Cyclic change of cytokines in a patient with cyclic thrombocytopenia

The serial change of various cytokines in the serum from a patient with cyclic thrombocytopenia is described. Interleukin 7, stem cell factor, and transforming growth factor β1 synchronized with the platelet count, and there was a significant positive correlation between the three cytokines and the platelet count. Levels of macrophage colony-stimulating factor, thrombopoietin, platelet-associated IgG and erythropoietin changed reciprocally with the platelet count, and there was a significant negative correlation between the platelet count and these cytokines except erythropoietin. No cyclic change was observed in IL-3, IL-6, IL-11, granulocyte-macrophage colony-stimulating factor, or leukaemia inhibitory factor. These observations suggest that this disease involves two cyclic changes: megakaryocytopoiesis and platelet destruction, in both of which the cytokines play an important role.     

Pathophysiology and management of chronic immune thrombocytopenia: focusing on what matters

Immune thrombocytopenia (ITP) is a common autoimmune disease characterized by low platelet counts and an increased risk of bleeding. Antibody-mediated platelet destruction has been the prevailing hypothesis to explain ITP pathogenesis, supported by the efficacy of B-cell depletion therapy; however, the recent success of thrombopoietin receptor agonists lends support to the notion that platelet production is also insufficient. Best practice for the management of chronic ITP has not yet been established because data from comparative trials are lacking. Despite renewed interest in novel drugs capable of increasing platelet counts, ultimate treatment goals for ITP patients must be kept in mind: to improve patients' health and well-being. In this article, the pathophysiology of ITP is reviewed and key remaining questions about mechanism are explored. A rational approach to the management of ITP in adults is outlined, acknowledging evidence and evidence gaps, and highlighting the need for clinically important endpoints in future clinical trials.     

Fatigue in adult patients with primary immune thrombocytopenia

Background: Patients with primary immune thrombocytopenia (ITP) commonly describe symptoms of fatigue. However, hematologists rarely consider fatigue a manifestation of ITP. Objectives: To document the prevalence of fatigue among patients with ITP and to determine the patient characteristics that are associated with fatigue. Methods: Using a cross‐sectional design, we surveyed 1871 members of the UK ITP Support Association [585 (31%) responded], and 93 patients enrolled in the Oklahoma (US) ITP Registry [68 (73%) responded] with questions about their ITP and with validated symptom assessment scales for fatigue, daytime sleepiness, and orthostatic symptoms. Results: The prevalence of fatigue among both UK (39%) and US (22%) patients was significantly greater than expected compared with normal subjects (P < 0.0001 and P < 0.0001 respectively). In univariate analysis of the combined cohorts, fatigue was associated with a platelet count <100 000/μL, treatment with steroids, bleeding symptoms, presence of other medical conditions, daytime sleepiness, and orthostatic symptoms. Fatigue was not associated with age, gender, duration of ITP, or splenectomy status. Multivariate analysis of the combined cohorts was stratified for the presence or absence of bleeding symptoms. Among 107 patients with bleeding symptoms, fatigue was independently associated with a platelet count <100 000/μL and female gender. Among 491 patients without bleeding symptoms, fatigue was independently associated with a platelet count <30 000/μL, presence of other medical conditions, daytime sleepiness, and orthostatic symptoms. Conclusions: Fatigue is a common symptom among patients with ITP. These data provide the basis for future studies to define the clinical importance of fatigue in ITP.     

Clonal T cell-mediated cyclic thrombocytopenia

Cyclic thrombocytopenia is a rare disorder characterized by periodic platelet count fluctuations of unknown aetiology. We report on a female patient with cyclic changes of platelet counts ranging from 6 x 10(9)/l to 753 x 10(9)/l in 4-week intervals. Platelet counts were inversely correlated to thrombopoietin levels suggesting production failure. Reticulocyte counts and neutrophil counts showed similar, but less prominent, fluctuations. Clonal T-cell receptor rearrangement was detected in bone marrow samples as well as in peripheral blood. Cell typing of blood lymphocytes revealed a relative increase in CD3+ T cells. Treatment with cyclosporine A resulted in a substantial improvement of platelet counts. Taken together, we provide evidence for clonal T-cell mediated bone marrow failure with cyclic impairment of thrombopoiesis responsive to cyclosporine therapy.     

