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Thromb Haemost 2021; 121(09): 1181-1192
DOI: 10.1055/a-1346-3178
Coagulation and Fibrinolysis

Hemostasis in Coronavirus Disease 2019—Lesson from Viscoelastic Methods: A Systematic Review

Artur Słomka 
1   Department of Pathophysiology, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum Bydgoszcz, Poland
,
Mariusz Kowalewski
2   Clinical Department of Cardiac Surgery, Central Clinical Hospital of the Ministry of Interior and Administration, Centre of Postgraduate Medical Education, Warsaw, Poland
3   Department of Cardio-Thoracic Surgery, Heart and Vascular Centre, Maastricht University Medical Centre, Maastricht, The Netherlands
4   Cardiothoracic Research Centre, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum Bydgoszcz, Poland
,
Ewa Żekanowska
1   Department of Pathophysiology, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum Bydgoszcz, Poland
› Institutsangaben Funding None.
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Abstract

Hemostatic unbalance is often observed in patients with coronavirus disease 2019 (COVID-19), and patients with severe disease are at high risk of developing thromboembolic complications. Viscoelastic methods (VEMs), including thrombelastography (TEG) and thromboelastometry (TEM), provide data on the nature of hemostatic disturbance. In this systematic review, we assessed the performance of TEG and TEM in the assessment of blood coagulation and fibrinolysis in patients with COVID-19. PubMed, Scopus, Web of Science Core Collection, medRxiv, and bioRxiv were systematically searched for clinical studies evaluating TEG and/or TEM variables in COVID-19 individuals. Ten studies, with a total of 389 COVID-19 patients, were included, and VEMs were performed in 292 of these patients. Most patients (90%) presented severe COVID-19 and required mechanical ventilation. TEG and TEM variables showed that these patients displayed hypercoagulability and fibrinolysis shutdown, despite the use of appropriate thromboprophylaxis. However, the mechanism underlying these phenomena and their clinical significance in COVID-19 patients who developed thrombosis are still not clear. Further studies are warranted if VEMs might help to identify those at highest risk of thrombotic events and who therefore may derive the greatest benefit from antithrombotic therapy.

Keywords

coronavirus disease 2019 - COVID-19 - viscoelastic methods - thrombelastography - thromboelastometry

