Pyruvate Kinase Deficiency 

Updated: Feb 22, 2019
Author: Hassan M Yaish, MD; Chief Editor: George T Griffing, MD 

Overview

Practice Essentials

Pyruvate kinase deficiency, one of the most common enzymatic defects of the erythrocyte, manifests clinically as a hemolytic anemia that can range from a mildly compensated anemia to severe anemia of childhood. It is caused by mutations in the PKLR gene. Surprisingly, however, the symptomatology is less severe than hematologic indices indicate. This is presumably due to enhanced oxygen delivery as a result of the defect.[1, 2, 3, 4, 5, 6, 7]

Most affected individuals do not require treatment, although in the most severe cases, death may occur in utero as a result of anemia, or blood transfusions or splenectomy may be required, but most of the symptomatology is limited to early life and to times of physiologic stress or infection.

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]

(See the image below.)

Peripheral blood smear in a child with splenectomy Peripheral blood smear in a child with splenectomy and pyruvate kinase deficiency.

Signs and symptoms

The following are evident in pyruvate kinase deficiency:

  • Mild to severe normochromic and normocytic anemia

  • Reticulocytosis

  • Symmetrical growth delay

  • Failure to thrive

  • Cholecystolithiasis: Usually after the first decade of life but possibly in childhood

  • Frontal bossing

  • Hyperbilirubinemia in the newborn

  • Icteric sclera

  • Mild to moderate splenomegaly

  • Upper-right-quadrant tenderness

  • Murphy sign

  • Chronic leg ulcers (adults)

The birth history of patients with pyruvate kinase deficiency includes severe anemia, severe jaundice,[8] kernicterus, and a history of exchange transfusion.

Diagnosis

The minimal tests required to guide the investigation of pyruvate kinase deficiency include the following:

  • Complete blood count (CBC)

  • Differential blood count

  • Reticulocyte count

  • Serum bilirubin level study

  • Peripheral blood film examination

Normochromic, normocytic, or macrocytic anemia, together with reticulocytosis in the absence of blood loss, is suggestive of hemolysis. A negative Coombs test result helps to exclude immune hemolysis.

The enzyme activity rate in most patients with pyruvate kinase deficiency is 5-25% of normal, with measurement of the intermediates (2,3-diphosphoglycerol and glucose-6-phosphate) proximal to the enzyme defect helping to confirm the diagnosis.

Other findings include the following:

  • Normoblastic erythroid hyperplasia of the bone marrow

  • Extramedullary hematopoiesis

  • Splenic and hepatic hemosiderosis and splenic congestion

  • Reticuloendothelial hyperplasia

  • Erythrophagocytosis

  • Increased iron stores

Enzyme assay, as well as deoxyribonucleic acid (DNA) analysis with a polymerase chain reaction (PCR) assay or single-strand conformation polymorphism, can also be used to confirm the diagnosis of pyruvate kinase deficiency.

Management

In patients with mild to moderate pyruvate kinase deficiency, care is predominantly supportive. Red blood cell transfusion may be necessary if the patient’s hemoglobin value falls significantly.

Supplemental folic acid is used extensively in individuals with hemolytic anemia to prevent the development of megaloblastic anemia.

Splenectomy

Splenectomy is indicated only for patients with severe anemia.[9] 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 transfusion.

Pathophysiology

Embden-Meyerhof pathway

Erythrocytes (mature red blood cells) completely depend on glucose as a source of energy. Glucose is usually catabolized to pyruvate and lactate in the Embden-Meyerhof pathway, which is the major anaerobic glycolytic pathway. In the process, adenosine triphosphate (ATP), which is essential to providing the erythrocyte with energy, is generated. ATP plays a major role in maintaining a cation gradient in the erythrocyte, thus protecting the cell from premature death.

Pyruvate kinase catalyzes the conversion of phosphoenolpyruvate to pyruvate in the Embden-Meyerhof pathway, resulting in the production of ATP.

(See the images below.)

The Embden-Meyerhof pathway. The Embden-Meyerhof pathway.
Pyruvate kinase in the Embden-Meyerhof pathway. Pyruvate kinase in the Embden-Meyerhof pathway.

