International collaboration as a tool for diagnosis of patients with inherited thrombocytopenia in the setting of a developing country

Abstract

Molinas FC, Heller PG. International collaboration as a tool for diagnosis of patients with inherited thrombocytopenia in the setting of a developing country. J Thromb Haemost 2012; 10: 1653-61.Summary. Background: Inherited thrombocytopenias (ITs) are heterogeneous genetic disorders that frequently represent a diagnostic challenge. The requirement of highly specialized tests for diagnosis represents a particular problem in resourcelimited settings. To overcome this difficulty, we applied a diagnostic algorithm and developed a collaboration program with a specialized international center in order to increase the diagnostic yield in a cohort of patients in Argentina. Methods: Based on the algorithm, initial evaluation included collection of clinical data, platelet size, blood smear examination and platelet aggregation tests. Confirmatory tests were performed according to diagnostic suspicion, which included platelet glycoprotein expression, immunofluorescence for myosin-9 in granulocytes and platelet thrombospondin-1 and molecular screening of candidate genes. Results: Thirty-one patients from 14 pedigrees were included; their median age was 32 (4-72) years and platelet count 72 (4-147) · 10 9 L )1 . Autosomal dominant inheritance was found in nine (64%) pedigrees; 10 (71%) had large platelets and nine (29%) patients presented with syndromic forms. A definitive diagnosis was made in 10 of 14 pedigrees and comprised MYH9-related disease in four, while classic and monoallelic Bernard-Soulier syndrome, gray platelet syndrome, X-linked thrombocytopenia, thrombocytopenia 2 (ANKRD26 mutation) and familial platelet disorder with predisposition to acute myelogenous leukemia were diagnosed in one pedigree each. Conclusions: Adoption of an established diagnostic algorithm and collaboration with an expert referral center proved useful for diagnosis of IT patients in the setting of a developing country. This initiative may serve as a model to develop international networks with the goal of improving diagnosis and care of patients with these rare diseases.

Mechanisms underlying platelet function defect in a pedigree with familial platelet disorder with a predisposition to acute myelogenous leukemia: potential role for candidate RUNX1 targets

“…Five or fewer a-granules per platelet was used as a stringent cut-off value for a-granule deficiency, as previously reported [18,19,22]. A mild but significant increase in the percentage of platelets with severe a-granule reduction was found in patients as compared with controls (15% AE 2.3% vs. 3.1% AE 1%, P = 0.03, Mann-Whitney-Wilcoxon test) (Fig.…”

“…Platelets were identified by F-actin labeling with tetramethylrhodamine isothiocyanate-conjugated phalloidin (Sigma-Aldrich), and at least 200 platelets were examined under a fluorescence microscope (Axiostar Plus; Zeiss, G€ ottingen, Germany) by two independent observers. For analysis, platelets were classified, according to the number of TSP1-positive granules, into platelets showing more than five granules and those showing five or fewer granules, as previously described [18,19].…”

Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and -granule deficiency

“…[12][13][14] In these subjects, macrothrombocytopenia and α-granule deficiency was sporadic or inherited as an autosomal dominant trait (Online Supplementary Table S3). All these patients had moderate to severe thrombocytopenia and most of them had increased MPV.…”

“…11 A clinical and cytopathological diagnosis of GPS was made in 6 of these probands (Families 1-5 and 11), 4 of which (Families 1, 3, 4, and 5) had been previously reported. [12][13][14] All the patients underwent immunofluorescence analysis of α-granule secretory proteins and DNA sequencing of NBEAL2 (see below). Their clinical and laboratory findings are reported in more detail in the Online Supplementary Appendix and Online Supplementary Tables S1-S3.…”

Exome sequencing reveals a thrombopoietin ligand mutation in a Micronesian family with autosomal recessive aplastic anemia

“…[25][26][27][28][29] Autosomal dominant thrombocytopenia is known to be caused by mutations in the ANKRD26, MASTL, ACBD5, and cytochrome c (CYCS) genes. [30][31][32][33][34][35][36] Mutations in the THPO receptor (MPL) cause various hematologic disorders, including congenital amegakaryocytic thrombocytopenia 37 and thrombocythemia. 38 The online version of this article contains a data supplement.…”