immune destruction of platelets. ITP can be managed by several lines of treatment. Glucocorticoids with or without intravenous immunoglobulins are recommended as the first line and splenectomy or thrombopoietin receptor agonists as the second line treatment. Rituximab or other immunosuppressive agents are suggested in the second or later treatment lines. The aim of this retrospective study is to evaluate efficacy of splenectomy as the second line treatment in patients with refractory or relapsed ITP. We have retrospectively analysed patients diagnosed with ITP followed at the University Hospital Center Zagreb from 2007 to 2017. We have identified 55 patients that had undergone splenectomy. The response to splenectomy was defined as complete response (CR), partial response (PR) and no response (NR) based on platelet count and signs of bleeding one month after the procedure. Following splenectomy, 41 (91.1%) patients had a complete response and 4 (8.9%) had a partial response. Ten (18.2%) patients did not respond to splenectomy. After the median follow-up of 10 (0.5-43) years, out of 45 (81.8%) patients who initially responded to splenectomy, 28 (62.2%) patients were still in remission and 17 (37.8%) relapsed. Splenectomy is very effective as the second and the third line treatment in patients with ITP and long-term remission is acchieved by numerous patients.
Splenic macrophage Fc ␥ receptors participate in the pathophysiology of immune cytopenias, and in such disorders, the beneficial effects of glucocorticoids are in part mediated by decreased expression of macrophage Fc ␥ receptors. In the animal model, progesterones, like glucocorticoids, inhibit expression of these receptors. Megestrol acetate (MA) is a progesterone frequently used for treating human immunodeficiency virus (HIV)- associated anorexia-cachexia. Twenty-eight patients with HIV-associated thrombocytopenia with shortened platelet survival and increased platelet-associated immunoglobulin G (IgG) who were being treated with MA for anorexia-cachexia were prospectively studied for a 6-month period to assess the potential role of proges- terones in the treatment of immunethrombocytopenia. Treatment with MA for nonconsecutive periods of 2 months and 1 month significantly increased platelet count and platelet survival without significant alteration of platelet-associated immunoglobulin levels. Of the 28 patients studied, 22 presented a complete response, 19 presented a complete response 1 month after finishing the MA treatment regimen, and 12 remained in complete response for a further month. Expression of Fc ␥ receptors (Fc ␥ RI and Fc ␥ RII) by peripheral blood monocytes and the in vitro recognition of IgG-sensitized cells by monocytes were significantly decreased by the MA treatment. Decreased expression and functioning of these receptors significantly correlated with platelet counts and survival times, but no relationship was found with platelet-associated immunoglobulin, circulating immune complexes, body mass index, plasma HIV load, or CD4 lymphocyte levels. These results suggest that treatment with progesterones, like MA, may be an alternative therapy for immune cytopenias, with few side effects.
Abstract: Romiplostim is a thrombopoietin receptor agonist (TPO-RA) used for the treatment of adult primary immunethrombocytopenia (ITP). ITP is an autoimmune condition characterized by low platelet counts due to increased destruction and reduced platelet production. First-line interventions include corticosteroids, anti-D, and intravenous immunoglobulins, while second- line therapies comprise splenectomy, rituximab, cyclosporine A, and TPO-RAs. The recognition that compromised platelet production is a critical part of the pathogenesis of ITP prompted the development of therapeutic strategies based on the stimulation of the TPO receptor. TPO-RAs enhance megakaryocyte proliferation, increase platelet production, and lead to a reduction in bleeding episodes in ITP patients. This review will summarize current data on the TPO-RA romiplostim, with a particular focus on its relation to splenectomy.
