Download PDF
Thromb Haemost 2021; 121(12): 1610-1621
DOI: 10.1055/a-1477-3829
Coagulation and Fibrinolysis

Platelet Count Rose While D-Dimer Levels Dropped as Deaths and Thrombosis Declined—An Observational Study on Anticoagulation Shift in COVID-19

Anna Sjöström 
1   Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
2   Clinical Chemistry, Karolinska University Laboratory, Stockholm, Sweden
,
Johanna Dehlsen Wersäll
2   Clinical Chemistry, Karolinska University Laboratory, Stockholm, Sweden
,
Anna Warnqvist
3   Division of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
,
Maria Farm
1   Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
2   Clinical Chemistry, Karolinska University Laboratory, Stockholm, Sweden
,
Maria Magnusson
1   Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
4   Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
5   Coagulation Unit, Department of Hematology, Karolinska University Hospital, Stockholm, Sweden
,
Anders Oldner
6   Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
7   Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden
,
Anna Ågren
1   Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
5   Coagulation Unit, Department of Hematology, Karolinska University Hospital, Stockholm, Sweden
8   Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
,
Jovan Antovic
1   Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
2   Clinical Chemistry, Karolinska University Laboratory, Stockholm, Sweden
,
Maria Bruzelius
1   Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
5   Coagulation Unit, Department of Hematology, Karolinska University Hospital, Stockholm, Sweden
9   Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
› Author Affiliations
› Further Information
Also available at
   Permissions and Reprints

Abstract

Background High levels of D-dimer and low platelet counts are associated with poor outcome in coronavirus disease 2019 (COVID-19). As anticoagulation appeared to improve survival, hospital-wide recommendations regarding higher doses of anticoagulation were implemented on April 9, 2020.

Objectives To investigate if trends in D-dimer levels and platelet counts were associated with death, thrombosis, and the shift in anticoagulation.

Methods Retrospective cohort study of 429 patients with COVID-19 at Karolinska University Hospital. Information on D-dimer levels and platelet counts was obtained from laboratory databases and clinical data from medical records.

Results Thirty-day mortality and thrombosis rates were 19% and 18%, respectively. Pulmonary embolism was common, 65/83 (78%). Increased D-dimer levels in the first week in hospital were significantly associated with death and thrombosis (odds ratio [OR]: 6.06; 95% confidence interval [CL]: 2.10–17.5 and 3.11; 95% CI: 1.20–8.10, respectively). If platelet count increased more than 35 × 109/L per day, the mortality and thrombotic risk decreased (OR: 0.16; 95% CI: 0.06–0.41, and OR: 0.36; 95% CI: 0.17–0.80). After implementation of updated hospital-wide recommendations, the daily mean significantly decreased regarding D-dimer levels while platelet counts rose; −1.93; 95% CI: −1.00–2.87 mg/L FEU (fibrinogen-equivalent unit) and 65; 95% CI: 54–76 ×109/L, and significant risk reductions for death and thrombosis were observed; OR: 0.48; 95% CI: 0.25–0.92 and 0.35; 95% CI: 0.17–0.72.

Conclusion In contrast to D-dimer levels, increase of platelet count over the first week in hospital was associated with improved survival and reduced thrombotic risk. The daily mean levels of D-dimer dropped while the platelet counts rose, coinciding with increased anticoagulation and a decline in thrombotic burden and mortality.

Keywords

COVID-19 - platelet count - thrombosis - low-molecular-weight heparin

Author Contributions

A. Sjöström, J. Antovic, and M. Bruzelius designed the study. A. Sjöström and J. D. Wersäll collected the data. A. Sjöström, M. Bruzelius, and A. Warnqvist performed data analysis and interpretation. A. Sjöström and M. Bruzelius drafted the first version of the manuscript. All authors contributed to the text and critically reviewed the final version of the article and they approved it for publication.


Data Sharing

The data that support the findings of this study are available on reasonable request from the corresponding author.


