Platelet-associated IgG in immune thrombocytopenic purpura

A method for the measurement of immunoglobulin G associated with gel- filtered platelets is described and finding in 70 control subjects and 37 patients with immune thrombocytopenic purpura (ITP) are reported. Control platelet-associated IgG (PAIgG) levels (nanograms IgG per 10(9) platelets) averaged (+/-SD) 1231+/-424; samples studied after 24 and 48 hr remained within the control range. PAIgG values of 19 adult and 12 childhood patients with chronic ITP averaged 4711+/-3025 and 4923+/- 3955, respectively, and differed significantly from controls (p less than 0.001). There was an inverse correlation between PAIgG values and the chronic ITP patient's platelet count. Six patients with childhood acute ITP had PAIgG levels ranging from 5588 to 56,250 and appeared to represent a different statistical population from those with chronic ITP. In chronic ITP patients responding to splenectomy, there was an immediate normalization of PAIgG levels; however, a certain percentage of patients studied several months after splenectomy evidenced elevated PAIgG levels in association with normal platelet counts. These data showed that the direct measurement of platelet associated antibody is a useful technique in the diagnosis and follow-up of patients with chronic ITP. Preliminary studies in patients with acute ITP have suggested that this method may be useful in differentiating acute and chronic childhood ITP.     

Secondary immune thrombocytopenic purpura

PURPOSE OF REVIEW: The American Society of Hematology and British Committee for Standards in Haematology guidelines for the diagnosis and management of immune thrombocytopenic purpura focused entirely on primary disease, and secondary forms were not addressed. The guidelines did not address thrombocytopenia resulting from autoimmune disorders or chronic infections such as Helicobacter pylori, hepatitis C virus or HIV. RECENT FINDINGS: Antiphospholipid antibodies can be detected in roughly 50% of patients diagnosed with primary immune thrombocytopenic purpura, and are not associated with distinctive clinical features. The incidence of thrombotic events is controversial. The prevalence of H. pylori infection in adult patients may not be different from that of the general healthy population matched for age and geographical area. Eradication of the infection can produce platelet responses in a variable number of individuals and is less costly and toxic when compared with standard therapy. Finally, patients with risk factors (multiple sex partners, intravenous drug abuse, blood transfusion recipients) and chronic thrombocytopenia should be screened for hepatitis C virus or HIV infection and should be treated for these infections, not immune thrombocytopenic purpura. SUMMARY: In secondary forms of immune thrombocytopenic purpura, when the hematologist plays a consultative role, priority should be treatment of the underlying disorder.     

Childhood immune thrombocytopenic purpura

Childhood immune thrombocytopenic purpura (ITP) is acute and generally seasonal in nature, suggesting that infectious or environmental agents may trigger the immune response to produce platelet-reactive autoantibodies 4 to 8 weeks following an infection. In general, the patient is well apart from the diffuse bruising and petechiae indicative of a profound thrombocytopenia. Over a period of 6 months, the thrombocytopenia resolves in approximately 85% of children, while the remaining 15% with persistent platelet consumption are designated as chronic ITP patients. The peak age of acute ITP is 2 to 5 years of age, a period when children experience the greatest frequency of viral infections. Children with the chronic form of ITP mirror the adult phenotype, in that females predominate, and there is no seasonal fluctuation of the disease. Evidence from our laboratory suggests that the activated platelet itself may play a role in perpetuating autoantibody production and immune dysregulation associated with ITP. Current data on lymphocyte studies and cytokine alterations noted in response to the variety of regimens used in children with ITP suggest that acute ITP is accompanied by autoantibodies to GPIb and a cytokine profile that is proinflammatory in nature. Early recognition of the immune dysregulation driving acute versus chronic ITP will distinguish those children who might benefit from immunotherapy versus those who will recover without therapeutic intervention.     

Pathophysiology of immune thrombocytopenic purpura

In 1951, the young hematologist in training, Dr. William Harrington, infused himself with plasma from a patient with immune thrombocytopenic purpura (ITP). He rapidly developed severe, but transient, thrombocytopenia and was at risk for serious hemorrhage. Thus, the humoral autoimmune cause of ITP was established. Since 1953, when Dr. Harrington's in vivo studies ended, in vitro investigations have aimed to determine the molecular and cellular details of immune-mediated platelet destruction.     

