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ABSTRACT: Chronic idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder in which the abnormality in cellular immunity has remained only vaguely defined. Previously we have shown that patients with ITP in its active phase have abnormal T cell subsets. We then examined the phenotypes of T and B lymphocytes in an additional 28 patients with ITP and 32 age- and sex-matched normal controls and compared the lymphocytes' capacity to respond to polyclonal T, T cell-dependent B, and B cell mitogens. Blastogenesis to optimal (5.0 micrograms/mL) and suboptimal (0.5 microgram/mL) concentrations of the polyclonal T cell mitogens were markedly depressed in patients compared with normal controls (P less than .0005). Similarly, a severe depression in response was noted with the polyclonal T cell-dependent B cell mitogen (P less than .000001). No difference was seen, however, with the polyclonal B cell mitogen. The proportions of pan-T and T helper/inducer lymphocytes were significantly depressed (P less than .005 and P less than .000005 respectively), and the T suppressor/cytotoxic lymphocytes increased (P less than .02) in patients relative to controls. But there was no difference in the proportion of B lymphocytes or in their functional response. The abnormal cellular immunity appears to be due to a defect in the T lymphocyte population without involvement of the B lymphocytes.
Blood 06/1988; 71(5):1455-60. · 9.90 Impact Factor
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ABSTRACT: Although danazol is effective in the treatment of idiopathic thrombocytopenic purpura, its long-term safety and optimal dosage are not well established. We compared low (50 mg/d) and conventional (400 to 800 mg/d) dosages in 24 patients. Thirteen patients received the low dose 1 to 24 months after conventional doses had been discontinued (group 1). Five patients received low doses immediately after the conventional doses (group 2). Six patients were treated with low doses from the outset (group 3). In group 1, similar responses to either dose were seen in 9 patients, whereas there were better responses to conventional doses in 3 and to the lower dose in 1. All patients in group 2 maintained remissions with low doses. There were two excellent-good responses, one fair, and three poor responses in group 3. Side effects were generally less frequent and severe with the low doses. Low-dose danazol is better tolerated but took longer to obtain remissions, and is useful for maintenance therapy in the management of idiopathic thrombocytopenic purpura.
Annals of internal medicine 09/1987; 107(2):177-81. · 16.73 Impact Factor
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ABSTRACT: Danazol, an attenuated androgen, has recently been introduced into the treatment of autoimmune thrombocytopenia. We studied its effects on T helper/inducer (Thi) and T suppressor/cytotoxic (Tsc) lymphocytes in these patients. Prospectively nine patients were studied with their T-cell subsets measured before and during danazol therapy. Increases in the percentage of Thi lymphocytes (P less than 0.05) and Thi/Tsc ratios (P less than 0.001) were observed at 1 and 3 months of treatment. Retrospectively T-cell subset data on 30 patients not treated with danazol and 36 patients on danazol were compared with those of 35 normal controls. The group not on danazol had lower percentages of Pan T (P less than 0.05), Thi (P less than 0.002), and Thi/Tsc ratios (P less than 0.00005), and had higher percentages of Tsc lymphocytes (P less than 0.01), than those of controls. In the group treated with danazol the percentages of Pan T, Thi, and Tsc lymphocytes were similar to those of controls. The percentage of Thi in the treated group was higher (P less than 0.002) than in the untreated group. Thus, danazol appears to be an effective immune modulator, correcting the abnormality of T-cell subsets seen in autoimmune thrombocytopenia by increasing the percentage of Thi lymphocytes.
Clinical Immunology and Immunopathology 04/1987; 42(3):281-7.
