Position paper on the safety/efficacy profile of direct oral anticoagulants in patients with chronic kidney disease. Consensus document from the SIN, FCSA and SISET.

Direct oral anticoagulants (DOAC) are mostly prescribed to prevent cardioembolic stroke in patients with non-valvular atrial fibrillation (AF). An increasing number of guidelines recommend DOAC in AF patients with preserved renal function for the prevention of thromboembolism, and an increased use of DOAC in daily practice has been recorded also in elderly patients. Ageing is associated with a reduction in glomerular filtration rate, and impaired renal function, regardless of the cause, increases the risk of bleeding. Multiple medication use (polypharmacy) for treating superimposed co-morbidities is common in both elderly and chronic kidney disease (CKD) patients and drug-drug interaction may cause accumulation of DOAC, thereby increasing the risk of bleeding. The safety profile of DOAC in patients with CKD has not been defined with any certainty, particularly in those with severely impaired renal function or end stage renal disease. This has been due to the heterogeneity of studies and the relative paucity of data. This document reports the position of three Italian scientific societies engaged in the management of patients with atrial fibrillation who are treated with DOAC and present with CKD.

Factors Affecting Trough Plasma Dabigatran Concentrations in Patients with Atrial Fibrillation and Chronic Kidney Disease.

INTRODUCTION: Dabigatran is effective and widely used to prevent ischemic stroke and systemic embolism (SE) in patients with atrial fibrillation (AF). Chronic kidney disease (CKD) also has implications for choice of any medications, as it alters pharmacokinetic parameters of drugs. AIM: To evaluate trough plasma dabigatran concentration (DTPC) and to analyse potential factors affecting these values in patients with AF and CKD. METHODS: Patients with AF and stage 3 CKD were treated with dabigatran 110 mg or 150 mg have been included in the study and allocated into D110 or D150 group. DTPC was evaluated with high-performance liquid chromatography. A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index. Factors affecting the DTPC were investigated. RESULTS: A total of 60 patients, aged 51-89 years, were evaluated. Compared with patients given 150 mg twice a day, those given 110 mg twice a day were older (79 vs 67.5, p < 0.0001) and had lower creatinine clearance (CrCl) (50.5 vs 60.5 mL/min/1.73 m2, p = 0.015). During the median follow up of 9.5 months there were 11 bleedings in 9 patients. The C/D ratio was higher in patients aged > 75 years (p = 0.024) and was also affected by CrCl (CrCl < 50 mL/min, p = 0.02). Individuals with CKD 3B had higher concentration of dabigatran were compared with those with 3A stage (488.7 vs 332 pg/ml: mg/day, p = 0.02). However, there was also negative correlation between C/D and CrCl (r = - 0.4, p = 0.0015). Co-prescribed medications did not influence DTPC. In addition, patients with bleeding events were additionally evaluated for C/D and no significant differences were found. CONCLUSION: Patients on dabigatran treatment showed highly variable trough plasma concentrations. C/D values were significantly higher in patients with CKD 3B stage and were influenced by elder age and comorbidities.

Bivalirudin for Pediatric Procedural Anticoagulation: A Narrative Review.

Bivalirudin (Angiomax; The Medicines Company, Parsippany, NJ), a direct thrombin inhibitor, has found increasing utilization as a heparin alternative in the pediatric population, most commonly for the treatment of thrombosis secondary to heparin-induced thrombocytopenia. Due to the relative rarity of heparin-induced thrombocytopenia as well as the lack of Food and Drug Administration-approved indications in this age group, much of what is known regarding the pharmacokinetics and pharmacodynamics of bivalirudin in this population has been extrapolated from adult data. This narrative review will present recommendations regarding the use of bivalirudin for procedural anticoagulation in the pediatric population based on the published literature.

[Effects of combined natural hirudin and hyperbaric oxygen therapy on survival of transplanted random-pattern skin flap in rats].

