Thrombogenicity and Antithrombotic Strategies in Structural Heart Interventions and Nonaortic Cardiac Device Therapy—Current Evidence and Practice

Abstract

As the number of, and the indications for, structural heart interventions are increasing worldwide, the optimal secondary prevention to reduce device thrombosis is becoming more important. To date, most of the recommendations are empiric. The current review discusses mechanisms behind device-related thrombosis, the available evidence with regard to antithrombotic regimen after cardiac device implantation, as well as providing an algorithm for identification of risk factors for device thrombogenicity and for management of device thrombosis after implantation of patent foramen ovale and left atrial appendage occluders, MitraClips/transcatheter mitral valve replacement, pacemaker leads, and left ventricular assist devices. Of note, the topic of antithrombotic therapy and thrombogenicity of prostheses in aortic position (transcatheter aortic valve replacement, surgical, mechanical, and bioprostheses) is not part of the present article and is discussed in detail in other contemporary focused articles.

Keywords

patent foramen ovale - left atrial appendage - MitraClip - left ventricular assist device - device-related thrombosis

• References

• 1 Jaffer IH, Fredenburgh JC, Hirsh J, Weitz JI. Medical device-induced thrombosis: what causes it and how can we prevent it?. J Thromb Haemost 2015; 13 (Suppl. 01) S72-S81
• 2 Wright SD, Weitz JI, Huang AJ, Levin SM, Silverstein SC, Loike JD. Complement receptor type three (CD11b/CD18) of human polymorphonuclear leukocytes recognizes fibrinogen. Proc Natl Acad Sci U S A 1988; 85 (20) 7734-7738
• 3 Baumgartner H, Falk V, Bax JJ. , et al; ESC Scientific Document Group. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2017; 38 (36) 2739-2791
• 4 Pristipino C, Sievert H, D'Ascenzo F. , et al. European position paper on the management of patients with patent foramen ovale. General approach and left circulation thromboembolism. Eur Heart J [Internet]; 2018. Available at: https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehy649/5144593 . Accessed January 2, 2019
• 5 Saver JL, Carroll JD, Thaler DE. , et al; RESPECT Investigators. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med 2017; 377 (11) 1022-1032
• 6 Søndergaard L, Kasner SE, Rhodes JF. , et al; Gore REDUCE Clinical Study Investigators. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med 2017; 377 (11) 1033-1042
• 7 Mas J-L, Derumeaux G, Guillon B. , et al; CLOSE Investigators. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med 2017; 377 (11) 1011-1021
• 8 Kuijpers T, Spencer FA, Siemieniuk RAC. , et al. Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy alone for management of cryptogenic stroke? A clinical practice guideline. BMJ 2018; 362: k2515
• 9 Snijder RJR, Renes LE, Suttorp MJ, Ten Berg JM, Post MC. Percutaneous patent foramen ovale closure using the Occlutech Figulla device: more than 1,300 patient-years of follow up. Catheter Cardiovasc Interv 2019; 93 (06) 1080-1084
• 10 Rudolph V, Augustin J, Hofmann T. , et al. Predictors of recurrent stroke after percutaneous closure of patent foramen ovale. EuroIntervention 2014; 9 (12) 1418-1422
• 11 Mariucci E, Donti A, Salomone L. , et al. Recurrent stroke after transcatheter PFO closure in cryptogenic stroke or TIA: long-term follow-up. Cardiol Res Pract 2017; 2017: 9849425
• 12 Wöhrle J, Bertrand B, Søndergaard L. , et al. PFO closuRE and CryptogenIc StrokE (PRECISE) registry: a multi-center, international registry. Clin Res Cardiol 2012; 101 (10) 787-793