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ABSTRACT: This study presents a quantitative comparison of the free cytoplasmic calcium concentration ([Ca2+]cyt) and the free concentration in the lumen of the dense tubules of the human platelet. The former was measured by the fluorescence of the high affinity indicator quin2 and latter by the fluorescence of chlorotetracycline (CTC). The CTC technique monitors calcium-CTC complex accumulation in the lumen of dense tubules and mitochondria when washed platelets were incubated in 2 mM Ca2+. Resting cytoplasmic and dense tubular Ca2+ concentrations were studied in platelets from patients suffering from venous and arterial thrombosis. Compared with normal controls (0.40 +/- 0.10, n = 54), the values of the calcium-CTC ratios were 0.68 +/- 0.19 (n = 16, p less than 0.005) in venous thrombosis; 0.75 +/- 0.18 (n = 14, p less than 0.005) in cardiovascular accident; 0.84 +/- 0.18 (n = 6, p less than 0.005) in occlusive peripheral vascular diseases; and 0.42 +/- 0.10 (n = 21, p greater than 0.1) in patient controls. The dense tubular Ca2+ levels for both patients and controls were perfectly correlated with the cytoplasmic levels using an equation that assumes that the dense tubular free calcium concentration ([Ca2+]dt) has a second power dependence on [Ca2+]cyt. The abnormal Ca2+ handling of platelets obtained from thrombotic patients could be completely reversed by preincubation with the calcium channel blocker verapamil. These observations suggest that the primary Ca2+ handling defect is the leakage through activated channels in the plasma membrane. The defect and the elevated resting [Ca2+]cyt and [Ca2+]dt are adequate to explain the observation of increased rates of collagen-activated aggregation in the above-mentioned group of patients. The results can be explained by platelets from thrombosis patients being exposed to activating factors in the circulation, resulting in Ca2+ channel activation. Channel activation persists through the process of platelet isolation and washing and is manifested in higher measured values of [Ca2+]cyt and [Ca2+]dt in the "resting state." This would bring the platelet closer to its aggregation when aggregation-inducing agents are added. The CTC test is shown to be a useful and convenient means of detecting this abnormality.
Circulation Research 04/1987; 60(3):346-55. · 9.49 Impact Factor
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ABSTRACT: Using chlorotetracycline (CTC) as a probe we studied calcium homeostasis of platelets in various disorders. Studied were healthy subjects and patients with disorders where platelets play an important role. These included thromboses, hypertension, diabetes mellitus, vasculitis, immune thrombocytopenia, thrombotic thrombocytopenic purpura, myelofibrosis, hemolytic anemias and uremia. Significant elevation of calcium levels were observed in all of these disorders except uremia. Nifedipine reduced or normalized the increased levels in most patients and its discontinuation resulted in a return of the abnormality. We propose that platelets in thromboses and related disorders are exposed to subcritical concentrations of activating factors, leading to enhanced calcium influx and elevated free cytoplasmic calcium followed by elevated resting dense tubular calcium. Nifedipine appears to protect platelets from these stimuli and coupled with their known action on vessel walls, calcium channel blockers show promise as antiatherogenic as well as antithrombotic agents.
Thrombosis Research 02/1987; 45(2):135-43. · 2.44 Impact Factor
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Advances in internal medicine 02/1987; 32:137-54.
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Methods in Enzymology 02/1987; 149:312-25. · 2.04 Impact Factor
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The Journal of the Florida Medical Association 12/1986; 73(11):847-8.
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ABSTRACT: Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder, occurring predominantly in women. We studied by flow cytofluorimetry the T cell subsets in men and women with ITP and compared them with healthy sex-matched volunteers. In healthy controls, women were found to have higher proportions of T helper/inducer (Th/i) and lower T suppressor/cytotoxic (Ts/c) lymphocytes and consequently higher Th/i:Ts/c ratios than men. Accordingly, in clinical surveys, patients and controls should be matched for sex for proper comparisons. In patients with ITP in its active phase, an imbalance in T cell subsets was found in both sexes. The perturbation was more severe in women who had a marked decrease in number and proportion of Th/i lymphocytes and an increase in the proportion of Ts/c lymphocytes, whereas in men only, the proportion of Th/i lymphocytes was decreased. When patients with active disease were compared to those with ITP in remission, the decrease in Th/i subsets still persisted in both sexes but the Ts/c subset in women had returned to normal proportions. Therefore, the immune imbalance in ITP is more marked in women than men; imbalances in both Th/i and Ts/c are present in women while Ts/c appears not to be involved in men.
