Biomedical subjects
J B Bussel
Publications and source records attributed to J B Bussel.
Favorable neurological outcome in 7 cases of perinatal intracranial hemorrhage due to immune thrombocytopenia.
Neonatal intracranial hemorrhage secondary to immune thrombocytopenia has been uniformly associated with neurological sequelae in survivors. These sequelae are seizures, hydrocephalus, mental retardation, and developmental delay. We report 7 survivors of intracranial hemorrhage who were prospectively evaluated regarding their long-term outcome at a mean of approximately 5 years of age. Five children were completely normal. One was delayed in speech, and one had a ventriculoperitoneal (VP) shunt in place and a residual hemiparesis. Four children had had seizures including the two with sequelae (speech delay and hemiparesis); only the patient with the VP shunt was still taking anticonvulsant medication. This latter patient was also the only one who required special education classes in which she was maintaining her grade level. In summary, a good long-term outcome can be expected in at least some patients with neonatal intracranial hemorrhage in cases of severe neonatal thrombocytopenia caused by maternal antiplatelet antibodies. This good outcome may be a result of, and should encourage, early diagnosis and vigorous supportive care in the neonatal intensive care unit.
Estimation of the risk of thrombocytopenia in the offspring of pregnant women with presumed immune thrombocytopenic purpura.
BACKGROUND AND METHODS: The optimal management of immune thrombocytopenic purpura during pregnancy remains controversial because the risk of severe neonatal thrombocytopenia remains uncertain. We studied the outcome of the index pregnancy in 162 women with a presumptive diagnosis of immune thrombocytopenic purpura to determine the frequency of neonatal thrombocytopenia and to determine whether neonatal risk could be predicted antenatally by history or platelet-antibody testing. RESULTS: Two maternal characteristics were identified as predicting a low risk of severe neonatal thrombocytopenia: the absence of a history of immune thrombocytopenic purpura before pregnancy, and the absence of circulating platelet antibodies in the women who did have a history of the condition. Eighteen of 88 neonates (20 percent; 95 percent confidence interval, 13 to 30 percent) born to women with a history of immune thrombocytopenic purpura had severe thrombocytopenia (platelet count less than 50 x 10(9) per liter at birth), as compared with 0 of 74 (0 percent; 95 percent confidence interval, 0 to 5 percent) born to women first noted to have thrombocytopenia during pregnancy (P less than 0.0001). Among the women with a history of immune thrombocytopenic purpura, 18 of 70 neonates (26 percent; 95 percent confidence interval, 16 to 38 percent) born to those with circulating platelet antibodies had severe thrombocytopenia, as compared with 0 of 18 infants (0 percent; 95 percent confidence interval, 0 to 18.5 percent) born to those without circulating antibodies (P less than 0.02). Thus, the risk of severe neonatal thrombocytopenia in the offspring of women without a history of immune thrombocytopenic purpura before pregnancy and of women with a history of the condition in whom circulating platelet antibodies are not detected was 0 percent (95 percent confidence intervals, 0 to 5 and 0 to 18.5 percent, respectively). CONCLUSIONS: The absence of a history of immune thrombocytopenic purpura or the presence of negative results on circulating-antibody testing in pregnant women indicates a minimal risk of severe neonatal thrombocytopenia in their offspring.
Alternation of two doses of intravenous gammaglobulin in the maintenance treatment of patients with immune thrombocytopenic purpura: more is not always better.
Intravenous infusion of gammaglobulin (IVGG) has been shown to be effective in the maintenance treatment of children and adults with immune thrombocytopenic purpura (ITP). The objective of this treatment is not to increase the platelet count into the normal range but rather to keep the platelet count above a safe level, usually 20,000-30,000/microliters. This use requires periodic infusion whenever the platelet count falls. The dose of gammaglobulin in previous studies was 1 gm/kg/infusion in the majority of patients. This study compared doses of 0.5 and 1.0 gm/kg/infusion by alternating the two doses in the maintenance treatment of 11 patients with ITP. There was no significant difference in the duration of response following single IVGG infusion between these two doses. This finding suggests that there is no advantage to the greater dose of IVGG and will substantially lower the cost of as well as facilitating IVGG maintenance treatment. It was not possible to determine whether a lower dose would impact adversely on the curative potential of IVGG. This effect of IVGG has never been proved and, if it exists, may be mediated by a different mechanism from the acute platelet response.
