Measurements of immature platelets with haematology analysers are of limited value to separate immune thrombocytopenia from bone marrow failure

Detection of immature platelets in the circulation may help to dissect thrombocytopenia due to platelet destruction from bone marrow failure (BMF ). We prospectively tested the predictive value of immature platelets, measured as immature platelet fraction (IPF ) on the XE‐5000 (Sysmex, Kobe, Japan) or percentage of reticulated platelets (rPT ) on the CD Sapphire (Abbott Diagnostics, Santa Clara, CA, USA) to separate immune thrombocytopenia (ITP ) from BMF (leukaemia, myelodysplastic syndrome, aplastic anaemia). We analysed 58 samples of patients with BMF , 47 samples of patients with ITP and 97 controls. Median rPT (CD Sapphire) was increased to 9·0% in ITP and to 10·9% in BMF , compared to 1·9% in controls. Median IPF (XE‐5000) was 16·2% in ITP , 10·2% in BMF and 2·5% in controls. We found an inverse correlation between high fractions of immature platelets and low platelet counts in thrombocytopenic samples regardless of the diagnosis. In conclusion, we observed a broad overlap of immature platelets between ITP and BMF , which may be caused by an accelerated release of immature platelets in any thrombocytopenic state and decreased production in many patients with ITP . Despite this, IPF (XE‐5000) had some power to discriminate ITP from BMF , whereas rPT (CD Sapphire) was of no predictive value.     

Advances in understanding the pathogenesis of familial myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are generally acquired as a result of a somatic stem cell mutation leading to clonal expansion of myeloid precursors. In addition to sporadic cases, familial MPN occurs when one or several MPN affect different relatives of the same family. MPN driver mutations (JAK2, CALR, MPL) are somatically acquired also in familial cases, so a genetic predisposition to acquire one of the MPN driver mutations would be inherited, even though the causative germline mutations underlying familial MPN remain largely unknown. Recently some germline variants [ATG2B and GSKIP duplication, RBBP6 mutations, SH2B3 (LNK) mutations], which can cause familial MPN, have been reported but these mutations are rare and do not explain most familial cases. Patients with familial MPN show the same clinical features and suffer the same complications as those with sporadic disease. This review aims to offer up‐to‐date information regarding the genetics of familial MPN.     

Validation of Modelflow Estimates of Cardiac Output in Hemodialysis Patients

Volume‐clamp technology (e.g. Finometer) has become a popular method of collecting continuous, non‐invasive, hemodynamic information during hemodialysis. There is minimal data validating the technique in this patient group. A gold standard cardiac output measurement can be obtained using ultrasound dilution in patients with arterio‐venous fistulae. Continuous cardiac output was measured in 124 hemodialysis sessions in 27 patients using a volume‐clamp device (Finometer PRO). Ultrasound dilution measurement was first taken at baseline (Transonic HD03), then used to calibrate the Finometer. Ultrasound dilution measurement was repeated 2 h into hemodialysis to assess drift following calibration. Pearson’s correlation and Bland–Altman statistics, modified for repeated measures, were used to assess agreement between methods. Linear mixed models were constructed to identify factors that could explain session‐level and patient‐level variation in agreement. For baseline cardiac output before calibration, agreement between volume‐clamp and ultrasound dilution measurements was poor, at 25 ± 75% (correlation 0.26, P < 0.001). There was significant variation in agreement between patients, with age, peripheral vascular disease and hemodialysis vintage contributing to poorer agreement. For cardiac output 2 h after calibration, agreement was ?5.2 ± 57.5% (correlation 0.6, P < 0.001). Dynamic changes in blood pressure and fluid balance during hemodialysis resulted in greater drift over time after calibration. There was a large error, both random and systematic, in volume‐clamp estimates of absolute, pre‐calibration cardiac output in this prevalent hemodialysis population. There was minimal bias and reasonable correlation for cardiac output 2 h post‐calibration, but limits of agreement remained too wide to meet current clinical standards.     

Identification and comparison of insulin pharmacokinetics injected with a new 4‐mm needle vs 6‐ and 8‐mm needles accounting for endogenous insulin and C‐peptide secretion kinetics in non‐diabetic adult males

Aims/Introduction

Many patients with diabetes now use 5‐, 6‐ or 8‐mm needles for insulin injection. However, it is unclear whether needle length, particularly for shorter needles, affects the pharmacokinetic properties of insulin.

