Detailed thrombogenicity phenotyping and 1 year outcomes in patients undergoing WATCHMAN implantation: (TARGET-WATCHMAN) a case–control study

Abstract

The relation of device related thrombosis (DRT) and major bleeding after left atrial appendage closure (LAAC) to laboratory thrombosis and hemostasis markers has not been studied. We performed a prospective case control study to identify clinical characteristics and laboratory markers in patients who developed DRT and major bleeding following WATCHMAN LAAC. Thromboelastography, platelet aggregation (PA), urinary 11-dehydrothromboxane B2 (UTX), fibrinogen, d-dimer, thrombin time and von Willebrand factor activity were determined at baseline, immediately following, and at 45 and 180 days post-LAAC (n = 32) and outcomes were followed for 1 year. Baseline characteristics and thrombogenic profiles of patients with and without DRT and/or BARC bleeding were compared. Mean age was 76 ± 8 years and CHADS2 VASc score was 4.4 ± 1.4. There were 3 DRTs (2 within 6 months, and 1 at 12 months), 4 Type 3A BARC bleeds, and 2 non-cardiac deaths. Patients with DRT had higher baseline thrombin-induced platelet–fibrin clot strength (68.0 ± 1.8 vs. 62.7 ± 4.7 mm, p = 0.06); FCS (35.6 ± 6.0 vs. 24.4 ± 6.6 mm, p = 0.009); and d-dimer (1712 ± 2330 vs. 283 ± 213 ng/mL, p = 0.001). At baseline, 5 patients had all 3 factors associated with high thrombotic risk and 2 experienced a DRT within 6 months. Patients with Type 3A BARC bleeding had lower baseline collagen-induced and 45-day ADP-induced PA (p < 0.01 for both). DRT following LAAC was associated with a baseline prothrombogenic profile whereas bleeding was associated with low platelet reactivity. These preliminary findings warrant further validation and have future implications on patient selection and adjunctive antithrombotic therapy following LAAC.

Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03040622.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Abbreviations

ADP:

Adenosine diphosphate

AF:

Atrial fibrillation

BARC:

Major bleeding using the Academic Research Consortium

DRT:

Device related thrombosis

FCS:

Fibrin clot strength

HPR:

High platelet reactivity

INR:

International normalized ratio

LAAC:

Left atrial appendage closure

NOAC:

Novel oral anticoagulant

PA:

Platelet aggregation

TEE:

Transesophageal echocardiography

TEG:

Thrombelastography

TT:

Thrombin time

TIP-FCS:

Thrombin induced platelet–fibrin clot strength

TRAP:

Thrombin receptor-activating peptide

UTX:

Urinary 11-dehydrothromboxane B2

ULN:

Upper limits normal

vWF:

Von Willebrand factor

References

  1. 1.

    Reddy VY, Doshi SK, Kar S, Gibson DN, Price MJ, Huber K, Horton RP, Buchbinder M, Neuzil P, Gordon NT, Holmes DR Jr, Prevail IPA (2017) 5-Year outcomes after left atrial appendage closure: from the PREVAIL and PROTECT AF trials. J Am Coll Cardiol 70(24):2964–2975. https://doi.org/10.1016/j.jacc.2017.10.021

    Article  PubMed  Google Scholar 

  2. 2.

    Holmes DR Jr, Kar S, Price MJ, Whisenant B, Sievert H, Doshi SK, Huber K, Reddy VY (2014) Prospective randomized evaluation of the Watchman left atrial appendage closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol 64(1):1–12. https://doi.org/10.1016/j.jacc.2014.04.029

    Article  PubMed  Google Scholar 

  3. 3.

    Belgaid DR, Khan Z, Zaidi M, Hobbs A (2016) Prospective randomized evaluation of the Watchman left atrial appendage closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial. Int J Cardiol 219:177–179. https://doi.org/10.1016/j.ijcard.2016.06.041

    Article  PubMed  Google Scholar 

  4. 4.

    Reddy VY, Doshi SK, Sievert H, Buchbinder M, Neuzil P, Huber K, Halperin JL, Holmes D, Investigators PA (2013) Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-year follow-up of the PROTECT AF (Watchman left atrial appendage system for embolic protection in patients with atrial fibrillation) trial. Circulation 127(6):720–729. https://doi.org/10.1161/CIRCULATIONAHA.112.114389

    Article  PubMed  Google Scholar 

  5. 5.

