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Biomedical subjects

M W Hilgartner

Publications and source records attributed to M W Hilgartner.

At least 73 records · Page 4Linked to original sources
PubMed1987

Use of intravenous gamma globulin for the treatment of autoimmune neutropenia of childhood and autoimmune hemolytic anemia.

Intravenous gamma globulin (IVIG) was used to treat autoimmune neutropenia of childhood and autoimmune hemolytic anemia, two autoimmune disorders not previously treated with this modality. Six children younger than two years of age, who presented with severe infections and persistent absolute neutrophil counts (300/mm3), were treated with 1 g of gamma globulin per kilo body weight until counts reached more than 1,000/mm3. The average response occurred with a dose of 3.0 g/kg within five to seven days and lasted an average of 14 days before counts decreased to baseline levels. Four patients with autoimmune hemolytic anemia were also treated with IVIG, 1 g/kg for five to seven days (average dose of 5 g/kg), for severe Coombs'-positive hemolytic anemia. Response of the hemolytic anemia to IVIG was excellent in one patient and good in two patients. No response occurred in the fourth patient. Response was slower in these patients than in patients treated for immune thrombocytopenic purpura (ITP). The average total amount of gamma globulin required for a response is markedly different: 1 g/kg for ITP, 3.0 g/kg for autoimmune neutropenia, and 5 g/kg for hemolytic anemia. Possible mechanisms of action include blockade of reticuloendothelial system Fc receptors, suppression of autoantibody production, and/or interference in the binding of autoantibodies to target cells.

Agranulocytosis↗
PubMed1987

HTLV-III neutralizing antibody development in transfusion-dependent seropositive patients with beta-thalassemia.

Sera collected in New York in 1984 from 77 patients with homozygous beta-thalassemia were assayed for antibodies to HTLV-III by ELISA and Western blot techniques. Eight (12%) of the 66 hypertransfused thalassemics were seropositive. Retrospective sera of these eight individuals were examined by radioimmune precipitation (RIP), and assays for neutralization of virus infectivity were performed. With seroconversion, antibodies to viral envelope proteins appeared first and were correlated with development of neutralizing antibody. Affinity purified gp120, the major envelope glycoprotein of HTLV-III, blocked viral infectivity and absorbed neutralizing antibody activity from a positive serum. Neutralizing antibody titers mirrored antibody titers to gp120 by RIP. Antibody to gp120 sometimes occurred in the absence of neutralizing antibody, although the reverse was not true. One thalassemia patient who exhibited antibody to gp120 for 3 yr post-seroconversion failed to develop neutralizing antibody, acquired the acquired immunodeficiency syndrome with central nervous system involvement and lymphoma, and subsequently died. In contrast, all other seropositive thalassemics possessed neutralizing antibodies, and were asymptomatic or exhibited only lymphadenopathy. These results indicate that gp120 elicits neutralizing antibodies in the course of natural infection with HTLV-III. The relationship seen here between neutralizing antibody and better clinical outcome needs to be verified by additional studies.

AIDS-Related Complex↗
PubMed1987

Reproductive choices in hemophilic men and carriers.

We have examined reproduction patterns in hemophilic men and carrier women seen at a hemophilia treatment center. The study group included 309 patients with hemophilia A or B: 194 adults and 115 children from 246 pedigrees; 93% of affected men and 96% of parents of affected children had received genetic counseling. In the collected pedigrees, 65% of affected males were born to women with family history of hemophilia. An additional 23% of mothers were later shown to be carriers. Fewer than 12% of cases could be due to a new mutation in the child. Among 209 hemophilia A carrier tests, 95% of obligate carriers were detectable, 87% of mothers of sporadic cases, 53% of sisters of hemophiliacs, and 24% of other relatives had a high risk of carriership. Of 49 high-risk women seen during or prior to pregnancy, one-half elected prenatal diagnosis. Amniocentesis was performed in 24 cases and 8 were referred for fetoscopy, resulting in 18 normal offspring. Among 25 pregnancies not tested, 14 continued and produced 3 affected males and 11 normal offspring. Of hemophilic men over age 25, 66% have married and 41% (62% of those married) have had children. These observations will serve as a baseline for assessing any change in reproductive patterns occurring with the introduction of new genetic techniques.

