key: cord-0917483-t1ih5h3o authors: Leucker, Thorsten M.; Osburn, William O.; Reventun, Paula; Smith, Kimberley; Claggett, Brian; Kirwan, Bridget-Anne; de Brouwer, Sophie; Williams, Marlene S.; Gerstenblith, Gary; Hager, David N.; Streiff, Michael B.; Solomon, Scott D.; Lowenstein, Charles J. title: Effect of Crizanlizumab, a P-Selectin Inhibitor, in COVID-19: A Placebo-Controlled, Randomized Trial date: 2021-12-08 journal: JACC Basic Transl Sci DOI: 10.1016/j.jacbts.2021.09.013 sha: 13f2f515ebbed52431103798edcbe15ddbb55c1c doc_id: 917483 cord_uid: t1ih5h3o COVID-19 is characterized by vascular inflammation and thrombosis, including elevations in P-selectin, a mediator of inflammation released by endothelial cells. We tested the effect of P-selectin inhibition on biomarkers of thrombosis and inflammation in patients with COVID-19. Hospitalized patients with moderate COVID-19 were randomly assigned to receive either placebo or crizanlizumab, a P-selectin inhibitor, in a double-blind fashion. Crizanlizumab reduced P-selectin levels by -89%. Crizanlizumab increased D-dimer levels by 77% and decreased prothrombin fragment. There were no significant differences between crizanlizumab and placebo for clinical endpoints. Crizanlizumab was well tolerated. Crizanlizumab may induce thrombolysis in the setting of COVID-19. (Crizanlizumab for Treating COVID-19 Vasculopathy [CRITICAL]; NCT04435184) SUMMARY COVID-19 is characterized by vascular inflammation and thrombosis, including elevations in P-selectin, a mediator of inflammation released by endothelial cells. We tested the effect of P-selectin inhibition on biomarkers of thrombosis and inflammation in patients with COVID-19. Hospitalized patients with moderate COVID-19 were randomly assigned to receive either placebo or crizanlizumab, a P-selectin inhibitor, in a double-blind fashion. Crizanlizumab reduced P-selectin levels by -89%. Crizanlizumab increased D-dimer levels by 77% and decreased prothrombin fragment. There were no significant differences between crizanli- (7, (10) (11) (12) (13) (14) . However, the role of these vascular mediators in the pathogenesis of COVID-19 is unknown (15) . We and others have hypothesized that endothelial cell release of vasoactive compounds may play a central role in the pathogenesis of severe COVID-19 (1, 2, 16) . Crizanlizumab is a humanized monoclonal antibody to P-selectin that decreases the occurrence of vaso-occlusive episodes in subjects with sickle cell disease (17) . We tested whether crizanlizumab de- Values are n (%) or mean AE SD. BMI ¼ body mass index; CAD ¼ coronary artery disease; CKD ¼ chronic kidney disease; COPD ¼ chronic obstructive pulmonary disease; DBP ¼ diastolic blood pressure; DVT ¼ deep vein thrombosis; HF ¼ heart failure; PAD ¼ peripheral artery disease; PE ¼ pulmonary embolism; SBP ¼ systolic blood pressure; TIA ¼ transient ischemic attack; WHO ¼ World Health Organization. were assessed in all randomized patients for whom study treatment was started. The primary endpoint, absolute change from baseline of P-selectin levels, was summarized for each treatment group with descriptive statistics, including mean, SD, median, and interquartile range, as appropriate. Evaluation of the between-group difference was assessed in an analysis of covariance, with baseline soluble P-selectin and treatment group as covariates. A soluble P-selectin value greater than the assay maximum measurement was imputed as The baseline clinical characteristics of the patients between the treatment groups were moderately well balanced for a small sample size, except for a history of coronary artery disease and race ( Table 1) . Baseline levels of blood biomarkers were similar between groups ( Table 2) . OUTCOMES. Baseline levels of P-selectin were similar between patient groups before receiving crizanlizumab (30 AE 20 ng/mL) and placebo (34 AE 15 ng/ mL). The mean AE SD changes from baseline to day 3 or before discharge were -23 AE 23 ng/mL and þ5 AE 18 ng/ mL. In baseline-adjusted models, crizanlizumab reduced P-selectin levels by 32 ng/mL (95% CI: 24-41; P < 0.001) by day 3 or before discharge (89% reduction from baseline), 38 ng/m: (95% CI: 28-48; P < 0.001) by day 7 (84% reduction from baseline), and Table 5 and Supplemental Table 4 ). There were no events for the endpoints of duration of mechanical ventilation, time to vascular event, stroke, or myocardial infarction. Several post hoc analyses were performed to better understand the effect of crizanlizumab on markers of thrombosis and fibrinolysis. Crizanlizumab had no effect on a wide variety of cytokine and chemokine biomarkers, except for IL-8 and IL-10, which were both significantly increased on day 3 postrandomization ( Table 6) . Crizanlizumab had no effect on plasmin-antiplasmin complex at 312 ng/mL (95% CI: 205-737) compared to placebo 345 ng/mL (95% CI: 180-788) with P ¼ 0.93 on day 3 ( Table 6) . Abbreviations as in Table 2 . Table 7) . Nonserious adverse events included headache, change in mental status, chest pain, urinary tract infection, and diarrhea. We found that crizanlizumab treatment resulted in Values are median (interquartile range) unless noted otherwise. The effect of crizanlizumab compared to placebo on biomarkers at day 3 or before discharge, day 7 or before discharge, and day 14 or before discharge is shown. Abbreviations as in Table 2 . We found that crizanlizumab was associated with an increase in D-dimer, a marker that has been associated with the severity of COVID-19 (21) (22) (23) . D-dimer, a fibrin degradation product, is typically elevated in the setting of thrombosis and concurrent thrombolysis (24, 25) , but can also be seen in the setting of therapies that stimulate thrombolysis (26) (27) (28) (29) (30) . Because we observed no evidence of increased mac- Endothelial cells release VWF and P-selectin from granules in response to vascular injury. Crizanlizumab did not affect levels of VWF in our subjects. We were unable to measure relative amounts of VWF multimers in our trial, and it is possible that crizanlizumab directly or indirectly changes the extent of VWF multimerization. Patients with any adverse events 6 4 10 Total moderate or severe adverse events 3 2 5 Patients with any moderate or severe adverse events 3 2 5 Total serious adverse events 1 0 1 Patients with any serious adverse events 1 0 1 Values are n. Adverse events in all subjects who received crizanlizumab or placebo are shown. CXCL10, pg/mL (n ¼ 38 CCL3, pg/mL Severe COVID-19 is a microvascular disease COVID-19 is, in the end, an endothelial disease Vascular endothelial damage in the pathogenesis of organ injury in severe COVID-19 Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science Endothelial cell infection and endotheliitis in COVID-19 Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19 Pathophysiology of SARS-CoV-2: the Mount Sinai COVID-19 autopsy experience Platelet and vascular biomarkers associate with thrombosis and death in coronavirus disease Endothelial injury and glycocalyx degradation in critically ill coronavirus disease 2019 patients: implications for microvascular platelet aggregation Erythrocyte, platelet, serum ferritin, and Pselectin pathophysiology implicated in severe hypercoagulation and vascular complications in COVID-19 Inflammatory and prothrombotic biomarkers associated with the severity of COVID-19 infection Markers of endothelial and epithelial pulmonary injury in mechanically ventilated COVID-19 ICU patients COVID-19 and its implications for thrombosis and anticoagulation The coagulopathy, endotheliopathy, and vasculitis of COVID-19 COVID-19 -2 0 2 Crizanlizumab for the prevention of pain crises in sickle cell disease WHO Working Group on the Clinical Characterisation and Management of COVID-19 Infection. A minimal common outcome measure set for COVID-19 clinical research Thrombosis and COVID-19: controversies and (tentative) conclusions Soluble Pselectin as a potential diagnostic and prognostic biomarker for COVID-19 disease: a case-control study Prevalence and outcomes of D-dimer elevation in hospitalized patients with COVID-19 Multiple biomarker approach to risk stratification in COVID-19 Association between D-dimer levels and mortality in patients with coronavirus disease 2019 (COVID-19): a systematic review and pooled analysis D-dimer antigen: current concepts and future prospects A test in context: D-dimer Recombinant tissue plasminogen activator in patients with pulmonary embolism: correlation of fibrinolytic specificity and efficacy Serial thrombolysis-related changes after thrombolytic therapy with TPA in patients with acute myocardial infarction Correlation between Ddimer levels and coronary artery reperfusion in acute myocardial infarction patients after thrombolytic treatment D-dimer in local thrombolytic therapy with low doses of recombinant human tissue-type plasminogen activator (rt-PA) in patients with peripheral arterial occlusive disease Assessment of fibrin degradation products during fibrinolytic therapy for acute myocardial infarction Evaluation of the prothrombin fragment 1.2 in patients with coronavirus disease 2019 (COVID-19) P-selectin promotes neutrophil extracellular trap formation in mice Pro-inflammatory cytokines associate with NETosis during sickle cell vaso-occlusive crises. Cytokine Neutrophil extracellular traps in COVID-19 The role of P-selectin in COVID-19 coagulopathy: an updated review