Antenatal management of fetal alloimmune and autoimmune thrombocytopenia.
Explore the source record for details and available documents.
Neonatal uses of intravenous immunoglobulin.
Intravenous gamma-globulin (IVGG) has several potential uses in neonates. A considerable amount of study is going into the evaluation of its role in neonatal sepsis. Preliminary results from two large controlled trials suggest that there may be a reduction in nosocomial sepsis following infusion of intravenous immunoglobulin (IVIG) in small premature infants, but the data are still incomplete. It is important to distinguish the two types of neonatal immune thrombocytopenia. In maternal autoimmune disease, neonatal intracranial hemorrhage has an incidence of only 1-2%, and treatment can be initiated postnatally in the thrombocytopenic neonate. Since antenatal hemorrhage is very rare, treatment of the mother for the sake of the fetus seems unnecessary. In alloimmune thrombocytopenia, on the other hand, intracranial hemorrhages occur in approximately 20% of all identified cases, and as many as one-half of these occur antenatally. Pilot studies of maternally administered IVGG have indicated that it may elevate the fetal platelet count and prevent intracranial hemorrhage.
Thrombocytopenia in newborns, infants, and children.
There are many causes of thrombocytopenia in infants and children. With experience, they can be readily identified and appropriate treatment instituted, if required. Particular attention should be paid to the well baby with unexplained thrombocytopenia, as alloimmune thrombocytopenia is the most common cause of intracranial hemorrhage due to thrombocytopenia and can be prevented if identified and treated early on. Autoimmune thrombocytopenia of childhood is generally benign, but children may require careful management until spontaneous resolution occurs. Human immunodeficiency virus infection should be looked for in these patients.
Autoimmune thrombocytopenic purpura.
The classic therapies of ITP are corticosteroids and splenectomy. These therapies will suffice to treat the majority of patients. In any patient with ITP in whom an urgent rise in the platelet count is required, especially children with acute ITP at diagnosis, gammaglobulin in combination with corticosteroids is very effective. In children with persistent ITP, avoiding splenectomy by using IVGG maintenance has been shown to be an effective form of therapy. For adults, most patients will be adequately treated by a short course of steroids followed by splenectomy, if needed. Other treatments are most needed in those adults whose ITP fails to respond to splenectomy or those who have special conditions. Danazol, vinca alkaloids, oral cyclophosphamide, and IVGG appear to be effective as chronic maintenance therapies, especially of splenectomized patients who are still thrombocytopenic. The role of newer therapies such as staph protein A pheresis and intravenous anti-D remains to be more completely explored.
Human megakaryocytes. VII. Analysis of megakaryocytes for nuclear DNA content distribution in whole marrow cell suspensions by flow cytometry.
These studies were designed to quantitate and determine the DNA content distribution of human marrow megakaryocytes using whole bone marrow. Cellular DNA content within megakaryocytic cells was established by measuring propidium iodide staining in marrow cells expressing platelet glycoprotein IIb/IIIa (Gp IIb/IIIa). These studies were based on the development of a method for rapid analysis of whole marrow cell preparations by a dual fluorescent system. DNA values ranging from 2 to 64 C were observed in all samples tested, with 16 C corresponding to the modal ploidy class representing almost one-half of the cells containing Gp IIb/IIIa. The second most frequent ploidy class corresponded to 32 C, followed by 8 C, with 20% and 15%, respectively. Virtually all high-ploidy megakaryocytes (greater than or equal to 8 C) were of low density (less than 1.050 g/cm3), whereas 2 and 4 C megakaryocytes were evenly distributed between less than or equal to 1.050 and greater than 1.050 g/cm3 marrow cells. These studies conclusively establish DNA content distribution of normal human marrow megakaryocytes and provide a basis for the study of states of altered megakaryocytopoiesis.