Chronic immune thrombocytopenic purpura in childhood

Immune thrombocytopenic purpura (ITP) is a bleeding disorder and is traditionally divided in acute and chronic forms based on the duration of the disease. Chronic ITP is characterized by a persistence of thrombocytopenia for more than 6 months. Ten to 20% of children with ITP and almost all adults will develop the chronic condition. Pathophysiology of chronic ITP suggests an autoimmune process and a dysregulated immune response. There are no risk factors to predict the clinical course of ITP. Controlled clinical trials are needed to clarify many diagnostic and therapeutic aspects of chronic ITP, as recently stated by a panel of pediatric and adult hematologists on behalf of The American Society of Hematology (ASH). In this article, we will focus on pathophysiological, diagnostic, and management aspects of chronic childhood ITP.     

Significance of cytokines and CD68-positive microparticles in immune thrombocytopenic purpura

Abstract: We investigated the significance of cytokines (soluble interleukin-2 receptor, granulocyte-macrophage colony-stimulating factor, interleukin-6, and interferon-gamma) and CD68-positive microparticles in immune thrombocytopenic purpura. Cytokines were measured by enzyme-linked immunosorbent assay and microparticles were detected by flow cytometry. CD68 expression by histiocytic U937 cells incubated with lipopolysaccharide or cytokines was also assessed in a control study. The level of CD68-positive microparticles was significantly higher in the patients with thrombocytopenia than in normal controls (p<0.01). The soluble interleukin-2 receptor level was also significantly higher in patients than in controls (p<0.01), but the other cytokines did not show a significant difference. However, patients with severe thrombocytopenia (platelet count >20000/μl) had significantly higher levels of granulocyte-macrophage colony-stimulating factor and interleukin-6 than the controls (p<0.05). When opsonized platelets were incubated with activated U937 cells, lipopolysaccharide and granulocyte-macrophage colony-stimulating factor caused an increase of CD68-positive microparticles in the supernatant. These results suggest that granulocyte-macrophage colony-stimulating factor is released by activated T cells in immune thrombocytopenic purpura and activates monocyte/macrophage phagocytosis, resulting in an increase of circulating CD68-positive microparticles and enhanced platelet destruction.     

CD4+ CD25+调节性T细胞在免疫性血小板减少性紫癜中的调节作用

目的检测免疫性血小板减少性紫癜(ITP)患者治疗前后CD4 CD2 5调节性T细胞(Treg)的比例以及变化规律,探讨Treg在ITP发病机制中的作用。方法收集42例ITP患者治疗前、后外周血标本,分离血单个核细胞,采用流式细胞术检测ITP患者治疗前后Treg的比例以及变化。结果ITP患者治疗前Treg比例明显低于正常对照组(P<0.01),治疗后Treg比例显著升高,明显高于治疗前,但仍低于正常对照组(P<0.01);治疗有效组ITP患者Treg比例显著高于治疗无效组(P<0.01),治疗显效组显著高于良效和进步组(P<0.01),良效和进步组与治疗无效组比较差别无显著性。(P>0.05)。结论ITP患者外周血Treg比例降低,提示Treg可能参与了ITP的发病机制。     

Bleeding manifestations in severely thrombocytopenic children with immune thrombocytopenic purpura