Supplementary Material



Publication History

Received: 04 February 2021

Accepted: 07 April 2021

Accepted Manuscript online:
08 April 2021

Article published online:
06 June 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020; 18 (05) 1094-1099
    CrossrefPubMedGoogle Scholar
  • 2 Paranjpe I, Fuster V, Lala A. et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol 2020; 76 (01) 122-124
    CrossrefPubMedGoogle Scholar
  • 3 Middleton EA, He XY, Denorme F. et al. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood 2020; 136 (10) 1169-1179
    CrossrefPubMedGoogle Scholar
  • 4 Goshua G, Pine AB, Meizlish ML. et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet Haematol 2020; 7 (08) e575-e582
    Google Scholar
  • 5 Ranucci M, Sitzia C, Baryshnikova E. et al. Covid-19-associated coagulopathy: biomarkers of thrombin generation and fibrinolysis leading the outcome. J Clin Med 2020; 9 (11) E3487
    Google Scholar
  • 6 Nougier C, Benoit R, Simon M. et al. Hypofibrinolytic state and high thrombin generation may play a major role in SARS-COV2 associated thrombosis. J Thromb Haemost 2020; 18 (09) 2215-2219
    CrossrefPubMedGoogle Scholar
  • 7 Campbell RA, Boilard E, Rondina MT. Is there a role for the ACE2 receptor in SARS-CoV-2 interactions with platelets?. J Thromb Haemost 2021; 19 (01) 46-50
    CrossrefPubMedGoogle Scholar
  • 8 Battinelli EM. COVID-19 concerns aggregate around platelets. Blood 2020; 136 (11) 1221-1223
    CrossrefPubMedGoogle Scholar
  • 9 Maquet J, Lafaurie M, Sommet A, Moulis G. Thrombocytopenia is independently associated with poor outcome in patients hospitalized for COVID-19. Br J Haematol 2020; 190 (05) e276-e279
    CrossrefPubMedGoogle Scholar
  • 10 Lippi G, Plebani M, Henry BM. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis. Clin Chim Acta 2020; 506: 145-148
    CrossrefPubMedGoogle Scholar
  • 11 Yang X, Yang Q, Wang Y. et al. Thrombocytopenia and its association with mortality in patients with COVID-19. J Thromb Haemost 2020; 18 (06) 1469-1472
    CrossrefPubMedGoogle Scholar
  • 12 Cohen SL, Gianos E, Barish MA. et al; Northwell Health COVID-19 Research Consortium. Prevalence and predictors of venous thromboembolism or mortality in hospitalized COVID-19 patients. Thromb Haemost 2021; DOI: 10.1055/a-1366-9656.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Di Minno A, Ambrosino P, Calcaterra I, Di Minno MND. COVID-19 and venous thromboembolism: a meta-analysis of literature studies. Semin Thromb Hemost 2020; 46 (07) 763-771
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Klok FA, Kruip MJHA, van der Meer NJM. et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020; 191: 145-147
    CrossrefPubMedGoogle Scholar
  • 15 Nopp S, Moik F, Jilma B, Pabinger I, Ay C. Risk of venous thromboembolism in patients with COVID-19: a systematic review and meta-analysis. Res Pract Thromb Haemost 2020; 4 (07) 1178-1191
    CrossrefPubMedGoogle Scholar
  • 16 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; 324 (08) 799-801
    CrossrefPubMedGoogle Scholar
  • 17 Smilowitz NR, Subashchandran V, Yuriditsky E. et al. Thrombosis in hospitalized patients with viral respiratory infections versus COVID-19. Am Heart J 2021; 231: 93-95
    CrossrefPubMedGoogle Scholar
  • 18 Helms J, Tacquard C, Severac F. et al; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 2020; 46 (06) 1089-1098
    CrossrefPubMedGoogle Scholar
  • 19 Al-Samkari H, Karp Leaf RS, Dzik WH. et al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood 2020; 136 (04) 489-500
    CrossrefPubMedGoogle Scholar
  • 20 Tritschler T, Mathieu ME, Skeith L. et al; International Network of VENous Thromboembolism Clinical Research Networks INVENT-VTE. Anticoagulant interventions in hospitalized patients with COVID-19: a scoping review of randomized controlled trials and call for international collaboration. J Thromb Haemost 2020; 18 (11) 2958-2967
    CrossrefPubMedGoogle Scholar
  • 21 Billett HH, Reyes-Gil M, Szymanski J. et al. Anticoagulation in COVID-19: effect of enoxaparin, heparin, and apixaban on mortality. Thromb Haemost 2020; 120 (12) 1691-1699
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Meizlish ML, Goshua G, Liu Y. et al. Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: a propensity score-matched analysis. Am J Hematol 2021; 96 (04) 471-479
    CrossrefPubMedGoogle Scholar
  • 23 Tacquard C, Mansour A, Godon A. et al. Impact of high-dose prophylactic anticoagulation in critically ill patients with coronavirus disease 2019 pneumonia. Chest 2021; DOI: 10.1016/j.chest.2021.01.017.
    CrossrefPubMedGoogle Scholar
  • 24 Jonmarker S, Hollenberg J, Dahlberg M. et al. Dosing of thromboprophylaxis and mortality in critically ill COVID-19 patients. Crit Care 2020; 24 (01) 653
    CrossrefPubMedGoogle Scholar
  • 25 Patell R, Midha S, Kimani S. et al. Variability in institutional guidance for COVID-19-associated coagulopathy in the United States. Thromb Haemost 2020; 120 (12) 1725-1732