Clinical trial of single-dose intravenous gamma globulin in acute Kawasaki disease. Preliminary report.
Gamma globulin administered in a single dose of 1 g/kg of body weight intravenously caused prompt clinical improvement in 27 of 32 consecutive children with Kawasaki disease treated by the 12th day of illness. Response was equally good for the 20 children treated in the first week and the 12 treated in the second week. Fever and clinical signs abated within the first day after treatment, the mean white blood cell count normalized by 48 hours, and the sedimentation rate continued to be elevated for about 2 weeks, while the platelet count rose during the first 2 weeks after treatment and returned to normal approximately 1 month after treatment. Five children with incomplete relief needed more than the single dose before resolution of signs and symptoms occurred. Coronary aneurysms in 2 patients before treatment regressed by 2 weeks. No patient developed coronary aneurysms. No child had sequelae of Kawasaki disease at a follow-up of 2 to 31 months. We believe that although this was a one-arm, uncontrolled pilot study, the results suggest that this protocol provides a safe, flexible, and effective treatment for acute Kawasaki disease.
Commentary on the management of autoimmune thrombocytopenia during pregnancy and in the neonatal period.
Explore the source record for details and available documents.
Antenatal treatment of fetal alloimmune cytopenias.
The antenatal use of intravenous immunoglobulin (IVG) was explored in 9 cases of alloimmune cytopenias affecting fetuses. In 7 cases of alloimmune thrombocytopenia, IVG at a dose of 1 gm/kg/week appeared to be uniformly effective in elevating the fetal platelet count and preventing a recurrence of antenatal intracranial hemorrhage (2 cases). In 2 cases of Rh disease the results were more equivocal. There did not appear to be any significant toxicity associated with its use. The mechanism of IVG effect in the successfully treated cases remains uncertain.
The use of intravenous gamma-globulin in idiopathic thrombocytopenic purpura.
In 1981, Imbach et al. (Lancet, 1, 1228-1231) reported that infusion of intravenous immunoglobulin (IVIG) would substantially elevate platelet counts in children with acute or chronic idiopathic thrombocytopenic purpura (ITP). Subsequent studies confirmed these findings and extended the effect to adults and to newborns with passive immune thrombocytopenia. Studies in children with acute ITP demonstrated that administration of IVIG was the fastest way to increase a patient's platelet count, and that this agent could be given at doses as high as 1 g/kg/day so that the course of therapy and response to treatment would be more rapid. Reports of effective treatment of patients with autoimmune neutropenia and autoimmune hemolytic anemia by IVIG broadened the scope of its usefulness. In addition, several studies in children and adults with chronic ITP suggested that repeated infusions were a safe and effective way to maintain an adequate platelet count in such patients, and might also gradually lead to lasting improvement. These studies and Imbach's controlled trial in children with acute ITP suggested that IVIG therapy might provide a curative effect in addition to the acute effect. To combine all of these clinical effects with a multitude of in vitro observations to explain the mechanism of action of IVIG is complicated. Fehr et al. (N. Engl. J. Med. 306, 1254-1258, 1982) showed that Fc receptor blockade occurs following administration of IVIG. This effect is clearly demonstrated in vivo by the delayed removal from the vascular space of antibody-coated red blood cells following infusion of IVIG. In addition, many less well-defined effects occur in relation to immunoglobulin production, induction of suppressor cells, antiplatelet antibody levels, and bone marrow platelet production. Studies continue to try to define which effects actually underlie the clinical effects seen, and which are merely test-tube phenomena.
Modulation of Fc receptor clearance and antiplatelet antibodies as a consequence of intravenous immune globulin infusion in patients with immune thrombocytopenic purpura.
