A novel gastrin-binding protein in the human eosinophil.

A specific and saturable interaction between 125I-gastrin and eosinophils was discovered in autoradiographs of human gastric mucosal tissue and confirmed in isolated and enriched preparations of WBC's. Gastrin displaced 125I-gastrin from eosinophils in a dose-dependent manner with a D50 = 11 uM. Scatchard analysis of the saturation curve indicated a single binding site of low affinity (Kd = 4.14 uM) and high capacity (Bmax = 430 umoles/mg protein). The gastrin binding protein was localized to the granular core of the eosinophil and found to have a molecular weight of approximately 15 kDa following chemical crosslinking of radioligand to granules and SDS/PAGE. Based on its molecular weight and granular location and the charge characteristics of gastrin, the gastrin binding protein in the human eosinophil is most likely major basic protein. In vivo this interaction might act to limit the cytotoxic potential of MBP on tissues and/or attentuate gastrin concentrations thereby helping regulate gastric acid secretion and mucosal growth.

Intracranial hemorrhage complicating acute myocardial infarction in the era of thrombolytic therapy.

Cerebrovascular accidents are one of the most serious causes of morbidity in patients sustaining an acute myocardial infarction. In patients who do not receive thrombolytic therapy, the most common form of stroke is thromboembolic, occurring in up to 2.4% of patients, predominantly in those sustaining large anterior infarctions. In patients receiving thrombolytic therapy, intracranial hemorrhage is the most common form of stroke, occurring in 0.1% to 1.4%. Predisposing conditions for intracranial bleeding include low body weight, female sex, advanced age, use of oral anticoagulant medication before the administration of lytic therapy, diastolic blood pressure greater than 110 mm Hg, and the specific thrombolytic agent administered. Hematologic management of the patient sustaining a hemorrhagic cerebrovascular accident should include (1) discontinuance of thrombolytic therapy, anticoagulants, and antiplatelet agents and (2) infusion of cryoprecipitate to replenish fibrinogen. In certain cases, administration of fresh frozen plasma, protamine sulfate, and exogenous platelets may be required. Finally, evacuation of the hematoma may provide the most definitive form of treatment in selected cases.

Thrombotic tendencies and correlation with clinical status in patients infected with HIV.

Previous publications have described thrombotic events with unclear causes in individuals infected with the human immunodeficiency virus (HIV). We stratified the cases of 52 individuals infected with HIV by degree of immunosuppression and the presence of complicating illnesses. Plasma from these individuals was screened for abnormalities that might predispose to thromboses. We found statistically significant differences between patients with CD4 counts < 200/mm3 and those whose CD4 counts were > 400/mm3 in the following: d-dimers, functional protein C, antigenic protein C, total protein S antigen, free protein S antigen, C4b-binding protein (C4b-BP), and von Willebrand antigen (vWD). Free protein S correlated inversely with C4b-BP; vWD directly with total protein S; and protein C inversely with d-dimers. D-dimers were significantly elevated only in immunosuppressed patients with complicating neoplastic/inflammatory disease. We propose that low-grade disseminated intravascular coagulopathy in severely immunosuppressed individuals with HIV and infectious, inflammatory, or neoplastic complications is responsible for depressed protein C, which, together with elevations in total protein S and vWD (markers of endothelial injury), indicates a thrombotic predisposition.

Hematocrit and bleeding time: an update.

The bleeding time is prolonged in anemic patients independent of their platelet count and is shortened by elevating the hematocrit. It is theorized that an increase in circulating red blood cells increases platelet radial movement and interaction with endothelium. Platelet dysfunction in uremia is well known but poorly understood. Anemia is one contributory factor; others may involve storage pool deficiency, increased vessel wall prostaglandin production, and abnormal platelet arachidonic acid metabolism. Ameliorating anemia with red blood cell transfusions has been shown to shorten the bleeding time without affecting other platelet function values. Recently, recombinant human erythropoietin has been shown to shorten the bleeding time, with a parallel rise in hematocrit level to 30%. Clinicians should be aware that a diminished hematocrit may contribute to the bleeding tendency already present in patients with thrombocytopenia.

The effect of parenteral lipid emulsion-induced hyperlipidemia on prostaglandin E1 modulation of platelet function.