Objective: To investigate the effect of natural hirudin combined with hyperbaric oxygen therapy on the survival of transplanted random-pattern skin flap in rats. Methods: A random-pattern skin flap in size of 10.0 cm×2.5 cm was elevated on the dorsum of 72 Sprague Dawley rats. Then the 72 rats were randomly divided into 4 groups ( n=18) according to the therapy method. At immediate and within 4 days after operation, the rats were treated with normal saline injection in control group, normal saline injection combined with hyperbaric oxygen treatment in hyperbaric oxygen group, the natural hirudin injection in natural hirudin group, and the natural hirudin injection combined with hyperbaric oxygen treatment in combined group. The flap survival was observed after operation, and survival rate was evaluated at 6 days after operation. The skin samples were collected for histological analysis, microvessel density (MVD) measurement, and evaluation of tumor necrosis factor α (TNF-α) expression level by the immunohistochemical staining at 2 and 4 days after operation. Results: Partial necrosis occurred in each group after operation, and the flap in combined group had the best survival. The survival rate of flap was significantly higher in hyperbaric oxygen group, natural hirudin group, and combined group than that in control group, and in combined group than in hyperbaric oxygen group and natural hirudin group ( P<0.05). There was no significant difference between hyperbaric oxygen group and natural hirudin group ( P>0.05). At 2 days, more microvascular structure was observed in hyperbaric oxygen group, natural hirudin group, and combined group in comparison with control group; while plenty of inflammatory cells infiltration in all groups. At 4 days, the hyperbaric oxygen group, natural hirudin group, and the combined group still showed more angiogenesis. Meanwhile, there was still infiltration of inflammatory cells in control group, inflammatory cells in the other groups were significantly reduced when compared with at 2 days. At 2 days, the MVD was significantly higher in hyperbaric oxygen group, natural hirudin group, and combined group than that in control group ( P<0.05); the expression of TNF-α was significantly lower in hyperbaric oxygen group, natural hirudin group, and combined group than that in control group ( P<0.05). There was no significant difference in above indexes between hyperbaric oxygen group, natural hirudin group, and combined group ( P>0.05). At 4 days, the MVD was significantly higher in hyperbaric oxygen group, natural hirudin group, and combined group than that in control group, in natural hirudin group and combined group than in hyperbaric oxygen group ( P<0.05). The expression of TNF-α was significantly lower in hyperbaric oxygen group, natural hirudin group, and combined group than that in control group, in combined group than in natural hirudin group and hyperbaric oxygen group ( P<0.05). Conclusion: Hyperbaric oxygen and natural hirudin therapy after random-pattern skin flap transplantation can improve the survival of flaps. Moreover, combined therapy is seen to exhibit significant synergistic effect. This effect maybe related to promotion of angiogenesis and the reduction of inflammation response.

Dabigatran - Metabolism, Pharmacologic Properties and Drug Interactions.

BACKGROUND: The superiority of dabigatran has been well proven in the standard dosing regimen in prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and extended venous thromboembolism (VTE) treatment. Dabigatran, an anticoagulant with a good safety profile, reduces intracranial bleeding in patients with atrial fibrillation and decreases major and clinically relevant non-major bleeding in acute VTE treatment. However, several important clinical issues are not fully covered by currently available directions with regard to dabigatran administration. The prominent one is reflected in the fact that dynamic impairment in renal function due to dehydratation may lead to haemorragic complications on the one hand, while on the other hand glomerular hyperfiltration may be a possible cause of dabigatran subdosing, hence reducing the drug's efficacy. Furthermore, limitations of the Cockcroft-Gault formula, considered a standard equation for assessing the renal function, may imply that other calculations are likely to obtain more accurate estimates of the kidney function in specific patient populations. Method and Conclusions: Although not routinely recommended, a possibility of monitoring dabigatran in special clinical settings adds to optimization of its dosage regimens, timely perioperative care and administration of urgently demanded thrombolytic therapy, therefore significantly improving this drug's safety profile. Despite the fact that dabigatran has fewer reported interactions with drugs, food constituents, and dietary supplements, certain interactions still remain, requiring considerable caution, notably in elderly, high bleeding risk patients, patients with decreased renal function and those on complex drug regimens. Additionally, upon approval of idarucizumab, an antidote to dabigatran solution, hitherto being a major safety concern, has been finally reached, which plays a vital role in life-threatening bleeding and emergency interventions and surgery.

