Association of anticoagulant therapy dosing with laboratory biomarkers and clinical outcomes in critically ill COVID-19 patients in the ICU

Igor Vasković; Marija  Marković; Ljiljana Arsenović; Aleksandra Ignjatović; Mihailo Stojić; Vojislava Nešković

doi:10.2298/VSP250606028V

Igor Vasković Military Medical Academy, *Clinic for Anesthesiology and Intensive Care, Belgrade, Serbia; †University of Defence, Faculty of Medicine of the Military Medical Academy, Belgrade, Serbia
Marija Marković Military Medical Academy, *Clinic for Anesthesiology and Intensive Care, Belgrade, Serbia; †University of Defence, Faculty of Medicine of the Military Medical Academy, Belgrade, Serbia
Ljiljana Arsenović Military Medical Academy, Institute for Medical Biochemistry, Belgrade, Serbia
Aleksandra Ignjatović Faculty of Medicine, Department of Medical Statistics and Informatics, Niš, Serbia
Mihailo Stojić Military Medical Academy, *Clinic for Anesthesiology and Intensive Care, Belgrade, Serbia
Vojislava Nešković Military Medical Academy, *Clinic for Anesthesiology and Intensive Care, Belgrade, Serbia; University of Defence, Faculty of Medicine of the Military Medical Academy, Belgrade, Serbia

DOI: https://doi.org/10.2298/VSP250606028V

Ključne reči: antikoagulansi;, biomarkeri;, covid-19;, faktor xa;, heparin;, intenzivna nega, odeljenja;, prognoza

Sažetak

Uvod/Cilj. Kod imunotrombotskih poremećaja kao što je bolest izazvana korona virusom 2019 (coronavirus disease 2019–COVID-19), nivoi D-dimera često su povišeni, što odražava povećano stvaranje i razgradnju fibrina. Dodatni biomarkeri, kao što su odnos neutrofila i limfocita (neutrophil-to-lymphocyte ratio – NLR) i nivoi C-reaktivnog proteina (CRP) i laktat dehidrogenaze (LDH), povezani su sa težinom i ishodima bolesti. Cilj rada bio je da se proceni uticaj dva različita antikoagulaciona protokola na nivoe biomarkera D-dimer, NLR, CRP i LDH u serumu, kao i njihova prognostička vrednost u pogledu kliničkih ishoda kod kritično obolelih od COVID-19. Metode. Retrospektivnom studijom obuhvaćeni su kritično oboleli od COVID-19, primljeni na Odeljenje intenzivne nege u periodu od aprila 2020. do decembra 2021. godine i upoređeni su protokoli za vođenje antikoagulantne terapije pomoću D-dimera i pomoću anti-Xa inhibitora. Bolesnici su prema režimu antikoagulantne terapije bili podeljeni u dve grupe: grupu u kojoj je primenjen protokol vođen anti-Xa vrednostima (AXa grupa – A-XaG) i grupu gde je primenjen protokol sa doziranjem prema D-dimer vrednostima (D-d grupa – D-dG). Rezultati. Analizirano je ukupno 395 bolesnika: 137 u A-XaG i 258 u D-dG. Vrednosti CRP, LDH i D-dimera bile su značajno niže u A-XaG u odnosu na D-dG (p < 0,001, p < 0,001, p = 0,001, redom). Univarijantnom analizom su kao prognostički faktori mortaliteta pokazani životno doba [odds ratio (OR): 1,064; p < 0,001)], LDH (OR: 1,002; p < 0,001), CRP (OR: 1,005; p < 0,001) i D-dimer (OR: 1,054; p = 0,020). Analizom multivarijantnog modela pokazano je da su samo životno doba > 64 godine (OR: 10,215; p < 0,001) i LDH > 395 U/L (OR: 5,491; p = 0,005) ostali nezavisno povezani sa smrtnim ishodom. Zaključak. Antikoagulantna terapija vođena anti-Xa vrednostima bila je povezana sa nižim vrednostima inflamacijskih biomarkera kod obolelih od COVID-19 na Odeljenju intenzivne nege. Iako su univarijantnom analizom kao potencijalni prognostički faktori mortaliteta identifikovani životno doba, LDH, CRP i D-dimer, samo su životno doba i LDH ostali statistički značajni pokazatelji u multivarijantnom modelu, što ukazuje na nezavisnu prognostičku vrednost kod te populacije bolesnika.