    Boersma LV, Ince H, Kische S, Pokushalov E, Schmitz T, Schmidt B, Gori T, Meincke F, Protopopov AV, Betts T, Mazzone P, Foley D, Grygier M, Sievert H, De Potter T, Vireca E, Stein K, Bergmann MW, following i, institutions participated in the Es (2019) Evaluating real-world clinical outcomes in atrial fibrillation patients receiving the WATCHMAN left atrial appendage closure technology. Circ Arrhythm Electrophysiol 12(4):e006841. https://doi.org/10.1161/CIRCEP.118.006841

    Article  PubMed  Google Scholar 

  6. 6.

    Reddy VY, Mobius-Winkler S, Miller MA, Neuzil P, Schuler G, Wiebe J, Sick P, Sievert H (2013) 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 61(25):2551–2556. https://doi.org/10.1016/j.jacc.2013.03.035

    Article  PubMed  Google Scholar 

  7. 7.

    Price MJ, Reddy VY, Valderrabano M, Halperin JL, Gibson DN, Gordon N, Huber KC, Holmes DR Jr (2015) Bleeding outcomes after left atrial appendage closure compared with long-term warfarin: a pooled, patient-level analysis of the WATCHMAN randomized trial experience. JACC Cardiovasc Interv 8(15):1925–1932. https://doi.org/10.1016/j.jcin.2015.08.035

    Article  PubMed  Google Scholar 

  8. 8.

    Holmes DR Jr, Doshi SK, Kar S, Price MJ, Sanchez JM, Sievert H, Valderrabano M, Reddy VY (2015) Left atrial appendage closure as an alternative to warfarin for stroke prevention in atrial fibrillation: a patient-level meta-analysis. J Am Coll Cardiol 65(24):2614–2623. https://doi.org/10.1016/j.jacc.2015.04.025

    Article  PubMed  Google Scholar 

  9. 9.

    Holmes DR, Reddy VY, Buchbinder M, Stein K, Elletson M, Bergmann MW, Schmidt B, Saw J (2017) The assessment of the Watchman device in patients unsuitable for oral anticoagulation (ASAP-TOO) trial. Am Heart J 189:68–74. https://doi.org/10.1016/j.ahj.2017.03.007

    Article  PubMed  Google Scholar 

  10. 10.

    Romero J, Briceno DF, Di Biase L (2019) NOACs versus VKAs during Watchman implantation in patients with atrial fibrillation: the end of an era. Pacing Clin Electrophysiol 42(10):1310–1311. https://doi.org/10.1111/pace.13797

    Article  PubMed  Google Scholar 

  11. 11.

    Gurbel PA, Bliden KP, Tantry US, Monroe AL, Muresan AA, Brunner NE, Lopez-Espina CG, Delmenico PR, Cohen E, Raviv G, Haugen DL, Ereth MH (2016) First report of the point-of-care TEG: a technical validation study of the TEG-6S system. Platelets 27(7):642–649. https://doi.org/10.3109/09537104.2016.1153617

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM (2003) Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 107(23):2908–2913. https://doi.org/10.1161/01.CIR.0000072771.11429.83

    Article  PubMed  Google Scholar 

  13. 13.

    Bliden KP, Singla A, Gesheff MG, Toth PP, Tabrizchi A, Ens G, Guyer K, Singh M, Franzese CJ, Stapleton D, Tantry US, Gurbel PA (2014) Statin therapy and thromboxane generation in patients with coronary artery disease treated with high-dose aspirin. Thromb Haemost 112(2):323–331. https://doi.org/10.1160/TH14-01-0094

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Milos M, Herak D, Kuric L, Horvat I, Zadro R (2009) Evaluation and performance characteristics of the coagulation system: ACL TOP analyzer—HemosIL reagents. Int J Lab Hematol 31(1):26–35. https://doi.org/10.1111/j.1751-553x.2007.00999.x

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Bliden KP, DiChiara J, Tantry US, Bassi AK, Chaganti SK, Gurbel PA (2007) Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate? J Am Coll Cardiol 49(6):657–666. https://doi.org/10.1016/j.jacc.2006.10.050

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Ndrepepa G, Schuster T, Hadamitzky M, Byrne RA, Mehilli J, Neumann FJ, Richardt G, Schulz S, Laugwitz KL, Massberg S, Schomig A, Kastrati A (2012) Validation of the Bleeding Academic Research Consortium definition of bleeding in patients with coronary artery disease undergoing percutaneous coronary intervention. Circulation 125(11):1424–1431. https://doi.org/10.1161/CIRCULATIONAHA.111.060871

    Article  PubMed  Google Scholar 

  17. 17.