The purpose of this study is to better understand how hyperlipidemia alters the modulating action of prostaglandin E1 (PGE1) on platelet function. Using our previously characterized rat model of atherogenesis, we demonstrate that the parenteral lipid emulsions, Lipofundin-S and Liposyn, significantly (p < or = 0.05) enhance baseline platelet aggregation. In addition, dose response curves show that in all animals, PGE1 substantially inhibits platelet aggregation at 10(-7) to 10(-6) M, while significantly stimulating platelet function at lower doses. However, at all PGE1 concentrations, aggregation values are higher in platelets from lipid-treated vs. control rats, showing that hyperlipidemia significantly reduces the ability of high concentrations of PGE1 to inhibit platelet activity, based on the absolute values of the controls. Also, dose response curves for PGE1 on platelet aggregation show a marked similarity in shape for control ratsvs. normal humans. Thus, this study demonstrates that hyperlipidemia significantly alters the platelet modulating action of prostaglandin E1, and it shows that PGE1 can either inhibit or stimulate platelet activity in both rat and human platelets.

Acquired protein C deficiency in patients with breast cancer receiving cyclophosphamide, methotrexate, and 5-fluorouracil.

Recent reports have documented an increase of thrombotic complications in patients with carcinoma of the breast receiving chemotherapy regimens containing cyclophosphamide, methotrexate, and 5-fluorouracil. The authors studied blood from nine such patients screening for abnormalities that might predispose to thrombosis or indicate that the coagulation cascade had been activated. Six of the patients were in the adjuvant setting, and three had metastatic disease. Samples were collected from each patient before, during, and after completion of the chemotherapy in question. In each patient a statistically significant decline in functional protein C activity (P = 0.001) was demonstrated at midtherapy. In seven of nine patients functional protein C level normalized after the cessation of therapy. No other positive results were found. The authors conclude that the combination of cyclophosphamide, methotrexate, and 5-fluorouracil, when administered to patients with a diagnosis of carcinoma of the breast, causes a reversible decline in the activity of protein C.

Platelet aggregability in rats with early atherosclerotic changes induced by parenterally-administered lipid emulsions.

The present study is the first work to evaluate thrombin-, ADP-, and collagen-induced platelet aggregation in laboratory rats receiving alimentation with the parenterally-administered lipid emulsion, Lipofundin-S, in doses sufficient to induce early atherosclerotic changes in the aorta. The aggregometry parameters of percent maximum aggregation, slope, and b2 or b20 almost uniformly indicate that such lipid treatments result in a statistically significant increased sensitivity of the platelets to ADP and collagen, while no change is noted with thrombin as the aggregating agent. By varying the amounts of ADP and collagen during aggregometry, we also demonstrate that the concentrations of these reagents necessary for equivalent platelet aggregation is substantially lower in lipid-infused rats than in controls. We conclude from this study that such lipid infusions can cause increased platelet aggregation, and that these lipids probably act in a synergistic fashion by affecting a variety of components which comprise the atherogenic process and its clinical endpoint. In addition, we believe that this experimental approach is of interest in that infusions of clinically-useful lipid emulsions are easily controlled, while alterations in platelet physiology and aortic structure occur concurrently and rapidly.

In vitro detection of heparin-induced humoral antiplatelet activity.

We investigated the etiology of thrombocytopenia, with or without platelet thrombi, occurring while patients are receiving parenteral heparin. We used two in vitro methods to detect possible humoral factors in the sera of patients who became thrombocytopenic while receiving heparin. In the presence of heparin, four of four such patients' serum caused platelet aggregation. Only serum from the patient most severely affected clinically caused release of platelet factor 3 (PF3). All control sera gave negative results by both methods. We propose that platelet aggregation studies may be a sensitive and reliable method of confirming that thrombocytopenia occurring during heparin therapy is due to a humoral factor requiring the presence of heparin.

A case of leukemic reticuloendotheliosis responding to oxymetholone.

A 63-year-old man presented with fever, easy bruisability, splenomegaly and pancytopenia. Bone marrow aspiration was unsuccessful, and marrow biopsy revealed crowding by sheets of mononuclear cells; a diagnosis of leukemic reticuloendotheliosis (LRE) was made and the patient underwent splenectomy. There was no hematologic improvement, and the patient continued to have a significant requirement for erythrocytes and platelet transfusions. Within two months of beginning oxymetholone therapy (50 mg orally three times a day) the patient's platelet count had normalized, followed by improved erythrocyte and leukocyte counts. When the drug was discontinued, the peripheral blood counts deteriorated drastically; he again demonstrated hematologic improvement when oxymetholone therapy was reinstated. We feel that by demonstrating a hematologic response to oxymetholone, relapse when it was withdrawn, and another remission upon readministration, that we have provided stronger evidence than previously reported for the efficacy of this drug in LRE.