Supplemental Fibrinogen Restores Platelet Inhibitor-Induced Reduction in Thrombus Formation without Altering Platelet Function: An In Vitro StudyFunding This research was supported by the Austrian Science Fund FWF (Grant P22521-B18 to A.H. and P26185-B19 to R.S.) and the Jubiläumsfonds of the Austrian National Bank (14263 to A.H.). T.B. was funded by the PhD Program DK-MOLIN (FWF–W1241). T.B. is a recipient of a DOC Fellowship of the Austrian Academy of Sciences and the Start Funding Program of the Medical University of Graz.
Background For patients treated with dual antiplatelet therapy, standardized drug-specific 3-to-7 day cessation is recommended prior to major surgery to reach sufficient platelet function recovery. Here we investigated the hypothesis that supplemental fibrinogen might mitigate the inhibitory effects of antiplatelet therapy.
Methods and Results To this end blood from healthy donors was treated in vitro with platelet inhibitors, and in vitro thrombus formation and platelet activation were assessed. Ticagrelor, acetylsalicylic acid, the combination of both, and tirofiban all markedly attenuated the formation of adherent thrombi, when whole blood was perfused through collagen-coated microchannels at physiological shear rates. Addition of fibrinogen restored in vitro thrombus formation in the presence of antiplatelet drugs and heparin. However, platelet activation, as investigated in assays of P-selectin expression and calcium flux, was not altered by fibrinogen supplementation. Most importantly, fibrinogen was able to restore in vitro thrombogenesis in patients on maintenance dual antiplatelet therapy after percutaneous coronary intervention.
Conclusion Thus, our in vitro data support the notion that supplementation of fibrinogen influences the perioperative hemostasis in patients undergoing surgery during antiplatelet therapy by promoting thrombogenesis without significantly interfering with platelet activation.
Thomas Bärnthaler, Gabor G. Toth, Rufina Schuligoi, Florian Prüller, and Eva Buschmann performed the experiments; Thomas Bärnthaler, Elisabeth Mahla, Akos Heinemann, Florian Prüller, and Rufina Schuligoi interpreted the results of the experiments; Thomas Bärnthaler and Rufina Schuligoi prepared the figures; Thomas Bärnthaler, Rufina Schuligoi, Akos Heinemann, and Elisabeth Mahla drafted the manuscript. Thomas Bärnthaler, Rufina Schuligoi, Akos Heinemann, and Elisabeth Mahla revised the manuscript; Thomas Bärnthaler, Gabor G. Toth, Rufina Schuligoi, Florian Prüller, Eva Buschmann, Akos Heinemann, and Elisabeth Mahla approved the final version of the manuscript; Akos Heinemann, Thomas Bärnthaler, Rufina Schuligoi, and Elisabeth Mahla conceptualized and designed the research.
Received: 30 September 2019
Accepted: 25 June 2020
09 August 2020 (online)
© 2020. Thieme. All rights reserved.
Georg Thieme Verlag KG
Stuttgart · New York
- 1 Hoffman M, Dargaud Y. Mechanisms and monitoring of bypassing agent therapy. J Thromb Haemost 2012; 10 (08) 1478-1485
- 2 Wallentin L, Becker RC, Budaj A. et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361 (11) 1045-1057
- 3 Wiviott SD, Braunwald E, McCabe CH. et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357 (20) 2001-2015
- 4 Holm M, Biancari F, Khodabandeh S. et al. Bleeding in patients treated with ticagrelor or clopidogrel before coronary artery bypass grafting. Ann Thorac Surg 2019; 107 (06) 1690-1698
- 5 Valgimigli M, Bueno H, Byrne RA. et al; ESC Scientific Document Group; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the task force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018; 39 (03) 213-260
- 6 Biancari F, Mariscalco G, Gherli R. et al. Variation in preoperative antithrombotic strategy, severe bleeding, and use of blood products in coronary artery bypass grafting: results from the multicentre E-CABG registry. Eur Heart J Qual Care Clin Outcomes 2018; 4 (04) 246-257
- 7 Hansson EC, Jideus L, Aberg B. et al. Coronary artery bypass grafting-related bleeding complications in patients treated with ticagrelor or clopidogrel: a nationwide study. Eur Heart J 2016; 37 (02) 189-197
- 8 Mahla E, Prueller F, Farzi S. et al. Does platelet reactivity predict bleeding in patients needing urgent coronary artery bypass grafting during dual antiplatelet therapy?. Ann Thorac Surg 2016; 102 (06) 2010-2017
- 9 O'Connor SA, Amour J, Mercadier A. et al; ACTION Study Group. Efficacy of ex vivo autologous and in vivo platelet transfusion in the reversal of P2Y12 inhibition by clopidogrel, prasugrel, and ticagrelor: the APTITUDE study. Circ Cardiovasc Interv 2015; 8 (11) e002786
- 10 Teng R, Carlson GF, Nylander S, Andersson TL. Effects of autologous platelet transfusion on platelet inhibition in ticagrelor-treated and clopidogrel-treated subjects. J Thromb Haemost 2016; 14 (12) 2342-2352
- 11 Kruger PC, Hirsh J, Bhagirath VC. et al. In vitro reversal of the anti-aggregant effect of ticagrelor using untreated platelets. Thromb Haemost 2018; 118 (11) 1895-1901
- 12 Zafar MU, Smith DA, Baber U. et al. Impact of timing on the functional recovery achieved with platelet supplementation after treatment with ticagrelor. Circ Cardiovasc Interv 2017; 10 (08) e005120