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Trombosprofylax och trombosbehandling vid Covid-19. 2020. Accessed May 3, 2021 at: https://www.karolinska.se/globalassets/global/1-teman/tema-cancer/hematologi/trombosprofylax-och-trombosbehandling-vid-covid-19—2020-06-08.pdf
    Google Scholar
  • 27 Spyropoulos AC, Levy JH, Ageno W. et al; Subcommittee on Perioperative, Critical Care Thrombosis, Haemostasis of the Scientific, Standardization Committee of the International Society on Thrombosis and Haemostasis. Scientific and Standardization Committee communication: clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (08) 1859-1865
    CrossrefPubMedGoogle Scholar
  • 28 IDSA. IDSA Guidelines on the Treatment and Management of Patients with COVID-19. 2020 . Accessed March 14, 2021 at: https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
    Google Scholar
  • 29 NIH. Clinical Spectrum of SARS-CoV-2 Infection. 2020 . Accessed March 14, 2021 at: https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/
    Google Scholar
  • 30 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
    CrossrefPubMedGoogle Scholar
  • 31 Rossi R, Coppi F, Talarico M, Boriani G. Protective role of chronic treatment with direct oral anticoagulants in elderly patients affected by interstitial pneumonia in COVID-19 era. Eur J Intern Med 2020; 77: 158-160
    CrossrefPubMedGoogle Scholar
  • 32 Wendel Garcia PD, Fumeaux T, Guerci P. et al; RISC-19-ICU Investigators. Prognostic factors associated with mortality risk and disease progression in 639 critically ill patients with COVID-19 in Europe: initial report of the international RISC-19-ICU prospective observational cohort. EClinicalMedicine 2020; 25: 100449
    CrossrefPubMedGoogle Scholar
  • 33 Middeldorp S, Coppens M, van Haaps TF. et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (08) 1995-2002
    CrossrefPubMedGoogle Scholar
  • 34 Avula A, Nalleballe K, Toom S. et al. Incidence of thrombotic events and outcomes in COVID-19 patients admitted to intensive care units. Cureus 2020; 12 (10) e11079
    PubMedGoogle Scholar
  • 35 Jimenez D, Garcia-Sanchez A, Rali P. et al. Incidence of VTE and bleeding among hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis. Chest 2021; 159 (03) 1182-1196
    CrossrefPubMedGoogle Scholar
  • 36 Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020; 135 (23) 2033-2040
    CrossrefPubMedGoogle Scholar
  • 37 Almskog LM, Wikman A, Svensson J. et al. Rotational thromboelastometry results are associated with care level in COVID-19. J Thromb Thrombolysis 2021; 51 (02) 437-445
    CrossrefPubMedGoogle Scholar
  • 38 Ye W, Chen G, Li X. et al. Dynamic changes of D-dimer and neutrophil-lymphocyte count ratio as prognostic biomarkers in COVID-19. Respir Res 2020; 21 (01) 169
    CrossrefPubMedGoogle Scholar
  • 39 Berger JS, Kunichoff D, Adhikari S. et al. Prevalence and outcomes of D-dimer elevation in hospitalized patients with COVID-19. Arterioscler Thromb Vasc Biol 2020; 40 (10) 2539-2547
    CrossrefPubMedGoogle Scholar
  • 40 Wright FL, Vogler TO, Moore EE. et al. Fibrinolysis shutdown correlation with thromboembolic events in severe COVID-19 infection. J Am Coll Surg 2020; 231 (02) 193.e1-203.e1 , e191
    Google Scholar
  • 41 Creel-Bulos C, Auld SC, Caridi-Scheible M. et al. Fibrinolysis shutdown and thrombosis in a COVID-19 ICU. Shock 2020; 55 (03) 316-320
    CrossrefPubMedGoogle Scholar
  • 42 Liu Y, Sun W, Guo Y. et al. Association between platelet parameters and mortality in coronavirus disease 2019: retrospective cohort study. Platelets 2020; 31 (04) 490-496
    CrossrefPubMedGoogle Scholar
  • 43 Parra-Izquierdo I, Aslan JE. Perspectives on platelet heterogeneity and host immune response in coronavirus disease 2019 (COVID-19). Semin Thromb Hemost 2020; 46 (07) 826-830
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Rapkiewicz AV, Mai X, Carsons SE. et al. Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: a case series. EClinicalMedicine 2020; 24: 100434
    CrossrefPubMedGoogle Scholar
  • 45 Strålin K, Wahlström E, Walther S. et al. Decline in mortality among hospitalised covid-19 patients in Sweden: a nationwide observational study. medRXiv 2020; DOI: 10.1101/2020.10.27.20220061.
    CrossrefPubMedGoogle Scholar
  • 46 Beigel JH, Tomashek KM, Dodd LE. et al; ACTT-1 Study Group Members. Remdesivir for the treatment of Covid-19 - final report. N Engl J Med 2020; 383 (19) 1813-1826
    CrossrefPubMedGoogle Scholar
  • 47 The RECOVERY Collaborative Group. Horby P, Lim WS. et al. Dexamethasone in hospitalized patients with Covid-19—preliminary report. N Engl J Med 2020; DOI: 10.1056/NEJMoa202143.
    CrossrefPubMedGoogle Scholar
  • 48 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
    CrossrefPubMedGoogle Scholar
  • 49 Buijsers B, Yanginlar C, de Nooijer A. et al. Increased plasma heparanase activity in COVID-19 patients. Front Immunol 2020; 11: 575047
    CrossrefPubMedGoogle Scholar
  • 50 Petito E, Falcinelli E, Paliani U. et al. Neutrophil more than platelet activation associates with thrombotic complications in COVID-19 patients. J Infect Dis 2020; DOI: 10.1093/infdis/jiaa756.
    CrossrefPubMedGoogle Scholar