An audit of paroxysmal nocturnal haemoglobinuria (PNH) requesting at University Hospitals of North Midlands

Early identification of PNH, a rare life-threatening disease is essential to ensure appropriate management via the UK PNH service. Since testing for PNH is expensive (75.97 per test), we set out to assess the suitability of PNH requests against guidelines with the aim to feedback to colleagues and reduce unnecessary testing. To determine whether PNH requests at UHNM were in line with criteria in British Society for Haematology (BSH) guidelines. All patients over 18 years of age who had PNH testing for the first time and those who had repeat testing for monitoring between 01/04/2019 and 31/03/2020 were included. Patients were selected from electronic records of PNH sample receipt to laboratories. Hospital records were reviewed for clinical details and investigation Results. 82 requests including 79 individual patients were audited. 57% were male and 43% were female. Median age was 56 years. 97.6% of PNH tests were requested by a haematologist whilst only 2.5% requests were done by non-haematology clinicians. 52.4% requests were in keeping with BSH recommendations, whilst 47.6% tests did not meet criteria for testing. All patients tested outside of guideline recommendations were negative. Of the reasonable requests, only 23.3% (10) were positive. Of the PNH positive patients, 8 patients were known to have a PNH clone with aplastic anaemia;one patient had a hypoplastic bone marrow and a known PNH clone whilst only one patient with cytopenia had a new positivity for PNH. The frequency monitoring for aplastic anaemia and a PNH clone was 100% concordant with BSH recommendations. With appropriate testing, only one new patient was identified. Our audit has limitations. We have not been able to assess whether any patients outside of those monitored for PNH in aplastic anaemia have been overlooked for testing. Also, the time period includes the COVID-19 pandemic so our findings may not reflect usual practice. New BSH guidelines for thrombophilia testing were published in 2022 and recommend testing for PNH in patients with thrombosis at unusual sites and abnormal haematological parameters and for patients with arterial thrombosis and abnormal blood parameters. This will likely limit excess tests although the sensitivity and specificity of such an approach has not been formally evaluated. In a finite health system, it is our responsibility to rationalise investigations. The cost of a year's testing was 6229.54 and that of inappropriate testing was 2962.83. As a department, we could, therefore, save 2962.83.

Managing severe warm autoimmune haemolytic anaemia after the SARS-Cov- 2 vaccine with emergency splenectomy and eculizumab

Autoimmune haemolytic anaemia (AIHA) is rare but described after the SARS-CoV- 2 Pfizer-BioNTech vaccine. We present a case of severe refractory warm AIHA after this vaccine, managed with emergency splenectomy and complement inhibition with eculizumab. A male in his teens with a history of liver transplant for biliary atresia (aged 2 years) and AIHA (aged 6 years) presented to his district general hospital with jaundice, dark urine, fatigue and chest discomfort 48 h after the first dose of SARS-CoV- 2 Pfizer-BioNTech vaccine (BNT162b2 mRNA). Investigations revealed haemoglobin (Hb) of 70 g/L and bilirubin of 98 mumol/L, which was treated as AIHA. The patient initially responded to prednisolone (1 mg/kg, 60 mg) but subsequently deteriorated and failed to respond to second-line rituximab (375 mg/m2) and two units of packed red blood cells (PRBC). By day 29 the patient had developed life-threatening anaemia culminating in a Hb of 35 g/L (after transfusion), lactate dehydrogenase (LD) of 1293 units/L and bilirubin of 228 mumol/L. This necessitated an immediate transfer to our tertiary centre for specialist support. Further investigations revealed a haptoglobin <0.1 g/L and direct antiglobulin test (DAT) strongly positive for IgG (4+) and negative for C3d. The peripheral blood film showed severe anaemia, nucleated red cells, anisocytosis and spherocytes with no autoagglutination, schistocytes or platelet clumps. Thrombocytopaenia (platelets 49 +/- 109/L) was present. Differentials were ruled out, such as paroxysmal nocturnal haemoglobinuria and heparin-induced thrombocytopaenia. HIV and hepatitis serology were negative, as were adenovirus, cytomegalovirus and Epstein-Barr virus PCR assays. A CT showed splenomegaly of 15.5 cm. Urinalysis found urobilinogen and bilirubin at high concentrations and negative urinary haemosiderin. Together, the investigations were consistent with warm AIHA. On day 29, four units of PRBC were transfused alongside 100 mg methylprednisolone and 1 g/kg IVIG. On day 30 the patient deteriorated despite the escalated treatment: Hb had only increased to 54 g/L, bilirubin was 200 mumol/L and LD was rising. Considering this life-threatening fulminant haemolysis, an emergency splenectomy was performed. This slowed haemolysis but did not completely ameliorate it: by day 33 the patient had received 15 units of PRBC. Thus, eculizumab, a terminal complement pathway inhibitor, was trialled to arrest intravascular haemolysis, alongside rituximab, repeat IVIG 1 g/kg, prednisolone 40 mg and tacrolimus 2 mg. This showed a favourable response, requiring less frequent transfusions and settling haemolysis. This case highlights the rare complication of warm AIHA with the SARS-CoV- 2 Pfizer-BioNTech vaccine, the use of emergency splenectomy for disease control, and the potential of eculizumab for refractory cases.