Reference

Lloyd-Jones G, Alcock R, Oudkerk M. COVID-19 lung disease is a pulmonary vasculopathy. Clin Radiol 2024; 79(7): e975–8. DOI: 10.1016/j.crad.2024.04.002.

Lloyd-Jones G, Shambrook J, Watson A, Freeman A, Wilkinson TMA. Chest computed tomography and plain radiographs demonstrate vascular distribution and characteristics in COVID-19 lung disease – a pulmonary vasculopathy. Ulster Med J 2025; 94(1): 4–12.

Connors JM, Levy JH. Thromboinflammation and the hyper-coagulability of COVID-19. J Thromb Haemost 2020; 18(7): 1559–61. DOI: 10.1111/jth.14849.

Grobler C, Maphumulo SC, Grobbelaar LM, Bredenkamp JC, Laubscher GJ, Lourens PJ, et al. COVID-19: The rollercoaster of fibrinogen, D-dimer, von Willebrand factor P-selectin and their interactions with endothelial cells, platelets and eryth-rocytes. Int J Mol Sci 2020; 21(14): 5168. DOI: 10.3390/ijms21145168.

Toori KU, Qureshi MA, Chaudhry A, Safdar MF. Neutrophil to lymphocyte ratio (NLR) in COVID-19: A cheap prognostic marker in a resource constraint setting. Pak J Med Sci 2021; 37(5): 1435–9. DOI: 10.12669/pjms.37.5.4194.

Yang AP, Liu JP, Tao WQ, Li HM. The diagnostic and predic-tive role of NLR, d-NLR, and PLR in COVID-19 patients. Int Immunopharmacol 2020; 84: 106504. DOI: 10.1016/j.intimp.2020.106504.

Akdogan D, Guzel M, Tosun D, Akpinar O. Diagnostic and early prognostic value of serum CRP and LDH levels in pa-tients with possible COVID-19 at the first admission. J In-fect Dev Ctries 2021; 15(6): 766–72. DOI: 10.3855/jidc.14072.

Poggiali E, Zaino D, Immovilli P, Rovero L, Losi G, Dacrema A, et al. Lactate dehydrogenase and C-reactive protein as pre-dictors of respiratory failure in COVID-19 patients. Clin Chim Acta 2020; 509: 135–8. DOI: 10.1016/j.cca.2020.06.012.

Nemec HM, Ferenczy A, Christie BD 3rd, Ashley DW, Montgom-ery A. Correlation of D-dimer and Outcomes in COVID-19 Patients. Am Surg 2022; 88(9): 2115–8. DOI: 10.1177/00031348221091940.

Beidollahkhani S, Fayedeh F, Shoja A, Nejad EH, Hoseinpour M, Fazlpour F, et al. D-dimer as a biomarker for COVID-19-associated pulmonary thromboembolism: a narrative review from molecular pathways to the imaging findings. Egypt J Bronchol 2023; 17: 44. DOI: 10.1186/s43168-023-00221-6.

Conway EM, Mackman N, Warren RQ, Wolberg AS, Mosnier LO, Campbell RA, et al. Understanding COVID-19-associated coagulopathy. Nat Rev Immunol 2022; 22(10): 639–49. DOI: 10.1038/s41577-022-00762-9.

Vasković I, Marković M, Udovičić I, Arsenović L, Stojić M, Ignja-tović A, et al. Effectiveness of Different Anticoagulation Reg-imens in Critically Ill Patients: experience from COVID-19 patients. Blood Coagul Fibrinolysis 2025; 36(3): 82–9. DOI: 10.1097/MBC.0000000000001354.

Mohseni Afshar Z, Tavakoli Pirzaman A, Hosseinzadeh R, Baba-zadeh A, Taghizadeh Moghadam MA, Miri SR, et al. Anticoagu-lant therapy in COVID-19: A narrative review. Clin Transl Sci 2023; 16(9): 1510–25. DOI: 10.1111/cts.13569.

Ambrosino P, Calcaterra IL, Mosella M, Formisano R, D'Anna SE, Bachetti T, et al. Endothelial Dysfunction in COVID-19: A Unifying Mechanism and a Potential Therapeutic Target. Biomedicines 2022; 10(4): 812. DOI: 10.3390/biomedicines10040812.

Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020; 135(23): 2033–40. DOI: 10.1182/blood.2020006000.

Moore P, Esmail F, Qin S, Nand S, Berg S. Hypercoagulability of COVID-19 and Neurological Complications: A Review. J Stroke Cerebrovasc Dis 2022; 31(1): 106163. DOI: 10.1016/j.jstrokecerebrovasdis.2021.106163.

Simadibrata DM, Calvin J, Wijaya AD, Ibrahim NAA. Neu-trophil-to-lymphocyte ratio on admission to predict the se-verity and mortality of COVID-19 patients: A meta-analysis. Am J Emerg Med 2021; 42: 60–9. DOI: 10.1016/j.ajem.2021.01.006.

Buonacera A, Stancanelli B, Colaci M, Malatino L. Neutrophil to Lymphocyte Ratio: An Emerging Marker of the Relation-ships between the Immune System and Diseases. Int J Mol Sci 2022; 23(7): 3636. DOI: 10.3390/ijms23073636.

Biswas M, Suvarna R, Krishnan S V, Devasia T, Shenoy Belle V, Prabhu K. The mechanistic role of neutrophil lymphocyte ra-tio perturbations in the leading non communicable lifestyle diseases. F1000Res 2022; 11: 960. DOI: 10.12688/f1000research.123245.1.

Sarkar PG, Pant P, Kumar J, Kumar A. Does Neutrophil-to-lymphocyte Ratio at Admission Predict Severity and Mortali-ty in COVID-19 Patients? A Systematic Review and Meta-analysis. Indian J Crit Care Med 2022; 26(3): 361–75. DOI: 10.5005/jp-journals-10071-24135.

Ahnach M, Zbiri S, Nejjari S, Ousti F, Elkettani C. C-reactive protein as an early predictor of COVID-19 severity. J Med Biochem 2020; 39(4): 500–7. DOI: 10.5937/jomb0-27554.

Fialek B, Pruc M, Smereka J, Jas R, Rahnama-Hezavah M, Dene-gri A, et al. Diagnostic value of lactate dehydrogenase in COVID-19: A systematic review and meta-analysis. Cardiol J 2022; 29(5): 751–8. DOI: 10.5603/CJ.a2022.0056.

Simadibrata DM, Lubis AM. D-dimer levels on admission and all-cause mortality risk in COVID-19 patients: a meta-analysis. Epidemiol Infect 2020; 148: e202. DOI: 10.1017/S0950268820002022.

Li Y, Deng Y, Ye L, Sun H, Du S, Huang H, et al. Clinical Significance of Plasma D-Dimer in COVID-19 Mortality. Front Med (Lausanne) 2021; 8: 638097. DOI: 10.3389/fmed.2021.638097.

Henry BM, Aggarwal G, Wong J, Benoit S, Vikse J, Plebani M, et al. Lactate dehydrogenase levels predict coronavirus disease 2019 (COVID-19) severity and mortality: A pooled analysis. Am J Emerg Med 2020; 38(9): 1722–6. DOI: 10.1016/j.ajem.2020.05.073.

Li C, Ye J, Chen Q, Hu W, Wang L, Fan Y, et al. Elevated Lactate Dehydrogenase (LDH) level as an independent risk factor for the severity and mortality of COVID-19. Aging (Albany NY) 2020; 12(15): 15670–81. DOI: 10.18632/aging.103770.

Gewurz H, Mold C, Siegel J, Fiedel B. C-reactive protein and the acute phase response. Adv Intern Med 1982; 27: 345–72.

Gruys E, Toussaint MJ, Niewold TA, Koopmans SJ. Acute phase reaction and acute phase proteins. J Zhejiang Univ Sci B 2005; 6(11): 1045–56. DOI: 10.1631/jzus.2005.B1045.

Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395(10229): 1054–62. DOI: 10.1016/S0140-6736(20)30566-3. Erratum in: Lancet 2020; 395(10229): 1038. DOI: 10.1016/S0140-6736(20)30606-1. Erratum in: Lancet 2020; 395(10229): 1038. DOI: 10.1016/S0140-6736(20)30638-3.