Conventional treatments for ITP include immunosup- pressive therapies that primarily aim to reduce platelet destruction (eg, corticosteroids, azathioprine, cyclosporine A, cyclophosphamide, mycophenolate mofetil, rituximab, and vinca alkaloids), Fc receptor blockade which prevents macrophage destruction of antibody-coated platelets (eg, intravenous immunoglobulin and intravenous anti-D), and surgical therapy which prevents platelet sequestration (ie, splenectomy). However, patients with ITP do not always respond to conventional “immunosuppressive” treatments, each of which carries its own risk of adverse side effects. For those patients whose platelet counts do not respond to steroids, there is little consensus as to how to layer additional therapies and only a handful of options are associated with strong evidence regarding their utility. 12 More importantly,
Splenectomy has historically been considered the second- line therapy of choice but has declined in recent years, 6,7 partially due to increased availability of medical options 8 including the thrombopoietin-receptor agonists (TPO-RAs), eltrombopag and romiplostim. These drugs were initially approved in the United States (US) in 2008 for adults with chronic ITP (ITP > 12 months), who have had an insuf ﬁ cient response to previous ITP treatments. 9,10 The label for romi- plostim in the US has recently been revised to include all patients who have had an insuf ﬁ cient response to previous ITP treatments, regardless of ITP duration. Randomized con- trolled trials (RCTs) and recent clinical studies in splenecto- mized and non-splenectomized patients have provided evidence for the long-term ef ﬁ cacy and safety of these drugs. 11–13 Additionally, fostamatinib, a spleen tyrosine kinase (Syk) inhibitor was approved in the US in April 2018 for the treatment of chronic ITP in adults who have had an insuf ﬁ cient response to prior therapy. 14
Immunethrombocytopenia is an autoimmune disease with abnormal T cell immunity. Cytotoxic T cells, abnormal T regulatory cells, helper T cell imbalance, megakaryocyte maturation abnormalities and abnormal T cell anergy are involved in the pathogenesis of this condition. The loss of T cell-mediated immune tolerance to platelet auto-antigens plays a crucial role in immunethrombocytopenia. The induction of T cell tolerance is an important mechanism by which the pathogenesis and treatment of immunethrombocytopenia can be studied. Studies regarding the roles of the new inducible costimulator signal transduction pathway, the ubiquitin proteasome pathway, and the nuclear factor kappa B signal transduction pathway in the induction of T cell tolerance can help improve our understanding of immune theory and may provide a new theoretical basis for studying the pathogenesis and treatment of immunethrombocytopenia.
The spleen has been considered the main site for the autoimmune processes in ITP pathophysiology . Splenectomy has proven to be a preferred treatment for ITP patients who do not respond to glucocorticoid treat- ment or continue to need high-dose glucocorticoids to maintain a safe platelet count. The results of numerous studies indicate that approximately two-thirds of adult patients and 70 to 80 percent of children achieve a dur- able response to splenectomy . However, splenectomy for ITP is often associated with the risk of major mor- bidity and mortality, and the long-term haematological outcomes of the procedure cannot be predicted through routinely available measures . Some studies reported that several variables may predict a stable response to splenectomy including younger age [5-7], previous response to steroids [6,7] and postoperative peak platelet count [8,9]. Other studies showed opposite results [10- 12]. Najean et al. found the site of autologous 111 In- labeled platelet sequestration to be a good prognostic parameter . However, the techniques of isotope assessments are often qualitative, rather than quantita- tive, and many patients with nonsplenic sequestration also respond well to splenectomy . Hence, the assess- ments of platelet sequestration are not widely accepted. The fear of failure to respond to the splenectomy ren- ders many patients reluctant to undergo surgery and haematologists hesitant to recommend the surgery. Therefore, it is imperative to identify a preoperative serum biomarker that can serve as a predictor of good response to splenectomy and help patients and physi- cians with the decision of using surgery to treat ITP.
with thrombocytopenia . This leads to consider the potential role of immune complexes promoted by the presence of cross-reactive antibodies or a compensating mechanism following a decrease in thrombopoietin produc- tion . A direct effect of the virus on megacaryocytes may also be suspected as HCV can bind to CD81 on the platelet membrane, and HCV-RNA has also been detected in washed platelets of infected patients . Platelets could thus either favour the spread of the virus or contribute to its immune recognition by providing targetable antigens . Moreover, detection of HCV-RNA with a higher frequency in platelets of thrombocytopenic patients suggest that HCV is directly involved in this process . At this time, there is no evidence for a particular association between specific HCV genotypes and inci- dence of ITP .
