eMedicine Specialties > Pediatrics: General Medicine > Hematology

Pyruvate Kinase Deficiency

Hassan M Yaish, MD, Professor of Pediatrics, University of Utah School of Medicine; Director of Hematology Services, Medical Director, Mountain States Hemophilia and Thrombophilia Treatment Center; Pediatric Hematologist/Oncologist, Department of Pediatrics, Primary Children's Medical Center

Updated: Oct 6, 2009

Introduction

Background

In 1952, Dacie described patients with congenital hemolytic anemia who presented with symptoms and clinical findings similar to those encountered in patients with hereditary spherocytosis (HS).¹ However, in the newly described anemia, the osmotic fragility was normal, and spherocytes were not encountered. In order to differentiate the 2 conditions, the term congenital nonspherocytic hemolytic anemia (CNSHA) type II was introduced. This term was used to describe a heterogenous group of congenital hemolytic anemias of the nonspherocytic type. When the addition of ATP to the incubated RBCs corrects the defect and stops the ongoing hemolysis, the condition is then characterized as CNSHA type II. The addition of glucose to the same specimen of incubated RBCs usually fails to correct the defect.

Pathophysiology

The Embden-Meyerhof pathway.

Pyruvate kinase in the Embden-Meyerhof pathway.

In patients with pyruvate kinase (PK) deficiency, a metabolic block is created in the pathway at the level of the deficient enzyme. Intermediate byproducts and various glycolytic metabolites proximal to the metabolic block accumulate in the RBCs, although such cells become depleted of the distal products in the pathway, such as lactate and ATP. The high level of 2,3-diphosphoglycerate (2,3-DPG; see Media file 1) increases the patient's exercise tolerance despite severe anemia. The tolerance increases as a result of the right shift in the hemoglobin-oxygen dissociation curve. However, the lack of ATP disturbs the cation gradient across the red cell membrane, causing the loss of potassium and water, which causes cell dehydration, contraction, and crenation (see Media file 3) and leads to premature destruction of the RBC.

However, 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 to adult red cells; 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.

Four tissue-specific subunits of pyruvate kinase are known; each subunit helps form an active enzyme for a specific tissue or organ. Both the R subunit (found in the red cell) and the L subunit (found in the liver) are produced from one gene: the PKLR gene, which is located on chromosome 1. For this reason, patients with pyruvate kinase–deficient red cells frequently manifest an associated deficiency in the liver. This fact may explain the high total bilirubin level and the occasional significant rise in the direct fraction in some newborns with pyruvate kinase deficiency. Approximately 180 different mutations of this gene are known to cause pyruvate kinase–deficient hemolytic anemia. The clinical manifestations in patients with pyruvate kinase and the molecular properties of the various mutations have poor correlation. Clinical severity depends on complex interaction of several factors other than the molecular property of the mutations.

However, the survival of patients with severe pyruvate kinase deficiency depends on a compensatory expression of an isoenzyme (M2PK) widely distributed in various tissues, including the RBCs. In a recent study, the life-threatening course of the anemia was reportedly related to the additional absence of the compensatory enzyme M2PK in the RBCs of a patient with homozygous null mutation of PKLR gene.²

A study of pyruvate kinase–deficient erythrocytes has shown such cells to be protected against infection with Plasmodium falciparum malaria.³

Frequency

United States

A recent population survey revealed the rate of heterozygotes (ie, carriers) for pyruvate kinase deficiency to be 0.14% in Ann Arbor, Michigan.

International

Although only several hundred cases of pyruvate kinase deficiency have been reported in the literature, the prevalence is probably much higher. The frequent reports of the predominance of pyruvate kinase deficiency among individuals of northern European ancestry can be questioned based on the increasing number of new cases reported in recent years in different countries and among various ethnic groups. Access to advanced medical facilities, which only recently became available to other ethnic groups, is assumed to be responsible for many of the recent reports, indicating that prevalence in other ethnic groups probably matches the prevalence previously reported among persons of northern European ancestry.

In India, in a study to screen newborns with jaundice for the presence of pyruvate kinase deficiency, 3.21% of all newborns with jaundice were found to be pyruvate kinase deficient, with a 30-40% reduction in the enzyme activity.⁴ A population survey demonstrated a heterozygote rate of 6% in Saudi Arabia, 1.4% in Germany, and only 0.14% in Ann Arbor, Michigan. As with any autosomal recessive condition, the incidence can be higher in ethnic groups and communities with history of consanguinity (eg, a high rate of pyruvate kinase deficiency has been reported among the Pennsylvania Amish).

