Thrombopoietin Receptor Research Articles

Immune thrombocytopenia in patients with systemic lupus erythematosus.

Immune thrombocytopenia (ITP) is a common hematological manifestation of systemic lupus erythematosus (SLE). The diversity of its clinical features and treatment responses may reveal the complex pathophysiological mechanisms of the disease. To enhance the therapeutic response rate and improve the prognosis for SLE patients with concurrent ITP, while reducing adverse events during the treatment process, it is crucial to accurately identify and apply clinical parameters to predict patients' responses to treatment. In addition to conventional therapeutic approaches such as glucocorticoids, immunosuppressants, and intravenous immunoglobulin (IVIG), a range of emerging therapies are gradually becoming the focus of research. These innovative therapeutic strategies include thrombopoietin receptor agonists (TPO-RAs), targeted therapies against B-cells, and plasma cell-targeted treatments. With a deepening understanding of the role of platelets in immune and inflammatory responses, novel platelet-targeted therapeutic agents in the field of SLE-ITP treatment may demonstrate significant potential. Despite this, to ensure the clinical efficacy and safety of these therapeutic approaches, we must rely on rigorously designed randomized controlled trials (RCTs) for further validation. This article provides a systematic review of the pathogenesis of systemic lupus erythematosus (SLE) complicated by immune thrombocytopenia (ITP) and conducts a comprehensive overview of current treatment strategies. The article also provides an in-depth exploration of the key biomarkers that may influence the therapeutic response in SLE-ITP patients. This comprehensive analysis aims to elucidate the factors that potentially affect the efficacy of treatments and contribute to a more personalized approach to patient care.

A study of platelet function in patients with chronic immune thrombocytopenia treated with thrombopoietin receptor agonists

BackgroundThrombopoietin receptor agonists (TPO-RAs) are widely used in immune thrombocytopenia (ITP) and are associated with increased thrombotic risk. However, data regarding their impact on platelet function is scarce. MethodsPlatelet function was evaluated in chronic ITP patients enrolled over one year, using light transmission aggregometry and platelet-derived microparticle (PMP) levels measurement with flow cytometry. Aggregation responses to various concentrations of ADP, collagen, ristocetin, and PMP levels were compared between TPO-RA-treated patients, patients treated with other agents and healthy individuals. ResultsTPO-RA-treated patients (n = 24) displayed significantly reduced aggregation responses to 2.5 μM, 5 μM, and 10 μM of ADP and collagen compared to 15 healthy individuals (59.5 % vs. 87.6 %, p < .0001, 43.6 % vs. 79.9 %, p < .0001, 26.1 % vs. 75.2 %, p < .0001, 67.2 % vs. 86 %, p < .0001, respectively). Reduced responses to ADP and collagen were also recorded in patients treated with other agents (n = 16) compared to healthy controls but without difference between the two treatment groups. Aggregation response to ristocetin was normal in all three groups. None of the patients yielded enhanced platelet aggregation. In TPO-RA-treated patients, a strong positive correlation between platelet counts and aggregation response to ristocetin was observed (rs = 0.65, p = .0005). PMP levels were significantly elevated in TPO-RA-treated patients compared to patients treated with other agents (49.5 vs 4.5 events/uL, p < .0001) and healthy controls (5 events/uL, p < .0001). ConclusionsThese results suggest that TPO-RAs may not enhance platelet aggregation responses, whereas impaired responses may be a disease feature. Furthermore, TPO-RAs may increase PMP levels and thus be implicated in the modulation of platelet function in ITP patients.

