Mayo Clinic Proceedings Home

Impact of Atrial Fibrillation and Sinus Rhythm Restoration on Reticulated Platelets

Published:October 30, 2015DOI:



      To assess the impact of nonvalvular atrial fibrillation (NVAF) and sinus rhythm restoration on the distribution of reticulated platelets (RPs), which are known to be associated with thrombotic propensity and have a greater predilection for thrombus participation.

      Participants and Methods

      The RP content was assessed by flow cytometry (thiazole orange/CD61) in 110 consecutive patients with NVAF before and 3 to 4 months after catheter ablation of the pulmonary veins. Results were compared with those of 55 age- and sex-matched controls with normal sinus rhythm.


      The mean ± SD percentage of RPs was higher in patients with NVAF compared with controls (28.5%±7.3% vs 6.4%±5.3%; P<.001). The RP content did not vary by CHA2DS2-VASc score. After catheter ablation of the pulmonary veins, 63 patients were available for follow-up assessment. A significant reduction of RPs was observed compared with preintervention values (29.85%±7.1% vs 20.79%±7.6%; P<.001). During follow-up, 19% of patients (12 of 63) had confirmed AF recurrence. The mean ± SD percentage of RPs was higher in this group than in those without a recurrence (24.7%±6.5% vs 18.9%±7.5%; P=.01).


      Nonvalvular atrial fibrillation affects the percentage of RPs, independent of the CHA2DS2-VASc score. After ablation, RP content dropped significantly. High RP content in patients with NVAF may explain the potential mechanism of thromboembolic complications and the lack of efficacy of currently available antiplatelet therapy for stroke prevention in this dysrhythmia.

      Abbreviations and Acronyms:

