Platelet and Vascular Biomarkers Associate With Thrombosis and Death in Coronavirus Disease
Authors: Tessa J. Barrett, Angela H. Lee, Yuhe Xia, Lawrence H. Lin, Margaret Black, Paolo Cotzia, Judith Hochman, Jeffrey S. Berger
Journal: Circulation Research (2020)

HomeCirculation ResearchVol. 127, No. 7Platelet and Vascular Biomarkers Associate With Thrombosis and Death in Coronavirus Disease Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBPlatelet and Vascular Biomarkers Associate With Thrombosis and Death in Coronavirus Disease Tessa J. Barrett, Angela H. Lee, Yuhe Xia, Lawrence H. Lin, Margaret Black, Paolo Cotzia, Judith Hochman and Jeffrey S. Berger Tessa J. BarrettTessa J. Barrett Department of Medicine (T.J.B., A.H.L., Y.X., J.H., J.S.B.), New York University Grossman School of Medicine, NY. , Angela H. LeeAngela H. Lee Department of Medicine (T.J.B., A.H.L., Y.X., J.H., J.S.B.), New York University Grossman School of Medicine, NY. , Yuhe XiaYuhe Xia Department of Medicine (T.J.B., A.H.L., Y.X., J.H., J.S.B.), New York University Grossman School of Medicine, NY. , Lawrence H. LinLawrence H. Lin https://orcid.org/0000-0001-9603-9783 Department of Pathology (L.H.L., M.B., P.C.), New York University Grossman School of Medicine, NY. , Margaret BlackMargaret Black Department of Pathology (L.H.L., M.B., P.C.), New York University Grossman School of Medicine, NY. , Paolo CotziaPaolo Cotzia Department of Pathology (L.H.L., M.B., P.C.), New York University Grossman School of Medicine, NY. Center for Biospecimen Research Development (P.C.), New York University Grossman School of Medicine, NY. , Judith HochmanJudith Hochman https://orcid.org/0000-0002-5889-5981 Department of Medicine (T.J.B., A.H.L., Y.X., J.H., J.S.B.), New York University Grossman School of Medicine, NY. and Jeffrey S. BergerJeffrey S. Berger Correspondence to: Jeffrey S. Berger, MD, MS, Center for the Prevention of Cardiovascular Disease, New York University School of Medicine, 530 First Ave, Skirball 9R, New York, NY 10016. Email E-mail Address: [email protected] https://orcid.org/0000-0001-8216-4647 Department of Medicine (T.J.B., A.H.L., Y.X., J.H., J.S.B.), New York University Grossman School of Medicine, NY. Department of Surgery (J.S.B.), New York University Grossman School of Medicine, NY. Originally published6 Aug 2020https://doi.org/10.1161/CIRCRESAHA.120.317803Circulation Research. 2020;127:945–947Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: August 6, 2020: Ahead of Print The SARS-CoV-2 (SARS-CoV-2 severe acute respiratory syndrome coronavirus 2) coronavirus disease (COVID-19) is a global pandemic. Laboratory testing suggests a coagulopathy with up to 30% of hospitalized patients with COVID-19 developing thrombotic events.1 Platelets are central protagonists in both arterial and venous thrombosis, and virus-platelet interactions contribute to thrombotic risk, promoting an overall procoagulant and inflammatory states during viral infection.2 Furthermore, recent studies report platelets to be hyperactivated in subjects with COVID-19.3We speculated that in COVID-19, biomarkers of platelet activation are associated with incident thrombosis or death. Thus, we investigated in vivo surrogate biomarkers of platelet activation and vascular inflammation collected in the early phase of COVID-19 hospitalization. Plasma levels of soluble CD40 ligand (sCD40L), P-selectin, the metabolite of thromboxane A2, thromboxane B2 (TxB2), and mean platelet volume (MPV) were assessd. Venous blood samples were collected within 24 hours of hospital admission to NYU Langone Health between March 15 and April 20, 2020, in accordance with the policies of the NYU Langone Health Institutional Review Board. Plasma was collected by centrifugation of PST tubes; MPV was measured during routine care from EDTA tubes on a SYSMEX analyzer.Among 100 randomly selected hospitalized patients with COVID-19, median age was 65 years, 39 were female, 48 were White, 53 had hypertension, and at admission, 27 were on antiplatelet therapy, of whom 24 (89%) were on aspirin. Thrombosis or death occurred in 32 subjects (24 deaths and 14 thrombotic events [8 VTE (venous thromboembolism), 5 myocardial infarction, and 1 