PDF herunterladen
Semin Thromb Hemost 2018; 44(03): 197-205
DOI: 10.1055/s-0038-1636901
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Toward Flow Cytometry Based Platelet Function Diagnostics

Ivar van Asten
1   Department of Clinical Chemistry and Haematology, Center for Circulatory Health, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
2   Van Creveld Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
3   Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
,
Roger E.G. Schutgens
3   Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
,
Rolf T. Urbanus
1   Department of Clinical Chemistry and Haematology, Center for Circulatory Health, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
19. März 2018 (online)

    Lizenzen und Reprints

Abstract

The laboratory diagnostics of (inherited) platelet function disorders mainly comprises aggregation and secretion assays, which may be suitable for diagnosing some specific severe platelet function disorders, but are not reliable enough for diagnosing mild platelet function disorders or disorders associated with low platelet count. Flow cytometric assessment of platelet reactivity will expectedly provide additional value during the diagnostic work-up of platelet function disorders because it only requires a small volume of whole blood and allows the measurement of platelet function in thrombocytopenic samples. Flow cytometry has frequently been used to evaluate platelet function in the research setting, and therefore, these assays will require clinical validation before they can be used as routine diagnostic tools. The main challenge in the validation of innovative platelet function diagnostic tests is the lack of a gold standard test for mild platelet function disorders. This review aims to address the many applications of flow cytometry in the current diagnostic work-up of platelet function testing and to discuss the challenges in introducing new tools for diagnosing platelet function disorders.

Keywords

flow cytometry - blood platelets - blood platelet disorders - platelet function tests
 

  • References

  • 1 Clemetson KJ. A short history of platelet glycoprotein Ib complex. Thromb Haemost 2007; 98 (01) 63-68
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 2 Savage B, Almus-Jacobs F, Ruggeri ZM. Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow. Cell 1998; 94 (05) 657-666
    CrossrefPubMedGoogle Scholar
  • 3 van Ommen CH, Peters M. The bleeding child. Part I: primary hemostatic disorders. Eur J Pediatr 2012; 171 (01) 1-10
    CrossrefPubMedGoogle Scholar
  • 4 Cattaneo M. Inherited platelet-based bleeding disorders. J Thromb Haemost 2003; 1 (07) 1628-1636
    CrossrefPubMedGoogle Scholar
  • 5 Freson K, Wijgaerts A, van Geet C. Update on the causes of platelet disorders and functional consequences. Int J Lab Hematol 2014; 36 (03) 313-325
    CrossrefPubMedGoogle Scholar
  • 6 Gresele P. ; Subcommittee on Platelet Physiology of the International Society on Thrombosis and Hemostasis. Diagnosis of inherited platelet function disorders: guidance from the SSC of the ISTH. J Thromb Haemost 2015; 13 (02) 314-322
    CrossrefPubMedGoogle Scholar
  • 7 Tosetto A, Castaman G, Rodeghiero F. Assessing bleeding in von Willebrand disease with bleeding score. Blood Rev 2007; 21 (02) 89-97
    CrossrefPubMedGoogle Scholar
  • 8 Tosetto A, Castaman G, Plug I, Rodeghiero F, Eikenboom J. Prospective evaluation of the clinical utility of quantitative bleeding severity assessment in patients referred for hemostatic evaluation. J Thromb Haemost 2011; 9 (06) 1143-1148
    CrossrefPubMedGoogle Scholar