Blood 11/1985; 66(4):967-72. · 9.90 Impact Factor
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ABSTRACT: We evaluated the use of danazol in 15 patients with autoimmune hemolytic anemia of the warm antibody type. Danazol, 600 to 800 mg/d, was added to previous regimens or given initially in conjunction with high-dose prednisone treatment. Twelve patients with autoimmune hemolytic anemia associated with nonmalignant disorders or idiopathic autoimmune hemolytic anemia and 1 of 3 patients with underlying neoplasms showed a rise in hematocrit within 1 to 3 weeks. Thereafter, glucocorticoid doses were tapered to a minimum requirement or stopped. Once remission was sustained, the dose of danazol was reduced to 200 to 400 mg/d. Although levels of erythrocyte-bound IgG antibody and C3 decreased with therapy, only the decrease in C3 was statistically significant (p less than 0.05) in this limited study. Danazol was effective regardless of the severity of the disorder and success or failure of previous treatments. Danazol is valuable in the treatment of autoimmune hemolytic anemia and may be better suited than glucocorticoids for long-term management.
Annals of internal medicine 04/1985; 102(3):298-301. · 16.73 Impact Factor
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ABSTRACT: To understand better the role of the mononuclear phagocytic system (MPS) in accelerated destruction of donor platelets in man following repeated platelet transfusions, an experimental model has been developed using genetically defined animals. Brown Norway rats were immunized with Lewis platelets. Antibodies were detected by immunofluorescence microscopy, and their effects demonstrated by 111In-labeled platelet clearances in vivo and by measurements of organ radioactivity in sacrificed animals. All immunized rats developed platelet alloantibodies and showed a significant decrease (P less than 0.001) in donor platelet survival with sequestration in both the liver and spleen. Liver to spleen radioactivity ratios in nonimmunized animals were less than 0.1, whereas immunized animals had a ratio between 0.6 and 1.0, indicating relatively greater hepatic clearance of allogenic platelets. Studies currently in progress on the administration of vinca alkaloids to immunized animals suggest that the MPS can be impaired from clearing allogenic platelets. This model, therefore, should be helpful in studying the role of the MPS in platelet destruction.
Clinical Immunology and Immunopathology 06/1984; 31(2):163-70.
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ABSTRACT: A case in which polycythemia vera and chronic lymphocytic leukemia (CLL) developed during the course of idiopathic thrombocytopenic purpura (ITP) is described. Observations in this case suggest that ITP was a pre-monitor of the clinical development of CLL and preceded the manifestation of polycythemia vera. The polycythemia was mild, requiring infrequent phlebotomies, and, as the CLL progressed, the requirement for phlebotomy diminished. Evidence of both CLL and myeloid proliferation, as well as severe immune thrombocytopenia, persisted throughout her course. Studies on lymphocytes revealed characteristics of those of CLL. Excellent therapeutic response of the CLL was observed with the use of vinblastine and steroids.
Cancer 05/1984; 53(8):1770-6. · 4.77 Impact Factor
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ABSTRACT: Vinca alkaloids are useful in the treatment of idiopathic thrombocytopenic purpura, a disorder in which macrophages remove platelets sensitized with antibody. Because vinca alkaloids avidly bind to platelets, drugs can be delivered selectively to macrophages. However, drugs given by bolus injection are cleared too rapidly to bind optimally to autologous platelets, and the use of allogeneic platelets loaded with drug in vitro is cumbersome, expensive, and dangerous. Therefore, slow infusions were devised to prolong the duration of enhanced plasma drug concentrations, thereby providing better conditions for in-vivo drug loading into autologous platelets. Twenty-four patients with refractory idiopathic thrombocytopenic purpura were given slow infusions; 17 had good to excellent responses. Eleven of eighteen patients who had been treated with bolus injections had better results when treated with slow infusions. Patients with improved responses had slower plasma clearance rates than did patients with poor responses. Slow infusion therapy had fewer side effects than bolus injection therapy. Slow infusions are the best method for long-term management.