Thrombotic and bleeding outcomes following perioperative interruption of direct oral anticoagulants in patients with venous thromboembolic disease.

Essentials Studies evaluating the procedural interruption of direct oral anticoagulants (DOACs) are lacking. We conducted a study of the interruption of DOACs for prior venous thromboembolic disease (VTE). The post-operative risks of recurrent VTE and major bleeding are low in this patient population. A scheme based on half-life and procedure-related bleeding appears safe and efficacious. SUMMARY: Background Direct oral anticoagulants (DOACs) are increasingly being used in the setting of venous thromboembolic disease (VTE). There is little evidence to guide the peri-procedural interruption of DOACs in this patient population. A number of studies have evaluated the perioperative interruption of DOACs based on half-life of the anticoagulant and the underlying procedural bleeding risk in patient with atrial fibrillation, but it remains unclear whether these findings can be extended to patients with VTE. Objective Evaluate thrombotic and bleeding outcomes following the perioperative interruption of direct oral anticoagulation in patients with prior VTE. Methods We conducted a retrospective analysis of consecutive patients on a DOAC for prior VTE requiring temporary interruption of anticoagulation for an invasive procedure. The primary efficacy outcome was the 30-day symptomatic VTE rate, and the primary safety outcome was the 30-day major bleeding rate. Secondary outcomes included overall mortality and the rate of clinically relevant non-major bleeding. Results A total of 190 patients were included in the analysis. The 30-day VTE rate was 1.05% (95% CI, 0.29-3.8%) and the 30-day major bleeding rate was 0.53% (95% CI, 0.09-2.93%). There were no deaths during the 30-day follow-up period. The rate of clinically relevant non-major bleeding was 3.16% (95%CI , 1.46-6.72%). Conclusions The perioperative interruption of DOACs in the setting of VTE, using a strategy that considers the half-life of the DOAC and the underlying procedural bleeding risk, appears to be both safe and effective.

Effect of bosutinib on the absorption of dabigatran etexilate mesylate, a P-glycoprotein substrate, in healthy subjects.

PURPOSE: Bosutinib, a dual Src and Abl tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia, demonstrated concentration-dependent inhibitory effects on P-glycoprotein (P-gp)-mediated digoxin efflux in vitro, suggesting that bosutinib may inhibit P-gp substrates. The effect of bosutinib on dabigatran etexilate mesylate (EM) absorption, a P-gp substrate, was evaluated. METHODS: In this open-label, randomized, single-dose, one-cohort, two-sequence, two-period crossover study, healthy, fed subjects received dabigatran EM (150 mg × 1 orally) alone or 1 h after receiving bosutinib tablets (100 mg × 5 orally). RESULTS: Dabigatran EM monotherapy and concurrent administration of dabigatran EM with bosutinib resulted in similar values for concentration time curves from time zero extrapolated to infinity (AUCinf), but slightly lower maximum plasma concentration (C max) values (AUCinf, 1182 and 1186 ng·h/mL, respectively; C max, 129.8 and 114.1 ng/mL). The time to maximum concentration for dabigatran was 2.99 and 3.99 h for combination therapy. The ratio of the adjusted geometric means (test/reference) of dabigatran AUCinf and C max (90 % confidence interval) were 101.4 % (89.6-114.9 %) and 89.7 % (77.8-103.4 %), respectively, following administration of dabigatran EM with bosutinib (test) relative to dabigatran EM administered alone (reference). Six subjects receiving combination treatment reported a total of seven adverse events (AEs) versus none for subjects receiving monotherapy alone. All AEs were mild to moderate and considered treatment related. CONCLUSION: These data demonstrate that single doses of bosutinib do not affect dabigatran exposure, suggesting that bosutinib is not a clinical inhibitor of P-gp. TRIAL REGISTRATION: ClinicalTrials.gov NCT02102633. https://clinicaltrials.gov/ct2/show/NCT02102633?term=NCT02102633&rank=1.