Materials and Methods

This was a three‐way, randomized, cross‐over, single‐center study involving 12 healthy Japanese adult males (age 27.4 ± 4.14 years; weight 64.2 ± 5.2 kg; body fat percentage 18.2 ± 1.5%). Participants received a subcutaneous (abdomen) dose of insulin lispro (1.5 U for participants weighing 55 to <65.0 kg; 2.0 U for participants weighing 65.0 to <80.0 kg) delivered using a 32‐G × 4 mm (32G × 4), 31‐G × 8 mm (31G × 8) or 32‐G × 6 mm (32G × 6) needle with a 3–7‐day washout between doses. Pharmacokinetic parameters of exogenous insulin were identified using non‐linear least squares, where the total insulin concentration was fit to the measured plasma insulin concentration using an overall combined model that accounted for C‐peptide/insulin secretion in addition to the injected dose.

Results

Maximum concentration and area under the curve for 0 to infinity min for insulin were bioequivalent for the 32G × 4 needle relative to the 32G × 6 and the 31G × 8 needles. The time to the maximum insulin concentration was bioequivalent for the 32G × 4 needle relative to the 32G × 6 needle, but not the 31G × 8 needle.

Conclusions

The use of 4‐mm needles is unlikely to change the pharmacokinetic properties of insulin when injected subcutaneously in adults. This trial was registered with UMIN‐CTR (no. UMIN000004469).     

Family history of diabetes,lifestyle factors,and the 7‐year incident risk of type 2 diabetes mellitus in middle‐aged Japanese men and women

Aims/Introduction

This cohort study of middle‐aged Japanese participants investigated the relationship between family history of diabetes, the incident risk of type 2 diabetes and the interaction of these variables with other factors.

Materials and Methods

Study participants were 3,517 employees (2,037 men and 1,480 women) of a metal products factory in Japan. Baseline health examinations included questions about medical history, physical examination, anthropometric measurements, questions about lifestyle factors, such as smoking, alcohol consumption and habitual exercise, and a self‐administered diet history questionnaire. Family history of diabetes was defined as having at least one‐first‐degree relative with diabetes. The incidence of diabetes was determined in annual medical examinations over a 7‐year period. Hazard ratios (HRs) for type 2 diabetes were estimated by Cox proportional hazards analysis.

Results

Of the 3,517 participants, 630 (18%) had a family history of diabetes mellitus. During the study, 228 participants developed diabetes. The age and sex‐adjusted HR for type 2 diabetes in participants with a family history of diabetes was 1.82 (95% confidence interval 1.36–2.43) as compared with those without a family history of diabetes. HRs did not change after adjustment for body mass index and lifestyle factors. We found no interactions with body mass index, insulin resistance, pancreatic β‐cell function or lifestyle factors.

Conclusions

Family history of diabetes was associated with the incident risk of diabetes, and these associations were independent of other risk factors, such as obesity, insulin resistance, and lifestyle factors in Japanese men and women.     

Diversity in Mechanisms of Endothelium‐Dependent Vasodilation in Health and Disease

Small arterioles (40–150 μm) contribute to the majority of vascular resistance within organs and tissues. Under resting conditions, the basal tone of these vessels is determined by a delicate balance between vasodilator and vasoconstrictor influences. Cardiovascular homeostasis and regional tissue perfusion is largely a function of the ability of these small blood vessels to constrict or dilate in response to the changing metabolic demands of specific tissues. The endothelial cell layer of these microvessels is a key modulator of vasodilation through the synthesis and release of vasoactive substances. Beyond their vasomotor properties, these compounds importantly modulate vascular cell proliferation, inflammation, and thrombosis. Thus, the balance between local regulation of vascular tone and vascular pathophysiology can vary depending upon which factors are released from the endothelium. This review will focus on the dynamic nature of the endothelial released dilator factors depending on species, anatomic site, and presence of disease, with a focus on the human coronary microcirculation. Knowledge how endothelial signaling changes with disease may provide insights into the early stages of developing vascular inflammation and atherosclerosis, or related vascular pathologies.