The treatment of immune thrombocytopenic purpura in children

Immune thrombocytopenic purpura (ITP) is an enigmatic, usually transient disorder in children, largely thought to be a self-limited, postinfectious, autoimmune phenomenon. The often strikingly low platelet count, coupled with the sometimes dramatic cutaneous manifestations of thrombocytopenia, compels most clinicians to prescribe drug therapy. However, closer scrutiny reveals that although most children with newly diagnosed ITP have platelet counts less than 10,000/microL, very few will experience severe or life-threatening hemorrhage, leading to perpetual controversy over whether to give drug therapy to minimally or moderately symptomatic children with ITP. This review focuses on when and how to use drug therapy to treat ITP in children.     

Complications de la splénectomie au cours du purpura thrombopénique immunologique. Revue de la littérature et mesures de prévention

Management of primary immune thrombocytopenia (ITP) has changed, and clinical practice broadens the use of thrombopoietin receptor agonists and anti-CD20 antibody as options for second-line therapy, as alternative to splenectomy. Splenectomy remains a successful, definitive curative treatment. The purpose of this review about the complications of the splenectomy, in the context of ITP, is to increase the awareness of clinicians towards the preventive measures, which are often not correctly applied.     

Treatment of idiopathic thrombocytic purpura in pregnancy by high-dose intravenous immunoglobulin

Summary ITP in pregnancy may lead to fetal thrombocytopenia caused by the transplacental passage of maternal antiplatelet antibody. The most hazardous complication in the infant is intracranial hemorrhage. In addition ITP in pregnancy is reported to be associated with an increased abortion rate and an elevated fetal morbidity and mortality. Therefore obstetric management must aim at increasing maternal and fetal platelets. Severel therapeutic approaches to the treatment of ITP in pregnancy are evaluated. Two cases of ITP in pregnancy are reported. Administration of high-dose intravenous immunoglobulin is introduced as a new therapy for ITP in pregnancy. The rapid reversal of thrombocytopenia following immunoglobulin G administration suggests that it is useful especially as emergency treatment for ITP in pregnancy.     

Detection of platelet-associated immunoglobulins by flow cytometry for the diagnosis of immune thrombocytopenia: a prospective study and critical review

BACKGROUND AND OBJECTIVE: Flow cytometry (FC) to identify platelet-associated (PA) immunoglobulin (Ig) is a potentially useful diagnostic test for idiopathic thrombocytopenic purpura (ITP). However, the restricted application of PAIg measurement to thrombocytopenic populations primarily comprised of ITP patients will artificially enhance the test's diagnostic specificity. For this reason, we performed a prospective study in which the results of a sensitive technique for detecting PAIg, as is FC, were correlated to the cause of the thrombocytopenia. DESIGN AND METHODS: A total of 118 patients with platelet counts <100 x 10(9)/L and 30 normal donors with a platelet count >200 x 10(9)/L were studied for PAIg employing a flow cytometer. Forty-two children and 20 adults were diagnosed as having immune thrombocytopenia and 27 children and 29 adults had nonimmune thrombocytopenia of different etiology. RESULTS: Raised levels of PAIg were found in 56/62 patients with immune thrombocytopenia and in 34/56 patients with non-immune thrombocytopenia. Diagnostic values of PAIg for the detection of immune thrombocytopenia were: sensitivity 90.3% and specificity 39. 3%. An enzyme-linked immunoabsorbant assay (ELISA) for the detection of autoantibodies to platelet glycoprotein (GP) complexes was used in adults, 9 with immune-related thrombocytopenia and 16 with non-immune thrombocytopenia, in order to determine the true non-specific nature of the positive PAIg test. By ELISA, 8/9 patients with immune thrombocytopenia and 7/16 with non-immune thrombocytopenic disorders showed autoantibodies to platelet GP complexes. INTERPRETATION AND CONCLUSIONS: PAIg detection by FC constitutes a sensitive but non-specific assay thus making it unnecessary and inappropriate for establishing the diagnosis of ITP.     