Esmailian M, Vakili Z, Nasr-Esfahani M, Heydari F, Masoumi B. D-dimer Levels in Predicting Severity of Infection and Outcome in Patients with COVID-19. Tanaffos 2022; 21(4): 419–33.

Sidhwani SK, Mirza T, Khatoon A, Shaikh F, Khan R, Shaikh OA, et al. Inflammatory markers and COVID-19 disease progression. J Infect Public Health 2023; 16(9): 1386–91. DOI: 10.1016/j.jiph.2023.06.018.

Engels SYH, van Veen IHPAA, Oudkerk M, van der Palen J, Heuvelmans MA. An optimized D-dimer cut-off value to pre-dict pulmonary thromboembolism in COVID-19 patients. J Thorac Dis 2023; 15(11): 6317–22. DOI: 10.21037/jtd-23-870.

Weitz JI, Fredenburgh JC, Eikelboom JW. A test in context: D-dimer. J Am Coll Cardiol 2017; 70(19): 2411–20. DOI: 10.1016/j.jacc.2017.09.024.

Cesarman-Maus G, Hajjar KA. Molecular mechanisms of fi-brinolysis. Br J Haematol 2005; 129(3): 307–21. DOI: 10.1111/j.1365-2141.2005.05444.x.

Longstaff C. Measuring fibrinolysis: from research to routine diagnostic assays. J Thromb Haemost 2018; 16(4): 652–62. DOI: 10.1111/jth.13957.

Iba T, Levy JH, Levi M, Thachil J. Coagulopathy in COVID-19. J Thromb Haemost 2020; 18(9): 2103–9. DOI: 10.1111/jth.14975.

Wright FL, Vogler TO, Moore EE, Moore HB, Wohlauer MV, Urban S, et al. Fibrinolysis shutdown correlation with throm-boembolic events in severe COVID-19 infection. J Am Coll Surg 2020; 231(2): 193–203.e1. DOI: 10.1016/j.jamcollsurg.2020.05.007.

Adam SS, Key NS, Greenberg CS. D-dimer antigen: current concepts and future prospects. Blood 2009; 113(13): 2878–87. DOI: 10.1182/blood-2008-06-165845.

Levi M, Thachil J, Iba T, Levy JH. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haema-tol 2020; 7(6): e438–40. DOI: 10.1016/S2352-3026(20)30145-9.

Nougier C, Benoit R, Simon M, Desmurs-Clavel H, Marcotte G, Argaud L, et al. Hypofibrinolytic state and high thrombin generation may play a major role in SARS-CoV-2 associated thrombosis. J Thromb Haemost 2020; 18(9): 2215–9. DOI: 10.1111/jth.15016.

REMAP-CAP Investigators; ACTIV-4a Investigators; AT-TACC Investigators; Goligher EC, Bradbury CA, McVerry BJ, Lawler PR, Berger JS, Gong MN, et al. Therapeutic anti-coagulation with heparin in critically ill patients with Covid-19. N Engl J Med 2021; 385(9): 777–89. DOI: 10.1056/NEJMoa2103417.

ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators; Lawler PR, Goligher EC, Berger JS, Neal MD, McVerry BJ, Nicolau JC, et al. Therapeutic anticoagula-tion with heparin in noncritically ill patients with Covid-19. N Engl J Med 2021; 385(9): 790–802. DOI: 10.1056/NEJMoa2105911.

Beun R, Kusadasi N, Sikma M, Westerink J, Huisman A. Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2. Int J Lab Hematol 2020; 42(Suppl 1): 19–20. DOI: 10.1111/ijlh.13230.

White D, MacDonald S, Bull T, Hayman M, de Monteverde-Robb R, Sapsford D, et al. Heparin resistance in COVID-19 pa-tients in the intensive care unit. J Thromb Thrombolysis 2020; 50(2): 287–91. DOI: 10.1007/s11239-020-02145-0. Erratum in: J Thromb Thrombolysis 2020; 50(2): 478. DOI: 10.1007/s11239-020-02196-3.

Van der Heijden CDCC, Ter Heine R, Kooistra EJ, Brüggemann RJ, Walburgh Schmidt JWJ, de Grouw EPLM, et al. Effects of dalteparin on anti-Xa activities cannot be predicted in criti-cally ill COVID-19 patients. Br J Clin Pharmacol 2022; 88(6): 2982–7. DOI: 10.1111/bcp.15208.