Vitreous and subretinal fluid concentrations of orally administered dabigatran in patients with rhegmatogenous retinal detachment.

PURPOSE: One of the factors that was shown to contribute to the development of proliferative vitreoretinopathy (PVR) is the coagulation factor thrombin. Therefore, a specific oral thrombin inhibitor such as dabigatran might be a possible therapeutic option. An oral drug has the advantage of patient-friendly prolonged administration in contrast to drugs that can only be applied during vitrectomy, on condition that the drug reaches the target site. We tested whether dabigatran reaches the vitreous and subretinal fluid (SRF) after a single oral dose of dabigatran. METHODS: Twenty-eight patients with a retinal detachment received a single dose of 220 mg dabigatran etexilate 2-8 hr prior to surgery. During surgery, we took a blood sample and a vitreous or subretinal fluid sample. The concentration of dabigatran was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: The dabigatran concentration between 2 and 9 hr after administration was higher in SRF than in vitreous (max 8.5 and 3.8 ng/ml). Corresponding plasma concentrations ranged from 15 to 225 ng/ml. There was a significant relationship between SRF levels and plasma levels (rs  = 0.68, p = 0.014); the levels in vitreous fluid showed no such relationship (rs  = 0.20, p = 0.48). In addition, we measured the vitreous concentration of a non-study patient using 150 mg dabigatran twice daily. The concentration was approximately 10 times higher than after a single dosage (25.8 ng/ml). CONCLUSION: We demonstrate that oral intake of dabigatran, a candidate drug to modulate PVR, results in potentially relevant intraocular concentrations. We suggest that repeated dosing may lead to higher concentrations, but this should be further explored.

Practical management of bleeding in patients receiving non-vitamin K antagonist oral anticoagulants.

Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used in the prevention and treatment of venous thromboembolism and in the prevention of stroke in patients with non-valvular atrial fibrillation. In phase III clinical trials and meta-analyses, the NOACs were at least as effective as vitamin K antagonists (VKAs) and were associated with a similar or lower incidence of major bleeding, including consistent and significant decreases in intracranial bleeding, although with an increase in gastrointestinal bleeding for some agents compared with VKAs. Subsequent real-world evidence supports these outcomes. Despite this, physicians have concerns about serious bleeding or emergencies because there are no specific reversal agents for the NOACs. However, in clinical trials, patients receiving NOACs generally had similar or better outcomes after these events than those taking VKAs. As with any bleeding, anticoagulant-related bleeding should first be stratified according to severity and location; risk can be minimised by ongoing assessment. Management protocols for NOAC-related bleeding are similar to those for VKAs but should take into account the pharmacological profile of the specific drug. Because of their short half-lives, NOAC-related mild bleeding can often be controlled by temporarily withholding treatment. More severe bleeding requires standard escalating haemodynamic support measures, and non-specific reversal agents can be considered in life-threatening situations, based on limited clinical data. Specific and rapid reversal agents are not currently available for any oral anticoagulant and restoration of coagulation may not necessarily lead to better outcomes. Nevertheless, specific NOAC reversal agents are in development and show promise in healthy volunteers.

[Management of new oral anticoagulants in gastrointestinal bleeding and endoscopy]. / Manejo de los nuevos anticoagulantes orales (NACO) en hemorragia digestiva y procedimientos endoscópicos.

New oral direct anticoagulants agents are alternatives to warfarin for long-term anticoagulation in a growing number of patients that require long-term anticoagulation for atrial fibrillation, deep venous thrombosis and pulmonary embolism. These new agents with predictable pharmacokinetic and pharmacodynamics profiles offer a favorable global safety profile, but increased gastrointestinal bleeding compared to the vitamin K antagonists. Many gastroenterologists are unfamiliar and may be wary of these newer drugs, since Clinical experience is limited and no specific antidote is available to reverse their anticoagulant effect. In this article the risk of these new agents and, how to manage these agents in both the presence of acute gastrointestinal bleeding and in patients undergoing endoscopic procedures is reviewed.