VTE and myocardial infarction]), 6 subjects experienced a thrombotic event and subsequently died. Patients with thrombosis or death were older and more likely to have chronic obstructive pulmonary disease than those without an event. There was no significant difference in platelet count or the use of antiplatelet therapy at presentation between groups (Table 1).Table 1. Baseline Characteristics of Patients With COVID-19 Stratified by the Incidence of Thrombosis or DeathNo Death or Thrombosis (N=68)Death or Thrombosis (N=32)P ValueAge, y, median [IQR]*63.50 [48.50–73.00]69.50 [63.00–80.00]0.002Female, n (%)†27 (39.7)12 (37.5)1Race, n (White, %)†30 (46.2)18 (58.1)0.383BMI, median [IQR], kg/m2*27.62 [24.77–31.45]28.88 [25.42–33.36]0.483Smoker, n (current/former, %)†13 (20.3)8 (25.8)0.733Hypertension, n (%)†33 (48.5)20 (62.5)0.275Hyperlipidemia, n (%)†17 (25.0)12 (37.5)0.294Diabetes mellitus, n (%)†13 (19.1)8 (25.0)0.681Coronary artery disease, n (%)†8 (11.8)5 (15.6)0.828Stroke or TIA, n (%)c3 (4.4)0 (0.0)0.549COPD, n (%)‡0 (0.0)5 (15.6)0.003Chronic kidney disease, n (%)†6 (8.8)4 (12.5)0.722Cancer, n (%)‡3 (4.4)4 (12.5)0.206Atrial fibrillation, n (%)‡2 (2.9)3 (9.4)0.324Antiplatelet therapy, n (%)†18 (26.5)9 (28.1)1Aspirin, n (%)†16 (23.5)8 (25.0)1Clinical labsWBC, median [IQR] cells/L*7.0 [5.2–8.9]8.1 [6.1–11.8]0.080Lymphocyte, median [IQR] cells/L*11.0 [8.0–14.3]10.50 [7.0–14.3]0.859Platelet count, median [IQR] 109/L*205.0 [164.8–253.8]187.5 [147.5–257.5]0.385Mean platelet volume, median [IQR] fL*10.55 [10.1–11.2]11.00 [10.5–11.9]0.022Hemoglobin, median [IQR] g/dL*13.15 [11.8–14.3]13.40 [11.8–14.4]0.894Two-sided P<0.05 were considered statistically significant. n=100 for all analyses. BMI indicates body mass index; COPD, chronic obstructive pulmonary disease; and IQR, interquartile range. TIA indicates transient ischemic attack; and WBC, white blood cell.* Continuous variables were compared with Mann-Whitney test.† Categorical variables were compared with χ2 test.‡ Categorical variables were compared with Fisher exact test.We analyzed banked samples collected on the day of COVID-19 diagnosis to investigate in vivo platelet activity and vascular health biomarkers. Following adjustment for age, sex, race/ethnicity, antiplatelet therapy, platelet count, and chronic obstructive pulmonary disease, TxB2 (P=0.006), P-selectin (P=0.005), sCD40L (P=0.016), and MPV (P=0.012) were independently associated with the composite of thrombosis or death. Of the 14 patients who experienced a thrombotic event, only TxB2 was associated with thrombosis after multivariable adjustment (P=0.013). Of the 24 patients who died TxB2 (P=0.006), P-selectin (P=0.005), sCD40L (P=0.016), and MPV (P=0.012) were associated with all-cause mortality after multivariable adjustment (Table 2). Aspirin was associated with a lower TxB2 (P<0.001; data not shown) and was not associated with other measured biomarkers. In a sensitivity analysis, the association between TxB2 and thrombosis or death remained robust (P=0.012) after excluding subjects on aspirin.Table 2. Multivariable Regression Models Predicting Thrombosis or All-Cause Mortality, Thrombosis, and All-Cause MortalityParameterThrombosis or All-Cause MortalityThrombosisAll-Cause MortalityOR [95% CI]P ValueOR [95% CI]P ValueOR [95% CI]P ValueTxB22.59 [1.37–5.43]0.0062.96 [1.36–7.75]0.0132.04 [1.07–4.11]0.036MPV2.17 [1.22–4.15]0.0122.05 [0.98–4.71]0.0662.33 [1.27–4.67]0.010sCD40L1.94 [1.15–3.43]0.0161.18 [0.55–2.33]0.6391.93 [1.1–3.43]0.019P-selectin2.36 [1.36–4.56]0.0051.36 [0.73–2.51]0.3122.22 [1.29–4.19]0.007OR from logistic regression analysis per SD increase for biomarker levels adjusted for age, sex, race, antiplatelet therapy, platelet count, and COPD. Plasma was collected in PST tubes, TxB2 levels were measured by ELISA (Cayman Chemical; 1:100 dilution), P-Selectin and sCD40L were measured by LEGENDplex bead-based immunoassay (1:50 dilution). MPV was measured via automated hemogram (Sysmex, Japan) from EDTA blood collection tubes. Multivariate logistic regression was performed with all-cause mortality, thrombosis, and death/thrombosis as dependent outcomes. Candidate covariates were chosen because of their known association with the