      CHF (congestive heart failure), CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years (doubled), diabetes mellitus, stroke (doubled)–vascular disease, age 65 to 74 years, and sex category (female)), EKG (electrocardiography), H/H (HEPES-buffered (20 mM) Hanks balanced salt solution glucose (0.05%)), LVEF (left ventricular ejection fraction), NSR (normal sinus rhythm), NVAF (nonvalvular atrial fibrillation), PRP (platelet-rich protein), RP (reticulated platelet), SEC (spontaneous echocardiographic contrast), TEE (transesophageal echocardiography), TIA (transient ischemic attack), TO (thiazole orange), WB (whole blood)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Mayo Clinic Proceedings
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Aberg H.
        Atrial fibrillation, I: a study of atrial thrombosis and systemic embolism in a necropsy material.
        Acta Med Scand. 1969; 185: 373-379
        • Manning W.J.
        • Silverman D.I.
        • Waksmonski C.A.
        • Oettgen P.
        • Douglas P.S.
        Prevalence of residual left atrial thrombi among patients with acute thromboembolism and newly recognized atrial fibrillation.
        Arch Intern Med. 1995; 155: 2193-2198
        • Klein A.L.
        • Grimm R.A.
        • Murray R.D.
        • et al.
        • Assessment of Cardioversion Using Transesophageal Echocardiography Investigators
        Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation.
        N Engl J Med. 2001; 344: 1411-1420
        • Wysokinski W.E.
        • Owen W.G.
        • Fass D.N.
        • Patrzalek D.D.
        • Murphy L.
        • McBane R.D.
        Atrial fibrillation and thrombosis: immunohistochemical differences between in situ and embolized.
        J Thromb Haemost. 2004; 2: 1637-1644
        • Gosk-Bierska I.
        • McBane R.D.
        • Wu Y.
        • et al.
        Platelet factor XIII gene expression and embolic propensity in atrial fibrillation.
        Thromb Haemost. 2011; 106: 75-82
        • Connolly S.
        • Pogue J.
        • Hart R.
        • et al.
        • ACTIVE Writing Group of the ACTIVE Investigators
        Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomized controlled trial.
        Lancet. 2006; 367: 1903-1912
        • Burkhart J.M.
        • Vaudel M.
        • Gambaryan S.
        • et al.
        The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways.
        Blood. 2012; 120: e73-e82
        • Fager A.M.
        • Wood J.P.
        • Bouchard B.A.
        • Feng P.
        • Tracy P.B.
        Properties of procoagulant platelets: defining and characterizing the subpopulation binding a functional prothrombinase.
        Arterioscler Thromb Vasc Biol. 2010; 30: 2400-2407
        • Mayda-Domaç F.
        • Misirli H.
        • Yilmaz M.
        Prognostic role of mean platelet volume and platelet count in ischemic and hemorrhagic stroke.
        J Stroke Cerebrovasc Dis. 2010; 19: 66-72
        • Harrison P.
        • Robinson M.S.C.
        • Mackie I.J.
        • Machin S.J.
        Reticulated platetets.
        Platelets. 1997; 8: 379-383
        • Lee L.G.
        • Chen C.H.
        • Chiu L.A.
        Thiazole orange: a new dye for reticulocyte analysis.
        Cytometry. 1986; 7: 508-517
        • Matic G.B.
        • Chapman E.S.
        • Zaiss M.
        • Rothe G.
        • Schmitz G.
        Whole blood analysis of reticulated platelets: improvements of detection and assay stability.
        Cytometry. 1998; 34: 229-234
        • Lakkis N.
        • Dokainish H.
        • Abuzahra M.
        • et al.
        Reticulated platelets in acute coronary syndrome: a marker of platelet activity.
        J Am Coll Cardiol. 2004; 44: 2087-2098
        • Perl L.
        • Lerman-Shivek H.
        • Rechavia E.
        • et al.
        Response to prasugrel and levels of circulating reticulated platelets in patients with ST-segment elevation myocardial infarction.
        J Am Coll Cardiol. 2014; 63: 513-517
        • Nakamura T.
        • Uchiyama S.
        • Yamazaki M.
        • Okubo K.
        • Takakuwa Y.
        • Iwata M.
        Flow cytometric analysis of reticulated platelets in patients with ischemic stroke.
        Thromb Res. 2002; 106: 171-177
        • Guthikonda S.
        • Alviar C.L.
        • Vaduganathan M.
        • et al.
        Role of reticulated platelets and platelet size heterogeneity on platelet activity after dual antiplatelet therapy with aspirin and clopidogrel in patients with stable coronary artery disease.
        J Am Coll Cardiol. 2008; 52: 743-749
        • Ammash N.
        • Konik E.A.
        • McBane R.D.
        • et al.
        Left atrial blood stasis and Von Willebrand factor-ADAMTS13 homeostasis in atrial fibrillation.
        Arterioscler Thromb Vasc Biol. 2011; 31: 2760-2766
        • Fatkin D.
        • Kelly R.P.
        • Feneley M.P.
        Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo.
        J Am Coll Cardiol. 1994; 23: 961-969
        • Oh J.K.
        • Seward J.B.
        • Tajik A.J.
        Assessment of Systolic Function and Quantification of Cardiac Chambers. In: The Echo Manual.
        3rd ed. Lippincott Williams & Wilkins, Philadelphia, PA1994: 109-119
        • Lip G.Y.
        • Nieuwlaat R.
        • Pisters R.
        • Lane D.A.
