Sarcoidosis-Associated Immune Thrombocytopenic Purpura and Focal Segmental Glomerulosclerosis

Purpose of study A 32-years old male with known multi-system sarcoidosis in remission for 5 years off treatment presented to the emergency room with complaints of generalized weakness, hematemesis, epistaxis, and bruises. Physical examination was notable for petechiae, ecchymosis along with papules and plaques suggestive of active sarcoid skin lesions on his extremities. Laboratory workup was significant for thrombocytopenia 3000/uL, acute kidney injury with sub-nephrotic proteinuria. Peripheral blood smear did not show evidence of hemolysis and direct Coombs test was negative. Infectious workup including COVID-19, HIV, and hepatitis serologies were negative. Computed Tomography (CT) of chest, abdomen, and pelvis showed mild splenomegaly and an increased number of sub-centimeter hilar and mediastinal lymph nodes. The patient was treated with dexamethasone 40 mg daily for 4 days and intravenousimmunoglobulins (IVIG-2 gm/kg) for possible Immune Thrombocytopenic Purpura (ITP) with improvement in platelet count to 42000/uL by day 3. His workup for AKI and sub-nephrotic proteinuria was negative apart from a positive ANA (1: 160) with low complements. The anti-phospholipid antibody panel was negative. The ACE level was markedly elevated (>80U/L). The patient could not get a renal biopsy due to severe thrombocytopenia. He was discharged but was re-admitted in 15 days for severe thrombocytopenia of 1000/uL, epistaxis, and bruising. We continued high dose steroids along with IVIG 1 gm/kg for refractory ITP with minimal response and started anti-CD20 agent (Rituximab) 375 mg/m2 weekly with thrombopoietin-receptor agonist (Eltrombopag). His platelets count improved in response to treatment and subsequent renal biopsy showed focal and segmental glomerulosclerosis along with mild interstitial fibrosis, tubular atrophy thought to be from long standing sarcoidosis. There was also evidence of focal arteriosclerosis with no evidence of granulomas, immune complex, complement, or IgG4 deposition. Given skin lesions, thrombocytopenia, extensive lymphadenopathy, and renal involvement with markedly elevated ACE levels the overall picture was consistent with active multi-system sarcoidosis. His platelet count increased to 177,000/uL at the time of discharge. Currently, the patient is on slow steroid taper along with Eltrombopag 25 mg every other day without any recurrence of his symptoms so far. Methods used We described one case of sarcoidosis with hematologic and renal involvement. Summary of results Our patient developed hematologic and renal complications approximately 6 years after being diagnosed with sarcoidosis. Initially, he did not demonstrate sufficient clinical response to IVIG and high dose steroids. However, after a course of anti-CD20 agent (Rituximab) and with the addition of thrombopoietin-receptor agonist (Eltrombopag) he showed improvement of platelet count and stabilization of the renal function. Currently, the patient is receiving maintenance therapy with Prednisone 7.5 mg daily along with Eltrombopag 25 mg twice weekly with no recurrence of ITP and stable renal function. A further decision on whether the patient needs another cycle of Rituximab will be determined by the patient's clinical course. Conclusions Highly variable manifestations of Sarcoidosis can pose a significant diagnostic and therapeutic challenge as can be seen from our case. ITP is a rare hematological manifestation of sarcoidosis and addition of anti-CD20 agents should be considered in refractory cases.

Successful Systemic Lysis Therapy of a Floating Carotid Thrombus in an Acute Stroke Patient with Known Immune Thrombocytopenia (ITP) on Ongoing Eltrombopag Therapy and Acute COVID-19 Infection: a Case Report.

Patients with immune thrombocytopenia (ITP) under eltrombopag therapy are vulnerable to thrombotic disbalance, both due to the disease itself and therapy-related hypercoagulability. Vascular events such as the development of a free-floating carotid thrombus are known rare complications of acute COVID-19 infections due to endothelial inflammation and presumptive underlying hypercoagulable state. In patients at risk, the onset of new focal neurological symptoms should prompt immediate angiographic diagnostics and, if necessary, appropriate treatment. Here, we report a case of a 38-year-old female with a medical history of ITP and the presence of COVID-19 infection presenting an acute sensorimotor hemiparesis of the right side while on eltrombopag therapy. Initial CT angiography revealed a free-floating thrombus in the left common carotid artery. Upon admission, the patient's platelet count was significantly elevated at 896 × 109/l. After systemic lysis therapy, the thrombus was fully dissolved. Follow-up diffusion-weighted imaging revealed multilocular cortical infarction of the left MCA territory. The patient soon recovered and was discharged with residual mild sensorimotor deficits in the right arm. Eltrombopag was paused at admission, and the patient's platelet count was quickly returning to normal. She was discharged with a daily intake of acetylsalicylic acid, a reduced daily dose of eltrombopag, and weekly monitoring of her platelet count for the next three months. This unique case highlights the need for caution in patients at vascular risk who contract COVID-19 and discusses thrombocytic derailment under thrombopoietin receptor agonist therapy in the context of an acute COVID-19 infection.

Current Concepts in the Diagnosis and Management of Adult Primary Immune Thrombocytopenia: Our Personal View.

Primary immune thrombocytopenia (ITP) is an acquired blood disorder that causes a reduction in circulating platelets with the potential for bleeding. The incidence of ITP is slightly higher in adults and affects more women than men until 60 years, when males are more affected. Despite advances in basic science, primary ITP remains a diagnosis of exclusion. The disease is heterogeneous in its clinical behavior and response to treatment. This reflects the complex underlying pathophysiology, which remains ill-understood. Platelet destruction plays a role in thrombocytopenia, but underproduction is also a major contributing factor. Active ITP is a proinflammatory autoimmune disease involving abnormalities within the T and B regulatory cell compartments, along with several other immunological abnormalities. Over the last several years, there has been a shift from using immunosuppressive therapies for ITP towards approved treatments, such as thrombopoietin receptor agonists. The recent COVID-19 pandemic has hastened this management shift, with thrombopoietin receptor agonists becoming the predominant second-line treatment. A greater understanding of the underlying mechanisms has led to the development of several targeted therapies, some of which have been approved, with others still undergoing clinical development. Here we outline our view of the disease, including our opinion about the major diagnostic and therapeutic challenges. We also discuss our management of adult ITP and our placement of the various available therapies.