Markers of refractory primary immune thrombocytopenia

Refractory immune thrombocytopenia (ITP) is a challenging disease that can be defined by refractoriness to second-line treatments. In this review, we list and comment available evidence about clinical and biological factors associated with refractoriness to splenectomy, thrombopoietin receptor agonists (TPO-RAs), rituximab and fostamatinib, as well as those associated with multirefractory ITP (active disease with failure of rituximab, TPO-RAs and splenectomy).     

Response loss and development of neutralizing antibodies during long‐term treatment with romiplostim in patients with immune thrombocytopenia: a case series

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet counts resulting from both immune‐mediated platelet destruction and inappropriate bone marrow platelet production. Therefore, in patients with ITP failing immunosuppressants/splenectomy, an alternative approach is to enhance platelet production stimulating thrombopoiesis. Studies on the development of recombinant thrombopoietins (rhTPO) were halted as a minority of patients developed an autoantibody that neutralized pegylated rhTPO and also cross‐reacted with and neutralized endogenous TPO resulting in thrombocytopenia. Clinical use of romiplostim, a second‐generation TPO‐RAs, has shown that during long‐term treatment, it may elicit the development of neutralizing antibodies to this agent resulting in acute thrombocytopenia. In our case series of 47 primary adult patients with ITP treated with romiplostim, 28 of 47 are evaluable for response loss. Among these, we observed eight patients who either progressively (3 of 8) or abruptly (5 of 8) lost response which accounts for a prevalence of 28.5%. Neutralizing antibody testing could be performed in 4 of 8 patients and 3 of 4 tested positive. These antibodies did not cross‐react with endogenous TPO and retesting of 2 patients at 9 and 7 months yielded a negative result. At follow‐up, 5 of 8 patients – including the 3 patients with neutralizing antibodies – went into long‐term complete response when switched to a different therapy while 3 of 8 patients never regained a response on subsequent lines of therapy. Response loss does not seem to be so rare an event during romiplostim administration (28.5% in our series) and in a minority of patients, it can be associated with development of drug neutralizing antibodies. Although recognized by the manufacturer as a possible adverse event ensuing during romiplostim administration, development of neutralizing antibody in everyday clinical practice has so far not been specifically addressed in reports on romiplostim use outside controlled studies. Unfortunately, testing for these antibodies requires adhesion to strict procedures which is not easily accomplished in everyday clinical practice. This complexity represents a significant drawback in extending antibody testing to all patients who lose response to romiplostim.     

Autoantibodies to thrombopoietin and the thrombopoietin receptor in patients with immune thrombocytopenia

Autoantibodies to thrombopoietin (TPO, also termed THPO) or the TPO receptor (cMpl, also termed MPL) could play a pathological role in immune thrombocytopenia (ITP). In this study, we tested for autoantibodies against TPO, cMpl, or the TPO/cMpl complex in ITP and other thrombocytopenic disorders. Using an inhibition step with excess TPO in fluid‐phase to improve binding specificity, the prevalence of anti‐TPO autoantibodies was: active ITP: 9/32 (28%); remission ITP: 0/14 (0%); non‐immune thrombocytopenias: 1/10 (10%); and healthy controls: 1/11 (9%). Similarly, using an inhibition step with excess cMpl, the prevalence of specific anti‐cMpl autoantibodies was: active ITP: 7/32 (22%); remission ITP: 1/14 (7%); non‐immune thrombocytopenias: 3/10 (30%); and healthy controls: 0/11 (0%). Two active ITP patients had autoantibodies against the TPO/cMpl complex, but not against TPO or cMpl alone. Anti‐TPO or anti‐cMpl autoantibodies were found in 44% of ITP patients, and in 40% of patients with other thrombocytopenic disorders. These autoantibodies did not correlate with ITP disease severity or number of ITP treatments received; however, in this cohort, 3 patients failed to respond to TPO receptor agonist medications, and of those, 2 had anti‐TPO autoantibodies. This suggests that anti‐TPO and anti‐cMpl autoantibodies are associated with thrombocytopenia, and may be clinically relevant in a subset of ITP patients.     