• 13 Abaci A, Unlu S, Alsancak Y, Kaya U, Sezenoz B. Short and long term complications of device closure of atrial septal defect and patent foramen ovale: meta-analysis of 28,142 patients from 203 studies. Catheter Cardiovasc Interv 2013; 82 (07) 1123-1138
• 14 Wahl A, Tai T, Praz F. , et al. Late results after percutaneous closure of patent foramen ovale for secondary prevention of paradoxical embolism using the Amplatzer PFO occluder without intraprocedural echocardiography: effect of device size. JACC Cardiovasc Interv 2009; 2 (02) 116-123
• 15 Klotz S, Gebhard M, Sievers HH. Late left atrial thrombosis of an Amplatzer patent foramen ovale occluder. J Thorac Cardiovasc Surg 2011; 142 (05) 1270-1271
• 16 Elgendy AY, Elgendy IY, Mojadidi MK. , et al. New-onset atrial fibrillation following percutaneous patent foramen ovale closure: a systematic review and meta-analysis of randomised trials. EuroIntervention 2019; 14 (17) 1788-1790
• 17 Luc JGY, Bakar SN, Kiaii B, Sridhar K. Thrombus in a hypercoagulable patient following patent foramen ovale closure with the gore septal occluder. JACC Cardiovasc Interv 2018; 11 (11) 1108-1109
• 18 Vanderheyden M, Willaert W, Claessens P, Branders I, Ex P, Vermeersch P. Thrombosis of a patent foramen ovale closure device: thrombolytic management. Catheter Cardiovasc Interv 2002; 56 (04) 522-526
• 19 Lempereur M, Aminian A, Freixa X. , et al. Device-associated thrombus formation after left atrial appendage occlusion: a systematic review of events reported with the Watchman, the Amplatzer Cardiac Plug and the Amulet. Catheter Cardiovasc Interv 2017; 90 (05) E111-E121
• 20 Reddy VY, Holmes D, Doshi SK, Neuzil P, Kar S. Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry. Circulation 2011; 123 (04) 417-424
• 21 Dukkipati SR, Kar S, Holmes DR. , et al. Device-related thrombus after left atrial appendage closure. Circulation 2018; 138 (09) 874-885
• 22 Cochet H, Iriart X, Sridi S. , et al. Left atrial appendage patency and device-related thrombus after percutaneous left atrial appendage occlusion: a computed tomography study. Eur Heart J Cardiovasc Imaging 2018; 19 (12) 1351-1361
• 23 Pracon R, Bangalore S, Dzielinska Z. , et al. Device thrombosis after percutaneous left atrial appendage occlusion is related to patient and procedural characteristics but not to duration of postimplantation dual antiplatelet therapy. Circ Cardiovasc Interv 2018; 11 (03) e005997 Page: 1
• 24 Sedaghat A, Schrickel J-W, Andrié R, Schueler R, Nickenig G, Hammerstingl C. Thrombus formation after left atrial appendage occlusion with the Amplatzer Amulet device. JACC Clin Electrophysiol 2017; 3 (01) 71-75
• 25 Kubo S, Mizutani Y, Meemook K, Nakajima Y, Hussaini A, Kar S. Incidence, characteristics, and clinical course of device-related thrombus after Watchman left atrial appendage occlusion device implantation in atrial fibrillation patients. JACC Clin Electrophysiol 2017; 3 (12) 1380-1386
• 26 Fauchier L, Cinaud A, Brigadeau F. , et al. Device-related thrombosis after percutaneous left atrial appendage occlusion for atrial fibrillation. J Am Coll Cardiol 2018; 71 (14) 1528-1536
• 27 Ketterer U, D'Ancona G, Siegel I, Ortak J, Ince H, Kische S. Percutaneous left atrial appendage occlusion: device thrombosis in clopidogrel non-responders. Int J Cardiol 2016; 204: 196-197
• 28 Dannenberg L, Mourikis P, Naguib D. , et al. Antiplatelet effects of aspirin and clopidogrel after left atrial appendage (LAA) occluder implantation. Int J Cardiol 2019; 275: 95-100
• 29 Reddy VY, Möbius-Winkler S, Miller MA. , et al. Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology). J Am Coll Cardiol 2013; 61 (25) 2551-2556
