Mitapivat versus Placebo for Pyruvate Kinase Deficiency.

BACKGROUND: Pyruvate kinase deficiency is a rare, hereditary, chronic condition that is associated with hemolytic anemia. In a phase 2 study, mitapivat, an oral, first-in-class activator of erythrocyte pyruvate kinase, increased the hemoglobin level in patients with pyruvate kinase deficiency. METHODS: In this global, phase 3, randomized, placebo-controlled trial, we evaluated the efficacy and safety of mitapivat in adults with pyruvate kinase deficiency who were not receiving regular red-cell transfusions. The patients were assigned to receive either mitapivat (5 mg twice daily, with potential escalation to 20 or 50 mg twice daily) or placebo for 24 weeks. The primary end point was a hemoglobin response (an increase from baseline of ≥1.5 g per deciliter in the hemoglobin level) that was sustained at two or more scheduled assessments at weeks 16, 20, and 24. Secondary efficacy end points were the average change from baseline in the hemoglobin level, markers of hemolysis and hematopoiesis, and the change from baseline at week 24 in two pyruvate kinase deficiency-specific patient-reported outcome measures. RESULTS: Sixteen of the 40 patients (40%) in the mitapivat group had a hemoglobin response, as compared with none of the 40 patients in the placebo group (adjusted difference, 39.3 percentage points; 95% confidence interval, 24.1 to 54.6; two-sided P<0.001). Patients who received mitapivat had a greater response than those who received placebo with respect to each secondary end point, including the average change from baseline in the hemoglobin level. The most common adverse events were nausea (in 7 patients [18%] in the mitapivat group and 9 patients [23%] in the placebo group) and headache (in 6 patients [15%] and 13 patients [33%], respectively). Adverse events of grade 3 or higher occurred in 10 patients (25%) who received mitapivat and 5 patients (13%) who received placebo. CONCLUSIONS: In patients with pyruvate kinase deficiency, mitapivat significantly increased the hemoglobin level, decreased hemolysis, and improved patient-reported outcomes. No new safety signals were identified in the patients who received mitapivat. (Funded by Agios Pharmaceuticals; ACTIVATE ClinicalTrials.gov number, NCT03548220.).

Understanding pulse oximetry in hematology patients: Hemoglobinopathies, racial differences, and beyond.

Pulse oximetry (SpO2 ) is a widely used, non-invasive method of estimating arterial oxygen saturation. Measurement of SpO2 relies on comparing the relative absorption of light in the red and infrared regions with the expected absorption pattern of oxygenated and deoxygenation adult hemoglobin. As this screening tool has entered common clinical use, test limitations have emerged, including concern about the risk of overestimation of oxygen saturation by pulse oximetry in a disproportionate number of people with dark skin pigment, leading to potential for underdiagnosis of true hypoxemia. In addition, a range of challenges may arise in patients with increased levels of methemoglobin - whether acquired or inherited - carboxyhemoglobin, or in patients with a subset of inherited variant hemoglobins. It is important for Hematologists, and indeed all clinicians who rely on pulse oximetry, to understand the principles and limitations of this ubiquitous test.

Combined preoperative plasma exchange and red blood cell exchange transfusion in a renal transplant patient with protein S deficiency and hemoglobin SC disease.

BACKGROUND: Protein S deficiency is associated with increased risk of venous thromboembolism, complicating the perioperative management of such patients. We present a patient with sickle cell disease (Hb SC genotype) and inherited protein S deficiency who underwent a living-donor renal transplant. To minimize thrombotic risk and sickle cell complications, both plasma exchange and red blood cell (RBC) exchange transfusion were performed pre-operatively. METHODS AND MATERIALS: Plasma exchange was utilized to increase protein S levels and to reduce the risk of post-operative venous thromboembolism, including allograft thrombosis, while RBC exchange was performed to reduce the risk of acute post-operative sickle cell disease complications. RESULTS: With the use of combined pre-operative plasma exchange and RBC exchange transfusion, this patient with protein S deficiency and Hb SC underwent a successful renal transplant without acute sickle cell complications or thrombotic complications. CONCLUSIONS: This case demonstrates the potential use of pre-operative plasma exchange in patients with protein S deficiency undergoing high thrombotic risk procedures.