Supplementary Material



Publikationsverlauf

Eingereicht: 16. Oktober 2020

Angenommen: 02. Januar 2021

Accepted Manuscript online:
05. Januar 2021

Artikel online veröffentlicht:
03. März 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 WHO. WHO coronavirus disease (COVID-19) dashboard. Accessed February 06, 2021 at: https://covid19.who.int/
  • 2 Romagnoli S, Peris A, De Gaudio AR, Geppetti P. SARS-CoV-2 and COVID-19: between pathophysiology complexity and therapeutic uncertainty. Physiol Rev 2020; 100 (04) 1455-1466
    CrossrefPubMedSuche in Google Scholar
  • 3 Neerukonda SN, Katneni U. A review on SARS-CoV-2 virology, pathophysiology, animal models, and anti-viral interventions. Pathogens 2020; 9 (06) E426
    CrossrefPubMedSuche in Google Scholar
  • 4 Singh VK, Mishra A, Singh S. et al. Emerging prevention and treatment strategies to control COVID-19. Pathogens 2020; 9 (06) E501
    CrossrefPubMedSuche in Google Scholar
  • 5 Murthy S, Gomersall CD, Fowler RA. Care for critically ill patients with COVID-19. JAMA 2020; 323 (15) 1499-1500
    CrossrefPubMedSuche in Google Scholar
  • 6 Zhang W, Zhao Y, Zhang F. et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China. Clin Immunol 2020; 214: 108393
    CrossrefPubMedSuche in Google Scholar
  • 7 Rabi FA, Al Zoubi MS, Kasasbeh GA, Salameh DM, Al-Nasser AD. SARS-CoV-2 and coronavirus disease 2019: what we know so far. Pathogens 2020; 9 (03) 231
    CrossrefPubMedSuche in Google Scholar
  • 8 Jordan RE, Adab P, Cheng KK. Covid-19: risk factors for severe disease and death. BMJ 2020; 368: m1198
    CrossrefPubMedSuche in Google Scholar
  • 9 Clark A, Jit M, Warren-Gash C. et al; Centre for the Mathematical Modelling of Infectious Diseases COVID-19 working group.. Global, regional, and national estimates of the population at increased risk of severe COVID-19 due to underlying health conditions in 2020: a modelling study. Lancet Glob Health 2020; 8 (08) E1003-E1017
    CrossrefPubMedSuche in Google Scholar
  • 10 Słomka A, Kowalewski M, Żekanowska E. Coronavirus disease 2019 (COVID-19): a short review on hematological manifestations. Pathogens 2020; 9 (06) E493
    CrossrefPubMedSuche in Google Scholar
  • 11 Bikdeli B, Madhavan MV, Jimenez D. et al; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol 2020; 75 (23) 2950-2973
    CrossrefPubMedSuche in Google Scholar
  • 12 Bikdeli B, Madhavan MV, Gupta A. et al; Global COVID-19 Thrombosis Collaborative Group. Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research. Thromb Haemost 2020; 120 (07) 1004-1024
    Thieme ConnectPubMedSuche in Google Scholar
  • 13 Iba T, Levy JH, Levi M, Connors JM, Thachil J. Coagulopathy of coronavirus disease 2019. Crit Care Med 2020; 48 (09) 1358-1364
    CrossrefPubMedSuche in Google Scholar
  • 14 Fraissé M, Logre E, Pajot O, Mentec H, Plantefève G, Contou D. Thrombotic and hemorrhagic events in critically ill COVID-19 patients: a French monocenter retrospective study. Crit Care 2020; 24 (01) 275
    CrossrefPubMedSuche in Google Scholar
  • 15 Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir Med 2020; 8 (06) e46-e47
    CrossrefPubMedSuche in Google Scholar
  • 16 Varga Z, Flammer AJ, Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395 (10234): 1417-1418
    CrossrefPubMedSuche in Google Scholar
  • 17 Escher R, Breakey N, Lämmle B. ADAMTS13 activity, von Willebrand factor, factor VIII and D-dimers in COVID-19 inpatients. Thromb Res 2020; 192: 174-175
    CrossrefPubMedSuche in Google Scholar
  • 18 Maier CL, Truong AD, Auld SC, Polly DM, Tanksley CL, Duncan A. COVID-19-associated hyperviscosity: a link between inflammation and thrombophilia?. Lancet 2020; 395 (10239): 1758-1759
    CrossrefPubMedSuche in Google Scholar
  • 19 Drumheller BC, Stein DM, Moore LJ, Rizoli SB, Cohen MJ. Thromboelastography and rotational thromboelastometry for the surgical intensivist: A narrative review. J Trauma Acute Care Surg 2019; 86 (04) 710-721
    CrossrefPubMedSuche in Google Scholar
  • 20 Hartmann J, Murphy M, Dias JD. Viscoelastic hemostatic assays: moving from the laboratory to the site of care-a review of established and emerging technologies. Diagnostics (Basel) 2020; 10 (02) 118
    Suche in Google Scholar
  • 21 Chaudhary R, Kreutz RP, Bliden KP, Tantry US, Gurbel PA. Personalizing antithrombotic therapy in COVID-19: role of thromboelastography and thromboelastometry. Thromb Haemost 2020; 120 (11) 1594-1596