• 30 Saw J, Tzikas A, Shakir S. , et al. Incidence and clinical impact of device-associated thrombus and peri-device leak following left atrial appendage closure with the Amplatzer Cardiac Plug. JACC Cardiovasc Interv 2017; 10 (04) 391-399
• 31 Tzikas A, Freixa X, Llull L. , et al. Patients with intracranial bleeding and atrial fibrillation treated with left atrial appendage occlusion: results from the Amplatzer Cardiac Plug registry. Int J Cardiol 2017; 236: 232-236
• 32 Tzikas A, Shakir S, Gafoor S. , et al. Left atrial appendage occlusion for stroke prevention in atrial fibrillation: multicentre experience with the AMPLATZER Cardiac Plug. EuroIntervention 2016; 11 (10) 1170-1179
• 33 Pison L, Potpara TS, Chen J, Larsen TB, Bongiorni MG, Blomström-Lundqvist C. ; Scientific Initiative Committee, European Heart Rhythm Association. Left atrial appendage closure-indications, techniques, and outcomes: results of the European Heart Rhythm Association Survey. Europace 2015; 17 (04) 642-646
• 34 Tilz RR, Potpara T, Chen J. , et al. Left atrial appendage occluder implantation in Europe: indications and anticoagulation post-implantation. Results of the European Heart Rhythm Association Survey. Europace 2017; 19 (10) 1737-1742
• 35 Lam SCC, Bertog S, Sievert H. Incomplete left atrial appendage occlusion and thrombus formation after Watchman implantation treated with anticoagulation followed by further transcatheter closure with a second-generation Amplatzer Cardiac Plug (Amulet device). Catheter Cardiovasc Interv 2015; 85 (02) 321-327
• 36 Stimpfle F, Müller K, Geisler T. , et al. Thromboembolic risk reduction via transseptal thrombus aspiration in a patient with spontaneous left atrial thrombus and stroke. JACC Cardiovasc Interv 2017; 10 (06) e57-e59
• 37 Obadia J-F, Messika-Zeitoun D, Leurent G. , et al; MITRA-FR Investigators. Percutaneous repair or medical treatment for secondary mitral regurgitation. N Engl J Med 2018; 379 (24) 2297-2306
• 38 Stone GW, Lindenfeld J, Abraham WT. , et al; COAPT Investigators. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med 2018; 379 (24) 2307-2318
• 39 Adelborg K, Szépligeti S, Sundbøll J. , et al. Risk of stroke in patients with heart failure: a population-based 30-year cohort study. Stroke 2017; 48 (05) 1161-1168
• 40 Puls M, Lubos E, Boekstegers P. , et al. One-year outcomes and predictors of mortality after MitraClip therapy in contemporary clinical practice: results from the German transcatheter mitral valve interventions registry. Eur Heart J 2016; 37 (08) 703-712
• 41 Huntgeburth M, Müller-Ehmsen J, Brase C, Baldus S, Rudolph V. Thrombus formation at the MitraClip system during percutaneous mitral valve repair. JACC Cardiovasc Interv 2014; 7 (09) e111-e112
• 42 Hamm K, Barth S, Diegeler A, Kerber S. Stroke and thrombus formation appending to the MitraClip: what is the appropriate anticoagulation regimen?. J Heart Valve Dis 2013; 22 (05) 713-715
• 43 Bekeredjian R, Mereles D, Pleger S, Krumsdorf U, Katus HA, Rottbauer W. Large atrial thrombus formation after MitraClip implantation: is anticoagulation mandatory?. J Heart Valve Dis 2011; 20 (02) 146-148
• 44 Glatthaar A, Seizer P, Patzelt J, Langer H, Schreieck J, Gawaz M. Formation of a left atrial thrombus during percutaneous mitral valve edge-to-edge repair induced by acute reduction of mitral regurgitation. J Cardiol Cases 2017; 17 (01) 33-35
• 45 Orban M, Braun D, Sonne C. , et al. Dangerous liaison: successful percutaneous edge-to-edge mitral valve repair in patients with end-stage systolic heart failure can cause left ventricular thrombus formation. EuroIntervention 2014; 10 (02) 253-259
