The effect of variation in donor platelet function on transfusion outcome: A semi-randomised controlled trial

The effect of variation in platelet function in platelet donors on patient outcome following platelet transfusion is unknown. This trial assessed the hypothesis that platelets collected from donors with highly responsive platelets to agonists in vitro assessed by flow cytometry (high-responder donors) are cleared more quickly from the circulation than those from low-responder donors, resulting in lower platelet count increments following transfusion. This parallel group, semirandomized double-blinded trial was conducted in a single center in the United Kingdom. Eligible patients were those 16 or older with thrombocytopenia secondary to bone marrow failure, requiring prophylactic platelet transfusion. Patients were randomly assigned to receive a platelet donation from a high- or low-responder donor when both were available, or when only 1 type of platelet was available, patients received that. Participants, investigators, and those assessing outcomes were masked to group assignment. The primary end point was the platelet count increment 10 to 90 minutes following transfusion. Analysis was by intention to treat. Fifty-one patients were assigned to receive platelets from low-responder donors, and 49 from high-responder donors (47 of which were randomized and 53 nonrandomized). There was no significant difference in platelet count increment 10 to 90 minutes following transfusion in patients receiving platelets from high-responder (mean, 21.0 × 109/L; 95% confidence interval [CI], 4.9-37.2) or low-responder (mean, 23.3 × 109/L; 95% CI, 7.8-38.9) donors (mean difference, 2.3; 95% CI, −1.1 to 5.7; P = .18). These results support the current policy of not selecting platelet donors on the basis of platelet function for prophylactic platelet transfusion.This work was supported in part by program grants from the NIHR (RP-PG-0310-1002), National Health Service Blood and Transplant (BS07/1R), and NIHR Cambridge BioResource

Proteomic and Phospho-Proteomic Profile of Human Platelets in Basal, Resting State: Insights into Integrin Signaling

During atherogenesis and vascular inflammation quiescent platelets are activated to increase the surface expression and ligand affinity of the integrin αIIbβ3 via inside-out signaling. Diverse signals such as thrombin, ADP and epinephrine transduce signals through their respective GPCRs to activate protein kinases that ultimately lead to the phosphorylation of the cytoplasmic tail of the integrin αIIbβ3 and augment its function. The signaling pathways that transmit signals from the GPCR to the cytosolic domain of the integrin are not well defined. In an effort to better understand these pathways, we employed a combination of proteomic profiling and computational analyses of isolated human platelets. We analyzed ten independent human samples and identified a total of 1507 unique proteins in platelets. This is the most comprehensive platelet proteome assembled to date and includes 190 membrane-associated and 262 phosphorylated proteins, which were identified via independent proteomic and phospho-proteomic profiling. We used this proteomic dataset to create a platelet protein-protein interaction (PPI) network and applied novel contextual information about the phosphorylation step to introduce limited directionality in the PPI graph. This newly developed contextual PPI network computationally recapitulated an integrin signaling pathway. Most importantly, our approach not only provided insights into the mechanism of integrin αIIbβ3 activation in resting platelets but also provides an improved model for analysis and discovery of PPI dynamics and signaling pathways in the future

Assessing the risks of haemolysis as an adverse reaction following the transfusion of ABO incompatible plasma-containing components - A scoping review.

Background The limited supply of universal plasma has resulted in transfusion of ABO incompatible plasma to patients. As the need to implement whole blood transfusion in pre-hospitals setting rises, the lowest cut-off for anti-A/anti-B that does not cause haemolysis remains unknown. In this first scoping review, we aimed to determine the lowest ABO titre and volume reported in the literature to cause haemolysis from ABO incompatible plasma transfusions (plasma, platelets, cryoprecipitate, and whole blood). Methods We searched several databases from inception to April 2022, including all study types. Three independent reviewers extracted and reviewed the data. Primary outcome was the anti-A and anti-B titre (measured by IgM or IgG) that resulted in measurable haemolysis following ABO incompatible plasma transfusion. Results We identified 5681 citations, of which 49 studies were eligible, reporting a total of 62 cases (34 adults, 14 children and 14 did not specify age). The methods for antibody measurement and antibody type (IgG or IgM) varied significantly between studies. Component volumes were poorly reported. The most common component responsible for the haemolysis was apheresis platelets followed by pooled platelets and whole blood. Most haemolytic cases reported were due to anti-A. The lowest anti-A titre reported to cause haemolysis (children and adults) was 32 (IgG), while for anti-B it was 512 (IgG and IgM) for adults, 16,384 for paediatrics (IgG and IgM) and 128 (IgM) in cases where the age was not specified. The lowest reported volume associated with haemolysis were 100 ml (adults) and 15 ml (children). Of the 62 15 (24%) died. Conclusion The lowest titre reported to cause haemolysis was an anti-A of 32. ABO mismatch plasma transfusion may be associated with significant mortality. There is a need to agree/standardise methods for ABO titration measurement internationally for plasma components and agree the lowest anti-A/anti-B titre for transfusing ABO mismatched plasma

Clinical progress in the two years following a course of exclusive enteral nutrition in 109 paediatric patients with Crohn's disease

