The interplay between the Rab27A effectors Slp4-a and MyRIP controls hormone-evoked Weibel-Palade body exocytosis.

Weibel-Palade body (WPB) exocytosis underlies hormone-evoked VWF secretion from endothelial cells (ECs). We identify new endogenous components of the WPB: Rab3B, Rab3D, and the Rab27A/Rab3 effector Slp4-a (granuphilin), and determine their role in WPB exocytosis. We show that Rab3B, Rab3D, and Rab27A contribute to Slp4-a localization to WPBs. siRNA knockdown of Slp4-a, MyRIP, Rab3B, Rab3D, Rab27A, or Rab3B/Rab27A, or overexpression of EGFP-Slp4-a or EGFP-MyRIP showed that Slp4-a is a positive and MyRIP a negative regulator of WPB exocytosis and that Rab27A alone mediates these effects. We found that ECs maintain a constant amount of cellular Rab27A irrespective of the WPB pool size and that Rab27A (and Rab3s) cycle between WPBs and a cytosolic pool. The dynamic redistribution of Rab proteins markedly decreased the Rab27A concentration on individual WPBs with increasing WPB number per cell. Despite this, the probability of WPB release was independent of WPB pool size showing that WPB exocytosis is not determined simply by the absolute amount of Rab27A and its effectors on WPBs. Instead, we propose that the probability of release is determined by the fractional occupancy of WPB-Rab27A by Slp4-a and MyRIP, with the balance favoring exocytosis.

Hyperkalaemia Following Blood Transfusion-a Systematic Review Assessing Evidence and Risks.

Hyperkalaemia following transfusion is widely reported in the literature. Our objective was to critically review recent evidence on hyperkalaemia in association with transfusion and to assess whether specific aspects of transfusion practice can affect the likelihood of developing hyperkalaemia. We searched 9 electronic databases (including MEDLINE, Embase, and Transfusion Evidence Library) using a predefined search strategy, from 2010 to April 8, 2021. Three reviewers performed dual screening, extraction, and risk of bias assessment. We used Cochrane risk of bias (ROB) 2 for assessment of RCTs, ROBINS-I for non-RCTs, and GRADE to assess the certainty of the evidence. We report 7 comparisons of interest in n = 3729 patients from 28 studies (11 RCTs, 4 prospective cohort studies, and 13 retrospective cohort studies): (1) age of blood, (2) washing, (3) filtration, (4) irradiation, (5) fluid type, (6) transfusion vs no transfusion, (7) blood volume/rate. Of the 28 studies included, 25 reported outcomes of potassium (K+) concentration, 17 the number developing hyperkalaemia, 13 mortality, 10 cardiac arrest, and 10 cardiac arrhythmia. Only 16 studies provided analysable data suitable for quantitative analysis. Evidence addressing our outcomes was of very low certainty (downgraded for incomplete outcome data, baseline imbalance, imprecision around the estimate, and small sample size). While 5 studies showed a difference in K+ concentration up to 6 hours posttransfusion for 3 comparisons (age of blood, washing, and transfusion volume/rate), and 3 studies showed a difference in the diagnosis of hyperkalaemia for 2 comparisons (age of blood, and transfusion volume/rate), the evidence was inconsistent across all included studies. There was no difference in any reported outcomes for 4 comparisons (filtration, irradiation, fluid type, or transfusion vs no transfusion). Overall, the reported evidence was too weak to support identification of groups most at risk of hyperkalaemia or to support recommendations on use of short-storage RBC. For other commonly used risk mitigations for hyperkalaemia in transfusion medicine, the (low certainty) evidence was either conflicting or not supportive.