Advertisement

Laboratory diagnosis of inherited platelet function disorders

  • Margaret L. Rand
    Correspondence
    Corresponding author at: Division of Haematology/Oncology, The Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8, Canada.
    Affiliations
    Division of Haematology/Oncology, Translational Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada

    Departments of Laboratory Medicine & Pathobiology, Biochemistry, and Paediatrics, University of Toronto, ON, Canada
    Search for articles by this author
  • Emily C. Reddy
    Affiliations
    Developmental & Stem Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada
    Search for articles by this author
  • Sara J. Israels
    Affiliations
    Research Institute of Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada

    Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada
    Search for articles by this author

      Abstract

      Platelets respond to vessel wall injury by forming a primary hemostatic plug to arrest blood loss. Hemostatic plug formation is complex, and involves platelet adhesion to the subendothelium that results in platelet activation and ultimately, aggregation. If any of these processes are deficient, primary hemostasis is impaired. Inherited platelet function disorders (IPFDs) are a heterogeneous group of defects in these processes, with patients experiencing mainly mucocutaneous bleeding symptoms that can range from very mild to life threatening, depending on the specific disorder. Here, we review the approach to an initial patient assessment required to inform laboratory testing, and the frequently used clinical laboratory assays for diagnostic evaluation of IPFDs. Newer testing approaches that may improve laboratory diagnosis in the near future are described.

      Keywords

      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:

