Novel Tissue Factor Inhibition for Thromboprophylaxis in COVID-19: Primary Results of the ASPEN-COVID-19 Trial

Abstract

BACKGROUND: Thrombo-inflammation is central to COVID-19-associated coagulopathy. TF (tissue factor), a driver disordered coagulation and inflammation in viral infections, may be a therapeutic target in COVID-19. The safety and efficacy of the novel TF inhibitor rNAPc2 (recombinant nematode anticoagulation protein c2) in COVID-19 are unknown. METHODS: ASPEN-COVID-19 was an international, randomized, open-label, active comparator clinical trial with blinded end point adjudication. Hospitalized patients with COVID-19 and elevated D-dimer levels were randomized 1:1:2 to lower or higher dose rNAPc2 on days 1, 3, and 5 followed by heparin on day 8 or to heparin per local standard of care. In comparisons of the pooled rNAPc2 versus heparin groups, the primary safety end point was major or nonmajor clinically relevant International Society of Thrombosis and Haemostasis bleeding through day 8. The primary efficacy end point was proportional change in D-dimer concentration from baseline to day 8, or discharge if before day 8. Patients were followed for 30 days. RESULTS: Among 160 randomized patients, median age was 54 years, 43.1% were female, and 38.8% had severe baseline COVID-19. There were no significant differences between rNAPc2 and heparin in bleeding or other safety events. Overall, median change in D-dimer was −16.8% (interquartile range, −45.7 to 36.8; P =0.41) with rNAPc2 treatment and −11.2% (−36.0 to 34.4; P =0.91) with heparin ( P intergroup =0.47). In prespecified analyses, in severely ill patients, D-dimer levels tended to increase more within the heparin (median, 29.0% [−14.9 to 145.2]; P =0.02) than the rNAPc2 group (median, 25.9% [−49.1 to 136.4]; P =0.14; P intergroup =0.96); in mildly ill patients, D-dimer levels were reduced within each group with a numerically greater reduction with rNAPc2 versus heparin (rNAPc2 median, −32.7% [−44.7 to 4.3]; P =0.007 and heparin median, −16.8% [−36.0 to 0.5]; P =0.008, P intergroup =0.34). CONCLUSIONS: rNAPc2 treatment in hospitalized patients with COVID-19 was well tolerated without excess bleeding or serious adverse events but did not significantly reduce D-dimer more than heparin at day 8. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04655586.

TF-FVIIa PAR2-β-Arrestin Signaling Sustains Organ Dysfunction in Coxsackievirus B3 Infection of Mice

“…9 More recently, NAPc2 was also evaluated in COVID19 and showed anticoagulant efficacy without apparent interference with antiviral immunity. 69 Whereas our study clearly defines the physiological importance of the TF-FVIIa-PAR2 axis in CVB3 infection, the phenotype differs from what was reported by Weithauser et al in PAR2 −/− mice. The investigators used the CVB3(N) strain to induce myocarditis and observed a reduction of viral load and myocardial inflammation.…”

Challenges to Laboratory Monitoring of Direct Oral Anticoagulants

“…With the recent phase 2 clinical trials of the use Factor XI inhibitors 92 , 93 and tissue factor inhibitors for anticoagulation therapy and thromboprophylaxis, 94 the list of medications in the “DOAC” will inevitably continue to expand. As the list of available anticoagulation medication grows and eventually become available for clinical use, it is in the best interest of the general patient population to develop and formalize guidelines and testing strategies, to improve anticoagulation stewardship.…”

Tissue Factor and COVID-19 Associated Thrombosis

“…The ASPEN-COVID-19 trial (Assessing Safety, Hospitalization and Efficacy of rNAPc2 in COVID-19) compared the effect of 8 days of treatment with recombinant NAPc2 to heparin (low molecular weight or unfractionated) on the activation of coagulation in patients with COVID-19. 38 Recombinant NAPc2 reduced plasma TF activity by 20.3%. However, it should be noted that measurement of TF in plasma is inferior to measurement of TF in isolated EVs, 37 and this low level of reduction may not accurately reflect the anticoagulant activity of rNAPc2.…”