Showing papers by "Peter L. Gross published in 2019"

Apixaban to Prevent Venous Thromboembolism in Patients with Cancer

Abstract: Background Patients with active cancer have an increased risk of venous thromboembolism, which results in substantial morbidity, mortality, and health care expenditures. The Khorana score (range, 0 to 6, with higher scores indicating a higher risk of venous thromboembolism) has been validated to identify patients with cancer at elevated risk for this complication and may help select those who could benefit from thromboprophylaxis. Methods We conducted a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score, ≥2) and were initiating chemotherapy. The primary efficacy outcome was objectively documented venous thromboembolism over a follow-up period of 180 days. The main safety outcome was a major bleeding episode. Results Of the 574 patients who underwent randomization, 563 were included in t...

Perioperative Management of Patients With Atrial Fibrillation Receiving a Direct Oral Anticoagulant

Abstract: Importance Patients with atrial fibrillation (AF) who use a direct oral anticoagulant (DOAC) and request elective surgery or procedure present a common clinical situation yet perioperative management is uncertain. Objective To investigate the safety of a standardized perioperative DOAC management strategy. Design, Setting, and Participants The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) cohort study conducted at 23 clinical centers in Canada, the United States, and Europe enrolled and screened patients from August 1, 2014, through July 31, 2018. Participants (n = 3007) had AF; were 18 years of age or older; were long-term users of apixaban, dabigatran etexilate, or rivaroxaban; were scheduled for an elective surgery or procedure; and could adhere to the DOAC therapy interruption protocol. Interventions A simple standardized perioperative DOAC therapy interruption and resumption strategy based on DOAC pharmacokinetic properties, procedure-associated bleeding risk, and creatinine clearance levels. The DOAC regimens were omitted for 1 day before a low–bleeding-risk procedure and 2 days before a high–bleeding-risk procedure. The DOAC regimens were resumed 1 day after a low–bleeding-risk procedure and 2 to 3 days after a high–bleeding-risk procedure. Follow-up of patients occurred for 30 days after the operation. Main Outcomes and Measures Major bleeding and arterial thromboembolism (ischemic stroke, systemic embolism, and transient ischemic attack) and the proportion of patients with an undetectable or minimal residual anticoagulant level ( Results The 3007 patients with AF (mean [SD] age of 72.5 [9.39] years; 1988 men [66.1%]) comprised 1257 (41.8%) in the apixaban cohort, 668 (22.2%) in the dabigatran cohort, and 1082 (36.0%) in the rivaroxaban cohort; 1007 patients (33.5%) had a high–bleeding-risk procedure. The 30-day postoperative rate of major bleeding was 1.35% (95% CI, 0%-2.00%) in the apixaban cohort, 0.90% (95% CI, 0%-1.73%) in the dabigatran cohort, and 1.85% (95% CI, 0%-2.65%) in the rivaroxaban cohort. The rate of arterial thromboembolism was 0.16% (95% CI, 0%-0.48%) in the apixaban cohort, 0.60% (95% CI, 0%-1.33%) in the dabigatran cohort, and 0.37% (95% CI, 0%-0.82%) in the rivaroxaban cohort. In patients with a high–bleeding-risk procedure, the rates of major bleeding were 2.96% (95% CI, 0%-4.68%) in the apixaban cohort and 2.95% (95% CI, 0%-4.76%) in the rivaroxaban cohort. Conclusions and Relevance In this study, patients with AF who had DOAC therapy interruption for elective surgery or procedure, a perioperative management strategy without heparin bridging or coagulation function testing was associated with low rates of major bleeding and arterial thromboembolism.

Factor XIII Prevents Pulmonary Emboli in Mice by Stabilizing Deep Vein Thrombi

Abstract: Background Deep vein thrombosis (DVT) can lead to pulmonary embolism (PE), but the mechanisms responsible for this progression are unknown. Previously, we showed that inhibition of thrombin-mediated activation of factor (F) XIII promotes venous thrombus stability in a murine model. Aim In this study, we investigate the consequence of attenuating fibrinolysis, using FXIII, α2-antiplasmin (α2-AP) or e-aminocaproic acid (EACA) supplementation, on clot lysis and venous thrombus stability using the same mouse model. Methods In vitro plasma clot lysis assay shows that EACA and α2-AP but not FXIII, inhibit fibrinolysis. Ferric chloride induced thrombi in the femoral vein of mice. After thrombus formation, mice received saline, EACA, α2-AP or FXIII, with or without dalteparin or dabigatran. Thrombus sizes and embolization over 2 hours were visualized using intravital videomicroscopy. Lungs were sectioned to quantify emboli presence via histology. Results The change in thrombus size over time was significantly greater after EACA treatment, but not FXIII or α2-AP supplementation, compared with saline. α2-AP-supplementation did not alter thrombus stability. Thrombi were more stable following EACA treatment and FXIII supplementation as evidenced by less embolic events and PE burden, even when they were anticoagulated with either dalteparin or dabigatran. Conclusion FXIII supplementation stabilized venous thrombi, even in the presence of anticoagulants, and did not alter thrombus size. Supplemental FXIII may be useful to stabilize DVT and be an alternative adjunctive treatment to minimize PE, even when anticoagulants are used.

Identification and characterization of a factor Va-binding site on human prothrombin fragment 2

Abstract: The fragment 2 domain (F2) of prothrombin and its interaction with factor (F) Va is known to contribute significantly to prothrombinase-catalyzed activation of prothrombin. The extent to which the F2-FVa interaction affects the overall thrombin generation, however, is uncertain. To study this interaction, nuclear magnetic resonance spectroscopy of recombinant F2 was used to identify seven residues within F2 that are significantly responsive to FVa binding. The functional role of this region in interacting with FVa during prothrombin activation was verified by the FVa-dependent inhibition of thrombin generation using peptides that mimic the same region of F2. Because six of the seven residues were within a 9-residue span, these were mutated to generate a prothrombin derivative (PT6). These mutations led to a decreased affinity for FVa as determined by surface plasmon resonance. When thrombin generation by an array of FXa containing prothrombinase components was monitored, a 54% decrease in thrombin generation was observed with PT6 compared with the wild-type, only when FVa was present. The functional significance of the specific low-affinity binding between F2 and FVa is discussed within the context of a dynamic model of molecular interactions between prothrombin and FVa engaging multiple contact sites.

Con: Tolvaptan for autosomal dominant polycystic kidney disease-do we know all the answers?

Abstract: According to recent literature, tolvaptan ameliorates the natural decline of renal function in autosomal dominant polycystic kidney disease. Tolvaptan is an orally available vasopressin V2 receptor antagonist. We describe herein the remaining questions and problems: it is unclear from the published work what influence tolvaptan has on total kidney volume. The consequences of hepatotoxicity for the subsequent dosing of tolvaptan have not been reported. A vasopressin V2 antagonist will cause polyuria and polydipsia and tolvaptan may influence quality of life (QOL), however, there are no QOL data. The cost-effectiveness of tolvaptan is borderline. It is unknown at which stage of renal failure tolvaptan therapy may have to be stopped. There are no established criteria to determine the ineffectiveness of tolvaptan. It is presently undecided whether a steady high water intake is able to imitate the renal effects of tolvaptan. Finally, the cause of worsening glomerular filtration rate after the start of tolvaptan is unknown.