Intravenous gammaglobulin treatment for immune thrombocytopenia associated with infectious mononucleosis

Severe thrombocytopenia is an uncommon (incidence less than 1%) but serious complication of infectious mononucleosis. Corticosteroids have been used for therapy with variable responses reported. Five consecutive patients with infectious mononucleosis-related severe thrombocytopenia were treated with intravenous gammaglobulin (IVIG) at a dose of 400 mg/kg/day for 2-5 days. All patients appear to have had an immunologic or consumptive etiology for their thrombocytopenia as determined by increased marrow megakaryocytes. All patients were initially treated with oral prednisone 1 mg/kg/day. Due to the relatively slow response to prednisone (platelet count less than 20,000/microliters on the 8th to 13th hospital day) or increased bleeding symptoms, IVIG was initiated. Four of the five patients rapidly developed significant increases in their platelet counts (range 44,000/microliters to 97,000/microliters). Two of these responses were sustained and two relapses occurred (while on continued steroid therapy) which again responded to booster doses of IVIG at similar doses. IVIG has been previously shown to be effective in treating patients with idiopathic thrombocytopenia purpura. Historically, patients with infectious mononucleosis-related severe thrombocytopenia often are refractory to corticosteroid therapy and our limited experience suggests that IVIG may also be effective in infectious mononucleosis-related severe thrombocytopenia.     

Cyclosporin A in the treatment of refractory immune thrombocytopenia purpura in children

Patients with refractory autoimmune thrombocytopenia do not respond to standard therapy with high-dose corticosteroids, intravenous immunoglobulin, and splenectomy. We describe the cases of two patients with refractory autoimmune thrombocytopenia treated with oral cyclosporin A (CsA) to evaluate the efficacy of this alternative therapy. Blood pressure and hepatic and renal function were in the normal range before initiation of treatment. Induction therapy with pulses of high-dose methylprednisolone was used for 3 consecutive days to improve the initial immune suppression. Gradual dose reduction of CsA, according the platelet count, minimized the long-term adverse effects of CsA. Oral CsA with pulses of high-dose methylprednisolone induced remission of the thrombocytopenia. Gradual weaning of CsA over months, according the platelet count, produced no observable adverse effects of the CsA. Rapid dose reduction caused thrombocytopenia, which resolved with higher dosages of CsA. Our cases show the efficacy of CsA for refractory immune thrombocytopenia. This therapeutic option with oral CsA as an additional salvage option may avoid splenectomy and the adverse effects of long-term corticosteroids. Larger clinical investigations are necessary to establish the indications and therapeutic regimen for CsA in immune thrombocytopenia.     

B cells and antibodies in refractory immune thrombocytopenia

Immune thrombocytopenia (ITP) is an acquired bleeding disorder mediated by pathogenic autoantibodies secreted by plasma cells (PCs) in many patients. In refractory ITP patients, the persistence of splenic and bone marrow autoreactive long-lived PCs (LLPCs) may explain primary failure of rituximab and splenectomy respectively. The reactivation of autoreactive memory B cells generating new autoreactive PCs contributes to relapses after initial response to rituximab. Emerging strategies targeting B cells and PCs aim to prevent the settlement of splenic LLPCs with the combination of anti-BAFF and rituximab, to deplete autoreactive PCs with anti-CD38 antibodies, and to induce deeper B-cell depletion in tissues with novel anti-CD20 monoclonal antibodies and anti-CD19 therapies. Alternative strategies, focused on controlling autoantibody mediated effects, have also been developed, including SYK and BTK inhibitors, complement inhibitors, FcRn blockers and inhibitors of platelet desialylation.     