In 1981 Paul Imbach first reported the usefulness of intravenous immune globulin infusions in the treatment of children with immune thrombocytopenic purpura. Other studies have shown that intravenous immune globulin was associated with the fastest platelet increase of any therapy, confirming the initial observation in children and adults. We and other investigators have used intravenous immune globulin as a maintenance therapy and speculated that repeated single infusions might have a curative value, in addition to an acute effect. The best-defined mechanism of intravenous immune globulin in this model autoimmune disease is Fc receptor blockade. This was first demonstrated by a slowing of antibody-coated, chromium-labeled red blood cell survival. Subsequent confirmation has come from the use of intravenous anti-D and a monoclonal anti-FcRIII that has been used in patients refractory to treatment. In vitro studies have demonstrated alteration in Fc receptor expression on circulating cells, and this mechanism is presumed to be related intimately to the acute platelet increase seen after intravenous immune globulin. Studies with the latest platelet antibody methodology do not support interference with binding of antiplatelet antibodies as an important mechanism, but there are in vitro data to support this hypothesis. Another leading hypothesis is that intravenous immune globulin decreases the production of autoantibodies. Clinically, this has been suspected in immune thrombocytopenic purpura in which there are apparent improvements in patients with chronic disease, but no controlled studies have been performed to verify this. In acquired hemophilia and von Willebrand's disease, however, it seems quite clear that there is direct neutralization of autoanti-factor VIII antibodies by intravenous immune globulin by a presumed Fab-mediated anti-idiotype mechanism. This hypothesis has appeal and has been postulated on the basis of in vitro studies, as well as looking directly at the B cell. Another study supporting this mechanism showed that intravenous immune globulin preparations with altered Fc portions still mediate some platelet increase, even if not as much as intact IgG molecules. It remains unclear whether any effects that are the result of a lower level of autoantibody could be mediated through T cells or macrophages, rather than having direct action on the B cell. In any event, these findings strongly support the hypothesis that decreased levels of autoantibody lead to intermediate (weeks) and long-term (months to years) responses after intravenous immune globulin treatment.
Antenatal treatment of neonatal alloimmune thrombocytopenia.
Neonatal alloimmune thrombocytopenia results from the formation of a maternal antibody to a paternal antigen on fetal platelets. Intracranial hemorrhage, which may be antenatal, occurs in approximately 15 to 20 percent of infants with this form of thrombocytopenia. In families with an affected infant, 75 percent of subsequent infants are affected. We report the results of antenatal treatment with intravenous gamma globulin, with or without dexamethasone, in seven pregnant women who had previously had infants who had severe alloimmune thrombocytopenia. The platelet count increased by a mean (+/- SD) of 72.5 +/- 62 x 10(9) per liter in the six fetuses in whom periumbilical blood sampling was performed. All seven treated fetuses had platelet counts above 30 x 10(9) at birth, and none had an intracranial hemorrhage, in contrast to all seven of their respective untreated siblings, who had lower platelet counts and three of whom had intracranial hemorrhages (antenatal in two infants). Mild intrauterine growth retardation was observed in one treated infant; all seven infants have developed normally in the two months to four years since birth. We conclude that intravenous gamma globulin, with or without dexamethasone, is effective in elevating the fetal platelet count in severe cases of neonatal alloimmune thrombocytopenia and in helping to avoid intracranial hemorrhage.
T cell antigen receptors in autoimmunity.
Three mAb to variable region determinants of the alpha/beta-chain TCR were used to detect discrete populations of peripheral blood T cells. T cells sharing a TCR determinant defined by such an antibody presumably use the same or similar TCR V or J genes for their alpha- or beta-chains. Thus analysis with these mAb provides a tool to investigate TCR gene usage and expression. Since autoantigen specific T cells may play an important role in initiating autoimmune diseases, TCR were analyzed in different autoimmune diseases and control groups including rheumatoid arthritis, Graves disease, idiopathic thrombocytopenic purpura, psoriasis, SLE, insulin-dependent diabetes mellitus, and in nonautoimmune control diseases and normals. Purified T cells were stained by indirect immunofluorescence with three mAb to TCR variable regions: mAb S511 stains 1.8 +/- 0.9% (mean +/- 2 SD), mAb C37 stains 3.4 +/- 1.5% and mAb OT145 stains from 0 to 6% of T cells from normal donors. Several individuals were identified with expanded subsets of positive T cells. One patient with adult ITP followed during a 12-mo period consistently had elevated percentages of T cells staining with the mAb OT145 (15.9 to 24.5%). These cells were found to be exclusively CD8+. By Southern blotting DNA prepared from these OT145+, CD8+ cells, but not DNA from the patient's OT145- T cells, revealed a clonal rearrangement using a beta-chain C region probe. Thus this patient had a monoclonal expansion of CD8+, OT145+ cells. Hyperexpression of a TCR variable region, as defined by the available mAb, could not be associated with any of the diseases studied. Examination of T cells at the site of autoimmunity, such as T cells from rheumatoid arthritis synovial fluid, revealed normal percentages of cells staining with these mAb. Immunoperoxidase staining of psoriatic lesional skin showed no striking enrichment of T cells bearing one or the other TCR type.
