Laboratory Techniques Used to Diagnose Constitutional Platelet Dysfunction

Abstract

Platelets play a major role in primary hemostasis, where activated platelets form plugs to stop hemorrhaging in response to vessel injuries. Defects in any step of the platelet activation process can cause a variety of platelet dysfunction conditions associated with bleeding. To make an accurate diagnosis, constitutional platelet dysfunction (CPDF) should be considered once von Willebrand disease and drug intake are ruled out. CPDF may be associated with thrombocytopenia or a genetic syndrome. CPDF diagnosis is complex, as no single test enables the analysis of all aspects of platelet function. Furthermore, the available tests lack standardization, and repeat tests must be performed in specialized laboratories especially for mild and moderate forms of the disease. In this review, we provide an overview of the laboratory tests used to diagnose CPDF, with a focus on light transmission platelet aggregation (LTA), flow cytometry (FC), and granules assessment. Global tests, mainly represented by LTA, are often initially performed to investigate the consequences of platelet activation on platelet aggregation in a single step. Global test results should be confirmed by additional analytical tests. FC represents an accurate, simple, and reliable test to analyze abnormalities in platelet receptors, and granule content and release. This technique may also be used to investigate platelet function by comparing resting- and activated-state platelet populations. Assessment of granule content and release also requires additional specialized analytical tests. High-throughput sequencing has become increasingly useful to diagnose CPDF. Advanced tests or external research laboratory techniques may also be beneficial in some cases.

Keywords

constitutional platelet dysfunction - diagnosis - light transmission aggregometry - granule deficiency - flow cytometry

Publikationsverlauf

Eingereicht: 14. Mai 2020

Angenommen: 20. Juli 2020

Artikel online veröffentlicht:
15. September 2020

• References

• 1 Gremmel T, Frelinger III AL, Michelson AD. Platelet physiology. Semin Thromb Hemost 2016; 42 (03) 191-204
• 2 Agbani EO, Poole AW. Procoagulant platelets: generation, function, and therapeutic targeting in thrombosis. Blood 2017; 130 (20) 2171-2179
• 3 Reddy EC, Rand ML. Procoagulant phosphatidylserine-exposing platelets in vitro and in vivo . Front Cardiovasc Med 2020; 7: 15
• 4 Gresele P, Orsini S, Noris P. et al; BAT-VAL Study Investigators. Validation of the ISTH/SSC bleeding assessment tool for inherited platelet disorders: a communication from the platelet physiology SSC. J Thromb Haemost 2020; 18 (03) 732-739
• 5 Tosetto A, Castaman G, Rodeghiero F. Bleeding scores in inherited bleeding disorders: clinical or research tools?. Haemophilia 2008; 14 (03) 415-422
• 6 Patscheke H. Shape and functional properties of human platelets washed with acid citrate. Haemostasis 1981; 10 (01) 14-27
• 7 Hechler B, Dupuis A, Mangin PH, Gachet C. Platelet preparation for function testing in the laboratory and clinic: historical and practical aspects. Res Pract Thromb Haemost 2019; 3 (04) 615-625
• 8 Hayward CPM, Moffat KA, Brunet J. et al. Update on diagnostic testing for platelet function disorders: What is practical and useful?. Int J Lab Hematol 2019; 41 (Suppl. 01) 26-32
• 9 George JN, Caen JP, Nurden AT. Glanzmann's thrombasthenia: the spectrum of clinical disease. Blood 1990; 75 (07) 1383-1395
• 10 Harrison P, Mackie I, Mumford A. et al; British Committee for Standards in Haematology. Guidelines for the laboratory investigation of heritable disorders of platelet function. Br J Haematol 2011; 155 (01) 30-44
• 11 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