<p>Background: Exclusive enteral nutrition (EEN) is an effective first line treatment for active paediatric Crohn's disease (CD).</p> <p>Aim: To examine the effect of EEN on short- and long-term clinical outcome together with anthropometric measurements.</p> <p>Methods: Retrospective case-note review in newly diagnosed CD (<16 years) who completed 8 weeks of EEN. Demographics, anthropometry, disease characteristics and inflammatory markers were collected at EEN initiation and at 1, 2, 6, 12 and 24 months post treatment initiation. EEN response was determined by a patient global assessment.</p> <p>Results: One hundred and nine patients were included (Males 68; Median age: 11.2 years). After 8 weeks EEN, 65 were in remission, 32 improved and 12 had no improvement. By 4 weeks, mean weight/BMI z-score (s.d.) increased (P < 0.02) and between 4 and 8 weeks (P < 0.05). Baseline inflammatory markers all improved significantly by week 4 (albumin, CRP and platelets; all P < 0.01) and ESR (P < 0.00001). 63/109(58%) relapsed during follow-up. 44/63(70%) patients completed a second course of EEN with similar response rate, but lower weight gain (3.3 vs. 5.1 kg, P < 0.05). Height z-score did not change significantly over the 24 months. Introduction of azathioprine within 6 months of diagnosis did not improve height outcomes at 24 months.</p> <p>Conclusions: Weight and BMI z-score improved with EEN and changes are sustained to 2 years, but height z-score did not. Seventy per cent of patients who relapsed during 2-year follow-up managed a 2nd course of EEN. The optimal therapeutic strategies for length of EEN course and to improve linear growth are awaited.</p&gt

Randomized trial of red cell washing for the prevention of transfusion-associated organ injury in cardiac surgery

Background: Experimental studies suggest that mechanical cell washing to remove pro-inflammatory components that accumulate in the supernatant of stored donor red blood cells (RBCs) might reduce inflammation and organ injury in transfused patients. Methods: Cardiac surgery patients at increased risk of large-volume RBC transfusion were eligible. Participants were randomized to receive either mechanically washed allogenic RBCs or standard care RBCs. The primary outcome was serum interleukin-8 measured at baseline and at four postsurgery time points. A mechanism substudy evaluated the effects of washing on stored RBCs in vitro and on markers of platelet, leucocyte, and endothelial activation in trial subjects. Results: Sixty adult cardiac surgery patients at three UK cardiac centres were enrolled between September 2013 and March 2015. Subjects received a median of 3.5 (interquartile range 2-5.5) RBC units, stored for a mean of 21 ( sd 5.2) days, within 48 h of surgery. Mechanical washing reduced concentrations of RBC-derived microvesicles but increased cell-free haemoglobin concentrations in RBC supernatant relative to standard care RBC supernatant. There was no difference between groups with respect to perioperative serum interleukin-8 values [adjusted mean difference 0.239 (95% confidence intervals -0.231, 0.709), P =0.318] or concentrations of plasma RBC microvesicles, platelet and leucocyte activation, plasma cell-free haemoglobin, endothelial activation, or biomarkers of heart, lung, or kidney injury. Conclusions: These results do not support a hypothesis that allogenic red blood cell washing has clinical benefits in cardiac surgery. Clinical trial registration: ISRCTN 27076315

A Comparison of Red Cell Rejuvenation versus Mechanical Washing for the Prevention of Transfusion-associated Organ Injury in Swine

BACKGROUND: We evaluated the effects of two interventions that modify the red cell storage lesion on kidney and lung injury in experimental models of transfusion. METHODS: White-landrace pigs (n = 32) were allocated to receive sham transfusion (crystalloid), 14-day stored allogeneic red cells, 14-day red cells washed using the red cells washing/salvage system (CATS; Fresenius, Germany), or 14-day red cells rejuvenated using the inosine solution (Rejuvesol solution; Zimmer Biomet, USA) and washed using the CATS device. Functional, biochemical, and histologic markers of organ injury were assessed for up to 24 h posttransfusion. RESULTS: Transfusion of 14 day red cells resulted in lung injury (lung injury score vs. sham, mean difference -0.3 (95% CIs -0.6, -0.1; P = 0.02), pulmonary endothelial dysfunction, and tissue leukocyte sequestration. Mechanical washing reduced red cell-derived microvesicles but increased cell-free hemoglobin in 14-day red cell units. Transfusion of washed red cells reduced leukocyte sequestration but did not reduce the lung injury score (mean difference -0.2; 95% CI -0.5, 0.1; P = 0.19) relative to 14-day cells. Transfusion of washed red cells also increased endothelial activation and kidney injury. Rejuvenation restored adenosine triphosphate to that of fresh red cells and reduced microvesicle concentrations without increasing cell-free hemoglobin release. Transfusion of rejuvenated red cells reduced plasma cell-free hemoglobin, leukocyte sequestration, and endothelial dysfunction in recipients and reduced lung and kidney injury relative to 14-day or washed 14-day cells. CONCLUSIONS: Reversal of the red cell storage lesion by rejuvenation reduces transfusion-associated organ injury in swine