Mortality/Morbidity

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. However, the severity of pyruvate kinase deficiency widely varies; it may be the cause of death in utero (or shortly after birth from nonimmune hydrops fetalis) or may be mild and asymptomatic. A recent report from the Netherlands revealed a fatal outcome in 2 newborns who presented with very severe pyruvate kinase–deficient hemolytic anemia that resulted in liver failure.⁵ No other explanation for the liver failure was identified.

Simple blood or exchange transfusions are of some concern despite the current safety measures used in blood preparation. Simple blood transfusion is an issue for the older patient who is transfusion dependent. Patients with splenectomies are at risk because of the procedure; such patients are susceptible to later infections. Another cause of morbidity is the development of gallstones.

Iron overload is another serious complication of pyruvate kinase deficiency. In a report of 2 patients with pyruvate kinase deficiency and severe chronic hemolytic anemia who developed iron overload that resulted in liver cirrhosis, both were negative for mutations in the HFE gene.⁶ Iron overload is not an unusual complication, 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 recently, when a hepatic peptide known as hepcidin was described as a negative master regulator of iron absorption and release. In inflammation, the upregulated hepcidin prevents iron absorption, whereas, in iron deficiency anemia, a downregulated 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 which abrogates the effect of hepcidin to allow iron absorption in such patients.⁷ In this study, 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.

Race

Pyruvate kinase deficiency occurs in all races, although it is thought to be more common in persons of northern European and Chinese ancestry.

Sex

Pyruvate kinase deficiency is inherited as an autosomal recessive trait; therefore, both sexes are usually equally affected.

Age

In severe forms, pyruvate kinase deficiency is usually symptomatic in newborns and may be life threatening. Milder cases of pyruvate kinase deficiency are usually missed earlier in life and may not produce any symptoms later in life.

Clinical

History

• Anemia, jaundice, and splenomegaly are the major findings in the newborn with pyruvate kinase (PK) deficiency.
• Heterozygotes have intermediate enzyme levels and are usually asymptomatic, while homozygotes manifest the clinical symptoms of pyruvate kinase deficiency.
• The severity of the condition widely varies, even among patients with the same level of deficiency. Such variability occurs because, in addition to the symptomatic homozygotes, compound heterozygotes with 2 different mutations (one can be qualitative and the other quantitative) also vary symptomatically.
• In older children, adolescents, and adults with pyruvate kinase deficiency, anemia may range from transfusion dependent to asymptomatic.

Physical

• See Pathophysiology and History.

Causes

• Pyruvate kinase deficiency is an inherited condition that is transmitted as an autosomal recessive gene.
• Affected individuals are either homozygous for a single mutation or doubly heterozygous for 2 different pyruvate kinase mutations.

Differential Diagnoses

Other Problems to Be Considered

In the newborn with jaundice and anemia, immune hemolysis (eg, ABO or Rh incompatibility) is easily identified. A diagnosis of pyruvate kinase (PK) 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 and speculated red cells (echinocytes) of the pyruvate kinase deficiency (see Media file 3). A normal osmotic fragility may help to differentiate pyruvate kinase deficiency from hereditary spherocytosis.

Other congenital hemolytic anemias of the nonspherocytic type, hemoglobinopathies, and thalassemia must also be differentiated. Specific tests and family history may help in the differentiation. In older children, autoimmune hemolytic anemia may also manifest with similar symptoms and, therefore, must be considered in the differential diagnosis. A positive Coombs test result, the presence of spherocytes, and the absence of the typical pyruvate kinase–deficient cells on the peripheral blood film examination are the main features in differentiating the conditions.