• 12 Alessi M-C, Sié P, Payrastre B. Strengths and weaknesses of light transmission aggregometry in diagnosing hereditary platelet function disorders. J Clin Med 2020; 9 (03) E763
• 13 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; DOI: 10.1111/jth.12231. (epub ahead of print)
• 14 Linnemann B, Schwonberg J, Mani H, Prochnow S, Lindhoff-Last E. Standardization of light transmittance aggregometry for monitoring antiplatelet therapy: an adjustment for platelet count is not necessary. J Thromb Haemost 2008; 6 (04) 677-683
• 15 Cattaneo M, Lecchi A, Zighetti ML, Lussana F. Platelet aggregation studies: autologous platelet-poor plasma inhibits platelet aggregation when added to platelet-rich plasma to normalize platelet count. Haematologica 2007; 92 (05) 694-697
• 16 Robert P, Canault M, Farnarier C. et al. A novel leukocyte adhesion deficiency III variant: kindlin-3 deficiency results in integrin- and nonintegrin-related defects in different steps of leukocyte adhesion. J Immunol 2011; 186 (09) 5273-5283
• 17 Canault M, Ghalloussi D, Grosdidier C. et al. Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding. J Exp Med 2014; 211 (07) 1349-1362
• 18 Quinton TM, Kim S, Dangelmaier C. et al. Protein kinase C- and calcium-regulated pathways independently synergize with Gi pathways in agonist-induced fibrinogen receptor activation. Biochem J 2002; 368 (Pt 2): 535-543
• 19 Quinton TM, Ozdener F, Dangelmaier C, Daniel JL, Kunapuli SP. Glycoprotein VI-mediated platelet fibrinogen receptor activation occurs through calcium-sensitive and PKC-sensitive pathways without a requirement for secreted ADP. Blood 2002; 99 (09) 3228-3234
• 20 Stefanini L, Roden RC, Bergmeier W. CalDAG-GEFI is at the nexus of calcium-dependent platelet activation. Blood 2009; 114 (12) 2506-2514
• 21 Canault M, Alessi M-C. RasGRP2 structure, function and genetic variants in platelet pathophysiology. Int J Mol Sci 2020; 21 (03) E1075
• 22 Lecchi A, Razzari C, Paoletta S. et al. Identification of a new dysfunctional platelet P2Y12 receptor variant associated with bleeding diathesis. Blood 2015; 125 (06) 1006-1013
• 23 Cattaneo M, Lecchi A, Randi AM, McGregor JL, Mannucci PM. Identification of a new congenital defect of platelet function characterized by severe impairment of platelet responses to adenosine diphosphate. Blood 1992; 80 (11) 2787-2796
• 24 Patel YM, Lordkipanidzé M, Lowe GC. et al. A novel mutation in the P2Y12 receptor and a function-reducing polymorphism in protease-activated receptor 1 in a patient with chronic bleeding. J Thromb Haemost 2014; 12 (05) 716-725
• 25 Shiraga M, Miyata S, Kato H. et al. Impaired platelet function in a patient with P2Y12 deficiency caused by a mutation in the translation initiation codon. J Thromb Haemost 2005; 3 (10) 2315-2323
• 26 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
• 27 Berrou E, Soukaseum C, Favier R. et al. A mutation of the human EPHB2 gene leads to a major platelet functional defect. Blood 2018; 132 (19) 2067-2077
• 28 Bellio M, Garcia C, Edouard T. et al. Catalytic dysregulation of SHP2 leading to Noonan syndromes affects platelet signaling and functions. Blood 2019; 134 (25) 2304-2317
• 29 Andrews RK, Berndt MC. Bernard-Soulier syndrome: an update. Semin Thromb Hemost 2013; 39 (06) 656-662
• 30 Takahashi H, Sakuragawa N, Shibata A. Von Willebrand disease with an increased ristocetin-induced platelet aggregation and a qualitative abnormality of the factor VIII protein. Am J Hematol 1980; 8 (03) 299-308
• 31 Othman M. Platelet-type von Willebrand disease: a rare, often misdiagnosed and underdiagnosed bleeding disorder. Semin Thromb Hemost 2011; 37 (05) 464-469
