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.

Blackwater Fever Treated with Steroids in Nonimmune Patient, Italy.

Causes of blackwater fever, a complication of malaria treatment, are not completely clear, and immune mechanisms might be involved. Clinical management is not standardized. We describe an episode of blackwater fever in a nonimmune 12-year-old girl in Italy who was treated with steroids, resulting in a rapid clinical resolution.

BSH 2023 Poster Abstract Book

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. Seven patients with progressive clinical features had ASCT consolidation (median age 59 years [range 43-68]): three patients had additional parenchymal intracranial disease on MRI and two patients also had peripheral nerve involvement, including one patient with suspicion of high-grade transformation (HGT) on CSF. Out of the 206 patients that received 1st line treatment, 92 (44%) patients proceeded to 2nd line treatment, 31 (15%) patients proceeded to 3rd line treatment and 21 (10%) of patients required treatment beyond 3rd line Within the poor risk category, 173 patients were identified with 38 had TP53 deletion or mutation and 135 patients had other poor risk mutations such as NOTCH1, SF3B1, ATM. Patients were risk stratified into good, poor or not poor risk categories as per Rodríguez-Vicente et al. SP 2 sp B Statistical Analysis and Results: b For 349 patients analysed, 143 (41%) patients were under active surveillance, and 206 (59%) patients received 1st line treatment. B Methodology: b Using a mixed methods approach we evaluated the app via: usage data from Google's Firebase platform (https://firebase.google.com/) healthcare professional benchmarking, using the Mobile App Rating Scale (MARS) questionnaire patient questionnaires, using the mHealth App Usability Questionnaire (MAUQ) patient focus groups one-to-one patient interviews Patient recruitment was undertaken via CML online support groups. [Extracted from the article] Copyright of British Journal of Haematology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

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.

Complete response to eculizumab in atypical hemolytic uremic syndrome with homozygous C3 mutation

Case Report: Atypical Hemolytic Uremic Syndrome (atypical HUS) is a rare and severe form of thrombotic microangiopathy (TMA) characterized by thrombocytopenia, intravascular hemolysis, and acute kidney injury with an incidence of 1 per million.1 Dysregulation and overactivation of the complement alternative pathway due to genetic mutations have been detected in 40-60% of patients with sporadic or familial atypical HUS.2,4 Triggers include viral illness, pregnancy, malignancy, sepsis, or sporadically with no known inciting event.1 Atypical HUS is a severe disease with a 2-10% risk of mortality, 33% risk of end-stage renal failure, and 50% chance of relapse.5 A 24-year-old female with prior history of atypical HUS at the age of 16 (with response to plasmapheresis) presented to the ER with a 5-day history of fever, chills, sore throat, nausea, vomiting, and dark urine. She tested positive for COVID-19. The exam revealed scleral icterus and scattered petechiae. Labs demonstrated nadir hemoglobin (Hgb) of 9.2 g/dL, platelet count of 52 000k/uL, haptoglobin < 30 mg/dL, peak LDH 1128U/L and creatinine 4.62 mg/dL. Urinalysis is consistent with hemoglobinuria. Schistocytes were noted on the peripheral smear. Rapid streptococcal antigen test and C3, C4, and IgA levels were unremarkable. Chest X-Ray, X-ray KUB, and ultrasound abdomen were unremarkable. The pregnancy test was negative. ADAMTS13 was >100%. Genetic analysis after the initial episode at age 16 revealed autosomal recessive inheritance c.193A > c gene mutations in C3. The patient received IV fluids, ceftriaxone for cystitis, and two units of Fresh Frozen Plasma. She initiated treatment with eculizumab. She also received the MENVEO and meningitis B vaccine per protocol due to the risk of meningitis from terminal complement deficiencies. After 4 infusions of eculizumab, patient's labs improved to platelet count of 307 000 k/uL, Hgb 12.2 g/ dL (nadir 9.2 g/dL), haptoglobin 78 mg/dL normalization of LDH and improved creatinine. Atypical HUS is a rare form of TMAwith mutations in C3 noted in 5% of cases. Complement cascade dysfunction leads to endothelial deposits and microvasculature damage. The resulting prothrombotic state causes obstructive microvascular thrombi predominantly affecting the kidneys but can cause multiorgan dysfunction. The SARS-CoV-2 virus may precipitate atypical HUS relapse due to endothelial damage and complement activation further intensified in patients with existing complement aberrations. Plasma exchange remains a standard of care for atypical HUS, as it effectively removes the antibodies and other proteins. Eculizumab a humanized monoclonal IgG antibody binds to complement proteins, preventing cleavage into C5a and C5b blocking C5b-9(MAC) activation. In patients with CFH, CFI, C3, and CFB mutations, eculizumab is the preferred intervention. Copyright © 2023 Southern Society for Clinical Investigation.

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

A RARE CASE OF ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES (ANCA)-ASSOCIATED VASCULITIS IN THE SETTING OF COVID-19 INFECTION

