Clinical and laboratory phenotype associated with the aspirin‐like defect – response to Dragani et al

Dr Dragani and colleagues question whether the criteria to diagnose Aspirin-like defect (ALD) as recently published by our group (Rolf et al, 2009) are rated correctly. In contrast to our approach they propose as main criteria the measurement of serum thromboxane B2 (TXB2) as mandatory for the diagnosis and phenotypic classification of ALD while other criteria chosen by our group, such as platelet aggregation induced by arachidonic acid (AA), should represent an optional method only or – with respect to PFA-100 and ADP aggregometry – should be excluded as a whole. Their criticism is mainly based on arguments depicted from the physiological biochemical pathway of AA metabolism leading to platelet activation via the pro-haemostatic function and regulation of cyclooxygenase-1 (COX-1)-dependent thromboxane-A and -B (TXA, TXB) formation. The cited biochemical pathways are correct and we fully agree that stable inactive TXB2 is the endpoint of the whole COX-1 dependent AA cascade. However, with respect to our methodological approach in diagnosing ALD we want to make some important points worthy of further debate. To the best of our knowledge, no published data exist regarding the reliability of serum TXB2 determination in patients who belong to the heterogenous group of the inherited ALD. Despite the variability in test procedures and in interpretation of test results, until now, the investigation of platelet aggregation in platelet rich plasma by the turbidimetric method represents the most established method in the coagulation laboratories for assessment of platelet function worldwide (Moffat et al, 2005;Streif et al, 2007). Based on extended experiences with this method the ‘British Guidelines for Diagnostics and Treatment of Patients with Hereditary Thrombocytopathies’ recommended performing aggregometry using AA as agonist to screen patients for the presence of AA-pathway defects (Bolton-Maggs et al, 2006). This was the principal reason why we selected the pathological results of AA-induced aggregation as the main mandatory criteria for the diagnosis of ALD. Especially as paediatricians, we share the concerns of Dr Dragani and colleagues that turbidimetric aggregometry requires a considerable amount of blood. In addition, we are aware that also other authors agree with Dragani et al and have stressed that whole blood methods admittedly are able to detect inherited AA-pathway defects but are hampered by the limitation of poor standardization and therefore should be further evaluated (McGlasson & Fritsma, 2009). Dragani et al also raise the point that the PFA 100® test is not recommended for monitoring aspirin-treated patients and that the test results depend not only on the function and numbers of platelets but also on extra-platelet factors such as the erythrocyte count and the von Willebrand factor antigen level. We completely agree with their critical assessment of this method and therefore the results of the PFA 100® test were included only as optional criteria for the diagnosis of the inherited platelet function disorder investigated. However, we cannot follow the proposal of Dragani and colleagues to exclude the PFA-100 and ADP aggregometry as a whole. ALD is a heterogenous group of underlying defects which awaits further molecular work-up and more subtle classification. While the value of PFA-100 and ADP aggregometry has critically been elucidated in aspirin-treated patients by Dragani et al and others, data are inconsistent within small series of patients with ALD. Our approach also is in agreement with the recommendations of the Platelet Physiology Subcommittee of Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis (Hayward et al, 2006) and with a recently published review of screening tests for platelet functions (Harrison & Mumford, 2009). The inclusion of PFA 100 test® results in our diagnostic work-up also reflects the fact that this test is widely used as screening test for disturbances of primary haemostasis in the coagulation laboratories of the German-speaking countries (Streif et al, 2007). In summary, we regard our approach for diagnosing ALD and the criteria selected as being in line with present international recommendations. As long as no convincing evidence is presented on the significance of TXB2 serum determinations in patients with ALD (nota bene: not in aspirin treated patients!) we would further propose and adhere to the classification schema and criteria as published by our group.