Comparison of intermittent and continuous extracorporeal treatments for the enhanced elimination of dabigatran.

CONTEXT: Severe bleeding associated with dabigatran frequently requires intensive care management. An antidote is currently unavailable and data reporting the effect of dialysis on elimination of dabigatran are encouraging, but limited. Objective. To report the effect of intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT) at enhancing elimination of dabigatran. MATERIALS AND METHODS: Patients were identified by existing collaborative networks. Pre-filter dabigatran plasma concentrations were measured in all patients, and in dialysate of three patients. RESULTS: Seven patients received dialysis, five with active bleeding and two requiring emergent surgery. Five received IHD and two received CRRT. The plasma elimination half-life of dabigatran was 1.5-4.9 h during IHD, and 14.0-27.5 h during CRRT. Mean dabigatran plasma clearance during IHD was 85-169 mL/min in three patients. Time to obtain a subtherapeutic dabigatran concentration depended on the initial concentration, being 8-18 h for IHD in three patients while 4 h was insufficient in a supratherapeutic case. A 38% rebound in dabigatran levels occurred after one case during IHD, and thrombin time increased after IHD in another, but not after 144 h CRRT or 17 h IHD in two others; data were incomplete in three cases. The amount removed during IHD was proportional to the pre-IHD concentration and clearance, but was consistently low at 3.3-17.4 mg in three patients where this was determined. Moderate bleeding occurred while obtaining vascular access in one patient. Two patients died from intracerebral bleeding, and the influence of treatments could not be determined in these cases. DISCUSSION AND CONCLUSIONS: IHD enhanced elimination of dabigatran more efficiently than CRRT, but their net effect remains poorly defined. Dialysis decisions, including modality and duration, must be individualized based on a risk-benefit assessment.

Enhanced elimination of dabigatran through extracorporeal methods.

Several pharmacokinetic studies have suggested that dabigatran possesses a number of ideal properties for expedited removal via extracorporeal methods. However, this practice has not been prospectively evaluated in patients with life-threatening bleeding or requiring emergency surgery secondary to dabigatran-associated coagulopathy. The purpose of this literature review is to evaluate the published evidence surrounding extracorporeal removal of dabigatran in the setting of emergency surgery or life-threatening bleeding. A query of MEDLINE, Web of Science, International Pharmaceutical Abstracts, and Google Scholar using the terms dabigatran, dabigatran etexilate, hemodialysis, renal replacement therapy, hemorrhage, and atrial fibrillation was used to retrieve relevant literature. Furthermore, a manual search of the references of the identified literature was performed to capture additional data. Current evidence suggests that extracorporeal removal of dabigatran may play a role in the setting of life-threatening bleeding and emergent surgery. Conflicting evidence exists with regard to the potential for redistribution based on serum dabigatran concentrations. In addition, a number of practicalities must be considered before incorporating this technique in the clinical setting. Extracorporeal removal of dabigatran may be a treatment modality in selected patients who require emergency reversal.

[Vaginal bleeding as symptom of a medical emergency--pitfalls of therapy with new oral anticoagulants - case 5/2014]. / Vaginale Blutung als Symptom eines internistischen Notfalls--Tücken der Therapie mit neuen oralen Antikoagulanzien - Fall 5/2014.

HISTORY AND ADMISSION FINDINGS: A 90-year-old female patient treated with dabigatran for atrial fibrillation presented emergently with a spontaneous vaginal bleeding due to endometrium carcinoma. INVESTIGATIONS: Laboratory analysis revealed azotemia consistent with acute-on-chronic renal failure. Coagulation was deranged (prolongation of activated partial thromboplastin time (aPTT) by 3.5-fold, international normalized ratio (INR) 7.8) due to a massive accumulation of dabigatran (measured plasma concentration 2230 ng/ml). DIAGNOSIS, TREATMENT AND COURSE: Vaginal bleedings were treated with external tamponade. Hemodialysis treatment was commenced due to uremia and dabigatran accumulation. Over night, the patient was dialysed with a SLED (sustained low efficiency dialysis) regimen. After volume resuscitation renal function promptly ensued indicating prerenal azotemia as a cause of renal failure. After two more hemodialysis sessions dabigatran concentrations were no longer detecable and this was paralleled by normalization of coagulation tests. CONCLUSIONS: Dabigatran can accumulate massively during acute renal failure and evoke a life-threatening bleeding diathesis. Dabigatran can be removed with low efficient dialysis (such as SLED).