outcome of interest as well as statistical differences on univariate testing. ORs and 95% CIs were reported. Two-sided P<0.05 were considered statistically significant. n=100 for all analyses. COPD indicates chronic obstructive pulmonary disease; MPV, mean platelet volume; OR, odds ratio; sCD40L, soluble CD40 ligand; and TxB2, thromboxane B2.Patients hospitalized with COVID-19 are at increased risk for thrombosis, and autopsy data from our group and others demonstrate micro- and macro-thrombi across vascular beds in patients with and without clinical thrombosis.4,5 Randomized trials are ongoing testing dosing strategies of anticoagulation. However, emerging data suggest that patients continue to accrue thrombotic events even on high-dose anticoagulation.We report for the first time that biomarkers of platelet activity and vascular health, are significantly associated with the composite outcome of thrombosis or death in hospitalized patients with COVID-19. A composite outcome was used due to a competing risk of death and likely underdiagnosing of thrombotic events in hospitalized patients with COVID-19. These findings suggest that multiple platelet-related processes contribute to thrombosis and mortality in patients with COVID-19. Increased plasma TxB2 levels indicate the activation of platelets via COX-1. Moreover, both platelet P-selectin and sCD40L contribute to thrombosis by supporting platelet-myeloid heteroaggregate formation and thrombi stability by interaction with PSGL-1 and αIIbβ3, respectively. Our current study does not characterize the cellular source of measured biomarkers, thus in addition to platelets, plasma P-selectin and sCD40L may originate from alternate sources including endothelial cells and T cells, respectively. However, consistent with our surrogate biomarkers of platelet activity is the similar association obtained with the platelet-specific marker, MPV, a biomarker of platelet hyperactivity.Our findings are consistent with recent reports of platelet hyperactivity in patients with COVID-19.3 We extend those finding and demonstrate that biomarkers of platelet activation are associated with thrombosis or death in patients hospitalized with COVID-19. Our findings suggest platelet activation mechanisms may contribute to adverse events and warrant further investigation into the mechanistic role of platelets in COVID-19 pathogenesis and highlight the potential role of antiplatelet therapy.Sources of FundingThis study was supported by National Institutes of Health (R35HL144993, J.S. Berger), American Society of Hematology (18-A0-00-1001884, T.J. Barrett), and the NYU CTSA grant UL1TR001445.DisclosuresNone.FootnotesFor Sources of Funding and Disclosures, see page 947.Correspondence to: Jeffrey S. Berger, MD, MS, Center for the Prevention of Cardiovascular Disease, New York University School of Medicine, 530 First Ave, Skirball 9R, New York, NY 10016. Email jeffrey.berger@nyulangone.orgReferences1. Bilaloglu S, Aphinyanaphongs Y, Jones S, Iturrate E, Hochman J, Berger JS. Thrombosis in hospitalized patients with COVID-19 in a New York city health system.JAMA. 2020:e2013372. doi: 10.1001/jama.2020.13372CrossrefGoogle Scholar2. Koupenova M, Clancy L, Corkrey HA, Freedman JE. Circulating platelets as mediators of immunity, inflammation, and thrombosis.Circ Res. 2018; 122:337–351. doi: 10.1161/CIRCRESAHA.117.310795LinkGoogle Scholar3. Manne BK, Denorme F, Middleton EA, Portier I, Rowley JW, Stubben CJ, Petrey AC, Tolley ND, Guo L, Cody MJ, et al. Platelet gene expression and function in COVID-19 patients.Blood. 2020:blood.2020007214. doi: 10.1182/blood.2020007214CrossrefGoogle Scholar4. Rapkiewicz AV, Xingchen M, Carsons SE, Pittalug S, Kleiner DE, Berger JS, Thomas S, Adler NM, Charytan DM, Gasmi B, et al. Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: a case series.EClinical Medicine. 2020. doi:10.1016/j.eclinm.2020.100434.CrossrefMedlineGoogle Scholar5. Levi M, Thachil J, Iba T, Levy JH. Coagulation abnormalities and thrombosis in patients with COVID-19.Lancet Haematol. 2020; 7:e438–e440. doi: 10.1016/S2352-3026(20)30145-9CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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