Erythrocytes in pyruvate kinase deficiency

In pyruvate kinase deficiency, an erythrocyte enzymopathy, a metabolic block is created in the Embden-Meyerhof pathway at the level of the deficient enzyme. Intermediate byproducts and various glycolytic metabolites proximal to the metabolic block accumulate in the erythrocyte, while the erythrocyte becomes depleted of the distal products in the pathway, such as lactate and ATP.

The lack of ATP disturbs the cation gradient across the erythrocytic cell membrane, causing the loss of potassium and water, which results in cell dehydration, contraction, and crenation (echinocytes) and leads to premature destruction of the erythrocyte.

Despite the resulting severe anemia, however, the high level of 2,3-diphosphoglycerate (2,3-DPG) increases the patient's exercise tolerance by causing a rightward shift in the hemoglobin-oxygen dissociation curve.

This is particularly advantageous during pregnancy because it enhances the transfer of oxygen to fetal blood, and it most likely adds to the particularly benign course of pyruvate kinase deficiency in many affected individuals. Women with the disorder typically do not require transfusions during pregnancy.

Pyruvate kinase–deficient reticulocytes can circumvent their defect by using the oxidative phosphorylation pathway to produce ATP. This ability is diminished when the reticulocytes are exposed to hypoxia or when they mature into erythrocytes. This may explain (1) the ineffective erythropoiesis in the spleen of patients with pyruvate kinase deficiency, (2) why most of the hemolysis occurs when the reticulocytes are trapped in the hypoxic environment of the spleen, and (3) the paradoxic increase in reticulocytes after splenectomy.

(See the image below.)

Peripheral blood smear in a child with splenectomy Peripheral blood smear in a child with splenectomy and pyruvate kinase deficiency.

Isoenzymes

Pyruvate kinase exists as 4 isoenzymes. Two isoenzymes (PKM1 and PKM2) are encoded by a genetic locus on band 15q22 and are found in striated muscle, the brain, fetal tissue, leukocytes, platelets, lungs, the spleen, the kidneys, and adipose tissue. The other 2 isoenzymes (PKL and PKR) are encoded by a genetic locus on band 1q21 and are found in the liver, normoblasts, reticulocytes, and erythrocytes.[10, 11, 12, 13] The liver and erythroid precursors are capable of activating PKM2 activity, but this is not the enzyme used under normal conditions.[14]

In persons with pyruvate kinase deficiency, band 1q21 is defective, resulting in deficient liver and red blood cell isoenzymes. The liver can compensate for the genetic defect in 2 ways. First, because the enzyme deficiency results in a less efficient enzyme rather than a nonfunctioning one, a greater quantity of enzyme can be produced. In addition, the liver can use residual PKM2 activity. Early in maturation, erythroid precursors use the PKM2 isoenzyme. As the cell matures, however, the PKR isoenzyme replaces the PKM2 enzyme. Because the erythrocyte cannot produce any new protein, it cannot compensate by increasing the quantity of isoenzyme or by using residual PKM2 isoenzyme.

Enzyme defects that have been described include decreased substrate affinity, increased product inhibition, decreased response to activator, and thermal instability. Mutations that strongly perturb enzyme kinetics and thermostability are associated with severe pyruvate kinase deficiency.[15] One severe form of the disease, pyruvate kinase Beppu, is associated with persistence of the PKM2 isoenzyme.

Iron overload

Iron overload is a serious, but not an unusual, complication in pyruvate kinase deficiency, even in patients not receiving chronic transfusion. These patients are not different from others with chronic hemolysis, who tend to absorb more iron regardless of their iron storage status because of the associated active erythropoiesis. Patients with iron overload not related to chronic hemolysis, such as in hemochromatosis, are usually protected from absorbing more iron.

The cause of such discrepancy was not clear until the discovery that a hepatic peptide known as hepcidin is a negative master regulator of iron absorption and release. In inflammation, the upregulated hepcidin prevents iron absorption, whereas, in iron deficiency anemia, a down-regulated hepcidin allows iron to be absorbed.

The loss of protection against iron absorption in patients with iron overload who have chronic hemolysis has been shown to be mediated by growth differentiation factor 15 (GDF15), a marrow factor that abrogates the effect of hepcidin.[16] In a study, the hepcidin level in patients with pyruvate kinase deficiency was 13-fold less than in the control group, whereas GDF15 was significantly higher in patients with pyruvate kinase than in control subjects.