Anticoagulation: a GP primer on the new oral anticoagulants.

BACKGROUND: The acceptability of warfarin has been limited by mandatory laboratory monitoring. A number of new orally active anticoagulants (NOACs), which can be used as alternatives to warfarin, are now available. OBJECTIVE: We review the clinical indications and considerations associated with the use of the NOACs. DISCUSSION: The NOACs currently approved in Australia are dabigatran, rivaroxaban and apixaban. Indications include thromboprophylaxis in non-valvular atrial fibrillation and following hip and knee replacement surgery. Rivaroxaban is also approved for treatment and secondary prevention of deep venous thrombosis (DVT) and pulmonary embolus (PE). The NOACs differ from warfarin in that they do not require laboratory monitoring. They need to be used cautiously in patients with renal impairment and are contraindicated in patients with renal failure. Bleeding may require blood product replacement aided by haematological advice and specialist investigations. Antidotes to the NOACS are undergoing clinical trials.

Use of continuous veno-venous haemodiafiltration therapy in dabigatran overdose.

CONTEXT: Dabigatran etexilate is one of the newer oral anticoagulants and a direct thrombin inhibitor. Concerns regarding dabigatran's use include its lack of validated laboratory markers for measuring its anticoagulation effect, the impact of renal impairment on its clearance, and the lack of effective strategies for reversal of anticoagulation. Hemodialysis has been utilized to reverse the anticoagulant effects of dabigatran in therapeutic doses. However, hemodialysis may not be feasible in hemodynamically unstable patients. There is little data on clearance rates of dabigatran by continuous renal replacement therapies. CASE DETAILS: A 66-year-old male presented following a poly-pharmacy overdose of 9 g of dabigatran in combination with metoprolol, amlodipine, olmesartan, and moxonidine. Eleven hours post overdose extracorporeal elimination was implemented as the patient developed worsening coagulopathy with an elevated international normalized ratio of 11 IU, an activated partial thromboplastin time of 115 s, and had renal impairment with a creatinine of 158 µmol/L. As the patient was hemodynamically unstable, continuous veno-venous hemodiafiltration was preferred over intermittent hemodialysis. Renal replacement therapy was performed for 32 h in total and the patient made a full recovery with no hemorrhagic complications or end organ injury. This patient developed a peak serum dabigatran level of 1560 ng/ml, 11 h postoverdose. Clearance of dabigatran via continuous veno-venous hemodiafiltration was calculated, using both the recovery and A-V pair methods, with a mean clearance of 58.1 and 31.9 ml/h, respectively, and a calculated mean extraction ratio of 0.2. CONCLUSION: There are few case reports and little experience when dabigatran is taken in overdose. This is a case report of a large dabigatran overdose presenting data on the extraction ratio and clearance of dabigatran using continuous veno-venous hemodiafiltration.

Pharmacokinetics of recombinant human antithrombin in delivery and surgery patients with hereditary antithrombin deficiency.

Population pharmacokinetic (PK) analyses were conducted to refine dosing recommendations for recombinant human anti-thrombin therapy in surgery and delivery patients with hereditary antithrombin deficiency (HD). Single-dose PK data from patients with HD and nonlinear mixed-effects modeling were used to devise a dosing regimen to target antithrombin (AT) activity levels between 80% and 120% of normal. External validation with data from a phase 3 trial confirmed the correctness of a covariate-free model for surgery patients, but dosing adjustment was necessary for delivery patients. After different covariates were tested, the model was updated to incorporate the influential covariate, delivery. Simulations were used to develop a therapeutic drug-monitoring scenario that results in steady state AT activity levels within the target range as quickly as practically feasible. Data from a second clinical trial provided additional external validation and confirmed the accuracy of the dosing model for both groups of patients.

