Approach Considerations
In patients with mild to moderate pyruvate kinase deficiency, care is predominantly supportive. High-impact contact sports are contraindicated in patients with significant splenomegaly.
Red blood cell transfusion may be necessary if the hemoglobin value falls significantly; this tends to occur in early childhood and during periods when physiologic stress is present, such as when an infection exists or during pregnancy. Approximately 53% of patients younger than age 5 years require regular transfusions, as do approximately 31% of those age 5-12 years. [3]
Iron chelation therapy may be necessary, especially for patients who receive frequent transfusions. Splenectomy is used in patients with severe anemia or symptomatic hypersplenism.
An international, multicenter registry that collected clinical data on patients with pyruvate kinase deficiency found that 93% of newborns were treated with phototherapy, and 46% were treated with exchange transfusions. Splenectomy was performed in 150 of 254 patients, or 59%, and was associated with a median increase in hemoglobin levels of 1.6 g/dL along with a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included higher presplenectomy hemoglobin, lower indirect bilirubin, and missense PKLR mutations. In total, 87 of 254 patients, or 34%, had both a splenectomy and cholecystectomy. In patients who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy. [6]
In pregnant patients with pyruvate kinase deficiency, uncomplicated pregnancy, delivery, and birth have been reported despite a decline in the hemoglobin value to 6.8 g/dL during pregnancy. [35] In one study of pregnant patients, significant puerperal jaundice was successfully treated with conservative measures. [36]
Supplemental folic acid and other B vitamins help to prevent deficiencies from increased erythrocyte production.
Mitapivat (Pyrukynd) is a pyruvate kinase activator that acts by allosterically binding to pyruvate kinase tetramer and increasing pyruvate kinase activity. It was approved for treatment of adults with hemolytic anemia due to pyruvate kinase deficiency by the US Food and Drug Administration in February 2022. [37]
Large doses of salicylates should be avoided in patients with severe anemia, because these inhibit oxidative phosphorylation, thereby causing further ATP depletion.
in preclinical studies, gene therapy for pyruvate kinase deficiency has demonstrated encouraging efficacy and safety. [7, 38]
Case reports describe successful liver transplantation in patients with severe progressive liver failure due to pyruvate kinase deficiency. [39, 40] Isolated reports of hematopoietic allogeneic stem cell transplantation (HSCT) for pyruvate kinase deficiency have been published. [41] However, HSCT is not considered a standard therapy for this disease; no defined conditioning regimen has been established, and the procedure is associated with extensive toxicity and incomplete engraftment. [38]
Activity
Patients with hemoglobin levels close to or slightly below the reference range can tolerate normal daily activities. Those with severe anemia demonstrate exercise intolerance, and their activity is limited as a result.
Transfusion
Transfusions can be used as follows in the management of pyruvate kinase deficiency:
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Intrauterine transfusion: Required in most patients with extremely severe fetal anemia associated with hydrops fetalis
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Phototherapy or exchange transfusion: Required for most newborns with severe hyperbilirubinemia
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Simple blood transfusion: Administered for anemia during early childhood and, occasionally, into adulthood.
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Sporadic blood transfusions: Required in most older patients when anemia becomes severe during infectious episodes, aplastic crisis, or pregnancy
Medical Care
Pharmacotherapy
Mitapivat, a first-in-class pyruvate kinase (PK) activator, improves hemoglobin values and reduces transfusion burden in adult patients with hemolytic anemia associated with pyruvate kinase deficiency by targeting the underlying defect. [10, 37] Mitapivat acts by allosterically binding to pyruvate kinase tetramer and increasing PK activity.
Iron chelation
Patients with PK deficiency can develop iron overload, even if they are not receiving transfusions. [42] Iron stores can be assessed by magnetic resonance imaging (MRI) scans of the liver and measurement of serum ferritin and transferrin saturation. In patients not receiving regular transfusions, ferritin should be measured annually; MRI, if available, should be performed once the patient is old enough to undergo the study without sedation and/or has a ferritin level > 500 μg/L and should be repeated annually if the liver iron concentration is > 5 mg/g and every 5 years in those with liver iron < 5 mg/g. In patients receiving regular transfusions, iron load should be assessed after 10-14 transfusions. Chelation therapy should be strongly considered if the ferritin concentration is > 800 μg/L and transferrin saturation > 60%. [3]
Splenectomy
Splenectomy is indicated only for patients with severe anemia or symptomatic hypersplenism. The procedure does not abolish hemolysis or improve mild anemia, but it can reduce severe anemia and is frequently performed to minimize or eliminate the patient's need for blood transfusions. Partial splenectomy has been used, but lack of efficacy has been reported in patients with pyruvate kinase deficiency. [43] The most appropriate age for splenectomy in patients with pyruvate kinase deficiency is from age 5 to 18 years; before age 5 years, splenectomy poses increased risk for sepsis from encapsulated bacteria. [3]
Procedure
Patients who require splenectomy should usually be prepared by starting prophylactic antibiotics before surgery.
Splenectomy should be performed by an experienced surgeon, especially in pediatric patients. After the surgery, the patient’s hemoglobin concentration typically increases by 1-3 g/dL. Transfusion requirements typically decrease, the danger of an aplastic crisis with infection is reduced, and growth delay, if present, may be reversed and catch-up growth ensue. Prophylactic antibiotics should be administered to young patients postsplenectomy. [44] Always monitor patients with splenectomies for possible fulminating infection.
Partial splenectomy
Partial splenectomy is used to preserve some splenic function and to protect against the following consequences of asplenia:
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Fulminating sepsis with encapsulated organisms: Streptococcus pneumoniae (in > 60%), Haemophilus influenzae, and Neisseria meningitidis
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Streptococcal and staphylococcal infections (which affect such patients with less frequency)
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Malaria and babesiosis (in endemic regions)
The procedure is very effective in persons with spleen trauma and in individuals with some of the hemolytic anemias.
Vaccination
Patients undergoing splenectomy should receive vaccines against the following encapsulated bacteria, preferably at least 14 days before or 14 days after surgery:
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Pneumococcal 13-valent conjugate (Prevnar 13)
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Haemophilus influenzae type b vaccine: The conjugate form is usually administered to children at age 2, 4, and 6 months; children who have already received their initial and 12-month booster doses are usually immune and do not require further vaccination before splenectomy
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Meningococcal vaccine (Menactra)
Hematopoietic Stem Cell Transplantation
Although hematopoietic stem cell transplantation may cure the defect in pyruvate kinase deficiency, the risks of the procedure outweigh those of the disease. Nonetheless, 16 cases of HSCT for pyruvate kinase deficiency have been reported from Europe and Asia; 5 of the 16 patients died, all from transplant-related causes. Compared with non-survivors, survivors were significantly younger (age < 10 years), were less likely to have undergone splenectomy, and had lower pre-transfusion hemoglobin levels prior to HSCT. [41]
Consultations
When necessary, the following specialists should be consulted:
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Hematologist: For management and treatment
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Surgeon: If splenectomy is considered
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Anesthesiologist: For presurgical management if anemia is severe
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Gastroenterologist: To help evaluate complications of the biliary tree
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Peripheral blood smear in a child with splenectomy and pyruvate kinase deficiency.
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The Embden-Meyerhof pathway.
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Pyruvate kinase in the Embden-Meyerhof pathway.