Workup

Laboratory Studies

• CBC count, differential blood counts, reticulocyte counts, a serum bilirubin level study, and peripheral blood film examination are the minimal tests required to guide the investigation of pyruvate kinase (PK) deficiency.
• 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 (PK) deficiency and does not necessarily indicate cholestasis, primary liver disease, or biliary obstruction. This finding was attributed to the deficient liver pyruvate kinase (LPK), an isoenzyme that is usually deficient whenever the red cell pyruvate kinase is deficient because of the common origin of both enzymes (the PKLR gene).
  • A recent report described hypertriglyceridemia in a female aged 6 months with pyruvate kinase deficiency resolving with hypertransfusion regimen. After a splenectomy at age 18 months, she remained transfusion independent with normal serum triglyceride levels.⁸
• Enzyme assay and, more recently, DNA analysis involving polymerase chain reaction or single-strand conformation polymorphism are available to confirm the diagnosis and to identify the carrier state, if necessary. However, the enzyme assay might not always be accurate. This inaccuracy is due to the typical selective removal of very deficient red cells from the circulation, leaving only normal cells. Furthermore, the pyruvate kinase activity is usually normal in white cells, platelets, and other tissues in the patient with pyruvate kinase deficiency hemolytic anemia; this may interfere with the enzyme assay.

Imaging Studies

• Ultrasonography is occasionally required to document gallbladder stones, which are known to complicate all forms of hemolytic anemias.

Histologic Findings

• As a result of the chronic hemolysis, a bone marrow examination reveals erythroid hyperplasia and active marrow.
• Iron stores may also be increased.

Treatment

Medical Care

• Extremely severe fetal anemia associated with hydrops fetalis usually requires intrauterine transfusion. Phototherapy or exchange transfusion is usually required for severe hyperbilirubinemia in the newborn. Simple blood transfusion is administered for anemia during early childhood and, occasionally, into adulthood.
• In older patients with pyruvate kinase (PK) deficiency, sporadic blood transfusions are usually required when the anemia becomes severe during infectious episodes, aplastic crisis, or pregnancy.
• Therapeutic intervention with agents that can stimulate the enzyme or circumvent the defect remains experimental.
• Bone marrow transplant may cure the defect; however, the risks of bone marrow transplant outweigh the risk of the disease.

Surgical Care

For surgical care, consider splenectomy and partial splenectomy. However, reports of both failure and success exist with partial splenectomy in patients with pyruvate kinase deficiency or idiopathic thrombocytopenic purpura (ITP).

• Presurgery antibiotics: Usually prepare patients who require splenectomy by starting prophylactic antibiotics before surgery.
• Presurgery vaccines
  • Polyvalent polysaccharide pneumococcal vaccine is usually administered 1-2 weeks before splenectomy (assuming such children are >2 y).
  • In the rare child younger than 2 years, use the conjugated pneumococcal vaccine.
  • Also administer Haemophilus influenzae type b vaccine; the conjugate form is usually administered in a series of 3 doses when the individual is aged 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 vaccine before splenectomy. Quadrivalent meningococcal vaccine, used only in children older than 2 years, is also recommended. This vaccine is serogroup specific against groups A, C, Y, and W-135; it is a polysaccharide vaccine (MPSV4) with limited efficacy. The response to this vaccine is not long lasting, and it lacks the anamnestic response on subsequent challenge. For this reason, a new vaccine was licensed in 2005, which is a conjugate tetravalent vaccine (MCV4 [Menactra]). This vaccine has shown a much more durable immunity and a good anamnestic response. Unlike the polysaccharide vaccine, which should not be given to children younger than 2 years, this vaccine is effective in children in this age group. Menactra vaccine will not stimulate protection against infection caused by Neisseria meningitidis other than serogroups A, C, Y, and W-135.
• Splenectomy
  • This surgical procedure is frequently performed to eliminate or to minimize the need for blood transfusion.
  • Always consider splenectomy in the patient who is transfusion dependent.
  • Splenectomy is not curative but may eliminate or decrease the need for blood transfusions.
    • In an attempt to preserve the splenic function in a young child, 80% of the spleen was removed, with no benefit.
    • A total splenectomy was performed later and proved to be effective.
• Partial splenectomy
  • Partial splenectomy has been used in an attempt to keep splenic tissue to preserve some splenic function.
  • Partial splenectomy is expected to protect the child from the following consequences of asplenia:
    • Fulminating sepsis with the encapsulated organisms (Streptococcus pneumoniae [in >60%], H influenzae, N meningitidis)
    • Streptococcal and staphylococcal infections, which affect such patients with less frequency
    • Malaria and babesiosis in endemic regions
  • Partial splenectomy has been attempted in various patients with different diagnoses.
  • The procedure is very effective in persons with traumatic splenectomy and in individuals with some of the hemolytic anemias.