Etiology

Acquired pyruvate kinase deficiency

Medical conditions such as acute leukemia, preleukemia, and refractory sideroblastic anemia, as well as complications from chemotherapy, can cause an acquired pyruvate kinase deficiency. This type is more common and milder than the hereditary type.

Hereditary pyruvate kinase deficiency

More than 180 genetic defects of the PK gene have been detected.[10, 11, 13, 17] Most of these are missense mutations, but splicing mutations, insertions, and deletions also have been identified. Although inheritance is clinically autosomal recessive, most affected individuals are compound heterozygous for 2 different mutant alleles. Homozygous individuals are usually the product of consanguineous mating.[13, 18, 19]

Heterozygotes have intermediate enzyme levels and are usually asymptomatic, while homozygotes manifest the clinical symptoms of pyruvate kinase deficiency.

The severity of the condition varies even among patients with the same level of deficiency because, in addition to the symptomatic homozygotes, compound heterozygotes with 2 different mutations (one can be qualitative and the other quantitative) also vary symptomatically.

Epidemiology

Occurrence in the United States

Pyruvate kinase deficiency and glucose-6-phosphate deficiency (G6PD) are the most common erythrocyte enzymopathies, with pyruvate kinase deficiency being the most common enzymopathy of anaerobic glycolysis. The prevalence rate of heterozygous carriers of 1 deficient PK gene is believed to be approximately 1%, although a population survey in Ann Arbor, Michigan, revealed a rate of 0.14%. Beutler and Gelbart estimated the incidence of PKD in the United States to be 1:20,000. It is known, however, that the incidence is much higher in remote and exclusive communities such as the Amish in Pennsylvania and Ohio and some communities in southern Utah.[20]

US population screening for the 4 most common gene mutations in pyruvate kinase deficiency demonstrated an estimated prevalence of 51 cases per million persons in the white population.[20] This is 50 times higher than the number of individuals who were diagnosed with the disease at a major pyruvate kinase assay laboratory in the United States over a 25-year period, suggesting that the deficiency is underdiagnosed.

As previously indicated, pyruvate kinase deficiency is particularly common among the Pennsylvania Amish, in whom the disorder can be traced to a single immigrant couple. Affected individuals can have severe, life-threatening manifestations and may require long-term transfusion therapy and splenectomy in early childhood.[21, 22]

International occurrence

Although pyruvate kinase deficiency occurs worldwide, most cases have been reported in northern Europe and Japan, as well as in the United States. In India, a study to screen newborns with jaundice for the presence of pyruvate kinase deficiency determined that 3.21% of all newborns with jaundice also had the deficiency, with a 30-40% reduction found in pyruvate kinase activity.[23]

Frequent reports of the predominance of pyruvate kinase deficiency in individuals of northern European ancestry can be questioned based on the increased number of cases that have been reported in different countries and in various non–northern European ethnic groups. Increased access to advanced medical facilities by these groups is assumed to be responsible for many of the reports, indicating that the prevalence of pyruvate kinase deficiency previously reported in persons of northern European ancestry matches that in persons of other ethnicities.[24]

The prevalence rate of heterozygous carriers with 1 deficient PK gene has been estimated to be 1% in Germany, 6% in Saudi Arabia, and 3% in Hong Kong.

Race-related demographics

The particular mutation responsible for pyruvate kinase deficiency differs between populations. For example, the 1529A mutation is believed to cause at least 1 gene mutation in most affected white persons from the United States and Europe. Other individuals, such as Portuguese, Spanish, and Italian persons, are affected by the 1456T, a mutation that impairs kinetic properties of the enzyme, resulting in a much milder clinical course . The authors have described a compound heterozygote for the known G1529A and a novel, previously undescribed frame shift mutation (1573 del T) whose clinical course was moderately severe, requiring several transfusions in the neonatal period (submitted for publication). Asian persons in the United States appear to be affected by the 1468T mutation.

Age-related demographics

The age of onset for inherited pyruvate kinase deficiency correlates with severity. Persons with severe disease usually have onset in the neonatal period or infancy. In most affected persons, the disorder is detected during childhood, but in individuals who are mildly affected, it may not be detected until late adulthood.

Acquired pyruvate kinase deficiency is usually secondary to a particular disease. In such cases, the age of onset varies with the primary disease.

Prognosis

PKD is associated with a wide range of morbidities. Some patients present with a mild, compensated, chronic hemolytic anemia that does not require medical intervention; others present with a severe hemolytic anemia that, in most cases, requires only transfusions during childhood.

