An Approach to the Investigation of Thrombocytosis: Differentiating between Essential Thrombocythemia and Secondary Thrombocytosis.

Background: Thrombocytosis is a common reason for referral to Hematology. Differentiating between secondary causes of thrombocytosis and essential thrombocythemia (ET) is often clinically challenging. A practical diagnostic approach to identify secondary thrombocytosis could reduce overinvestigation such as next generation sequencing (NGS) panel. Methods and Results: All adult patients with thrombocytosis (≥450 × 109/L) who underwent molecular testing at a single tertiary care centre between January 1, 2018 and May 31, 2021 were evaluated. Clinical and laboratory variables were compared between patients with secondary thrombocytosis vs. ET. Clinical variables included smoking, thrombosis, splenectomy, active malignancy, chronic inflammatory disease, and iron deficiency anemia. Laboratory variables included complete blood count (CBC), ferritin, and myeloid mutations detected by NGS. The overall yield of molecular testing was 52.4%; 92.1% of which were mutations in JAK2, CALR, and/or MPL. Clinical factors predictive of ET included history of arterial thrombosis (p < 0.05); active malignancy, chronic inflammatory disease, splenectomy, and iron deficiency were associated with secondary thrombocytosis (p < 0.05). A diagnosis of ET was associated with higher hemoglobin, mean corpuscular volume (MCV), red cell distribution width (RDW), and mean platelet volume (MPV), while secondary thrombocytosis was associated with higher body mass index, white blood cells, and neutrophils (p < 0.01). Conclusion: A practical approach to investigating patients with persistent thrombocytosis based on clinical characteristics such as active malignancy, chronic inflammatory disease, splenectomy, and iron deficiency may assist in accurately identifying patients more likely to have secondary causes of thrombocytosis and reduce overinvestigation, particularly costly molecular testing.

Secondary causes of elevated hemoglobin in patients undergoing molecular testing for suspected polycythemia vera in southwestern Ontario: a chart review.

BACKGROUND: Molecular testing for JAK2 mutations is part of the standard diagnostic workup for patients with suspected polycythemia vera. We sought to characterize evolving practice patterns in the investigation of erythrocytosis and the prevalence of secondary causes, including use of medications such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, among patients who underwent molecular testing. METHODS: We reviewed charts of all consecutive patients investigated for erythrocytosis (hemoglobin > 160 g/L for women, > 165 g/L for men) with JAK2 testing between 2015 and 2021 at London Health Sciences Centre, a tertiary referral centre in Ontario, Canada, to assess changes in rates of JAK2 mutation positivity, average hemoglobin levels and the prevalence of secondary causes of erythrocytosis. RESULTS: A total of 891 patients with erythrocytosis underwent JAK2 mutation testing with an increase in number of tests (particularly from 2017 to 2018), a decrease in the rate of JAK2 positivity and similar average hemoglobin levels over the study period. We observed a high proportion of patients with secondary causes of erythrocytosis, ranging from 59% to 74% over the study period, including medications associated with erythrocytosis, namely testosterone (6%-11%) and SGLT2 inhibitors (2%-19%). Stopping SGLT2 inhibitors was associated with a significant decrease in hemoglobin levels (mean -14.7 g/L, 95% confidence interval -18.9 to -10.5 g/L) compared with continuation. INTERPRETATION: Use of SGLT2 inhibitors may be a common and underrecognized secondary cause of elevated hemoglobin levels in patients investigated for erythrocytosis. Our findings underscore the importance of a detailed medical history to support judicious use of molecular testing, in adherence with the current guideline on the investigation of erythrocytosis.

Cortical Responses to the Amplitude Envelopes of Sounds Change with Age.

Many older listeners have difficulty understanding speech in noise, when cues to speech-sound identity are less redundant. The amplitude envelope of speech fluctuates dramatically over time, and features such as the rate of amplitude change at onsets (attack) and offsets (decay), signal critical information about the identity of speech sounds. Aging is also thought to be accompanied by increases in cortical excitability, which may differentially alter sensitivity to envelope dynamics. Here, we recorded electroencephalography in younger and older human adults (of both sexes) to investigate how aging affects neural synchronization to 4 Hz amplitude-modulated noises with different envelope shapes (ramped: slow attack and sharp decay; damped: sharp attack and slow decay). We observed that subcortical responses did not differ between age groups, whereas older compared with younger adults exhibited larger cortical responses to sound onsets, consistent with an increase in auditory cortical excitability. Neural activity in older adults synchronized more strongly to rapid-onset, slow-offset (damped) envelopes, was less sinusoidal, and was more peaked. Younger adults demonstrated the opposite pattern, showing stronger synchronization to slow-onset, rapid-offset (ramped) envelopes, as well as a more sinusoidal neural response shape. The current results suggest that age-related changes in the excitability of auditory cortex alter responses to envelope dynamics. This may be part of the reason why older adults experience difficulty understanding speech in noise.SIGNIFICANCE STATEMENT Many middle-aged and older adults report difficulty understanding speech when there is background noise, which can trigger social withdrawal and negative psychosocial health outcomes. The difficulty may be related to age-related changes in how the brain processes temporal sound features. We tested younger and older people on their sensitivity to different envelope shapes, using EEG. Our results demonstrate that aging is associated with heightened sensitivity to sounds with a sharp attack and gradual decay, and sharper neural responses that deviate from the sinusoidal features of the stimulus, perhaps reflecting increased excitability in the aged auditory cortex. Altered responses to temporal sound features may be part of the reason why older adults often experience difficulty understanding speech in social situations.