Consultations

• A hematologist should perform the initial diagnostic workup.
• Advise genetic counseling.
• Consult with a surgeon if splenectomy is considered.

Activity

• Patients with hemoglobin levels close to or slightly below the reference range tolerate normal daily activities. Those with severe anemia demonstrate exercise intolerance, and their activity is limited as a result.
• However, exercise tolerance in children with pyruvate kinase deficiency is somewhat higher than expected given their hemoglobin level. This higher tolerance is thought to be related to the fact that the block in the glycolytic pathway is distal to the production of 2,3-DPG, which accumulates in the RBC, resulting in shift of the hemoglobin-oxygen dissociation curve to the right and enabling a faster oxygen release to the tissues.

Medication

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 (PK) deficiency can be prevented by administering 1 mg/d of folic acid. Packed RBC transfusion is reserved for persons who develop significant anemia.

Vitamins

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

Folic acid (Folvite)

Important cofactor for enzymes used in production of RBCs.

Dosing

Adult

5 mg/d PO

Pediatric

1 mg/d PO

Interactions

Coadministration with phenytoin decreases serum phenytoin concentration, thereby increasing risk of seizures

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Patients with alcoholism and deficiencies of other vitamins may develop resistance to treatment

Antibiotics

Patients who undergo splenectomy are prone to fulminating infections with encapsulated organisms, and most are sensitive to penicillins. Some clinicians recommend administration of prophylactic penicillin for 2-3 years following the procedure. Other clinicians recommend administration of prophylactic penicillin for life.

Administer erythromycin instead if the child is sensitive to penicillin.

Penicillin V potassium (Beepen-VK, Betapen-VK, Pen. VEE K)

Inhibits biosynthesis of cell wall mucopeptide.

Dosing

Adult

Pediatric

<5 years: 125 mg PO bid
>5 years: 250 mg PO bid

Interactions

Probenecid may increase effectiveness by decreasing clearance; tetracyclines are bacteriostatic, causing decrease in effectiveness of penicillins when administered concurrently

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus

Precautions

PO route is not adequate in severe infections; minimum of 10 d of therapy when treating streptococcal infections

Erythromycin (E.E.S., E-Mycin, Eryc, Ery-Tab, Erythrocin)

Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Dosing

Adult

Pediatric

<5 years: 125 mg PO bid
>5 years: 250 mg PO bid

Interactions

Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin increases risk of rhabdomyolysis

Contraindications

Documented hypersensitivity; hepatic impairment

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in liver disease; estolate formulation may cause cholestatic jaundice; GI adverse effects are common (administer doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occurs

Vaccines

Pneumococcal polyvalent vaccination (PPV-23) contains 23 serotypes that cause approximately 70% of invasive diseases caused by these organisms. Administer this vaccination 1-2 wk prior to surgery to prevent or minimize future complications. Pneumococcal 7-valent conjugate vaccine (PCV-7) contains 7 serotypes of pneumococcal bacteria largely responsible for invasive disease in young children.

Pneumococcal polyvalent vaccine, 23-valent (Pneumovax-23)

23-Polyvalent vaccine used for prophylaxis against infection from Streptococcus pneumoniae. Used in populations at increased risk of pneumococcal pneumonia (ie, >55 y, chronic infection, asplenia, immunocompromise).

Dosing

Adult

0.5 mL IM/SC as a single dose

Pediatric

<2 years: Immunity may not be conferred; antibody response poor in this age group
>2 years: 0.5 mL IM/SC as single dose; repeat dose after 5 y for high-risk children (eg, functional or anatomic asplenia, conditions associated with rapid antibody decline after initial vaccination)
Note: Administer PVV-23 6-8 wk after PCV-7 (see schedule in medication table for PCV-7)

Interactions

Immunosuppressive agents (large amounts of corticosteroids, antimetabolites, alkylating agents, cytotoxic agents) may reduce effectiveness; therapy with immunoglobulin preparations is likely to block active immunity induced with pneumococcal vaccination (withhold for 3 mo after discontinuation of immunoglobulin therapy)

Contraindications

Documented hypersensitivity to any component or thimerosal; severe or even moderate febrile illness; thrombocytopenia or any coagulation disorder that contraindicates IM injection unless potential benefit clearly outweighs risk of administration