Morbidity and mortality correlate with disease severity and usually depend on complications. Mild and moderate forms of the disease are associated with an excellent prognosis. Severe forms of the disease are mostly symptomatic during early childhood. Following early childhood, the disorder is much better tolerated. Hydrops fetalis has been reported in a severely affected fetus.[25]

Morbidity and mortality

Complications associated with pyruvate kinase deficiency include the following:

  • Cholecystolithiasis is common in the first decade of life in children with severe anemia

  • Splenectomy increases the risk of sepsis by encapsulated bacteria in children and the risk of thromboembolic disease in adults[26]

  • Sudden worsening of anemia associated with viral infections (eg, parvovirus B19) can occur, leading to a transient decrease in red cell production (ie, aplastic crisis)

  • Severe anemia may result in heart failure

  • Ischemic stroke has been reported in previously undiagnosed young adults with pyruvate kinase deficiency[27]

  • Multiple transfusion therapy can cause iron overload[28, 29]

  • Blood transfusions expose a person to the risk of contracting certain infections that are not well detected (eg, human immunodeficiency virus (HIV) disease, hepatitis C)

  • Repeated transfusions during pregnancy increase the risk of alloimmunization, which may lead to fetal complications

Morbidity in the newborn with pyruvate kinase deficiency is usually the result of severe anemia, hyperbilirubinemia, or both combined with the adverse effects associated with the management of such conditions. A report from the Netherlands described a fatal outcome in 2 newborns who suffered liver failure as a result of very severe pyruvate kinase–deficient hemolytic anemia. No other explanation for the liver failure was identified.[30]

Patient Education

Patients should understand their need to regularly use folic acid and vitamin B supplements and to avoid salicylates.

The risk regarding splenectomy versus that of multiple transfusions should be discussed with the parents of children with severe anemia. If a child has splenomegaly, parents should be instructed to have the child refrain from participating in contact sports.

Because the inheritance of pyruvate kinase deficiency is phenotypically autosomal recessive, parents and patients should be informed that the risk of recurrence is low.

 

Presentation

History and Physical Examination

The birth history of patients with pyruvate kinase deficiency includes severe anemia, severe jaundice,[8] kernicterus, and a history of exchange transfusion. The patient’s family history will be consistent with autosomal recessive inheritance. Patients may become symptomatic during times of physiologic stress, including during acute illness (particularly viral disorders) and pregnancy.

The following are evident in pyruvate kinase deficiency:

  • Mild to severe anemia

  • Symmetrical growth delay

  • Failure to thrive

  • Cholecystolithiasis: Usually after the first decade of life but possibly in childhood

  • Frontal bossing

  • Icteric sclera

  • Mild to moderate splenomegaly

  • Upper-right-quadrant tenderness

  • Murphy sign

  • Chronic leg ulcers

 

DDx

Diagnostic Considerations

Neonates with jaundice caused by pyruvate kinase deficiency may respond to phototherapy and, later, follow a mild clinical course. In such cases, the jaundice may be mistakenly attributed to other, more common causes.

In the newborn with jaundice and anemia, immune hemolysis (eg, ABO or Rh incompatibility) is easily identified. A diagnosis of pyruvate kinase deficiency is favored based on a negative Coombs test result, blood group setups, and a peripheral blood film examination that demonstrates no spherocytes but reveals contracted, shrunken, spiculated red cells (echinocytes) of the pyruvate kinase deficiency.

(See the image below.)

Peripheral blood smear in a child with splenectomy Peripheral blood smear in a child with splenectomy and pyruvate kinase deficiency.

A normal osmotic fragility (which has its limitation in the newborn) may help to differentiate pyruvate kinase deficiency from hereditary spherocytosis.

Other congenital hemolytic anemias of the nonspherocytic type, hemoglobinopathies, other enzyme deficiencies, and some thalassemic syndromes must also be differentiated from pyruvate kinase deficiency. Specific tests and family history may help in this.

In older children, autoimmune hemolytic anemia may also manifest with symptoms that are similar to pyruvate kinase deficiency and, therefore, must be considered in the differential diagnosis. A positive Coombs test result, the presence of spherocytes, and the absence of typical pyruvate kinase ̶ deficient cells on the peripheral blood film examination are the main features that differentiate the conditions.

