Disruption of AP3B1 by a chromosome 5 inversion: a new disease mechanism in Hermansky-Pudlak syndrome type 2.

Background: Hermansky-Pudlak syndrome 2 (HPS2; OMIM #608233) is a rare, autosomal recessive disorder caused by loss-of-function genetic variations affecting AP3B1, which encodes the β3A subunit of the adaptor-related protein complex 3 (AP3). Phenotypic characteristics include reduced pigmentation, absent platelet dense granule secretion, neutropenia and reduced cytotoxic T lymphocyte (CTL) and natural killer (NK) cell function. To date HPS2 has been associated with non-synonymous, stop-gain or deletion-insertion nucleotide variations within the coding region of AP3B1.

Clinical phenotype, laboratory features and genotype of 35 patients with heritable dysfibrinogenaemia.

Heritable dysfibrinogenaemia (HD) is a rare qualitative disorder of fibrinogen (FGN). To better describe the clinical, laboratory and genotypic spectrum of HD, we evaluated 35 subjects identified at two UK centres using laboratory criteria. 12/35(34%) subjects with HD experienced bleeding (bleeding score >1 at any site), 3/35(9%) thrombosis and 20/35(57%) were asymptomatic.

Low serum iron levels are associated with elevated plasma levels of coagulation factor VIII and pulmonary emboli/deep venous thromboses in replicate cohorts of patients with hereditary haemorrhagic telangiectasia.

Background: Elevated plasma levels of coagulation factor VIII are a strong risk factor for pulmonary emboli and deep venous thromboses.

Objectives: To identify reversible biomarkers associated with high factor VIII and assess potential significance in a specific at-risk population.

Patients/methods: 609 patients with hereditary haemorrhagic telangiectasia were recruited prospectively in two separate series at a single centre.

Monitoring heparin anticoagulation in the acute phase response.

The anticoagulant effect of unfractionated heparin (UFH) is monitored using the activated partial thromboplastin time (APTT). An APTT of 1.5-2.

Endothelial cell processing and alternatively spliced transcripts of factor VIII: potential implications for coagulation cascades and pulmonary hypertension.

Background: Coagulation factor VIII (FVIII) deficiency leads to haemophilia A. Conversely, elevated plasma levels are a strong predictor of recurrent venous thromboemboli and pulmonary hypertension phenotypes in which in situ thromboses are implicated. Extrahepatic sources of plasma FVIII are implicated, but have remained elusive.

Low-density lipoprotein receptor-related protein polymorphisms in patients with elevated factor VIII coagulant activity and venous thrombosis.

Elevated factor VIII coagulant activity (FVIII:C) levels (>150 IU/dl) represent a prevalent independent risk factor for venous thromboembolism (VTE). Low-density lipoprotein receptor-related protein (LRP) is involved in factor VIII clearance in vivo, and elevated FVIII:C was a feature of the LRP knockout mouse model. Three coding polymorphisms of LRP1 (exon 3, C766T; exon 14, A217V; and exon 39, D2080N), together with an insertion/deletion polymorphism within the first intron of lipoprotein receptor-associated protein (LRPAP1), have been identified.

Beta-adrenergic receptor polymorphisms in patients with elevated factor VIII levels with venous thrombosis.

Beta-blockers significantly reduce elevated factor VIII (FVIII) levels in patients with venous thromboembolism (VTE). To determine whether beta-adrenergic receptors are important in the aetiology of high FVIII levels, we investigated four coding polymorphisms of the beta1- and beta2-receptor genes in 64 patients with high FVIII and VTE and 100 healthy controls. Genotypic and allelic frequencies were not significantly different between the patient and control groups.

A Tyr346-->Cys substitution in the interdomain acidic region a1 of factor VIII in an individual with factor VIII:C assay discrepancy.

The interdomain acidic region a1 is a unique structural feature of coagulation factor VIII (FVIII) and may mediate the proteolytic activation of FVIII and the inactivation of FVIIIa. We report an individual with a Tyr346-->Cys substitution within region a1, who presented with a one-stage FVIII activity (FVIII:C) of 0.34 iu/ml (normal range 0.

Genotype at the secretor blood group locus is a determinant of plasma von Willebrand factor level.

Previous reports on the effect of Secretor and Lewis blood groups on plasma factor VIII-von Willebrand factor (FVIII-VWF) levels have produced conflicting findings. To determine whether either or both loci can influence plasma FVIII-VWF complex levels, we studied the relationship between Secretor and Lewis genotypes, determined definitively using polymerase chain reaction-restriction fragment length polymorphism analysis, and plasma FVIII coagulant activity (FVIII:C) and VWF antigen (VWF:Ag) levels in 136 healthy volunteers. Overall, significantly higher VWF:Ag levels were found in those individuals homozygous for the Se allele (genotype SeSe) than in those heterozygous for the Se allele (P < 0.

Amount of H antigen expressed on circulating von Willebrand factor is modified by ABO blood group genotype and is a major determinant of plasma von Willebrand factor antigen levels.

To investigate whether the effect of ABO blood group on plasma von Willebrand factor (vWF) levels is mediated by the ABH antigenic determinants carried on N-linked glycans of vWF, we studied 158 group A and group O healthy volunteers. vWF antigen (vWF:Ag) and factor VIII antigen (FVIII:Ag) levels were highest in A(1)A(1) individuals and higher in A(1)O(1) than in A(2)O(1) or O(1)O(1) individuals. Plasma A transferase activity and the amount of A antigen expressed per unit vWF (AvWF) were significantly higher in A(1)A(1) than in A(1)O(1) individuals and higher in A(1)O(1) than in A(2)O(1) individuals.