Risk Of Systemic Bleeding Research Articles

A Meta-Analysis of Extracorporeal Anticoagulants in Pediatric Continuous Kidney Replacement Therapy.

Continuous kidney replacement therapy (CKRT) is the primary therapeutic modality utilized in hemodynamically unstable patients with severe acute kidney injury. As the circuit is extracorporeal, it poses an increased risk of blood clotting and circuit loss; frequent circuit losses affect the provider's ability to provide optimal treatment. The objective of this meta-analysis is to evaluate the safety and efficacy of the extracorporeal anticoagulants in the pediatric CKRT population. We conducted a literature search on PubMed/Medline and Embase for relevant citations. Studies were included if they involved patients under the age of 18 years undergoing CKRT, with the use of anticoagulation (heparin, citrate, or prostacyclin) as a part of therapy. Only English articles were included in the study. Initial search yielded 58 articles and a total of 24 articles were included and reviewed. A meta-analysis was performed focusing on the safety and effectiveness of regional citrate anticoagulation (RCA) vs unfractionated heparin (UFH) anticoagulants in children. RCA had statistically significantly longer circuit life of 50.65 hours vs. UFH of 42.10 hours. Two major adverse effects metabolic alkalosis and electrolyte imbalance seen more commonly in RCA compared to UFH. There was not a significant difference in the risk of systemic bleeding when comparing RCA vs. UFH. RCA is the preferred anticoagulant over UFH due to its significantly longer circuit life, although vigilant circuit monitoring is required due to the increased risk of electrolyte disturbances. Prostacyclin was not included in the meta-analysis due to the lack of data in pediatric patients. Additional studies are needed to strengthen the study results further.

Decreased INR on LVAD Support: To Bridge or Not to Bridge?

In volume 6, issue 2 of The VAD Journal, we published a paper by Rainess et al. who reported their experience with managing subtherapeutic INRs, mostly in patients with HeartMate II (Thoratec, Pleasanton, CA). Although, the cohort did include some HeartMate 3-supported patients. In their program (Wake Forest University), pharmacists manage anticoagulation according to the institutional protocol, which allows bridging with low molecular weight heparin when INR decreases to less than 1.8. The study is unique because the patients did NOT require interruption of anticoagulation for any purpose. In all instances, the INR decreased because of dietary variations, recent dose changes, skipped doses, medication interactions, etc. Almost half of their patients had a history of hemolysis or pump thrombosis. After analyzing 155 bridging episodes, the authors reported systemic bleeding events in 9% of the patients and localized bleeding in 10%. Importantly, no event resulted in hospitalization or blood transfusion; this rate seems to be excessive considering a relatively minor deviation of INR from the therapeutic range, and it raises a question about an appropriate threshold for bridging initiation. Studies such as Rainess et al. fill an important knowledge gap. From our standpoint, a 20% risk in bleeding, which includes a 9% risk of systemic bleeding, is a too high price to pay for such a minor decrease in INR. Perhaps tolerating a subtherapeutic INR for a few days would be a safer approach. A specific cutoff of the INR value triggering bridging should be a subject of a randomized study, but setting the bar at 1.8 may represent an excessively aggressive strategy.

0991. Nebulized heparin reduces pulmonary inflammatory responses in a rat model of acute lung injury

Sepsis is a mayor cause of acute lung injury (ALI). Pulmonary coagulopathy is intrinsic to ALI and in sepsis, anticoagulant system is impaired, due to consumption and downregulation by inflammatory mediators. Several studies, in ALI patients and in ALI experimental models, inconsistently suggest beneficial effects of systemic anticoagulants which affect systemic coagulation. Nebulization of anticoagulants might allow for higher pulmonary concentration and reduce the risk of systemic bleeding.

Dose escalation trial of the efficacy, safety, and pharmacokinetics of a novel fibrinolytic agent, BB-10153, in patients with ST elevation MI: Results of the TIMI 31 trial

Currently available fibrinolytic agents are limited by their ability to restore normal blood flow in only half of patients, the risk of reocclusion, and the risk of intracranial hemorrhage. The genetically engineered agent BB-10153 is activated by thrombin, not plasminogen activator enzymes, which limits its activity to the site of thrombus which may in turn reduce the risk of systemic bleeding. BB-10153 also has a relatively long half-life of 3-4 hours, which may also limit the potential for early reocclusion [1, 2]. The study was a phase II, open-label, multi-center, dose escalation, single-dose administration study to determine the efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics of BB-10153 in ST segment elevation MI (STEMI). STEMI patients (n = 50) received a single dose of BB-10153 at one of six dose levels (1.0, 2.0, 3.0, 5.0, 7.5 and 10 mg/kg). The primary endpoint was TIMI flow grade (TFG) 3 at 60 minutes following the intravenous bolus of BB-10153. Mean area under the curve for drug concentration ranged from 48.0 microg.h/mL in the 1 mg/kg dose group to 788.6 microg.h/mL in the 10 mg/kg dose group. Likewise, mean Cmax generally increased with dose over the entire dose range, from 4.9 microg/mL in the 1 mg/kg dose group to 139.6 microg/mL in the 10 mg/kg dose group. The mean apparent terminal half-life (t1/2) was 4.4 hours (range 2.2 to 7.6 hours). Few patients in the 1-3 mg/kg dosage groups achieved TFG 3 on the one-hour post-dose angiogram (4/20, 20%), and no patients achieved complete ST segment resolution. The 5, 7.5 and 10 mg/kg doses were associated with similar rates of TIMI grade 3 flow of approximately three per seven patients. Pooling TFG 3 data from the 5, 7.5 and 10 mg/kg groups yielded a TIMI grade 3 flow rate of 34% (n = 10/29; range 29-43%). No patients experienced 30-day death, recurrent acute MI, cardiogenic shock, stroke or anaphylaxis during the study. One patient experienced recurrent angina and developed recurrent myocardial ischemia requiring urgent revascularization. Three patients sustained TIMI major bleeding events (one in 1 mg/kg group, two in 7.5 mg/kg group), six patients sustained TIMI minor bleeds (one in the 2, 3, 7.5 and 10 mg/kg groups, two in the 5 mg/kg group), twp patients sustained TIMI minimal bleeds (one in each of the 2 and 10 mg/kg groups) and no patients sustained intracranial hemorrhage (ICH). In a dose escalation study of a single intravenous bolus, the novel fibrinolytic agent, BB-10153 was associated with a rise in the mean area under the curve and Cmax for drug concentration over the dose range 1 to 10 mg/kg. Higher doses were associated with a range of TIMI grade 3 flow of 29-43%, and no patients experienced 30-day death, recurrent acute MI, cardiogenic shock, stroke or anaphylaxis during the study. In a dose escalation study of a single intravenous bolus, the novel fibrinolytic agent, BB-10153 was associated with a rise in the mean area under the curve and Cmax for drug concentration over the dose range 1 to 10 mg/kg. Higher doses were associated with a range of TIMI grade 3 flow of 29-43%, and no patients experienced 30-day death, recurrent acute MI, cardiogenic shock, stroke or anaphylaxis during the study.