    Dukkipati SR, Kar S, Holmes DR, Doshi SK, Swarup V, Gibson DN, Maini B, Gordon NT, Main ML, Reddy VY (2018) Device-related thrombus after left atrial appendage closure. Circulation 138(9):874–885. https://doi.org/10.1161/CIRCULATIONAHA.118.035090

    Article  PubMed  Google Scholar 

  18. 18.

    Pracon R, Bangalore S, Dzielinska Z, Konka M, Kepka C, Kruk M, Kaczmarska-Dyrda E, Petryka-Mazurkiewicz J, Bujak S, Solecki M, Pskit A, Dabrowska A, Sieradzki B, Plonski A, Ruzyllo W, Witkowski A, Demkow M (2018) 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 11(3):e005997. https://doi.org/10.1161/CIRCINTERVENTIONS.117.005997

    Article  PubMed  Google Scholar 

  19. 19.

    Fauchier L, Cinaud A, Brigadeau F, Lepillier A, Pierre B, Abbey S, Fatemi M, Franceschi F, Guedeney P, Jacon P, Paziaud O, Venier S, Deharo JC, Gras D, Klug D, Mansourati J, Montalescot G, Piot O, Defaye P (2018) Device-related thrombosis after percutaneous left atrial appendage occlusion for atrial fibrillation. J Am Coll Cardiol 71(14):1528–1536. https://doi.org/10.1016/j.jacc.2018.01.076

    Article  PubMed  Google Scholar 

  20. 20.

    Lempereur M, Aminian A, Freixa X, Gafoor S, Kefer J, Tzikas A, Legrand V, Saw J (2017) 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 90(5):E111–E121. https://doi.org/10.1002/ccd.26903

    Article  PubMed  Google Scholar 

  21. 21.

    Gurbel PA, Bliden KP, Guyer K, Cho PW, Zaman KA, Kreutz RP, Bassi AK, Tantry US (2005) Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol 46(10):1820–1826. https://doi.org/10.1016/j.jacc.2005.07.041

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neumann FJ, Metzger DC, Henry TD, Cox DA, Duffy PL, Mazzaferri E, Gurbel PA, Xu K, Parise H, Kirtane AJ, Brodie BR, Mehran R, Stuckey TD, Investigators A-D (2013) Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet 382(9892):614–623. https://doi.org/10.1016/S0140-6736(13)61170-8

    Article  PubMed  Google Scholar 

  23. 23.

    Meus R, Son M, Sobczyk D, Undas A (2016) Prothrombotic state in patients with a left atrial appendage thrombus of unknown origin and cerebrovascular events. Stroke 47(7):1872–1878. https://doi.org/10.1161/STROKEAHA.116.012856

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Johnson ED, Schell JC, Rodgers GM (2019) The d-dimer assay. Am J Hematol 94(7):833–839. https://doi.org/10.1002/ajh.25482

    Article  PubMed  Google Scholar 

  25. 25.

    Bliden KP, Chaudhary R, Navarese EP, Sharma T, Kaza H, Tantry US, Gurbel PA (2018) Thrombogenicity and central pulse pressure to enhance prediction of ischemic event occurrence in patients with established coronary artery disease: the MAGMA-ischemia score. Atherosclerosis 268:55–62. https://doi.org/10.1016/j.atherosclerosis.2017.11.018

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Bliden KP, Raviv G, Tantry US, Chaudhary R, Cochran JW, Navarese EP, Brannan T, Vyas A, Gurbel PA (2019) "Blueprinting" thrombogenicity and antithrombotic drug response at the bedside in patients presenting emergently with symptoms of acute stroke. J Thromb Thrombolysis 47(2):192–199. https://doi.org/10.1007/s11239-019-01813-0