Adult↗
PubMed1987

Intravenous immunoglobulin therapy of idiopathic thrombocytopenic purpura in childhood and adolescence.

Intravenous immunoglobulin is not only a dramatic clinical therapy, but it is also extremely interesting in regard to mechanism of action. The high cost of therapy limits its application, yet it appears to be equal to or perhaps slightly more effective than corticosteroids as a treatment of ITP and is far less toxic with prolonged use. The appropriate place for its exact use remains to be determined but probably includes patients urgently requiring rapid platelet increases (in conjunction with steroids), treatment of immunocompromised patients, and treatment of chronic patients, either children to avoid splenectomy or adults with severe disease after splenectomy. Controlled trials to resolve these clinical questions are urgently needed. Existing studies on its mechanisms of actions are very interesting and have furthered our understanding of the pathophysiology of ITP. Although future work may lead to further applications, initial enthusiasm for the use of IVGG in the treatment of other autoimmune diseases with the exception of myasthenia gravis has been limited by subsequent clinical experience.

Acute Disease↗
PubMed1987

Modulation of the defective natural killer activity seen in thalassaemia major with desferrioxamine and alpha-interferon.

We previously observed that natural killer (NK) activity toward K562 cells is markedly depressed in patients with beta-thalassaemia major. Here we report that these patients also exhibit significantly decreased (P less than 0.005) NK cytotoxicity against human fibroblasts infected with herpes simplex virus-type 1 (HSV-1) and that the amount of alpha-interferon (alpha-IFN) generated during the latter assays is significantly less than normal (P less than 0.005). This decreased production of alpha-IFN may account in part for the decreased NK activity seen in the thalassaemia patients. On the other hand, the cytotoxicity of their mononuclear cells (MNC) toward both K562 cells and HSV-1-infected fibroblasts could be augmented to the same extent as that of normal MNC by preincubation with alpha-IFN suggesting that thalassaemia MNC are capable of responding to this lymphokine despite their reduced ability to produce it. Moreover, preincubation of thalassaemia MNC with desferrioxamine (DFO), an iron-chelating agent, consistently increased the lysis of K562 cells indicating that the transfusion-induced iron overload which these patients experience may also contribute to the defective NK function seen in this disease. We have now found that preincubation of such MNC with DFO has no effect upon production of alpha-IFN when the MNC are cocultured with either HSV-1-infected fibroblasts or K562 cells. Combining DFO and alpha-IFN resulted in an increase in the NK activity of both normal and thalassaemia MNC against the two targets which was greater than that with alpha-IFN alone. In fact, preincubation of thalassaemia cells with this combination increased their NK activity toward K562 targets to that of untreated normal cells. This was true when either unfractionated MNC or NK-enriched fractions were used as effector cells. These results suggest that DFO and alpha-IFN enhance NK activity by different mechanisms, both of which appear to be reversibly impaired in thalassaemia patients.

Cytotoxicity, Immunologic↗
PubMed1986

PROPLEX vs. PROPLEX SX: a controlled double blind study of the effectiveness in treating acute hemarthroses in hemophilia A patients with inhibitors to factor VIII.

A blinded randomized multicenter trial of two non-activated prothrombin complex concentrates was carried out to determine the clinical effectivity in the treatment of acute hemarthrosis in hemophiliac patients with inhibitors. The one product was prepared via DEAE Sephadex chromatography, while the second was fractionated via various precipitation procedures including polyethylene glycol. Equivalence of the two products was established with less than 15% difference in efficacy rates.

Blood Coagulation Factors↗
PubMed1986

Decreased natural killer activity in thalassemia major: a possible consequence of iron overload.