Differentials

Anemia, Acute

Anemia, Chronic

Carnitine Deficiency

Glycogen-Storage Disease Type III

Hemoglobin H Disease

Hydrops Fetalis

Pyruvate Carboxylase Deficiency

Pyruvate Dehydrogenase Complex Deficiency

Thalassemia

Thalassemia Intermedia

 

Workup

Approach Considerations

Prenatal enzymatic testing is not optimal, because a large amount of fetal blood is required, and the test has a high rate of false-negative results.

The minimal tests required to guide the investigation of pyruvate kinase deficiency include the following:

  • Complete blood count (CBC)

  • Differential blood count

  • Reticulocyte count

  • Serum bilirubin level study

  • Peripheral blood film examination

Normochromic, normocytic, or macrocytic anemia, together with reticulocytosis in the absence of blood loss, is suggestive of hemolysis. A negative Coombs test result helps to exclude immune hemolysis.

An elevated direct bilirubin level in the presence of indirect hyperbilirubinemia is not unusual in individuals with pyruvate kinase deficiency and does not necessarily indicate cholestasis, primary liver disease, or biliary obstruction.[28, 29]

Other findings include the following:

  • Normoblastic erythroid hyperplasia of the bone marrow

  • Extramedullary hematopoiesis

  • Splenic and hepatic hemosiderosis and splenic congestion

  • Reticuloendothelial hyperplasia

  • Erythrophagocytosis

  • Increased iron stores

Enzyme activity rate

The enzyme activity rate in most patients is 5-25% of normal, but false-negative results can occur, especially when the deficiency results from a compound heterozygous mutation; kinetic variables are not measured accurately under such circumstances. Measurement of the intermediates (2,3-diphosphoglycerol and glucose-6-phosphate) proximal to the enzyme defect helps to confirm the diagnosis.

Imaging studies

In severe anemia, radiographs may demonstrate findings of marrow expansion. Ultrasonography is occasionally required to document gallbladder stones, which are known to complicate all forms of hemolytic anemias.

Follow-up

Periodic follow-up care is required in patients with pyruvate kinase deficiency to monitor their hemoglobin level and reticulocyte count and to look for possible gallstones.

Cell Indices

The hematocrit value in pyruvate kinase deficiency ranges from 17-37%. Lower values occur in early childhood and during the neonatal period, with a 3- to 9-point rise after early childhood. Erythrocytes are usually normochromic and normocytic. High reticulocyte counts may raise the mean cell volume, giving the impression that the anemia is macrocytic. Monitor the hematocrit value carefully during times of physiologic stress.

The reticulocyte count in pyruvate kinase deficiency may be increased by 5-15%. Paradoxically, a reticulocyte count of as high as 70% may occur after splenectomy. Leukocyte and platelet counts range from normal to slightly increased, unless the patient develops hypersplenism, which may result in lower cell lines.

Cell Morphology

Morphologic abnormalities are not a prominent finding in pyruvate kinase deficiency, but hallmarks of accelerated erythropoiesis, such as polychromatophilia, anisocytosis, poikilocytosis, and nucleated red blood cells, may be present.

Following splenectomy, the following may be observed:

  • Siderocytes

  • Target cells

  • Pappenheimer bodies

  • Howell-Jolly bodies

  • Crenated red blood cells

Hemoglobin Indices

Concurrent with the hematocrit value, the hemoglobin concentration in pyruvate kinase deficiency varies from 6-12 g/dL, with a lower concentration early in life. Hemoglobin electrophoresis reveals normal hemoglobin, as well as normal levels of F and A2 hemoglobins.

Hemoglobin metabolic indices

Indirect hyperbilirubinemia reflects the severity of the hemolytic process. levels of 6 mg/dL are not uncommon, and levels greater than 20 mg/dL have been reported. Haptoglobin is reduced in proportion to disease severity.

Hemolytic Anemia Studies

Depending on the severity of the anemia, erythrocytes have a moderately to severely reduced lifespan in pyruvate kinase deficiency. Radiochromium labeling reveals an immediate period of destruction, followed by a shortened lifespan for the remainder of labeled cells. The results of this test can help to determine whether a patient is a candidate for splenectomy, because a high rate of immediate destruction suggests significant splenic activity.