• 32 Freson K, Hoylaerts MF, Jaeken J. et al. Genetic variation of the extra-large stimulatory G protein alpha-subunit leads to Gs hyperfunction in platelets and is a risk factor for bleeding. Thromb Haemost 2001; 86 (03) 733-738
• 33 Cardinal DC, Flower RJ. The electronic aggregometer: a novel device for assessing platelet behavior in blood. J Pharmacol Methods 1980; 3 (02) 135-158
• 34 Fritsma GA, McGlasson DL. Whole Blood Platelet Aggregometry. Methods Mol Biol 2017; 1646: 333-347
• 35 Sweeney JD, Hoernig LA, Michnik A, Fitzpatrick JE. Whole blood aggregometry. Influence of sample collection and delay in study performance on test results. Am J Clin Pathol 1989; 92 (05) 676-679
• 36 Sweeney JD, Labuzetta JW, Fitzpatrick JE. The effect of the platelet count on the aggregation response and adenosine triphosphate release in an impedance lumi-aggregometer. Am J Clin Pathol 1988; 89 (05) 655-659
• 37 Dyszkiewicz-Korpanty AM, Frenkel EP, Sarode R. Approach to the assessment of platelet function: comparison between optical-based platelet-rich plasma and impedance-based whole blood platelet aggregation methods. Clin Appl Thromb Hemost 2005; 11 (01) 25-35
• 38 Albanyan A, Al-Musa A, AlNounou R. et al. Diagnosis of Glanzmann thrombasthenia by whole blood impedance analyzer (MEA) vs. light transmission aggregometry. Int J Lab Hematol 2015; 37 (04) 503-508
• 39 Awidi A, Maqablah A, Dweik M, Bsoul N, Abu-Khader A. Comparison of platelet aggregation using light transmission and multiple electrode aggregometry in Glanzmann thrombasthenia. Platelets 2009; 20 (05) 297-301
• 40 Quick AJ. The bleeding time as a test of hemostatic function. Am J Clin Pathol 1975; 64 (01) 87-94
• 41 Rodgers RP, Levin J. A critical reappraisal of the bleeding time. Semin Thromb Hemost 1990; 16 (01) 1-20
• 42 Favaloro EJ. Clinical utility of closure times using the platelet function analyzer-100/200. Am J Hematol 2017; 92 (04) 398-404
• 43 Mulliez SMN, Hallaert G, Van Roost D, Vantilborgh A, Devreese KMJ. Influence of platelet clumps on platelet function analyser (PFA)-200® testing. Int J Lab Hematol 2015; 37 (05) e103-e105
• 44 Favaloro EJ. Utility of the platelet function analyser (PFA-100/200) for exclusion or detection of von Willebrand disease: a study 22 years in the making. Thromb Res 2020; 188: 17-24
• 45 Kerényi A, Schlammadinger A, Ajzner E. et al. Comparison of PFA-100 closure time and template bleeding time of patients with inherited disorders causing defective platelet function. Thromb Res 1999; 96 (06) 487-492
• 46 Shenkman B, Einav Y, Salomon O, Varon D, Savion N. Testing agonist-induced platelet aggregation by the Impact-R [Cone and plate(let) analyzer (CPA)]. Platelets 2008; 19 (06) 440-446
• 47 Paniccia R, Priora R, Liotta AA, Abbate R. Platelet function tests: a comparative review. Vasc Health Risk Manag 2015; 11: 133-148
• 48 Campbell J, Ridgway H, Carville D. Plateletworks: a novel point of care platelet function screen. Mol Diagn Ther 2008; 12 (04) 253-258
• 49 Barg AA, Hauschner H, Misgav M. et al. A novel approach using ancillary tests to guide treatment of Glanzmann thrombasthenia patients undergoing surgical procedures. Blood Cells Mol Dis 2018; 72: 44-48
• 50 Grassetto A, Fullin G, Lazzari F. et al. Perioperative ROTEM and ROTEM platelet monitoring in a case of Glanzmann's thrombasthenia. Blood Coagul Fibrinolysis 2017; 28 (01) 96-99
• 51 Whiting D, DiNardo JA. TEG and ROTEM: technology and clinical applications. Am J Hematol 2014; 89 (02) 228-232
• 52 Savage B, Saldívar E, Ruggeri ZM. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell 1996; 84 (02) 289-297
• 53 Mangin PH, Gardiner EE, Nesbitt WS. et al; Subcommittee on Biorheology. In vitro flow based systems to study platelet function and thrombus formation: Recommendations for standardization: communication from the SSC on Biorheology of the ISTH. J Thromb Haemost 2020; 18 (03) 748-752
