Clinical spectrum of pyruvate kinase deficiency: data from the Pyruvate Kinase Deficiency Natural History Study

Abstract

An international, multicenter registry was established to collect retrospective and prospective clinical data on patients with pyruvate kinase (PK) deficiency, the most common glycolytic defect causing congenital nonspherocytic hemolytic anemia. Medical history and laboratory and radiologic data were retrospectively collected at enrollment for 254 patients with molecularly confirmed PK deficiency. Perinatal complications were common, including anemia that required transfusions, hyperbilirubinemia, hydrops, and prematurity. Nearly all newborns were treated with phototherapy (93%), and many were treated with exchange transfusions (46%). Children age 5 years and younger were often transfused until splenectomy. Splenectomy (150 [59%] of 254 patients) was associated with a median increase in hemoglobin of 1.6 g/dL and a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included higher presplenectomy hemoglobin ( = .007), lower indirect bilirubin ( = .005), and missense mutations ( = .0017). Postsplenectomy thrombosis was reported in 11% of patients. The most frequent complications included iron overload (48%) and gallstones (45%), but other complications such as aplastic crises, osteopenia/bone fragility, extramedullary hematopoiesis, postsplenectomy sepsis, pulmonary hypertension, and leg ulcers were not uncommon. Overall, 87 (34%) of 254 patients had both a splenectomy and cholecystectomy. In those who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy. Although the risk of complications increases with severity of anemia and a genotype-phenotype relationship was observed, complications were common in all patients with PK deficiency. Diagnostic testing for PK deficiency should be considered in patients with apparent congenital hemolytic anemia and close monitoring for iron overload, gallstones, and other complications is needed regardless of baseline hemoglobin. This trial was registered at www.clinicaltrials.gov as #NCT02053480.

Phase 1 Single‐ and Multiple‐Ascending‐Dose Randomized Studies of the Safety, Pharmacokinetics, and Pharmacodynamics of AG‐348, a First‐in‐Class Allosteric Activator of Pyruvate Kinase R, in Healthy Volunteers

“…15 Together, these studies, and AG-348, could contribute to advances in the treatment of PK deficiency, providing clinical benefits to patients with this rare chronic anemia and potentially to those with other conditions characterized by hemolytic anemia. Accordingly, DRIVE-PK, a multicenter study of the safety and efficacy of AG-348 in adults with PK deficiency, is ongoing (ClinicalTrials.gov: NCT02476916).…”

“…[6][7][8] The exact prevalence of PK deficiency is uncertain; estimates range from approximately 1 in 20 000 to approximately 1 in 485 000, [9][10][11][12] with higher prevalence in certain populations such as the Amish. 14,15 Chronic hemolysis results in iron overload and is a frequent complication of PK deficiency. Clinical features range from mild to severe and include anemia, jaundice, gallstones, and splenomegaly.…”

“…14,15 Chronic hemolysis results in iron overload and is a frequent complication of PK deficiency. 15,17 AG-348 is a novel, first-in-class, orally bioavailable, small-molecule allosteric activator of PK-R. 16 Current treatments are supportive only and include exchange transfusions and phototherapy for newborns and blood transfusions, splenectomy, and cholecystectomy as needed in children and adults.…”

Addressing the diagnostic gaps in pyruvate kinase deficiency: Consensus recommendations on the diagnosis of pyruvate kinase deficiency

“…Early onset of anemia is usually associated with a more severe clinical course. 4,42,44,45 Notably, since splenectomy is not indicated in some other forms of chronic hemolytic anemia, such as hereditary stomatocytosis, 46 the diagnosis of PK deficiency should be established and comorbidity of stomatocytosis or other thrombophilic disorders should be excluded before splenectomy is performed. The anemia tends to improve with age, and is relatively constant in adulthood, although exacerbations requiring occasional transfusion may occur because of the stress of acute infections or pregnancy.…”

Function and dysfunction

“…1 Using conditional Ezh2 deletion approaches, these investigators demonstrate that Ezh2 maintains appropriate levels of membrane-bound Kit ligand (mKitL) by repressing endothelial expression of matrix metallopeptidase 9 (Mmp9). These data provide a striking demonstration of how epigenetic factors not only act as cell-intrinsic regulators of hematopoietic stem cell (HSC) fate but can also impact cell-extrinsic signals provided by the hematopoietic niche.…”