The Effect of Respiratory Viral Infections on Breakthrough Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by hemolysis and thrombosis and is associated with significant morbidity and mortality. Although complement inhibitors have significantly changed the outcomes in PNH patients, breakthrough hemolysis (BTH) may still occur as a response to stress factors such as pregnancy, surgery, and infections. Despite the well-described association between bacterial infections and hemolysis in PNH patients, little is known about the effect of respiratory viruses on triggering hemolytic episodes. This is the first study, to our knowledge, addressing this question. We retrospectively analyzed 34 patients with PNH disease between 2016 and 2018, who were on eculizumab treatment and who presented with respiratory symptoms and were subsequently tested for 10 respiratory viruses (influenza A, influenza B, parainfluenza, respiratory syncytial virus, adenovirus, rhinovirus, and human metapneumovirus). NTS+ patients had higher inflammatory markers, with the majority requiring antibiotics. Acute hemolysis, along with a significant drop in hemoglobin, was noted in the NTS+ group, with three of them requiring a top-up transfusion and two requiring an extra dose of eculizumab. Furthermore, the time from the last eculizumab dose was longer in the NTS+ patients who had BTH, than those who did not. Our data indicate that respiratory virus infections pose a significant risk for BTH in PNH patients on complement inhibitor treatment, underlining the need for regular screening and close monitoring of patients with respiratory symptoms. Furthermore, it implies a higher risk for patients who are not established on complement inhibitors, suggesting the necessity for greater vigilance in these patients.

Thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): Real world data of a Greek nationwide multicenter retrospective study.

Thrombosis is the most common and a life-threatening complication in patients with Paroxysmal Nocturnal Hemoglobinuria. One-third of patients with PNH experience at least one thromboembolic event during the course of the disease, with thrombosis being the most common cause of death in these patients. The mechanism of thrombosis in PNH is complex and continues to be of great research interest. Since the introduction of C5 complement inhibitors in the treatment of PNH, the incidence of thromboembolic events has decreased substantially. We retrospectively analyzed data concerning the thrombotic episodes of 41 patients with PNH from 14 different national hematology centers in Greece. Sixteen patients (39%) experienced at least one episode of thrombosis, including, seven (43.8%) at diagnosis, seven (43.8%) during the course of the disease and two (12.5%) patients prior to PNH diagnosis. Nearly half of these individuals (n=7, 43.8%) had multiple episodes of thrombosis during the course of their disease. The most common sites of thrombosis were intra-abdominal veins. Three out of 26 patients developed thrombosis while on eculizumab. In none of the 16 patients, the thrombotic event was fatal. Our findings, despite the small number of patients, confirmed that thrombosis continues to be a significant complication of PNH affecting more than one third of the patients.

Cardiac Arrest Secondary to Inferior ST-Segment-Elevation Myocardial Infarction in Patient with Paroxysmal Nocturnal Hemoglobinuria and COVID-19 Infection.

Patients with paroxysmal nocturnal hemoglobinuria (PNH) have transient attacks of complement-mediated hemolysis and thrombosis that can be spontaneous or secondary to precipitating factors such as infections. We present a case of a 63-year-old male patient with a medical history of PNH who presented with typical chest pain, fever, cough, jaundice, and dark-colored urine. On examination, he was hemodynamically stable but had conjunctival icterus. A few minutes after presentation, the patient suffered a ventricular fibrillation cardiac arrest and then achieved a return of spontaneous circulation after receiving two defibrillator shocks. EKG showed inferior wall ST-segment elevation myocardial infarction. Labs showed hemoglobin of 6.4 g/dl, elevated cardiac markers, serum lactate dehydrogenase, and indirect bilirubin. Serum haptoglobin was < 1 mg/dl. His COVID-19 polymerase chain reaction test was positive. Immediately, the patient received 2 units of packed RBCs and underwent a coronary angiogram (CA), which revealed total proximal occlusion of the right coronary artery. He underwent successful percutaneous coronary intervention (PCI), and two drug-eluting stents were placed. His peripheral blood immunophenotyping and flow cytometry showed loss of glycosylphosphatidylinositol-linked antigens and decreased expression of CD 59/14/24. He was started on ravulizumab, a humanized monoclonal antibody complement five inhibitor. Both PNH and COVID-19 increase the risk of thrombosis. Endothelial injury and cytokine storm increase the risk of thrombosis in COVID-19 patients, whereas the activation of the coagulation system and the impairment of the fibrinolytic system by complement cascade leads to thrombosis in PNH patients. Regardless of which pathway leads to coronary artery thrombosis, CA and PCI can be life-saving.

[COVID-19 development during the treatment of paroxysmal nocturnal hemoglobinuria].

Paroxysmal nocturnal hemoglobinuria (PNH) is a disorder in which an activated complement causes intravascular hemolysis of erythrocytes that do not have complement regulators. It is critical to monitor the rapid progression of hemolysis caused by infection and thrombosis. As far as we can tell, this is the first report of 5 COVID-19 patients with PNH in Japan. Three patients were being treated with ravulizumab, one with eculizumab, and one with crovalimab. All five cases had received two or more COVID-19 vaccinations. COVID-19 was classified as mild in four cases and moderate in one. None of the cases required the use of oxygen, and none became severe. All of them experienced breakthrough hemolysis, and two required red blood cell transfusions. In any case, no thrombotic complications were observed.

COVID-19 induced mesenteric ischemia in a patient with ulcerative colitis and paroxysmal nocturnal haemoglobinuria despite thromboprophylaxis.

Inflammatory bowel disease and paroxysmal nocturnal hemoglobinuria (PNH) are both well-known prothrombotic states. However, ongoing thromboprophylaxis is usually effective in such conditions. We report an imbalance that was triggered by COVID-19 infection. There is evidence that COVID-19 infection leads to thrombosis of vessels. The thrombosis of mesenteric vessels can be multifocal and without respiratory symptoms and leads to devastating consequences like resection of large segments of the bowel and lifelong requirement of parenteral nutritional support. We report about a case of ulcerative colitis (in remission) and PNH where COVID-19 resulted in mesenteric ischemia.

Breakthrough Hemolysis Associated With COVID-19 Vaccination and Active COVID-19 Infection in a Patient With Paroxysmal Nocturnal Hemoglobinuria Maintained on Pegcetacoplan: A Case Report.

