Platelet Dysfunction in Noonan and 22q11.2 Deletion Syndromes in Childhood

Abstract

Introduction An underlying thrombocytopathy seems to be responsible for hemorrhagic symptoms in patients diagnosed with 22q11.2 deletion syndrome (22q11DS) or Noonan syndrome (NS). In 22q11DS, it is explained by a defect in the membrane glycoprotein (GP) complex Ib-V-IX. The cause of thrombocytopathy in NS remains unclear.

Aim The objective is to study the incidence of thrombocytopathy in pediatric patients diagnosed with 22q11DS or NS assessing the utility of ISTH-BAT questionnaire and laboratory techniques.

Materials and Methods Prospective study between March and December 2018 in children (2–18 years old) diagnosed with 22q11DS or NS. Hemorrhagic symptoms using ISTH-BAT score, total cell blood count, platelet indices, PFA-200 closure times, and platelet aggregation were evaluated in all patients and membrane GP expression in 22q11DS patients.

Results Nearly 70% of NS patients (n = 22) had a platelet aggregation defect without thrombocytopenia. A defect of platelet aggregation with adenosine diphosphate (ADP) and epinephrine was the most frequent pattern. A statistically significant inverse correlation between closure times and aggregation with arachidonic acid (p = 0.049, p = 0.043) and epinephrine (p = 0.021, p = 0.035), and ADP (p = 0.117, p = 0.05) was found. Total 5 out of 29 patients diagnosed with 22q11DS had macrothrombocytopenia; more noteworthy in older patients. Twenty-six patients showed an impairment in ristocetin-induced platelet aggregation that correlated with prolonged collagen/epinephrine (p = 0.034) and collagen/ADP (p = 0.01). A significant association between ISTH-BAT score >3 and closure times (p = 0.022, p = 0.002) and aggregation defect with ristocetin (p = 0.043) was also demonstrated.

Conclusion Most NS and 22q11DS patients show an impairment of platelet aggregation that correlates with closure times. In 22q11DS patients, these results were also related to hemorrhagic symptoms.

Keywords

thrombocytopathy - DiGeorge syndrome - 22q11.2 deletion syndrome - noonan syndrome - childhood - pediatrics

• References

• 1 Liang HP, Morel-Kopp MC, Curtin J. , et al. Heterozygous loss of platelet glycoprotein (GP) Ib-V-IX variably affects platelet function in velocardiofacial syndrome (VCFS) patients. Thromb Haemost 2007; 98 (06) 1298-1308
• 2 Artoni A, Selicorni A, Passamonti SM. , et al. Hemostatic abnormalities in Noonan syndrome. Pediatrics 2014; 133 (05) e1299-e1304
• 3 McDonald-McGinn DM, Sullivan KE, Marino B. , et al. 22q11.2 deletion syndrome. Nat Rev Dis Primers 2015; 1: 15071
• 4 Turner AM. Noonan syndrome. J Paediatr Child Health 2014; 50 (10) E14-E20
• 5 Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet 2013; 381 (9863): 333-342
• 6 Derbent M, Öncel Y, Tokel K. , et al. Clinical and hematologic findings in Noonan syndrome patients with PTPN11 gene mutations. Am J Med Genet A 2010; 152A (11) 2768-2774
• 7 Orsini S, Noris P, Bury L. , et al; European Hematology Association - Scientific Working Group (EHA-SWG) on thrombocytopenias and platelet function disorders. Bleeding risk of surgery and its prevention in patients with inherited platelet disorders. Haematologica 2017; 102 (07) 1192-1203
• 8 Pallotta R, Evangelista V, Margaglione M, Bucci I, Saponari A. Macrothrombocytopenia in velocardiofacial syndrome. J Thromb Haemost 2005; 3 (03) 601-603
• 9 Witt DR, McGillivray BC, Allanson JE. , et al. Bleeding diathesis in Noonan syndrome: a common association. Am J Med Genet 1988; 31 (02) 305-317
• 10 Stoffman JM, Mcnicol A, Zelinski T, Chodirker BN, Israels SJ. The association between SHP-2 mutations and platelet function in Noonan syndrome. Blood 2008; 112: 1239
• 11 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
• 12 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
• 13 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
• 14 Tartaglia M, Kalidas K, Shaw A. , et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 2002; 70 (06) 1555-1563
• 15 Bolton-Maggs PHB, Chalmers EA, Collins PW. , et al; UKHCDO. A review of inherited platelet disorders with guidelines for their management on behalf of the UKHCDO. Br J Haematol 2006; 135 (05) 603-633
• 16 Flick JT, Singh AK, Kizer J, Lazarchick J. Platelet dysfunction in Noonan's syndrome. A case with a platelet cyclooxygenase-like deficiency and chronic idiopathic thrombocytopenic purpura. Am J Clin Pathol 1991; 95 (05) 739-742
• 17 Koç A, Kösecik M, Tatlı MM, Atas A, Emiroğlu HH. Bernard-Soulier syndrome like platelet defect in a patient with Noonan syndrome; a case report. Turk J Haematol 2001; 18 (03) 191-193
• 18 Wiegand G, Hofbeck M, Zenker M, Budde U, Rauch R. Bleeding diathesis in Noonan syndrome: is acquired von Willebrand syndrome the clue?. Thromb Res 2012; 130 (05) e251-e254
• 19 Gokturk B, Guner SN, Kara R. , et al. Would mean platelet volume/platelet count ratio be used as a novel formula to predict 22q11.2 deletion syndrome?. Asian Pac J Allergy Immunol 2016; 34 (02) 166-173
• 20 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; 11: 1183-1189
• 21 Nurden AT, Nurden P. Congenital platelet disorders and understanding of platelet function. Br J Haematol 2014; 165 (02) 165-178
• 22 Mammen EF, Comp PC, Gosselin R. , et al. PFA-100 system: a new method for assessment of platelet dysfunction. Semin Thromb Hemost 1998; 24 (02) 195-202
• 23 Kottke-Marchant K, Corcoran G. The laboratory diagnosis of platelet disorder: an algorithmic approach. Arch Pathol Lab Med 2002; 126 (02) 133-146