Platelet size deviation width, platelet large cell ratio, and mean platelet volume have sufficient sensitivity and specificity in the diagnosis of immune thrombocytopenia

We investigated the significance of the platelet indices, mean platelet volume (MPV), platelet size deviation width (PDW), and platelet-large cell ratio (P-LCR), in the diagnosis of thrombocytopenia by comparing these levels in 40 patients with hypo-productive thrombocytopenia (aplastic anaemia; AA) and 39 patients with hyper-destructive thrombocytopenia (immune thrombo-cytopenia; ITP). The sensitivity and specificity of platelet indices to make a diagnosis of ITP were also compared. All platelet indices were significantly higher in ITP than in AA, and platelet indices showed sufficient sensitivity and specificity. The area under the curve (AUC) of the receiver operating characteristics curve of platelet indices was large enough to enable the diagnosis of ITP. P-LCR and PDW had the largest AUCs, which indicated that these values were very reliable for immune thrombocytopenia. Our results suggest that these indices provide clinical information about the underlying conditions of thrombocytopenia. More attention should be paid to these indices in the diagnosis of thrombocytopenia.     

The place of intravenous immunoglobulin (IgG i.v.) therapy in thrombocytopenia

Summary Acute ITP following infection in children has a high rate of spontaneous remission. Since the platelet count is not uncommonly profoundly depressed, ITP is associated with a mortality of around 1%. The aim of treatment in ITP is to prevent bleeding. As a rule, this can only be achieved by normalizing the platelet count. Intravenous immunoglobulin offers certain advantages over conventional steroid therapy. Moreover, two out of three patients with chronic ITP respond to IgG i.v. The characteristic features of ITP in pregnancy, thrombocytopenia in babies born to mothers with ITP and neonatal isoimmune thrombocytopenia are discussed.     

Evaluation of the immature platelet fraction in the diagnosis and prognosis of childhood immune thrombocytopenia

Rapid assessment of platelet production would distinguish between thrombocytopenia due to decreased platelet production or increased peripheral platelet destruction. We evaluated the value of immature platelet fraction (IPF) in differentiating immune thrombocytopenia (ITP) from thrombocytopenia secondary to bone marrow failure and its potential use as a prognostic marker. Forty-one young patients with ITP were compared with 14 patients with hematological malignancies under chemotherapy, representing a control group with thrombocytopenia due to bone marrow suppression and 30 age- and sex-matched healthy controls. Patients were studied stressing on bleeding manifestations, organomegaly/lymphadenopathy and therapy. Complete blood count including IPF was performed using Sysmex XE-2100. ITP patients were classified into two subgroups: acute ITP with spontaneous resolution within 3 months from diagnosis and chronic ITP that lasted ≥1 year from diagnosis. Median IPF was 11.8% in patients with ITP, 7% in those with hematological malignancy and 3% in the control group (p?<?0.001). ITP patients had significantly higher mean platelet volume (MPV), platelet distribution width (PDW), platelet large cell ratio (P-LCR) and IPF compared with patients with malignancy or healthy controls, while plateletcrit (PCT) was significantly lower in ITP patients than other groups (p?<?0.001). IPF was increased in patients with chronic ITP compared with acute ITP group (p?<?0.001). Patients with active ITP had the highest IPF followed by those in partial remission, while ITP patients in remission had the lowest IPF. IPF was positively correlated to the number of lines of treatment used, MPV, PDW and P-LCR, while negatively correlated to platelet count and PCT among ITP patients (p?<?0.001). Multiple regression analysis showed that platelet count and P-LCR were independently related to IPF. ROC curve analysis revealed that the cut-off value of IPF at 9.4% could be diagnostic for ITP patients with a sensitivity of 88% and a specificity of 85.7%. We suggest that IPF may be a rapid and inexpensive automated marker for etiology of thrombocytopenia and can be integrated as a standard parameter to evaluate the thrombopoietic state of the bone marrow. It may be considered as a potential prognostic marker for the development of chronic ITP.     

<Emphasis Type="Italic">Mycoplasma pneumonia</Emphasis> Infection: A Possible Trigger for Immune Thrombocytopenia

Mycoplasma pneumonia (M. pneumonia) is usually not considered among the several pathogens that induce immune thrombocytopenia (ITP). We report a child with a clinical diagnosis of severe ITP that was associated with M. pneumonia pneumonia, and review the few cases described in the English literature. We suggest that thrombocytopenia associated with M. pneumonia infection may constitute a subset of ITP, although unlike ITP it occurs concomitantly with the infection and tends to be more severe than “classic” ITP. We recommend that prompt specific antibiotic and immune modulating treatment should be initiated in appropriate clinical settings.     