Breakthrough hemolysis (BTH) is the return of hemolytic disease resulting in an overall increase in complement activation in a patient being treated for paroxysmal nocturnal hemoglobinuria (PNH) with complement inhibitors (CI). BTH after COVID-19 vaccination has only been reported in PNH patients treated with the traditional C5 CI eculizumab and ravulizumab. We report on a new association of BTH in a newly COVID-19 vaccinated, previously stable PNH patient treated with pegcetacoplan, a C3 CI. The patient is a 29-year-old female diagnosed with PNH in 2017 and was started on eculizumab but was switched to pegcetacoplan in 2021 after continuing to exhibit symptomatic hemolysis. Subsequently, the patient returned to PNH remission serologically and symptomatically until her first COVID-19 vaccination. Since then, her lactate dehydrogenase (LDH) and hemoglobin counts have not fully returned to previous baseline levels, with significant exacerbations after her second COVID-19 vaccine and de novo COVID-19 infection. As of May 2022, the patient requires packed red blood cell transfusions every two to three months and has undergone a bone marrow transplant evaluation. This case study suggests that the administration of the upstream C3 CI, pegcetacoplan, is associated with active extravascular hemolysis in the setting of COVID-19 vaccinations and active COVID-19 infection. The pathophysiology of this hemolysis is unclear as hemolysis could be related to the underlying complement factor deficiency or amplification of complement factors causing extravascular hemolysis. There are conflicting reports in the literature regarding the mechanism by which COVID-19 vaccination and infection cause BTH in PNH patients, regardless of the choice of CI treatment. Bringing awareness to this case of BTH secondary to COVID-19 in a PNH patient treated with pegcetacoplan can further warrant the investigation of the role of COVID-19 in complement disruption and its role in BTH.

Perniosis: a rare cutaneous manifestation of paroxysmal nocturnal haemoglobinuria

Perniosis is a vaso-occlusive phenomenon that features the formation of discrete erythematous papules, macules, nodules or patches. Perniotic lesions are induced by the cold and are symptomatic in terms of burning, pain or itching. Secondary complications such as overlying infections and ulceration may occur (Takci Z, Vahaboglu G, Eksioglu H. Epidemiological patterns of perniosis, and its association with systemic disorder. Clin Exp Dermatol 2012;37: 844-9). While most cases of perniosis are idiopathic, studies have shown a link between secondary perniosis, connective tissue diseases and haematological disorders. Paroxysmal nocturnal haemoglobinuria (PNH) is a haematological aberrant stem cell disorder. It is a very rare condition (1-1 5 cases per million population) and results in the death of approximately 50% of affected individuals as a result of thrombotic complications. Cutaneous sequelae are uncommon and may present as purpura due to dermal vein thrombosis (Zhao H, Shattil S. Cutaneous thrombosis in PNH. Blood 2013;122: 3249). To date, there have been no previously reported cases of perniosis as a cutaneous manifestation of PNH. A 42-year-old man, with a background of PNH and aplastic anaemia, presented with recurrent painful, erythematous macules and blisters along the palmar and plantar aspects of his fingers and toes. These lesions occurred over 4 years previously, coinciding with the diagnosis of PNH and aplastic anaemia. Physical examination revealed a solitary blistering lesion on the palmar aspect of his third right finger. In addition, there were multiple erythematous macules on the plantar aspect of the first and second toe of his left foot. A biopsy was performed. An autoimmune screen and antibodies for COVID-19 were all negative. Histopathological findings showed epidermal blister formation with the presence of some apoptotic keratinocytes admixed with superficial chronic perivascular inflammatory infiltrate. The inflammatory infiltrate was predominantly chronic lymphocytic and locally involved perieccrine glands noted to be underlying the blister formation, consistent with perniosis. The patient is currently awaiting treatment with eculizumab. This is a case of perniosis occurring as a cutaneous manifestation of PNH. Perniosis typically requires investigation for connective tissue diseases;however, we also warn dermatologists that perniosis could be a presenting feature of underlying paroxysmal nocturnal haemoglobinuria, a rare, life-threatening condition with a high mortality rate related to thromboembolism. This case highlights an interesting and previously unreported cutaneous manifestation of PNH.

Phase 3 Study of Subcutaneous Versus Intravenous Ravulizumab in Eculizumab-Experienced Adult Patients with PNH: Primary Analysis and 1-Year Follow-Up.

