Hypoalbuminemia, Coagulopathy, and Vascular Disease in COVID-19
Authors: Francesco Violi, Giancarlo Ceccarelli, Roberto Cangemi, Francesco Alessandri, Gabriella D’Ettorre, Alessandra Oliva, Daniele Pastori, Lorenzo Loffredo, Pasquale Pignatelli, Franco Ruberto, Mario Venditti, Francesco Pugliese, Claudio Maria Mastroianni
Journal: Circulation Research (2020)

HomeCirculation ResearchVol. 127, No. 3Hypoalbuminemia, Coagulopathy, and Vascular Disease in COVID-19 Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBHypoalbuminemia, Coagulopathy, and Vascular Disease in COVID-19 Francesco Violi, Giancarlo Ceccarelli, Roberto Cangemi, Francesco Alessandri, Gabriella D'Ettorre, Alessandra Oliva, Daniele Pastori, Lorenzo Loffredo, Pasquale Pignatelli, Franco Ruberto, Mario Venditti, Francesco Pugliese and Claudio Maria Mastroianni Francesco VioliFrancesco Violi Correspondence to: Francesco Violi, Sapienza-University of Rome, I Clinica Medica, Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Viale del Policlinico 155, Rome 00161, Italy. Email E-mail Address: [email protected] https://orcid.org/0000-0002-6610-7068 From the I Clinica Medica, Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Italy (F.V., D.P., L.L., P.P.) , Giancarlo CeccarelliGiancarlo Ceccarelli Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy (G.C., G.D., A.O., M.V., C.M.M.) , Roberto CangemiRoberto Cangemi Department of General Surgery Paride Stefanini, Sapienza University of Rome, Italy (R.C., F.A., F.R., F.P.). , Francesco AlessandriFrancesco Alessandri Department of General Surgery Paride Stefanini, Sapienza University of Rome, Italy (R.C., F.A., F.R., F.P.). , Gabriella D'EttorreGabriella D'Ettorre Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy (G.C., G.D., A.O., M.V., C.M.M.) , Alessandra OlivaAlessandra Oliva Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy (G.C., G.D., A.O., M.V., C.M.M.) , Daniele PastoriDaniele Pastori From the I Clinica Medica, Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Italy (F.V., D.P., L.L., P.P.) , Lorenzo LoffredoLorenzo Loffredo From the I Clinica Medica, Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Italy (F.V., D.P., L.L., P.P.) , Pasquale PignatelliPasquale Pignatelli From the I Clinica Medica, Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Italy (F.V., D.P., L.L., P.P.) , Franco RubertoFranco Ruberto Department of General Surgery Paride Stefanini, Sapienza University of Rome, Italy (R.C., F.A., F.R., F.P.). , Mario VendittiMario Venditti Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy (G.C., G.D., A.O., M.V., C.M.M.) , Francesco PuglieseFrancesco Pugliese Department of General Surgery Paride Stefanini, Sapienza University of Rome, Italy (R.C., F.A., F.R., F.P.). and Claudio Maria MastroianniClaudio Maria Mastroianni Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy (G.C., G.D., A.O., M.V., C.M.M.) Originally published8 Jun 2020https://doi.org/10.1161/CIRCRESAHA.120.317173Circulation Research. 2020;127:400–401Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 8, 2020: Ahead of Print Coagulopathy has been suggested to complicate the clinical course of coronavirus 2019 (COVID-19), but the underlying mechanism is unclear.1 Previous study showed that hypoalbuminemia, that is, serum albumin (SA) <35 g/L, is associated with an elevated D-dimer and enhanced risk of artery and venous thrombosis.2 However, data regarding SA, coagulopathy, and vascular disease in COVID-19 are unknown.This observational study included adult (≥18 years) patients with laboratory-confirmed COVID-19 according to the WHO interim guidance.3 During the intrahospital stay, any vascular event was registered. The study was approved by local Ethics Committee (ID Prot. 109/2020). Characteristics of patients according to ICU admission are reported in the Table. All patients were treated with low-molecular weight heparin. Among the variables examined, ICU patients showed higher D-dimer and lower SA compared with non-ICU ones (Table). SA inversely correlated with D-dimer (Rs=−0.385; P<0.001) and hs-CRP (high-sensitivity C-reactive protein; Rs=−0.418; P<0.001).Table. Clinical and Laboratory Characteristics of Study Patients, according to the Intensive Care Unit (ICU) AdmissionAll PatientsNon-ICUICUP ValueAlbumin <35 g/LAlbumin ≥35 g/LP ValueNo.732053…5419…Age (years)67.1±13.866.8±15.267.2±13.40.932*66.9±12.968.0±16.20.780*Men81%75%83%0.50978%90%0.331Creatinine, mg/dL1.25±0.821.01±0.331.34±0.930.028*1.29±0.91.13±0.410.028*High sensitivity C-reactive protein, mg/L100 (35–193)47 (15–94)114 (67–207)0.001†115 (55–214)45 (21–103)0.002†sPO2 (%)92±894±483±120.007*91±784±150.736*White blood cells (×1000/mm3)6.9±3.06.8±2.17.9±4.30.034*6.9±2.96.8±3.40.908*D-dimer, ng/mL3166 (992–4655)1218 (750–4020)4610 (1385–4700)0.005†4610 (1519–4700)965 (654–3377)0.002†Albumin, g/L31.7±5.133.6±5.930.9±4.50.041*………Albumin <35 g/L74%55%81%0.036………Differences between percentages were assessed by Fisher exact tests. All continuous variables were tested for normality with the Shapiro-Wilk test.