  • 9 Rodeghiero F, Tosetto A, Abshire T. , et al; ISTH/SSC joint VWF and Perinatal/Pediatric Hemostasis Subcommittees Working Group. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost 2010; 8 (09) 2063-2065
    CrossrefPubMedGoogle Scholar
  • 10 Rashid A, Moiz B, Karim F, Shaikh MS, Mansoori H, Raheem A. Use of ISTH bleeding assessment tool to predict inherited platelet dysfunction in resource constrained settings. Scand J Clin Lab Invest 2016; 76 (05) 373-378
    CrossrefPubMedGoogle Scholar
  • 11 Elbatarny M, Mollah S, Grabell J. , et al; Zimmerman Program Investigators. Normal range of bleeding scores for the ISTH-BAT: adult and pediatric data from the merging project. Haemophilia 2014; 20 (06) 831-835
    CrossrefPubMedGoogle Scholar
  • 12 Gresele P, Harrison P, Bury L. , et al. Diagnosis of suspected inherited platelet function disorders: results of a worldwide survey. J Thromb Haemost 2014; 12 (09) 1562-1569
    CrossrefPubMedGoogle Scholar
  • 13 Quiroga T, Goycoolea M, Muñoz B. , et al. Template bleeding time and PFA-100 have low sensitivity to screen patients with hereditary mucocutaneous hemorrhages: comparative study in 148 patients. J Thromb Haemost 2004; 2 (06) 892-898
    CrossrefPubMedGoogle Scholar
  • 14 Hoffmann JJML. Reticulated platelets: analytical aspects and clinical utility. Clin Chem Lab Med 2014; 52 (08) 1107-1117
    CrossrefPubMedGoogle Scholar
  • 15 Saito H, Kunishima S. Historical hematology: May-Hegglin anomaly. Am J Hematol 2008; 83 (04) 304-306
    CrossrefPubMedGoogle Scholar
  • 16 Michelson AD. Gray platelet syndrome. Blood 2013; 121 (02) 250-250
    CrossrefPubMedGoogle Scholar
  • 17 Cattaneo M, Cerletti C, Harrison P. , et al. Recommendations for the standardization of light transmission aggregometry: a consensus of the Working Party from the Platelet Physiology Subcommittee of SSC/ISTH. J Thromb Haemost 2013; ; (July): 1183-1189
    PubMedGoogle Scholar
  • 18 Tóth O, Calatzis A, Penz S, Losonczy H, Siess W. Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood. Thromb Haemost 2006; 96 (06) 781-788
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 19 Dawood BB, Lowe GC, Lordkipanidzé M. , et al. Evaluation of participants with suspected heritable platelet function disorders including recommendation and validation of a streamlined agonist panel. Blood 2012; 120 (25) 5041-5049
    CrossrefPubMedGoogle Scholar
  • 20 Nieuwenhuis HK, Akkerman JW, Sixma JJ. Patients with a prolonged bleeding time and normal aggregation tests may have storage pool deficiency: studies on one hundred six patients. Blood 1987; 70 (03) 620-623
    CrossrefPubMedGoogle Scholar
  • 21 Amesse LS, Pfaff-Amesse T, Gunning WT, Duffy N, French II JA. Clinical and laboratory characteristics of adolescents with platelet function disorders and heavy menstrual bleeding. Exp Hematol Oncol 2013; 2 (01) 3
    CrossrefPubMedGoogle Scholar
  • 22 Quiroga T, Goycoolea M, Panes O. , et al. High prevalence of bleeders of unknown cause among patients with inherited mucocutaneous bleeding. A prospective study of 280 patients and 299 controls. Haematologica 2007; 92 (03) 357-365
    CrossrefPubMedGoogle Scholar
  • 23 Slichter SJ. Relationship between platelet count and bleeding risk in thrombocytopenic patients. Transfus Med Rev 2004; 18 (03) 153-167
    CrossrefPubMedGoogle Scholar
  • 24 Hayward CPM, Moffat KA, Raby A. , et al. Development of North American consensus guidelines for medical laboratories that perform and interpret platelet function testing using light transmission aggregometry. Am J Clin Pathol 2010; 134 (06) 955-963
    CrossrefPubMedGoogle Scholar