Immune thrombocytopenia: current diagnostics and therapy : The new 2023 expert report in brief

Immune thrombocytopenia (ITP) is an acquired thrombocytopenia caused by an autoimmune reaction against platelets in the blood and against megakaryocytes in the bone marrow. The indication for treatment is based on the bleeding symptoms and patient-specific factors. This article presents the current 2023 expert report that also forms the basis for the updated version of the Onkopedia guideline, which is expected in the course of 2024. In addition to the background to pathogenesis and pathophysiology, the article discusses clinical manifestations and diagnostics, as well as first-, second- and third-line therapy, including the management of emergency situations. Practice-relevant recommendations are given on the use and side effects of glucocorticoids, as well as on therapy with thrombopoietin receptor agonists (TRA), including the withdrawal regimen, and on treatment with asyk inhibitor.

Romiplostim, low-dose rituximab and high-dose dexamethasone for newly diagnosed immune thrombocytopenia: A pilot study.

Therapies such as corticosteroids, thrombopoietin receptor agonists and immunomodulators have been consistently under the spotlight in the search for a better treatment for immune thrombocytopenia (ITP). However, none of them has been widely embraced as a new standard. In this pilot study, we investigated feasibility, safety and preliminary efficacy of romiplostim, low-dose rituximab and high-dose dexamethasone for newly diagnosed ITP. We conducted a single-centre single-arm pilot. One-month treatment adherence was 100%. The 1-month overall response rate was 92.3%. Complete response occurred in 11 (84.6%) patients. Median duration of response was 4.13 monts (range 0.2-25). No serious adverse events presented.

A real-world disproportionality analysis of FDA adverse event reporting system (FAERS) events for avatrombopag

Avatrombopag is a next-generation thrombopoietin receptor agonist approved for the treatment of thrombocytopenia in patients with chronic liver disease scheduled to undergo surgery and thrombocytopenia in patients with chronic immune thrombocytopenia. However, realistic data on its post-marketing long-term safety and tolerability in large sample populations are incomplete. The adverse event (AE) reports of avatrombopag were analyzed based on the FAERS database. By extracting large-scale data from the FAERS database, this study used various signal quantification techniques such as reporting odds ratios, proportional reporting ratios, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker to calculate and evaluate the ratio and association between avatrombopag and specific AEs. In the FAERS database, data from the second quarter of 2018 to the fourth quarter of 2023 were extracted for this study, a total of 1217 avatrombopag-related AEs reports were included for analysis. Based on four calculation methods, this study identified and 32 preferred terms associated with avatrombopag. Common AEs in the product label such as thrombosis, headache, contusion, petechiae, and gingival bleeding were detected. AEs not mentioned in the product label, such as photopsia and ear discomfort were also detected. The first 30 days after initiation of medication were the most common period for both serious and non-serious AEs. This study demonstrates the common AEs and the potential AEs associated with avatrombopag in real-world practice, which could provide valuable cautionary evidence for clinicians and pharmacists to manage safety issues with avatrombopag.

Thrombopoietin mimetic reduces mouse lung inflammation and fibrosis after radiation by attenuating activated endothelial phenotypes.

Radiation-induced lung injury (RILI) initiates radiation pneumonitis and progresses to fibrosis as the main side effect experienced by patients with lung cancer treated with radiotherapy. There is no effective drug for RILI. Sustained vascular activation is a major contributor to the establishment of chronic disease. Here, using a whole thoracic irradiation (WTI) mouse model, we investigated the mechanisms and effectiveness of thrombopoietin mimetic (TPOm) for preventing RILI. We demonstrated that administering TPOm 24 hours before irradiation decreased histologic lung injury score, apoptosis, vascular permeability, expression of proinflammatory cytokines, and neutrophil infiltration in the lungs of mice 2 weeks after WTI. We described the expression of c-MPL, a TPO receptor, in mouse primary pulmonary microvascular endothelial cells, showing that TPOm reduced endothelial cell-neutrophil adhesion by inhibiting ICAM-1 expression. Seven months after WTI, TPOm-treated lung exhibited less collagen deposition and expression of MMP-9, TIMP-1, IL-6, TGF-β, and p21. Moreover, TPOm improved lung vascular structure, lung density, and respiration rate, leading to a prolonged survival time after WTI. Single-cell RNA sequencing analysis of lungs 2 weeks after WTI revealed that TPOm shifted populations of capillary endothelial cells toward a less activated and more homeostatic phenotype. Taken together, TPOm is protective for RILI by inhibiting endothelial cell activation.