Intramuscular Anti-D treatment for immune thrombocytopenia: A single centre experience

Intravenous Anti-Rhesus-D immunoglobulin (Anti-D) is a first-line treatment option for immune thrombocytopenia in non-splenectomised and RhD-positive patients. In this report, we retrospectively review our experience with intramuscular (IM) Anti-D treatment in 74 adult patients between 1990 and 2018. We found that 73% of patients showed a response; almost all of them had complete responses (68.9%), and 26% achieved complete responses sustained at least 6 months after treatment discontinuation. [Correction added on 02 December 2022, after first online publication: In the preceding sentence, ‘(68.89%)’ has been corrected to ‘(68.9%)’ in this version.] No significant side effects were observed with no cases of acute haemolysis or anaemia reported. We conclude from this study that IM Anti-D is an effective and safe treatment for immune thrombocytopenia.     

How we manage immune thrombocytopenia in the elderly

With prolonged life expectancy, immune thrombocytopenia (ITP) is frequent in elderly people. In this setting, ITP diagnosis is challenging because of the concern about an underlying myelodysplastic syndrome. Studies of older adults are lacking, and recommendations for treatment are based mainly on expert opinion. The therapeutic strategy differs from that for younger patients and must take into account the greater risk of bleeding and thrombosis, presence of comorbidities, possible impaired cognitive performance or poor life expectancy and concomitant medications, such as anticoagulant and antiplatelet therapy. Steroids and intravenous immunoglobulin (IVIg) therapy remain the first‐line treatments in elderly patients, but prolonged treatment with steroids should be avoided and IVIg treatment may lead to renal failure. Splenectomy is less effective than in young patients and risk of thrombosis is increased. Severe co‐morbidities can also contraindicate surgery. Therefore, other second‐line treatments are frequently preferred. Danazol and dapsone can be an option for the less severe ITP form. Rituximab is a good option except in patients with a history of infection or with hypogammaglobulinaemia. Thrombopoietin agonists are attractive, especially for patients with severe comorbidities or with limited life expectancy but the risk of thrombosis is a concern.     

Thrombopoietin and its receptor expression in pediatric patients with chronic immune thrombocytopenia

Objectives: Chronic immune thrombocytopenia (cITP) is common in children. However, the pathogenesis has not been fully elucidated. This study aimed to determine whether thrombopoietin (TPO) and its receptor c-mannosylation of the TPO receptor (c-Mpl) have an impact on childhood cITP.

Methods: Sixty-four patients with newly diagnosed ITP (nITP), 64 patients with persistent ITP, 80 patients with cITP, and 64 healthy children (control) were enrolled in this study. Plasma TPO was measured with an ELISA, and c-Mpl was determined by flow cytometry.

Results: Plasma TPO levels showed differences among the four groups (p?=?0.001). TPO levels in the cITP group were significantly decreased compared to those in the nITP group (p?p?=?0.0275). c-Mpl MFI was lower in the cITP group than in the nITP group(p?p?p?=?0.023). The control group, compared with the other groups, had lower levels of c-Mpl mRNA.

Conclusions: The expression of TPO and c-Mpl was significantly decreased in the cITP group compared to the nITP group, suggesting that TPO and its receptor may play important roles in childhood cITP pathogenesis.     