We have investigated the natural killer (NK) activity of both fractionated (Percoll density gradient) and unfractionated mononuclear cells from patients with beta-thalassemia major who are iron overloaded as a consequence of chronic transfusion therapy. These patients were found to have significantly decreased NK activity against K562 targets at all effector:target ratios tested (p less than 0.001). Both splenectomized and nonsplenectomized patients had normal proportions of Leu-11b-staining (NK) cells. Since they had normal to elevated absolute white cell and lymphocyte counts, a change in the absolute number of NK cells could not account for the decreased killing. We also found that the decrease in NK activity was transfusion related (r = -0.603, p less than 0.005). To determine whether or not this decrease in NK activity could be related to iron overload, we preincubated patient effector cells with desferrioxamine (DFO) or 2,3-dihydroxybenzoic acid (DHB) for 6 hr before addition of K562 targets. Both of these iron-chelating agents consistently increased the NK activity of cells from thalassemia patients. DHB had the greater effect, being able to increase patient NK activity to virtually normal levels. On the other hand, preincubation of cells from normal controls with DHB caused only a slight increase in NK activity, while similar treatment with DFO had little or no effect. When target cells were preincubated with the chelating agents before addition of either normal or patient effector cells, no change in cytotoxicity was seen, demonstrating that the chelating agents act at the effector cell level. Furthermore, if the chelating agents were saturated with iron prior to preincubation with the effectors, no increase in the cytotoxicity of thalassemic NK cells was observed. These results indicate that thalassemia patients have a reversible, transfusion-related decrease in NK function which may arise as a consequence of iron overload.

Cell Separation↗
PubMed1986

Concurrence of von Willebrand's disease and hemophilia A: implications for carrier detection and prevalence.

Five families with concurrent von Willebrand's disease (VWD) and classic hemophilia (hemophilia A) are described. Three were ascertained through women undergoing hemophilia carrier testing, one through an obligate carrier who also has VWD, and one through the affected father of a hemophiliac. The VWD probands exhibited Type I VWD with reduced Factor VIII-related antigen (VIIIR:Ag) and/or von Willebrand factor on more than one occasion, normal VIIIR:Ag on crossed immunoelectrophoresis, and mild symptoms. No male had both disorders, but two obligate hemophilia carriers also had VWD. Neither was detectable as a carrier by discriminant analysis. Four possible carriers of hemophilia had VWD and would also be classified as noncarriers statistically. These findings suggest that the presence of VWD may invalidate hemophilia carrier testing by conventional methods. The independent entry into the family of the two genes by mating of a hemophilia carrier and a VWD male is documented in two cases and probable in two. The observed frequency of such matings supports the hypothesis that VWD is a common disorder.

Adolescent↗
PubMed1986

Current treatment of patients with inhibitors to factor VIII.

The development of inhibitors against factor VIII or IX in hemophilic or nonhemophilic patients is a relatively rare condition, but basic and clinical studies of these inhibitors have been extremely fruitful and have led to the following: a better understanding of the structure-function relationships of the factor VIII and IX molecules; increased knowledge of the genetic defect in classic hemophilia and hemophilia B; newer insights into antibody formation against clotting factors; and an increased number of therapeutic options for the treatment of patients who have inhibitors to factor VIII or IX. The prevalence of inhibitors to factor VIII:C in the hemophiliac population of the U.S. was obtained in the NHLBI multi-center trial using 1500 patients and is estimated to be 14.5%. The vast majority of these inhibitors occurred in severely affected hemophiliacs less than twenty years of age with factor VIII:C levels of less than 0.03 u/ml. However, occasional older patients or those with F. VIII:C greater than 0.03 u/ml did develop inhibitors.

Blood Coagulation Disorders↗
PubMed1985

Treatment of acute idiopathic thrombocytopenia of childhood with intravenous infusions of gammaglobulin.