LMAN1 serves as a cargo receptor for thrombopoietin.

Thrombopoietin (TPO) is a plasma glycoprotein that binds its receptor on megakaryocytes (MK) and MK progenitors, resulting in enhanced platelet production. The mechanism by which TPO is secreted from hepatocytes remains poorly understood. LMAN1 and MCFD2 form a complex at the endoplasmic reticulum membrane, recruiting cargo proteins into COPII vesicles for secretion. In this study, we showed that LMAN1 deficient mice (with complete germline LMAN1 deficiency) exhibited mild thrombocytopenia, whereas the platelet count was entirely normal in mice with approximately 7% Lman1 expression. Surprisingly, mice deleted for Mcfd2 did not exhibit thrombocytopenia. Analysis of peripheral blood from LMAN1 deficient mice demonstrated normal platelet size and normal morphology of dense and alpha granules. LMAN1 deficient mice exhibited a trend toward reduced MK and MK progenitors in the bone marrow. We next showed that hepatocyte-specific but not hematopoietic Lman1 deletion results in thrombocytopenia, with plasma TPO level reduced in LMAN1 deficient mice, despite normal Tpo mRNA levels in LMAN1 deficient livers. TPO and LMAN1 interacted by co-immunoprecipitation in a heterologous cell line and TPO accumulated intracellularly in LMAN1 deleted cells. Altogether, these studies confirmed the hepatocyte as the cell of origin for TPO production in vivo and were consistent with LMAN1 as the endoplasmic reticulum cargo receptor that mediates the efficient secretion of TPO. To our knowledge, TPO is the first example of an LMAN1-dependent cargo that is independent of MCFD2.

Long-term follow-up of the STOPAGO study

AbstractIn an open prospective, multicenter study enrolling 48 selected patients with chronic immune thrombocytopenia who achieved complete response for 1 year on thrombopoietin receptor agonists, half of the patients maintained a sustained response off treatment 4 years after treatment discontinuation.

Extension of impurity profiling on eltrombopag olamine to in-silico predictions: An effort to exploit correlated forced degradation products and known drug-related substances in drug discovery

The recent pandemic has highlighted the impact of diseases on global health and the economy. The rapid discovery of new hit molecules remains a tough challenge. Pharmaceutical impurity profiling can be linked to drug discovery through the identification of new hits from compounds identified during the analytical profiling. The present study demonstrates this linkage through the extension of the impurity (forced degradation) profiling of eltrombopag (ELT) olamine, a thrombopoietin (TPO) receptor agonist. The drug was exposed to standard degradation and the degradation products were primarily resolved and identified by UPLC-ESI-MS. This led to the identification of five forced degradation products (FDP). Thirty-three other known related substances (RS) of ELT, identified in the literature, were also considered. Molecular similarity checks were performed using Tanimoto/Jaccard's similarity searches. A set of structurally and topologically similar molecules, including ELT and 15 RS, was established and subjected to in-silico toxicity-, absorption-, distribution-, metabolism-, and elimination (ADME) predictions. The RS, predicted with similar or lower toxicity than ELT and a comparable ADME profile, were subjected to molecular docking to trace changes in TPO receptor affinity. The results indicated that five RS had a high Jaccard’s similarity with ELT and higher or comparable docking scores. These compounds, along with few other impurities were predicted to have lower toxicity, better or comparable absorption, distribution, metabolism, and also a better excretion profile than ELT. This justifies their entry as potential novel TPO receptor agonists in drug discovery.

