Long-term imatinib treatment does not cause testicular toxicity in male adolescents with chronic myeloid leukemia and in a juvenile rat model.

BACKGROUND: The impact of exposure to the tyrosine kinase inhibitor (TKI) imatinib (IMA) on the male reproductive endocrine system is still discussed controversially. We therefore investigated testosterone (Testo) and inhibin B (InB) in blood serum from male adolescents with chronic myeloid leukemia (CML) under long-term TKI treatment. Also long-term exposure to TKIs was studied in a juvenile rat model. METHODS: Serum was collected at 3 months intervals from 13 boys (age: 7.8-18.9 years, median: 12.8 years) with CML receiving TKI treatment over 3-58 months (median: 18 months). 4 weeks (w) old male rats were exposed, either chronically or intermittently, via the drinking water to a standard (SD) and a high dose (=2-fold SD) of IMA, dasatinib (DASA), or bosutinib (BOSU) over a 10 w period. Controls received water only. Animals were sacrificed after 2 w (prepubertal), 4 w (pubertal), and 10 w (postpubertal) of exposure. Testo and InB serum levels were measured by ELISA. RESULTS: Boys exhibited Testo and InB levels within normal age-related reference ranges and no pattern of rising or falling levels during TKI treatment could be observed. In rats, Testo levels under IMA exposure tended to be non-significantly lowered at postpubertal age compared to controls while no significant differences were found under DASA and BOSU exposure. Animals' InB levels did not significantly differ from controls for all TKIs, at all doses, and by all application schemes tested. CONCLUSION: With the limitation that the number of individuals tested was rather small, testicular toxicity due to TKI seems unlikely as no alterations of Testo and InB blood levels neither in male adolescent patients nor in rats under long-term TKI exposure was observed.

Desmopressin testing in haemophilia A patients and carriers: results of a multi centre survey.

INTRODUCTION: Desmopressin (DDAVP) testing (DT) in patients (pts) with haemophilia A (HA) and carriers (CHA) is up to now not standardized. This prompted us to evaluate results of DT carried out between 1996 and 2011 in centres of the Competence Network Haemorrhagic Diatheses East. PATIENTS AND METHOD: An increase of the factor VIII activity (FVIII) above 50% or at least the two fold of initial values within 120 min after DDAVP was defined as complete response (CR). Data from 80 patients (31 children, 49 adults) of whom 64 suffered from HA (sub-HA: n=48; mild: n=14; moderate: n=2) and 16 patients CHA were evaluated. RESULTS: In 34 patients DDAVP was given i.v. (dose range: 0.26-0.6 µg/kg body weight, mean: 0.33), in 31 intranasally (i.n. 300-600 µg) and in 15 s.c. (15-40 µg). The maximal FVIII increase was reached 60 min after DDAVP. For i.v. application the mean FVIII increase was 3.1-fold, for i.n. 2.1-fold and for s.c. 2.4-fold. A CR was detected in 71 patients, a non-response in 9. Mild side effects such as flush, headaches or nausea were observed in 11 patients (14%). CONCLUSION: For desmopressin testing in patients with haemophilia A and carriers i.v. application at 0.3 µg/kg body weight and the determination of FVIII before and 60 min after desmopressin infusion is recommended.

Therapy refractory menorrhagia as first manifestation of Hermansky-Pudlak syndrome.

INTRODUCTION: Oculocutaneous albinism (OCA) in combination with a platelet function defect caused by a disturbed release reaction from platelet δ-granules (storage pool defect - SPD) is typical for the autosomal recessive inherited Hermansky-Pudlak syndrome (HPS). CASE REPORT: A girl (age: 13 years) with OCA was hospitalized with transfusion-requiring menorrhagia. The suspicion of HPS was confirmed by results of lumi-aggregometry. Suspecting a disorder in primary haemostasis treatment with tranexamic acid (10 mg/kg body weight every 8 h i. v.), desmopressin (0.3 µg/kg body weight every 8 to 12 h) and hormonal therapy (norethisterone) was started but the menorrhagia persisted. Clinical response was finally achieved by a single injection of 100 µg/kg body weight recombinant factor VIIa (rFVIIa). CONCLUSION: The diagnosis of HPS should be suspected in patients with OCA and bleeding symptoms and is confirmed by the proof of SPD. In case of absent clinical response to desmopressin the application of rFVIIa should be considered. Hormones and antifibrinolytics are useful options in the treatment of extensive menorrhagia.

Evaluation of desmopressin effect on primary haemostasis in pediatric patients with aspirin-like defect as hereditary thrombocytopathy.

OBJECTIVES: Despite about 3 decades of clinical experience with the therapy of inherited thrombocytopathies (HTP) with desmopressin (DDAVP) the mechanisms of haemostatic effects of DDAVP in these diseases remain unclear. Therefore platelet function diagnostics was carried out in whole blood (WB) from children with aspirin-like defect as one of the clinically mild forms of HTP after DDAVP administration. DESIGN AND METHODS: 11 children (age range: 3-16 years) were treated with DDAVP i.v. (0.3 µg/kg as short infusion). Before, after 120, and 240 min of DDAVP administration the following parameters were measured: platelet aggregation (PA) and ATP release induced by ADP, collagen, ristocetin and thrombin; PFA-100 closure times (CT), factor VIII activity (FVIII:C), Von Willebrand factor antigen (VWF:Ag), collagen binding activity (VWF:CB) and blood count. RESULTS: PA, ATP release and blood count were not influenced by DDAVP administration. PFA-100 CTs were markedly reduced at 120 and 240 min after DDAVP, respectively. FVIII:C, VWF:Ag and VWF:CB were increased after 120 min. CONCLUSION: The DDAVP-induced improvement of primary haemostasis in patients with aspirin-like defect is mainly due to the marked increase of the VWF. For the evaluation of the clinical effect of DDAVP administration in patients with aspirin-like defect the investigation of a larger group of patients is needed.