  • 25 Hayward CPM, Moffat KA, Pai M. , et al. An evaluation of methods for determining reference intervals for light transmission platelet aggregation tests on samples with normal or reduced platelet counts. Thromb Haemost 2008; 100 (01) 134-145
    PubMedGoogle Scholar
  • 26 Cattaneo M, Hayward CPM, Moffat KA, Pugliano MT, Liu Y, Michelson AD. Results of a worldwide survey on the assessment of platelet function by light transmission aggregometry: a report from the platelet physiology subcommittee of the SSC of the ISTH. J Thromb Haemost 2009; 7 (06) 1029
    CrossrefPubMedGoogle Scholar
  • 27 Israels SJ, Kahr WHA, Blanchette VS, Luban NLC, Rivard GE, Rand ML. Platelet disorders in children: a diagnostic approach. Pediatr Blood Cancer 2011; 56 (06) 975-983
    CrossrefPubMedGoogle Scholar
  • 28 van Bladel ER, Laarhoven AG, van der Heijden LB. , et al. Functional platelet defects in children with severe chronic ITP as tested with 2 novel assays applicable for low platelet counts. Blood 2014; 123 (10) 1556-1563
    CrossrefPubMedGoogle Scholar
  • 29 Batman B, van Bladel ER, van Hamersveld M. , et al. Agonist-induced platelet reactivity correlates with bleeding in haemato-oncological patients. Vox Sang 2017; 112 (08) 773-779
    CrossrefPubMedGoogle Scholar
  • 30 Frelinger III AL, Grace RF, Gerrits AJ. , et al. Platelet function tests, independent of platelet count, are associated with bleeding severity in ITP. Blood 2015; 126 (07) 873-879
    CrossrefPubMedGoogle Scholar
  • 31 Shattil SJ, Cunningham M, Hoxie JA. Detection of activated platelets in whole blood using activation-dependent monoclonal antibodies and flow cytometry. Blood 1987; 70 (01) 307-315
    PubMedGoogle Scholar
  • 32 Morton LF, Hargreaves PG, Farndale RW, Young RD, Barnes MJ. Integrin alpha 2 beta 1-independent activation of platelets by simple collagen-like peptides: collagen tertiary (triple-helical) and quaternary (polymeric) structures are sufficient alone for alpha 2 beta 1-independent platelet reactivity. Biochem J 1995; 306 (Pt 2): 337-344
    CrossrefPubMedGoogle Scholar
  • 33 Rubak P, Nissen PH, Kristensen SD, Hvas A-M. Investigation of platelet function and platelet disorders using flow cytometry. Platelets 2016; 27 (01) 66-74
    CrossrefPubMedGoogle Scholar
  • 34 Dovlatova N, Lordkipanidzé M, Lowe GC. , et al; UK GAPP Study Group. Evaluation of a whole blood remote platelet function test for the diagnosis of mild bleeding disorders. J Thromb Haemost 2014; 12 (05) 660-665
    CrossrefPubMedGoogle Scholar
  • 35 Shattil SJ, Hoxie JA, Cunningham M, Brass LF. Changes in the platelet membrane glycoprotein IIb.IIIa complex during platelet activation. J Biol Chem 1985; 260 (20) 11107-11114
    PubMedGoogle Scholar
  • 36 Entcheva E. Cardiac optogenetics. Am J Physiol Heart Circ Physiol 2013; 304 (09) H1179-H1191
    CrossrefPubMedGoogle Scholar
  • 37 Bengtson CP, Freitag HE, Weislogel J-M, Bading H. Nuclear calcium sensors reveal that repetition of trains of synaptic stimuli boosts nuclear calcium signaling in CA1 pyramidal neurons. Biophys J 2010; 99 (12) 4066-4077
    CrossrefPubMedGoogle Scholar
  • 38 Cattaneo M. Light transmission aggregometry and ATP release for the diagnostic assessment of platelet function. Semin Thromb Hemost 2009; 35 (02) 158-167
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 39 Mumford AD, Frelinger III AL, Gachet C. , et al. A review of platelet secretion assays for the diagnosis of inherited platelet secretion disorders. Thromb Haemost 2015; 114 (01) 14-25
