Adverse effects of estrogen therapy in a subset of women with ITP.
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Adolescent↗
Biomedical subjects
J B Bussel
Publications and source records attributed to J B Bussel.
T cell receptor VB repertoire diversity in patients with immune thrombocytopenia following splenectomy.
In recent years, a pathophysiological role for T cells in immune thrombocytopenia (ITP) has been established. We applied cDNA size distribution analysis of the T cell receptor (TCR) beta-variable (VB) complementarity-determining region 3 (CDR3) in order to investigate T cell repertoire diversity among immune thrombocytopenia patients who had either responded or not responded to splenectomy, and compared them to normal controls. ITP patients who had had a durable platelet response to splenectomy showed a mean 2.8 +/- 2.1 abnormal CDR3 size patterns per patient, similar to healthy volunteers (2.9 +/- 2.0 abnormal CDR3 size patterns). In contrast, patients unresponsive to splenectomy demonstrated evidence of significantly more clonal T cell expansions than patients who had responded to splenectomy or controls (11.3 +/- 3.3 abnormal CDR3 size patterns per patient; P < 0.001). Of the VB subfamilies analysed, VB3 and VB15 correlated with response or non-response to splenectomy, each demonstrating oligoclonality in non-responding patients (P < 0.05). These findings suggest that removal of the spleen may lead directly or indirectly to reductions in T cell clonal expansions in responders, or that the extent of T cell clonality impacts responsiveness to splenectomy in patients with ITP.
Adult↗
Anti-platelet antibodies associated with the Canale-Smith syndrome bind to the same platelet glycoprotein complexes as those of idiopathic thrombocytopenic purpura patients.
The Canale-Smith syndrome (CSS) is an inherited disease characterized by massive lymphadenopathy, hepatosplenomegaly and systemic autoimmunity to erythrocytes and platelets. Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease in which approximately 60-80% of patients have anti-platelet antibodies directed against specific platelet glycoprotein complexes (GPCs) located on their membrane: GP IIb/IIIa, GPIb/IX, and GPIa/IIa. Almost all (95-100%) of the antibody-positive patients have antibodies directed against GPIIb/IIIa alone, or in combination with other glycoprotein targets. Our objective was to determine the specificities of the anti-platelet antibodies in CSS patients. The detection of anti-platelet antibodies was performed using a commercially available ELISA, the Pak-AUTO (GTI, Brookfield, WI), in which highly purified GPIIb/IIIa, GPIb/IX, and GPIa/IIa are immobilized on microtitre plates, incubated with serum or plasma, and subsequently developed with an antihuman polyclonal immunoglobulin. Of 14 CSS patients tested, 11 (79%) had anti-platelet antibodies in their serum directed toward at least one of the three major GPC, nine (82%) of which were against GPIIb/IIIa alone or in combination. Antibodies detected in the sera of ITP patients had similar specificities. No such antibodies were detected in samples from 25 consecutive normal controls. These results demonstrate that a genetically defined defect in lymphocyte apoptosis results in a humoral autoimmune response with anti-platelet specificities very similar to the common idiopathic form of autoimmune thrombocytopenia.
Adolescent↗
Novel approaches to refractory immune thrombocytopenic purpura.
Chronic immune thrombocytopenic purpura (ITP) is an organ-specific autoimmune bleeding disorder in which autoantibodies are directed against the individual's own platelets, resulting in increased Fc-mediated platelet destruction by macrophages in the reticuloendothelial system. Although ITP is primarily mediated by IgG autoantibodies, the production of these autoantibodies is regulated by the influence of T lymphocytes and antigen-presenting cells (APC). There is evidence that enhanced T-helper cell/APC interactions in patients with ITP may play an integral role in IgG antiplatelet autoantibody production. New therapies may improve platelet production, decrease platelet antibody production, and decrease monocyte function and/or B-cell and T-cell activities. Understanding these cellular immune responses in ITP may lead to the development of more specific immunoregulatory therapies for the management of this disease.