Analysis of Molecular Testing for Suspected Myeloproliferative Neoplasm at a Hybrid Community-Academic Health System

Testing for somatic mutations in JAK2, MPL, and CALR genes is a crucial element in the diagnosis of myeloproliferative neoplasms (MPN). This may have inadvertently led to increased requests for testing to “rule out MPN,” including clinical situations with low pre-test probability. This paper examines JAK2, MPL, and CALR testing by next generation sequencing (NGS) with the goal of formulating practical guidelines to make test utilization more efficient and effective. NGS results from 1482 patients tested between 2015 and March 2022 were retrieved, along with corresponding bone marrow biopsies and CBC results performed within 90 days prior to NGS and 245 (16.5%) cases were positive for pathogenic variants in JAK2, MPL, or CALR genes.The findings showed an increase in the proportion of positive cases with patient age, and a statistically significant difference in RBC counts and platelet counts among patients with positive versus negative results. Utilizing these factors, simple algorithms were constructed to predict positive results with a maximum sensitivity of 91%, while potentially eliminating 28% of negative tests. However, these models still failed to identify ∼9% of patients with MPNs. Among these “missed” patients, many had either primary myelofibrosis or MDS/MPN. Considering a simple triage model to help guide MPN testing could represent a more cost effective approach, particularly if “missed” patients could be further reduced.

Predictors for spontaneous remission in childhood chronic immune thrombocytopenia.

This study examined the factors associated with spontaneous remission in children with chronic immune thrombocytopenia (ITP). We retrospectively analyzed the medical records of patients diagnosed with ITP from January 1988 to December 2019 at our institute. A total of 104 children with chronic ITP were identified. The median follow-up time from diagnosis of chronic ITP was 3.6 years (IQR 1.2-8.3, range 0.1-31.4). Fifteen (14.4%) patients with severe symptoms received specific platelet-elevating therapies, including splenectomy, rituximab, and thrombopoietin receptor agonists. Seven of them achieved remission. Among the patients with a platelet count < 30 × 109/L at the time of diagnosis of chronic ITP, those who received specific platelet-elevating therapies had a higher remission rate compared to those who did not (HR: 4.66, 95% CI: 1.36-16.0). Sixteen patients (15.4%) developed systemic lupus erythematosus, 46 (44.2%) still had thrombocytopenia after a median follow-up of 6.8 years, and 42 (40.4%) achieved remission with a median time to remission of 2.0 years (IQR 0.6-4.1, range 0.1-15.7). The two independent predictive factors for spontaneous remission in childhood chronic ITP were platelet counts > 30 × 109/L at the time of diagnosis of chronic ITP (HR: 3.16, 95% CI: 1.51-6.62) and persistently negative ANA at follow-up (HR: 6.12, 95% CI: 1.46-25.7). The cumulative probabilities of spontaneous remission at 10 years post-diagnosis of chronic ITP were 72.2% for patients without risk factor compared to 0% for patients with two risk factors.

New approaches to standard of care in early-phase myeloproliferative neoplasms: can interferon-α alter the natural history of the disease?

The classical BCR::ABL-negative myeloproliferative neoplasms (MPN) include Polycythemia Vera (PV), Essential Thrombocytemia (ET), and Primary Myelofibrosis (PMF). They are acquired clonal disorders of the hematopoietic stem cells (HSC) leading to hyperplasia of one or several myeloid lineages. MPN are caused by three main recurrent mutations, JAK2V617F and mutations in the calreticulin (CALR) and the thrombopoietin receptor (MPL) genes. Here, we review the general diagnosis, the complications, and the management of MPN. Second, we explain the physiopathology of the natural disease development and its regulation, which contributes to MPN heterogeneity. Thirdly, we describe the new paradigm of the MPN development highlighting the early origin of driver mutations decades before the onset of symptoms and the consequence on early detection of MPN cases in the general population for early diagnosis and better medical management. Finally, we present the interferon alpha (IFNα) therapy as a potential early disease-modifying drug after reporting its good hematological and molecular efficacies in ET, PV and early MF in clinical trials as well as its mechanism of action in pre-clinical studies. As a result, we may expect that, in the future, MPN patients will be diagnosed very early during the course of disease and that new selective therapies under development, such as IFNα, JAK2V617F inhibitors and CALRmut monoclonal antibodies, would be able to intercept the mutated clones.

