A bleeding diathesis is a common feature of Noonan syndrome, and various coagulation abnormalities have been reported. Platelet function has never been carefully investigated.
The degree of bleeding diathesis in a cohort of patients with Noonan syndrome was evaluated by a validated bleeding score and investigated with coagulation and platelet function tests. If ratios of prothrombin time and/or activated partial thromboplastin time were prolonged, the activity of clotting factors was measured. Individuals with no history of bleeding formed the control group.
The study population included 39 patients and 28 controls. Bleeding score was ≥2 (ie, suggestive of a moderate bleeding diathesis) in 15 patients (38.5%) and ≥4 (ie, suggestive of a severe bleeding diathesis) in 7 (17.9%). Abnormal coagulation and/or platelet function tests were found in 14 patients with bleeding score ≥2 (93.3%) but also in 21 (87.5%) of those with bleeding score <2. The prothrombin time and activated partial thromboplastin time were prolonged in 18 patients (46%) and partial deficiency of factor VII, alone or in combination with the deficiency of other vitamin K–dependent factors, was the most frequent coagulation abnormality. Moreover, platelet aggregation and secretion were reduced in 29 of 35 patients (82.9%, P < .01 for all aggregating agents).
Nearly 40% of patients with the Noonan syndrome had a bleeding diathesis and >90% of them had platelet function and/or coagulation abnormalities. Results of these tests should be taken into account in the management of bleeding or invasive procedures in these patients.
Author names: Mehmet Yekta ONCEL, M.D.1, Murat DERBENT, Prof.2*, Namik OZBEK, Prof.3 1Division of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey 2Department of Pediatrics and Genetics, Baskent University Faculty of Medicine, Ankara, Turkey 3Department of Pediatric Hematology, Ankara Child Health and Diseases, Hematology and Oncology Training and Research Hospital, Ankara, Turkey.
* Deceased during preparation of this letter.
To the Editor, We read with great interest the recent article by Artoni et al.1 revealing coagulation and platelet function testing abnormalities in children with Noonan syndrome (NS). In this manuscript, they correlated these abnormalities with the severity of bleeding as assessed by a validated bleeding score, and explored the potential of therapeutic options to prevent or control bleeding. The study disclosed that prothrombin time (PT) and activated partial thromboplastin time (aPTT) were prolonged in 18 patients (46%) and partial deficiency of factor VII, alone or in combination with the deficiency of other vitamin K-dependent factors, was the most frequent coagulation abnormality. In a recent study, we sought to evaluate hematological and coagulation parameters [PT, aPTT, INR, bleeding time with ADP-Collagen (BT-I) and epinephrine-Collagen (BT-II) obtained by Platelet Function Analyzer (PFA- 100), levels of Factor (F) VIII, FXI, FXII, and protein C] in 30 clinically diagnosed cases.2 Genetic analysis revealed PTPN11 mutations in 11 (36.7%) of the 30 NS cases. Hematological parameters were compared to those of a control group of 30 healthy children. None of the 30 NS patients exhibited thrombocytopenia; however, the NS group had a significantly lower mean platelet count and significantly lower mean activity levels of FXI, FXII, and protein C compared to the control group. The NS group results for PT, aPTT, INR, and BT II were also statistically different from the corresponding control findings. However, BT-I obtained with ADP-collagen closure time by means of PFA-100 was similar in patient and control groups. In the study by Artoni et al,1 platelet function tests obtained by Chrono-log lumi aggregometer using platelet rich plasma also revealed normal secretion of platelets in response to ADP, as in our study. However, since Chrono-log machine has been designed to measure platelet functions by means of whole blood, the results of the study by Artoni et al. using platelet rich plasma should be interpreted with caution.3 Furthermore, having defective platelet function obtained by a platelet function analyzer does not necessarily indicates a bleeding problem. It is well known that platelet functions of neonates obtained by aggregometric method as in the study by Artolni et al. are less mature than older children4; however, bleeding time of them, both with template method and PFA, is shorter due to several factors such as increased high molecular weight-von Willebrand factor, increased hematocrit and others5. In our study, results of BT-II were longer in the NS patients compared to those of controls. However, even though they were longer than controls, the results were within normal reference ranges in most of the patients. Since in the study by Artoni et al. there is no reference concerning normal ranges of platelet function tests, it is not possible to draw conclusion whether the results of these tests were within the normal range or not. Confirming our results, 24 of the 30 NS patients underwent corrective heart surgery in our center and none of these individuals had a clinical bleeding problem. In our study, we reached a conclusion that coagulation tests including platelet function analysis by means of PFA is necessary for all children with NS. Since PFA has a strong negative predictive value, further testing of platelet functions is unnecessary in patients who had normal PFA values. We suggested that, if these initial tests are normal, complications related to coagulation are unlikely and more extensive testing such as platelet function analysis by means of agonists such as ADP, epinephrine, TRAP is unnecessary.
References
1. Artoni A, Selicorni A, Passamonti SM, et al. Hemostatic Abnormalities in Noonan Syndrome. Pediatrics 2014; 133:e1299-e1304.
2. Derbent M, Oncel 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.
3. Harrison P, Lordkipanidz M. Testing platelet function. Hematol Oncol Clin North Am. 2013; 27(3):411-441.
4. Ucar T, Gurman C, Arsan S, Kemahli S. Platelet aggregation in term and preterm newborns. Pediatr Hematol Oncol. 2005; 22(2):139-145.
5. Boudewijns M, Raes M, Peeters V, Mewis A, Cartuyvels R, Magerman K, et al. Evaluation of platelet function on cord blood in 80 healthy term neonates using the Platelet Function Analyser (PFA-100); shorter in vitro bleeding times in neonates than adults. Eur J Pediatr 2003; 162(3):212- 213.
Conflict of Interest:
None declared