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 40 Carmody MW, Ault KA, Mitchell JG, Rote NS, Ng AK. Production of monoclonal antibodies specific for platelet activation antigens and their use in evaluating platelet function. Hybridoma 1990; 9 (06) 631-641
    CrossrefPubMedGoogle Scholar
  • 41 Nieuwenhuis HK, van Oosterhout JJ, Rozemuller E, van Iwaarden F, Sixma JJ. Studies with a monoclonal antibody against activated platelets: evidence that a secreted 53,000-molecular weight lysosome-like granule protein is exposed on the surface of activated platelets in the circulation. Blood 1987; 70 (03) 838-845
    PubMedGoogle Scholar
  • 42 Silverstein RL, Febbraio M. Identification of lysosome-associated membrane protein-2 as an activation-dependent platelet surface glycoprotein. Blood 1992; 80 (06) 1470-1475
    PubMedGoogle Scholar
  • 43 Israels SJ, Gerrard JM, Jacques YV. , et al. Platelet dense granule membranes contain both granulophysin and P-selectin (GMP-140). Blood 1992; 80 (01) 143-152
    PubMedGoogle Scholar
  • 44 Nishibori M, Cham B, McNicol A, Shalev A, Jain N, Gerrard JM. The protein CD63 is in platelet dense granules, is deficient in a patient with Hermansky-Pudlak syndrome, and appears identical to granulophysin. J Clin Invest 1993; 91 (04) 1775-1782
    CrossrefPubMedGoogle Scholar
  • 45 Heijnen H, van der Sluijs P. Platelet secretory behaviour: as diverse as the granules … or not?. J Thromb Haemost 2015; 13 (12) 2141-2151
    CrossrefPubMedGoogle Scholar
  • 46 Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol 2008; 70: 23-49
    CrossrefPubMedGoogle Scholar
  • 47 Cai H, Mullier F, Frotscher B. , et al. Usefulness of flow cytometric mepacrine uptake/release combined with CD63 assay in diagnosis of patients with suspected platelet dense granule disorder. Semin Thromb Hemost 2016; 42 (03) 282-291
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 48 Halliez M, Fouassier M, Robillard N. , et al. Detection of phosphatidyl serine on activated platelets' surface by flow cytometry in whole blood: a simpler test for the diagnosis of Scott syndrome. Br J Haematol 2015; 171 (02) 288-290
    CrossrefPubMedGoogle Scholar
  • 49 Thiagarajan P, Tait JF. Binding of annexin V/placental anticoagulant protein I to platelets. Evidence for phosphatidylserine exposure in the procoagulant response of activated platelets. J Biol Chem 1990; 265 (29) 17420-17423
    PubMedGoogle Scholar
  • 50 Albanyan AM, Murphy MF, Rasmussen JT, Heegaard CW, Harrison P. Measurement of phosphatidylserine exposure during storage of platelet concentrates using the novel probe lactadherin: a comparison study with annexin V. Transfusion 2009; 49 (01) 99-107
    CrossrefPubMedGoogle Scholar
  • 51 Giannini S, Cecchetti L, Mezzasoma AM, Gresele P. Diagnosis of platelet-type von Willebrand disease by flow cytometry. Haematologica 2010; 95 (06) 1021-1024
    CrossrefPubMedGoogle Scholar
  • 52 Lindahl TL, Fagerberg IH, Larsson A. A new flow cytometric method for measurement of von Willebrand factor activity. Scand J Clin Lab Invest 2003; 63 (03) 217-223
    CrossrefPubMedGoogle Scholar
  • 53 Shrivastava M. The platelet storage lesion. Transfus Apheresis Sci 2009; 41 (02) 105-113
    CrossrefPubMedGoogle Scholar
  • 54 Johnson L, Loh YS, Kwok M, Marks DC. In vitro assessment of buffy-coat derived platelet components suspended in SSP+ treated with the INTERCEPT Blood system. Transfus Med 2013; 23 (02) 121-129
    CrossrefPubMedGoogle Scholar
  • 55 Zhang JG, Carter CJ, Culibrk B. , et al. Buffy-coat platelet variables and metabolism during storage in additive solutions or plasma. Transfusion 2008; 48 (05) 847-856
    CrossrefPubMedGoogle Scholar
