Ringed sideroblasts in βâ thalassemia

Symptomatic βâ thalassemia is one of the globally most common inherited disorders. The initial clinical presentation is variable. Although common hematological analyses are typically sufficient to diagnose the disease, sometimes the diagnosis can be more challenging. We describe a series of patients with βâ thalassemia whose diagnosis was delayed, required bone marrow examination in one affected member of each family, and revealed ringed sideroblasts, highlighting the association of this morphological finding with these disorders. Thus, in the absence of characteristic congenital sideroblastic mutations or causes of acquired sideroblastic anemia, the presence of ringed sideroblasts should raise the suspicion of βâ thalassemia.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136352/1/pbc26324.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136352/2/pbc26324_am.pd

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.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154955/1/ajh25753.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154955/2/ajh25753_am.pd

Characterization of the severe phenotype of pyruvate kinase deficiency

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162766/2/ajh25926.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162766/1/ajh25926_am.pd

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

Fetal presentation of congenital dyserythropoietic anemia type 1 with novel compound heterozygous CDAN1 mutations

The congenital dyserythropoietic anemias are a heterogeneous group of disorders characterized by anemia and ineffective erythropoiesis. Congenital dyserythropoietic anemia type I (CDA1) can present in utero with hydrops fetalis, but more often it presents in childhood or adulthood with moderate macrocytic anemia, jaundice, and progressive iron-overload. CDA1 is inherited in an autosomal recessive manner, with biallelic pathogenic variants in CDAN1 or C15orf41. This case report documents a severe fetal presentation of CDA1 where we identified two novel compound heterozygous mutations in CDAN1 and describes the associated pathologic findings and levels of iron-regulatory proteins hepcidin, erythroferrone, and GDF15

