. Atherosclerotic burden was assessed by (immuno)histochemistry. Additionally, in vitro effects of warfarin, thrombin, and dabigatran on primary vascular smooth muscle cells (VSMC) were assessed. ResultsShort‐term treatment with warfarin promoted formation of atherosclerotic lesions with a pro‐inflammatory phenotype, and more rapid plaque progression compared with control and dabigatran. In contrast, dabigatran significantly reduced plaque progression compared with control. Long‐term warfarin treatment significantly increased both presence and activity of plaque calcification compared with control and dabigatran. Calcification induced by warfarin treatment was accompanied by increased presence of uncarboxylated matrix Gla protein. In vitro, both warfarin and thrombin significantly increased VSMC oxidative stress and extracellular vesicle release, which was prevented by dabigatran. ConclusionWarfarin aggravates atherosclerotic disease activity, increasing plaque inflammation, active calcification, and plaque progression. Dabigatran lacks undesired vascular side effects and reveals beneficial effects on atherosclerosis progression and calcification. The choice of anticoagulation impacts atherosclerotic disease by differential off target effect. Future clinical studies should test whether this beneficial effect also applies to patients.

Alzheimer's Disease-Rationales for Potential Treatment with the Thrombin Inhibitor Dabigatran.

Alzheimer’s disease (AD) is caused by neurodegenerative, but also vascular and hemostatic changes in the brain. The oral thrombin inhibitor dabigatran, which has been used for over a decade in preventing thromboembolism and has a well-known pharmacokinetic, safety and antidote profile, can be an option to treat vascular dysfunction in early AD, a condition known as cerebral amyloid angiopathy (CAA). Recent results have revealed that amyloid-β proteins (Aβ), thrombin and fibrin play a crucial role in triggering vascular and parenchymal brain abnormalities in CAA. Dabigatran blocks soluble thrombin, thrombin-mediated formation of fibrin and Aβ-containing fibrin clots. These clots are deposited in brain parenchyma and blood vessels in areas of CAA. Fibrin-Aβ deposition causes microvascular constriction, occlusion and hemorrhage, leading to vascular and blood–brain barrier dysfunction. As a result, blood flow, perfusion and oxygen and nutrient supply are chronically reduced, mainly in hippocampal and neocortical brain areas. Dabigatran has the potential to preserve perfusion and oxygen delivery to the brain, and to prevent parenchymal Aβ-, thrombin- and fibrin-triggered inflammatory and neurodegenerative processes, leading to synapse and neuron death, and cognitive decline. Beneficial effects of dabigatran on CAA and AD have recently been shown in preclinical studies and in retrospective observer studies on patients. Therefore, clinical studies are warranted, in order to possibly expand dabigatran approval for repositioning for AD treatment.

Effectiveness and safety of idarucizumab in the management of perioperative complications of atrial fibrillation catheter ablation in atrial fibrillation patients under dabigatran therapy

