Pyruvate Kinase Deficiency

Mendelian MONDO:0009950 Pathograph 12 Show in embeddings browser Inborn Error of Metabolism

Pyruvate kinase deficiency (PKD) is an autosomal-recessive inborn error of erythrocyte glycolysis caused by biallelic loss-of-function variants in PKLR, the gene encoding the liver/red-cell (R-type) isozyme of pyruvate kinase. It is the most frequent enzyme defect of the glycolytic pathway causing hereditary nonspherocytic hemolytic anemia. Pyruvate kinase catalyzes the final, ATP-generating step of glycolysis (phosphoenolpyruvate → pyruvate with transfer of a phosphate to ADP). Because the mature erythrocyte lacks mitochondria and depends entirely on glycolysis for its ATP, reduced pyruvate kinase activity depletes red-cell ATP and causes accumulation of the upstream intermediate 2,3-diphosphoglycerate; the ATP-starved, metabolically compromised erythrocytes are recognized and prematurely destroyed (predominantly by splenic macrophages), shortening red-cell lifespan and producing chronic hemolysis. The clinical severity is highly variable, ranging from fully compensated hemolysis without overt anemia to life-threatening neonatal anemia and jaundice requiring exchange transfusion, and even fetal hydrops. Long-term sequelae — iron overload (which occurs even in non-transfused patients), bilirubin gallstones, splenomegaly, and extramedullary hematopoiesis — arise from the chronic hemolytic state and its management. Historically treated only supportively (transfusion, splenectomy, chelation), PKD is now also targeted by mitapivat, an oral small-molecule allosteric activator of pyruvate kinase.

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1
Inheritance
4
Pathophys.
8
Phenotypes
12
Pathograph
1
Genes
4
Medical Actions
6
References
🏷

Classifications

ICIMD (Inherited Metabolic Disorders)
glycolysis
👪

Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:32702739 SUPPORT Human Clinical
"Pyruvate kinase deficiency (PKD) is an autosomal-recessive enzyme defect of the"
States explicitly that PKD is inherited as an autosomal-recessive enzyme defect.
⚙