• 54 Hézard N, Potron G, Schlegel N, Amory C, Leroux B, Nguyen P. Unexpected persistence of platelet hyporeactivity beyond the neonatal period: a flow cytometric study in neonates, infants and older children. Thromb Haemost 2003; 90 (01) 116-123
• 55 Ignatova AA, Ponomarenko EA, Polokhov DM. et al. Flow cytometry for pediatric platelets. Platelets 2019; 30 (04) 428-437
• 56 Nomura S, Nagata H, Kitada T. et al. [Analysis of Glanzmann's thrombasthenia and Bernard-Soulier syndrome using flow cytometry]. Rinsho Ketsueki 1987; 28 (03) 377-385
• 57 Jennings LK, Ashmun RA, Wang WC, Dockter ME. Analysis of human platelet glycoproteins IIb-IIIa and Glanzmann's thrombasthenia in whole blood by flow cytometry. Blood 1986; 68 (01) 173-179
• 58 Handa M, Watanabe K, Kawai Y. et al. Platelet unresponsiveness to collagen: involvement of glycoprotein Ia-IIa (alpha 2 beta 1 integrin) deficiency associated with a myeloproliferative disorder. Thromb Haemost 1995; 73 (03) 521-528
• 59 van Asten I, Schutgens REG, Urbanus RT. Toward flow cytometry based platelet function diagnostics. Semin Thromb Hemost 2018; 44 (03) 197-205
• 60 Pasalic L, Pennings GJ, Connor D, Campbell H, Kritharides L, Chen VM. Flow cytometry protocols for assessment of platelet function in whole blood. Methods Mol Biol 2017; 1646: 369-389
• 61 Sims PJ, Wiedmer T, Esmon CT, Weiss HJ, Shattil SJ. Assembly of the platelet prothrombinase complex is linked to vesiculation of the platelet plasma membrane. Studies in Scott syndrome: an isolated defect in platelet procoagulant activity. J Biol Chem 1989; 264 (29) 17049-17057
• 62 Prodan CI, Joseph PM, Vincent AS, Dale GL. Coated-platelet levels are influenced by smoking, aspirin, and selective serotonin reuptake inhibitors. J Thromb Haemost 2007; 5 (10) 2149-2151
• 63 Dale GL. Coated-platelets: an emerging component of the procoagulant response. J Thromb Haemost 2005; 3 (10) 2185-2192
• 64 Abaeva AA, Canault M, Kotova YN. et al. Procoagulant platelets form an α-granule protein-covered “cap” on their surface that promotes their attachment to aggregates. J Biol Chem 2013; 288 (41) 29621-29632
• 65 Prodan CI, Stoner JA, Dale GL. Lower coated-platelet levels are associated with increased mortality after spontaneous intracerebral hemorrhage. Stroke 2015; 46 (07) 1819-1825
• 66 Colucci G, Stutz M, Rochat S. et al. The effect of desmopressin on platelet function: a selective enhancement of procoagulant COAT platelets in patients with primary platelet function defects. Blood 2014; 123 (12) 1905-1916
• 67 Brooks MB, Catalfamo JL, Friese P, Dale GL. Scott syndrome dogs have impaired coated-platelet formation and calcein-release but normal mitochondrial depolarization. J Thromb Haemost 2007; 5 (09) 1972-1974
• 68 Saxena K, Pethe K, Dale GL. Coated-platelet levels may explain some variability in clinical phenotypes observed with severe hemophilia. J Thromb Haemost 2010; 8 (05) 1140-1142
• 69 Kirkpatrick AC, Vincent AS, Dale GL, Prodan CI. Increased platelet procoagulant potential predicts recurrent stroke and TIA after lacunar infarction. J Thromb Haemost 2020; 18 (03) 660-668
• 70 Zighetti ML, Carpani G, Sinigaglia E, Cattaneo M. Usefulness of a flow cytometric analysis of intraplatelet vasodilator-stimulated phosphoprotein phosphorylation for the detection of patients with genetic defects of the platelet P2Y(12) receptor for ADP. J Thromb Haemost 2010; 8 (10) 2332-2334
• 71 Gachet C. P2 receptors, platelet function and pharmacological implications. Thromb Haemost 2008; 99 (03) 466-472
• 72 Murugappa S, Kunapuli SP. The role of ADP receptors in platelet function. Front Biosci 2006; 11: 1977-1986
• 73 Cattaneo M, Canciani MT, Lecchi A. et al. Released adenosine diphosphate stabilizes thrombin-induced human platelet aggregates. Blood 1990; 75 (05) 1081-1086
