Familial thrombocytopenia with micromegakaryocytes: what is the defect in thrombopoiesis?
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Blood Platelets↗
Biomedical subjects
J B Bussel
Publications and source records attributed to J B Bussel.
Antenatal treatment of alloimmune thrombocytopenia.
OBJECTIVE: Neonatal alloimmune thrombocytopenia is caused by platelet antigen incompatibility between the mother and fetus. Affected fetuses may have severe thrombocytopenia leading to intracranial hemorrhage before or at birth. We sought to treat this condition in utero to prevent these hemorrhages. METHODS: Eighteen women who had previously delivered infants with severe alloimmune thrombocytopenia were treated with weekly infusions of intravenous gamma globulin from the diagnosis of fetal thrombocytopenia until birth; nine were also treated with corticosteroids. RESULTS: There were no intracranial hemorrhages in the treated fetuses, compared with ten cases among the 21 untreated siblings (48%). Only three treated fetuses, compared with 16 of 20 untreated siblings, had platelet counts of less than 30,000/microL, with no bleeding complications. CONCLUSION: Antenatal treatment of alloimmune thrombocytopenia with weekly gamma globulin effectively improves the fetal platelet count and prevents intracranial hemorrhage.
Adrenal Cortex Hormones↗
Prenatal diagnosis of neonatal alloimmune thrombocytopenia using allele-specific oligonucleotide probes.
The prediction of neonatal alloimmune thrombocytopenia (NATP) in affected families has, in the past, been based on information about gene frequencies of the antigen systems involved, parental phenotyping, and fetal platelet counts. We explored the feasibility of allele-specific oligonucleotide probe typing for PIA antigens to determine the risk of second or subsequent fetuses in families where one infant had a diagnosis of anti-PIA1-mediated NATP. A total of eight families at risk for delivering an affected fetus were studied with both serologic and oligonucleotide typing. The correlation between serologic and oligonucleotide PIA types was 100%. Similarly, in an additional eight families not at risk for PIA1-mediated NATP, serologic and oligonucleotide typing maintained a perfect correlation. DNA isolated from fetal leukocytes as well as fetal amniocytes was successfully typed using this technology. Oligonucleotide-based typing of fetuses at risk for NATP whose fathers are heterozygous for the PIA antigens allows early recognition of affected fetuses so that prenatal therapy of mothers can be instituted if necessary. When fetuses are found to be unaffected, invasive, and/or expensive, prenatal interventions can be avoided.
Adult↗
Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect.
The efficacy, toxicity, and mechanism of effect of intravenous Anti-D (Winrho) were studied in 43 Rh+ patients with immune thrombocytopenia purpura (ITP) who had not undergone splenectomy and in three already splenectomized patients. The mean platelet increase for the 43 nonsplenectomized patients was 95,000/microL (median 43,000/microL). Children had greater acute platelet responses than did adults. Human immunodeficiency virus status and duration of thrombocytopenia did not affect response. Maintenance treatment was given to patients as needed: the average interval between infusions was 24 days. The three splenectomized patients had no platelet response whatsoever. Toxicity was minimal; infusions were completed in less than 5 minutes. The generally accepted mechanism of effect of Anti-D has been Fc receptor blockade by substitution of antibody-coated red blood cells for antibody-coated platelets. Evidence is presented suggesting that the effect of IV Anti-D is not limited to Fc receptor blockade, including: (1) no correlation of parameters of hemolysis with platelet increase; (2) a 48- to 72-hour delay before platelet increase; (3) a tendency of the change in monocyte Fc receptor I expression to correlate with platelet increase; and (4) increased in vitro production of antibodies to sheep red blood cells following IV Anti-D infusion.
Adult↗
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.
Cerebral Hemorrhage↗
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.
Autoantibodies↗
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.
Dose-Response Relationship, Drug↗
Antenatal management of fetal alloimmune and autoimmune thrombocytopenia.
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Adrenal Cortex Hormones↗
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.
Bacterial Infections↗
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 Diseases↗
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.
Adrenal Cortex Hormones↗
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.
Bone Marrow Cells↗
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.
Acute Disease↗
Commentary on the management of autoimmune thrombocytopenia during pregnancy and in the neonatal period.
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Autoimmune Diseases↗
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.
Erythroblastosis, Fetal↗
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.
Agranulocytosis↗
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.
Autoantibodies↗