Additional findings in hemolytic anemia include the following:

  • Osmotic fragility of erythrocytes is normal

  • Coombs test result is negative

  • Ham test result is negative

  • Donath-Landsteiner antibody is absent

  • Cold agglutinins are absent

  • Incubated Heinz body formation is usually abnormal

Enzyme and PCR Assays

A precise diagnosis of pyruvate kinase deficiency depends on the detection of the deficient enzyme.[31] Enzyme assays, as well as deoxyribonucleic acid (DNA) analysis with a polymerase chain reaction (PCR) assay or single-strand conformation polymorphism, can be used to confirm the diagnosis and identify the carrier state, if necessary.

Enzyme assays, however, are not always accurate; the typical selective removal of very deficient red cells from the circulation can leave only normal cells. The assay may also be affected by the fact that pyruvate kinase activity is usually normal in white cells, platelets, and other tissues in patients with pyruvate kinase deficiency hemolytic anemia.

Deoxyribonucleic acid (DNA) analysis can be limited as well, owing to the large number of gene mutations that cause pyruvate kinase deficiency.

Targeted next-generation sequencing (NGS) has been very valuable in confirming the diagnosis of pyruvate kinase deficiency, as well as identifying new novel undescribed mutations in the gene, which result in hemolytic anemia.

 

Treatment

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.

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.[32] In one study of pregnant patients, significant puerperal jaundice was successfully treated with conservative measures.[33]

Supplemental folic acid and other B vitamins help to prevent deficiencies from increased erythrocyte production.

Large doses of salicylates should be avoided in patients with severe anemia, because these inhibit oxidative phosphorylation, thereby causing further ATP depletion.

Therapeutic intervention with agents that can stimulate pyruvate kinase or circumvent the deficiency defect remains experimental.[34]

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]

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:

  • Intrauterine transfusion: Required in most patients with extremely severe fetal anemia associated with hydrops fetalis

  • Phototherapy or exchange transfusion: Required for most newborns with severe hyperbilirubinemia

  • Simple blood transfusion: Administered for anemia during early childhood and, occasionally, into adulthood.

  • Sporadic blood transfusions: Required in most older patients when anemia becomes severe during infectious episodes, aplastic crisis, or pregnancy

Bone Marrow Transplantation

Although a bone marrow transplant may cure the defect in pyruvate kinase deficiency, the risks of the procedure outweigh those of the disease. Nonetheless, it was reported that a boy aged 5 years with severe hemolytic anemia due to pyruvate kinase deficiency and heterozygous hemoglobin E underwent bone marrow transplantation using ABO-identical and human leukocyte antigen (HLA) ̶ identical marrow from his sister. More than 3 years posttransplant, the patient was still healthy, without symptomatology.[35]

Splenectomy

For surgical care, consider splenectomy or partial splenectomy, although both failure and success have been reported in patients with pyruvate kinase deficiency or idiopathic thrombocytopenic purpura who underwent partial splenectomy.

Presurgery antibiotics

Patients who require splenectomy should usually be prepared by starting prophylactic antibiotics before surgery.

Presurgery vaccines

Vaccines used prior to splenectomy include the following:

  • Polyvalent polysaccharide pneumococcal vaccine: Administered 1-2 weeks before splenectomy in patients over age 2 years

  • Conjugated pneumococcal vaccine: Administered to patients younger than 2 years, although such patients are rare[36, 37]

  • 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

Quadrivalent meningococcal vaccine (MPSV4), a polysaccharide vaccine used only in patients over age 2 years, is also recommended. It is serogroup specific for groups A, C, Y, and W-135. Its efficacy, however, is limited; response to the vaccine is not long lasting, and it lacks an anamnestic response on subsequent challenge.

For this reason, the conjugate tetravalent vaccine MCV4 (Menactra) was licensed in 2005. It has a much more durable immunity, as well as a good anamnestic response, and unlike the polysaccharide vaccine, it can be administered to children younger than 2 years.

Procedure

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 transfusion.

Splenectomy should be performed by an experienced surgeon, especially in pediatric patients. Consider the susceptibility to infection following splenectomy, especially in children younger than 5 years. Prophylactic antibiotics should be administered to young patients postsplenectomy.[38] Always monitor patients with splenectomies for possible fulminating infection.

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.