• 46 Maleki K, Mohammadi R, Hart D, Cotiga D, Farhat N, Steinberg JS. Intracardiac ultrasound detection of thrombus on transseptal sheath: incidence, treatment, and prevention. J Cardiovasc Electrophysiol 2005; 16 (06) 561-565
• 47 Eng MH, Greenbaum A, Wang DD. , et al. Thrombotic valvular dysfunction with transcatheter mitral interventions for postsurgical failures. Catheter Cardiovasc Interv 2017; 90 (02) 321-328
• 48 Dangas GD, Weitz JI, Giustino G, Makkar R, Mehran R. Prosthetic heart valve thrombosis. J Am Coll Cardiol 2016; 68 (24) 2670-2689
• 49 Regueiro A, Granada JF, Dagenais F, Rodés-Cabau J. Transcatheter mitral valve replacement: insights from early clinical experience and future challenges. J Am Coll Cardiol 2017; 69 (17) 2175-2192
• 50 Muller DWM, Farivar RS, Jansz P. , et al; Tendyne Global Feasibility Trial Investigators. Transcatheter mitral valve replacement for patients with symptomatic mitral regurgitation: a global feasibility trial. J Am Coll Cardiol 2017; 69 (04) 381-391
• 51 Frerker C, Schlüter M, Sanchez OD. , et al. Cerebral protection during MitraClip implantation: initial experience at 2 centers. JACC Cardiovasc Interv 2016; 9 (02) 171-179
• 52 Seeger J, Markovic S, Kessler M, Rottbauer W, Wöhrle J. Apixaban after percutaneous edge-to-edge mitral valve repair in patients with maintained sinus rhythm. JACC Cardiovasc Interv 2019; 12 (02) 214-216
• 53 Eggebrecht H, Schelle S, Puls M. , et al. Risk and outcomes of complications during and after MitraClip implantation: experience in 828 patients from the German TRAnscatheter mitral valve interventions (TRAMI) registry. Catheter Cardiovasc Interv 2015; 86 (04) 728-735
• 54 Geis N, Raake P, Kiriakou C. , et al. Temporary oral anticoagulation after MitraClip - a strategy to lower the incidence of post-procedural stroke?. Acta Cardiol 2019; 1-7
• 55 Nishimura RA, Otto CM, Bonow RO. , et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017; 70 (02) 252-289
• 56 Rahbar AS, Azadani PN, Thatipelli S, Fleischmann KE, Nguyen N, Lee BK. Risk factors and prognosis for clot formation on cardiac device leads. Pacing Clin Electrophysiol 2013; 36 (10) 1294-1300
• 57 Supple GE, Ren J-F, Zado ES, Marchlinski FE. Mobile thrombus on device leads in patients undergoing ablation: identification, incidence, location, and association with increased pulmonary artery systolic pressure. Circulation 2011; 124 (07) 772-778
• 58 D'Aloia A, Bonadei I, Vizzardi E, Curnis A. Right giant atrial thrombosis and pulmonary embolism complicating pacemaker leads. BMJ Case Rep 2013; 2013: bcr2012008017-bcr2012008017
• 59 Karavidas A, Lazaros G, Matsakas E. , et al. Early pacemaker lead thrombosis leading to massive pulmonary embolism. Echocardiography 2004; 21 (05) 429-432
• 60 Salaun E, Deharo J-C, Casalta JP. , et al. An oscillating mass attached to a pacemaker lead: thrombus or vegetation? A fishing story. JACC Clin Electrophysiol 2017; 3 (08) 915-916
• 61 Korkeila P, Mustonen P, Koistinen J. , et al. Clinical and laboratory risk factors of thrombotic complications after pacemaker implantation: a prospective study. Europace 2010; 12 (06) 817-824
• 62 Ghanbari H, Nallamothu BK, Wang Y, Curtis JP. Antithrombotic therapy and outcomes after ICD implantation in patients with atrial fibrillation and coronary artery disease: an analysis from the National Cardiovascular Data Registry (NCDR)®. J Am Heart Assoc 2015; 4 (02) pii: e001331
• 63 Steffel J, Verhamme P, Potpara TS. , et al; ESC Scientific Document Group. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018; 39 (16) 1330-1393
• 64 May Jr KJ, Cardone JT, Stroebel PP, Riba AL. Streptokinase dissolution of a right atrial thrombus associated with a temporary pacemaker. Arch Intern Med 1988; 148 (04) 903-904