  • 56 Rinder HM, Smith BR. In vitro evaluation of stored platelets: is there hope for predicting posttransfusion platelet survival and function?. Transfusion 2003; 43 (01) 2-6
    CrossrefPubMedGoogle Scholar
  • 57 Kicken CH, Roest M, Henskens YMC, de Laat B, Huskens D. Application of an optimized flow cytometry-based quantification of platelet activation (PACT): monitoring platelet activation in platelet concentrates. PLoS One 2017; 12 (02) e0172265
    CrossrefPubMedGoogle Scholar
  • 58 Aleil B, Ravanat C, Cazenave JP, Rochoux G, Heitz A, Gachet C. Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases. J Thromb Haemost 2005; 3 (01) 85-92
    CrossrefPubMedGoogle Scholar
  • 59 Pampuch A, Cerletti C, de Gaetano G. Comparison of VASP-phosphorylation assay to light-transmission aggregometry in assessing inhibition of the platelet ADP P2Y12 receptor. Thromb Haemost 2006; 96 (06) 767-73
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 60 Gorog DA, Fuster V. Platelet function tests in clinical cardiology: unfulfilled expectations. J Am Coll Cardiol 2013; 61 (21) 2115-2129
    CrossrefPubMedGoogle Scholar
  • 61 Malfait F, De Paepe A. Bleeding in the heritable connective tissue disorders: mechanisms, diagnosis and treatment. Blood Rev 2009; 23 (05) 191-197
    CrossrefPubMedGoogle Scholar
  • 62 Friberg B, Ornö AK, Lindgren A, Lethagen S. Bleeding disorders among young women: a population-based prevalence study. Acta Obstet Gynecol Scand 2006; 85 (02) 200-206
    CrossrefPubMedGoogle Scholar
  • 63 Israels SJ, McNicol A, Robertson C, Gerrad M. Platelet storage pool deficiency: diagnosis in patients with prolonged bleeding times and normal platelet aggregation. Br J Haematol 1990; 75: 118-121
    CrossrefPubMedGoogle Scholar
  • 64 Leo VC, Morgan NV, Bem D. , et al; UK GAPP Study Group. Use of next-generation sequencing and candidate gene analysis to identify underlying defects in patients with inherited platelet function disorders. J Thromb Haemost 2015; 13 (04) 643-650
    CrossrefPubMedGoogle Scholar
  • 65 Lentaigne C, Freson K, Laffan MA, Turro E, Ouwehand WH. ; BRIDGE-BPD Consortium and the ThromboGenomics Consortium. Inherited platelet disorders: toward DNA-based diagnosis. Blood 2016; 127 (23) 2814-2823
    CrossrefPubMedGoogle Scholar
  • 66 Watson SP, Lowe GC, Lordkipanidzé M, Morgan NV. ; GAPP consortium. Genotyping and phenotyping of platelet function disorders. J Thromb Haemost 2013; 11 (Suppl. 01) 351-363
    CrossrefPubMedGoogle Scholar
  • 67 MacArthur DG, Manolio TA, Dimmock DP. , et al. Guidelines for investigating causality of sequence variants in human disease. Nature 2014; 508 (7497): 469-476
    CrossrefPubMedGoogle Scholar
  • 68 Nurden AT, Nurden P. Inherited disorders of platelet function: selected updates. J Thromb Haemost 2015; 13 (Suppl. 01) S2-S9
    CrossrefPubMedGoogle Scholar
  • 69 Maclachlan A, Watson SP, Morgan NV. Inherited platelet disorders: insight from platelet genomics using next-generation sequencing. Platelets 2017; 28 (01) 14-19
    CrossrefPubMedGoogle Scholar
  • 70 Daly ME, Dawood BB, Lester WA. , et al. Identification and characterization of a novel P2Y 12 variant in a patient diagnosed with type 1 von Willebrand disease in the European MCMDM-1VWD study. Blood 2009; 113 (17) 4110-4113
    CrossrefPubMedGoogle Scholar
  • 71 Quiroga T, Mezzano D. Is my patient a bleeder? A diagnostic framework for mild bleeding disorders. Hematology (Am Soc Hematol Educ Program) 2012; 2012: 466-474
    CrossrefPubMedGoogle Scholar
  • 72 Kirchmaier CM, Pillitteri D. Diagnosis and management of inherited platelet disorders. Transfus Med Hemother 2010; 37 (05) 237-246
    PubMedGoogle Scholar