A Multisite Retrospective Review of Direct Oral Anticoagulants Compared to Warfarin in Adult Fontan Patients.

PURPOSE: Direct oral anticoagulants (DOACs) are not recommended in adult Fontan patients (Level of Evidence C). We hypothesized that DOACs are comparable to warfarin and do not increase thrombotic and embolic complications (TEs) or clinically significant bleeds. METHODS: We reviewed the medical records of adult Fontan patients on DOACs or warfarin at three major medical centers. We identified 130 patients: 48 on DOACs and 107 on warfarin. In total, they were treated for 810 months on DOACs and 5637 months on warfarin. RESULTS: The incidence of TEs in patients on DOACs compared to those on warfarin was not increased in a statistically significant way (hazard ratio [HR] 1.7 and p value 0.431). Similarly, the incidence of nonmajor and major bleeds in patients on DOACs compared to those on warfarin was also not increased in a statistically significant way (HR for nonmajor bleeds in DOAC patients was 2.8 with a p value of 0.167 and the HR for major bleeds was 2.0 with a p value 0.267). In multivariate analysis, congestive heart failure (CHF) was a risk factor for TEs across both groups (odds ratio [OR] = 4.8, 95% confidence interval [CI] = 1.3-17.6) and bleed history was a risk factor for clinically significant bleeds (OR = 6.8, 95% CI = 2.7-17.2). CONCLUSION: In this small, retrospective multicenter study, the use of DOACs did not increase the risk of TEs or clinically significant bleeds compared to warfarin in a statistically significant way.

Novel oral anticoagulant use in adult Fontan patients: A single center experience.

OBJECTIVE: Adult Fontan patients are at increased risk for thrombosis and thromboembolic complications leading to increased morbidity and mortality. Most are prescribed antiplatelet or anticoagulant therapy for thromboprophylaxis; novel oral anticoagulants (NOACs) are uncommonly used given lack of data on their use in this population and generalized concerns regarding Fontan patients' abnormal coagulation. We report the largest single-center experience with the use of NOACs for treatment and prophylaxis of thrombosis and thromboembolism in adult Fontan patients. RESULTS: A retrospective chart review identified 21 patients (11 female, 10 male), median age 33 years (18-50) at first initiation, who were prescribed a NOAC on 27 different occasions. The main indications for anticoagulation were arrhythmia (N = 12), thrombosis (N = 8), and persistent right to left shunts (N = 2); one patient was initially on anticoagulation for arrhythmia but restarted for thrombosis. The most common indications for initiation of a NOAC over warfarin were patient/provider preference (N = 11), labile international normalized ratio (INR) (N = 5), initiation of therapy elsewhere (N = 3), and history of poor clinical follow-up (N = 2). Over a cumulative 316 months of patient therapy, one new thrombotic event was noted. No major or nonmajor bleeding events occurred, and 10 patients experienced minor bleeding that did not require the cessation of therapy. One patient died from multiorgan system failure following an unwitnessed, out of hospital arrest. At present, 10 patients remain on NOAC therapy in the setting of ongoing arrhythmia (N = 4), history of stroke (N = 2), history of pulmonary embolism (N = 2), history of deep vein thrombosis (N = 1), and history of right ventricle thrombus (N = 1). CONCLUSIONS: While our study is limited by size, our results suggest that NOACs may be a non-inferior alternative to traditional anticoagulation and that further study is warranted.

Poly(A) signal-dependent degradation of unprocessed nascent transcripts accompanies poly(A) signal-dependent transcriptional pausing in vitro.

The poly(A) signal has long been known for its role in directing the cleavage and polyadenylation of eukaryotic mRNA. In recent years its additional coordinating role in multiple related aspects of gene expression has also become increasingly clear. Here we use HeLa nuclear extracts to study two of these activities, poly(A) signal-dependent transcriptional pausing, which was originally proposed as a surveillance checkpoint, and poly(A) signal-dependent degradation (PDD) of unprocessed transcripts from weak poly(A) signals. We confirm directly, by measuring the length of RNA within isolated transcription elongation complexes, that a newly transcribed poly(A) signal reduces the rate of elongation by RNA polymerase II and causes the accumulation of elongation complexes downstream from the poly(A) signal. We then show that if the RNA in these elongation complexes contains a functional but unprocessed poly(A) signal, degradation of the transcripts ensues. The degradation depends on the unprocessed poly(A) signal being functional, and does not occur if a mutant poly(A) signal is used. We suggest that during normal 3'-end processing the uncleaved poly(A) signal continuously samples competing reaction pathways for processing and for degradation, and that in the case of weak poly(A) signals, where poly(A) site cleavage is slow, the default pathway to degradation predominates.

The conserved AAUAAA hexamer of the poly(A) signal can act alone to trigger a stable decrease in RNA polymerase II transcription velocity.

In vivo the poly(A) signal not only directs 3'-end processing but also controls the rate and extent of transcription. Thus, upon crossing the poly(A) signal RNA polymerase II first pauses and then terminates. We show that the G/U-rich region of the poly(A) signal, although required for termination in vivo, is not required for poly(A)-dependent pausing either in vivo or in vitro. Consistent with this, neither CstF, which recognizes the G/U-rich element, nor the polymerase CTD, which binds CstF, is required for pausing. The only part of the poly(A) signal required to direct the polymerase to pause is the AAUAAA hexamer. The effect of the hexamer on the polymerase is long lasting--in many situations polymerases over 1 kb downstream of the hexamer continue to exhibit delayed progress down the template in vivo. The hexamer is the first part of the poly(A) signal to emerge from the polymerase and may play a role independent of the rest of the poly(A) signal in paving the way for subsequent events such as 3'-end processing and termination of transcription.

The RNA tether from the poly(A) signal to the polymerase mediates coupling of transcription to cleavage and polyadenylation.

We have investigated the mechanism by which transcription accelerates cleavage and polyadenylation in vitro. By using a coupled transcription-processing system, we show that rapid and efficient 3' end processing occurs in the absence of crowding agents like polyvinyl alcohol. The continuity of the RNA from the poly(A) signal down to the polymerase is critical to this processing. If this tether is cut with DNA oligonucleotides and RNaseH during transcription, the efficiency of processing is drastically reduced. The polymerase is known to be an integral part of the cleavage and polyadenylation apparatus. RNA polymerase II pull-down and immobilized template experiments suggest that the role of the tether is to hold the poly(A) signal close to the polymerase during the early stages of processing complex assembly until the complex is sufficiently mature to remain stably associated with the polymerase on its own.