• 74 Sandrock-Lang K, Wentzell R, Santoso S, Zieger B. Inherited platelet disorders. Hamostaseologie 2016; 36 (03) 178-186
• 75 Sharda A, Flaumenhaft R. The life cycle of platelet granules. F1000 Res 2018; 7: 236
• 76 Israels SJ, El-Ekiaby M, Quiroga T, Mezzano D. Inherited disorders of platelet function and challenges to diagnosis of mucocutaneous bleeding. Haemophilia 2010; 16 (Suppl. 05) 152-159
• 77 Rand ML, Reddy EC, Israels SJ. Laboratory diagnosis of inherited platelet function disorders. Transfus Apheresis Sci 2018; 57 (04) 485-493
• 78 Mezzano D, Quiroga T. Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research. J Thromb Haemost 2019; 17 (02) 257-270
• 79 Cattaneo M. Light transmission aggregometry and ATP release for the diagnostic assessment of platelet function. Semin Thromb Hemost 2009; 35 (02) 158-167
• 80 Callan MB, Bennett JS, Phillips DK. et al. Inherited platelet delta-storage pool disease in dogs causing severe bleeding: an animal model for a specific ADP deficiency. Thromb Haemost 1995; 74 (03) 949-953
• 81 Cortese M, Delporte C, Dufour D. et al. Validation of a LC/MSMS method for simultaneous quantification of 9 nucleotides in biological matrices. Talanta 2019; 193: 206-214
• 82 Pai M, Wang G, Moffat KA. 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 (03) 350-358
• 83 Badin MS, Graf L, Iyer JK, Moffat KA, Seecharan JL, Hayward CPM. Variability in platelet dense granule adenosine triphosphate release findings amongst patients tested multiple times as part of an assessment for a bleeding disorder. Int J Lab Hematol 2016; 38 (06) 648-657
• 84 Saultier P, Vidal L, Canault M. et al. Macrothrombocytopenia and dense granule deficiency associated with FLI1 variants: ultrastructural and pathogenic features. Haematologica 2017; 102 (06) 1006-1016
• 85 Andres O, Wiegering V, König E-M. et al. A novel two-nucleotide deletion in HPS6 affects mepacrine uptake and platelet dense granule secretion in a family with Hermansky-Pudlak syndrome. Pediatr Blood Cancer 2017; 64 (05) DOI: 10.1002/pbc.26320.
• 86 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
• 87 Billio A, Moeseneder C, Donazzan G, Triani A, Pescosta N, Coser P. Hermansky-Pudlak syndrome: clinical presentation and confirmation of the value of the mepacrine-based cytofluorimetry test in the diagnosis of delta granule deficiency. Haematologica 2001; 86 (02) 220
• 88 Wall JE, Buijs-Wilts M, Arnold JT. et al. A flow cytometric assay using mepacrine for study of uptake and release of platelet dense granule contents. Br J Haematol 1995; 89 (02) 380-385
• 89 van Asten I, Blaauwgeers M, Granneman L. et al. Flow cytometric mepacrine fluorescence can be used for the exclusion of platelet dense granule deficiency. J Thromb Haemost 2020; 18 (03) 706-713
• 90 Lorez HP, Richards JG, Da Prada M. et al. Storage pool disease: comparative fluorescence microscopical, cytochemical and biochemical studies on amine-storing organelles of human blood platelets. Br J Haematol 1979; 43 (02) 297-305
• 91 Korse CM, Buning-Kager JCGM, Linders TC. et al. A serum and platelet-rich plasma serotonin assay using liquid chromatography tandem mass spectrometry for monitoring of neuroendocrine tumor patients. Clin Chim Acta 2017; 469: 130-135
• 92 Maurer-Spurej E, Dyker K, Gahl WA, Devine DV. A novel immunocytochemical assay for the detection of serotonin in platelets. Br J Haematol 2002; 116 (03) 604-611
• 93 Quiroga T, Goycoolea M, Matus V. et al. Diagnosis of mild platelet function disorders. Reliability and usefulness of light transmission platelet aggregation and serotonin secretion assays. Br J Haematol 2009; 147 (05) 729-736
• 94 Hayward CPM, Moffat KA, Spitzer E. et al; 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 (05) 671-675