• 65 Goldhaber SZ, Nagel JS, Théard M, Levine JD, Sutton MG. Treatment of right atrial thrombus with urokinase. Am Heart J 1988; 115 (04) 894-897
• 66 Cooper CJ, Dweik R, Gabbay S. Treatment of pacemaker-associated right atrial thrombus with 2-hour rTPA infusion. Am Heart J 1993; 126 (01) 228-229
• 67 Mandal S, Pande A, Mandal D. , et al. Permanent pacemaker-related upper extremity deep vein thrombosis: a series of 20 cases. Pacing Clin Electrophysiol 2012; 35 (10) 1194-1198
• 68 Fuchs G, Berg N, Broman LM, Prahl Wittberg L. Flow-induced platelet activation in components of the extracorporeal membrane oxygenation circuit. Sci Rep 2018; 8 (01) 13985
• 69 Kirklin JK, Naftel DC, Pagani FD. , et al. Long-term mechanical circulatory support (destination therapy): on track to compete with heart transplantation?. J Thorac Cardiovasc Surg 2012; 144 (03) 584-603 , discussion 597–598
• 70 Rogers JG, Pagani FD, Tatooles AJ. , et al. Intrapericardial left ventricular assist device for advanced heart failure. N Engl J Med 2017; 376 (05) 451-460
• 71 Slaughter MS, Rogers JG, Milano CA. , et al; HeartMate II Investigators. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009; 361 (23) 2241-2251
• 72 Kirklin JK, Naftel DC, Kormos RL. , et al. Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis of pump thrombosis in the HeartMate II left ventricular assist device. J Heart Lung Transplant 2014; 33 (01) 12-22
• 73 Miller LW, Pagani FD, Russell SD. , et al; HeartMate II Clinical Investigators. Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med 2007; 357 (09) 885-896
• 74 Pagani FD, Miller LW, Russell SD. , et al; HeartMate II Investigators. Extended mechanical circulatory support with a continuous-flow rotary left ventricular assist device. J Am Coll Cardiol 2009; 54 (04) 312-321
• 75 Starling RC, Moazami N, Silvestry SC. , et al. Unexpected abrupt increase in left ventricular assist device thrombosis. N Engl J Med 2014; 370 (01) 33-40
• 76 Klodell CT, Massey HT, Adamson RM. , et al. Factors related to pump thrombosis with the Heartmate II left ventricular assist device. J Card Surg 2015; 30 (10) 775-780
• 77 Mehra MR, Goldstein DJ, Uriel N. , et al; MOMENTUM 3 Investigators. Two-year outcomes with a magnetically levitated cardiac pump in heart failure. N Engl J Med 2018; 378 (15) 1386-1395
• 78 Goldstein DJ, John R, Salerno C. , et al. Algorithm for the diagnosis and management of suspected pump thrombus. J Heart Lung Transplant 2013; 32 (07) 667-670
• 79 Sylvia LM, Ordway L, Pham DT, DeNofrio D, Kiernan M. Bivalirudin for treatment of LVAD thrombosis: a case series. ASAIO J 2014; 60 (06) 744-747
• 80 Badiye A, Hernandez GA, Chaparro S. Argatroban as novel therapy for suspected thrombosis in patients with continuous-flow left ventricle assist device and hemolysis. ASAIO J 2014; 60 (03) 361-365
• 81 Muthiah K, Robson D, Macdonald PS. , et al. Thrombolysis for suspected intrapump thrombosis in patients with continuous flow centrifugal left ventricular assist device. Artif Organs 2013; 37 (03) 313-318
• 82 Tellor BR, Smith JR, Prasad SM, Joseph SM, Silvestry SC. The use of eptifibatide for suspected pump thrombus or thrombosis in patients with left ventricular assist devices. J Heart Lung Transplant 2014; 33 (01) 94-101
• 83 Schlendorf K, Patel CB, Gehrig T. , et al. Thrombolytic therapy for thrombosis of continuous flow ventricular assist devices. J Card Fail 2014; 20 (02) 91-97
• 84 Garbade J, Bittner HB, Mohr F-W, Barten MJ. Fluoroscopy-guided resolution of ingested thrombus leading to functional disturbance of a continuous-flow left ventricular assist device. Case Rep Surg 2012; 2012: 791056
