Background: Myelodysplastic Syndrome (MDS) and Aplastic Anemia (AA) are often associated with clinical immune manifestations. An abnormal profile of the T-cell repertoire can be detected in these patients (pts) and is thought to play a role in bone marrow (BM) insufficiency. The presence of a co-existent large granular lymphocytic (LGL) clone may exacerbate cytopenias independent of the primary disease mechanism and offers another target for therapeutic intervention. Treatment for LGL proliferation is usually immunosuppressive therapy but there is no accepted standard of care.Methods: We explored the role of intravenous immunoglobulin (IVIG) as a treatment for immune-related cytopenias, i.e. Coombs negative (C-) hemolytic anemia, in a series of 12 consecutive pts with an LGL clonal proliferation documented by flow cytometry and TCR clonal rearrangements. Of the 12 cases, 9 had MDS (7 lower-risk), 1 AA with LGL liver involvement, and 1 primary myelofibrosis. One patient (pt) had suspected MDS.
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BACKGROUND: Recently, there is an increased focus on waiting time as a barrier to access to treatment in outpatient services. The aim of this study is to determine related factors to outpatient waiting time in specialty levels. METHOD: This was a cross sectional study. The target population of this study consisted of specialist’s and subspecialist’s offices in Tehran.
Overall response was assessed by MDS IWG criteria 2006. We defined a hemolysis response (HLR) as complete normalization (CR) or, a greater than 50% improvement (PR) in deviation from normal values of LDH, reticulocytes, indirect bilirubin and haptoglobin. Duration of HLR was defined as the time from onset of HLR to the time of resumption of hemolysis and loss of effect of IVIG.Results: All pts were treated with IVIG administered at a dose of 500mg/kg of IVIG once per week, in repeated cycles, with a duration ranging from 1-4 week(s) per cycle. Clinical characteristics (Table 1): M/F ratio 10/2; median age 69. Ten pts had a CD3+ T-LGL and 2 had a CD3-/CD16+/CD56+ NK-LGL circulating clone. Karyotype abnormalities were non-specific; 8 pts had 1-3+ reticulin BM fibrosis; 4 had mutations in RNA-splicing genes: SF3B1 (2); SETBP1 (1); SRSF2 (1). Ten pts were evaluable for response: 8 pts responded (ORR 80%): Hematological improvement (HI-erythroid) 8/8 (100%); a hemolysis CR (HLR-CR) occurred in 7 (87.5%) and hemolysis PR (HLR-PR) in 1 pt (12.5%).
Median number of cycles, follow up, and duration of treatment were 16, 21.5 and 9.5 months (mo), respectively. The HLR-CR was durable and prolonged in 3/8 (38%) pts; 2 of these 3 pts (67%) did not require maintenance IVIG. Relapse from HLR occurred in 4, during infection or chemotherapy, but the response returned to the original level by shortening the intervals between administration of IVIG. One pt had relapsed after an initial response and then became refractory to IVIG.
In follow up at month 38, 75% of pts were still responding to treatment, and 1 pt was still in remission after 46 mo. In 4 of 6 pts, corticosteroid treatment was discontinued and no longer required for chronic hemolysis, with general improvement of steroid related symptoms. Some patients had been on steroids maintenance for periods ranging from months to years. Response was more durable with continuous rather than sporadic dosing. Adverse events were not specific: 1 pt with self-limited isolated palpitations; 1 pt with hypertension not requiring intervention.Conclusions: Treatment with IVIG of immune cytopenias associated with LGL clones and BMF yields durable responses in 80% of pts. IVIG, especially at high concentrations, may enhance apoptosis, suppress proliferation of T-cells and induce immune-regulation. Given the relative rarity of LGL clones in MDS, further investigational studies will help define the role of IVIG and clarify the mechanism of action in this group of pts with MDS and BMF associated with LGL clones.
Variable.Observed.%.Symptomatic anemia (fatigue, SOB)9/1275B symptoms (recurrent fever)2/1216.6Infections(bacteremia Campylobacter with migratory arthritis and dermatitis; cellulitis bacteremia S. Variable.Observed.%.Symptomatic anemia (fatigue, SOB)9/1275B symptoms (recurrent fever)2/1216.6Infections(bacteremia Campylobacter with migratory arthritis and dermatitis; cellulitis bacteremia S.