Objective: To investigate the efficacy and safety of idarucizumab in the treatment of perioperative cardiac tamponade and thromboembolic events during catheter ablation in atrial fibrillation (AF) patients under dabigatran therapy. Methods: This study was a retrospective analysis enrolling patients under dabigatran therapy, who underwent catheter ablation for AF at Beijing Anzhen Hospital from January 2019 to December 2020 and developed perioperative cardiac tamponade or acute ischemic stroke (AIS) and received idarucizumab to reverse the anticoagulant effect of dabigatran. Patients' age, sex, renal function, coagulation test and safety events at 30 d after idarucizumab administration were collected and analyzed. The clinical presentation and prognosis were also analyzed. Results: A total of 7 patients were included, 2 (2/7) were male, mean age was (66.3±11.2) years, serum creatinine level was (66.3±13.6) μmol/L, estimated glomerular filtration rate was (89.4±11.2) ml·min-1·1.73 m-2, CHA2DS2-VASc and HAS-BLED scores were (3.2±1.9) and (1.3±1.3), respectively. Five patients (5/7) developed cardiac tamponade during the perioperative period and the time interval to the last dose of dabigatran was (6.3±2.6) h. Idarucizumab was given at (36.4±16.7) min after the definitive diagnosis of cardiac tamponade. A significant decrease of activated partial thromboplastin time was achieved after idarucizumab administration in all five cases. Pericardial puncture and drainage were applied to all patients (5/5) with cardiac tamponade, the drainage volume was (1 037.0±846.9) ml, the retention time of pericardial drainage catheter was (27.9±13.9) h, and the recovery time of anticoagulation was (28.4±13.2) h. One patient (1/5) underwent thoracotomy for hemostasis due to excessive blood loss with the aim of ensuring complete hemostasis. Bleeding occurred in 1 patient (1/5) after the first restart of anticoagulation. AIS occurred in 2 patients (2/7) after operation. One case (1/2) received intravenous thrombolysis after receiving 5.0 g idarucizumab, no hemorrhagic transformation was observed, and the recovery process was satisfactory. Another patient in this group experienced significantly prolonged onset time and 5.0 g idarucizumab was applied before intravascular thrombectomy, there was no bleeding complication in this patient after thrombectomy. At the time of discharge, the consciousness was not significantly improved, and the muscle strength of the right lower limb was recovered somehow compared with that before operation. No hypersensitivity reactions or thrombotic events occurred in these patients within 30 days of the administration of idarucizumab. Conclusion: In AF catheter ablation-associated cardiac tamponade and AIS, idarucizumab is safe and effective in rapidly reversing the anticoagulant effect of dabigatran, use of thrombectomy saves valuable time for timely hemostasis and improvement of cerebral blood circulation.

Influence of PAR-1 in patients with non-valvular atrial fibrillation: The antiplatelet effect of dabigatran

IntroductionDabigatran, a direct thrombin inhibitor, has been widely used in patients with non-valvular atrial fibrillation (NVAF) and is considered to have an antiplatelet effect. However, the mechanisms remain unclear. We evaluated protease-activated receptor-1 (PAR-1) expression and activation by thrombin on platelets from NVAF patients, before and after dabigatran treatment, in addition to the expression of platelet activation marker CD62P. Materials and methodsThe study included 18 NVAF patients. We used flow cytometry to measure the binding of PAR-1 monoclonal antibodies (SPAN12 and WEDE15) and the expression of CD62P with and without thrombin stimulation, before, 14 days after, and 28 days after treatment with dabigatran. Coagulation fibrinolysis markers were also measured. ResultsPAR-1 expression was significantly lower in NVAF patients than in healthy controls (HC); it was further reduced by thrombin stimulation. CD62P expression was almost absent on the platelets in NVAF patients, but was significantly increased by thrombin stimulation. PAR-1 expression was not significantly different before and after treatment; CD62P expression was inhibited by dabigatran. The levels of coagulation markers were significantly higher in NVAF patients than in HC, and decreased after treatment. ConclusionsLower expression of PAR-1 in NVAF patients resulted from the cleavage of PAR-1 on some platelets, by exposure to small amounts of thrombin in vivo. The therapeutic effect of dabigatran in NVAF patients was demonstrated by inhibition of CD62P expression on the platelet upon thrombin stimulation in vitro. Our results indicate that dabigatran may reveal antithrombotic activity with antiplatelet and anticoagulant effects.

Successful emergency surgery in a patient on dabigatran, after reversing the anticoagulation effect using Idarucizumab – A case report

Surgeons are required to keep themselves updated on ever-increasing list of drugs that may influence the outcomes of surgeries, especially in an emergency scenario. Here, we report a case of acute abdomen, wherein the patient was on dabigatran, a ‘Non-vit. K/Direct Oral Anti-Coagulant’ (NOAC/DOAC). NOACs are relatively recent additions to anticoagulation care. In our patient, dabigatran was prescribed by a cardiologist to prevent the occurrence of stroke in the patient who was suffering from atrial fibrillation. In case of uncontrolled bleeding, or when an emergency surgery is needed, the effect of dabigatran can be reversed with the use of a specific monoclonal antibody – idarucizumab. Knowledge about the drug &amp; its reversal agent, and a multi-disciplinary approach, could make it possible for us to operate on the patient, and avoid excessive bleeding during the surgery.