Acute thrombocytopenia associated with preexisting ulcerative colitis successfully treated with colectomy

We report a case of successfully treated acute thrombocytopenia associated with preexisting ulcerative colitis (UC). The patient had typical symptoms of UC, and colonoscopy showed pancolitis. During treatment with sulfasalazopyridine (SASP) and steroids, thrombocytopenia was observed. Despite the cessation of drugs, severe thrombocytopenia was noted. Immune thrombocytopenic purpura (ITP) was suspected based on a normal bone marrow megakaryocyte count, positive autoantibody to platelet membrane antigen, and the absence of splenomegaly. Medical treatment, including increased dosage of steroids, failed to control UC and acute thrombocytopenia in this patient. Moreover, acute severe pancreatitis developed and abdominal computed tomography showed toxic megacolon. Platelet count recovered after urgent total colectomy without splenectomy. When patients with UC develop thrombocytopenia, particularly in the presence of extensive and significant colonic inflammation, a diagnosis of ITP should be considered. In such patients, preexisting UC might be involved in the immunological causal mechanism of ITP. In this situation, colectomy might cure both UC and resistant thrombocytopenia. Steroid-refractory and life-threatening UC complicated by thrombocytopenia presumably caused by ITP is therefore a possible indication for colectomy.     

Exacerbation of autoantibody-mediated thrombocytopenic purpura by infection with mouse viruses

Antigenic mimicry has been proposed as a major mechanism by which viruses could trigger the development of immune thrombocytopenic purpura (ITP). However, because antigenic mimicry implies epitope similarities between viral and self antigens, it is difficult to understand how widely different viruses can be involved by this sole mechanism in the pathogenesis of ITP. Here, we report that in mice treated with antiplatelet antibodies at a dose insufficient to induce clinical disease by themselves, infection with lactate dehydrogenase-elevating virus (LDV) was followed by severe thrombocytopenia and by the appearance of petechiae similar to those observed in patients with ITP. A similar exacerbation of antiplatelet-mediated thrombocytopenia was induced by mouse hepatitis virus. This enhancement of antiplatelet antibody pathogenicity by LDV was not observed with F(ab')2 fragments, suggesting that phagocytosis was involved in platelet destruction. Treatment of mice with clodronate-containing liposomes and with total immunoglobulin G (IgG) indicated that platelets were cleared by macrophages. The increase of thrombocytopenia triggered by LDV after administration of antiplatelet antibodies was largely suppressed in animals deficient for gamma-interferon receptor. Together, these results suggest that viruses may exacerbate autoantibody-mediated ITP by activating macrophages through gamma-interferon production, a mechanism that may account for the pathogenic similarities of multiple infectious agents.     

Recent Advances in the Treatment of Chronic Refractory Immune Thrombocytopenic Purpura

We define chronic refractory immune thrombocytopenic purpura (ITP) as ITP with persistent thrombocytopenia following treatment with glucocorticoids and splenectomy. Chronic refractory ITP is uncommon, occurring in fewer than 10% of all adult patients with ITP diagnoses. The goal of treatment is only to achieve a safe platelet count with minimal treatment-related risk. A safe platelet count may be considered to be as low as 10,000/microL, because the risk for major bleeding in otherwise healthy subjects is great only when the platelet count is less than 10,000/microL. Observation without specific treatment is appropriate for patients with moderate thrombocytopenia and no clinically important bleeding symptoms. For patients with chronic refractory ITP who require treatment, there is no consensus for what therapies to use or the sequence in which to use them. For patients with severe and symptomatic thrombocytopenia, the use of anti-CD20 (rituximab) and immunosuppressive agents, alone or in combination, may be most effective. The mechanism of all current therapies is to decrease the accelerated platelet destruction brought about by immunosuppression. An alternative approach, the stimulation of platelet production with thrombopoietic agents, has been successful in investigational studies and may provide a new management option.     

The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia

Immune thrombocytopenia (ITP) is commonly encountered in clinical practice. In 1996 the American Society of Hematology published a landmark guidance paper designed to assist clinicians in the management of this disorder. Since 1996 there have been numerous advances in the management of both adult and pediatric ITP. These changes mandated an update in the guidelines. This guideline uses a rigorous, evidence-based approach to the location, interpretation, and presentation of the available evidence. We have endeavored to identify, abstract, and present all available methodologically rigorous data informing the treatment of ITP. We provide evidence-based treatment recommendations using the GRADE system in those areas in which such evidence exists. We do not provide evidence in those areas in which evidence is lacking, or is of lower quality--interested readers are referred to a number of recent, consensus-based recommendations for expert opinion in these clinical areas. Our review identified the need for additional studies in many key areas of the therapy of ITP such as comparative studies of "front-line" therapy for ITP, the management of serious bleeding in patients with ITP, and studies that will provide guidance about which therapy should be used as salvage therapy for patients after failure of a first-line intervention.     