Desialylation and Apoptosis in Immune Thrombocytopenia: Implications for Pathogenesis and Treatment.

Immune thrombocytopenia (ITP) is an autoimmune disease in which platelet autoantibodies play a significant role in its pathogenesis. Regulatory T cell dysfunction and T cell-mediated cytotoxicity also contribute to thrombocytopenia. Current therapies are directed towards immune suppression and modulation as well as stimulation of platelet production with thrombopoietin receptor agonists. Additional mechanisms of the pathogenesis of ITP have been suggested by recent experimental data. One of these processes, known as desialylation, involves antibody-induced removal of terminal sialic acid residues on platelet surface glycoproteins, leading to hepatic platelet uptake and thrombocytopenia. Apoptosis, or programmed platelet death, may also contribute to the pathogenesis of ITP. The extent of the impact of desialylation and apoptosis on ITP, the relative proportion of patients affected, and the role of antibody specificity are still the subject of investigation. This review will discuss both historical and new evidence of the influence of desialylation and apoptosis in the pathogenesis of ITP, with an emphasis on the clinical implications of these developments. Further understanding of both platelet desialylation and apoptosis might change current clinical practice and improve patient outcomes.

Avatrombopag for the treatment of patients with chemotherapy-induced thrombocytopenia: A case series.

Management of chemotherapy-induced thrombocytopenia (CIT) is challenging, often resulting in chemotherapy treatment delays, dose reduction, and treatment interruption. Randomized trials support the potential efficacy and safety of thrombopoietin receptor agonists in CIT management. A phase III trial of avatrombopag (AVA) demonstrated increased platelet counts (PC) in patients with solid tumours experiencing CIT. To complement those findings, this case series of six patients with solid tumours and CIT is presented. Results from these cases support the clinical benefit of AVA in improving PC and reducing the impact of CIT on tumour treatment, allowing continued therapy without dose reduction or treatment interruption.

Clinical research progress of lusutrombopag for the treatment of thrombocytopenia in chronic liver disease

Thrombocytopenia is one of the common complications with the hematologic system in patients with chronic liver disease, which often causes poor quality of life and high risk of bleeding, thereby affecting their diagnosis, treatment, and prognosis. Platelet transfusion can improve the patient's declining platelet count to a certain extent, but it has problems such as high price and being easy to cause immune rejection. Thrombopoietin (TPO), as an important cytokine that affects platelet production, can bind to TPO receptors and activate megakaryocytes to produce platelets. Lusutrombopag is a newly developed small-molecule TPO receptor agonist that can induce bone marrow progenitor cells to differentiate into megakaryocytes and increase platelet production, posing characteristics of oral convenience, safety and effectiveness; thus, it has been used in many countries and regions for the treatment of patients with chronic liver diseases concurrent with thrombocytopenia. Herein, the pharmacological features and clinical research are reviewed.

Thromboembolism adverse event profiles of thrombopoietin receptor agonists: a real-world, pharmacovigilance study