Thrombocytopenia in the Course of COVID-19 Infection.

We report three cases of severe thrombocytopenia during COVID-19 infection associated with either cutaneous purpura or mucosal bleeding. The initial investigations ruled out other causes of thrombocytopenia. Two of the patients were treated with intravenous immunoglobulins and eltrombopag, while the third recovered spontaneously. A good clinical and biological response was achieved in all patients leading to hospital discharge. LEARNING POINTS: Immune thrombocytopenia should be considered in COVID-19-infected patients presenting with thrombocytopenia.Coronavirus-related thrombocytopenia can be severe and life-threatening.Despite the severity of coronavirus-related immune thrombocytopenia, recovery may be spontaneous or achieved following immunoglobulin or platelet growth factor administration.

Use of thrombopoietin receptor agonists in adults with immune thrombocytopenia: a systematic review and Central European expert consensus.

There are currently three thrombopoietin receptor agonists (TPO-RAs) approved in Europe for treating patients with immune thrombocytopenia (ITP): romiplostim (Nplate®), eltrombopag (Revolade®), and avatrombopag (Doptelet®). However, comparative clinical data between these TPO-RAs are limited. Therefore, the purpose of this study was to perform a literature review and seek expert opinion on the relevance and strength of the evidence concerning the use of TPO-RAs in adults with ITP. A systematic search was conducted in PubMed and Embase within the last 10 years and until June 20, 2022. A total of 478 unique articles were retrieved and reviewed for relevance. The expert consensus panel comprised ITP senior hematologists from eight countries across Central Europe. The modified Delphi method, consisting of two survey rounds, a teleconference and email correspondence, was used to reach consensus. Forty articles met the relevancy criteria and are included as supporting evidence, including five meta-analyses analyzing all three European-licensed TPO-RAs and comprising a total of 31 unique randomized controlled trials (RCTs). Consensus was reached on seven statements for the second-line use of TPO-RAs in the management of adult ITP patients. In addition, the expert panel discussed TPO-RA treatment in chronic ITP patients with mild/moderate COVID-19 and ITP patients in the first-line setting but failed to reach consensus. This work will facilitate informed decision-making for healthcare providers treating adult ITP patients with TPO-RAs. However, further studies are needed on the use of TPO-RAs in the first-line setting and specific patient populations.

Resposta Ao Tratamento: Eltrombopag Na Pediatria

Objetivos: Descrever dois casos clinicos de pacientes Portadores de Trombocitopenia Imune (PTI) cronica que apresentaram boa resposta terapeutica ao uso do Eltrombopag. Materiais e metodos: As informacoes foram obtidas atraves de revisao de prontuario eletronico. Relato de caso: Caso 1: Paciente 7 anos, diagnostico de PTI ha 1 ano e 4 meses, refratario a tratamento com corticoterapia e imunoglobulina. Iniciado Eltrombopag com dose primaria de 25 mg dia, sem resposta apos 1 mes, progredida dose para 50 mg dia com uma resposta plaquetaria apos 34 dias de 21000 U/mm3 para 169000 U/mm3, sem intercorrencias clinicas. Caso 2: Paciente 14 anos, PTI pos COVID, diagnosticado ha 1 ano e 11 meses, refratario a terapia com corticoide, imunoglobulina e azatioprina, iniciado Eltrombopag 50 mg dia com resposta plaquetaria apos 1 mes de 15000 para 401000 U/mm3, sem intercorrencias clinicas. Discussao: A trombocitopenia imune caracteriza-se por um processo imunomediado, onde ocorre a degradacao de plaquetas com contagem total menor 100,000U/mm3. e classificada como cronica quando o tempo de doenca ultrapassa 12 meses e pode trazer grande morbidade aos seus pacientes, nao so pelos sintomas e prejuizo na qualidade de vida, como pelos efeitos colaterais das terapias a longo prazo. o presente estudo relata 2 casos de trombocitopenia imune cronica em criancas, refrataria as terapias tradicionais, que apresentaram boa resposta terapeutica ao uso de Eltrombopag. O Eltrombopag e um agonista oral nao peptidico do receptor da trombopoietina que age estimulando a producao de plaquetas. Um estudo randomizado, multicentrico, controlado por placebo, PETIT 2, comprovou a eficacia e seguranca do uso do Eltrombopag na faixa etaria pediatrica, estabelecendo as doses iniciais de 25 a 50 mg/dia para pacientes de 6 a 17 anos, sendo sua dose maxima diaria recomendada de 75 mg. Nos estudos PETIT e PETIT 2, o tratamento com Eltrombopag demonstrou uma resposta plaquetaria satisfatoria, contagem de plaquetas de pelo menos 50,000U/mm3, entre 1 e 6 semanas de uso, sem necessidade de terapia de resgate. foram observados tambem uma reducao nos sangramentos e de medicacoes concomitantes. nao foram constatados eventos adversos graves, e os efeitos relativos a medicacao encontrados se relacionavam a alteacoes laboratoriais hepatobiliares, logo tendo seus parametros de normalidade restabelecidos apos descontinuacao do uso.resultados semelhantes tambem foram encontrados em um estudo observacional de centro unico realizado na china. Embora ainda haja poucos estudos sobre o uso do eltrombopag na faixa etaria pediatrica, estes tem apresentado resultados semelhantes aos encontrados em adultos, porem sem descricao de eventos tromboticos ou malignidade. Copyright © 2022

A CASE OF REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA INDUCED IMMUNE THROMBOCYTOPENIC PURPURA SUCCESSFULLY TREATED WITH VENETOCLAX