Pitfalls in the assessment of disseminated intravascular coagulation in patients on dabigatran

Dabigatran is an orally administrated anticoagulant that directly inhibits thrombin. However, the drug can affect routine coagulation tests such as prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time (TT), as well as haemostasis assays, (e.g., clot-based coagulation factor assays). There are limited data on the effect of dabigatran on some fibrinogen measurements and on D-dimer assays, both important components in the laboratory assessment of disseminated intravascular coagulation (DIC). The objectives of this study were: (1) to determine the effects of various concentrations of dabigatran on fibrinogen and D-Dimer assays; and (2) to compare the von Clauss method of fibrinogen measurement using two reagents with differing thrombin concentrations (35 UNIH/mL and 100 UNIH/mL) and PT-derived fibrinogen measurement in the presence of the drug. Aliquots of pooled normal plasma were spiked with different concentrations of dabigatran to reflect invivo on-therapy levels as well as levels observed in cases of massive accumulation of the drug. Of the routine coagulation assays, in ascending order of sensitivity to dabigatran were PT, APTT and TT. The von Clauss method of measuring fibrinogen using a reagent with low thrombin concentration was affected even at drug levels corresponding to invivo trough concentrations, whereas the reagent with higher thrombin concentration was only affected at drug levels that were above observed peak concentrations in patients taking 150 mg of the drug twice daily. PT-derived fibrinogen was affected at approximately invivo peak drug concentrations. The D-dimer assay was affected only at drug concentrations well above peak drug levels. Attempts at invitro neutralisation of the drug with DOAC-Stop resulted in 'correction' of some of these measurements depending on drug concentration. Like the routine coagulation assays, there is a dabigatran concentration dependent effect on the accuracy of fibrinogen and D-dimer assays. Falsely low fibrinogen results due to dabigatran may confound the assessment of DIC and diagnostic laboratories need to evaluate the performance of their own reagents.

Dabigatran mitigates cisplatin-mediated nephrotoxicity through down regulation of thrombin pathway

IntroductionCisplatin (CDDP) nephrotoxicity is one of the most significant complications limiting its use in cancer therapy. ObjectivesThis study investigated the pivotal role played by thrombin in CDDP-mediated nephrotoxicity. This work also aimed to clarify the possible preventive effect of Dabigatran (Dab), a direct thrombin inhibitor, on CDDP nephrotoxicity. MethodsAnimals were grouped as follow; normal control group, CDDP nephrotoxicity group, CDDP + Dab 15, and CDDP + Dab 25 groups. Four days following CDDP administration, blood and urine samples were collected to evaluate renal function. Moreover, tissue samples were collected from the kidney to determine apoptosis markers, oxidative stress and histopathological evaluation. An immunofluorescence analysis of tissue factor (TF), thrombin, protease-activated receptor-2 (PAR2), fibrin, pERK1/2 and P53 proteins expression was also performed. ResultsThrombin, pERK, cleaved caspase-3, and oxidative stress markers were significantly elevated in CDDP-treated group. However, pretreatment of animals with either low or high doses of Dab significantly improved kidney function and decreased oxidative stress and apoptotic markers. ConclusionWe conclude that thrombin is an important factor in the pathogenesis of CDDP kidney toxicity via activation of ERK1/2, P53 and caspase-3 pathway, which can be effectively blocked by Dab.

Impact of Dabigatran Treatment on Rotation Thromboelastometry.