ABSTRACT Background Thrombopoietin receptor agonists (TPO-RAs) are currently approved for the treatment of thrombocytopenia in different conditions. The relationship between TPO-RAs and thromboembolic events (TEEs) remains controversial. Research design and methods We extracted TPO-RAs adverse reaction reports after their marketing until now, using the FDA adverse event reporting system (FAERS). Positive signals were detected by reporting odds ratios (RORs). And the Weibull shape parameter test was utilized to analyze the time-to-onset profiles. Result Thromboembolic events accounted for 8.97% among TPO-RAs reports. Increased reporting of TEEs was related to TPO-RAs treatment compared with the entire FAERS database [ROR = 2.65 (2.56, 2.73)]. In addition, venous thrombotic events [ROR = 4.13 (3.92, 4.35)] were reported more frequently than arterial events ROR = 1.81 (1.7, 1.93)]. Age over 60 years [odds ratio (OR) = 1.10 (1.01, 1.20), p = 0.029] and weight over 80 kg [OR = 1.36 (1.17, 1.58), p < 0.001] of patients might have higher risk of TEEs during TPO-RAs therapy. Conclusion Evidence from the real world suggested that TPO-RAs were associated with higher incidence of TEEs, particularly venous thrombosis. The risk of TPO-RAs-associated TEEs mostly happened in the early stages of treatment and decreased over time.

Possibilities for diagnosing essential thrombocythemia at the stage of primary health care

This clinical case presents a 39-year-old woman diagnosed with essential thrombocythemia, accompanied by a review of the epidemiology, clinical and diagnostic criteria, and patient management strategies. The case also includes a discussion of potential complications and prognosis associated with the condition. The importance of thorough outpatient monitoring is emphasized, which should include regular assessments of clinical symptoms, changes in blood count parameters, bone marrow trephine biopsy, and molecular genetic testing for MPL and CALR gene mutations. The report highlights gaps in the current medical examination process, suggesting that addressing these deficiencies could improve early detection of essential thrombocythemia and enable timely pathogenetic therapy with antiplatelet agents to prevent complications.

The Establishment of a Novel Murine Model of Immune Thrombocytopenia in Pregnancy and the Impacts of Thrombopoietin Receptor Agonist on Platelet Production.

Objective Immune thrombocytopenia (ITP) is frequently associated with pregnancy. However, treatment options for ITP in pregnancy are limited, and there are few animal models available for the establishment of treatments. Here, we aimed to establish a novel murine pregnant model of ITP and to investigate the impacts of thrombopoietin receptor agonist (TPO-RA) on platelet production and reproductive outcomes. Methods Anti-glycoprotein Ib-alpha (GPIbα) antibody, which binds to megakaryocytes and platelets, was subcutaneously administered to pregnant mice in order to develop an ITP model (ITP group). TPO-RA was given in doses of 1 µg/kg, 10 µg/kg, and 100 µg/kg (low-dose group, mid-dose group, and high-dose group, respectively) for the treatment of ITP in pregnancy. Results The ITP group showed a significant reduction of platelet counts of less than 15% of healthy pregnant mice (control group) and also showed a significant increase in miscarriage rate (control group, 3.8%; ITP group, 44.4%; p < 0.05). Striking increases in platelet counts were observed in every TPO-RA group without any negative effects on fetal growth and placental pathology. No abnormality was noted in the external examination of fetal mice. Interestingly, a significant recovery of miscarriage rate was observed in the mid-dose group (23.5%) compared with the ITP group (p < 0.05). Conclusion A novel ITP model in pregnant mice was induced by injection of an anti-GPIbα antibody, and sufficient effects of TPO-RA on platelet production were observed in the present study. Furthermore, the positive impacts of TPO-RA on reproductive outcomes were revealed in the ITP model.

Avatrombopag in immune thrombocytopenia: A real-world study of the Spanish ITP Group (GEPTI).