In unstable coronary syndromes, von Willebrand Factor (VWF) adheres to exposed subendothelial matrix. Initial platelet interaction with immobilised VWF is rapidly reversible, shear dependent, and includes characteristic start-stop translocation of platelets. Platelets tether to bound VWF via the glycoprotein (GP)Ib receptor and initiate a complex signalling cascade, ultimately activating the integrin αIIbβ3 receptor that crosslinks fibrinogen and causes platelet arrest. We have developed a microfluidic assay utilizing video microscopy to accurately measure dynamic platelet behaviour in microliters of blood perfused across VWF at arterial shear rates (1500 s-1). Tracking multiple individual platelets from frame to frame with unique motion-analysis software, the assay measures the total number of platelets 1) interacting with VWF, 2) translocating across VWF (GPIb dependent), and 3) stably adhered to the surface (αIIbβ3 dependent), as well as 4) the development rate of thrombi, and 5) the percent surface coverage at 17 sec (the end of the assay).
Variations in platelet function associated with acute coronary syndromes (ACS) and stable coronary artery disease (CAD) are poorly understood. We hypothesise that platelet function differs between normal donors, patients with stable CAD taking aspirin (ASA), and patients with ACS on dual anti-platelet therapy (DAPT). We characterised dynamic platelet function in 66 healthy donors, 67 patients with stable CAD on long-term ASA alone and 85 patients recruited within 3 days of a cardiac event on DAPT (ACS group). All patients had an appropriate response to either ASA alone or DAPT as defined by consensus guidelines using light transmission aggregometry (LTA) in response to 500 mg/mL arachidonic acid and 20 mM ADP. Compared to healthy controls and despite an adequate LTA response to DAPT, patients with ACS had significantly more platelets interacting with VWF (534±281 vs 424±198 (mean±SD), p ² 0.01), stably adhered platelets (237±118 vs 189±69, p ² 0.01), translocating platelets (365±186 vs 303±141, p ² 0.04) and final surface coverage (12.8±3.7% vs 11.2±2.7%, p ² 0.002). The differences between CAD patients on ASA alone and those with ACS were even more striking: long-term-ASA CAD patients had fewer stably adhered (181±83 vs 237±118, p ² 0.002) and translocating platelets (271±141 vs 365±186, p ² 0.0006). Both the rate of thrombus growth (9.8±2.7 vs 8.6±2.7, p ² 0.005) and the percent surface coverage (12.8±3.7% vs 10.8±3.4%, p ² 0.0007) were significantly greater in ACS patients.
Conclusion: Despite nominal LTA-measured response to DAPT, the profile of dynamic platelet behaviour measured by novel platelet function parameters is remarkably different in patients with ACS from those with stable CAD (Figure 1). Platelets from patients with ACS interact more with VWF compared to healthy controls and patients with stable coronary artery disease. Our dynamic platelet function assay describes for the first time novel platelet interactions with VWF suggesting a new way to guide antiplatelet therapy.
The profile of platelet interactions with VWF is markedly different in patients with ACS. Dynamic platelet interaction with VWF in patients with ACS and stable CAD was normalised against healthy controls (bars represent normalised 95% confidence intervals). Platelets from patients with ACS have a higher rate of interaction with the surface compared to healthy controls and stable patients on aspirin alone.
The profile of platelet interactions with VWF is markedly different in patients with ACS. Dynamic platelet interaction with VWF in patients with ACS and stable CAD was normalised against healthy controls (bars represent normalised 95% confidence intervals). Platelets from patients with ACS have a higher rate of interaction with the surface compared to healthy controls and stable patients on aspirin alone.
Dunne:Science Foundation Ireland: Research Funding. Ralph:Science Foundation Ireland: Research Funding. Ricco:Science Foundation Ireland: Research Funding. Kenny:Science Foundation Ireland: Research Funding; Enterprise Ireland: Research Funding.
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January 2023
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