The Belgian Hematological Society (BHS) guideline panel on adult primary immunethrombocytopenia (ITP) reviewed the recent literature on diagnosis and treatment to make recommendations on the best strategies for frontline and subsequent-line treat- ment. No treatment is necessary for patients with platelet counts higher than 30000/μl in the absence of bleeding symptoms. Patients newly diagnosed or relapsing after a long-term treatment-free period can be managed with corticosteroids with or without intravenous immunoglobulins. A second line therapy is indicated for those patients who are intolerant or unresponsive to or relapse after initial corticosteroid treatment and have a risk of bleeding. The guideline panel recommends splenectomy as it is the treatment with the highest curative potential and an acceptable safety profi le. If possible, splenectomy should be delayed to at least twelve months after diagnosis as spontaneous remission can occur in this time period. Thrombopoietin receptor (TPO-R) agonists are recommended for patients who are refractory to or relapse after splenectomy or who have a contra-indication to splenectomy irrespective of the duration of ITP. The guideline panel agrees that rituximab, azathioprine, cyclophosphamide, cyclosporine A, danazol, dapsone, mycophenolate mofetil and vincristine/vinblastine are potential treatment options, especially for patients refractory to TPO-R agonists.
If significant adverse HRQoL is detected, intervention would depend on which symptoms are present and what the underlying cause, or causes, may be; for example, modify- ing drug regimens in response to side effects or treating iron deficiency in fatigued patients. The approach to social or work limitations will also depend on the root cause. For example, activity restriction and/or social embarrassment due to thrombocytopenia, bruising and fear of bleeding may favor a therapeutic intervention with a high response rate (eg, splenectomy, TPO-RA) over alternative medical therapies. In contrast, work and social limitations caused by frequent hospital attendance and treatment side effects may respond to a treatment switch or discontinuation and a watch-and-wait strategy. HRQoL is important to patients; for example, fatigue is consistently identified by those with rheumatoid arthritis as one of their top outcome priorities. 62
Many ITP patients will experience a range of emotions that can differ according to the disease course and their stage of life. These emotions can be the result of the disease itself, because of treatments they are taking, or part of coping with the disease. The 10–20% of children who develop chronic ITP may struggle with the burden of disease and side effects of treatment. Children tend to be more concerned about their appearance and restrictions on their lifestyle than adults. 28 For example, some ITP treatments can cause significant weight gain, which can lead to depression in many patients. Children can also feel isolated by not being able to take part in everyday activities with their friends. In adults, ITP is associated with fear and anxiety about uncontrolled bleeding and long-term consequences of treatments such as splenectomy. 28 The symptoms of ITP can have a significant impact on a patient’s
logit models for treatment effect adjusted for splenectomy status are set out in Supplementary Table 1. All analyses were conducted using Markov chain Monte Carlo (MCMC) sampling within OpenBUGS (OpenBUGS, v 3.0) (24). Two chains were run for 50,000 samples (each) of the joint posterior distribution of the parameters in the models described above using separate sets of initial values. Convergence of the posterior distribution was then assessed (and confirmed in all cases) by viewing the resulting Brooks- Gelman-Rubin (BGR) plots (17). Moderate autocorrelation between chain samples was noted for a couple of parameters in most analyses and was removed by using the thin option during generation of Markov chain samples, by which only every k-th sample is used for estimation. In this case, k = 50 and k = 100 were used, respectively, for overall and durable responses. A further 50,000 samples were generated (from each chain), and these were used to estimate the model parameters. Parameter estimates and kernel probability density function plots were obtained for each analysis.
and splenectomy effect were allocated noninformative Normal prior distributions with mean = 0 and SD = 1,000, again ac- cording to standard practice (25). Each study effect was allo- cated a separate parameter (16). A random effects model was assumed for treatment effects, based on a Normal distribution. The model estimated a treatment effect (log OR) for romiplostim versus placebo and eltrombopag versus placebo. The indirect log OR for eltrombopag versus romiplostim was estimated from the posterior distribution for the difference between the two treatment effects (16). The between-trial variance for treatment effect was assumed to be common across all trials (according to standard practice) because there was little data from which to estimate a separate variance for each treatment. The prior distribution for treatment effect standard deviation (uniform distribution between 0 and 0.6) reflected a general suggestion from Sutton et al., so that any observed OR may vary by up to 4.6 times greater (or 0.22 times smaller) than the true OR with equal probability (25). Analyses were conducted using Markov chain Monte Carlo (MCMC) sampling within OpenBUGS, the open software license equivalent of WinBUGS (OpenBUGS, v 3.0) (24).