A rapid and reliable assessment of the dabigatran effect is desirable in dabigatran treated patients with uncontrolled bleeding or before acute surgery. The aim of this study was to study the anticoagulant effects of dabigatran in patients with atrial fibrillation (AF) as assessed by the whole blood assays ROTEM, and how data from these methods correlate to plasma dabigatran concentrations measured by Hemoclot. ROTEM was performed with ROTEM Gamma (Pentapharm GmbH, Munich, Germany). The assays used in our study were Ex-tem and In-tem assay. Plasma dabigatran concentrations were determined by hemoclot thrombin inhibitor assay (Hyphen BioMed, France) at trough and post-dose in 27 patients on dabigatran 150 mg BID. Median plasma dabigatran concentrations at trough were 74 ng/mL (11.2–250) and post-dose (2 h after ingestion) 120 ng/mL (31–282). The ROTEM clotting time (CT) and maximum clot firmnes (MCF) correlated strongly with dabigatran concentrations when activated with the reagents Ex-tem (p < 0.0001) and In-tem (p < 0.0001). In summary, in our study, we have found that the ROTEM variable CT and MCF, when activated with triggers Ex-tem and In-tem, has a strong and highly significant correlation with the plasma dabigatran concentration in a real-life population of AF-patients and could thereby be an alternative to estimate dabigatran concentration in emergency situations. However, additional studies are needed to further validate these findings.

The Comparison of Therapeutic Efficacy Between Dabigatran Versus Warfarin in Patients With Nonvalvular Atrial Fibrillation.

BackgroundNovel oral anticoagulants and warfarin are widely used for stroke prevention in patients with atrial fibrillation. The anticoagulation status of patients receiving warfarin or rivaroxaban has been studied. In this study, we aimed to evaluate the effect of dabigatran and warfarin on preventing thrombin generation (TG).MethodsThis retrospective study enrolled 237 nonvalvular atrial fibrillation (NVAF) subjects treated with 110 mg dabigatran etexilate twice daily and 224 NVAF patients received adjusted-dose warfarin (international normalized ratio [INR] of 2 to 3)). Coagulation assays, prothrombin fragment 1 + 2 (F1+2), calibrated automated thrombogram, and thrombin–antithrombin complex (TAT) were detected at the steady state.ResultsActivated partial thromboplastin time (APTT), antithrombin III activity, fibrinogen, and lag time showed no difference between the two groups. Compared to the dabigatran group, prothrombin time and INR values were higher in the warfarin group (all P < .001). Thrombin time, endogenous thrombin potential, peak TG (Cmax), F1+2, and TAT were lower in the warfarin group. The inhibition of TG was still stronger in the warfarin group when the patients were divided into subgroups.ConclusionConventional coagulation assays are suboptimal for assessing the coagulation status of dabigatran. TG could be used as supplementary assays to evaluate the anticoagulation effect of oral anticoagulants. Our results suggest that warfarin may inhibit TG more aggressively than dabigatran in patients regardless of age and kidney function.

The protective effect of dabigatran and rivaroxaban on DNA oxidative changes in a model of vascular endothelial damage with oxidized cholesterol

Background: Atherosclerotic plaques are unstable, and their release may result in thrombosis; therefore, currently, antiplatelet therapy with anticoagulants is recommended for the treatment of acute coronary syndrome. The aim of this study was to assess the effect of oxidized cholesterol on human umbilical vascular endothelial cells (HUVECs). The study also examines the protective and repairing effect of dabigatran and rivaroxaban in a model of vascular endothelial damage with 25-hydroxycholesterol (25-OHC). Methods: HUVECs were treated with compounds induce DNA single-strand breaks (SSBs) using the comet assay. Oxidative DNA damage was detected using endonuclease III (Nth) or human 8 oxoguanine DNA glycosylase (hOOG1). Reactive oxygen species (ROS) formation was determined using flow cytometry. Results: 25-hydroxycholesterol caused DNA SSBs, induced oxidative damage and increased ROS in the HUVECs; ROS level was lowered by dabigatran and rivaroxaban. Only dabigatran was able to completely repair the DNA SSBs induced by oxysterol. Dabigatran was able to reduce the level of oxidative damage of pyrimidines induced by oxysterol to the level of control cells. Conclusions: Observed changes strongly suggest that the tested anticoagulants induced indirect repair of DNA by inhibiting ROS production. Furthermore, dabigatran appears to have a higher antioxidant activity than rivaroxaban.