Bone Marrow Transplantation↗
Fetal and neonatal thrombopoietin levels in alloimmune thrombocytopenia.
Thrombopoietin (Tpo) is the main hematopoietic growth factor for platelet production. Plasma Tpo levels in autoimmune thrombocytopenic patients are normal or slightly elevated. Although thrombocytopenia exists, Tpo levels are not increased because the produced megakaryocytes and platelets can bind circulating Tpo, thereby normalizing Tpo levels. In this study, plasma samples from fetuses and neonates with neonatal alloimmune thrombocytopenia (NAIT), a different form of immune thrombocytopenia, were measured. Umbilical cord samples from 50 fetuses before treatment because of severe thrombocytopenia and 51 fetuses after treatment, and peripheral blood samples of 21 untreated newborns with NAIT were analyzed. As controls, plasma Tpo levels were determined in 21 umbilical cord samples of 14 nonthrombocytopenic fetuses with hemolytic disease resulting from red blood cell alloimmunization and in umbilical cord samples of 51 healthy newborns. The values were also compared with the plasma Tpo levels in 193 healthy adults. Mean Tpo levels from the groups of fetuses and neonates, including both NAIT and control plasma, were slightly but significantly elevated compared with levels in healthy adults. Tpo levels in NAIT samples were not significantly different from the levels in hemolytic disease samples or in samples from healthy newborns. Thus, as in autoimmune thrombocytopenic patients, normal Tpo levels are present in NAIT patients.
Fetus↗
A pilot study of rhuIL-11 treatment of refractory ITP.
The objective of this research was to determine whether rhuIL-11 is an effective treatment in patients with refractory immune thrombocytopenic purpura (ITP). Platelet production is decreased in certain cases of refractory ITP. IL-11 stimulates megakaryocytopoiesis in vitro and was licensed for its clinical effects to ameliorate chemotherapy-induced thrombocytopenia. A pilot study was initiated, intending to enroll 12 patients with ITP. These patients were to receive rhuIL-11 (Neumega) at a dose of 50 microg/kg subcutaneously daily for 21 consecutive days and be observed afterward for 21 additional days. CBC with platelets were obtained twice weekly with visits and physical examinations weekly. The study was terminated after 7 patients were enrolled because of toxicity and lack of efficacy. All 7 patients had had ITP for >9 years and had failed splenectomy, intravenous gammaglobulin, corticosteroids, and a variety of other treatments. The patients at entry all had platelet counts <20,000/microl; 5 of 7 had counts <10,000/microl. The maximal median increase for any day of the study was 6,000/microl. No patient achieved a count of 30,000/microl, and only 3 patients achieved (once each) a platelet count >20,000/microl. Substantial toxicity was seen. The nadir hemoglobin decrease was a mean of 2 g/dl. rhuIL-11 was not effective at increasing the platelet count in any of these patients with refractory ITP. Toxicity was substantial. The lack of platelet response to rhuIL-11 in this study does not exclude the possibility of better effects at other doses and/or in less refractory patients.
Adolescent↗
Do the acute platelet responses of patients with immune thrombocytopenic purpura (ITP) to IV anti-D and to IV gammaglobulin predict response to subsequent splenectomy?
The acute platelet response to Intravenous Gammaglobulin (IVIG) has been reported to predict response to subsequent splenectomy of patients with ITP. The current study was undertaken to determine if the platelet response to IV anti-D (Winrho-SDF) predicts response to subsequent splenectomy. The 61 HIV-uninfected children and adults in this study had taken part in the pre-licensing studies of IV anti-D and were all those who not only had evaluable platelet responses to IV anti-D but also had undergone splenectomy and had information available describing its 1-year outcome. Results of treatment with IVIG were available in 38 of these 61 patients. Neither response to the initial infusion of IV anti-D, nor response to the initial or last IVIG, predicted the response in either children or adults to subsequent splenectomy. However, response to the last anti-D infusion in adults was strongly correlated (P = 0.003) to response to subsequent splenectomy as was hemolysis >/=2.0 gm/dl after IV anti-D (P = 0.03). There was no overall relationship between response to IV anti-D or IVIG, and response to subsequent splenectomy. However, a good platelet response in adults to the last IV anti-D and a hemoglobin decrease >/=2.0 gm/dl both appeared to predict response to subsequent splenectomy.