OBJECTIVE: To report the observations on various bleeding manifestations in children with immune thrombocytopenic purpura (ITP) having severe thrombocytopenia (platelet count (PC) < 20,000/microl) and to compare the differences in bleeding manifestations at levels of PC at < 10,000/microl compared with between 10,000 and 20,000/microl. STUDY DESIGN: It is a retrospective analysis of bleeding manifestations in children with ITP (n = 58) having severe thrombocytopenia recorded between July 1999 and June 2002. A total of 164 episodes of severe thrombocytopenia were observed. During 31 episodes (18.9%), no bleeding manifestations were observed. When bleeding was observed cutaneous bleeds were the commonest manifestations occurring in 124 episodes. Of these 124 instances, in 82 (66.1%) episodes only cutaneous bleeding was observed while in remaining 42 (33.9%) episodes cutaneous bleeding was associated with other bleeding sites. Other common bleeds observed included epistaxis 22 (13.4%), oral bleeding 21 (12.8%) and gastro-intestinal bleeding 5 (3.04%). Comparison of the bleeding manifestations during episodes when the PC was < 10,000/microl and those between 10,000 and 20,000/microl showed that in 76.6% episodes with the count at > 10,000/microl no or only cutaneous bleeds were observed (clinically mild disease) compared to 59.45% episodes with episodes having PC < 10,000/microl (z score 2.37, p < 0.05). There was no statistically significant difference in proportion of patients having clinically mild disease during acute or chronic phase of the disease. CONCLUSION: During episodes of severe thrombocytopenia, most children have clinically mild disease. When the PC is < 10,000/microl clinically mild disease is observed less often compared to episodes with PC 10,000-20,000/microl. Based on these observations, it can be recommended that during severe thrombocytopenia, particularly when the PC is between 10,000-20,22,000/microl, patients can be safely managed with watchful waiting without any specific therapeutic intervention.     

Diagnosis of immune thrombocytopenic purpura in children

PURPOSE OF REVIEW: This review updates the differential diagnosis between inherited and acquired immune thrombocytopenic purpura as well as clinical practice on the initial diagnosis of children with the disease. RECENT FINDINGS: A diagnosis of immune thrombocytopenic purpura may be based on an evaluation of the history, physical findings such as petechiae, bruising and mucous membrane bleeding, examination of peripheral blood films stained with Wright's or May-Grünwald-Giemsa, determination of blood counts, platelet size and appearance. Recently, diagnostic assays have been developed to detect platelet-bound antibodies. The sensitivity of these assays, however, is suboptimal, with a positive predictive value of 80-83%. If the diagnosis of immune thrombocytopenic purpura is in question due to the presence of atypical features, or if a patient with findings typical of the disease does not respond to therapy, bone marrow aspiration and biopsy are indicated to confirm the diagnosis. SUMMARY: The diagnosis of immune thrombocytopenic purpura is a process of elimination of other sources of thrombocytopenia. If the criteria discussed above are inconclusive and if the patient does not respond to therapy in 6-12 months (this is especially true in children) then a bone marrow aspiration is required to confirm the diagnosis, especially before initiating corticosteroid therapy.     

Treatment advances in adult immune thrombocytopenic purpura

Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by autoantibody-mediated destruction of platelets. The disease generally runs a mild clinical course, though significant morbidity and mortality can occur. Steroids and/or splenectomy are effective in treating the disease in approximately 70% of patients. These treatments have been well established with approximately 50 years of clinical experience. While open splenectomy is the traditional surgical procedure, laparoscopic splenectomy, splenic artery embolization, and splenic irradiation are viable alternatives. For patients who relapse after the above therapies, treatment is more difficult and seldom results in a cure. The goals of therapy involve maintaining a safe platelet count while minimizing toxicities from the treatment. Multiple treatment options exist including corticosteroids, androgens, immunomodulatory drugs, cytotoxic chemotherapy, immunoglobulin preparations, bone marrow transplantation, Helicobacter pylori eradication, and others. While the standard treatment of steroids and splenectomy has changed little over the past decades, a number of promising new therapies on the horizon may soon join the armamentarium upon which the clinician can draw to fight the disease. In this review, we will examine treatment for chronic ITP in adults in the pre-splenectomy, splenectomy, and post-splenectomy settings.     