*Student unpaired t-test was used for normally distributed continuous variables (expressed as mean±SD).†Mann-Whitney U test was used for not-normally distributed continuous variables (expressed as median [interquartile range]).Patients with SA <35 g/L showed higher levels of creatinines, hs-CRP, and D-dimer compared with patients with SA >35 g/L (Table). Also, the percentage of patients with D-dimer 4-fold above upper normal limit was 66% (36/54) in patients with SA <35 g/L versus 31% (6/19) in those with ≥35 g/L (P=0.008).Median in-hospital stay was 15 days (interquartile range, 10–22). Seventeen patients experienced ischemic events: 11 acute limb ischemia, 2 pulmonary embolisms, 3 myocardial infarctions, 3 strokes/transient ischemic attacks. Compared with vascular-free patients, those with events showed lower SA (32.2±5.3 versus 29.6±3.5 g/L; P=0.023) and higher D-dimer (2154 [853–4610] versus 4610 [1814–4700] ng/mL; P=0.013), respectively. SA <35 g/L were present in 94% of patients who experienced ischemic/embolic events versus 68% of vascular-free patients (P=0.031).SA <35 g/L was detected in 74% of the patients with COVID-19 with a higher prevalence in ICU ones. Hypoalbuminemia is explained by the acute-phase response property of albumin, increased vascular permeability, and kidney or liver disease2; in our cohort, SA was associated with hs-CRP and creatinine but not with liver damage or albuminuria (not shown). SA <35 g/L was associated with a higher percentage of D-dimer values 4-fold above upper normal limit, which is considered a marker of thrombin generation.1 The association between hypoalbuminemia and hypercoagulability may be explained by its anticoagulant and antiplatelet activities4,5; also, a pilot study showed that albumin infusion is associated with platelet inhibition.5 The coexistence of hypoalbuminemia with elevated D-dimer could negatively influence outcomes of patients with COVID-19. Thus, the 17 patients with ischemic events had lower SA and higher D-dimer compared with vascular event-free patients; of note, 16 of them had SA <35 g/L. However, a cause-effect relationship between hypoalbuminemia and hypercoagulability cannot be established and further study is needed to support this hypothesis. In conclusion, hypoalbuminemia and coagulopathy coexist in patients with severe COVID-19 and are associated with vascular disorders.Nonstandard Abbreviations and AcronymsCOVID-19coronavirus 2019SAserum albuminDisclosuresNone.FootnotesFor Disclosures, see page 401.Correspondence to: Francesco Violi, Sapienza-University of Rome, I Clinica Medica, Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Viale del Policlinico 155, Rome 00161, Italy. Email francesco.violi@uniroma1.itReferences1. Thachil J, Tang N, Gando S, Falanga A, Cattaneo M, Levi M, Clark C, Iba T. ISTH interim guidance on recognition and management of coagulopathy in COVID-19.J Thromb Haemost. 2020; 18:1023–1026. doi: 10.1111/jth.14810CrossrefMedlineGoogle Scholar2. Ronit A, Kirkegaard-Klitbo DM, Dohlmann TL, Lundgren J, Sabin CA, Phillips AN, Nordestgaard BG, Afzal S. Plasma albumin and incident cardiovascular disease: results from the CGPS and an updated meta-analysis.Arterioscler Thromb Vasc Biol. 2020; 40:473–482. doi: 10.1161/ATVBAHA.119.313681LinkGoogle Scholar3. World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: Interim guidance V 1.2. 13 March 2020.Available at https://apps.who.int/iris/rest/ bitstreams/1272156Google Scholar4. Jøorgensen KA, Stoffersen E. Heparin like activity of albumin.Thromb Res. 1979; 16:569–574. doi: 10.1016/0049-3848(79)90105-1CrossrefMedlineGoogle Scholar5. Basili S, Carnevale R, Nocella C, Bartimoccia S, Raparelli V, Talerico G, Stefanini L, Romiti GF, Perticone F, Corazza GR, et al; PRO-LIVER Collaborators. Serum albumin is inversely associated with portal vein thrombosis in cirrhosis.Hepatol Commun. 2019; 3:504–512. doi: 10.1002/hep4.1317CrossrefMedlineGoogle 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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July 17, 2020Vol 127, Issue 3 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.120.317173PMID: 32508261 Originally publishedJune 8, 2020 KeywordsCOVID-19creatininehypoalbuminemiavascular diseasesthrombosisPDF download Advertisement SubjectsThrombosisVascular Disease