Adolescent↗
A dose of 75 microg/kg/d of i.v. anti-D increases the platelet count more rapidly and for a longer period of time than 50 microg/kg/d in adults with immune thrombocytopenic purpura.
Treatment with 75 microg/kg/d intravenous (i.v.) anti-D was compared with 50 microg/kg/d in a prospective randomized study of 27 RhD-positive, human immunodeficiency virus-negative, adult, acute, non-splenectomized patients with immune thrombocytopenic purpura (ITP) and platelet counts < or = 30 x 109/l. The higher dose resulted in greater median d 1 (43 x 109/l vs. 7.5 x 109/l; P = 0.012) and d 7 (153 x 109/l vs. 64.5 x 109/l; P = 0.001) platelet increases despite no greater haemoglobin decrease. Children with acute ITP receiving 75 microg/kg/d had overnight platelet increases in seven out of nine cases. The duration of effect at the 75 microg/kg/d dose was 46 d vs. 21 d (P = 0.03). Adverse events were mild to moderate and ameliorated with prednisone and acetaminophen premedication.
Acetaminophen↗
Alloimmune thrombocytopenia in the fetus and newborn.
Alloimmune thrombocytopenia is an interesting and challenging disease. Identification in the fetus and newborn by screening remains to be clarified. The primary clinical criterion for neonatal diagnosis appears to be a neonatal platelet count of <50 x 10(9)/L. Treatment of the neonate can be accomplished with intravenous immunoglobulin (IVIG) +/- steroids or with matched platelet transfusion. Cranial ultrasonography is important. Testing can be performed on the parents and requires a highly experienced laboratory. If an affected fetus is identified, based on a previous affected neonate and a homozygous father, antenatal management is needed. Studies have been completed that inform the still controversial decision. IVIG remains the basis of therapy but appears to require a higher dose (2 g/kg/week) and/or the addition of 1 mg/kg of prednisone in the highest risk cases, those with antenatal intracranial hemorrhage.
Antigens, Human Platelet↗
Initial fetal platelet counts predict the response to intravenous gammaglobulin therapy in fetuses that are affected by PLA1 incompatibility.
OBJECTIVE: Fetal alloimmune thrombocytopenia is the result of maternal fetal platelet antigen incompatibility; intracranial hemorrhage is its most serious complication. Our previous studies have demonstrated an inability to accurately predict fetal platelet counts in this disorder. The goal of the present investigation was to identify factors that would predict the response of the fetal platelet count to therapy so that use of fetal blood sampling could be minimized. STUDY DESIGN: Patients who were eligible for the study were all those who (1) had alloimmune thrombocytopenia secondary to Pl(A1) (HPA-1a, Zw(A)) platelet antigen incompatibility, (2) were treated with maternally administered intravenous immunoglobulin at 1 g/kg of body weight per week, with or without low dose steroids, and (3) had percutaneous fetal blood sampling before the initiation of therapy (first fetal blood sampling) and again 3 to 7 weeks afterwards (second fetal blood sampling). RESULTS: In this retrospective review, 74 patients who were affected by alloimmune thrombocytopenia had a median platelet count of 21,000 per microliter at the first fetal blood sampling and 47,000 per microliter at the second fetal blood sampling, with a median increase in platelet count of 24,000 per microliter. Response to treatment was defined as either (1) an improvement in platelet count (the second fetal blood sampling greater than the first fetal blood sampling, and second fetal blood sampling > 20,000 per microliter) or (2) a minimal decline in platelet count (the first fetal blood sampling > or = 40,000 per microliter and the difference between the first and second fetal blood sampling < or = 10,000 per microliter). The first fetal blood sampling had prognostic value for the second fetal blood sampling (P = .0001), although the previous sibling birth platelet count and history of sibling intracranial hemorrhage did not predict the platelet count at the first or second fetal blood sampling or the change in platelet count between the samplings. When the patients were segregated to first fetal blood sampling of > 20,000 per microliter versus < or = 20,000 per microliter, the response rates for the 2 groups were 89% (33/37 patients) versus 51% (19/37 patients; P = .001). CONCLUSION: In fetal alloimmune thrombocytopenia secondary to Pl(A1) platelet antigen incompatibility, fetuses with platelet counts > 20,000 per microliter at the initiation of therapy were predicted to maintain their platelet count at the second fetal blood sampling at > 20,000 per microliter. The characteristics of the previous sibling, as previously reported, did not predict the initial fetal blood sampling, the second fetal blood sampling, or the response to treatment.