Background: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. Approximately 2% of patients with CLL develop immune thrombocytopenic purpura (ITP) during the course of the disease. When resistant to steroids, this constitutes as indication for treatment of the CLL. Here we report a patient with refractory ITP secondary to CLL successfully treated with venetoclax. Aims: To present an interesting case with CLL related refractory ITP treated successfully with novel agent venetoclax. Methods: Patient data was taken from the patient herself and Hospital records. Informed consent to publish the case is obtained from patient. Permission for off-label venetoclax and eltrombopag was obtained from Ministry of Health of Turkey. Results: 46-year-old female patient presented with lumps on her neck that were present for the last 9 months in November 2020. She has a history of frequent pneumonia and otitis but no constitutional symptoms. Her physical examination reveals multiple 2cm lymphadenopathies on her neck and no organomegaly or other pathological features. Blood work shows mild lymphocytosis (6800/mm3) with no serious cytopenias. Peripheral blood smear, flow cytometry and bone marrow biopsy were all compatible with CLL. She was classified as Binet A CLL and was followed up with no treatment after appropriate vaccinations against capsulated pathogens. In July and August 2021 she received two doses of mRNA vaccination against COVID-19. On 1st November 2021 she experienced excessive menstrual bleeding and blood work showed platelet count of 23000/mm3, she was started on steroids (1 mg/kg/day) and after 4 days platelet count has risen to 55000/mm3, she discontinued steroids on her own against medical advice. On 13th of November she presented with extensive petechiae and purpura and was again started on steroids and was given the courses of intravenous immunoglobulins (IVIG) without any sustained response. She was refractory to platelet transfusions too. She was transferred to our clinic. She was found to have del11q and del13q. She refused bone marrow examination. She was treated with rituximab, steroids, vincristine, IVIG and eltrombopag for ITP without success (Fig. 1). She had a minimal response to IVIG only. She received two courses of bendamustine (90 mg/kg for two days) also without success. Three courses of plasmapheresis yielded no response either. After mild success with immunadsorbtion apharesis she was started on venetoclax plus rituximab with ramp-up. Sustained response was achieved within the first week of venetoclax therapy. (Figure Presented ) Summary/Conclusion: Gordon et al. reported 2 CLL cases one with ITP and other with Evans syndrome successfully treated with venetoclax. We think, this treatment should be considered in patients with refractory immune cytopenias secondary to CLL and assessed with prospective clinical trials.

ELTROMBOPAG (EPAG) INDUCES HEMATOLOGIC RESPONSES FOR PATIENTS WITH POST-ALLOGENIC HEMATOPOIETIC STEM CELL TRANSPLANT POOR GRAFT FUNCTION (POST-ALLO HSCT PGF): RESULTS OF THE ELTION STUDY IN SPAIN

Background: Persistent cytopenia due to poor graft function (PGF) is a life-threatening complication in patients undergoing allogeneic HSCT (allo-HSCT). Several therapeutic approaches have been tested in this subset of patients with poor clinical results. Aims: The objective of this multicenter open-label interventional prospective phase II Novartis study (ELTION, ClinicalTrials.gov id: NCT03718533), was to analyze efficacy and safety of EPAG in patients with post-allo-HSCT poor graft function. Methods: Adult patients diagnosed with PGF (defined as severe cytopenia after day +30 post-transplant, with two or more of the following: platelets <20000/μL-mandatory-, ANC <1000/μL, hemoglobin< 10 g/dL), and full donor chimerism, were eligible to enter the trial. Study treatment consisted of EPAG. at 150 mg/day administered up to 36 weeks;dose adjustments were contemplated as per protocol on an individual basis. The primary efficacy endpoint was the overall hematologic response (partial and complete), as determined by platelet, hemoglobin and neutrophil counts by 16 weeks after the initiation of EPAG. Results: Although the aim of the study was to include 33 patients, recruitment stopped prematurely due to the difficulties for hospital visits posed during COVID-19 pandemic, and eventually only 10 patients were included. The decision for this premature termination is not related to any safety concern related to the drug. Patient characteristics are shown in the table 1 attached below. At EPAG. initiation, all 10 patients showed thrombocytopenia (<20000/μcL), 5 presented with anemia (Hgb <10 g/dL), and 4 had neutropenia (ANC <1000/μcL). Four patients discontinued EPAG before week 12 due to: disease progression/relapse (2 patients), protocol deviation (1 patient), and CMV infection (1 patient). In none of the cases, the event was related to study drug. At week 16, 4 patients (4/10, 40%) and at week 24, 5 patients, showed improvement in at least one of the 3 hematologic cell lines (partial response), respectively. Counts pre-and post-EPAG and global response in patients who stayed on treatment > 12 weeks are displayed below: Image: Summary/Conclusion: In our experience, EPAG worked well in subjects with PGF, an otherwise life-threatening condition for patients, and its use at 150 mg/day is safe and well tolerated in this setting. Our data suggest that eltrombopag might improve hematologic cell counts in patients with PGF, especially in those patients who remained on treatment at week 24, however further research is warranted to extend its applicability for larger cohorts.

PROSPECTIVE OBSERVATIONAL STUDY IN PATIENTS WITH IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP) TREATED WITH TPO-R AGONISTS (TPO-RA): ELTROMBOPAG (EPAG) AND ROMIPLOSTIM (ROMI) - THE PEPITE STUDY