Pathogenesis of chronic immune thrombocytopenic purpura

PURPOSE OF REVIEW: This article summarizes recent insights into the pathophysiology of immune thrombocytopenic purpura, a disorder in which autoantibodies against cell-specific glycoproteins (GPIIb-IIIa, GPIb-IX and others) accelerate platelet destruction. RECENT FINDINGS: Autoantibodies are produced by a limited number of B-cell clones. Platelet antibodies may also impair megakaryocyte development and platelet turnover, thromobopoietin levels are normal or only modestly increased and a compensatory increase in platelet production is not effective in many patients. Patients may show impaired immune regulation manifested by increased proliferation of helper T lymphocytes. Cytotoxic T lymphocytes from patients can lyse platelets in vitro. If cytotoxic T lymphocytes are also capable of perturbing megakaryocyte function, this mechanism may contribute to impaired platelet production. Polymorphisms in the Fcgamma-RIIIa gene may correlate with response to certain forms of therapy and similar genetic approaches may help to identify subsets of patients that differ in their natural history and response to various interventions. SUMMARY: Better understanding of autoantibody development, inhibition of thrombopoiesis and Fcgamma receptor and other polymorphisms will assume increased importance in elucidating the pathogenesis and targeting treatment of chronic immune thrombocytopenic purpura.     

Pregnancy in women with immune thrombocytopenic purpura

Thirty-six women with immune thrombocytopenic purpura were studied during 37 pregnancies, and maternal characteristics with predictive value for the fetal platelet count were determined. Nine neonates were thrombocytopenic, with a platelet count of less than 50 x 10(9)/L in eight. Four of these nine neonates delivered to a subgroup of 31 mothers were studied prospectively; the frequency of thrombocytopenia in neonates of women with immune thrombocytopenic purpura was thus 13%. Only two of these nine neonates presented with hemorrhagic syndromes (two, petechial purpura; one, intracranial bleeding). The frequency of neonatal thrombocytopenia was higher in mothers with deep thrombocytopenia and in those who had not responded to corticosteroid treatment following diagnosis. No prognostic value could be assigned to the other maternal characteristics studied, such as a history of splenectomy, maternal treatment at the time of delivery, or the presence of platelet autoantibodies evaluated either with the platelet immunofluorescence test or the platelet Western blot immunoassay.     

The epidemiology of immune thrombocytopenic purpura

PURPOSE OF REVIEW: This review updates the American Society of Hematology and British guidelines on immune thrombocytopenic purpura incidence, prevalence, and natural history, with recent observations from the peer-reviewed medical literature. RECENT FINDINGS: This analysis was conducted using literature-indexing systems to identify relevant articles. Information about the incidence and prevalence of immune thrombocytopenic purpura is limited, with nearly all data coming from Europe. Recent reports have confirmed earlier studies suggesting that the disease occurs in five out of 100,000 children per year, and that spontaneous recovery is typical. Intracranial hemorrhage occurs in 0.5-1.0% of affected children, and half are fatal. The incidence in adults is roughly two in 100,000 per year and may be more common in older adults than previously recognized. A female predominance occurs only among middle-aged patients, and there is no racial variation in incidence. Spontaneous remission rates vary by report and range from 5 to 11%. SUMMARY: Spontaneous remission occurs more frequently in children than in adults, and intracranial bleeding is uncommon. The incidence increases with age, with a female predominance only among middle-aged adults. Adult patients with chronic disease may have a better prognosis than previously recognized, although only a small minority recover spontaneously.     

New therapies for immune thrombocytopenic purpura

PURPOSE OF REVIEW: The treatment landscape of immune thrombocytopenic purpura has the potential for dramatic change in the near future as promising new agents and adaptations of older therapies enter clinical study. An update on the status of current research in immune thrombocytopenic purpura and a preview of agents in development are provided here. RECENT FINDINGS: The recent literature shows a multitude of strategies employed in the treatment of immune thrombocytopenic purpura. These therapies under active investigation include the use of the B-cell-depleting monoclonal antibody rituximab, higher doses of dexamethasone and anti-D immunoglobulin, and thrombopoiesis-stimulating agents that are in early clinical development. SUMMARY: Clinical investigation of novel therapies in immune thrombocytopenic purpura is undergoing a revolution that has the potential to change the standard of care. While older therapies are experiencing a rebirth by being given a new spin, newer agents such as thrombopoietins are showing significant promise.