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus

Precautions

Moderate or severe illness with or without fever; may cause arthralgia, fever, urticaria, Guillain-Barré syndrome (rare)

Pneumococcal 7-valent conjugate vaccine (Prevnar)

Sterile solution of saccharides of capsular antigens of S pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F individually conjugated to diphtheria CRM197 protein. These 7 serotypes have been responsible for >80% of invasive pneumococcal disease in children <6 y in the United States. Also accounted for 74% of penicillin-nonsusceptible S pneumoniae (PNSP) and 100% of pneumococci with high-level penicillin resistance.
Customary age for first dose is 2 mo but can be given to infants as young as 6 wk. Preferred sites of IM injection are anterolateral aspect of the thigh in infants or deltoid muscle of upper arm in toddlers and young children. Do not inject vaccine in gluteal area or areas that may contain a major nerve trunk or blood vessel. A 3-dose series, 0.5 mL each, is initiated in infants aged 7-11 mo (4 wk apart; third dose after first birthday). Children aged 12-23 mo are given 2 doses (2 mo apart). Children >24 mo through 9 y are given 1 dose. Minor illnesses, such as a mild upper respiratory tract infection, with or without low-grade fever, are not generally considered contraindications.

Dosing

Adult

Not established

Pediatric

Series initiated at age 2 months: 0.5 mL IM x 3 doses at 4-8 wk intervals, followed by a fourth dose of 0.5 mL at age 12-15 mo; administer fourth dose 2 mo or later following the third dose
Series initiated at age 7-11 months: 0.5 mL IM x 2 doses at 4 wk intervals, followed by third dose after 1-year birthday, separate second and third dose by at least 2 mo
Series initiated at age 12-23 months: 0.5 mL IM x 2 doses administered 2 mo apart
Initiated at age 2-9 years: 0.5 mL IM once
Administration of pneumococcal polysaccharide-23 (PPV-23) and pneumoccal-7 (PCV-7) vaccines should follow the schedule below for patients undergoing splenectomy at a young age.
Age 24-59 months and 4 PCV-7 doses were previously given:
PPV-23: 1 dose at 24 mo, 6-8 wk after last PCV-7; repeat 3-5 y later
Age 24-59 months and 1-3 PCV-7 doses were previously given:
PCV-7: 1 dose
PPV-23: 1 dose 6-8 wk after PCV-7; repeat 3-5 y later
Age 24-59 months and 1 PPV-23 was previously given:
PCV-7: 2 doses given 6-8 w apart
PPV-23: Repeat 3-5 y later
Age 24-59 months and no PPV-23 or PCV-7 previously given:
PCV-7: 2 doses given 6-8 w apart
PPV-23: 1 dose 6-8 wk after PCV-7; repeat 3-5 y later

Interactions

Effects may decrease with immunosuppressive agents (immunosuppressive doses of corticosteroids, antimetabolites, alkylating agents, cytotoxic agents); pneumococcal 7-valent conjugate vaccine may increase effects of anticoagulant therapy; globulin preparations may interfere with immune response to PPV-23 and reduce efficacy (do not administer within 6-8 wk of vaccine)

Contraindications

Documented hypersensitivity to any component or diphtheria toxoid; severe or moderate febrile illness; infants or children with thrombocytopenia or coagulation disorder that contraindicates IM injection (unless benefits outweigh risks of administration)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus

Precautions

For IM use only (do not administer IV under any circumstances); take special care to prevent injection into or near a blood vessel or nerve; caution in patients with possible history of latex sensitivity (packaging contains dry natural rubber); use of pneumococcal conjugate vaccine does not replace use of PPV-23 in children >24 mo with sickle cell disease, asplenia, HIV infection, chronic illness, or those who are immunocompromised; caution in patients with coagulation disorders

Haemophilus b conjugate vaccine (ActHIB, HibTITER, PedvaxHIB)

Used for routine immunization of children against invasive diseases caused by H influenzae type b. Decreases nasopharyngeal colonization. The 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 mo. Conjugate forms are usually given in series of 3 doses at ages 2, 4, and 6 mo. Children who have received primary vaccinations and booster dose at age 12 mo or older are usually protected and do not need further vaccinations prior to splenectomy.