Background: Initially, the marketing authorization (MA) of EPAG and ROMI was to adult patients (p.) with ITP ≥12 months (m.) and refractory to other treatments (t.), splenectomized or contraindicated to splenectomy. The MA was extended for EPAG in 2019 to p. aged ≥1 year with ITP ≥6 m., refractory to other t. (corticoids (CS), IgIV). In 2017, French national guidelines suggested the use of TPO-RA as an option of t. in 2nd line (L). Aims: The PEPITE study, still ongoing, aims to assess the modalities of use, effectiveness and safety of TPO-RAs in reallife. Methods: Prospective, observational, multicenter study including adult p. who initiated TPO-RA with persistent (pITP) or chronic (cITP) ITP. Inclusions occurred between 12/21/2018 and 07/17/2020. Here's the interim analysis, cut-off date: 03/22/2021. Characteristics at baseline were presented in 114 p. (analyzed pop). Efficacy analysis of TPO-RA was assessed in p. with a platelet count (PLAT) <100 G/L at TPO-RA initiation (efficacy pop 113 p.). Responses were defined as: response (R) = PLAT ≥30 G/L, complete response (CR) = PLAT ≥100 G/L and non-response (NR) = PLAT <30 G/L. Results: 123 p. included through 40 centers by 25 hematologists and 15 internists, and 77 p. were still on TPO-RA at 6 m. At baseline, mean age 62.7 ± 20.1 years, 55% men, 29% with at least 1 cardiovascular risk factor. At diagnosis: median PLAT = 26 G/L [0 to 134 G/L], 31% of p. with bleedings. 97% of p. received at least one L of t. before TPO-RA: CS 96%, IVIG 56%, rituximab 47%, dapsone 18%, hydroxychloroquine 11%, danazol 6% and 7% of p. were splenectomized. Median number L of t. = 2 and 8% of p. had more than 4 L. Median time between diagnosis and TPO-RA initiation was 2.6 years [0.3 to 49.3 years], 33% of p. with pITP (n=21 with ITP 3 -<6 months, n=16 with ITP 6 - <12 months) and 67% with cITP. At TPO-RA initiation: 9% of p. were on CS and 48% p. had PLAT <30 G/L (median PLAT = 30 G/L), 95 p. (83%) received EPAG and 19 p. (17%) ROMI. For the 77 p. still on TPO-RA at 6 m., R rate = 97% and CR = 60%. Within 6 m., 10 p. had permanently (perm.) discontinued TPO-RA, main causes were therapeutic effect deemed sufficient (TEDS) for 6 p. and NR for 2 p. For the 27 p. still treated with TPO-RA at 18 m., R rate = 93% and CR = 48%. Within 18 m., 12 p. had perm. stopped TPO-RA, including 7 p. for TEDS and 1 p. NR. P. initiated TPO-RA with ITP 3 -<6 months (N = 21), 9 (43%) p. were still on TPO-RA at 6 months, 5 (56%) in CR. Over the entire follow-up, 24p. (21%) perm. discontinued TPO-RA, main causes were TEDS for 9 p., adverse event (AE) for 5 p. and absence of R for 4 p. Of the 105 p. treated with EPAG at least once, 62 (59%) experienced at least one AE, and 26 SAE occurred in 17 p. The most common AEs were respectively 6% for headache and 3% for SARS-CoV-2 infections, diarrhea, asthenia, insomnia, arthralgia and alopecia. Of the 40 p. treated with ROMI at least once, 19 (48%) experienced at least one AE and 17 SAEs occurred in 10 p. The most common AEs: SARS-CoV-2 infections (5%) and arthralgias (5%). No deaths related to TPO-RA was reported. Summary/Conclusion: Preliminary data from the PEPITE study show that TPO-RA are prescribed in early ITP, including 33% with pITP (18% with ITP 3-<6 m.) and are used in 7% of cases after splenectomy. At 6 m. R on t. was 97% and CR on t. was 60%. Within 6 m., 6 p. had perm. stopped TPO-RA due to TEDS. The real-life effectiveness and safety data for EPAG and ROMI are consistent with data reported in extension studies, with the specificity of occurrence of SARS-CoV-2. The final analysis is scheduled after 24 m.

Pulmonary embolism in a patient with eltrombopag-treated aplastic anaemia and paroxysmal nocturnal haemoglobinuria clone during COVID-19 pneumonia.

Thrombosis in patients with thrombocytopenia has several risk factors, both disease-related and treatment-associated. Recently, COVID-19 infection was recognized as an additional risk factor, further complicating the delicate balance between thrombosis and bleeding in these patients. Here we describe the case of a patient with aplastic anaemia on eltrombopag who developed pulmonary embolism during COVID-19 pneumonia, despite receiving oral anticoagulation with edoxaban. Notably, he was also carrying a large paroxysmal nocturnal haemoglobinuria clone, although without evidence of haemolysis. The presented case recapitulates some of the open questions in thrombotic risk management of cytopenic patients, such as the management of thrombopoietin receptor agonists and the choice of anticoagulation in PNH, while also accounting for the additional thrombotic risk linked to COVID-19.

Emerging Roles of the Iron Chelators in Inflammation.

Iron is a crucial element for mammalian cells, considering its intervention in several physiologic processes. Its homeostasis is finely regulated, and its alteration could be responsible for the onset of several disorders. Iron is closely related to inflammation; indeed, during inflammation high levels of interleukin-6 cause an increased production of hepcidin which induces a degradation of ferroportin. Ferroportin degradation leads to decreased iron efflux that culminates in elevated intracellular iron concentration and consequently iron toxicity in cells and tissues. Therefore, iron chelation could be considered a novel and useful therapeutic strategy in order to counteract the inflammation in several autoimmune and inflammatory diseases. Several iron chelators are already known to have anti-inflammatory effects, among them deferiprone, deferoxamine, deferasirox, and Dp44mT are noteworthy. Recently, eltrombopag has been reported to have an important role in reducing inflammation, acting both directly by chelating iron, and indirectly by modulating iron efflux. This review offers an overview of the possible novel biological effects of the iron chelators in inflammation, suggesting them as novel anti-inflammatory molecules.

Immune thrombocytopenic purpura: an early cutaneous manifestation of a dangerous and not yet fully understood complication of COVID-19 infection

COVID-19 has created a series of clinical conundrums since its emergence. We report a case of severe immune thrombocytopenic purpura (ITP) in a 67-year-old gentleman in April 2020. He presented to hospital with a rapidly evolving rash, 3 weeks following infection with COVID-19. Clinically he had a widespread non palpable petechial rash, haemorrhagic blisters across his oral mucosa and severe epistaxis. His platelet count was 2 × 109 L-1 (150-450 × 109 L-1). Full blood count and clotting studies were otherwise normal. With ITP not yet well reported as a complication of COVID-19, there was a treatment dilemma. ITP is an acquired autoimmune-mediated disorder (often with a viral or vaccine precipitant) and first-line treatment is immunosuppression. However, due to concurrent infection with the novel COVID-19 virus, a thrombopoietin receptor agonist (TPO-RA) (eltrombopag 50 mg once daily) was instead commenced. Persistent epistaxis, oral bleeding and a platelet count < × 109 L-1 required intravenous immunoglobulin (1 g kg-1) to be administered on day 7 of TPO-RA treatment. By day 12 of TPO-RA treatment the platelet count had successfully normalized. The patient remains in remission 18 months on. Since this case, ITP has become a recognized phenomenon of both COVID-19 infection and COVID-19 vaccination (Pishko AM, Bussel JB, Cines DB. COVID-19 vaccination and immune thrombocytopenia. Nat Med 2021;27: 1145-6). Moreover, corticosteroid therapy has become the first evidence-based therapy for severe COVID-19 infection (Horby P, Lim WS, Emberson J et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med 2021;384: 693-704), although their use in COVID-19- related ITP remains unclear. This case demonstrates an important cutaneous manifestation of the COVID-19-provoked disrupted haemostasis pathways, which results in significant morbidity and mortality. Additionally, this case describes practical real-life multidisciplinary team decision-making to emerging complications of a uniquely studied virus.