Many alphaIIbbeta3 autoepitopes in chronic immune thrombocytopenic purpura are localized to alphaIIb between amino acids L1 and Q459

In chronic immune thrombocytopenic purpura (ITP), autoantibodies bind to platelet surface proteins, particularly alphaIIb, resulting in platelet destruction by the reticulo-endothelial system. In order to better localize the autoepitopes on alphaIIb, we studied the binding of antibodies to Chinese hamster ovary (CHO) cells expressing either alphaIIbbeta3 or alphaIIb-alphavbeta3 chimaeras in which a segment of alphaIIb (either amino acids L1-Q459, L1-F223 or F223-Q459) was substituted for that portion of alphav. We evaluated platelet-associated autoantibodies from 14 ITP patients with alphaIIb-dependent antibodies. Ten of 14 bound to alphaIIb (L1-Q459)-alphavbeta3, showing that autoepitopes were often localized to this region of alphaIIb. In addition, each of the autoantibodies binding to alphaIIb (L1-Q459)-alphavbeta3, also bound to CHO cells expressing either alphaIIb(L1-F223)-alphavbeta3 or alphaIIb(F223-Q459)-alphavbeta3). In two of the three eluates tested, > 95% of the autoantibody binding to alphaIIb could be adsorbed using CHO cells expressing any of the three chimaeras, showing that the epitope(s) have contact points on either side of amino acid F223; in the third eluate, only a portion ( approximately 40%) could be adsorbed by the chimaeric cell lines showing that, in this patient, an additional antibody was also present, directed to a site distal to amino acid Q459. The remaining four eluates bound to CHO cells expressing alphaIIbbeta3 but to none of the chimaeras, suggesting that these epitopes are also distal to amino acid Q459. We conclude that the binding of many anti-alphaIIbbeta3 autoantibodies is dependent on the presence of alphaIIb amino acids L1-Q459.     

Cyclic thrombocytopenia associated with IgM anti-GPIIb-IIIa autoantibodies

Summary. We studied a female patient with cyclic fluctuation in platelet count following splenectomy for autoimmune thrombocytopenia. The cyclical fluctuation appeared to be in phase with her menstrual cycle and her platelet count was low during menses. Bone marrow examinations performed at the peak as well as the bottom of the platelet count showed normal or increased numbers of megakaryocytes. The patient's platelet count increased rapidly after intravenous gamma-globulin (IVIgG) therapy, suggesting that a failure of platelet production is unlikely to account for the cycle. Platelet-associated IgM (PAIgM) was markedly elevated, whereas PAIgG was normal at any stage of the cycle. MACE assay demonstrated that PAIgM contained IgM anti-glycoprotein (GP) IIb-IIIa autoantibodies. Comparison between MACE assay using untreated and EDTA-treated platelets at 3 7°C demonstrated that the platelet-associated IgM autoantibodies mainly recognized divalent cation-dependent conformation(s) of GPUb-IIIa. No antibodies were, however, detected in her serum. The levels of IgM anti-GPIIb-IIIa showed an inverse relationship with the platelet count. In spite of the marked increase in platelet count after IVIgG, however, the levels of IgM anti-GPIIb-IIIa remained elevated. These findings suggest that plateletassociated IgM anti-GPIIb-IIIa autoantibodies are of pathogenic significance in this patient.     

High dose dexamethasone therapy shows better responses in acute immune thrombocytopenia than in chronic immune thrombocytopenia

Oral high dose dexamethasone (HDD) was given as a single daily dose for four consecutive days, every 14 days for four courses. Twenty-nine patients were enrolled. Overall 20 patients (69%) responded: complete response (CR) was achieved in 16 (55%) patients, partial response (PR) in three (10%) patients and MR in one (3%) patient. In acute immune thrombocytopenic purpura (ITP) response rates after the first, second, third and fourth cycles were as follows: 64% (9/14), 64% (9/14), 79% (11/14), and 85.7% (12/14), respectively. In chronic ITP, overall response rates after the first, second, third and fourth cycles were as follows: 33% (5/15), 40% (6/15), 53% (8/15) and 53% (8/15) respectively. The median time to response was 14 days (4–42 days). Twelve out of 20 patients (5/12 acute ITP and 7/8 chronic ITP) relapsed; median relapse free survival till last follow-up in the remaining eight patients was 130 days (65–365 days).     