Race-based data collection among COVID-19 inpatients: A retrospective chart review.

Public health data have demonstrated disproportionate COVID-19 morbidity and mortality among racialized populations. However, limited hospital data may prevent research into racial disproportionality among inpatients. We conducted a retrospective cross-sectional study of patients admitted with or without COVID-19 to an Ontario tertiary hospital between March and October 2020 to determine the percentage of inpatients with a formal race or ethnicity assessment in their medical record. The COVID-19 group included inpatients with concurrent COVID-19 positivity; the reference group included a random sample of General Medicine inpatients without COVID-19. We reviewed 80 patients with COVID-19 and 80 patients without COVID-19. Formal ethnicity assessments were recorded among 44% of the COVID-19 group and 49% of the reference group. Race and ethnicity data collection was less than 50% among inpatients with and without COVID-19 in one Ontario hospital. Adequate data collection is necessary to study racial health disparities in the hospital setting.

Comorbidities and complications in adults with pyruvate kinase deficiency.

OBJECTIVES: Pyruvate kinase (PK) deficiency is caused by PKLR gene mutations, leading to defective red blood cell glycolysis and hemolytic anemia. Rates of comorbidities and complications by transfusion history and relative to the general population remain poorly quantified. METHODS: Data for patients aged ≥ 18 years with two confirmed PKLR mutations were obtained from the PK deficiency Natural History Study (NCT02053480). Frequencies of select conditions were compared with an age- and sex-matched cohort from a general insured US population without PK deficiency. RESULTS: Compared with the matched population (n = 1220), patients with PK deficiency (n = 122) had significantly higher lifetime rates of osteoporosis, liver cirrhosis, and pulmonary hypertension; splenectomy and cholecystectomy rates were also significantly higher in the 8 years before the index date. Sixty-five (53.3%) patients with PK deficiency were classified as regularly transfused, 30 (24.6%) as occasionally transfused, and 27 (22.1%) as never transfused. Regularly transfused patients were significantly more likely than never transfused patients to have had splenectomy, cholecystectomy, and/or thrombosis. Liver iron overload was reported in 62% of patients and occurred regardless of transfusion cohort. CONCLUSIONS: Even never transfused patients with PK deficiency had higher rates of select comorbidities and complications than individuals without PK deficiency.

Genotype-phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency.

Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non-missense, including 20 stop-gain, 11 affecting splicing, five large deletions, four in-frame indels, and three promoter variants. Within the 177 unrelated patients, 35 were homozygous and 142 compound heterozygous (77 for two missense, 48 for one missense and one non-missense, and 17 for two non-missense variants); the two most frequent mutations were p.R510Q in 23% and p.R486W in 9% of mutated alleles. Fifty-five (21%) patients were found to have at least one previously unreported variant with 45 newly described mutations. Patients with two non-missense mutations had lower hemoglobin levels, higher numbers of lifetime transfusions, and higher rates of complications including iron overload, extramedullary hematopoiesis, and pulmonary hypertension. Rare severe complications, including lower extremity ulcerations and hepatic failure, were seen more frequently in patients with non-missense mutations or with missense mutations characterized by severe protein instability. The PKLR genotype did not correlate with the frequency of complications in utero or in the newborn period. With ICCs ranging from 0.4 to 0.61, about the same degree of clinical similarity exists within siblings as it does between siblings, in terms of hemoglobin, total bilirubin, splenectomy status, and cholecystectomy status. Pregnancy outcomes were similar across genotypes in PK deficient women. This report confirms the wide genetic heterogeneity of PK deficiency.

Pharmacy hydroxyurea education materials for patients with sickle cell disease: An environmental scan and assessment of accuracy.