A Rare Case of Eltrombopag-Induced Pneumonitis

Introduction Immune thrombocytopenia (ITP) is an acquired thrombocytopenia due to autoantibodies. Eltrombopag is a thrombopoietin receptor agonist (TPO-RA) used as a second-line agent in the setting of persistent or chronic ITP. Potential severe adverse effects include hepatotoxicity, thromboembolism, and increased risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Upper respiratory infections and pharyngitis have also been described, but to our knowledge, no known cases of eltrombopag-induced pneumonitis have been reported to date. Case Presentation We present a 68-year-old male with a history of recent onset ITP, stage IV mantle cell lymphoma (in remission), and Pneumocystis pneumonia who was initiated on eltrombopag 11 days prior to admission for ITP refractory to corticosteroid therapy. Three weeks prior to admission, the patient underwent a bone marrow biopsy without evidence of monoclonal B cells or immunophenotypically abnormal T cell populations. Following initiation of eltrombopag, the patient had progressive dyspnea on exertion associated with subjective fevers and chills requiring hospitalization. Oxygen saturation was 88% on room air with exam notable for coarse crackles to the bilateral lung bases. CT angiogram of the chest revealed bilateral pulmonary emphysema, ground glass opacities, and bilateral bronchiectasis most pronounced in the lower lobes (Figure 1). No pulmonary embolism or mediastinal adenopathy was identified. Cytomegalovirus DNA, aspergillus antigen, and COVID-19 NAAT testing were negative. A respiratory viral panel was positive for Rhinovirus. Bronchoalveolar lavage (BAL) and right middle lobe lung parenchymal biopsy were subsequently performed. Pathology demonstrated focal intra-alveolar organization and fibroblast plugs, interstitial fibrosis, pneumocyte hyperplasia, and mixed (predominantly chronic) inflammatory infiltrate (Figure 2a & 2b). BAL was negative for malignant cells. Pneumocystis jirovecii DNA was detected, but < 250 copies/mL were identified and thus was thought to be less likely contributing to the disease process.Given the suspicion for eltrombopag-induced pneumonitis, the patient was initiated on high-dose corticosteroid therapy with a slow taper over the span of several weeks. Following initiation of corticosteroids, the patient was noted to have gradual improvement in his respiratory status. The patient was ultimately discharged on room air 1 month later due to other hematologic complications necessitating a prolonged hospital stay. Discussion The exact mechanism of eltrombopag-induced pneumonitis is unclear, although we postulate that it is related to an exaggerated immune response involving T-cell homeostasis resulting in alveolarcapillary permeability, inflammation, and fibrosis. Suspicion for eltrombopag-induced pneumonitis should prompt initiation of early corticosteroid therapy to prevent acute and chronic complications of pneumonitis. (Figure Presented).

Thrombopoietin receptor agonists for treatment of new and relapsed immune thrombocytopenia in children-A single-centre experience

Immune thrombocytopenia (ITP) is the most common bleeding disorder in paediatrics. ITP is usually a self-limiting disorder;however, it can be associated with significant and life-threatening bleeding. Outside the context of the COVID-19 pandemic, the first-line treatment for newly diagnosed or relapsed ITP is corticosteroids or intravenous immunoglobulin (IVIg). Treatment of ITP in the COVID-19 era became more challenging due to the shortage of IVIg, the continuous fear of immunosuppression, and the need for hospital contact. Because of these additional burdens, NHS England established a rapid policy in February 2021 to aid clinicians in offering the best care and advice to ITP patients. This policy recommended the use of thrombopoietin receptor agonists (TPO RAs) as first-line therapy for new or relapsed ITP in adults and children over the age of 1 year. TPO RAs including eltrombopag and romiplostim have been shown to be safe and effective in chronic ITP in children. Data on its safety and efficacy in acute ITP are limited. We conducted a retrospective observational study at Birmingham Children's Hospital between February 2021 and December 2021. The study aimed to assess the response to TPO RAs as first-line therapy in newly diagnosed or relapsed paediatric ITP patients. Eleven paediatric patients were included, nine were acute ITP and two had relapse of chronic ITP. All patients had baseline platelet count less than 10 × 10 9 /l. They presented with either moderate, severe or life-threatening bleeding requiring rescue treatment with steroids and/or IVIG. The 11 patients were commenced on eltrombopag. Two patients did not tolerate dietary restrictions with eltrombopag, and therefore they were switched to romiplostim. Nine out of the 11 patients who continued on TPO RAs had good and sustained response to TPO RAs with a platelet count more than 50 × 109 /l. No adverse events to the treatment have been reported during the study period. Four patients stopped treatment after sustained platelet count more than 200 × 10 9 /l, and they are currently off treatment for 4-9 months without rebound thrombocytopenia. Two out of the 11 patients did not respond to TPO RAs. One of them had poor response to romiplostim and hence it was discontinued, after a maximum dose of 10 mcg/Kg. This child then received rituximab and is currently stable with a platelet count of >50 × 10 9 /l. The clinical trials of using TPO RAs in the setting of acute ITP are still ongoing. However, after the current recommendations of their use in acute ITP, we expect TPO RAs to be increasingly brought forward in the management pathway of ITP. Although we are unable to quantify, but this NHS England policy has had a significant positive impact on the need for rescue therapy, hospital admissions, need for IVIG, in this cohort of patients. Further studies would be helpful to confirm these initial observations..