Platelets adhere and release activating mediators to release thrombin and the coagulation cascade begins. When a similar process occurs at an atherosclerotic plaque it can cause occlusive platelets and result in thrombosis. One of the mechanisms is that platelets are involved in the pro inflammatory mechanism promoting atherosclerosis. Platelet are involved in the immune defence as key mediators off inflammatory processes, releasing cytokines among other functions (4). In ITP the platelets are targeted by autoantibodies resulting in increased destruction furthermore there is decreased production. In the bone marrow the megakaryocytes are increased. Having thrombocytopenia can lead to symptoms of bleeding and an excessive amount of bleeding. Thrombosis is a deviation from the normal haemostasis that occurs after an injury and bleeding. Apart from the coagulation and platelet activation in thrombosis there is clot formation and vessel occlusion that can become life threatening (42). Patients with ITP have been found to have increased risk of thrombosis, a risk partly linked to their treatment especially to splenectomy (43, 44) even a long time after the splenectomy (45). The risk of thrombosis is also associated with
immunoglobulins (Ig), there is no clearly defined treatment pathway, and evidence from randomized controlled trials is scarce (6). Management of ITP is generally tailored to the individual patient depending on their symptoms, platelet count, lifestyle, and adverse events (AEs) associated with different therapies. Splenectomy is a potentially curative treatment option for cITP but is invasive, irreversible, and not appropriate for all patients (6). Patients typically cycle through several treatment options with differing lengths of response, some of which have significant side effects and most of which are not licensed treatments for ITP (6). Rescue treatments such as intravenous (IV) corticosteroids or IVIg may be given when a patient bleeds or is considered at high risk of bleeding (7). These are used either as an adjunct to the patient’s primary therapy or once non -rescue treatment options have been exhausted.
Evidence suggests that chronic ITP is associated with risk for morbidity and impairment in HRQOL among children. Commonly used therapeutic agents in children with chronic ITP are limited in number and efficacy. Moreover, many commonly used agents have a spectrum of toxicities. TPO receptor agonists represent a new therapeutic option in the treatment of children with chronic ITP. Although not conclusive, the available data suggest that treatment with romiplostim may be beneficial. Limited data document that romiplostim may be able to increase platelet counts and lessen the burden of bleeding manifestations in some children with chronic ITP. Responses to romiplostim vary widely in magnitude and duration and the ability to predict children who will respond robustly is not available at this time. In addition to a need for frequent titration in some patients, bleeding manifestations continue to require the use of rescue medications in some patients. Important questions remain with respect to the efficacy and long- term safety of romiplostim in children with chronic ITP. The potential benefit of romiplostim as it relates to patient reported outcomes including HRQOL is also unknown. Although serious adverse events are uncommon in children treated with romiplostim, we must continue to evaluate more fully the long-term safety of romiplostim. Future studies must focus on documenting the long-term safety of romiplostim. As an example, the collection of bone marrow data should be considered to evaluate for risks of myelofibrosis. Additional efficacy data are also desperately needed. This will require robust study designs incorporat- ing adequate sample sizes. Cost-effectiveness and patient reported outcome measures such as HRQOL as well as parent and family impact must also be incorporated into these future studies. These data will help us better clarify the role romiplostim should play in the care of children with chronic ITP.
response to ﬁ rst-line therapies, bleeding symptoms or risk of bleeding, side effects of ﬁ rst-line therapies, signi ﬁ cantly impaired HRQoL, and activity restrictions. Due to a lack of head-to-head prospective comparisons of second-line agents utilized in ITP, there has not been clear guidance regarding the initiation and choice of second-line therapies. Published guidelines have previously not provided a distinct treatment algorithm for management of patients who necessitate second-line therapy which has led to signi ﬁ cant variability in institutional preference and physician practice. The 2019 ASH Guidelines include suggestions when comparing second-line therapies that may provide more clin- ical direction for physicians. 1 The decision to initiate treat- ment and which therapy to utilize requires shared decision making given decisions are in ﬂ uenced by numerous factors including patient co-morbidities and clinical status, medica- tion side effect pro ﬁ le, and physician and patient preference. For patients who have an insuf ﬁ cient response to ﬁ rst-line therapies or who require more long-term treatment, various other options for medical management exist in addition to TPO-RAs. The majority aim to decrease platelet destruction via immunosuppression and include rituximab, mercaptopur- ine, azathioprine, mycophenolate, and sirolimus, among others. These agents, along with splenectomy, carry the long- term risk of serious infection. Morbidity and mortality sec- ondary to infection is of concern, and the risk-bene ﬁ t ratio of using these individual therapies must be weighed in light of the relatively low risk of ITP related mortality.