INTRODUCTION: This study compared the pharmacokinetics (PK) of the ravulizumab on-body delivery system for subcutaneous (SUBQ) administration with intravenous (IV) ravulizumab in eculizumab-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). METHODS: Patients with PNH received SUBQ ravulizumab (n = 90) or IV ravulizumab (n = 46) during the 10-week randomized treatment period; all patients then received SUBQ ravulizumab during an extension period (< 172 weeks; data cutoff 1 year). Primary endpoint was day 71 serum ravulizumab trough concentration (Ctrough). Secondary endpoints were ravulizumab Ctrough and free C5 over time. Efficacy endpoints included change in lactate dehydrogenase (LDH), breakthrough hemolysis (BTH), transfusion avoidance, stabilized hemoglobin, and Treatment Administration Satisfaction Questionnaire (TASQ) score. Safety, including adverse events (AEs) and adverse device effects (ADEs), was assessed until data cutoff. RESULTS: SUBQ ravulizumab demonstrated PK non-inferiority with IV ravulizumab (day 71 SUBQ/IV geometric least-squares means ratio 1.257 [90% confidence interval 1.160-1.361; p < 0.0001]). Through 1 year of SUBQ administration, ravulizumab Ctrough values were > 175 µg/mL (PK threshold) and free C5 < 0.5 µg/mL (PD threshold). Efficacy endpoints remained stable: mean (standard deviation, SD) LDH percentage change was 0.9% (20.5%); BTH events, 5/128 patients (3.9%); 83.6% achieved transfusion avoidance; 79.7% achieved stabilized hemoglobin. Total TASQ score showed improved satisfaction with SUBQ ravulizumab compared with IV eculizumab (mean [SD] change at SUBQ day 351, - 69.3 [80.1]). The most common AEs during SUBQ treatment (excluding ADEs) were headache (14.1%), COVID-19 (14.1%), and pyrexia (10.9%); the most common ADE unrelated to a device product issue was injection site reaction (4.7%). Although many patients had ≥ 1 device issue-related ADE, full SUBQ dose administration was achieved in 99.9% of attempts. CONCLUSIONS: SUBQ ravulizumab provides an additional treatment choice for patients with PNH. Patients may switch to SUBQ ravulizumab from IV eculizumab or ravulizumab without loss of efficacy. TRIAL REGISTRATION: NCT03748823.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by the destruction of red blood cells (hemolysis) within blood vessels. In addition to hemolysis, patients with PNH are susceptible to life-threatening blood clots (thromboses). Eculizumab and ravulizumab are types of treatments for PNH, called C5 inhibitors. In the blood, these treatments bind to C5 protein and prevent the destruction of red blood cells, reducing the symptoms and complications of PNH. Both treatments are approved for use via intravenous (through the vein) administration. Ravulizumab is also approved in the USA for use via subcutaneous (under the skin) administration. This study compared subcutaneous ravulizumab with intravenous ravulizumab in patients with PNH who had previously been treated with eculizumab. During the initial treatment period of 71 days, 90 patients received subcutaneous ravulizumab and 46 received intravenous ravulizumab. Following this period, all patients received subcutaneous ravulizumab. At day 71, the amount of ravulizumab in the blood of patients taking subcutaneous ravulizumab was no less than in patients taking intravenous ravulizumab and was maintained over 1 year of treatment. Efficacy measures (how well it works) remained stable in patients taking subcutaneous ravulizumab for 1 year and side effects were comparable with those of intravenous ravulizumab. Patients reported more satisfaction with subcutaneous ravulizumab than intravenous eculizumab, as assessed by the Treatment Administration Satisfaction Questionnaire. This study showed that patients with PNH can switch from intravenous eculizumab or ravulizumab to subcutaneous ravulizumab without loss of efficacy. Subcutaneous ravulizumab provides an additional treatment choice for patients with PNH.

HEMOLYTIC ANEMIA EXACERBATION IN CHRONIC PAROXYSMAL NOCTURNAL HEMOGLOBINURIA AFTER COVID-19 VACCINATION

SESSION TITLE: Issues After COVID-19 Vaccination Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder that can lead to thrombosis, hemolytic anemia and leukemia. Though there are documented relationships between autoimmune hemolytic anemia (AIHA) and COVID-19 infection, this is the first to highlight aa potential association between PNH exacerbations and COVID vaccinations. CASE PRESENTATION: A 38 year-old female with a history of chronic paroxysmal nocturnal hemoglobinuria (PNH) currently on maintenance ravculizumab therapy presented with 3 days of generalized fatigue, chills, and worsening scleral icterus. She reports being unable to move out of the bed with concomitant somnolence. Of note, she received her second dose of the Moderna COVID-19 vaccine 2 days prior to symptom onset and not had any similar symptoms prior to this episode. Patient was hemodynamically stable on admission and afebrile. Physical exam revealed generalized lethargy/weakness and jaundice. Chest x-ray did not demonstrate any evidence of infection or pleural effusions. Initial complete blood count showed a hemoglobin of 5.9 g/dL, compared to her baseline of 9 without any evidence of bleeding. Absolute reticulocyte and bilirubin levels were elevated to 295.2 x 109 and 4.7 mg/dL respectively with a haptoglobin of <20 mg/dL. She received a total of 3 units of packed red-blood cells with subsequent stable hemoglobin levels and did not require emergent use of glucocorticoids or plasma exchange. Her lethargy improved slowly, and within a week, she returned back to her baseline functional status. She was ultimately stable and discharged for follow up with her hematologist without any complications. DISCUSSION: Though the sequelae of COVID-19 infections and associated hematologic diseases have been extensively established, the pathogenesis of COVID-19 vaccinations associated exacerbations remain unclear. Given the timing of the onset of our patient's symptoms, it is highly suggestive that her second COVID-19 vaccination was the inciting factor for her acute hemolytic anemia. It is crucial to be cognizant of the potential hematologic side effects in individuals with rare auto-immune disorders such as PNH and take into consideration the timing of vaccination or booster administrations. CONCLUSIONS: While COVID-19 vaccination benefit most likely outweighs the risks for this specific patient population, our case raises the question about the need for extra precautions in patients with known PNH associated AIHA including the timing of PNH treatment before receiving the vaccination. Reference #1: Algassim AA, Elghazaly AA, Alnahdi AS, Mohammed-Rahim OM, Alanazi AG, Aldhuwayhi NA, Alanazi MM, Almutairi MF, Aldeailej IM, Kamli NA, Aljurf MD. Prognostic significance of hemoglobin level and autoimmune hemolytic anemia in SARS-CoV-2 infection. Annals of Hematology. 2021 Jan;100(1):37-43. DISCLOSURES: No relevant relationships by Suhwoo Bae No relevant relationships by Edward Bae No relevant relationships by Joseph You

Society for the Advancement of Patient Blood Management 2022 Scientific Abstracts

The proceedings contain 46 papers. The topics discussed include: anemia assessment with benchmarking of red blood cell transfusion risk in cardiac surgery;clinical outcomes and therapeutic strategies for gastrointestinal bleeding in patients who decline transfusion;effect of patient blood management program on outcomes of the elderly with femur fracture who underwent orthopedic surgery;effect of ultrafiltration during cardiopulmonary bypass on viscoelastic profiles in cardiac surgery: retrospective analysis;hemoglobin based oxygen carrier treatment and clinical outcomes in severe anemia when blood is not an option;hemoglobin, lactate dehydrogenase, and FACIT-fatigue normalization in pegcetacoplan-treated patients with paroxysmal nocturnal hemoglobinuria;implementing three key blood management measures during COVID-19 related inventory shortages;and managing preoperative anemia using a novel algorithm to determine the preoperative target hemoglobin.

