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Variants of the Diaphanous-Related Formin 1 (DIAPH-1) gene have recently been reported causing inherited macrothrombocytopenia. The essential/"diagnostic" characteristics associated with the disorder are emerging; however, robust and complete criteria are not established. Here, we report the first cases of DIAPH1-related disorder in Australia caused by the autosomal dominant gain-of-function DIAPH1 R1213X variant formed by truncation of the protein within the diaphanous auto-regulatory domain (DAD) with loss of regulatory motifs responsible for autoinhibitory interactions within the DIAPH1 protein. We affirm phenotypic changes induced by the DIAPH1 R1213X variant to include macrothrombocytopenia, early-onset progressive sensorineural hearing loss, and mild asymptomatic neutropenia. High-resolution microscopy confirms perturbations of cytoskeletal dynamics caused by the DIAPH1 variant and we extend the repertoire of changes generated by this variant to include alteration of procoagulant platelet formation and possible dental anomalies. [ABSTRACT FROM AUTHOR]

Inherited disorders of platelet function (IPFD) and/or number (IPND) are heterogeneous conditions that result in variable mucocutaneous bleeding symptoms as a result of deranged primary haemostasis caused by platelet dysfunction or thrombocytopenia. Diagnosis is important to guide post-operative bleeding prophylactic strategies, to avoid treatment with inappropriate medications, and inform prognosis. Achieving an accurate diagnosis has traditionally been hampered by the requirement of multiple, often complex, laboratory tests that are not always available at single centres. To improve the diagnosis of these disorders a research collaborative was established, the Sydney Platelet Group, that explored an integrated approach combining traditional and contemporary platelet phenotypic and genetic diagnostic platforms available at four Sydney tertiary hospitals. Herein we report the outcomes of the first 50 patients evaluated using this approach. The cohort included 22 individuals with suspected IPFD and 28 with thrombocytopenia. Bleeding scores were higher in individuals with IPFD (mean 5.75; SD 4.83) than those with IPNDs (mean 2.14; SD 2.45). In cases with suspected IPFD, diagnosis to the level of the defective pathway was achieved in 71% and four individuals were found not to have a definitive platelet function defect. Dense granule secretion disorders were the most common platelet pathway abnormality detected (n=5). Mean bleeding scores in these individuals were not significantly different to individuals with defects in other commonly detected platelet pathways (dense granules, signal transduction and 'undetermined'). A molecular diagnosis was achieved in 52% of individuals with IPNDs and 5% with IPFD. Likely pathogenic and pathogenic variants detected included variants associated with extra-haematological complications (DIAPH1, MYH9) and potential for malignancy (ANKRD26 and RUNX1). The level of platelet investigation undertaken by this initiative is currently not available elsewhere in Australia and initial results confirm the utility of this integrated phenotypic-genetic approach., (Copyright © 2019. Published by Elsevier B.V.)

Introduction: Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder that occurs following the administration of heparin and is caused by antibodies to platelet factor 4 and heparin. Diagnosis of HIT is essential to guide treatment strategies using non-heparin anticoagulants and to avoid unwanted and potential fatal thromboembolic complications. This consensus statement, formulated by members of the Thrombosis and Haemostasis Society of Australia and New Zealand, provides an update on HIT pathogenesis and guidance on the diagnosis and management of patients with suspected or confirmed HIT., Main Recommendations: A 4Ts score is recommended for all patients with suspected HIT prior to laboratory testing. Further laboratory testing with a screening immunoassay or confirmatory functional assay is not recommended in individuals with a low 4Ts score. However, if there are missing or unreliable clinical data, then laboratory testing should be performed. A positive functional assay result confirms the diagnosis of HIT and should be performed to confirm a positive immunoassay result. Heparin exposure must be ceased in patients with suspected or confirmed HIT and initial treatment with a non-heparin alternative instituted. Non-heparin anticoagulants (danaparoid, argatroban, fondaparinux and bivalirudin) used to treat HIT should be given in therapeutic rather than prophylactic doses. Direct oral anticoagulants may be used in place of warfarin after patients with HIT have responded to alternative parenteral anticoagulants with platelet count recovery., Changes in Management as a Result of This Statement: These are the first Australasian recommendations for diagnosis and management of HIT, with a focus on locally available diagnostic assays and therapeutic options. The importance of examining both clinical and laboratory data in considering a diagnosis of HIT cannot be overstated., (© 2019 AMPCo Pty Ltd.)

Heparin-induced thrombocytopenia (HIT) remains a challenge, with diagnosis confirmed only by functional assays. The gold standard 14C-serotonin release assay (SRA) is highly sensitive but technically challenging and unsuitable for routine use. We conducted a large study to validate whole blood impedance aggregometry (WBIA) as a suitable diagnostic tool for HIT. WBIA and SRA were used to test 181 samples positive for H-PF4 antibodies by PaGIA or ELISA. Using the same high responder donor, 77 samples were positive by WBIA (aggregation with low-dose but not high-dose heparin). Using the strict definition for SRA positivity, 72 samples were true HIT. In nine samples, serotonin release with high-dose heparin dropped by > 50% but was still >20%; these were retested after a one-half dilution and 8/9 became positive. Ten other samples were discrepant between the two assays: one strongly positive (89% release) and six weakly positive samples by SRA (average release 56%) were WBIA negative. When these samples were retested using a random donor, only two remained SRA positive. Three samples were strongly WBIA positive but SRA negative; two were retested by SRA with 0.5IU/ml heparin and one became positive. Under controlled conditions, using the same selected high-responder donor, WBIA and SRA performed similarly with slightly increased sensitivity of the WBIA when using the strict definition of SRA positivity. WBIA is easy to perform with rapid turn-around time and warrants a multi-laboratory trial to complete its validation as a confirmatory assay for platelet-activating HIT antibodies.

Bernard-Soulier syndrome (BSS) is an extremely rare hereditary bleeding disorder, caused by mutations occurring in the Glycoprotein (GP) Ibalpha, GPIbbeta and GP9 genes that encode for the corresponding subunits of platelet GPIb-V-IX adhesion receptor complex. BSS has been reported in many populations, mostly behaving in an autosomal-recessive manner.While the great majority of BSS mutations are unique to a single individual or family, the GP9 1828A>G Asn45Ser mutation, which we have identified in an undocumented Australian Caucasian, has already been reported in multiple unrelated Caucasian families from various Northern and Central European countries. Haplotype analysis of 19 BSS patients from 15 unrelated Northern European families (including 2 compound heterozygote siblings from a British family previously published, and 17 1828A>G Asn45Ser homozygotes), showed that 14 of these BSS patients from 11 of the 1828A>G Asn45Ser homozygote families share a common haplotype at the chromosomal region 3' to the GP9 gene. Hence, the results suggest that the GP9 1828A>GAsn45Ser mutation in these families is ancient, and its frequent emergence in the European population is the result of a founder effect rather than recurrent mutational events. Association of the 1828A>G Asn45Ser mutation with variant haplotypes in 4 other Northern European BSS families raised the possibility of a second founder event, or rare recombinations in these families. Additional members from these 'atypical' lineages would need to be screened to resolve this question.