Pathophysiology

4
Erythrocyte Pyruvate Kinase Loss of Function
Biallelic loss-of-function or missense variants in PKLR reduce the activity of the red-cell (R-type) pyruvate kinase isozyme, the enzyme catalyzing the final, ATP-generating step of glycolysis (phosphoenolpyruvate → pyruvate). PKLR is located on chromosome 1, and more than 150 different mutations in it have been associated with PK deficiency, giving a wide spectrum of residual enzyme activity that underlies the clinical heterogeneity. This is the disease-specific lesion that reduces erythrocyte metabolic integrity, the generic entry point of the conserved hemolytic-anemia module.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
glycolytic ATP generation GO:0006096 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glycolytic ATP generation, annotated with glycolytic process (GO:0006096). GO:0006096 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Erythrocyte ATP Depletion and 2,3-DPG Accumulation Reduced pyruvate kinase activity lowers glycolytic ATP output and causes the upstream glycolytic intermediate 2,3-diphosphoglycerate to accumulate.
Show evidence (3 references)
PMID:15982340 SUPPORT Human Clinical
"of the glycolytic pathway causing hereditary non-spherocytic haemolytic anaemia"
Establishes red-cell pyruvate kinase deficiency as the most frequent glycolytic enzyme defect causing hereditary nonspherocytic hemolytic anemia.
PMID:15982340 SUPPORT Human Clinical
"different mutations in the PK-LR gene have been associated with PK deficiency"
More than 150 PKLR mutations underlie the deficiency, accounting for its wide biochemical and clinical spectrum.
PMID:32702739 SUPPORT Human Clinical
"glycolytic pathway that causes congenital nonspherocytic hemolytic anemia"
Confirms PKD is a glycolytic-pathway enzyme defect producing congenital nonspherocytic hemolytic anemia.
Erythrocyte ATP Depletion and 2,3-DPG Accumulation
Because the mature erythrocyte has no mitochondria and relies entirely on glycolysis for ATP, the block at the pyruvate kinase step depletes red-cell ATP and leads to accumulation of the upstream intermediates, most characteristically 2,3-diphosphoglycerate (2,3-DPG). ATP depletion compromises cation-pump-dependent volume and membrane homeostasis, producing a rigid, metabolically damaged erythrocyte that is marked for destruction. The 2,3-DPG rise shifts the hemoglobin-oxygen dissociation curve, partly mitigating the functional impact of anemia.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
reduced erythrocyte ATP generation GO:0046034 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased reduced erythrocyte ATP generation, annotated with ATP metabolic process (GO:0046034). GO:0046034 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Premature Splenic Destruction of Metabolically Damaged Erythrocytes ATP-depleted, metabolically compromised erythrocytes are recognized and prematurely removed, mainly by splenic macrophages.
Show evidence (2 references)
PMID:34744776 SUPPORT Human Clinical
"red cells depend almost entirely on glycolysis for energy production"
Establishes the erythrocyte dependence on glycolysis that makes a pyruvate-kinase block an energy-metabolism lesion.
PMID:34744776 SUPPORT Human Clinical
"pyruvate kinase is responsible for catalyzing the ATP producing conversion"
Directly supports the ATP-producing pyruvate-kinase step modeled in this node.
Premature Splenic Destruction of Metabolically Damaged Erythrocytes
The metabolically damaged, ATP-depleted erythrocytes are prematurely cleared from the circulation, predominantly by macrophages of the spleen (extravascular hemolysis). This shortens erythrocyte lifespan and drives the chronic hemolytic anemia; the resulting splenic workload and reticuloendothelial activity underlie splenomegaly and the therapeutic rationale for splenectomy.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
increased splenic erythrocyte clearance GO:0034102 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased splenic erythrocyte clearance, annotated with erythrocyte clearance (GO:0034102). GO:0034102 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Chronic Hemolytic Anemia Shortened erythrocyte lifespan from premature destruction produces the chronic hemolytic anemia and its compensatory reticulocytosis.
Reticulocytosis Compensatory marrow response to shortened red-cell survival.
Splenomegaly Splenic sequestration and reticuloendothelial workload enlarge the spleen.
Jaundice Heme catabolism from hemolysis elevates unconjugated bilirubin, producing jaundice.
Hyperbilirubinemia Increased bilirubin turnover from hemolysis.
Prolonged neonatal jaundice Neonatal hemolysis can cause severe/prolonged jaundice requiring phototherapy or exchange transfusion.
Cholelithiasis Chronic bilirubin overproduction predisposes to pigment gallstones.
Secondary iron overload Chronic hemolysis with ineffective erythropoiesis drives iron loading even without regular transfusion.
Show evidence (1 reference)
PMID:26087744 SUPPORT Human Clinical
"splenectomy to decrease transfusion requirements"
Splenectomy reduces transfusion requirements, reflecting that premature red-cell destruction in PKD is predominantly splenic/extravascular.
Chronic Hemolytic Anemia
The net result is a lifelong hemolytic anemia of highly variable severity, from fully compensated hemolysis without apparent anemia to life-threatening neonatal anemia and jaundice necessitating exchange transfusion, and, at the extreme, fetal hydrops. This is the disease-specific terminal state of the conserved hemolytic-anemia module.
abnormal erythrocyte homeostasis GO:0034101 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal erythrocyte homeostasis, annotated with erythrocyte homeostasis (GO:0034101). GO:0034101 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (2 references)
PMID:15982340 SUPPORT Human Clinical
"The degree of haemolysis varies widely, ranging from very mild or fully"
Documents the wide severity spectrum of the hemolysis, from compensated to life-threatening.
PMID:32702739 SUPPORT Human Clinical
"ranging from fetal hydrops and symptomatic anemia requiring"
Confirms the severity range from fetal hydrops and transfusion-dependent anemia to compensated hemolysis.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Pyruvate Kinase Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