EFFICACY, TREATMENT ADMINISTRATION SATISFACTION AND SAFETY OF SUBCUTANEOUS RAVULIZUMAB THROUGH 1 YEAR IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA WHO RECEIVED PRIOR INTRAVENOUS ECULIZUMAB

Background: The efficacy of ravulizumab (intravenous [IV] formulation;administered every 8 weeks) for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) has been demonstrated in several randomized trials (NCT02946463, NCT03056040, NCT03406507). In study 303 (NCT03748823), subcutaneous (SC) ravulizumab, administered weekly via an on-body delivery system, showed pharmacokinetic non-inferiority to IV ravulizumab in adult patients with PNH who were clinically stable on prior IV eculizumab treatment. Here, we report results from the first 1 year of SC treatment, starting at day 15 for patients who continued SC ravulizumab during the extension period (SC/SC) and day 71 for patients who switched from IV ravulizumab to SC ravulizumab (IV/SC). Aims: To evaluate the efficacy, treatment administration satisfaction and safety of SC ravulizumab through the first 1 year (day 351) of treatment in adult patients with PNH previously treated with eculizumab. Methods: Patients (≥ 18 years) with clinically stable PNH (lactate dehydrogenase [LDH] levels ≤ 1.5 × upper limit of normal [246 U/L]) and ≥ 3 months prior eculizumab treatment were enrolled in the study, which consisted of a screening period (day-1 to day-30), a 10-week randomized treatment period and an extension period of up to 172 weeks. During the randomized treatment period, patients were assigned (2:1 ratio) to receive either SC ravulizumab or IV ravulizumab;all patients received SC ravulizumab during the extension period. Efficacy endpoints included: change in LDH from baseline;incidence of breakthrough hemolysis;transfusion avoidance;and stabilized hemoglobin (avoidance of a ≥ 2 g/dL decrease in hemoglobin in the absence of transfusion). Treatment administration satisfaction was assessed via the Treatment Administration Satisfaction Questionnaire (TASQ), which has been validated in a PNH population. Safety, including adverse events (AEs), serious AEs (SAEs) and adverse device effects (ADEs), were also assessed up to the 1-year data cut-off. Results: In total, 128 patients received SC ravulizumab (SC/SC: n = 84;IV/SC: n = 44;mean [range] duration of SC treatment: 486.4 [37-709] days). Efficacy endpoints (SC/SC and IV/SC) remained stable over time through 1 year of SC ravulizumab treatment. Mean (standard deviation [SD]) percentage change in LDH from baseline to SC day 351 was 0.9% (20.5%). Breakthrough hemolysis events were infrequent: 5/128 patients (3.9%);no event was considered free C5-related. Transfusion avoidance was maintained in 83.6% of patients during SC treatment, and 79.7% achieved stabilized hemoglobin. Improvement in total TASQ score with SC ravulizumab (compared with baseline IV eculizumab) was apparent at the first post-SC treatment assessment (SC day 29) and maintained until data cut-off (Figure). The most common AEs (reported by ≥ 10% of patients, excluding ADEs related to device product issues) during SC treatment were headache (14.1%, all grade ≤ 2), COVID-19 (14.1%, one death) and pyrexia (10.9%);injection site reaction (4.7%) was the most common non-device related ADE. Treatment-emergent SAEs were experienced by 21.1% of patients through to data cut-off. Although many patients had ≥ 1 device issue ADE, full SC dose administration was achieved in 99.9% of attempts. ADE incidence decreased over time. Image: Summary/Conclusion: The SC method of administration provides an additional treatment option for patients with PNH receiving ravulizumab therapy. Patients may be switched from IV eculizumab or IV ravulizumab to SC ravulizumab without loss of efficacy.

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.

Abstracts of the 62nd Annual Scientific Meeting of the British Society for Haematology

The proceedings contain 252 papers. The topics discussed include: immunogenicity of Covid-19 vaccination in patients with myelodysplastic syndromes;antibody responses to SARS-CoV-2 vaccination in patients with acute leukemia and high-risk MDS on active anti-cancer therapies;CD9 derepression drives cellular differentiation and restores immune recognition in pediatric acute myeloid leukemia;follow-up of patients with FLT3-mutated relapsed or refractory acute myeloid leukemia in the phase 3 ADMIRAL trial;efficacy and safety of Maribavir as a rescue treatment for investigator assigned therapy in transplant recipients with refractory or resistant cytomegalovirus infections in the SOLSTICE study: phase 3 trial results;long-term survival benefit of eculizumab treatment in patients with paroxysmal nocturnal hemoglobinuria: data from the international PNH registry;and analysis of anemia persistence and related adverse events in patients with paroxysmal nocturnal hemoglobinuria treated with pegcetacoplan.

COVID19 infection in a patient undergoing treatment for Paroxysmal Nocturnal Hemoglobinuria (PNH) with Ravulizumab.

BACKGROUND: In the recent COVID19 pandemic, patients with hematological disorders were considered at high risk for severe disease. Limited data is available regarding the course of COVID19 infection in this subgroup. CASE PRESENTATION: We describe a case of a 32-year-old man with paroxysmal nocturnal hemoglobinuria (PNH) undergoing treatment with ravulizumab (Ultomiris) who presented with COVID19 infection. He experienced only mild symptoms and had a rapid recovery from COVID19 infection. CONCLUSION: This case may demonstrate the beneficial effects of ravulizumab on complement mediated inflammatory damage linked with COVID19 infection especially in PNH patients.