Annals of internal medicine 03/1984; 100(2):192-6. · 16.73 Impact Factor
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Springer Seminars in Immunopathology 02/1984; 7(1):35-42. · 4.17 Impact Factor
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ABSTRACT: ITP is a common disease that is sorely in need of better management. Treatment strategy requires consideration of both long-term benefits and long-term hazards of each available therapeutic option. This discussion reviews conventional therapy as well as newer approaches to refractory ITP, including immunosuppressants, vinca alkaloids, colchicine, androgens, tamoxifen, and plasmapheresis.
Hospital practice (Office ed.) 10/1983; 18(9):205-10, 215, 218-20.
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ABSTRACT: Idiopathic thrombocytopenic purpura is an autoimmune disorder, most common in young women. We treated 22 patients with this disorder (12 of whom were women) with danazol, an androgen with reduced virilizing capability, for two months or longer. Fifteen had undergone splenectomy, all were receiving glucocorticoids, and 18 had also been given other treatments. Fifteen of the patients were benefited, 11 with sustained normalization of their platelet counts. Six of eight patients tested had initial increases in circulating platelet-reactive IgG; in all six there was a marked decrease concomitant with danazol therapy. Danazol was effective in both men and women, irrespective of previous treatments. The duration of remissions ranged from 2 to 13 months. The drug was well tolerated and appears to be better suited than glucocorticoids for long-term management of idiopathic thrombocytopenic purpura, but the exact indications for the use of danazol in this disorder remain to be determined.
New England Journal of Medicine 07/1983; 308(23):1396-9. · 53.30 Impact Factor
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Advances in internal medicine 02/1980; 25:453-73.
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ABSTRACT: We devised a method to enhance delivery of vinblastine to macrophages, the cells believed to be responsible for platelet destruction in idiopathic thrombocytopenic purpura. Our strategy was based on the ability of platelets to bind vinca alkaloids such as vinblastine. Platelets were incubated with an excess of vinblastine, concentrated and then, after excess alkaloid had been removed, given to 11 patients with idiopathic thrombocytopenia refractory to other treatment (including intravenous injections of vinca alkaloids). Platelet antibodies in the patients' plasma led to ingestion of the vinca-laden platelets by macrophages. There were six complete remissions, three partial remissions and two failures. Side effects in a few patients, reversible but annoying, were minimized as technics were refined. We conclude that in patients with idiopathic thrombocytopenia refractory to all other measures, including the use of vinca alkaloids, platelet-vinca complex may be effective.
New England Journal of Medicine 06/1978; 298(20):1101-7. · 53.30 Impact Factor
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ABSTRACT: In summary, idiopathic thrombocytopenic purpura (as defined here) should be treated initially with glucocorticoids unless there is life-threatening hemorrhage (such as intracranial bleeding), in which case emergency splenectomy is indicated, since it generally gives the most prompt improvement in platelet count of all modes of the disease and to better define the cause of the thrombocytopenia. A complete, sustained remission following treatment with steroids may occasionally be obtained. In most cases the steroid response is transient, and splenectomy is the most definitive measure with respect to a lifelong cure. Complete clinical cure is obtained in 70-80% of instances following splenectomy, with a very low operative risk. The remainder either fail to respond or experience relapse. In this group of patients steroids should again be tried; if a good response is obtained, steroids should be given every second or third day to lessen long-term side effects. If these measures fail, the use of immunosuppressive agents is justified. Both vinca alkaloids and cyclophosphamide are especially useful. Vinca alkaloids act more promptly, but cyclophosphamide may have a more lasting effect. Azathioprine may also be used; however, it appears to yield a lower remission rate. Nonsteroidal immunosuppressive agents should not be used as the primary modality of therapy. And, due to their carcinogenic and teratogenic potential, they should be avoided, if possible, especially in children and in women during their childbearing years.
Annual Review of Medicine 02/1977; 28:299-309ENG. · 9.94 Impact Factor
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Advances in internal medicine 02/1975; 20:379-98.