• 95 Brunet JG, Iyer JK, Badin MS. 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; 40 (04) 400-407
• 96 Knight AE, Gomez K, Cutler DF. Super-resolution microscopy in the diagnosis of platelet granule disorders. Expert Rev Hematol 2017; 10 (05) 375-381
• 97 Nurden AT, Nurden P. Congenital platelet disorders and understanding of platelet function. Br J Haematol 2014; 165 (02) 165-178
• 98 Gunay-Aygun M, Huizing M, Gahl WA. Molecular defects that affect platelet dense granules. Semin Thromb Hemost 2004; 30 (05) 537-547
• 99 Wei ML. Hermansky-Pudlak syndrome: a disease of protein trafficking and organelle function. Pigment Cell Res 2006; 19 (01) 19-42
• 100 Introne W, Boissy RE, Gahl WA. Clinical, molecular, and cell biological aspects of Chediak-Higashi syndrome. Mol Genet Metab 1999; 68 (02) 283-303
• 101 White JG, Thomas A. Platelet structural pathology in a patient with the X-linked GATA-1, R216Q mutation. Platelets 2009; 20 (01) 41-49
• 102 Mao GF, Goldfinger LE, Fan DC. et al. Dysregulation of PLDN (pallidin) is a mechanism for platelet dense granule deficiency in RUNX1 haplodeficiency. J Thromb Haemost 2017; 15 (04) 792-801
• 103 Berrou E, Adam F, Lebret M. et al. Heterogeneity of platelet functional alterations in patients with filamin A mutations. Arterioscler Thromb Vasc Biol 2013; 33 (01) e11-e18
• 104 Nurden AT, Nurden P. The gray platelet syndrome: clinical spectrum of the disease. Blood Rev 2007; 21 (01) 21-36
• 105 Zhou Y, Zhang J. Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features. Ital J Pediatr 2014; 40: 77
• 106 Spurgeon BEJ, Aburima A, Oberprieler NG, Taskén K, Naseem KM. Multiplexed phosphospecific flow cytometry enables large-scale signaling profiling and drug screening in blood platelets. J Thromb Haemost 2014; 12 (10) 1733-1743
• 107 Greinacher A, Pecci A, Kunishima S. et al. Diagnosis of inherited platelet disorders on a blood smear: a tool to facilitate worldwide diagnosis of platelet disorders. J Thromb Haemost 2017; 15 (07) 1511-1521
• 108 FitzGerald GA, Brash AR, Oates JA, Pedersen AK. Endogenous prostacyclin biosynthesis and platelet function during selective inhibition of thromboxane synthase in man. J Clin Invest 1983; 72 (04) 1336-1343
• 109 Muir AR, McMullin MF, Patterson C, McKeown PP. Assessment of aspirin resistance varies on a temporal basis in patients with ischaemic heart disease. Heart 2009; 95 (15) 1225-1229
• 110 Gremmel T, Perkmann T, Seidinger D. et al. Differential impact of inflammation on six laboratory assays measuring residual arachidonic acid-inducible platelet reactivity during dual antiplatelet therapy. J Atheroscler Thromb 2013; 20 (07) 630-645
• 111 Hayward CP, Rivard GE, Kane WH. et al. An autosomal dominant, qualitative platelet disorder associated with multimerin deficiency, abnormalities in platelet factor V, thrombospondin, von Willebrand factor, and fibrinogen and an epinephrine aggregation defect. Blood 1996; 87 (12) 4967-4978
• 112 Diamandis M, Paterson AD, Rommens JM. et al. Quebec platelet disorder is linked to the urokinase plasminogen activator gene (PLAU) and increases expression of the linked allele in megakaryocytes. Blood 2009; 113 (07) 1543-1546
• 113 Kahr WH, Zheng S, Sheth PM. et al. Platelets from patients with the Quebec platelet disorder contain and secrete abnormal amounts of urokinase-type plasminogen activator. Blood 2001; 98 (02) 257-265
• 114 Diamandis M, Adam F, Kahr WHA. et al. Insights into abnormal hemostasis in the Quebec platelet disorder from analyses of clot lysis. J Thromb Haemost 2006; 4 (05) 1086-1094
• 115 Freson K, Turro E. High-throughput sequencing approaches for diagnosing hereditary bleeding and platelet disorders. J Thromb Haemost 2017; 15 (07) 1262-1272