SESSION TITLE: Management of COVID-19-Induced Complications SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Anti-neutrophil cytoplasmic antibody-associated vasculitis (ANCA-AV) is an autoimmune mediated inflammation of small and medium sized vessel walls. The occurrence of this autoimmune vasculitis is typically associated with underlying infection, medications, and genetic predisposition.(1) The objective of this case report is to describe a rare presentation of ANCA-AV in the setting of COVID-19 infection. CASE PRESENTATION: A 67-year-old male presented to the hospital with a three-week history of cough productive of brown sputum, epistaxis, fatigue, decreased appetite, and unintentional weight loss. During the previous week, he experienced worsening dyspnea and bilateral lower extremity swelling. On physical examination, he was hypoxic requiring 4L of supplemental oxygen to maintain saturations greater than 90%. Diffuse and bilateral wheezes were heard on auscultation of his lungs. A tender petechial rash was dispersed over his limbs, trunk, oropharynx, and nasopharynx. A basic metabolic panel revealed a mild, acute renal impairment. Urinalysis showed new onset proteinuria and hemoglobinuria. Nasopharyngeal swab was positive for SARS-COV-2. Contrast-enhanced computed tomography of the chest revealed diffuse, bilateral ground glass opacities and interstitial changes. Therapy with piperacillin-tazobactam was started for presumed superimposed bacterial community acquired pneumonia in the setting of COVID-19 infection. On day three of hospitalization, the petechial rash progressed to hemorrhagic blisters. His oral petechiae were now ulcerated. A punch biopsy of the affected skin showed leukocytoclastic vasculitis. Anti-Proteinase 3 (PR3) antibodies were positive. Subsequent renal biopsy showed pauci-immune focal necrotizing crescentic glomerulonephritis consistent with ANCA-AV. Therapy with intravenous pulse dose corticosteroids led to improvement in his rash and body aches, and he was discharged home on oral steroids ten days after admission. DISCUSSION: This report describes a rare case of ANCA-AV in the setting of recent COVID-19 infection. Differentiation of ANCA-AV, bacterial and COVID-19 pneumonia can be challenging on chest imaging alone.(1) New onset renal impairment, hematuria, proteinuria and the presence of the petechial rash were suspicious for co-existing ANCA-AV in this patient. COVID-19- associated cytokine storm and formation of neutrophil extracellular traps (NETs) is postulated to be the underlying cause.(1-3) NETs present myeloperoxidase (MPO) and PR3 antigens to the immune system. Formation of auto-antibodies to MPO and PR3 lead to the development of ANCA-AV. The findings of NETs on kidney biopsy specimens in patients with ANCA-AV supports this hypothesis.(1,2) CONCLUSIONS: To avoid the misdiagnosis of COVID-19-induced vasculitis, a low threshold to investigate co-existing vasculitis in patients with COVID-19 and associated clinical findings is highly recommended. Reference #1: Izci Duran T, Turkmen E, Dilek M, Sayarlioglu H, Arik N. ANCA-associated vasculitis after COVID-19. Rheumatol Int. 2021;41(8):1523-1529. Reference #2: Uppal NN, Kello N, Shah HH, et al. De Novo ANCA-Associated Vasculitis With Glomerulonephritis in COVID-19. Kidney Int Rep. 2020;5(11):2079-2083. Reference #3: Cobilinschi C, Cobilinschi C, Constantinescu A, Draniceanu I, Ionescu R. New-Onset ANCA-Associated Vasculitis in a Patient with SARS-COV2. Balkan Med J. 2021;38(5):318-320. DISCLOSURES: No relevant relationships by Andrei Hastings No relevant relationships by Jason Lane No relevant relationships by Tanya Marshall No relevant relationships by Palak Rath No relevant relationships by Sterling Shriber No relevant relationships by inderprit Singh No relevant relationships by Samuel Wiles

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.

Challenges Faced by an ECMO Patient

Aim and objective: To elaborate the challenges faced by an ECMO patient and the issues to be overcome and how to address them and combat with the help of a multidisciplinary team. This is a case of a 34-year-old male patient without any comorbidities who tested positive for COVID on 08/07/21 who was on home quarantine for 8 days and reported to hospital on 16/07 in view of breathlessness, was started on oxygen, bipap and tried on remdesivir, steroids, and tocilizumab and baricitinib. The patient was not maintaining saturations and was intubated on 26/07 and as there was refractory hypoxaemia was initiated on ECMO on the next day. The patient was started on ceftazidime and levoflox along with voriconazole as serum galactomannan was positive and ET cultures showed Stenotrophomonas maltophilia. The patient was tracheostomized on 01/08 and was keeping well till 12/08 when there were episodes of desaturation and tachypnoea and blood culture showed Candida auris and BAL culture showed Chryseobacterium and MDR Klebsiella with NDM, OXA-48 AND VIM+. The patient developed septic shock and required dual vasopressors. BAL galactomannan had titres of 4.5 and the patient was initiated on a mixture of ceftazidime, avibactum, voriconazole, and anidulafungin. The patient started having hemoglobinuria subsequently and acute kidney injury secondary to this and required 3 sessions of dialysis and the whole ECMO circuit was changed. Improvement in the parameters followed with normalization of blood pressure and urine output too. When there was a sigh of relief as things were getting normal patient started having heavy bouts of tracheal bleeding and bronchoscopy was done again with endobronchial biopsy showing CMV endobronchitis with focal ulceration and was started on ganciclovir. There were maleana episodes too which normalized after initiation of antivirals and CMV enterocolitis was suspected to be the cause. Now the patient is on trial off mode with decannulation being planned.

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.

Adult paroxysmal cold hemoglobinuria following mRNA COVID-19 vaccination.

Paroxysmal cold hemoglobinuria (PCH) is an extremely rare subtype of autoimmune hemolytic anemia (AIHA) in adults. PCH is caused by the biphasic Donath-Landsteiner (DL) antibody which fixes complement to red blood cells at low temperatures and dissociates at warmer temperatures, leading to complement-mediated intravascular hemolysis. Autoimmune hematological disorders including AIHA and immune thrombocytopenia have been reported to develop following the mRNA COVID-19 vaccination. However, PCH developing subsequent to mRNA vaccination has never been reported. We report a 59-year-old male who developed PCH approximately a month after his second mRNA COVID-19 vaccination.