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Aradi D, Gross L, Trenk D, Geisler T, Merkely B, Kiss RG, Komocsi A, Dezsi CA, Ruzsa Z, Ungi I, Rizas KD, May AE, Mugge A, Zeiher AM, Holdt L, Huber K, Neumann FJ, Koltowski L, Huczek Z, Hadamitzky M, Massberg S, Sibbing D (2019) Platelet reactivity and clinical outcomes in acute coronary syndrome patients treated with prasugrel and clopidogrel: a pre-specified exploratory analysis from the TROPICAL-ACS trial. Eur Heart J 40(24):1942–1951. https://doi.org/10.1093/eurheartj/ehz202

    Article  PubMed  Google Scholar 

  28. 28.

    Gurbel PA, Bliden KP, DiChiara J, Newcomer J, Weng W, Neerchal NK, Gesheff T, Chaganti SK, Etherington A, Tantry US (2007) Evaluation of dose-related effects ofaspirin on platelet function: results from the Aspirin-Induced Platelet Effect (ASPECT) study. Circulation 115(25):3156–3164.

    CAS  Article  Google Scholar 

  29. 29.

    Olson JD (2015) D-dimer: an overview of hemostasis and fibrinolysis, assays, and clinical applications. Adv Clin Chem 69:1–46.

    CAS  Article  Google Scholar 

  30. 30.

    Shahidi M (2017) Thrombosis and von Willebrand factor. Adv Exp Med Biol 906:285–306.

    CAS  Article  Google Scholar 

  31. 31.

    Kattula S, Byrnes JR, Wolberg AS (2017) Fibrinogen and fibrin in hemostasis and thrombosis. Arterioscler Thromb Vasc Biol 37(3):e13–e21.

    CAS  Article  Google Scholar 

  32. 32.

    Undas A (2017) Determination of fibrinogen and thrombin time (TT). Methods Mol Biol 1646:105–110.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We wish to acknowledge Andrea Fitzgerald BSN-RN, MA for her contributions to this study

Funding

This study was funded by Boston Scientific Corporation (300 Boston Scientific Way Marlborough, MA).

Author information

Affiliations

Authors

Contributions

MS: Conceptualization, Methodology, Roles/Writing—original draft; KPB: Conceptualization, Data curation, Formal analysis, Roles/Writing—original draft; LI: Methodology, Project administration, Resources; GV: Supervision, Validation, Visualization; AS: Funding acquisition, Investigation, Methodology, Project administration; SY: Formal analysis, Methodology, Software; RM: Conceptualization, Methodology; HR: Project administration, Resources; EPN: Formal analysis, Writing—review & editing; TP: Data curation, Formal analysis; WB: Software, Investigation, Methodology, Project administration; RC: Validation; Visualization, Writing—review & editing; UST: Conceptualization, Data curation, Writing—review & editing, PAG: Conceptualization, Funding acquisition, Investigation, Writing—review & editing.

Corresponding author

Correspondence to Paul A. Gurbel.

Ethics declarations

Conflict of interest

Dr. Gurbel receives honoraria for lectures, consultations, including service on speakers’ bureaus from Bayer, Merck, Janssen, Medicure, and World Medical; receiving grants from the National Institutes of Health, Janssen, Merck, Bayer, Haemonetics, Instrumentation Labs, and Amgen. Dr. Gurbel is holding stock or stock options in Merck, Medtronic, and Pfizer; and holding patents in the area of personalized antiplatelet therapy and interventional cardiology. Dr. Sherwood receives honoraria from Medtronic. Dr. Navarese reports honoraria and payment for lectures from Astra Zeneca, Daiichi Sankyo/Lilly, Sanofi-Regeneron and Amgen; and receipt of grants from Amgen. Dr. Batchelor reports honoraria from Boston Scientific Corporation. Other authors report no disclosures.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 15 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sherwood, M., Bliden, K.P., Ilkhanoff, L. et al. Detailed thrombogenicity phenotyping and 1 year outcomes in patients undergoing WATCHMAN implantation: (TARGET-WATCHMAN) a case–control study. J Thromb Thrombolysis (2020). https://doi.org/10.1007/s11239-020-02205-5

Download citation

Keywords

  • Watchman
  • Thrombotic risk
  • TEG
  • Platelet aggregation
  • Antithrombotic therapy