    Thieme ConnectPubMedSuche in Google Scholar
  • 22 Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. PLoS Med 2009; 6 (07) e1000097
    CrossrefPubMedSuche in Google Scholar
  • 23 Kwon D. How swamped preprint servers are blocking bad coronavirus research. Nature 2020; 581 (7807): 130-131
    CrossrefPubMedSuche in Google Scholar
  • 24 Theusinger OM, Nürnberg J, Asmis LM, Seifert B, Spahn DR. Rotation thromboelastometry (ROTEM) stability and reproducibility over time. Eur J Cardiothorac Surg 2010; 37 (03) 677-683
    CrossrefPubMedSuche in Google Scholar
  • 25 Corey FS, Walker WF. Sonic estimation of elasticity via resonance: a new method of assessing hemostasis. Ann Biomed Eng 2016; 44 (05) 1405-1424
    CrossrefPubMedSuche in Google Scholar
  • 26 Wells GA, Shea B, O'Connell D. et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Accessed July, 2020 at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
  • 27 Słomka A, Kowalewski M, Żekanowska E, Suwalski P, Lorusso R, Eikelboom JW. Plasma levels of protein Z in ischemic stroke: a systematic review and meta-analysis. Thromb Haemost 2020; 120 (05) 815-822
    Thieme ConnectPubMedSuche in Google Scholar
  • 28 Panigada M, Bottino N, Tagliabue P. et al. Hypercoagulability of COVID-19 patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost 2020; 18 (07) 1738-1742
    CrossrefPubMedSuche in Google Scholar
  • 29 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
    Suche in Google Scholar
  • 30 Maatman TK, Jalali F, Feizpour C. et al. Routine venous thromboembolism prophylaxis may be inadequate in the hypercoagulable state of severe coronavirus disease 2019. Crit Care Med 2020; 48 (09) e783-e790
    CrossrefPubMedSuche in Google Scholar
  • 31 Mortus JR, Manek SE, Brubaker LS. et al. Thromboelastographic results and hypercoagulability syndrome in patients with coronavirus disease 2019 who are critically ill. JAMA Netw Open 2020; 3 (06) e2011192
    Suche in Google Scholar
  • 32 Patel BV, Arachchillage DJ, Ridge CA. et al. Pulmonary angiopathy in severe COVID-19: physiologic, imaging, and hematologic observations. Am J Respir Crit Care Med 2020; 202 (05) 690-699
    CrossrefPubMedSuche in Google Scholar
  • 33 Spiezia L, Boscolo A, Poletto F. et al. COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure. Thromb Haemost 2020; 120 (06) 998-1000
    Thieme ConnectPubMedSuche in Google Scholar
  • 34 Pavoni V, Gianesello L, Pazzi M, Stera C, Meconi T, Frigieri FC. Evaluation of coagulation function by rotation thromboelastometry in critically ill patients with severe COVID-19 pneumonia. J Thromb Thrombolysis 2020; 50 (02) 281-286
    CrossrefPubMedSuche in Google Scholar
  • 35 Madathil RJ, Tabatabai A, Rabin J. et al. Thromboelastometry and D-dimer elevation in coronavirus-2019. J Cardiothorac Vasc Anesth 2020; 34 (12) 3495-3496
    CrossrefPubMedSuche in Google Scholar
  • 36 Ibañez C, Perdomo J, Calvo A. et al. High D dimers and low global fibrinolysis coexist in COVID19 patients: what is going on in there?. J Thromb Thrombolysis 2021; 51 (02) 308-312
    CrossrefPubMedSuche in Google Scholar
  • 37 Almskog L, Wikman A, Svensson J. et al. Rotational thromboelastometry predicts care level in Covid-19. MedRxiv 2020;
    CrossrefPubMedSuche in Google Scholar
  • 38 Scarpelini S, Rhind SG, Nascimento B. et al. Normal range values for thromboelastography in healthy adult volunteers. Braz J Med Biol Res 2009; 42 (12) 1210-1217
    CrossrefPubMedSuche in Google Scholar
  • 39 Kaufmann CR, Dwyer KM, Crews JD, Dols SJ, Trask AL. Usefulness of thrombelastography in assessment of trauma patient coagulation. J Trauma 1997; 42 (04) 716-720
    CrossrefPubMedSuche in Google Scholar
  • 40 Lang T, Bauters A, Braun SL. et al. Multi-centre investigation on reference ranges for ROTEM thromboelastometry. Blood Coagul Fibrinolysis 2005; 16 (04) 301-310
    CrossrefPubMedSuche in Google Scholar
  • 41 Görlinger K, Dirkmann D, Hanke AA. Rotational thromboelastometry (ROTEM ® ). In: Gonzalez E, Moore HB, Moore EE. eds. Trauma induced coagulopathy. Cham: Springer International Publishing; 2016: 267-298
    CrossrefSuche in Google Scholar
  • 42 Müller MC, Meijers JC, Vroom MB, Juffermans NP. Utility of thromboelastography and/or thromboelastometry in adults with sepsis: a systematic review. Crit Care 2014; 18 (01) R30
