Relative hypercoagulopathy of the SARS-CoV-2 Beta and Delta variants when compared to the less severe Omicron variants is related to TEG parameters, the extent of fibrin amyloid microclots, and the severity of clinical illness. (preprint)

Earlier variants of SARS-CoV-2 have been associated with plasma hypercoagulability (as judged by thromboelastography) and an extensive formation of fibrin amyloid microclots, which are considered to contribute to the pathology of the coronavirus 2019 disease (COVID-19). The newer Omicron variants appear to be far more transmissible, but less virulent, even when taking immunity acquired from previous infections or vaccination into account. We here show that while the clotting parameters associated with Omicron variants are significantly raised over those of healthy, matched controls, they are only raised to levels significantly lower than those seen with more severe variants such as Beta and Delta. We also observed that individuals infected with Omicron variants manifested less extensive microclot formation in platelet poor plasma compared to those harbouring the more virulent variants. The measurement of clotting effects between the different variants acts as a kind of ‘internal control’ that demonstrates the relationship between the extent of coagulopathies and the virulence of the variant of interest. This adds to the evidence that microclots play an important role in determining the severity of symptoms observed in COVID-19.

STudy of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19 (STARS): A Vanguard Multicenter, Rapidly Adaptive, Pragmatic, Randomized, Controlled Trial (preprint)

Background: Pulmonary vascular microthrombi have been proposed as a mechanism of COVID19 respiratory failure. We hypothesized that early administration of tissue-plasminogen activator(tPA) followed by therapeutic heparin would improve pulmonary function in these patients.Methods: Adults with COVID-19-induced respiratory failure were randomized May14, 2020-March 3, 2021 in two phases: Phase-1(n=36): control (standard-of-care) vs tPA-Bolus (50mg tPA IV-bolus followed by 7 days of heparin (goal aPTT=60-80s); Phase-2(n=14): control vs tPA-Drip (50 mg of tPA IV-bolus, followed by tPA drip 2mg/hr plus heparin 500U/hour over 24 hours, then heparin to maintain aPTT 60-80s/7 days). The primary outcome was PaO2/FiO2 improvement at 48 hours post-randomization. Secondary outcomes included: PaO2/FiO2 improvement>50% or PaO2/FiO2>=200 at 48hrs(COMPOSITE), ventilator-free days(VFD) and mortality.Findings: Fifty patients were randomized: Phase 1:17 control, 19 tPA-Bolus; Phase 2: 8 control, 6 tPA-Drip. There were no severe bleeding events in intervention groups. In tPA-Bolus patients, PaO2/FiO2 was significantly(p<0.017) higher than baseline at 6 through 168 hours post-randomization; controls experienced no significant improvements. Compared to controls, tPA-Bolus patients showed larger, but non-significant, improvements in PaO2/FiO2 at 48hours[16.9%(-8.3–36.8) vs 29.8%(4.5–88.7),p=0.11], resulting in more patients reaching the COMPOSITE outcome (11.8% vs 47.4%,p=0.03). Controls had less VFD[0.0(0.0–9.0) vs 12.0(0.0–19.0),p=0.11] and higher mortality(41.2% vs 21.1%,p=0.19) than tPA-Bolus patients, although not significantly. tPA-Drip patients did not experience benefit compared to simultaneously enrolled controls.Interpretation: The combination tPA-Bolus+heparin is safe in severe COVID-19 respiratory failure. A Phase 3 study is warranted given promising improvements in oxygenation, VFD, and mortality.Trial Registration: The trial was performed according to the Food and Drug Administration (FDA) Investigational New Drug regulations (IND 149634) and registered with ClinicalTrials.gov (NCT04357730).Funding: This investigator-initiated trial (NCT04357730) was funded by Genentech, Inc.Declaration of Interests: CDB, HBM, EEM, and MBY have patents pending related to both coagulation/fibrinolysis diagnostics and therapeutic fibrinolytics, and are passive co-founders and holds stock options in Thrombo Therapeutics, Inc. HBM and EEM have received grant support from Haemonetics and Instrumentation Laboratories. MBY has previously received a gift of Alteplase (tPA) from Genentech, and owns stock options as a co-founder of Merrimack Pharmaceuticals. CDB, HBM, EEM, JW, NH, DST, AS, and MBY have received research grant funding from Genentech. JW receives consulting fees from Camurus A. B.. All other authors have nothing to disclose.Ethics Approval Statement: All participating trial sites had study approval and oversight from their respective Institutional Review Boards. Due to the nature of the study, which enrolled critically ill patients on mechanical ventilation, informed consent for trial participation was obtained from each patient’s Legally Authorized Representative. An independent Data Safety Monitoring Board (DSMB) oversaw the safety of the trial with mandatory reviews at each interim analysis and for all suspected serious adverse events. Data were stored in a REDCap instrument sponsored by NIH/NCATS Colorado CTSA Grant Number UL1 TR002535.