BACKGROUND: Hydroxyurea (HU) remains a cornerstone of sickle cell disease (SCD) therapy; however, its use is limited by poor patient adherence owing to concerns about side effects. Pharmacies routinely provide patients with handouts about HU, which, we hypothesized, contain inaccuracies that may contribute to negative patient perceptions of HU. METHODS: We used a systematic approach to collect and review patient information handouts (PIHs) on HU from pharmacies in Ontario, Canada. PIHs were evaluated according to: i. Number of inaccurate statements, ii. Percentage of essential statements based on comparison with a reference standard PIH developed by the Canadian Haemoglobinopathy Association (CanHaem), and iii. Reading level. RESULTS: PIHs were collected from 98% of chain and community pharmacies registered in Ontario. All PIHs contained inaccurate statements, most frequently relating to the risk of developing cancer. Only 33% of PIHs identified SCD as an indication for HU use. Pharmacy PIHs contained 45% of the essential statements present within the CanHaem HU PIH, neglecting to mention use of HU for management of SCD and benefits of HU in preventing SCD complications. Moreover, the reading level across pharmacy PIHs was 1.8 grades higher than that advised for written patient education materials. CONCLUSION: Patients who are prescribed HU are likely to be provided with PIHs that contain inaccuracies that are weighted toward the risks of HU therapy and run contrary to published literature. This study identifies a gap in the care of patients with SCD and an opportunity to improve the quality of HU PIHs to help patients make well-informed decisions about their health.

Utilising red cell antigen genotyping and serological phenotyping in sickle cell disease patients to risk-stratify patients for alloimmunisation risk.

BACKGROUND: Alloimmunisation and haemolytic transfusion reactions (HTRs) can occur in patients with sickle cell disease (SCD) despite providing phenotype-matched red blood cell (RBC) transfusions. Variant RBC antigen gene alleles/polymorphisms can lead to discrepancies in serological phenotyping. We evaluated differences between RBC antigen genotyping and phenotyping methods and retrospectively assessed if partial antigen expression may lead to increased risk of alloimmunisation and HTRs in SCD patients at a tertiary centre in Canada. METHODS: RBC antigen phenotyping and genotyping were performed by a reference laboratory on consenting SCD patients. Patient demographic, clinical and transfusion-related data were obtained from a local transfusion registry and chart review after research ethics board approval. RESULTS: A total of 106 SCD patients were enrolled, and 91% (n = 96) showed additional clinically relevant genotyping information when compared to serological phenotyping alone. FY*02N.01 (FY*B GATA-1) (n = 95; 90%) and RH variant alleles (n = 52, 49%; majority accompanied by FY*02N.01) were common, the latter with putative partial antigen expression in 25 patients. Variability in genotype-phenotype antigen prediction occurred mostly in the Rh system, notably with the e antigen (kappa: 0.17). Fifteen (14.2%) patients had a history of alloimmunisation, with five having HTR documented; no differences in clinical outcomes were found in patients with partial antigen expression. Genotype/extended-phenotype matching strategies may have prevented alloimmunisation events. CONCLUSION: We show a high frequency of variant alleles/polymorphisms in the SCD population, where genotyping may complement serological phenotyping. Genotyping SCD patients before transfusion may prevent alloimmunisation and HTRs, and knowledge of the FY*02N.01 variant allele increases feasibility of finding compatible blood.

Novel High Oxygen Affinity Hemoglobin Variant in a Patient with Polycythemia: Hb Kennisis [ß85(F1)Phe→Leu (TTT>TTG); HBB: c.258T>G].

We report the case of a 61-year-old Canadian male of Maltese descent investigated for unexplained polycythemia. Decreased p50 suggested the presence of a high oxygen affinity hemoglobin (Hb) variant. Molecular genetic testing demonstrated that he carries a novel missense mutation (HBB: c.258T>G), resulting in a Phe→Leu substitution at position 85 of the ß chain. The novel Hb variant has been designated Hb Kennisis in recognition of where the proband resides. Two other missense mutations have been reported at this position [Hb Bryn Mawr or Hb Buenos Aires, ß85(F1)Phe→Ser (HBB: c.257T>C); Hb Grantham, ß85(F1)Phe→Cys; (HBB: c.257T>G)], both of which have increased oxygen affinity.

How we diagnose and manage altered oxygen affinity hemoglobin variants.