Vandiver JW, Vondracek TG. Antifactor Xa levels versus acti-vated partial thromboplastin time for monitoring unfraction-ated heparin. Pharmacotherapy 2012; 32(6): 546–58. DOI: 10.1002/j.1875-9114.2011.01049.x.

Spyropoulos AC, Goldin M, Giannis D, Diab W, Wang J, Khanijo S, et al. Efficacy of Therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparns for thrombo-prophylaxis in high-risk hospitalized COVID-19 patients with COVID-19: the HEP-COVID randomized clinical tri-al. JAMA Intern Med 2021; 181(12): 1612–20. DOI: 10.1001/jamainternmed.2021.6203. Erratum in: JAMA In-tern Med 2022; 182(2): 239. DOI: 10.1001/jamainternmed.2021.7668.

Zaid Y, Puhm F, Allaeys I, Naya A, Oudghiri M, Khalki L, et al. Platelets can associate with SARS-CoV-2 RNA and are hy-peractivated in COVID-19. Circ Res 2020; 127(11): 1404–18. DOI: 10.1161/CIRCRESAHA.120.317703.

Manne BK, Denorme F, Middleton EA, Portier I, Rowley JW, Stubben C, et al. Platelet gene expression and function in pa-tients with COVID-19. Blood 2020; 136(11): 1317–29. DOI: 10.1182/blood.2020007214.

Hottz ED, Azevedo-Quintanilha IG, Palhinha L, Teixeira L, Barreto EA, Pão CRR, et al. Platelet activation and platelet–monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19. Blood 2020; 136(11): 1330–41. DOI: 10.1182/blood.2020007252.

Young E. The anti-inflammatory effects of heparin and relat-ed compounds. Thromb Res 2008; 122(6): 743–52. DOI: 10.1016/j.thromres.2006.10.026.

Cornet AD, Smit EG, Beishuizen A, Groeneveld AB. The role of heparin and allied compounds in the treatment of sepsis. Thromb Haemost 2007; 98(3): 579–86.

Veraldi N, Hughes AJ, Rudd TR, Thomas HB, Edwards SW, Hadfield L, et al. Heparin derivatives for the targeting of multiple activities in the inflammatory response. Carbohydr Polym 2015; 117: 400–7. DOI: 10.1016/j.carbpol.2014.09.079.

Buijsers B, Yanginlar C, Maciej-Hulme ML, de Mast Q, van der Vlag J. Beneficial non-anticoagulant mechanisms underlying heparin treatment of COVID-19 patients. EBioMedicine 2020; 59: 102969. DOI: 10.1016/j.ebiom.2020.102969.

Mousavi S, Moradi M, Khorshidahmad T, Motamedi M. Anti-Inflammatory Effects of Heparin and Its Derivatives: A Sys-tematic Review. Adv Pharmacol Sci 2015; 2015: 507151. DOI: 10.1155/2015/507151.

Wang C, Chi C, Guo L, Wang X, Guo L, Sun J, et al. Heparin therapy reduces 28-day mortality in adult severe sepsis pa-tients: a systematic review and meta-analysis. Crit Care 2014; 18(5): 563. DOI: 10.1186/s13054-014-0563-4.

Zarychanski R, Abou-Setta AM, Kanji S, Turgeon AF, Kumar A, Houston DS, et al; Canadian Critical Care Trials Group. The ef-ficacy and safety of heparin in patients with sepsis: a system-atic review and meta-analysis. Crit Care Med 2015; 43(3): 511–8. DOI: 10.1097/CCM.0000000000000763.

Uaprasert N, Tangcheewinsirikul N, Rojnuckarin P, Patell R, Zwicker JI, Chiasakul T. Heparin-induced thrombocytopenia in patients with COVID-19: a systematic review and meta-analysis. Blood Adv 2021; 5(21): 4521–34. DOI: 10.1182/bloodadvances.2021005314.

Povezanost doziranja antikoagulantne terapije sa laboratorijskim biomarkerima i kliničkim ishodima kod kritično obolelih od COVID-19 u odeljenju intenzivne nege

Sažetak

Reference