- 13 Fries D, Krismer A, Klingler A. et al. Effect of fibrinogen on reversal of dilutional coagulopathy: a porcine model. Br J Anaesth 2005; 95 (02) 172-177
- 14 Lang T, Johanning K, Metzler H. et al. The effects of fibrinogen levels on thromboelastometric variables in the presence of thrombocytopenia. Anesth Analg 2009; 108 (03) 751-758
- 15 Li JY, Gong J, Zhu F. et al. Fibrinogen concentrate in cardiovascular surgery: a meta-analysis of randomized controlled trials. Anesth Analg 2018; 127 (03) 612-621
- 16 Bolliger D, Mauermann E, Tanaka KA. Thresholds for perioperative administration of hemostatic blood components and coagulation factor concentrates: an unmet medical need. J Cardiothorac Vasc Anesth 2015; 29 (03) 768-776
- 17 Levy JH, Welsby I, Goodnough LT. Fibrinogen as a therapeutic target for bleeding: a review of critical levels and replacement therapy. Transfusion 2014; 54 (05) 1389-1405
- 18 Pasterk L, Philipose S, Eller K, Marsche G, Heinemann A, Schuligoi R. The EP3 agonist sulprostone enhances platelet adhesion but not thrombus formation under flow conditions. Pharmacology 2015; 96 (3-4): 137-143
- 19 Philipose S, Konya V, Lazarevic M. et al. Laropiprant attenuates EP3 and TP prostanoid receptor-mediated thrombus formation. PLoS One 2012; 7 (08) e40222
- 20 Philipose S, Konya V, Sreckovic I. et al. The prostaglandin E2 receptor EP4 is expressed by human platelets and potently inhibits platelet aggregation and thrombus formation. Arterioscler Thromb Vasc Biol 2010; 30 (12) 2416-2423
- 21 Hosokawa K, Ohnishi-Wada T, Sameshima-Kaneko H. et al. Plasminogen activator inhibitor type 1 in platelets induces thrombogenicity by increasing thrombolysis resistance under shear stress in an in-vitro flow chamber model. Thromb Res 2016; 146: 69-75
- 22 Prüller F, Rosskopf K, Mangge H. et al. Implementation of buffy-coat-derived pooled platelet concentrates for internal quality control of light transmission aggregometry: a proof of concept study. J Thromb Haemost 2017; 15 (12) 2443-2450
- 23 Michelson AD. ed. Platelets. 2nd ed. San Diego, CA: Elsevier; 2007
- 24 Gurbel PA, Tantry US. Combination antithrombotic therapies. Circulation 2010; 121 (04) 569-583
- 25 Cristal N, Slonim A, Bar-Ilan I, Hart A. Plasma fibrinogen levels and the clinical course of acute myocardial infarction. Angiology 1983; 34 (11) 693-698
- 26 Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998; 338 (21) 1488-1497
- 27 Cartwright BL, Kam P, Yang K. Efficacy of fibrinogen concentrate compared with cryoprecipitate for reversal of the antiplatelet effect of clopidogrel in an in vitro model, as assessed by multiple electrode platelet aggregometry, thromboelastometry, and modified thromboelastography. J Cardiothorac Vasc Anesth 2015; 29 (03) 694-702
- 28 Schenk B, Lindner AK, Treichl B. et al. Fibrinogen supplementation ex vivo increasesclot firmness comparable to platelet transfusion in thrombocytopenia. Br J Anaesth 2016; 117 (05) 576-582
- 29 Rahe-Meyer N, Levy JH, Mazer CD. et al. Randomized evaluation of fibrinogen vs placebo in complex cardiovascular surgery (REPLACE): a double-blind phase III study of haemostatic therapy. Br J Anaesth 2016; 117 (01) 41-51
- 30 Ranucci M, Baryshnikova E, Crapelli GB, Rahe-Meyer N, Menicanti L, Frigiola A. Surgical Clinical Outcome REsearch (SCORE) Group. Randomized, double-blinded, placebo-controlled trial of fibrinogen concentrate supplementation after complex cardiac surgery. J Am Heart Assoc 2015; 4 (06) e002066
- 31 Bilecen S, de Groot JA, Kalkman CJ. et al. Effect of fibrinogen concentrate on intraoperative blood loss among patients with intraoperative bleeding during high-risk cardiac surgery: a randomized clinical trial. JAMA 2017; 317 (07) 738-747
- 32 Davis AK. When more is less efficacious: fibrinogen concentrate in complex cardiac surgery. Br J Anaesth 2016; 117 (04) 415-417
- 33 Prüller F, Münch A, Preininger A. et al. Comparison of functional fibrinogen (FF/CFF) and FIBTEM in surgical patients - a retrospective study. Clin Chem Lab Med 2016; 54 (03) 453-458
- 34 Buchanan A, Newton P, Pehrsson S. et al. Structural and functional characterization of a specific antidote for ticagrelor. Blood 2015; 125 (22) 3484-3490
- 35 Hosokawa K, Ohnishi T, Sameshima H. et al. Analysing responses to aspirin and clopidogrel by measuring platelet thrombus formation under arterial flow conditions. Thromb Haemost 2013; 109 (01) 102-111
- 36 Ogawa S, Ohnishi T, Hosokawa K, Szlam F, Chen EP, Tanaka KA. Haemodilution-induced changes in coagulation and effects of haemostatic components under flow conditions. Br J Anaesth 2013; 111 (06) 1013-1023
- 37 Hosokawa K, Ohnishi T, Sameshima H. et al. Comparative evaluation of direct thrombin and factor Xa inhibitors with antiplatelet agents under flow and static conditions: an in vitro flow chamber model. PLoS One 2014; 9 (01) e86491
- 38 Kaikita K, Hosokawa K, Dahlen JR, Tsujita K. Total Thrombus-Formation Analysis System (T-TAS): clinical application of quantitative analysis of thrombus formation in cardiovascular disease. Thromb Haemost 2019; 119 (10) 1554-1562