Gammaglobulin treatment was given at a dose of 1 gm/kg/day intravenously in 29 patients with acute idiopathic thrombocytopenic purpura: 15 previously untreated, 10 resistant to steroids, and four who were steroid dependent. The average platelet increase in 24 hours was greater than 50,000/microliter; the average peak platelet count was 194,000/microliter. Eighteen of 25 patients required only one infusion; 10 of these 18 never required any additional (maintenance) therapy. Outcome in previously untreated and steroid-resistant patients was identical; however, previously untreated patients required only 1.8 gm/kg total dose of gammaglobulin, whereas steroid-resistant patients received 3.9 gm/kg. Only one steroid-dependent child of the 29 patients still requires maintenance therapy, at 6-week intervals. Toxicity was minimal. Cost was minimized by not admitting patients and by giving treatment in one visit, rather than five.

Acute Disease↗
PubMed1985

Characterization of an occult inhibitor to factor IX in a haemophilia B patient.

Six haemophilia B patients were studied while undergoing infusion with factor IX concentrate. All were negative for factor IX antigen (IX:AG) and inhibitor to factor IX coagulant activity (IX:C). One patient showed an atypical response pattern, with prolonged survival of IX:C and IX:Ag. This patient remained under prophylactic treatment and more than 1 year later developed an inhibitor to IX:C of clinical significance. Retrospective study revealed that this patient had significantly higher levels of circulating immune complexes than other haemophilia B patients and in vivo formation of immune complexes containing IX:Ag prior to detection of his inhibitor in conventional clotting assays, suggesting long-term persistence of an occult inhibitor. The inhibitor was shown to be an IgG antibody with both kappa and lambda light chains.

Adult↗
PubMed1985

Disproportionate lymphoid cell subsets in thalassaemia major: the relative contributions of transfusion and splenectomy.

The relative proportions of T-cell (OKT3-positive, OKT4-positive and OKT8-positive) and B-cell (SIg-positive) populations in peripheral blood obtained from 29 chronically transfused patients with beta-thalassaemia major were compared with those of 17 healthy controls. Changes attributable to blood transfusion and/or splenectomy are described. The percentage of OKT8-positive (T-suppressor) cells found in the thalassaemic patients increased linearly (P less than 0.001) with the number of units transfused, irrespective of splenectomy. The percentage of OKT4-positive (T-helper) cells varied inversely with increasing transfusion in nonsplenectomized patients while in those who were splenectomized no significant correlation was apparent. Thus, in both groups of patients the T4/T8 ratio declined in a transfusion-related manner. The splenectomized patients experienced a marked and persistent lymphocytosis due to an increase in the number of both T- and B-cells. When the results were expressed as percentages, the greatest increase occurred in the number of B-cells, this increase being unrelated to the number of transfusions received. None of the serum parameters usually associated with iron overload or abnormal liver function correlated with the observed increases in T-suppressor and SIg-positive cells. These findings corroborate reports that transfusion of blood products may lead to decreased T4/T8 ratios. However, none of the patients studied manifested clinical signs of acquired immune deficiency syndrome (AIDS). Accordingly, studies which define transfusion related AIDS on the basis of analyses with monoclonal antibodies must be viewed with caution.

Adolescent↗
PubMed1985

Immunological abnormalities in thalassaemia major. I. A transfusion-related increase in circulating cytoplasmic immunoglobulin-positive cells.

Multiply transfused patients with beta-thalassaemia major have elevated serum immunoglobulin levels and a transfusion-related increase in (T8+) T-suppressor cells. We report here that these patients also have a significantly increased (P less than 0.001) proportion of B-cells that contain cytoplasmic immunoglobulin when visualized immediately upon isolation. On the other hand, the same cell populations do not exhibit an increase in the proportion of immunoglobulin-secreting cells as measured by a reverse haemolytic plaque assay. These results, together with those of ongoing studies, suggest that the cells containing the cytoplasmic immunoglobulin are likely to be terminally differentiated B-cells which persist in the circulation. While the reason for this phenomenon is not yet known, we have found that the increase in these cells is transfusion-related.

B-Lymphocytes↗