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Cancers 14(5), 1261 (2022). doi:10.3390/cancers14051261, Published by MDPI, Basel

Glanzmann Thrombasthenia is a rare platelet function disorder which is characterized by decreased expression and/or dysfunction of the platelet receptor αIIbβ3 (GPIIb/IIIa). The disease is due to alterations in ITGA2B or ITGB3 the genes encoding for the receptor subunits αIIb (GPIIb) and β3 (GPIIIa) and mostly inherited autosomal recessively. We report about a one-year old girl presenting with petechiae and hematomas shortly after birth. Platelet light transmission aggregometry was impaired after stimulation with ADP, arachidonic acid and collagen. Stimulation with ristocetin reached normal values, but showed an undulating course. Flow cytometry revealed severely decreased expression of CD41 (αIIbβ3). Molecular genetic analysis of the candidate genes and family genotyping identified two compound heterozygous variants in Exon 10 of ITGB3: c.1552C>T (p.Gln518*) and c.1639T>G (p.Cys547Gly). According to the guidelines of ACMG the variants were classified as pathogenic (Class 5). The nonsense variant c.1552C>T has not been reported before.

SummaryGlanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder characterised by quantitative and/or qualitative defects of the platelet glycoprotein (GP) IIb/IIIa complex, also called integrin αIIbβ3. αIIbβ3 is well known as a platelet fibrinogen receptor and mediates platelet aggregation, firm adhesion, and spreading. This study describes the molecular genetic analyses of 19 patients with GT who were diagnosed on the basis of clinical parameters and platelet analyses. The patients’ bleeding signs include epistaxis, mucocutaneous bleeding, haematomas, petechiae, gastrointestinal bleeding, and menorrhagia. Homozygous or compound heterozygous mutations in ITGA2B or ITGB3 were identified as causing GT by sequencing of genomic DNA. All exons including exon/intron boundaries of both genes were analysed. In a patient with an intronic mutation, splicing of mRNA was analysed using reverse transcriptase (RT)-PCR of platelet-derived RNA. In short, 16 of 19 patients revealed 27 different mutations (ITGA2B: n=17, ITGB3: n=10). Seventeen of these mutations have not been published to date. Mutations in ITGA2B or ITGB3 were identified as causing GT in 16 patients. We detected a total of 27 mutations in ITGA2B and ITGB3 including 17 novel missense, nonsense, frameshift and splice site mutations. In addition, three patients revealed no molecular genetic anomalies in ITGA2B or ITGB3 that could explain the suspected diagnosis of GT. We assume that these patients may harbour defects in a regulatory element affecting the transcription of these genes, or other proteins may exist that are important for activating the αIIbβ3 complex that may be affected.

To the editor: During the last few years, the Ca2+ sensor stromal interaction molecule 1 (STIM1) and the channel protein Orai1 have emerged as critical components of store operated Ca2+ entry in platelets.[1][1] In human platelets, both proteins were detected in dense granules and lysosome-related

Background Numerous trials have demonstrated high efficacy and safety of artemisinin-based combination therapy (ACT) under supervised treatment. In contrast, effectiveness studies comparing different types of ACT applied unsupervised are scarce. The aim of this study was to compare effectiveness, tolerability and acceptance of artesunate plus amodiaquine (ASAQ) against that of artemether-lumefantrine (AL) in Ghanaian children with uncomplicated Plasmodium falciparum malaria. Methods A randomized open-label trial was conducted at two district hospitals in the Ashanti region, Ghana, an area of intense malaria transmission. A total of 246 children under five years of age were randomly assigned to either ASAQ (Arsucam®) or AL (Coartem®). Study participants received their first weight-adjusted dose under supervision. After the parent/guardian was advised of times and mode of administration the respective three-day treatment course was completed unobserved at home. Follow-up visits were performed on days 3, 7, 14 and 28 to evaluate clinical and parasitological outcomes, adverse events, and haematological recovery. Length polymorphisms of variable regions of msp1 and msp2 were determined to differentiate recrudescences from reinfections. Acceptance levels of both treatment regimens were assessed by means of standardized interviews. Results Adequate clinical and parasitological responses after AL and ASAQ treatment were similar (88.3% and 91.7%, respectively). Interestingly, more late clinical failures until day 28 occurred in AL-treated children than in those who received ASAQ (17.5% and 7.3%, respectively; Hazard Ratio 2.41, 95% CI 1.00–5.79, p < 0.05). Haematological recovery and drug tolerability were not found to be significantly different in both study arms. The acceptance of treatment with ASAQ was higher than that with AL (rank-scores 10.6 and 10.3, respectively; p < 0.05). Conclusion Unobserved AL and ASAQ treatment showed high adequate clinical and parasitological responses, though AL was inferior in preventing late clinical failures.