POS-162 'COLA COLOURED URINE' : NOT ALWAYS GLOMERULAR HEMATURIA

Introduction: Hematuria is a common condition for which a patient seeks nephrology consultation. The presence of gross hematuria is a frightening experience for patient. The reasons for this gross hematuria can be various like nephrolithiasis, malignancies, glomerular diseases, trauma, urinary tract infections, drugs, hemoglobinuria, etc. To differentiate between the various causes of gross hematuria one must begin by taking good history and clinical examination, followed by urine examination and then other tests. Glomerular hematuria is smoky or cola coloured and is usually accompanied by signs and symptoms of fluid overload, high blood pressure, and proteinuria. However cola coloured urine should not be considered synonymous with glomerular hematuria Methods: We report a case of 22 year old pregnant female who was Gravida-3 (22 weeks gestation) but no live issues. Her previous 2 pregnancies ended up in Intra Uterine Death (IUD) of foetus at 6 months gestation. She was referred to us in view of history of cola coloured urine. History of similar episodes of hematuria in previous 2 pregnancies were also present.The history taking was limited because of the prevailing 2ndpeak of COVID-19 pandemic in India and hence most history taking was done indirectly via phone. Clinically she had mild pedal edema and her BP was 110/70 mm of Hg. Her workup showed that she had severe anaemia. Her Complete Blood Count showed Hb-5.8 gm/dL,TLC-3600/mm3,Plt-1.64lakh/mm3,PBS-Microcytic hypochromic with target cells. Renal function was normal. Liver function showed mild indirect hyperbilirubinemia. Urinalysis showed 3+ protein, 50-60 RBCs, 5-10 Pus cell, No casts. Urine culture was sterile. 24 hour urine protein was 1.29 grams. Ultrasonography-bilateral normal sized kidneys. Her COVID-19 RTPCR was negative Results: Differentials we considered were : Primary Glomerulonephritis;Pregnancy Induced Hypertension (PIH);Anti-Phospholipid Antibody Syndrome (APLA) & Atypical Hemolytic Uremic Syndrome (a-HUS). These were ruled out based on further relevant tests.Kidney biopsy was not offered as there was no nephrotic syndrome. Anti-Nuclear Antigen was negative. Complements were normal. APLA antibodies were negative.BP was always normal making PIH less likely. However LDH was raised (2700 U/L) & serum haptoglobulin was low. So a clear cut evidence of hemolytic anaemia but normal renal function, compelled us to revisit the history by calling the patient in-person despite the pandemic. She admitted that anaemia was present since her childhood days and she had suppressed this history due to social issues. Also the hematuria was episodic with clear urine in between. Hence Flowcytometry for Paroxysmal Nocturnal Hemoglobinuria was done which confirmed the diagnosis as PNH. Conclusions: Our case report highlights the fact that while evaluating cases of hematuria one must keep all possibilities open. Especially when dealing with cola coloured urine it should not be assumed to be glomerular hematuria It also stresses the well established fact that history taking is the key to making any diagnosis. In situations where social factors may lead to suppression of facts,efforts must be made to gain the confidence of patient and provide a conducive environment for complete history. Finally, even after diagnosis of PNH, the definitive treatment is still out of reach for many patients in this part of world. No conflict of interest

Acquired Aplastic Anemia in Immunocompetent Pediatric Patients with Asymptomatic COVID-19 Infection: A Case Series

Background: In pediatrics, acquired aplastic anemia (AA) is most commonly due to infection, particularly viruses, when a cause can be identified. Coronavirus disease 2019 (COVID-19) has affected more than 197 million people worldwide, and children typically experience a less severe disease course. COVID-19 is known to cause transient hematologic abnormalities, including leukopenia, lymphopenia, anemia and thrombocytosis or thrombocytopenia in severe cases. Objectives: Describe three cases of COVID-19 associated acquired aplastic anemia in immunocompetent pediatric patients. Design/Methods: Case series established by retrospective review of the electronic medical record. Results: Case 1: An 8-year-old Hispanic male presented with a three-week history of increased bruising and a one-week history of progressive exercise intolerance, shortness of breath, pallor and fatigue. Labs showed pancytopenia. Bone marrow aspirate and biopsy was markedly hypocellular at 5-10% consistent with aplastic anemia (Figure 1). Work-up for the etiology of his aplastic anemia was only significant for positive SARS-COV-2 antibodies and a SEC23B variant of unknown significance on a comprehensive bone marrow failure (BMF)/myelodysplastic syndrome (MDS)/leukemia panel from the Children's Hospital of Philadelphia (CHOP). He was treated with eltrombopag olamine and then proceeded to immunotherapy with cyclosporine (CsA) and horse antithymocyte globulin (ATG) when a sibling match was not identified for hematopoietic stem cell transplant (HSCT). Three months later, his peripheral blood counts have improved, and he is no longer transfusion-dependent. Repeat bone marrow aspirate and biopsy continues to show markedly hypocellularity at <5%. Case 2: A 5-year-old non-Hispanic white female presented with a two-week history of easy bruising, petechial rash, fatigue and bone pain. Labs showed pancytopenia, and bone marrow aspirate and biopsy showed marked hypocellularity at 5-10% consistent with aplastic anemia (Figure 2). Her aplastic anemia work-up was significant for positive SARS-COV-2 antibodies and subclinical RBC and WBC paroxysmal nocturnal hemoglobinuria (PNH) clones. She was started on eltrombopag olamine and then proceeded to immunotherapy with CsA and ATG when a matched sibling donor was not identified. Three months later, she continues to be severely neutropenic, anemic and thrombocytopenic requiring multiple transfusions. Repeat bone marrow aspirate and biopsy showed variable cellularity with some areas 10-20% and others 70% with an overall cellularity of 50%. Case 3: An 8-year-old non-Hispanic white female presented with a 10-day history of fatigue, bilateral leg pain and pallor. Labs showed pancytopenia, elevated inflammatory markers and elevated hemoglobin F. Bone marrow aspirate and biopsy demonstrated mild-moderate hypocellularity at 40-50%, left-shifted myelopoiesis and dyspoiesis in the erythroid and megakaryocytic cell lines (Figure 3). MDS and acute lymphoblastic leukemia (ALL) fluorescence in situ hybridization (FISH) panels were negative. Additional work-up revealed positive SARS-COV-2 antibodies. Her pancytopenia resolved within two weeks of her initial hospitalization. Four months later, she presented with increased bruising and fatigue. Labs showed leukocytosis, thrombocytopenia, anemia and circulating peripheral blasts. Bone marrow aspirate and biopsy was consistent with B-cell ALL. She is receiving chemotherapy on study COG AALL1732. Conclusion: Severe aplastic anemia (SAA) has high morbidity and mortality, and timely diagnosis is needed for appropriate treatment. Multiple different viral infections have been known to cause acquired aplastic anemia. Data on all the sequelae of COVID-19 infection is still emerging, but it is plausible that COVID-19 infection may cause SAA. All three patients were found to have positive COVID-19 antibodies but did not have any evidence of previous COVID-19 infection. Further research and follow-up is needed to determine if previous COVID-19 infection is indeed a risk factor for development of S A. [Formula presented] Disclosures: No relevant conflicts of interest to declare.