Dosing

Adult

Not indicated

Pediatric

Regimens vary depending on product; the use of HibTITER is the example that follows:
2-6 months: 0.5 mL IM q2mo for 3 doses
7-11 months: 0.5 mL IM q2mo for 2 doses if previously unvaccinated
12-14 months: 0.5 mL IM once if previously unvaccinated
Booster dose: All children receive 0.5 mL at age 15 mo or at least 2 mo after last dose of immunization series; for children aged 15-71 mo and previously unvaccinated, 0.5 mL IM is given only once

Interactions

Immunoglobulins given within 1 mo or concurrent administration with immunosuppressive agents may inhibit full immunologic response

Contraindications

Documented hypersensitivity; immunosuppressed children or those receiving immunosuppressive therapy; IV/ID/SC administration

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus

Precautions

Delay immunization upon evidence of febrile illness; may cause local erythema, swelling, or tenderness; risk of Haemophilus type b infections increases the week after vaccination; cause-effect relationship with observed postvaccine Guillain-Barré syndrome has not been established; serious adverse reactions should be reported to
US Department of Health and Human Services (800-822-7967)

Follow-up

Further Inpatient Care

• Periodic follow-up care is required in patients with pyruvate kinase (PK) deficiency to monitor the hemoglobin level, reticulocyte counts, and possible development of gallbladder stones.
• Always monitor patients with splenectomies for possible fulminating infections. Ensure that such patients continue to receive prophylactic penicillin.

Deterrence/Prevention

• In families known to be affected by pyruvate kinase deficiency, genetic counseling is the only practical means to prevent the condition. Genetic counseling offers an understanding of the potential risks involved with having children with another carrier.
• Prenatal diagnosis is feasible;⁹ however, the unpredictability of the condition's severity cannot justify advising the termination of pregnancies if the fetus is affected.

Complications

• Severe anemia may result in heart failure.
• The development of gallbladder stones is a known complication of all hemolytic anemias.
• Fulminating infection in patients with splenectomies and transmission of infections due to blood transfusions may occur.
• 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).

Prognosis

• Most patients maintain an adequate hematocrit level, especially after splenectomy; such patients live a relatively normal life.

Patient Education

• Prevention of complications depends on educating the patient and the parents about the nature of the condition, its genetic nature, expected complications, and all precautions to avoid some of the preventable complications.

Miscellaneous

Medicolegal Pitfalls

• The potential medicolegal pitfalls are those related to failure to diagnose pyruvate kinase (PK) deficiency in a neonate with jaundice. The condition 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 and the parents would not receive genetic counseling, increasing the chance that they will have other children with the same condition.
• Conversely, if the condition is moderately severe and requires repeated blood transfusion, failure to recognize the value of splenectomy in reducing or even eliminating the need for transfusion may represent a liability.

Multimedia

Media file 1: The Embden-Meyerhof pathway.

Media file 2: Pyruvate kinase in the Embden-Meyerhof pathway.

Media file 3: Peripheral blood smear in a child with splenectomy and pyruvate kinase deficiency.

References

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Keywords

pyruvate kinase deficiency, PK deficiency, PKD, congenital nonspherocytic hemolytic anemia type II, CNSHA type II, hereditary spherocytosis, HS, adenosine triphosphate, ATP, hemolysis, 2, 3-diphosophoglycerate, 2, 3-DPG, PK-deficient reticulocytes, bilirubin level, anemia, idiopathic thrombocytopenic purpura, ITP, immune hemolysis, anaerobic glycolytic pathway, lactate, hemoglobin-oxygen dissociation curve, splenectomy, hyperbilirubinemia, nonimmune hydrops fetalis, jaundice, splenomegaly, gallbladder stones, exercise tolerance, fulminating infections

Contributor Information and Disclosures

Author

Hassan M Yaish, MD, Professor of Pediatrics, University of Utah School of Medicine; Director of Hematology Services, Medical Director, Mountain States Hemophilia and Thrombophilia Treatment Center; Pediatric Hematologist/Oncologist, Department of Pediatrics, Primary Children's Medical Center
Hassan M Yaish, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Michigan State Medical Society, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Medical Editor

Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories
Gary R Jones, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
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Managing Editor

James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center
James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society
Disclosure: Nothing to disclose.

CME Editor

Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada
Helen SL Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Professor of Pediatrics, Oncology and the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine
Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

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