PLASMAFÉRESE COMO TERAPIA AUXILAR NA TROMBOCITOPENIA TROMBÓTICA INDUZIDA POR VACINA (VITT) CONTRA COVID

A Trombocitopenia Trombótica induzida por vacina (VITT) tem sido relatada como um efeito adverso raro e grave após a administração de vacinas contra o COVID-19 que usam adenovírus não replicante como vetor. A VITT caracteriza-se pela presença de: (1) trombose em sítios não usuais (e.g., seio venoso sagital, veias esplênicas e renais), (2) plaquetopenia, (3) aumento importante dos valores de D-dímero e (4) elevação do Fator anti-plaquetário 4. Ocorre geralmente cerca de 3 a 30 dias após a vacinação. Segundo a Organização Mundial de Saúde, sua incidência é de 0,5 a 6,8 casos/100.000 vacinados. A fisiopatologia da VITT ainda não é bem esclarecida, porém existe relação com mecanismos relacionados a Trombocitopenia induzida pela Heparina. A maioria dos relatos de reação estão associados a primeira dose da vacina, porém também há casos na segunda dose. Devido a potencial gravidade na evolução, o tratamento não deve ser retardado. A terapia inicial inclui o uso de Imunoglobulina 2 g/kg (em 2 dias). O uso de corticoide em alguns casos pode ser feito como adjuvante, porém ainda não há comprovação de sua eficácia. A plasmaférese deve ser feita de imediato em pacientes com Trombose em Seio Venoso Sagital ou em casos refratários a Imunoglobulina. Não deve ser realizado transfusão de plaquetas e o uso de heparina como anticoagulante deve ser evitado. Faremos o relato de 2 casos em que a plasmaférese foi utilizada como terapia auxiliar ao tratamento: Paciente 1: Paciente mulher, jovem, 24 anos, foi admitida no Hospital 10 dias após a primeira dose da vacina Astrazeneca com quadro de cefaleia persistente refratária a analgésicos e petéquias em face e tronco iniciado 3 dias da internação. Admitida com plaquetopenia 2000, fibrinogênio 190 e D dímero 12000. Iniciado Imunoglobulina 2 g/kg (dois dias seguidos). Foi associado corticoide 1 mg/kg/dia. No nono dia de tratamento, evoluiu com 50 mil plaquetas, D dímero 7400 e PF4 3,34 U/mL. Evoluiu com Crise Convulsiva sendo diagnosticado Trombose Venosa de Seio Sagital. Iniciada Plásmaferese (feito 5 sessões em dias alternados com troca por albumina). Na quinta sessão de plasmaférese estava com D dímero 880, plaquetas 71 mil e fibrinogênio 58. Após 4 dias do término da plasmaférese, paciente apresentou retorno da cefaleia. Dosado D dímero 2300. Reiniciado Plasmaférese (Plasma 1:Albumina 1). Foram realizadas mais 2 sessões com plaquetas acima de 150 mil. Após a quarta sessão, no D27 internação estava com D dímero 470, plaquetas 362 mil e PF4 2,2. Paciente 2: Paciente do sexo masculino, 85 anos, foi admitido no hospital 21 dias após a segunda dose da vacina da AstraZeneca com quadro de fraqueza, astenia, confusão mental e inapetência, associado a tromboembolismo pulmonar. Paciente previamente renal crônico não dialítico, hipertenso, diabético, 2 cirurgias cardíacas prévias (2014 e 2017) e púrpura trombocitopênica idiopática crônica sem necessidade de tratamento prévio. A admissão, exames demonstravam plaquetas de 47.000, TTPa 35,8, INR 1,5 e fibrinogênio de 234. O Anticorpo anti-PF4 foi de 4,8 U/mL, e as plaquetas chegaram a 19.000. Foram realizados dois ciclos de IGIV, sem resposta, e mesmo com associação de corticóide 1 mg/kg/dia, não houve resposta. Foi optado por realizar plasmaférese terapêutica com realização em dias seguidos com troca de 1 volemia plasmática e reposição realizada com plasma fresco congelado em todas as sessões. Após 4 sessões, paciente apresentou melhora clinica, a despeito de manter plaquetopenia. Nesse momento, devido a historia de PTI previa, foi optado por iniciar eltrombopag. Conclusão: Relatamos 2 casos clínicos, nos quais a plasmaférese terapêutica pode contribuir para evitar um desfecho desfavorável na VITT.

APLASIA GRAVE DE MEDULA ÓSSEA EM REMISSÃO COMPLETA APÓS TRANSPLANTE DE MEDULA ÓSSEA COM DOADOR HAPLOIDÊNTICO (PAI)- RELATO DE CASO

Introdução: A aplasia de medula óssea grave (AAG) adquirida é uma doença rara e de origem desconhecida (80% dos casos). É caracterizada por pancitopenia e medula óssea (MO) hipocelular na ausência de infiltração anormal de células na medula ou aumento da trama de reticulina. Trata-se de doença com alta mortalidade e necessidade de intervenção precoce em serviço especializado. Para o diagnóstico de AAG faz-se necessário avaliação da celularidade da MO por biópsia (<25–30% celularidade);além de 2 de 3 critérios no sangue periférico: Neutrófilos <500/uL;plaquetas <20.000/uL e reticulócitos <60.000/uL(1%). O transplante de MO com doador aparentado (irmão) deve ser inicialmente indicado para todos os pacientes com AAG adquirida. Na ausência desse doador é recomendado terapia imunossupressora;e naqueles pacientes sem resposta ou com perda de resposta uma das opções é a escolha de doador alternativo. Relato do caso: J.F.S., 15 anos, atendida em 05/03/2017 no pronto atendimento com queixa de dor abdominal difusa e astenia. Hemograma da admissão com pancitopenia e USG abdominal total com esplenomegalia leve. Dosagens de vitamina B12, ácido fólico, ferritina, DHL, sorologias virais e triagem reumatológica normais. Realizada Biópsia de MO que revelou intensa hipocelularidade geral (<5 % de tecido hematopoético). Cariótipo: 46 XX sem anormalidade. Pesquisa de HPN e Deb test para anemia de fanconi negativos. HLA do irmão não revelou compatibilidade sendo imediatamente inscrita no Rereme (Registro Nacional de Receptores de Medula Óssea). Paciente evoluiu com piora da pancitopenia (Hb 6,0, neutrófilos 483, Plaq 16mil) e alta necessidade transfusional. Em 5/07/2017 foi submetida ao protocolo de imunosupressão com Thymoglobulina de coelho /corticoide /Ciclosporina. Após 2 meses apresentou resposta parcial com neutrófilos >500 e plaquetas >20mil e independência transfusional. A Ciclosporina foi mantida até março de 2019. Paciente ficou estável até out de 2019 quando progrediu com pancitopenia e necessidade transfusional principalmente de plaquetas, porém evoluiu com reações anafiláticas à transfusão de plaquetas além de pouco incremento plaquetário, mantendo plaquetas <10 mil. Em 12/02/2020, diante desse cenário de dificuldade transfusional (refratariedade e reação anafilática) e manutenção de plaquetopenia grave, optou-se por Eltrombopag, com dose máxima de 250mg/dia também com reposta insatisfatória após 11 meses (mantinha plaquetas <10 mil). Neste momento (pandemia COVID-19) nos foi sinalizado pelo Rereme doador compatível 9×10. O serviço de transplante, convocou o pai da paciente e optou-se pelo transplante de MO alogênico com doador haploidêntico (pai) que ocorreu em 12/03/2021. A paciente evoluiu com remissão completa da doença e atualmente apresenta-se assintomática com hemograma normal (Hb 12,5, Neutrófilos 3500, Plaq 274 mil). Discussão e considerações finais: O transplante de MO através de doador irmão HLA compatível é o tratamento de escolha para paciente com AAG. Esse relato nos mostra que dentro as duas opções disponíveis (pai haploidêntico e doador Rereme não aparentado 9×10) o pai foi o escolhido como doador e obtivemos remissão completa da doença. Uma das hipóteses para tal escolha também inclui a dificuldade de viabilizar a medula de doador não aparentado em um momento pandemia mundial de COVID-19.