Adult↗
Anti-HPA-3A induces severe neonatal alloimmune thrombocytopenia.
OBJECTIVE: Fetal and neonatal alloimmune thrombocytopenia (AIT) caused by feto-maternal incompatibility at the HPA-1a (PLA-1) locus is well characterized. Alloimmunization and disease caused by HPA-3a is rare. STUDY DESIGN: We conducted a retrospective analysis of all known cases of AIT caused by HPA-3a incompatibility identified at 3 major reference laboratories from 1986 to 1996. Platelet antigen typing and antibody specificity were determined by serologic evaluation. In some cases confirmatory genotyping was performed. RESULTS: Fourteen cases of anti-HPA-3a-induced AIT in 11 families were identified. Five patients had a previous affected sibling, and 2 cases were firstborn children. All patients had severe thrombocytopenia at birth (platelet count <20 x 10(9)/L). Regardless of therapy, the median time to platelet recovery was 6 days (range, 3 to 23 days). Two (15%) patients had documented intracranial hemorrhage, 1 with severe sequelae including apnea and convulsions. A literature review describing 16 additional patients corroborates the finding of severe thrombocytopenia and a significant incidence of intracranial hemorrhage caused by HPA-3a incompatibility. CONCLUSION: AIT caused by incompatibility of HPA-3a is similar in severity to disease caused by incompatibility of HPA-1a. Affected families should be appropriately counseled and considered for antenatal therapy.
Antigens, Human Platelet↗
Platelets: an update on diagnosis and management of thrombocytopenic disorders.
Thrombocytopenia in the pregnant patient may result from a number of causes, most of which involve either immune-mediated platelet destruction or platelet consumption. Many of these disorders share clinical and laboratory features, making accurate diagnosis difficult. Moreover, uterine evacuation is indicated in the therapy of some disorders, while in others alternative interventions may allow the pregnancy to be carried to term. These and other issues are discussed as part of a comprehensive review of the differential diagnosis and management of thrombocytopenia in pregnancy. The term "refractory ITP" is used with reference to two distinct groups of patients: 1) patients in whom the platelet count cannot be easily increased, including those who are poorly responsive to initial single agent treatment, and 2) those with persistent thrombocytopenia despite the use of conventional therapies. An approach to management of the former group will be presented, followed by a discussion of patients with chronic refractory ITP. The latter will include presentation of new data on the role of Helicobacter pylori in ITP and whether its treatment ameliorates thrombocytopenia, as well as the use of rituximab and other modalities. Thrombotic microangiopathies such as thrombotic thrombocytopenic purpura (TTP) are rare, but life threatening causes of thrombocytopenia. Ultra-large multimers of von Willebrand factor (vWF) aggregate platelets intravascularly, and congenital or immune-mediated deficiencies of a metalloprotease that cleaves these ultra-large multimers may cause TTP. However, little information exists concerning the behavior of this protease in other physiological and pathological conditions. Levels of this protease have now been measured in healthy individuals of different ages, full-term newborns, pregnant women and a patients with variety of pathologic conditions, and these data will be reviewed herein. Heparin-induced thrombocytopenia/thrombosis (HIT/T) remains the most common antibody-mediated, drug-induced thrombocytopenic disorder, and a leading cause of morbidity and mortality. Based on clinical correlations and murine models, there is increasing evidence that antibodies to complexes between platelet factor 4 (PF4) and heparin cause HIT/T, and the molecular composition of the relevant antigen has also become better defined. However, the introduction of sensitive ELISAs to measure anti-PF4/heparin antibodies has complicated diagnosis in some settings in which the incidence of such antibodies in unaffected patients exceeds the incidence of the disease. In addition, the FDA approval of Lepirudin and Argatroban has expanded the repertoire of agents available for therapy of HIT/T and may change the approach to management of asymptomatic patients with thrombocytopenia. However, the optimal use of these drugs in commonly encountered settings remains in evolution, and a need for alternative approaches to prevention and treatment is evident.