Outcomes of Patients with Budd-Chiari Syndrome and Factors Predicting the Need for TIPS & Liver Transplantation - a Single-Center Long-Term Experience

Background: Budd-Chiari Syndrome (BCS) is a complex thrombotic disorder caused due to obstruction of hepatic venous outflow involving anywhere from small hepatic venules to the entrance of inferior vena cava into the right atrium. This leads to venous stasis and ischemic injury of hepatic parenchyma and sinusoids, with the risk of liver failure. The prognosis of patients with BCS had improved significantly with long-term anticoagulation and measures like Trans-Jugular-Intrahepatic-Porto-Systemic shunt (TIPS) and liver transplantation. We report the outcomes of patients who follow in our hematology practice and describe the factors predicting the need for TIPS/Liver Transplant. Methods: After appropriate Investigational Review Board permission, we identified patients with a history of BCS following in our thrombosis clinical practice from the year 2010 onwards. We evaluated their laboratory, demographic, anticoagulation data, Model of End-stage Liver Disease (MELD) score, Child-Pugh (CP) score at diagnosis or when earliest available, and other relevant clinical information as outlined. Descriptive statistics with medians, quartiles, frequencies, and percentages are reported. Further, we compared the two categories of patients who needed TIPS/Liver transplants versus those who did not. SAS version 9.4 was used for analysis. For continuous variables, a univariate nonparametric Mann-Whitney test was used. The Fisher's Exact Test was used to associate each variable with the need for TIPS/Liver Transplant. Results: Our study included 23 patients with baseline characteristics, including median age of 36 years (11-59 years), 91% whites, 61% females, 44% smokers, 61% obese(median BMI 29.9 kg/m 2), 6 of 14 women on oral contraceptive pills, 22% with thrombosis history, 17% with stroke history, median hemoglobin 13.4 gm/dL(8.9-20 gm/dL), white blood cell count 9,400/L (3,050-31,500/L), platelet count 294,000/L(14,000-767,000/L), serum creatinine 0.87 mg/L (0.55-2.52 mg/dL), total protein 6.3 gm/dL (5.2-8.8 gm/dL), Bilirubin 2.1 mg/dL(0.1-20.2 mg/dL), Aspartate Aminotransferase (AST) 61 U/L(16-1037 U/L), Alanine Aminotransferase (ALT) 43U/L(18-1694 U/L), MELD score 15 (range 7-38), CP score 9 (5-14), 74% with cirrhosis, 82% with ascites at one point, 57% with myeloproliferative neoplasm (MPN), 4.3% with Paroxysmal Nocturnal Hemoglobinuria (PNH), 17% with Antiphospholipid antibodies positive (APS), 13% had positive antinuclear antibodies, 35% needed TIPS and 44% required liver transplantation. 57% with Janus Kinase (JAK2) V617F mutation (1 patient with a low variant allele frequency of 1%), 1 patient (4.3%) had Calreticulin (CALR) mutation positive MPN, 91% remained on long-term anticoagulation with 40% using warfarin, 35% apixaban, 9% Enoxaparin or Rivaroxaban for long-term anticoagulation, 13% developed heparin-induced thrombocytopenia (HIT). 8.7% had developed BCS after Ad26.COV2.S vaccine to prevent SARS-CoV-2 infection. Excluding the patients with missing variables, 5 of 12 had Protein C deficiency, 3 or 10 had Protein S deficiency, 8 of 20 with Antithrombin (AT) deficiency, 4 of 14 with heterozygous factor V Leiden mutation, 0 of 10 with prothrombin gene mutation, 1 of 13 with hyper-homocysteinemia. 35% had gastrointestinal bleeding though 65% of patients had evidence of varices by endoscopy. When the group needing TIPS/Liver transplant/died is compared to those who did not, they had higher bilirubin, MELD, PC score, AT deficiency, cirrhosis, ascites, and JAK2 mutation (p-value significant: Table 1). With a median follow-up of 90 months, overall survival was not statistically significant between the two groups (Figure 1). Two patients (8.7%) died out of a total of 23. Conclusions: Our data indicate that in patients with BCS, neoplasms (61%), particularly MPN (57%), are very commonly diagnosed. Compared to the historical data in patients with BCS with dismal prognosis (60-80% six-month mortality rate), the overall survival had significantly improved, likely due to supportive measures like TIPS/Liver transplant and long-ter anticoagulation. Outside the established variables like CP and MELD, lower antithrombin activity and positive JAK2 mutation status also predicted a higher TIPS/Liver transplant need. [Formula presented] Disclosures: Bhatt: Partnership for health analytic research, LLC: Consultancy;Abbvie: Consultancy, Research Funding;Jazz: Research Funding;Incyte: Consultancy, Research Funding;Pfizer: Research Funding;Tolero Pharmaceuticals, Inc: Research Funding;National Marrow Donor Program: Research Funding;Abbvie: Consultancy, Research Funding;Genentech: Consultancy;Servier Pharmaceuticals LLC: Consultancy;Rigel: Consultancy. Gundabolu: BioMarin Pharmaceuticals: Consultancy;Blueprint Medicines: Consultancy;Bristol-Myers Squibb Company: Consultancy;Pfizer: Research Funding;Samus Therapeutics: Research Funding.