Partial splenectomy

Partial splenectomy is used to preserve some splenic function in the patient and to protect against the following consequences of asplenia:

  • Fulminating sepsis with encapsulated organisms: Streptococcus pneumoniae (in >60%), H influenzae, and Neisseria meningitidis

  • Streptococcal and staphylococcal infections (which affect such patients with less frequency)

  • Malaria and babesiosis (in endemic regions)

The procedure is very effective in persons with traumatic splenectomy and in individuals with some of the hemolytic anemias.

Consultations

When necessary, the following specialists should be consulted:

  • Hematologist: For management and treatment

  • Surgeon: If splenectomy is considered

  • Anesthesiologist: For presurgical management if anemia is severe

  • Gastroenterologist: To help evaluate complications of the biliary tree

 

Medication

Medication Summary

As in all persons with hemolytic anemias and because of the severe demand for folic acid, the potential for developing megaloblastic anemia in patients with pyruvate kinase deficiency can be prevented by administering supplemental folic acid. Packed red blood cell transfusion is reserved for persons who develop significant anemia.

Large doses of salicylates should be avoided in patients with severe anemia, because these inhibit oxidative phosphorylation, thereby causing further ATP depletion.

Presurgical vaccines

Vaccines used prior to splenectomy include the following:

  • Polyvalent polysaccharide pneumococcal vaccine: Administered 1-2 weeks before splenectomy in patients over age 2 years

  • Conjugated pneumococcal vaccine: Administered to patients under age 2 years, although such patients are rare

  • H influenzae type b vaccine: The conjugate form is usually administered to children at age 2, 4, and 6 months

Vitamins, Water-Soluble

Class Summary

Folic acid is used extensively in individuals with hemolytic anemia. Megaloblastic anemia may develop if folic acid is not supplied.

Folic acid (FA-8)

Folic acid is an important cofactor for enzymes used in the production of red blood cells.

Antibiotics

Class Summary

Patients who undergo splenectomy are prone to fulminating infections with encapsulated organisms, most of which are sensitive to penicillins. Some clinicians recommend administration of prophylactic penicillin for 2-3 years following the procedure, while others recommend administration of prophylactic penicillin for life. Administer erythromycin instead if the child is sensitive to penicillin.

Penicillin VK

Penicillin VK inhibits the biosynthesis of cell wall mucopeptide.

Erythromycin (E.E.S., PCE, Ery-Tab, Erythrocin)

This antibiotic inhibits bacterial growth, possibly by blocking the dissociation of peptidyl transfer ribonucleic acid (tRNA) from ribosomes, causing RNA-dependent protein synthesis to arrest.

Vaccines

Class Summary

Polyvalent pneumococcal vaccine (PPV-23) protects against 23 serotypes of S pneumoniae; approximately 70% of invasive diseases caused by S pneumoniae result from these serotypes. This vaccine should be administered 1-2 weeks prior to splenectomy, to prevent or minimize future complications.

Pneumococcal 13-valent conjugate vaccine (PCV-13) protects against the 13 serotypes of S pneumoniae that cause the most severe pneumococcal infections in children. It replaced an earlier vaccine, PCV-7.[36, 37]

Pneumococcal vaccine polyvalent (Pneumovax-23)

PPV-23 is used for prophylaxis against infection with S pneumoniae. It is employed in populations at increased risk of pneumococcal pneumonia (ie, >55 y, chronic infection, asplenia, immunocompromise). It contains capsular polysaccharides of pneumococcal types 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F.

Pneumococcal 13-valent conjugate vaccine (Prevnar 13)

Pneumococcal 13-valent conjugate vaccine promotes active immunization against invasive disease caused by S pneumonia. It is a sterile solution of saccharides of capsular antigens of S pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F individually conjugated to diphtheria CRM197 protein.

Haemophilus influenza type b vaccine (ActHIB, Hiberix, PedvaxHIB)

This vaccine, which is used for routine immunization of children against invasive diseases caused by H influenzae type b, decreases nasopharyngeal colonization. The Centers for Disease Control and Prevention's (CDC's) Advisory Committee on Immunization Practices (ACIP) recommends that all children receive one of the conjugate vaccines licensed for infant use beginning routinely at age 2 months.

Conjugate forms are usually given in a series of 3 doses, at ages 2, 4, and 6 months. Children who have received primary vaccinations and a booster dose at age 12 months or older are usually protected and do not need further vaccination prior to splenectomy.