ADAM Proteins↗
Spontaneous remission of congenital acute nonlymphoblastic leukemia with normal karyotype in twins.
BACKGROUND: Congenital acute nonlymphoblastic leukemia (cANLL) is an extremely rare event and represents only 0.5-1% of the leukemias in the first year of life. It is usually more common among patients with chromosomal abnormalities. Transient myeloproliferative disease (TMD) is an hyperleukocytosis entity that occurs almost exclusively in Down syndrome patients and remits spontaneously. Spontaneous remission of congenital leukemia has been reported and related to the presence of an extra chromosome 21. PROCEDURE: A pair of non-Down syndrome newborn twins presented with a clinical picture of skin rash and hyperleukocytosis. Twin B had full-blown cANLL with bone marrow, peripheral blood, skin, CSF, and placental invasion. Twin A presented transient peripheral blood and skin involvement by the same type of blast cells. No cytotoxic therapy was given. With 2 years follow-up, they continue to do well. RESULTS: Histologic and immunophenotypical analysis of placentas, cord blood, skin, CSF, bone marrows, and peripheral blood revealed a consistent picture of intrautero cANLL in twin B, with transplacental invasion of twin A. Normal and blast cells were found to be karyotypically normal. Spontaneous remission occurred. CONCLUSIONS: cANLL with karyotypically normal blasts can develop a self-limited clinical course, which has resemblances to TMD.
Bone Marrow↗
Idiopathic immune thrombocytopenic purpura: an update.
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Autoantibodies↗
Fc receptor blockade and immune thrombocytopenic purpura.
Inhibition of antibody-coated platelet destruction in patients with immune thrombocytopenic purpura (ITP) is a well-known mechanism of treatment effect. A number of interventions that would ameliorate the thrombocytopenic effect of ITP patient plasma when infused into normal recipients were demonstrated in 1965. Subsequently, the antibody-coated chromium-labeled red blood cell clearance study was developed to allow direct in vivo assessment of Fc receptor (FcR) blockade. This was first demonstrated for corticosteroids but more extensive investigation began with the study of intravenous infusions of gammaglobulin (IVIg). The unequivocal demonstration of FcR blockade following IVIg Initiated novel approaches. One involved the infusion of a monoclonal anti-FcRIII ligand-blocking antibody into patients with refractory ITP. The efficacy of this treatment demonstrated that FcR blockade was not an epiphenomenon but rather an important mechanism of the increase in the platelet count in patients with ITP. Confirmation of its importance was obtained from the infusion of intravenous (IV) anti-D and the use of the isolated Fc piece of IgG. Recent studies have begun to explore the possibility of a monoclonal anti-FcRI and monoclonal anti-Ds. In summary, FcR blockade is an important mechanism of treatment effect in patients with ITP. Cytokine release as a consequence of this interaction and other immunomodulatory effects have only begun to be studied.
Adrenal Cortex Hormones↗
Splenectomy-sparing strategies for the treatment and long-term maintenance of chronic idiopathic (immune) thrombocytopenic purpura.