      Subscribe to Transfusion and Apheresis Science
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ruggeri Z.M.
        • Jackson S.
        Platelet thrombus formation in flowing blood.
        in: Michelson A.D. Platelets. 3rd ed. Academic Press, 2013 (p. 399–424)
        • Israels S.J.
        • Rand M.L.
        What we have learned from inherited platelet disorders.
        Pediatr Blood Cancer. 2013; 60: S2-S7
        • Quiroga T.
        • Goycoolea M.
        • Panes O.
        • Aranda E.
        • Martínez C.
        • Belmont S.
        • 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: 357-365
        • Noris P.
        • Pecci A.
        Hereditary thrombocytopenias: a growing list of disorders.
        Hematol Am Soc Hematol Educ Program. 2017; 2017: 385-399
        • Balduini C.L.
        • Melazzini F.
        • Pecci A.
        Inherited thrombocytopenias-recent advances in clinical and molecular aspects.
        Platelets. 2017; 28: 3-13
        • Israels S.J.
        • Kahr W.H.
        • Blanchette V.S.
        • Luban N.L.
        • Rivard G.E.
        • Rand M.L.
        Platelet disorders in children: a diagnostic approach.
        Pediatr Blood Cancer. 2011; 56: 975-983
        • Gresele P.
        • Bury L.
        • Falcinelli E.
        Inherited platelet function disorders: algorithms for phenotypic and genetic investigation.
        Semin Thromb Hemost. 2016; 42: 292-305
        • Favaloro E.J.
        • Lippi G.
        • Franchini M.
        Contemporary platelet function testing.
        Clin Chem Lab Med. 2010; 48: 579-598
        • Lambert M.P.
        What to do when you suspect an inherited platelet disorder.
        Hematol Am Soc Hematol Educ Program. 2011; 2011: 377-383
        • 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: 314-322
        • Bowman M.L.
        • James P.D.
        Bleeding scores for the diagnosis of von Willebrand disease.
        Semin Thromb Hemost. 2017; 43: 530-539
        • Lowe G.C.
        • Lordkipanidzé M.
        • Watson S.P.
        • UK GAPP study group
        Utility of the ISTH bleeding assessment tool in predicting platelet defects in participants with suspected inherited platelet function disorders.
        J Thromb Haemost. 2013; 11: 1663-1668
        • Scharf R.E.
        Drugs that affect platelet function.
        Semin Thromb Hemost. 2012; 38: 865-883
        • Harrison P.
        • Mackie I.
        • Mumford A.
        • Briggs C.
        • Liesner R.
        • Winter M.
        • et al.
        Guidelines for the laboratory investigation of heritable disorders of platelet function.
        Br J Haematol. 2011; 155: 30-44
        • Nurden A.T.
        • Nurden P.
        Congenital platelet disorders and understanding of platelet function.
        Br J Haematol. 2014; 165: 165-178
        • Cattaneo M.
        Are the bleeding time and PFA-100 useful in the initial screening of patients with mucocutaneous bleedings of hereditary nature?.
        J Thromb Haemost. 2004; 2: 890-891
        • Quiroga T.
        • Goycoolea M.
        • Muñoz B.
        • Morales M.
        • Aranda E.
        • Panes O.
        • 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: 892-898
        • Harrison P.
        • Lordkipanidzé M.
        Testing platelet function.
        Hematol Oncol Clin North Am. 2013; 27: 411-441
        • Gresele P.
        • Harrison P.
        • Bury L.
        • Falcinelli E.
        • Gachet C.
        • Hayward C.P.
        • et al.
        Diagnosis of suspected inherited platelet function disorders: results of a worldwide survey.
        J Thromb Haemost. 2014; 12: 1562-1569
        • Favaloro E.J.
        Clinical utility of closure times using the platelet function analyzer-100/200.
        Am J Hematol. 2017; 92: 398-404
        • Rand M.L.
        • Leung R.
        • Packham M.A.
        Platelet function assays.
        Transfus Apher Sci. 2003; 28: 307-317
        • Hayward C.P.
        • Harrison P.
        • Cattaneo M.
        • Ortel T.L.
        • Rao A.K.
        Platelet physiology subcommittee of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Platelet function analyzer (PFA)-100 closure time in the evaluation of platelet disorders and platelet function.
        J Thromb Haemost. 2006; 4: 312-319
        • Lordkipanidze M.
        Platelet function tests.
        Semin Thromb Hemost. 2016; 42: 258-267
        • Hayward C.P.
        • Moffat K.A.
        • Raby A.
        • Israels S.
        • Plumhoff E.
        • Flynn G.
        • 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: 955-963
        • Cattaneo M.
        • Cerletti C.
        • Harrison P.
        • Hayward C.P.
        • Kenny D.
        • Nugent D.
        • 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; 11: 1183-1189
        • Hayward C.P.
        • Pai M.
        • Liu Y.
        • Moffat K.A.
        • Seecharan J.
        • Webert K.E.
        • et al.
        Diagnostic utility of light transmission platelet aggregometry: results from a prospective study of individuals referred for bleeding disorder assessments.
        J Thromb Haemost. 2009; 7: 676-684
        • Dawood B.B.
        • Lowe G.C.
        • Lordkipanidze M.
        • Bem D.
        • Daly M.E.
        • Makris M.
        • et al.
        Evaluation of participants with suspected heritable platelet function disorders including recommendation and validation of a streamlined agonist panel.
        Blood. 2012; 120: 5041-5049
        • Christie D.J.
        • Avari T.
        • Carrington L.R.
        • Cohen E.
        • DeBaise B.A.
        • Harrison P.
        • et al.
        Platelet function testing by aggregometry; approved guideline. CLSI document H58-A.
        Clinical and Laboratory Standards Institute, Wayne, PA2008