Direct thrombin inhibitors: a case indicating benefit from 'plasmapheresis' in toxicity: a call for establishing "guidelines" in overdose and to find an "antidote"!

Patient presented with passage of fresh blood mixed with clots per rectum. In the ER, she was found to have bright red blood per rectum with clots, with frank blood on nasogastric tube. She was on dabigatran for atrial fibrillation and aspirin, with intermittent intake of ibuprofen. Vitals were positive for orthostatic hypotension. The pertinent findings in the physical examination were altered mental status with orientation*1, weak peripheral pulses, irregularly irregular heart rate, and bilateral pitting edema 2+ in bilateral lower extremities. Patient was intubated and put on mechanical ventilation. A massive transfusion protocol was followed. Laboratories and imaging: hemoglobin/hematocrit, 7.2/22.1; white blood cells, 7.7, platelet, 210; international normalized ratio, 2.5; prothrombin time, 19.2; activated partial thromboplastin time, 88.2; CMP was WNL; BNP, 621; fibrinogen, 500 mg/dL. Electrocardiogram showed atrial fibrillation with inferolateral ischemia. Ultrasonography of the liver and gallbladder showed no acute pathology. Echocardiogram showed an EF of 70% with hyperdynamic LV. Patient was transferred to the intensive care unit. Dabigatran, aspirin, and nonsteroidal anti-inflammatory drugs were discontinued, and antihypertensives were held. She was given blood and FFPs. Hemoglobin, hematocrit, and coagulation profile was monitored every 6 hours. Gastroenterology, general surgery, interventional radiology, and hematology services were called stat. IR placed a double-lumen, power central venous catheter. In gastroenterology, EGD and colonoscopy was performed, which showed active bleed at distal esophagus, stopped with local epinephrine. No active bleed seen on colonoscopy. The patient was put on Nexium drip. Hematology service recommended thrombin time (>200) and factors 2, 5, 7, 9, 10-41(l), 80, 68, 48(l), 61. Prothrombin time and activated partial thromboplastin time mixing studies were done, which indicated the presence of thrombin inhibition. Prothrombin complex concentrate at 50 U/kg was started to reverse the effect of dabigatran, and platelets were transfused to reverse the effect of aspirin. They also discussed that the half-life of dabigatran being 17 hours, and the drug would not be toxic at this point, as the patient was already 24-hour inpatient by now. The hemoglobin trend: 7.4→6.4→8.2→7.5→6.6. At this point, the need for further intervention in form of hemodialysis or plasmapheresis was considered. The patient was given plasmapheresis and hemoglobin and hematocrit stabilized. The patient was kept on continued mechanical ventilator support for the night and extubated next day. The hemodynamics stabilized and the patient was transferred to the general medical floors after 1 day of observation, after extubation.

Delivery of neurotherapeutics across the blood brain barrier in stroke.

Stroke is a devastating disease with few therapeutic options. Despite our growing understanding of the critical mechanistic events in post-stroke brain injury, the clinical translation of these findings has been less effective. A monumental hurdle to the field has been the inability of many systemically applied therapies to efficiently cross the blood brain barrier (BBB) and enter brain cells. Over the last two decades, however, significant technological achievements have overcome this obstacle to facilitate central nervous system (CNS) drug delivery. Noninvasive drug carriers, especially cell penetrating peptide (CPP) show great potential to deliver neurotherapeutics across the BBB for the treatment of ischemic brain injury. This review begins with a brief introduction to the BBB in relation to drug delivery and then provides an overview of the development of drug carriers for neurotherapeutics, with a focus on CPP-mediated transduction. We discuss recent advances and limitations in this field, as well as mechanisms underlying CPP-mediated brain targeting. We also summarize the application of CPPs in stroke research. Continuing modifications and improvements of CPPs are expected to enhance both their feasibility in clinical stroke management and their specificity towards particular cell types.