ANEMIA APLÁSTICA ADQUIRIDA SECUNDÁRIA À INFECÇÃO PELO SARS-COV-2

Introdução: A anemia aplástica adquirida (AAA) é uma condição rara, com alta morbidade. Em 70-80% dos casos é idiopática e ocorre por destruição das células tronco-hematopoiéticas por fenômeno autoimune. Com as terapias imunossupressoras e o transplante de medula óssea (TMO), a AAA teve excelentes resultados com taxas de sobrevida de 80% em 10 anos. Pode estar relacionada à outros mecanismos, como exposição a agentes tóxicos e infecções virais, especialmente vírus Epstein Barr, vírus de hepatite, HIV e parvovírus B19. A recente pandemia pelo vírus SARS-Cov-2 foi relacionada ao desenvolvimento de doenças autoimunes, corroborando a associação entre infecção viral e desbalanço imune. Apresentamos o caso de uma paciente, previamente hígida, que 60 dias após infecção pelo Sars-Cov-2 iniciou plaquetopenia, evoluindo para pancitopenia. Relato de caso: Paciente feminina, 29 anos, infecção pelo Sars-Cov-2 em agosto/20, quadro leve, sem necessidade de internação hospitalar. Em outubro/2020, apresentou equimoses persistentes, procurou atendimento médico, com os exames: Hb 11,5 g/dL;neutrófilos 1054/mm3 e 130.000/mm3 plaquetas, com conduta expectante nesse momento. Em janeiro/2021, com piora das equimoses e fadiga, retornou em atendimento com Hb 9,8 g/dL, neutrófilos 1278/mm3 e plaquetas 45.000/mm3. Iniciada investigação com sorologias para hepatites virais, HIV, sífilis, provas reumatológicas, vitamina B12, ácido fólico, função renal, hepática, tireoidiana e pesquisa de clone HPN, todos dentro da normalidade. Como tratamento, foi iniciado prednisona 1 mg/kg/dia e agendado retorno ambulatorial. Antes do previsto, procurou novamente atendimento por gengivorragia com plaquetas de 19.000/mm3, Hb 9,8 g/dL, neutrófilos 900/mm3 e Reticulócitos 46,536/mm3. Submetida a avaliação medular, com biópsia evidenciando hipocelularidade (cerca de 30%) com hipoplasia de todas as séries. O estudo imunofenotípico não mostrou proliferação de células imaturas, anômalas ou displásicas, cariótipo XX, FISH para síndrome mielodisplásica e DEB test negativos. Como pesquisas virais, citomegalovírus e parvovírus B19, além de RNA do vírus SARS-Cov-2 na extração de DNA em medula óssea, resultaram todos negativos. O diagnóstico de AAA foi estabelecido, evoluindo com piora progressiva da pancitopenia e necessidade de suporte transfusional recorrente. Apesar de candidata a transplante alogênico de medula óssea, a paciente não tinha irmãos e então, iniciado tratamento timoglobulina de coelho 3,5 mg/kg/dia por 5 dias, ciclosporina 10 mg/kg/dia e eltrombopag 150 mg/dia, além eritropoetina 40.000 UI/semana. O último exame de 29/06/2021 mostra resposta parcial a terapia estabelecida com Hb 11,7 g/dL, neutrófilos 1889/mm3 e 90.000/mm3 plaquetas. Conclusão: A AAA é uma condição que necessita de rápido diagnóstico e tratamento. O desbalanço imunológico, especialmente a hiperativação de linfócitos T citotóxicos CD8+, desencadeado por infecção viral pode ser gatilho para a condição em predispostos. Outros relatos semelhantes corroboram a associação temporal entre a infecção do SARS-Cov-2 e AAA. Sendo assim, consideramos importante compartilhar essa informação no meio científico.

Monitoring of Patients with Autoimmune Cytopenias during Sars-Cov-2 Vaccination Campaign: The Experience of a Reference Center

[Formula presented] SARS-CoV-2 infection and vaccination have raised concern in immune mediated diseases, including autoimmune cytopenias (AIC, i.e. autoimmune hemolytic anemia, AIHA;autoimmune thrombocytopenia, ITP;autoimmune neutropenia, AIN;aplastic anemia, AA;and their combination, termed Evans syndrome, ES). The latter are highly heterogeneous conditions with variable severity and a clinical course marked by several relapses often triggered by immune-activating events (infections, traumas, surgery, etc.) including vaccines. Some reports of ITP and AIHA post-SARS-CoV-2 vaccines have been described but no population studies have been conducted in AIC patients. Here we systematically studied a large series of 100 patients with AIC (44 AIHA, 38 ITP, 7 AIN, 6 ES, and 5 AA) prospectively followed at a reference center in Milan, Italy, who underwent SARS-CoV-2 vaccination from 24 th of March until the end of June 2021. Patients (median age 62 years, range 25-89, female/male ratio 1.7) were monitored with whole blood counts and LDH testing the week before and the week after each vaccination dose. Importantly, ongoing AIC therapy (38% of cases, including steroids, cyclosporine, eltrombopag, and complement inhibitor sutimlimab) were kept stable within the 2 weeks before vaccination. Patients mainly received Pfizer-BioNtech vaccine (N=88), followed by Moderna (N=10), and Astra-Zeneca (N=2). Table 1 summarizes hematologic trends and side effects observed after each dose in patients with ITP and AIHA. Regarding the former, a delta percentage reduction of 10% or higher was observed in up to 13% of cases after the first and the second dose, requiring therapy adjustment in 2 patients. They were two elderly male subjects on low dose eltrombopag treatment and experienced a severe/moderate relapse (platelets 28 and 21x10