ITP diagnosis was verified according to the International Consensus Report on the Inves- tigation and Management of Primary ITP . Patients were aged 18 years and older and had primary ITP of more than 6 months duration, had baseline platelet counts of lower than 30,000/μL, and had relapsed after two or more previous treatments for their disorder. Date of the first diagnosis of the patients, demographic data, and time to splenectomy, previous treat- ments and response to treatments, side effects, posttreatment follow-up period, and other such records were retrospectively evalu- ated. Bleeding was assessed with the World Health Organization bleeding scale (grade 0: no bleeding, grade 1: petechiae, grade 2: mild blood loss, grade 3: gross blood loss, grade 4: debilitating blood loss) . Response rates were defined as follows: complete response
The extensive performance of splenectomy worldwide for patients suffered from splenic trauma has given rise to high risks of postoperative complications, which has been attracting increasing attention in recent years. Nowadays the spleen is regarded as a versatile organ of the human body, invested with various excellent properties. The spleen has been recognized to take a great part in lipid metabolism. While removal of the spleen intends to alter lipid values, especially with an elevated LDL, splenic autotransplantation is able to normalize these lipid alterations. What is more, conservative surgical procedures like subtotal or partial splenectomy, could as well, afford a correction of dyslipidemia. At the same time, clinically, splenectomy demonstrates a high rate of atherosclerosis (AS), whereas non-surgical treatment after splenic trauma shows unchanged propagation of AS. Based on the intimate relationship between serum lipids and AS, the lipid changes modulated by splenectomy are believed to be responsible for the development of AS. Therefore, a “ splenic factor ” is most likely present in the regulation of lipidation and AS. Several theories have been postulated to elucidate the possible mechanism involved, among which most are primarily based on its forceful natural immune function, that is to say, the mononuclear phagocytic system.However, the accurate mechanisms behind this mysterious phenomenon still remain unclear so far. Of importance, lipid fractions should be monitored consecutively in case of inevitable splenectomy.
As emerging roles of autophagy in megakaryopoiesis, thrombopoiesis, and platelet function have been revealed in patients with thrombocytopenic disorders, insights into signalling pathways may guide future research in this field. The rapamycin-sensitive protein mTORC1 plays an important role in the regulation of T cell differentia- tion and metabolism , and it may represent a new therapeutic target for ITP. mTOR inhibitors rapamycin and WYE-354 (which can induce autophagy) promote autophagosome formation and induce autophagy. More- over, they display protective and beneficial effects on murine lupus nephritis [96, 97] and patients with lupus nephritis . Unfortunately, the characteristic poor water solubility of rapamycin limits its clinical applica- tion. A more water-soluble drug against mTOR, sirolimus (CC1779), has been approved for the clinical treatment of renal cell carcinoma, and other similar drugs have been approved for the reduction of renal transplant rejection and clinical treatment of coronary artery stenosis . Another mTOR inhibitor, AZD8055, is used as a spare drug treatment for SLE . AZD8055 is taken orally, and its mode of action involves inhibiting the activa- tion of mTORC1 and mTORC2. Therefore, these drugs can reduce the risk of tumours in SLE patients . The clinical application of autophagy therapy for SLE may be enlightening for the future therapy of ITP. In vitro experi- ments with MKs from mutant mice showed that rapa- mycin induced autophagy and decreased the size and ploidy of megakaryocytes . Moreover, results from a clinical trial on ITP patients suggest that rapamycin is an effective treatment against immune-induced thrombo- cytopenia . Therefore, targeting autophagy may yield a promising approach for thrombocytopenic diseases. Other studies have revealed that low-dose DAC (Decit- abine) (10 nM) could significantly increase the number of mature polyploid (≥ 4 N) megakaryocytes . Finally, lapatinib treatment induces ATG-mediated autophagy and megakaryocytic differentiation in K562 cells of CML . In summary, the above autophagy-targeted therapies might lead to novel clinical treatments in ITP patients.