A case of isolated thrombocytopenia due to cobalamin deficiency

The most common form of isolated thrombocytopenia is idiopathic thrombocytopenic purpura (ITP) in childhood. Hence, pediatricians consider a possible diagnosis of ITP in patients with isolated thrombocytopenia who are admitted to hospital with complaints of skin findings such as petechiae, purpura, and ecchymosis. It is well known that cobalamin deficiency may also cause thrombocytopenia together with anemia and leukopenia in children. However, isolated thrombocytopenia due to cobalamin deficiency has rarely been reported in literature. In this case report, we present a 7-year-old female patient with isolated thrombocytopenia that was improved by cyanocobalamin therapy.     

Prise en charge du purpura thrombopénique immunologique multiréfractaire

Multirefractory immune thrombocytopenia (ITP) is defined by the absence of response to TPO receptor agonists, rituximab and splenectomy (or contraindicated or refused) and the need of treatment. The approach to multirefractory ITP must be systematic and firstly involves reconsidering the diagnosis. Inherited thrombocytopenia, lymphoid hemopathies and myelodysplastic syndrome are the main causes to be mentioned. Multirefractory ITP is often associated with secondary ITP with signs of clinical or biological autoimmunity, monoclonal gammopathy of undetermined significance and a poor response to corticosteroids. Therapeutic management is complex and is based on the combination of treatments. New treatments are being developed.     

Management of patients with chronic, refractory idiopathic thrombocytopenic purpura

Chronic refractory idiopathic thrombocytopenic purpura (ITP) is defined as ITP with persistent thrombocytopenia despite conventional initial management with prednisone and splenectomy. Rare in children, It may occur in as many as one third of adults with ITP. The goal of treatment is not cure of the ITP, but only to achieve a safe platelet count, which is arbitrarily assumed to be greater than 30,000 to 50,000/microL. The risk for major bleeding seems great only when the platelet count is less than 10,000/microL. Treatment of patients with moderate thrombocytopenia and no clinically important bleeding symptoms should be avoided. There is no accepted algorithm for management of patients with chronic refractory ITP. Observation without specific treatment must be considered a cornerstone of management. Combination regimens of Immunosuppressive agents may be required for patients with severe and symptomatic thrombocytopenia. Additional supportive care measures are also important.     

Unusual myelodysplastic syndrome with the initial presentation mimicking idiopathic thrombocytopenic purpura

Idiopathic thrombocytopenic purpura (ITP) and primary myelodysplastic syndrome (MDS) are hematological disorders that are frequently associated with thrombocytopenia, and both are heterogeneous disorders of uncertain etiology. Their diagnosis requires the exclusion of other hematological or immunological disorders whose diagnosis is usually not difficult. However, in some patients presenting with thrombocytopenia, the differential diagnosis is complex. We performed a retrospective study of 47 consecutive patients treated between 1990 and 2001; in 25 patients the initial diagnosis was ITP, in 22 it was MDS; we compared their backgrounds, laboratory data and clinical outcomes. Among the 25 ITP patients, there were 5 confusing cases. Following treatment, they presented with inexplicable refractory anemia and/or neutropenia. Cytopenia, the polyploidization pattern of megakaryocytes, and chromosomal aberrations were of diagnostic relevance in these patients' defective hematopoiesis. Their cytopenia progressed relatively slowly and none progressed to leukemic transformation. We suggest that these 5 patients should be classified into an unusual subtype of MDS with clinical characteristics resembling ITP.     