Patients with idiopathic thrombocytopenic purpura (ITP) have vulnerability to additional bleeding, leaving them susceptible to severe hemorrhaging. Low platelet counts contribute to this rare, but significant outcome, but may not be the sole determinant. Although the only current treatment of ITP felt to be curative is surgical removal of the spleen, the long-term outcome for these patients is not well defined. Our group Investigated the use of Intravenous gamma-globulin in the treatment of children with chronic ITP as a means to defer splenectomy. A variation of this approach uses anti-D to block splenic macrophages with antibody-coated red blood cells. There may be a correlation between response to anti-D and response to splenectomy in adults with ITP. Because the long-term results of splenectomy are not well defined, additional clinical studies are warranted. Questions requiring further study Include whether repeated Infusions of anti-D could allow the postponement and ultimate avoidance of splenectomy and whether the role of anti-D may be for pregnant women who are not readily eligible for splenectomy. Such an analysis should include information on the long-term outcome of splenectomy as well as information on whether patients have a durable improvement. Such studies about the potential outcomes of splenectomy and of avoidance of splenectomy will help identify new treatment strategies that may help to eliminate the need for this procedure in patients with chronic ITP.
Adult↗
The potential for treatment of idiopathic thrombocytopenic purpura with anti-D to prevent splenectomy: a predictive cost analysis.
Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder affecting both children and adults that can be manifested by severe bleeding episodes. Adult ITP patients have a low rate of spontaneous remission, and symptomatic patients commonly undergo splenectomy; however, maintenance therapy may increase the rate of remission, allowing splenectomy to be avoided. Anti-D is a recently licensed treatment for ITP that has the potential to delay, and possibly avoid, the need for splenectomy. We used preliminary data from an ongoing clinical trial to evaluate the costs involved in using anti-D therapy for 1 year with the intent of avoiding the need for splenectomy. We accounted for different possible outcomes at the completion of the clinical trial. An economic model with a theoretical cohort of 100 patients was developed using the model of an ongoing clinical trial. The average wholesale price was used to determine the cost of an infusion of anti-D based on an average dose ($1,213 per infusion). The cost of splenectomy was determined by a literature review ($16,000). Costs were calculated for all known patient outcomes; where outcomes were unknown and likely to vary, all possible outcomes were accounted for (splenectomy or no splenectomy). In our theoretical cohort, 31 of 100 patients were taken off anti-D and received splenectomy, 32 of 100 were stable after receiving anti-D and would not need splenectomy, and 37 of 100 had Indeterminate outcomes after receiving anti-D. When compared with the cost of the hypothetical scenario of initially giving all 100 patients splenectomy ($1.6 million), a minimum of 47 patients would have to avoid splenectomy to result in a cost savings for our cohort of 100 patients. The group of 47 patients avoiding splenectomy would be composed of the 32 patients comprising the stable group and at least 15 of the 37 patients comprising the group with indeterminate outcomes. If all 37 of the patients in the group with indeterminate outcomes avoid splenectomy, $363,000 and 69 spleens would be saved. Our data suggest that in the phase III trial of maintenance anti-D therapy versus immediate splenectomy, anti-D therapy will be a cost-effective option if 47% or more of patients avoid splenectomy.
Adult↗
Th1 and Th2 cytokines in a patient with Evans' syndrome and profound lymphopenia.
A case of Evans' syndrome with IgM deficiency and lymphopenia was studied before and after splenectomy. The lymphopenia was as a result of profound reduction of CD4 and CD8 cells. Study of cytokine secretion before splenectomy revealed a spontaneous Th1- and Th2-type cytokine production, and complete suppression of transforming growth factor (TGF)-beta. After splenectomy, the patient achieved clinical remission, the natural killer (NK) cell number increased and the pattern of cytokine production showed normalization of interleukin (IL)-2, IL-4, IL-10, TGF-beta and abolition of interferon (IFN)-gamma production. We conclude that splenectomy had a beneficial effect owing to an increase in NK cells and an associated increase in TGF-beta production.
Anemia, Hemolytic, Autoimmune↗