Bone Marrow Failure Disorders

Section Editor

Natasha L. Johnson, MSN, APRN, AOCNP®

Moffitt Cancer Center

Case Study

Identification and Management of Pyruvate Kinase Deficiency

Presentation and History
The patient is a 50-year-old female with a past medical history of chronic hemolytic anemia due to pyruvate kinase deficiency (PKD) diagnosed in early childhood. She has post-splenectomy status (asplenic) with subsequent thrombocytosis. She requires red blood cell (RBC) transfusion when her hemoglobin (Hgb) level is < 9 g/dL and is unable to tolerate erythropoiesis-stimulating agents, with a history of reactions. She suffers from iron overload due to frequent RBC transfusions, and for a variety of reasons does not tolerate iron chelation therapy well.

She makes monthly clinic visits for lab assessment and transfusion support for PKD. At a recent visit, she admits to not taking the iron chelating agent deferasirox as prescribed due to frequent diarrhea and difficulty obtaining insurance approval for the newer formulation despite understanding the purpose of this drug and the potential consequences of iron overload.

Relevant laboratory and clinical findings are as follows: CBC: WBC 13.7, Hgb 8.4, platelets 496,000, elevated mean corpuscular volume. Reticulocytosis and elevated total bilirubin are chronically present. Lactate dehydrogenase levels are normal, and a Coombs test is negative. The patient has chronic jaundice. Her ferritin levels have exceeded 1000 ng/mL for many years, and her most recent ferritin level was 1447 ng/mL.

Differential Diagnosis
Differential diagnoses for PKD include:

  • Inherited RBC enzyme deficiencies such as glucose-6-phospate dehydrogenase deficiency and deficiencies of other glycolytic pathway enzymes including glutathione synthase deficiency, associated with Heinz bodies; pyrimidine-5'-nucleotidase-1 deficiency; and glucose-6-phosphate isomerase deficiency.
  • Inherited anemias such as hemoglobinopathies (disorders due to Hgb mutations, eg, sickle cell disease), unstable hemoglobins and rare hemoglobin H disease, or RBC membrane defects (eg, disorders due to mutations in membrane components, such as hereditary spherocytosis or hereditary elliptocytosis); and
  • Congenital dyserythropoietic anemias and other intrinsic and extrinsic causes of acquired hemolysis.

Diagnosis and Recommendations for Treatment
A diagnosis of PKD should be suspected in individuals with unexplained anemia or hemolysis who have a family history of PKD. Suspicion of PKD is also warranted in patients who have a Coombs-negative congenital hemolytic anemia without morphological abnormalities that are present in other conditions of congenital anemias. Work-up includes laboratory testing to confirm Coombs-negative hemolytic anemia and rule out other possible etiologies. Subsequent testing includes testing for PKD by measuring pyruvate kinase activity in RBCs, with low activity indicating the presence of PKD. Testing can also be targeted at identifying a pathogenic mutation of the PKLR gene. This test is performed at specialized laboratories.

Treatment is aimed at supportive care rather than cure. Infants with bilirubinemia should receive phototherapy. In patients 5 years and older who require frequent blood transfusion or have symptomatic anemia, splenectomy is an option to reduce RBC destruction. Patients who undergo splenectomy should be given pneumococcal vaccine as prophylaxis. Gallbladder monitoring needs to be performed, and cholecystectomy may be considered at the time of splenectomy and in patients with symptomatic gallstones. To support bone health, supplementation with folic acid, vitamin D, and calcium can be considered, and patients should be encouraged to exercise. Genetic counseling is recommended for patients with families.

Mitapivat, an allosteric activator of RBC pyruvate kinase, was studied in the phase 3 ACTIVATE-T trial in 27 regularly transfused adults with PKD; use of this agent was associated with a statistically significant and clinically meaningful 33% reduction in predefined transfusion burden. Similarly, results from ACTIVATE, a global, randomized, double-blind, placebo-controlled phase 3 trial of mitapivat in adults with PKD who do not receive regular transfusions, showed 40% of patients randomized to mitapivat achieved Hb response, defined as a ≥ 1.5 g/dL sustained increase in Hb concentration from baseline, compared with 0 patients randomized to placebo. The manufacturer of mitapivat (Agios Pharmaceuticals, Inc.) announced FDA acceptance and priority review of mitapivat for treatment of adults with PKD in August 2021.

Iron overload is a serious concern in patients with PKD. It results from increased iron absorption due to ineffective erythropoiesis and can also be caused by frequent blood transfusions. Iron overload can lead to serious organ toxicity to the liver, heart, and endocrine organs. Patients' iron levels need to be checked periodically, and iron chelation therapy should be implemented for patients with early signs of iron overload. The advanced practice provider should educate the patient about the variety of available chelating agents, common side effects of chelation therapy, prevention/management of these side effects, and most importantly, the rationale for treating iron overload.

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