Response to immunosuppressive therapy (IST) in younger patients with myelodysplastic syndrome (MDS) has been linked to a T-cell-dominant autoimmune process that impairs hematopoiesis. Analysis of the age-adjusted CD4:CD8 ratio in 76 MDS patients compared with 54 healthy controls showed that inadequate CD4+, rather than expansion of CD8+ T cells, was associated with a lower ratio in a group that included both lower and higher risk MDS patients defined by the International Prognostic Scoring System. In younger MDS patients, naive and memory phenotypes defined by CD45RA and CD62L display showed depletion of naive CD4+ and CD8+ T cells, suggesting a possible relationship to IST responsiveness. To determine the correlation between T-cell subset distribution, T-cell turnover and autoimmunity, a cohort of 20 patients were studied before and after IST. The CD4:CD8 ratio correlated inversely with the proliferative T-cell index before treatment in IST-responsive patients, suggesting that proliferation may be linked to accelerated CD4+ T-cell turnover and hematopoietic failure. Our data show seminal findings that both CD4+ and CD8+ T-cell subsets are dysregulated in MDS. Association between these T-cell defects and response to IST suggests that aberrant T-cell homeostasis and chronic activation are critical determinants influencing autoimmune hematopoietic suppression in younger patients.
Patients with uraemia have abnormal platelet function that may be partially corrected by haemodialysis, cryoprecipitate or 1-desamino-8-D-arginine vasopressin (DDAVP). We studied the platelet von Willebrand factor receptor, glycoprotein Ib (GPIb), and plasma von Willebrand factor (vWF) in uraemic patients undergoing chronic haemodialysis. Using the slope of agglutination of formalin-fixed platelets as an index of response to ristocetin (with a constant amount of normal plasma as a source of vWF), we found the response of platelets from uraemic patients, both before (2.7 +/- 1.5, n = 40) and after dialysis (1.2 +/- 1.2, n = 40) to be significantly less than that for normal controls (14.1 +/- 10.2, n = 20; P less than 0.001). In addition, the agglutination response of platelets obtained after dialysis was less than that of platelets obtained before dialysis (P less than 0.001). Immunoblotting demonstrated decreased or absent staining of glycocalicin, a subunit of GPIb, in platelet lysates from 25 patients. All platelet samples with reduced glycocalicin also had decreased responses to ristocetin. Tritium-labelled platelets from seven patients showed decreased labelling of a protein with an electrophoretic mobility equivalent to that of GPIb (140,000 daltons). In addition, platelets with the lowest levels of surface GPIb, as demonstrated by flow cytometry, also had decreased ristocetin agglutination and decreased staining on immunoblot. Levels of von Willebrand factor antigen and ristocetin cofactor in plasma from 10 patients were generally within the normal range, although postdialysis levels tended to be higher than pre-dialysis levels. The pre- and post-dialysis plasma vWF multimeric patterns were normal.
Platelet aggregation and bleeding time abnormalities are reported in patients receiving beta-lactam antibiotics (beta LAs), although clinical bleeding most frequently occurs in chronically ill, malnourished patients. Although most beta LAs bind to serum albumin, the relative influence of bound versus unbound beta LAs on platelet function is unknown. We examined the effect of beta LAs on the aggregation of gel-filtered platelets from normal subjects and on platelet-rich plasma (PRP) from hypoalbuminemic patients. Therapeutic concentrations of five beta LAs were added to normal platelets at different albumin concentrations (1.5 to 4.5 g/dL). Inhibition of aggregation by the beta LAs was inversely proportional to the albumin concentration, and most antibiotic-treated samples showed more than 50% inhibition at albumin levels below 2.0 g/dL. When PRPs from hypoalbuminemic patients were incubated with cephalothin, aggregation was completely inhibited, in contrast to samples from patients with normal albumin levels, and this decreased platelet aggregation was partially restored (25% to 75%) by increasing the albumin concentration above 4.0 g/dL. Specific binding of [35S]-benzylpenicillin to normal platelets decreased proportionately as the albumin concentration increased in the range of 1.0 to 5.0 g/dL. The inhibitory effects of beta LAs on platelets in vitro appear to be influenced by albumin concentration. Plasma albumin concentration may influence bleeding in patients receiving beta LAs.
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