Altered oxygen affinity variant hemoglobins (Hbs) are caused by mutations of the globin genes. Changes in Hb oxygen affinity shift the oxygen dissociation curve, and can be identified by abnormal p50 measurements of patient red blood cells. Variants are categorized as either low oxygen affinity (high p50) or high oxygen affinity (low p50). Accurate diagnosis requires recognition of typical clinical and laboratory findings. In this case-based review, we present two patients with altered oxygen affinity variants, illustrating barriers to prompt and accurate diagnosis, and issues in management. We then review pathophysiology, diagnostic tests, clinical features, and management strategies.

Strategies for eliciting and synthesizing evidence for guidelines in rare diseases.

BACKGROUND: Rare diseases are a global public health priority. Though each disease is rare, when taken together the thousands of known rare diseases cause significant morbidity and mortality, impact quality of life, and confer a social and economic burden on families and communities. These conditions are, by their nature, encountered very infrequently by individual clinicians, who may feel unprepared to address their diagnosis and treatment. Clinical practice guidelines are necessary to support clinical and policy decisions. However, creating guidelines for rare diseases presents specific challenges, including a paucity of high certainty evidence to inform panel recommendations. METHODS: This paper draws from the authors' experience in the development of clinical practice guidelines for three rare diseases: hemophilia, sickle cell disease, and catastrophic antiphospholipid syndrome. RESULTS: We have summarized a number of strategies for eliciting and synthesizing evidence that are compatible with the rigorous, internationally accepted standards for guideline development set out by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. These strategies include: use of pre-existing and ad hoc qualitative research, use of systematic observation forms, use of registry data, and thoughtful use of indirect evidence. Their use in three real guideline development efforts, as well as their theoretical underpinnings, are discussed. Avenues for future research to improve clinical practice guideline creation for rare diseases - and any disease affected by a relative lack of evidence - are also identified. CONCLUSIONS: Rigorous clinical practice guidelines are needed to improve the care of the millions of people worldwide who suffer from rare diseases. Innovative evidence elicitation and synthesis methods will benefit not only the rare disease community, but also individuals with common diseases who have rare presentations, suffer rare complications, or require nascent therapies. Further refinement and improved uptake of these innovative methods should lead to higher quality clinical practice guidelines in rare diseases.

Hb Grifton [α87(F8)His→Pro; HBA1: C.263A > C (or HBA2)] Causes Abnormal Pulse Oximetry Measurements.

An asymptomatic toddler and his mother consistently demonstrated low transcutaneous pulse oximetry (SpO2) measurements, discordant with normal arterial blood gas analyses while breathing room air. Previous evaluations by medical teams were unable to identify an etiology of their perceived hypoxia. Further investigation revealed that the boy carried an abnormal variant, Hb Grifton or α87(F8)His→Pro; HBA1: c.263A > C (or HBA2), discovered on newborn screening, which was not suspected as the underlying cause of his abnormal pulse oximetry readings until an inpatient admission to our hospital for asymptomatic "hypoxia," where he was found to share these same characteristics with his mother. We showed that a difference in light absorption between the oxygenated Hb Grifton variant and oxygenated Hb A resulted in erroneous pulse oximetry values. This phenomenon has previously been reported in a handful of other variant Hbs. Astute clinical suspicion, in conjunction with laboratory testing leading to correct diagnoses of variant Hbs, may prevent expensive work-ups and unnecessary medical treatments for asymptomatic patients falsely presumed to be hypoxemic based on low pulse oximetry measurements.

Haptoglobin testing in hemolysis: measurement and interpretation.

Haptoglobin is primarily produced in the liver and is functionally important for binding free hemoglobin from lysed red cells in vivo, preventing its toxic effects. Because haptoglobin levels become depleted in the presence of large amounts of free hemoglobin, decreased haptoglobin is a marker of hemolysis. Despite its ubiquity and importance, a paucity of literature makes testing difficult to interpret. This review highlights the many physiological roles that have been recently elucidated in the literature. Different methodologies have been developed for testing, including spectrophotometry, immunoreactive methods, and gel electrophoresis. These are covered along with their respective advantages and disadvantages. As there is no single gold standard for hemolysis, validation studies must rely on a combination of factors, which are reviewed in this article. Pitfalls and limitations of testing are also addressed. False positives can occur in improper specimen preparations, cirrhosis, elevated estrogen states, and hemodilution. False negatives can occur in hypersplenism and medications such as androgens and corticosteroids. Haptoglobin testing in the setting of inflammation is additionally discussed as interpretation can be difficult in this setting. Given the widespread use of haptoglobin testing, it is vital that clinicians and laboratory staff understand the principles and correct interpretation of this test.