Von Willebrand Factor for Menorrhagia: A Survey and Literature Review

Abstract Background: von Willebrand disease (VWD) is the most common congenital bleeding disorder. In affected women, menorrhagia is the most common bleeding symptom. Combined oral contraceptives (COCs), the first choice therapy recommended by NHLBI 2007 guidelines, reduce menstrual loss by increasing coagulation factor levels, but at least 30% are unresponsive or intolerant. Non-hormonal options include the antifibrinolytic tranexamic acid (TA), reduces menstrual bleeding by 30-50%, but requires dosing three times a day. Intranasal desmopressin (Stimate) is simpler to use, but ineffective in ~20%. Effective treatment for menorrhagia, thus, remains the greatest unmet health need in women with VWD. Von Willebrand factor (VWF) is used typically when first-line and second-line treatments fail, but few data exist regarding its effectiveness in reducing menorrhagia. Methods: We therefore conducted a survey of U.S. hemophilia treatment centers (HTCs) of current therapy for menorrhagia in VWD, utilizing Centers for Disease Control (CDC) website https://www2a.cdc.gov/ncbddd/htcweb/Main.asp, and the Hemostasis and Research Society (HTRS) site http://htrs.org. To specifically assess the use of VWF concentrate for menorrhagia, we also performed a literature review using medical subject heading (MeSH) search terms "von Willebrand factor," "menorrhagia," and "von Willebrand disease." Statistical analysis was by descriptive statistics. Results: Of 83 surveys distributed to hemophilia treatment centers (HTCs) caring for adult patients, 35 HTC MDs responded (42.2%) but only 20 HTC MDs (24.1%) provided sufficient data for analysis. These 20 HTC MDs reported a total of 1,321 women with VWD age 18-45 years seen during the 3-year period 2011-2014, of whom 816 (61.8%) had menorrhagia. Among these women, the most common first-line therapy was COCs, reported by 50.0% of the 20 HTC MDs, TA in 30.0% and desmopressin (DDAVP) in 20.0%. Overall, including all therapies (first-, second-, third-line), DDAVP was prescribed by 90.0% of the 20 HTC MDs, TA in 80.0%, COCs in 70.0%, aminocaproic acid (amicar) in 25.0%, and the levonorgestrel-releasing intrauterine system (Mirena IUD) in 15.0%. Only 4 HTC MDs (20.0%) prescribed VWF concentrate (VWF) for menorrhagia: all used VWF as third-line therapy after first-line and second-line treatments had failed. In the 13 women with type 1, 2, or 3 VWD and menorrhagia treated with intravenous VWF by these 4 HTC MDs, there was reduction in menorrhagia in all 13 (100%), with no adverse effects. These patients learned intravenous technique and infused VWF at 40-50 IU/kg at home for up to 5 days of menstrual bleeding each cycle, with good acceptability. In the literature search, we identified six published studies, including two prospective clinical trials, two retrospective observational trials, and two observational network studies. A total of 455 subjects with VWD reported in these six studies were treated with either plasma-derived (pdVWF) or recombinant (rVWF) VWF for bleeds. Of these, nearly one-third or 138 (30.3%) were women with type 1, 2, or 3 VWD and menorrhagia who were treated with pdVWF or rVWF at a dose of 36-50 IU/kg for 1-6 days of menstrual cycle bleeding. In these studies, 95-100% of these women reported reduction in menorrhagia, with no reported adverse events. Discussion: This survey and literature review of 151 women with VWD and menorrhagia represent the largest treatment experience to date. DDAVP, TA, and COCs are the most common first-line therapies. VWF is a third-line therapy but safely and effectively reduces menorrhagia in at least 95% of women with VWD. Prospective clinical trials of VWF are needed to establish the minimal dose required for menorrhagia, to determine patient acceptability of this intravenous therapy, and to compare safety and efficacy with standard therapy. Disclosures Off Label Use: recombinant VWF and plasma-derived VWF for treatment of menorrhagia in VWD. Ragni:Bristol Myers Squibb: Research Funding; Biogen: Research Funding; Bayer: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; Dimension Therapeutics: Research Funding; CSL Behring: Research Funding; Foundation Women Girls Blood Disorders: Membership on an entity's Board of Directors or advisory committees; Genentech Roche: Research Funding; Medscape, Web MD: Honoraria; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; SPARK: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; Ferring Pharmceuticals: Research Funding; Biomarin: Research Funding; Vascular Medicine Institute: Research Funding. Malec:Baxalta: Research Funding; Biogen: Research Funding. Coyle:Bayer: Membership on an entity's Board of Directors or advisory committees. Drygalski:Biogen: Consultancy; Baxalta: Consultancy; Novo Nordisk: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Hematherix Inc: Equity Ownership; Biogen: Research Funding; Baxalta: Research Funding; Novo Nordisk: Research Funding; Bayer: Research Funding; CSL Behring: Speakers Bureau; Hematherix Inc: Membership on an entity's Board of Directors or advisory committees. James:CSL Behring: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees. Jobe:Biogen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Membership on an entity's Board of Directors or advisory committees. Konkle:Octapharma: Research Funding; Baxalta: Consultancy; CSL Behring: Consultancy; Baxalta: Research Funding. Kouides:CSL Behring: Membership on an entity's Board of Directors or advisory committees. Kuriakose:Kedrion: Speakers Bureau. Ma:Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Nance:Patient Services, Inc.: Membership on an entity's Board of Directors or advisory committees. Neff:Alexion: Membership on an entity's Board of Directors or advisory committees; Novonordisk: Research Funding; Baxter: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novonordisk: Membership on an entity's Board of Directors or advisory committees. Philipp:Baxter: Research Funding. Yaish:Agios: Membership on an entity's Board of Directors or advisory committees

Pyruvate kinase deficiency in children

BackgroundPyruvate kinase deficiency (PKD) is a rare, autosomal recessive red blood cell enzyme disorder, which leads to lifelong hemolytic anemia and associated complications from the disease and its management.MethodsAn international, multicenter registry enrolled 124 individuals younger than 18 years old with molecularly confirmed PKD from 29 centers. Retrospective and prospective clinical data were collected.ResultsThere was a wide range in the age at diagnosis from 0 to 16 years. Presentation in the newborn period ranged from asymptomatic to neonatal jaundice to fulminant presentations of fetal distress, myocardial depression, and/or liver failure. Children 12 to <18 years (53% vs. 14%, p = .0006), which correlated with the timing of splenectomy. Regular transfusions were most common in children with two severe PKLR variants. In regularly transfused children, the nadir hemoglobin goal varied considerably. Impact on quality of life was a common reason for treatment with regular blood transfusions and splenectomy. Splenectomy increased the hemoglobin and decreased transfusion burden in most children but was associated with infection or sepsis (12%) and thrombosis (1.3%) even during childhood. Complication rates were high, including iron overload (48%), perinatal complications (31%), and gallstones (20%).ConclusionsThere is a high burden of disease in children with PKD, with wide practice variation in monitoring and treatment. Clinicians must recognize the spectrum of the manifestations of PKD for early diagnostic testing, close monitoring, and management to avoid serious complications in childhood.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/168466/1/pbc29148_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/168466/2/pbc29148.pd