    CrossrefPubMedSuche in Google Scholar
  • 43 Tsantes AE, Tsantes AG, Kokoris SI. et al. COVID-19 infection-related coagulopathy and viscoelastic methods: a paradigm for their clinical utility in critical illness. Diagnostics (Basel) 2020; 10 (10) 817
    CrossrefPubMedSuche in Google Scholar
  • 44 Katneni UK, Alexaki A, Hunt RC. et al. Coagulopathy and thrombosis as a result of severe COVID-19 infection: a microvascular focus. Thromb Haemost 2020; 120 (12) 1668-1679
    Thieme ConnectPubMedSuche in Google Scholar
  • 45 Shen W, Zhou JY, Gu Y, Shen WY, Li M. Establishing a reference range for thromboelastography maximum amplitude in patients administrating with antiplatelet drugs. J Clin Lab Anal 2020; 34 (04) e23144
    CrossrefPubMedSuche in Google Scholar
  • 46 McCrath DJ, Cerboni E, Frumento RJ, Hirsh AL, Bennett-Guerrero E. Thromboelastography maximum amplitude predicts postoperative thrombotic complications including myocardial infarction. Anesth Analg 2005; 100 (06) 1576-1583
    CrossrefPubMedSuche in Google Scholar
  • 47 Harahsheh Y, Duff OC, Ho KM. Thromboelastography predicts thromboembolism in critically ill coagulopathic patients. Crit Care Med 2019; 47 (06) 826-832 [Erratum in: Crit Care Med. 2019;47(10):e853]
    CrossrefPubMedSuche in Google Scholar
  • 48 Hincker A, Feit J, Sladen RN, Wagener G. Rotational thromboelastometry predicts thromboembolic complications after major non-cardiac surgery. Crit Care 2014; 18 (05) 549
    CrossrefPubMedSuche in Google Scholar
  • 49 Kamel Y, Hassanin A, Ahmed AR. et al. Perioperative thromboelastometry for adult living donor liver transplant recipients with a tendency to hypercoagulability: a prospective observational cohort study. Transfus Med Hemother 2018; 45 (06) 404-412
    CrossrefPubMedSuche in Google Scholar
  • 50 Roncon L, Zuin M, Barco S. et al. Incidence of acute pulmonary embolism in COVID-19 patients: systematic review and meta-analysis. Eur J Intern Med 2020; 82: 29-37
    CrossrefPubMedSuche in Google Scholar
  • 51 Porfidia A, Valeriani E, Pola R, Porreca E, Rutjes AWS, Di Nisio M. Venous thromboembolism in patients with COVID-19: systematic review and meta-analysis. Thromb Res 2020; 196: 67-74
    CrossrefPubMedSuche in Google Scholar
  • 52 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
    CrossrefPubMedSuche in Google Scholar
  • 53 Weitz JI, Fredenburgh JC, Eikelboom JW. A test in context: D-dimer. J Am Coll Cardiol 2017; 70 (19) 2411-2420
    CrossrefPubMedSuche in Google Scholar
  • 54 Pulivarthi S, Gurram MK. Effectiveness of d-dimer as a screening test for venous thromboembolism: an update. N Am J Med Sci 2014; 6 (10) 491-499
    CrossrefPubMedSuche in Google Scholar
  • 55 Zhang L, Yan X, Fan Q. et al. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemost 2020; 18 (06) 1324-1329
    CrossrefPubMedSuche in Google Scholar
  • 56 Shah S, Shah K, Patel SB. et al. Elevated D-dimer levels are associated with increased risk of mortality in coronavirus disease 2019: a systematic review and meta-analysis. Cardiol Rev 2020; 28 (06) 295-302
    CrossrefPubMedSuche in Google Scholar
  • 57 Moll M, Zon RL, Sylvester KW. et al. VTE in ICU patients with COVID-19. Chest 2020; 158 (05) 2130-2135
    CrossrefPubMedSuche in Google Scholar
  • 58 Dujardin RWG, Hilderink BN, Haksteen WE. et al. Biomarkers for the prediction of venous thromboembolism in critically ill COVID-19 patients. Thromb Res 2020; 196: 308-312
    CrossrefPubMedSuche in Google Scholar
  • 59 Mouhat B, Besutti M, Bouiller K. et al. Elevated D-dimers and lack of anticoagulation predict PE in severe COVID-19 patients. Eur Respir J 2020; 56 (04) 2001811
    CrossrefPubMedSuche in Google Scholar
  • 60 Al-Samkari H, Song F, Van Cott EM, Kuter DJ, Rosovsky R. Evaluation of the prothrombin fragment 1.2 in patients with coronavirus disease 2019 (COVID-19). Am J Hematol 2020; 95 (12) 1479-1485
    CrossrefPubMedSuche in Google Scholar
  • 61 Hadid T, Kafri Z, Al-Katib A. Coagulation and anticoagulation in COVID-19. Blood Rev 2020;
    CrossrefPubMedSuche in Google Scholar
  • 62 Thachil J. The protective rather than prothrombotic fibrinogen in COVID-19 and other inflammatory states. J Thromb Haemost 2020; 18 (08) 1849-1852
    CrossrefPubMedSuche in Google Scholar