Immune Thrombocytopenia Post Covishield Vaccination

Introduction: Immune thrombocytopenia (ITP) after COVID-19vaccination is being increasingly reported worldwide.Aims &Objectives: We present five cases of ITP following theAstraZeneca Covishield vaccination.Materials &Methods: We retrospectively collected data on patientspresenting with immune thrombocytopenia post-Covishield vaccination at the Department of Hematology, AIIMS, New Delhi.Result: 5 patients diagnosed with ITP followingAstraZeneca Covishieldvaccination were included. Themedian age at diagnosis in our cohortwas44 years (21-67 years). Of the 5 patients, 2 are female and 3 aremale. Allof them received the Astrazeneca Covishield vaccine. Most of thepatients presented with petechiae and wet purpura with the onset ofsymptoms between 7-20 days (median 15 days) post-vaccination. All ofthese patients had severe thrombocytopenia at presentationwith amedianplatelet count of 7 × 109/l (range 1-14 × 109/l). Anti PF4 antibodytesting was done in two patients which were negative.Therapy details include IVIG (3), steroids (4), eltrombopag (2),azathioprine (1), and platelet transfusions (2). Of these, two patientshad no response to first-line therapies. One patient did not respond toIVIG, steroids, azathioprine, and subsequently developed anintracranial bleed. He was managed with platelet transfusions, IVIG,steroids, and eltrombopag. His platelet counts have stabilized at50 × 109/l and he did not have further bleeding manifestations. Atthe last follow-up, 80% (n = 4) of our patients have achieved aresponse.Conclusions: Immune thrombocytopenia is being increasingly recognized post-COVID vaccination. All our patients had severethrombocytopenia requiring therapy. The question of whether thesecases are actually primary ITP coinciding with the administration ofthe vaccine or ITP secondary to vaccination remains unanswered.Additional surveillance is needed to determine the true incidence ofCOVID-19 vaccine-induced ITP.

Sars-Cov-2 Infection Associated with Aplastic Anemia and Pure Red Cell Aplasia

Introduction: Aplastic anemia (AA) is a life-threatening disorder characterized by pancytopenia and a hypocellular bone marrow. Pure red cell aplasia (PRCA) is a similar disorder with primary reduction in the red blood cell population and virtual absence of erythroid precursors in the bone marrow. While the etiology of immune mediated marrow failure is multifactorial, preceding viral infections have been associated with the disease;these include parvovirus B19, cytomegalovirus, and Epstein-Barr virus. We present four cases of immune mediated marrow failure with either preceding or simultaneous SARS-CoV-2 infection. Methods: The medical records of patients treated for AA or PRCA at the University of Texas Southwestern Medical Center, Parkland Hospital, and the National Institutes of Health (NIH) were reviewed for SARS-CoV-2 infection. Four patients without prior hematological diseases were identified who had SARS-CoV-2 infection prior to or with simultaneous the diagnosis of AA or PRCA. Results: Patient #1 was a 22-year-old white female who was diagnosed with asymptomatic COVID-19 10 days prior to her pancytopenia and AA diagnosis was confirmed by bone marrow biopsy (5% cellularity;Table 1). Her extensive work-up including HIV, hepatitis panel, immunoglobulins, B12 and folate was negative, and she underwent HLA-matched family donor hematopoietic stem cell transplant. Patient #2 was a 69-year-old Asian female who presented to her primary care physician with symptoms of fatigue and was found to be pancytopenic. CBC from a few months prior was completely normal. Further work-up was positive for COVID-19 and negative for HIV, nutritional deficiency, or hemolysis. She did not have respiratory symptoms, was eventually diagnosed with pRBC and platelet transfusion-dependent severe AA (5-10% cellularity on bone marrow), and underwent treatment with cyclosporine, equine antithymocyte globulin, and eltrombopag. She has had a partial response to this therapy. Both patients had bone marrow specimens stained for SARS-CoV-2 by immunohistochemistry that were negative. Patient #3 was a 76-year-old white male who was diagnosed with COVID-19 4 months prior to presenting with a non-ST segment myocardial infarction and found to be profoundly anemic, requiring pRBC transfusion. He re-presented with chest pain one week later and was found to be anemic again, and required transfusion. A trial of darbepoetin alfa was unsuccessful. Extensive work-up for malignancy, infection, and autoimmune etiologies were negative. He was diagnosed with PRCA based on the bone marrow biopsy and initiated treatment with cyclosporine. Patient # 4 was diagnosed with severe AA (presenting as pancytopenia) and COVID-19 infection. He had fatigue for one month and fever, chills and sore throat one-week prior seeking medical care. Testing for hepatitis, HIV, EBV, and CMV was negative. He was treated on a clinical trial (NCT04304820) at NIH with cyclosporine and eltrombopag until SARS-CoV-2 PCR was negative then received equine anti-thymocyte globulin. He has achieved a complete hematologic response at 6 months and remains well at last follow-up. Conclusion: The four patients described had minimal respiratory COVID-19 symptoms, but they presented with cytopenia and were eventually diagnosed with bone marrow failure. It is possible that this is co-incidental due to the high prevalence of SARS-CoV-2. However, there is emerging evidence that COVID-19 pneumonia is a hyperinflammatory and immune dysregulated state improved by dexamethasone therapy. Other immune mediated hematologic conditions, such as autoimmune hemolytic anemia and immune thrombocytopenia, have been reported. The onset from infection to cytopenia appears rapid, although patients often presented with symptoms for many days prior to diagnosis and thus testing may have been delayed from the onset of infection. This case series does not provide a mechanistic link between SARS-CoV-2 infection and bone marrow failure, but it raises the possibility that SARS-CoV-2 may mediate an immunologic response that cont ibutes to marrow failure. Patients appear to respond well to standard immunosuppressive treatment. Further cases and studies are needed to determine if this is directly linked to SARS-CoV-2 and whether the natural history and response to standard therapy is different than idiopathic cases. [Formula presented] Disclosures: Young: Novartis: Research Funding.