Avatrombopag is the newest thrombopoietin receptor agonist (TPO-RA) approved to treat immune thrombocytopenia (ITP). Real-world evidence regarding effectiveness/safety is limited. The Spanish ITP Group (GEPTI) performed a retrospective study with patients starting avatrombopag for the first time. A total of 268 ITP patients were recruited. The median (interquartile range [IQR]) follow-up time was 47.5 (30.4-58.9) weeks. Among the 193 patients with baseline platelet counts <50 × 109/L, 174 (90.1%) of them achieved response (PC ≥50 × 109/L), and 113 (87.6%) of the 129 who persisted on avatrombopag at last visit had platelet levels above such threshold. Results were similar when only those patients switching to avatrombopag due to previous treatment failure were considered (n = 104). Patients reached response in 13 (7-21) days. Among patients with baseline levels ≥50 × 109/L, 73/75 (97.3%) reported response, which was maintained by 53 (94.6%) of the 56 who continued on avatrombopag at the end of the study. Loss-of-response was always <10%. ITP duration did not influence response. Approximately 79% (34/43) of heavily pretreated (≥4 lines) patients with baseline platelet counts <50 × 109/L switching after previous failure achieved PC ≥50 × 109/L. Previous use of eltrombopag and/or romiplostim did not influence response, regardless of whether previous TPO-RA(s) succeeded or failed. Avatrombopag allowed dose-reduction/suspension of corticosteroids in 40/50 (80.0%) patients with baseline platelet counts <50 × 109/L. Overall, 40/268 (14.9%) thrombocytosis and 12/268 (4.5%) thromboembolic events were reported. Our real-world cohort supports the use of avatrombopag to manage ITP, regardless of disease severity and treatment history.

6601 A Case of Recurrent Painless Thyroiditis and Discussion of Management

Abstract Disclosure: M.C. Slack: None. S. Grock: None. Introduction: Painless (silent) thyroiditis is characterized as a subacute and generally self-limited disease process in which patients develop transient thyrotoxicosis, which is often followed by a hypothyroid phase before entering the recovery euthyroid phase. Given high frequency of positive thyroid antibodies, it may be autoimmune-mediated; recurrence is rare. Here we present a case of recurrent painless thyroiditis and discuss management options. Clinical Case: A Korean woman was followed by endocrinology from age 38 to 60 and experienced at least seven episodes of painless thyroiditis over this time. The episodes occurred without an identifiable trigger and were not preceded by viral illness. During episodes she developed palpitations, hair loss, and dyspnea on exertion and biochemical evidence of thyrotoxicosis with TSH suppressed to &amp;lt;0.2 mIU/mL (normal 0.3-4.7) and elevated free T4 levels as high as 5.4 ng/dL (normal 0.8-1.7). TSI, TPO, and TSH receptor antibodies were checked during multiple episodes and resulted negative, though thyroglobulin antibody was significantly elevated. A radioactive iodine uptake scan was obtained during an active episode of thyroiditis and revealed diffusely low uptake. The patient’s episodes lasted approximately two to three months before normalization of her TSH and FT4. She had at least one instance of transient hypothyroidism after thyrotoxicosis with a TSH of 13.2 and FT4 of 0.6 which subsequently normalized 6 weeks later. The patient did not have known cardiovascular disease and DXA scans revealed mild osteopenia with the lowest T-score -1.3. RAI was considered for the patient based on the total number and increasing frequency of her episodes. She ultimately declined treatment with RAI and continues to follow with endocrinology. Clinical Lessons: While the deleterious effects of prolonged hyperthyroidism (e.g. osteoporosis, arrhythmia, cardiovascular disease) are well known, it is unclear what risk recurrent painless thyroiditis episodes pose. As there are no guidelines regarding treatment, clinical gestalt incorporating frequency and duration of episodes, as well as symptoms, is often used to determine if definitive management is indicated. There are case reports in the literature of treatment of recurrent thyroiditis with RAI ablation performed during a euthyroid state, which eliminated recurrence of episodes but did lead to permanent hypothyroidism necessitating hormone replacement. Surgical thyroidectomy may also be considered in select patients. This case highlights the challenges in treating rare cases of recurrent painless thyroiditis given the lack of research or established guidelines. It is reasonable to consider the frequency, severity, and total number of episodes, as well as patient risk factors, symptoms, and preferences when making recommendations regarding management. Presentation: 6/1/2024