• 85 Köksel U, Erbasan O, Bayezid Ö. , et al. Thrombosis in continuous flow left ventricular assist devices: our clinical experience with medical and surgical management. Transplant Proc 2016; 48 (06) 2162-2167
• 86 Bartoli CR, Ailawadi G, Kern JA. Diagnosis, nonsurgical management, and prevention of LVAD thrombosis. J Card Surg 2014; 29 (01) 83-94
• 87 Radwan M, Risteski P, Hoffmann R, Popov AF. Repeat left ventricular assist device exchange with inflow or outflow correction for recurrent pump thrombosis and cerebral haemorrhage through limited incisions. Eur J Cardiothorac Surg 2018; 54 (04) 781-783
• 88 Hanke JS, Rojas SV, Dogan G. , et al. First series of left ventricular assist device exchanges to HeartMate 3. Eur J Cardiothorac Surg 2017; 51 (05) 887-892
• 89 Birnie DH, Healey JS, Wells GA. , et al; BRUISE CONTROL Investigators. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med 2013; 368 (22) 2084-2093
• 90 Birnie DH, Healey JS, Wells GA. , et al. Continued vs. interrupted direct oral anticoagulants at the time of device surgery, in patients with moderate to high risk of arterial thrombo-embolic events (BRUISE CONTROL-2). Eur Heart J 2018; 39 (44) 3973-3979
• 91 Widimský P, Kočka V, Roháč F, Osmančík P. Periprocedural antithrombotic therapy during various types of percutaneous cardiovascular interventions. Eur Heart J Cardiovasc Pharmacother 2016; 2 (02) 131-140
• 92 Meier B, Blaauw Y, Khattab AA. , et al; Document Reviewers. EHRA/EAPCI expert consensus statement on catheter-based left atrial appendage occlusion. Europace 2014; 16 (10) 1397-1416
• 93 Feldman T, Wasserman HS, Herrmann HC. , et al. Percutaneous mitral valve repair using the edge-to-edge technique: six-month results of the EVEREST Phase I Clinical Trial. J Am Coll Cardiol 2005; 46 (11) 2134-2140
• 94 Droppa M, Vaduganathan M, Venkateswaran RV. , et al. Cangrelor in cardiogenic shock and after cardiopulmonary resuscitation: A global, multicenter, matched pair analysis with oral P2Y12 inhibition from the IABP-SHOCK II trial. Resuscitation 2019; 137: 205-212
• 95 Ciolek AM, Ma K, Jennings DL. , et al. Use of cangrelor during venoarterial extracorporeal membrane oxygenation following percutaneous coronary intervention. J Heart Lung Transplant 2019; 38: S307
• 96 Krajewski S, Kurz J, Neumann B. , et al. Short-acting P2Y12 blockade to reduce platelet dysfunction and coagulopathy during experimental extracorporeal circulation and hypothermia. Br J Anaesth 2012; 108 (06) 912-921
• 97 Alhussein M, Moayedi Y, Posada JD. , et al. Ventricular Thrombosis Post-Venoarterial Extracorporeal Membrane Oxygenation. Circ Heart Fail 2017; 10 (02) pii: e003757
• 98 Batra S, Kamran H, Lech T. , et al. High thromboembolic event rate in patients supported with an Impella CP device with an anti-Xa level of less than 0.1 u/mL. J Heart Lung Transplant 2018; 37: S59
• 99 Potapov EV, Antonides C, Crespo-Leiro MG. , et al. 2019 EACTS Expert Consensus on long-term mechanical circulatory support. Eur J Cardiothorac Surg 2019; 2019: ezz098
• 100 Ichikawa J, Mori T, Kodaka M, Nishiyama K, Ozaki M, Komori M. Changes in heparin dose response slope during cardiac surgery: possible result in inaccuracy in predicting heparin bolus dose requirement to achieve target ACT. Perfusion 2017; 32 (06) 474-480
• 101 Baumann Kreuziger LM, Kim B, Wieselthaler GM. Antithrombotic therapy for left ventricular assist devices in adults: a systematic review. J Thromb Haemost 2015; 13 (06) 946-955
• 102 Larsson M, Rayzman V, Nolte MW. , et al. A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk. Sci Transl Med 2014; 6: 222ra17-222ra17
• 103 Weitz JI, Fredenburgh JC. Factors XI and XII as targets for new anticoagulants. Front Med (Lausanne) 2017; 4: 19