Differences in platelet alpha-granule release between normals and immune thrombocytopenic patients and between young and old platelets.

The risk of serious bleeding in patients with immune thrombocytopenic purpura (ITP) appears to be less than in comparably thrombocytopenic patients with megakaryocytic hypoplasia. It has been proposed that this difference is due to enhanced hemostatic activity of young platelets, which are increased in the circulation during ITP. We examined alpha-granule release in reticulated platelets (RP), which are thought to be the youngest circulating platelets, and in older non-reticulated platelets (non-RP) in normal human controls and ITP patients. Normal controls had a mean RP of 7%, compared with 42% in ITP patients. The mean concentration of thrombin receptor agonist peptide (TRAP) causing 50% of control RP to express CD62P (EC50) was 0.82+/-0.08 microM (SEM), significantly higher than the TRAP CD62P EC50 for RP in ITP, 0.57+/-0.06 microM (p = 0.04). Similarly, the TRAP EC50 for non-RP in controls, 0.84+/-0.09 microM, was significantly higher than in ITP, 0.56+/-0.07 microM (p = 0.03), suggesting that all platelets in ITP have an enhanced alpha-granule threshold response to TRAP compared with controls, while RP and older platelets within each patient group have similar threshold sensitivities to TRAP. By contrast, high-dose TRAP caused RP to express twice as much mean and total CD62P as non-RP in both ITP patients and controls (p <0.05 for both comparisons). We conclude that compared with controls, all platelets in ITP are primed to undergo alpha-granule release to TRAP, while in both ITP and controls, the newly circulating, reticulated platelets have the potential to contribute greater amounts of CD62P surface ligand compared with older platelets (non-RP) after stimulation. Both the increased RP% and enhanced platelet response to agonist in ITP may contribute to maintenance of hemostasis despite thrombocytopenia.

Cyclosporine inhibition of calcineurin activity in human leukocytes in vivo is rapidly reversible.

Despite increasing information about the mechanism of action of cyclosporine A (CsA), little is known about the way lymphocytes recover from CsA. Recovery is central to understanding the pharmacodynamics of CsA in vivo. We studied the recovery of calcineurin phosphatase (CN) activity in CsA-treated cells. Single dose kinetics in renal transplant patients showed that inhibition of CN activity in PBL increased and fell concomitant with CsA blood vessels. In vitro, control PBL treated with CsA 100 micrograms/l, washed, and resuspended in CsA-free medium showed little recovery (0-20%) after 24 h. Erythrocytes or anti-CsA Ab added to the recovery medium increased recovery to 50% within 4 h. Similar recovery was seen in the ability of cells to produce IFN-gamma after OKT3 stimulation. Recovery of CN activity was associated with the efflux of [3H]CsA, was not blocked by cycloheximide and was temperature sensitive. A cell line with high expression of surface P glycoprotein (PGP), showed rapid recovery. However, PGP blockade did not prevent recovery in PBL, indicating a different PGP-independent mechanism. In PBL, recovery from CsA is slow and limited in vitro, but rapid in vivo, where CsA equilibrates among a complex set of extralymphocytic binding sites.

Hypercalcemia complicating childhood malignancies: a report of seven cases with some pathophysiological considerations.

A group of seven children with different malignant processes presenting with hypercalcemia was studied. Bone destruction, diffuse metabolic abnormalities, abnormal acid-base homeostasis and recurrent hypercalcemia characterized these patients. A different mechanism leading to the production of hypercalcemia and/or bone destruction by cancer cells is considered. The results of this report suggest that parathyroid hormone production (P.T.H.) by the parathyroid glands is normal and that ectopic secretion of PTH or PTH-like material is negligible in these cases.

Complete remodeling of the vertebrae in a child successfully treated for acute lymphocytic leukemia (ALL).

This report describes a 10-year-old white boy who presented with acute lymphocytic leukemia (ALL) and several collapsed thoracolumbar vertebrae in 1965. His ALL was successfully treated, and he has been disease-free for over 10 years. He has now completely remodeled all of the collapsed vertebrae.

Infections in children with acute leukemia.

Twenty children with ALL that died in 1959-1960 and 59 children with ALL that died in 1969-1970 were analyzed according to the infections at both their terminal illness and their initial presentations. Despite the availability of more effective agents for pseudomonas and staphylococcus, the pattern of infecting organisms at the terminal illness did not change appreciably in this decade. E. coli, pseudomonas, staphylococcus, and candida were the principal organisms involved as a cause of death. Thirty-five of these 79 patients were febrile when they initially presented, prior to the institution of chemotherapy. Seven of the 35 patients (20%) had proved infections. It appears that the fever in the majority of patients at their initial presentations was noninfectious in origin. In 1969-1970, 13 pulmonary aspirates were performed to aid in the etiological diagnosis of diffuse interstitial pneumonia. Only a single case (8%) of pneumonia due to pneumocystis carinii was detected, and it is our suspicion that the majority of these interstitial pneumonias were viral in origin.