Patient-important upper gastrointestinal bleeding in the ICU: A mixed-methods study of patient and family perspectives.

INTRODUCTION: The objective of this study was to create a definition of patient-important upper gastrointestinal bleeding during critical illness as an outcome for a randomized trial. DESIGN: This was a sequential mixed-methods qualitative-dominant multi-center study with an instrument-building aim. In semi-structured individual interviews or focus groups we elicited views from survivors of critical illness and family members of patients in the intensive care unit (ICU) regarding which features indicate important gastrointestinal bleeding. Quantitative demographic characteristics were collected. We analyzed qualitative data using inductive content analysis to develop a definition for patient-important upper gastrointestinal bleeding. SETTING: Canada and the United States. PARTICIPANTS: 51 ICU survivors and family members of ICU patients. RESULTS: Participants considered gastrointestinal bleeding to be important if it resulted in death, disability, or prolonged hospitalization. The following also signaled patient-important upper gastrointestinal bleeding: blood transfusion, vasopressors, endoscopy, CT-angiography, or surgery. Whether an intervention evinced concern depended on its effectiveness, side-effects, invasiveness and accessibility; contextual influences included participant familiarity and knowledge of interventions and trust in the clinical team. CONCLUSIONS: Survivors of critical illness and family members described patient-important upper gastrointestinal bleeding differently than current definitions of clinically-important upper gastrointestinal bleeding.

What counts as patient-important upper gastrointestinal bleeding in the ICU? A mixed-methods study protocol of patient and family perspectives.

INTRODUCTION: Clinically important upper gastrointestinal bleeding is conventionally defined as bleeding accompanied by haemodynamic changes, requiring red blood cell transfusions or other invasive interventions. However, it is unclear if this clinical definition reflects patient values and preferences. This protocol describes a study to elicit views from patients and families regarding features, tests, and treatments for upper gastrointestinal bleeding that are important to them. METHODS AND ANALYSIS: This is a sequential mixed-methods qualitative-dominant multi-centre study with an instrument-building aim. We developed orientation tools and educational materials in partnership with patients and family members, including a slide deck and executive summary. We will invite intensive care unit (ICU) survivors and family members of former ICU patients to participate. Following a virtual interactive presentation, participants will share their perspectives in an interview or focus group. Qualitative data will be analysed using inductive qualitative content analysis, wherein codes will be derived directly from the data rather than using preconceived categories. Concurrent data collection and analysis will occur. Quantitative data will include self-reported demographic characteristics. This study will synthesise the values and perspectives of patients and family members to create a new trial outcome for a randomised trial of stress ulcer prophylaxis. This study is planned for May 2022 to August 2023. The pilot work was completed in Spring 2021. ETHICS AND DISSEMINATION: This study has ethics approval from McMaster University and the University of Calgary. Findings will be disseminated via manuscript and through incorporation as a secondary trial outcome on stress ulcer prophylaxis. TRIAL REGISTRATION NUMBER: NCT05506150.

Severe fetal and neonatal hemolytic anemia due to a 198 kb deletion removing the complete ß-globin gene cluster.

Fetal and neonatal hemolytic anemia can be caused by (γδß)(0)-thalassemia deletions of the ß-globin gene cluster. Many of these deletions have not been well characterized, and diagnostic tests are not readily available, thus hampering carrier detection, family counseling, and antenatal diagnosis. We report and define a 198 kb deletion removing the entire ß-globin gene cluster, which was found in members of a multigeneration family of Irish/Scottish descent. The proband had life-threatening fetal and neonatal hemolytic anemia which subsided by 1 year of age.