        • Lordkipanidze M.
        • Lowe G.C.
        • Kirkby N.S.
        • Chan M.V.
        • Lundberg M.H.
        • Morgan N.V.
        • et al.
        Characterization of multiple platelet activation pathways in patients with bleeding as a high-throughput screening option: use of 96-well Optimul assay.
        Blood. 2014; 123: e11-22
        • McGlasson D.L.
        • Fritsma G.A.
        Whole blood platelet aggregometry and platelet function testing.
        Semin Thromb Hemost. 2009; 35: 168-180
        • Peerschke E.I.
        • Castellone D.D.
        • Stroobants A.K.
        • Francis J.
        Reference range determination for whole-blood platelet aggregation using the multiplate analyzer.
        Am J Clin Pathol. 2014; 142: 647-656
        • Moenen F.
        • Vries M.J.A.
        • Nelemans P.J.
        • van Rooy K.J.M.
        • Vranken J.R.R.A.
        • Verhezen P.W.M.
        • et al.
        Screening for platelet function disorders with multiplate and platelet function analyzer.
        Platelets. 2017; : 1-7https://doi.org/10.1080/09537104.2017.1371290
        • Al Ghaithi R.
        • Drake S.
        • Watson S.P.
        • Morgan N.V.
        • Harrison P.
        Comparison of multiple electrode aggregometry with lumi-aggregometry for the diagnosis of patients with mild bleeding disorders.
        J Thromb Haemost. 2017; 15: 2045-2052
        • Jackson S.P.
        The growing complexity of platelet aggregation.
        Blood. 2007; 109: 5087-5095
        • de Witt S.M.
        • Swieringa F.
        • Cavill R.
        • Lamers M.M.
        • van Kruchten R.
        • Mastenbroek T.
        • et al.
        Identification of platelet function defects by multi-parameter assessment of thrombus formation.
        Nat Commun. 2014; 5: 4257
        • Pai M.
        • Wang G.
        • Moffat K.A.
        • Liu Y.
        • Seecharan J.
        • Webert K.
        • et al.
        Diagnostic usefulness of a lumi-aggregometer adenosine triphosphate release assay for the assessment of platelet function disorders.
        Am J Clin Pathol. 2011; 136: 350-358
        • Cattaneo M.
        Light transmission aggregometry and ATP release for the diagnostic assessment of platelet function.
        Semin Thromb Hemost. 2009; 35: 158-167
        • Mumford A.D.
        • Frelinger 3rd, A.L.
        • Gachet C.
        • Gresele P.
        • Noris P.
        • Harrison P.
        • et al.
        A review of platelet secretion assays for the diagnosis of inherited platelet secretion disorders.
        Thromb Haemost. 2015; 114: 14-25
        • Berny-Lang M.A.
        • Frelinger 3rd, A.L.
        • Barnard M.R.
        • Michelson A.D.
        Flow cytometry.
        in: Michelson A.D. Platelets. 3rd ed. Academic Press, 2013 (p. 581–602)
        • Frelinger 3rd, A.L.
        • Grace R.F.
        • Gerrits A.J.
        • Berny-Lang M.A.
        • Brown T.
        • Carmichael S.L.
        • et al.
        Platelet function tests, independent of platelet count, are associated with bleeding severity in ITP.
        Blood. 2015; 126: 873-879
        • Israels S.J.
        Diagnostic evaluation of platelet function disorders in neonates and children: an update.
        Semin Thromb Hemost. 2009; 35: 181-188
        • Dovlatova N.
        Current status and future prospects for platelet function testing in the diagnosis of inherited bleeding disorders.
        Br J Haematol. 2015; 170: 150-161
        • Lhermusier T.
        • Chap H.
        • Payrastre B.
        Platelet membrane phospholipid asymmetry: from the characterization of a scramblase activity to the identification of an essential protein mutated in Scott syndrome.
        J Thromb Haemost. 2011; 9: 1883-1891
        • van Asten I.
        • Schutgens R.E.G.
        • Baaij M.
        • Zandstra J.
        • Roest M.
        • Pasterkamp G.
        • et al.
        Validation of flow cytometric analysis of platelet function in patients with a suspected platelet function defect.
        J Thromb Haemost. 2018; 16: 689-698
        • Hayward C.P.
        • Moffat K.A.
        • Timleck M.
        • Plumhoff E.
        • Israels S.J.
        • White J.
        NASCOLA working group on platelet dense granule deficiency. Results of an external proficiency testing exercise on platelet dense-granule deficiency testing by whole mount electron microscopy.
        Am J Clin Pathol. 2009; 131: 671-675
        • Brunet J.G.
        • Iyer J.K.
        • Badin M.S.
        • Graf L.
        • Moffat K.A.
        • Timleck M.
        • et al.
        Electron microscopy examination of platelet whole mount preparations to quantitate platelet dense granule numbers: implications for diagnosing suspected platelet function disorders due to dense granule deficiency.
        Int J Lab Hematol. 2018; ([Epub ahead of print])https://doi.org/10.1111/ijlh.12801
        • White J.G.
        • Krumwiede M.
        Some contributions of electron microscopy to knowledge of human platelets.
        Thromb Haemost. 2007; 98: 69-72
        • FitzGerald G.A.
        • Oates J.A.
        • Hawiger J.
        • Maas R.L.
        • Roberts 2nd, L.J.
        • Lawson J.A.
        • et al.
        Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man.
        J Clin Invest. 1983; 71: 676-688
        • Lentaigne C.
        • Freson K.
        • Laffan M.A.
        • Turro E.
        • Ouwehand W.H.
        BRIDGE-BPD consortium and the ThromboGenomics consortium. Inherited platelet disorders: toward DNA-based diagnosis.
        Blood. 2016; 127: 2814-2823
        • Heremans J.
        • Freson K.
        High-throughput sequencing for diagnosing platelet disorders: lessons learned from exploring the causes of bleeding disorders.
        Int J Lab Hematol. 2018; 40: 89-96