Isolated thrombocytopenia in patients infected with HIV: treatment with intravenous gammaglobulin.
Isolated thrombocytopenia occurs frequently in patients infected with HIV. Studies of mechanisms of thrombocytopenia and clinical response to therapy suggest that the thrombocytopenia is often antibody mediated (ITP). The best approach to treatment of these patients is uncertain in that the routine modalities (steroids, splenectomy, vinca alkaloids) that are used to increase the platelet count in patients with classic ITP are known to be immunosuppressive. We report here the results of intravenous gammaglobulin (IVGG) treatment of 22 patients with HIV-related acute and chronic ITP who had severe thrombocytopenia and bleeding symptoms. Only one patient had an opportunistic infection at the time of treatment. Eight patients were homosexual, eight had hemophilia, three were i.v. drug abusers, two children had congenital acquisition of HIV, and one was the wife of an HIV + i.v. drug abuser. The average pretreatment platelet count was 22,000/microliter (hemophiliacs were treated at higher platelet counts than were the other patients), and the mean peak platelet count measured on days 5 to 8 was 182,000/microliter. Nineteen of 22 patients had peak platelet counts greater than 50,000/microliter following IVGG and 17/22 had peak counts greater than 100,000/microliter. After the initial infusions, all but three refractory patients could maintain adequate platelet counts with IVGG alone infused no more often than once every 2 weeks. The outcomes for the 22 patients after multiple maintenance IVGG infusions were remission, 5; stable without therapy, 1; maintenance, 13; and refractory, 3. The eight hemophiliacs with ITP responded better than did the eight homosexual ITP patients; their mean peak platelet count was 227,000/microliter versus 142,000/microliter in the homosexuals. In summary, patients with HIV-related ITP without opportunistic infections responded well to IVGG, with peak platelet counts comparable to those of ITP patients not infected with HIV. IVGG may be a useful therapy of ITP in HIV+ patients, since it appears to be less immunosuppressive than are conventional therapies, and none of the 22 HIV+ patients developed an opportunistic infection while receiving IVGG alone.
Cost-effectiveness of splenectomy versus intravenous gamma globulin in treatment of chronic immune thrombocytopenic purpura in childhood.
Infusions of intravenous gamma-globulin (IVGG) are an effective, nontoxic therapy for chronic idiopathic thrombocytopenic purpura (ITP) that would be more widely accepted if the therapeutic agent were not so expensive. The costs and outcomes of managing such children with splenectomy and IVGG were modeled with Markov processes. Children unresponsive to one treatment were considered to have received the alternative. The model accounted for spontaneous remissions, therapeutic responses, traumatic events, episodes of sepsis, and operative deaths. For a 10-year-old child with chronic ITP, the strategy of initial treatment with splenectomy had associated costs of $17,000 and a 97.9% ten-year survival rate, whereas the strategy of initial treatment with IVGG had associated costs of $21,000 but a 98.6% survival rate. Each additional life saved by employing the IVGG strategy cost $540,000, or $8,000 per year for a life expectancy of 70 years. Sensitivity analyses demonstrated that for older children the IVGG strategy continued to result in improved survival rates but was more costly than the splenectomy strategy. For younger children, the IVGG strategy dominated, with improved survival rates and lower costs.