Investigation of megakaryocyte apoptosis in children with acute and chronic idiopathic thrombocytopenic purpura

OBJECTIVE: Although the platelet destruction shows a primary role in the thrombocytopenia of idiopathic thrombocytopenic purpura (ITP), it has been demonstrated that impaired platelet production may also contribute to the severity of thrombocytopenia in ITP. The present study examined megakaryocyte apoptosis in bone marrow aspirates of children with acute and chronic ITP and investigated the role of megakaryocyte apoptosis in ITP pathophysiology. METHODS: Thirteen children diagnosed with acute ITP and eight children diagnosed with chronic ITP comprised the study group. Ten children, who were hospitalized for scoliosis operation but healthy otherwise, comprised the control group. In all children, megakaryocytes were isolated from the same amount of bone marrow aspirate samples using MACS CD61 MicroBeads (Miltenyl Biotec, Auburn, CA, USA). Megakaryocyte apoptosis was studied with transferase-mediated d-UTP-bitin nick end-labeling method. RESULTS: Isolated megakaryocyte counts did not differ significantly between acute ITP, chronic ITP and control groups. The percentage of apoptotic megakaryocytes did not differ significantly between acute ITP group and control group and between chronic ITP group and control group. The percentage of apoptotic megakaryocytes in patients with chronic ITP was significantly lower than the patients with acute ITP. There was no correlation between the percentage of apoptotic megakaryocytes and platelet counts of the cases. CONCLUSIONS: Increased megakaryocytic apoptosis does not play a role in the pathogenesis of dysmegakaryopoiesis and impaired platelet production in children with ITP. Decreased megakaryocyte apoptosis in cases with chronic ITP may be due to suppression of megakaryocyte maturation, as the terminal phase of the megakaryocyte lifespan is characterized by the onset of apoptosis.     

Alternate considerations for current concepts in ITP

Immune thrombocytopenia (ITP) is one of the most common forms of autoimmune disease affecting both adults and children. In recent years, there have been tremendous developments in the understanding of the pathogenesis and treatment of this condition. However, certain concepts related to ITP are worth consideration in view of alternative explanations and evidence available. These include (i) ITP is a disorder where thrombocytopenia is induced by autoantibodies against platelets or megakaryocytes, (ii) the mechanism of action of corticosteroids in ITP is through suppression of these autoantibodies, (iii) splenectomy is effective in ITP since spleen is the site of platelet destruction, and (iv) splenectomized ITP patients are at a major risk of infections.     

Is it necessary to test patients with immune thrombocytopenic purpura (ITP) for seropositivity to HTLV-1?

HTLV-111 (HIV-1) has been shown to be associated with thrombocytopenia of a type resembling immune thrombocytopenic purpura (ITP). HTLV-1 is a retrovirus similar to HIV-I (HTLV-III) in a number of features, such as CD4 tropism. It is responsible for several clinical entities, including adult T-cell leukemia/lymphoma. The relationship, if any, of HTLV-1 and thrombocytopenia has not been systematically studied. To determine how frequently ITP patients are commonly infected with HTLV-1, the following study was performed. Frozen serum samples from 123 randomly selected patients with ITP were thawed and tested for antibodies to HTLV-1 by enzyme-linked immunoabsorbent assay. Positives were confirmed by Western blot. Three patients were initially found to be positive for HTLV-1. One was a female of Caribbean ancestry, one was a male HIV-1+ patient, and one was an adolescent female with no known risk factors for HIV-1. The two females later tested negative for HTLV-1. As a screening program for HTLV-1 antibodies was not introduced into blood banks until November 1988, there may have been passive transfer of the virus from intravenous immunoglobulin that these patients had received. This study of a large number of ITP patients shows that it is extremely unlikely that they are infected with HTLV-1, and, therefore, it is unnecessary to screen ITP patients for seropositivity to HTLV-1.     

Idiopathic cyclic thrombocytopenia

Cyclic thrombocytopenia (CTP) is an uncommon disorder characterized by periodic fluctuations in platelet counts, typically resulting in episodes of thrombocytopenia alternating with normal platelet counts. While some CTP cases are associated with a primary hematologic disease, most are idiopathic. Patients with CTP are frequently misdiagnosed as idiopathic thrombocytopenic purpura (ITP) because CTP has clinical features very similar to ITP. When evaluating patients with suspected ITP, CTP should always be included in the differential diagnoses because CTP generally does not respond to standard ITP treatments, including corticosteroids, splenectomy, and intravenous immunoglobulin. Two clinical features relatively unique to CTP besides periodic thrombocytopenia are rebound thrombocytosis unrelated to recent splenectomy and platelet nadirs occurring during menses. When a diagnosis of CTP is made, patients must be offered a period of observation, as many may not require treatment. If treatment is clinically indicated, the literature suggests that hormonal therapy provides the best response.