        • Crijns H.J.
        Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation.
        Chest. 2010; 137: 263-272
        • Genuth S.
        • Alberti K.G.
        • Bennett P.
        • et al.
        • Expert Committee on the Diagnosis and Classification of Diabetes Mellitus
        Follow-up report on the diagnosis of diabetes mellitus.
        Diabetes Care. 2003; 26: 3160-3167
        • Gillum R.F.
        • Fortmann S.P.
        • Prineas R.J.
        • Kottke T.E.
        International diagnostic criteria for acute myocardial infarction and acute stroke.
        Am Heart J. 1984; 108: 150-158
        • Fuster V.
        • Rydén L.E.
        • Cannom D.S.
        • et al.
        ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines.
        Circulation. 2006; 114: e257-e354
        • McBane II, R.D.
        • Gonzalez C.
        • Hodge D.O.
        • Wysokinski W.E.
        Propensity for young reticulated platelet recruitment into arterial thrombi.
        J Thromb Thrombolysis. 2014; 37: 148-154
        • Koh K.R.
        • Yamane T.
        • Ohta K.
        • Hino M.
        • Takubo T.
        • Tatsumi N.
        Pathophysiological significance of simultaneous measurement of reticulated platelets, large platelets and serum thrombopoietin in non-neoplastic thrombocytopenic disorders.
        Eur J Haematol. 1999; 63: 295-301
        • Engelmann M.D.
        • Svendsen J.H.
        Inflammation in the genesis and perpetuation of atrial fibrillation.
        Eur Heart J. 2005; 26: 2083-2092
        • Xu J.
        • Cui G.
        • Esmailian F.
        • et al.
        Atrial extracellular matrix remodeling and the maintenance of atrial fibrillation.
        Circulation. 2004; 109: 363-368
        • Nakano Y.
        • Niida S.
        • Dote K.
        • et al.
        Matrix metalloproteinase-9 contributes to human atrial remodeling during atrial fibrillation.
        J Am Coll Cardiol. 2004; 43: 818-825
        • Sasaki N.
        • Okumura Y.
        • Watanabe I.
        • et al.
        Increased levels of inflammatory and extracellular matrix turnover biomarkers persist despite reverse atrial structural remodeling during the first year after atrial fibrillation ablation.
        J Interv Card Electrophysiol. 2014; 39: 241-249
        • Akar J.G.
        • Jeske W.
        • Wilber D.J.
        Acute onset human atrial fibrillation is associated with local cardiac platelet activation and endothelial dysfunction.
        J Am Coll Cardiol. 2008; 51: 1790-1793
        • Sohara H.
        • Amitani S.
        • Kurose M.
        • Miyahara K.
        Atrial fibrillation activates platelets and coagulation in a time-dependent manner: a study in patients with paroxysmal atrial fibrillation.
        J Am Coll Cardiol. 1997; 29: 106-112
        • Choudhury A.
        • Chung I.
        • Blann A.D.
        • Lip G.Y.
        Platelet surface CD62P and CD63, mean platelet volume, and soluble/platelet P-selectin as indexes of platelet function in atrial fibrillation: a comparison of “healthy control subjects” and “disease control subjects” in sinus rhythm.
        J Am Coll Cardiol. 2007; 49: 1957-1964
        • Colkesen Y.
        • Acil T.
        • Abayli B.
        • et al.
        Mean platelet volume is elevated during paroxysmal atrial fibrillation: a marker of increased platelet activation?.
        Blood Coagul Fibrinolysis. 2008; 19: 411-414
        • Hoffmann J.J.
        • van den Broek N.M.
        • Curvers J.
        Reference intervals of reticulated platelets and other platelet parameters and their associations.
        Arch Pathol Lab Med. 2013; 137: 1635-1640
        • Weyrich A.S.
        • Dixon D.A.
        • Pabla R.
        • et al.
        Signal-dependent translation of a regulatory protein, Bcl-3, in activated human platelets.
        Proc Natl Acad Sci U S A. 1998; 95: 5556-5561
        • Jakubowski J.A.
        • Thompson C.B.
        • Vaillancourt R.
        • Valeri C.R.
        • Deykin D.
        Arachidonic acid metabolism by platelets of differing size.
        Br J Haematol. 1983; 53: 503-511
        • Martin J.F.
        • Trowbridge E.A.
        • Salmon G.L.
        • Slater D.N.
        The biological significance of platelet volume: its relationship to bleeding time, platelet thromboxane B2 production and megakaryocyte nuclear DNA concentration.
        Thromb Res. 1983; 32: 443-460
        • Tschoepe D.
        • Roesen P.
        • Kaufmann L.
        • et al.
        Evidence for abnormal platelet glycoprotein expression in diabetes mellitus.
        Eur J Clin Invest. 1990; 20: 166-170
        • Lim H.S.
        • Willoughby S.R.
        • Schultz C.
        • et al.
        Effect of atrial fibrillation on atrial thrombogenesis in humans: impact of rate and rhythm.
        J Am Coll Cardiol. 2013; 61: 852-860
        • Fang M.C.
        • Singer D.E.
        • Chang Y.
        • et al.
        Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) study.
        Circulation. 2005; 112: 1687-1691
        • Rastegar R.
        • Harnick D.J.
        • Weidemann P.
        • et al.
        Spontaneous echo contrast videodensity is flow-related and is dependent on the relative concentrations of fibrinogen and red blood cells.
        J Am Coll Cardiol. 2003; 41: 603-610