Clinical Pathways and Outcomes of Andexanet Alfa Administration for the Reversal of Critical Bleeding in Patients on Oral Direct Factor Xa Inhibitors.

Background Andexanet is U.S. Food and Drug Administration (FDA) approved for the reversal of critical bleeding from factor Xa inhibitors and off-label for surgical reversal. Data are lacking on andexanet administration processes. Methods We retrospectively studied patients at a 23-hospital system who received andexanet from November 2019 to March 2023. Abstractors coded demographics, comorbidities, anticoagulant use, andexanet indication, and process times. The primary outcome was presentation-to-andexanet time; diagnosis, ordering, and administration times were calculated. Secondary outcomes included in-hospital postandexanet major thromboembolism/bleeding and mortality. Results In total, 141 patients were analyzed. Andexanet indications were predominantly neurologic bleeding (85.8%). Twenty-four patients (17.0%) were transferred from nontertiary/academic centers to tertiary/academic centers. The median presentation-to-administration time was 192.5 minutes (interquartile range [IQR]: 108.0-337.0 minutes). Components were as follows: 72.5 minutes (IQR: 39.0-137.5 minutes) for bleeding diagnosis; 35.5 minutes (IQR: 0-96.5 minutes) for andexanet ordering; and 53.0 minutes (IQR: 38.5-78.5 minutes) for administration, which was longer at tertiary/academic hospitals (ratio 1.5, 95% confidence interval [CI]: 1.2-2.0, p = 0.002). Gastrointestinal or other critical bleeding (ratio 2.59, 95% CI: 1.67-4.02, p < 0.001), and tertiary/academic center treatment (ratio 1.58, 95% CI: 1.15-2.18, p = 0.005), were associated with increased time. Major thromboembolism, bleeding, and mortality occurred in 10.6, 12.0, and 22.9% of patients, respectively. Conclusions In our cohort, the median presentation-to-administration time was over 3 hours. Cumulative times were longer at tertiary/academic hospitals and for gastrointestinal/other bleeding. Postandexanet major thromboembolism/bleeding occurred more at tertiary/academic hospitals, possibly related to transfers. Prospective studies may elucidate clinical decision-making bottlenecks.

Streptococcus mutans endocarditis resulting in severe aortic and mitral valve dysfunction and congestive heart failure.

A patient in his 40s with no known cardiac history presented to the emergency department with midsternal chest pain worse on inspiration for the past 1 week. He also complains of recent weight loss, dry cough and night sweats during this time. He describes significant dental pain as well. Electrocardiogram showed no acute ischemic changes. Transesophageal echocardiography showed a nodular echodensity affecting the mitral valve with severe regurgitation, and echodensity affecting the aortic valve with severe regurgitation. Blood cultures grew Streptococcus mutans in multiple samples. He was treated with intravenous antibiotics and had a mechanical aortic and mitral valve replacement. He continued to have persistent left and right ventricular dysfunction several months later despite medical and surgical treatment.

Fulminant lymphocytic myocarditis secondary to Coxsackie A virus with full myocardial recovery following venoarterial extracorporeal membrane oxygenation.

We present a case of a 30-year-old female with no pertinent medical history who presented with 4 days of chest pressure, dyspnea and fever. She had hemodynamic compromise and had elevated cardiac and inflammatory markers consistent with cardiogenic shock. ECG demonstrated anterior ST-segment elevations with reciprocal changes. Coronary angiography revealed normal coronaries and echocardiogram showed severe biventricular dysfunction. Endomyocardial biopsy showed signs of lymphocytic myocarditis and viral testing was positive for Coxsackie A. She was initially supported with an intra-aortic balloon pump and later escalated to venoarterial extracorporeal membrane oxygenation due to electromechanical compromise. With supportive care, she was weaned off venoarterial extracorporeal membrane oxygenation and made a full myocardial recovery on follow up echocardiogram and cardiac MRI.

The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery.

BACKGROUND: Heterozygous loss of function mutations in the KCNK3 gene cause hereditary pulmonary arterial hypertension (PAH). KCNK3 encodes an acid-sensitive potassium channel, which contributes to the resting potential of human pulmonary artery smooth muscle cells. KCNK3 is widely expressed in the body, and dimerizes with other KCNK3 subunits, or the closely related, acid-sensitive KCNK9 channel. METHODS AND RESULTS: We engineered homomeric and heterodimeric mutant and nonmutant KCNK3 channels associated with PAH. Using whole-cell patch-clamp electrophysiology in human pulmonary artery smooth muscle and COS7 cell lines, we determined that homomeric and heterodimeric mutant channels in heterozygous KCNK3 conditions lead to mutation-specific severity of channel dysfunction. Both wildtype and mutant KCNK3 channels were activated by ONO-RS-082 (10 µmol/L), causing cell hyperpolarization. We observed robust gene expression of KCNK3 in healthy and familial PAH patient lungs, but no quantifiable expression of KCNK9, and demonstrated in functional studies that KCNK9 minimizes the impact of select KCNK3 mutations when the 2 channel subunits co-assemble. CONCLUSIONS: Heterozygous KCNK3 mutations in PAH lead to variable loss of channel function via distinct mechanisms. Homomeric and heterodimeric mutant KCNK3 channels represent novel therapeutic substrates in PAH. Pharmacological and pH-dependent activation of wildtype and mutant KCNK3 channels in pulmonary artery smooth muscle cells leads to membrane hyperpolarization. Co-assembly of KCNK3 with KCNK9 subunits may provide protection against KCNK3 loss of function in tissues where both KCNK9 and KCNK3 are expressed, contributing to the lung-specific phenotype observed clinically in patients with PAH because of KCNK3 mutations.