  • 63 Price LC, McCabe C, Garfield B, Wort SJ. Thrombosis and COVID-19 pneumonia: the clot thickens!. Eur Respir J 2020; 56 (01) 2001608
    CrossrefPubMedSuche in Google Scholar
  • 64 Hardy M, Michaux I, Lessire S. et al. Prothrombotic disturbances of hemostasis of patients with severe COVID-19: a prospective longitudinal observational study. Thromb Res 2021;
    CrossrefPubMedSuche in Google Scholar
  • 65 Hardy M, Michaux I, Lessire S. et al. Prothrombotic hemostasis disturbances in patients with severe COVID-19: individual daily data. Data Brief 2020; 33: 106519
    CrossrefPubMedSuche in Google Scholar
  • 66 Martín-Rojas RM, Pérez-Rus G, Delgado-Pinos VE. et al. COVID-19 coagulopathy: an in-depth analysis of the coagulation system. Eur J Haematol 2020; 105 (06) 741-750
    CrossrefPubMedSuche in Google Scholar
  • 67 Moore HB, Moore EE, Neal MD. et al. Fibrinolysis shutdown in trauma: historical review and clinical implications. Anesth Analg 2019; 129 (03) 762-773
    CrossrefPubMedSuche in Google Scholar
  • 68 Moore HB, Moore EE, Liras IN. et al. Acute fibrinolysis shutdown after injury occurs frequently and increases mortality: a multicenter evaluation of 2,540 severely injured patients. J Am Coll Surg 2016; 222 (04) 347-355
    CrossrefPubMedSuche in Google Scholar
  • 69 Meizoso JP, Karcutskie CA, Ray JJ, Namias N, Schulman CI, Proctor KG. Persistent fibrinolysis shutdown is associated with increased mortality in severely injured trauma patients. J Am Coll Surg 2017; 224 (04) 575-582
    CrossrefPubMedSuche in Google Scholar
  • 70 Roberts DJ, Kalkwarf KJ, Moore HB. et al. Time course and outcomes associated with transient versus persistent fibrinolytic phenotypes after injury: a nested, prospective, multicenter cohort study. J Trauma Acute Care Surg 2019; 86 (02) 206-213
    CrossrefPubMedSuche in Google Scholar
  • 71 Gall LS, Vulliamy P, Gillespie S. et al; Targeted Action for Curing Trauma-Induced Coagulopathy (TACTIC) partners. The S100A10 pathway mediates an occult hyperfibrinolytic subtype in trauma patients. Ann Surg 2019; 269 (06) 1184-1191
    CrossrefPubMedSuche in Google Scholar
  • 72 Hunt BJ, Levi M. Re The source of elevated plasma D-dimer levels in COVID-19 infection. Br J Haematol 2020; 190 (03) e133-e134
    CrossrefPubMedSuche in Google Scholar
  • 73 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
    CrossrefPubMedSuche in Google Scholar
  • 74 Weiss E, Roux O, Moyer JD. et al. Fibrinolysis resistance: a potential mechanism underlying COVID-19 coagulopathy. Thromb Haemost 2020; 120 (09) 1343-1345
    Thieme ConnectPubMedSuche in Google Scholar
  • 75 Sukhomlin T. Fibrinolysis shutdown in COVID-19-infected patients can result from iron-induced stabilization of fibril clots. J Am Coll Surg 2020; 231 (05) 607-608
    CrossrefPubMedSuche in Google Scholar
  • 76 Rovina N, Akinosoglou K, Eugen-Olsen J, Hayek S, Reiser J, Giamarellos-Bourboulis EJ. Soluble urokinase plasminogen activator receptor (suPAR) as an early predictor of severe respiratory failure in patients with COVID-19 pneumonia. Crit Care 2020; 24 (01) 187
    CrossrefPubMedSuche in Google Scholar
  • 77 Azam TU, Shadid HR, Blakely P. et al; International Study of Inflammation in COVID-19. Soluble urokinase receptor (SuPAR) in COVID-19-related AKI. J Am Soc Nephrol 2020; 31 (11) 2725-2735
    CrossrefPubMedSuche in Google Scholar
  • 78 Hardy M, Douxfils J, Bareille M. et al. Studies on hemostasis in COVID-19 deserve careful reporting of the laboratory methods, their significance, and their limitations. J Thromb Haemost 2020; 18 (11) 3121-3124
    CrossrefPubMedSuche in Google Scholar
  • 79 Thachil J, Tang N, Gando S. et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost 2020; 18 (05) 1023-1026
    CrossrefPubMedSuche in Google Scholar
  • 80 Hardy M, Lecompte T, Douxfils J. et al. Management of the thrombotic risk associated with COVID-19: guidance for the hemostasis laboratory. Thromb J 2020; 18: 17
    CrossrefPubMedSuche in Google Scholar
  • 81 Hans GA, Besser MW. The place of viscoelastic testing in clinical practice. Br J Haematol 2016; 173 (01) 37-48
    CrossrefPubMedSuche in Google Scholar
  • 82 Tanaka KA, Henderson RA, Strauss ER. Evolution of viscoelastic coagulation testing. Expert Rev Hematol 2020; 13 (07) 697-707
    CrossrefPubMedSuche in Google Scholar