8
Blood 1
Reticulocytosis HP:0001923 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reticulocytosis (HP:0001923). HP:0001923 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34744776 SUPPORT Human Clinical
"high reticulocyte counts (20–40%)"
Reports high reticulocyte counts in PKD patients with compensated hemolytic anemia.
Cardiovascular 1
Splenomegaly HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26087744 SUPPORT Human Clinical
"splenectomy to decrease transfusion requirements"
The role of splenectomy reflects the splenic sequestration/enlargement caused by chronic hemolysis in PKD.
Digestive 3
Jaundice HP:0000952 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Jaundice (HP:0000952). HP:0000952 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15982340 SUPPORT Human Clinical
"compensated forms, to life-threatening neonatal anaemia and jaundice"
Documents jaundice (with neonatal anemia) as part of the clinical spectrum of PKD.
Prolonged neonatal jaundice HP:0006579 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neonatal jaundice, annotated with Prolonged neonatal jaundice (HP:0006579), qualified as neonatal onset. HP:0006579 is a phenotype from the Human Phenotype Ontology.
Onset: NEONATAL
Show evidence (1 reference)
PMID:26087744 SUPPORT Human Clinical
"Treatment remains supportive with phototherapy and/or exchange transfusion in"
Phototherapy and exchange transfusion in the newborn period address the severe neonatal jaundice of PKD.
Cholelithiasis HP:0001081 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilirubin gallstones, annotated with Cholelithiasis (HP:0001081). HP:0001081 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32702739 SUPPORT Human Clinical
"Complications, including iron overload, bilirubin gallstones, extramedullary"
Lists bilirubin gallstones among the complications of the chronic hemolytic anemia of PKD.
Metabolism 1
Secondary iron overload Increased circulating ferritin concentration HP:0003281 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating ferritin concentration (HP:0003281). HP:0003281 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30213831 SUPPORT Human Clinical
"iron overload as defined by ferritin"
Documents ferritin-defined iron overload in a substantial fraction of non-regularly-transfused PKD patients.
PMID:30213831 SUPPORT Human Clinical
"Regular red cell transfusions are known to"
Contextualizes that while transfusion causes iron overload, PKD patients develop it even without regular transfusion.
Other 2
Chronic hemolytic anemia HP:0004870 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic hemolytic anemia (HP:0004870), qualified as temporality chronic. HP:0004870 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:30213831 SUPPORT Human Clinical
"Pyruvate kinase (PK) deficiency is the most common"
Establishes PKD as the most common red-cell glycolytic enzyme defect causing hereditary nonspherocytic hemolytic anemia.
Hyperbilirubinemia HP:0002904 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperbilirubinemia (HP:0002904). HP:0002904 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30213831 SUPPORT Human Clinical
"had a higher median total bilirubin"
Reports elevated total bilirubin in PKD patients, reflecting hemolytic hyperbilirubinemia.
🧬

Genetic Associations

1
PKLR pathogenic variants
Gene: PKLR hgnc:9020 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PKLR (hgnc:9020). hgnc:9020 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Show evidence (2 references)
PMID:15982340 SUPPORT Human Clinical
"different mutations in the PK-LR gene have been associated with PK deficiency"
More than 150 PKLR mutations have been associated with PK deficiency, establishing broad allelic heterogeneity.
PMID:15982340 SUPPORT Human Clinical
"control of the PK-LR gene located on chromosome 1"
Localizes erythrocyte pyruvate kinase synthesis to the PKLR gene on chromosome 1.
💊