Sars-Cov-2 Vaccination in Patients with Paroxysmal Nocturnal Hemoglobinuria: An Italian Multicenter Survey

SARS-CoV-2 infection and vaccination have raised concerns in paroxysmal nocturnal hemoglobinuria (PNH). In fact, PNH patients carry an increased infectious risk secondary to complement inhibition treatment or associated bone marrow failure (BMF), and may therefore benefit from preventive strategies such as vaccinations. On the contrary, vaccines can be numbered among inflammatory complement amplifiers (e.g., infections, traumas, surgery), potentially triggering a disease exacerbation. In PNH patients on complement inhibitors, this phenomenon has been defined pharmacodynamic breakthrough hemolysis (BTH). Based on isolated reports of BTH following SARS-CoV-2 vaccines, we conducted a survey among 5 Italian reference centers to evaluate complications and BTH occurrence in PNH patients who completed the SARS-CoV-2 vaccination schedule from January, 2 2021 until the time of writing. Adverse events, hematologic and hemolytic parameters were recorded within 7-10 days before and after each dose of vaccine. A total of 67 patients (females/males 43/24, median age 47.6 years, range 21-90.5) were eligible for the analysis. According to the International PNH Interest Group classification, 45 patients suffered from hemolytic PNH, 20 from PNH in the context of BMF syndromes (aplastic anemia or myelodysplastic syndrome), and 2 from subclinical PNH. Fifty-five subjects (82%) were on regular complement inhibition therapy, i.e., eculizumab (N=35), ravulizumab (N=13), subcutaneous anti-C5 (N=3), anti-factor B (N=2) and ravulizumab + anti-factor D combination (N=2). Vaccines (Comirnaty/Pfizer-BioNTech N=53, mRNA-1273/Moderna N=12, and ChAdOx1 nCov-19/AstraZeneca N=2) were complessively well-tolerated, with 3 non-hematologic adverse events after the first dose (2 fever and 1 exercise-induced tachycardia, grade 1 according to CTCAE v5.0) and 2 after the second one (fever, accompanied by vomit in one patient, grade 1). During the observation period, 3 BTH and 1 hemolytic exacerbation were recorded (5.9% of patients), as detailed in Table 1. The most severe episode occurred in a young woman (Patient 3) on subcutaneous ravulizumab who experienced a hemoglobin (Hb) drop >2 g/dL, marked clinical signs of intravascular hemolysis and lactate dehydrogenase (LDH) increase >1.5 x upper limit of normal (ULN) from baseline, which is considered a clinical BTH according to the criteria proposed by the Severe Aplastic Anemia Working Party of the European group for Bone Marrow Transplantation. The patient required hospitalization for additional treatment with recombinant erythropoietin and anti-thombotic/bacterial prophylaxis. The second more severe BTH was registered in a male patient (Patient 1) on oral anti-factor B who experienced a Hb drop >2 g/dL without an overt hemolytic flare, and required hospitalization for intravenous antibiotic therapy (concomitant urinary tract infection). The remaining two patients experienced a subclinical BTH (Patient 2) and a hemolytic flare (Patient 4, not on complement inhibition). On the whole, a median delta variation from usual values of Hb and LDH of -25% (range -26+3%) and +80% (+18+105%) were observed, respectively. Of note, 3 episodes occurred after the second dose of vaccine, generally within 24-48 hours. Anti-complement drugs were not modified/discontinued in any of the 3 patients on regular treatment. Patients not experiencing BTH (94.1%) showed stable hematologic parameters after the first dose (Hb/LDH median delta variations from baseline -1%/+1%, range -14+12%/-32+40%) and the second dose of vaccine (Hb/LDH median delta variations from baseline +1%/0%, range -18+47%/-76+41%). Of note, 4 patients with a previous SARS-CoV-2 infection completed the vaccination without any complication/PNH exacerbation. In conclusion, this survey shows that BTH/hemolytic flares following SARS-CoV-2 vaccines are observed in about 6% of PNH patients, may be clinically relevant but manageable, and should not discourage vaccination. BTH has been registered mostly few days after the second dose of vaccine, suggesting a “booster⠝ effect favoring a higher inflammatory response. Watchful clinical and laboratory monitoring is advised, in order to promptly recognize severe hemolytic flares in both treated and naïve patients. [Formula presented] Disclosures: Fattizzo: Novartis: Speakers Bureau;Kira: Speakers Bureau;Alexion: Speakers Bureau;Annexon: Consultancy;Momenta: Honoraria, Speakers Bureau;Apellis: Speakers Bureau;Amgen: Honoraria, Speakers Bureau. Bianchi: Agios pharmaceutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sica: Jazz Pharma: Consultancy;Alexion: Consultancy. Barcellini: Novartis: Other: Invited speaker, Research Funding;Agios: Membership on an entity's Board of Directors or advisory committees;Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Other: Invited speaker, Research Funding;Bioverativ: Membership on an entity's Board of Directors or advisory committees;Incyte: Membership on an entity's Board of Directors or advisory committees.