Use of eltrombopag for secondary immune thrombocytopenia in clinical practice

Eltrombopag is a second‐line treatment in primary immune thrombocytopenia (ITP). However, its role in secondary ITP is unknown. We evaluated the efficacy and safety of eltrombopag in secondary ITP in daily clinical practice. Eighty‐seven secondary ITP patients (46 with ITP secondary to autoimmune syndromes, 23 with ITP secondary to a neoplastic disease subtype: lymphoproliferative disorders [LPDs] and 18 with ITP secondary to viral infections) who had been treated with eltrombopag were retrospectively evaluated. Forty‐four patients (38%) had a platelet response, including 40 (35%) with complete responses. Median time to platelet response was 15 days (95% confidence interval, 7–28 days), and was longer in the LPD‐ITP group. Platelet response rate was significantly lower in the LPD‐ITP than in other groups. However, having achieved response, there were no significant differences between the durable response of the groups. Forty‐three patients (49·4%) experienced adverse events (mainly grade 1–2), the commonest being hepatobiliary laboratory abnormalities. There were 10 deaths in this case series, all of which were related to pre‐existing medical conditions. In routine clinical practice, eltrombopag is effective and well‐tolerated in unselected patients with ITP secondary to both immune and infectious disorders. However, the response rate in LPD‐ITP is low.     

Development of romiplostim for the treatment of patients with chronic immune thrombocytopenia: from bench to bedside

Immune thrombocytopenia (ITP) is an autoimmune disorder characterised by abnormally low platelet counts (<100 × 10⁹/l), purpura, and bleeding episodes, and can be categorised in three phases: newly‐diagnosed, persistent, and chronic. As many patients become refractory to standard treatments (corticosteroids, danazol, azathioprine, splenectomy), there is an urgent need for alternative treatments. The successful isolation and cloning of thrombopoietin (TPO) in the mid‐1990s and identification of its key role in platelet production was a major breakthrough, rapidly followed by the development of the recombinant thrombopoietins, recombinant human TPO and a pegylated truncated product, PEG‐rHuMGDF. Both agents increased platelet counts but development was halted because of the development of antibodies that cross‐reacted with native TPO, resulting in prolonged treatment‐refractory thrombocytopenia. Experimentation with novel platforms for extending the circulating half‐life of therapeutic peptides by combining them with antibody fragment crystallisable (Fc) constructs led to the development of a new family of molecules termed ‘peptibodies’. The 60Da recombinant peptibody romiplostim was finally produced by linking several copies of an active TPO‐binding peptide sequence to a carrier Fc fragment. In clinical trials, romiplostim was effective in ameliorating thrombocytopenia in patients with chronic ITP, was well tolerated and did not elicit cross‐reacting antibodies. Romiplostim has recently been approved for the treatment of adults with chronic ITP.     

Perinatal management of idiopathic thrombocytopenic purpura in pregnancy: risk factors for passive immune thrombocytopenia

Summary Thirty-nine pregnant women with idiopathic thrombocytopenic purpura (ITP) were studied in order to evaluate the influence of therapies for maternal ITP on fetal passive immune thrombocytopenia (PIT). Neonatal platelet counts were also compared with platelet counts, amount of PAIgG, and presence of circulating antiplatelet antibody in maternal blood. Eight of 41 neonates (19.5%) presented PIT without neonatal mortality. A higher incidence of PIT was observed in women with prior splenectomy than in women without splenectomy (66.7% vs 11.4%). Neither a therapeutic effect nor an increased risk of PIT was observed with steroids or gammaglobulin administration. No correlation was found between neonatal platelet counts and maternal platelet counts or maternal PAIgG, while positive cases for circulating antiplatelet antibody assay presented a higher incidence of PIT than negative cases. Additionally, a higher incidence of PIT was observed in women with a history of previous PIT than in women with a history of normal delivery. Prior splenectomy, presence of antiplatelet antibody in maternal blood, and a history of previous PIT seem to be risk factors for fetal PIT.