Medical Actions

4
Red Cell Transfusion
Action: red blood cell transfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is red blood cell transfusion, annotated with Blood Transfusion (NCIT:C15192). NCIT:C15192 is a clinical intervention from the NCI Thesaurus. Ontology label: Blood Transfusion NCIT:C15192
Regular or intermittent red-cell transfusions treat symptomatic anemia, especially in severe or transfusion-dependent disease and in the newborn period; they contribute to iron overload requiring monitoring and chelation.
Show evidence (1 reference)
PMID:32702739 SUPPORT Human Clinical
"approaches are supportive and include transfusions, splenectomy, and chelation"
Transfusion is a core supportive treatment for PKD.
Splenectomy
Action: splenectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is splenectomy (NCIT:C15328). NCIT:C15328 is a clinical intervention from the NCI Thesaurus. Ontology label: Splenectomy NCIT:C15328
Splenectomy reduces the rate of extravascular (splenic) hemolysis, decreasing transfusion requirements and anemia-related symptoms; it typically raises hemoglobin and reticulocyte counts.
Show evidence (1 reference)
PMID:26087744 SUPPORT Human Clinical
"splenectomy to decrease transfusion requirements"
Splenectomy is used to decrease transfusion requirements and hemolysis-related symptoms in PKD.
Iron Chelation Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: iron chelator (e.g., deferasirox) CHEBI:49005 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses iron chelator (e.g., deferasirox), annotated with deferasirox (CHEBI:49005). CHEBI:49005 is a therapeutic agent from Chemical Entities of Biological Interest.
Iron chelation (e.g., deferasirox, deferiprone, or deferoxamine) manages the iron overload that arises from chronic hemolysis and transfusion, including in non-regularly transfused patients.
Show evidence (1 reference)
PMID:32702739 SUPPORT Human Clinical
"approaches are supportive and include transfusions, splenectomy, and chelation"
Chelation is part of the supportive management of PKD-associated iron overload.
Mitapivat
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: mitapivat NCIT:C157039 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses mitapivat (NCIT:C157039). NCIT:C157039 is a therapeutic agent from the NCI Thesaurus.
Mitapivat is an oral, first-in-class small-molecule allosteric activator of erythrocyte pyruvate kinase. In a phase 3, randomized, placebo-controlled trial (ACTIVATE) in adults with PKD not receiving regular transfusions, it significantly increased hemoglobin and decreased markers of hemolysis, a disease-modifying rather than purely supportive approach.
Mechanism Target:
ACTIVATES Erythrocyte Pyruvate Kinase Loss of Function — Mitapivat allosterically activates residual erythrocyte pyruvate kinase, partially restoring glycolytic ATP output and reducing hemolysis.
Show evidence (2 references)
PMID:35417638 SUPPORT Human Clinical
"oral, first-in-class activator of erythrocyte pyruvate kinase, increased the"
Defines mitapivat as an oral activator of erythrocyte pyruvate kinase that increases hemoglobin.
PMID:35417638 SUPPORT Human Clinical
"significantly increased the hemoglobin level, decreased hemolysis, and improved"
Phase 3 trial shows mitapivat significantly increases hemoglobin and decreases hemolysis in PKD.
🔬

Biochemical Markers

2
2,3-diphosphoglycerate (2,3-DPG) (Increased)
Erythrocyte pyruvate kinase activity (Decreased)
Show evidence (1 reference)
PMID:35417638 SUPPORT Human Clinical
"oral, first-in-class activator of erythrocyte pyruvate kinase, increased the"
A pharmacologic activator of erythrocyte pyruvate kinase raises hemoglobin, confirming the reduced red-cell enzyme activity central to the disease.
{ }

Source YAML

click to show 
name: Pyruvate Kinase Deficiency
category: Mendelian
creation_date: "2026-07-07T00:00:00Z"
synonyms:
- PK deficiency
- PKD
- Red cell pyruvate kinase deficiency
- Erythrocyte pyruvate kinase deficiency
- Hemolytic anemia due to red cell pyruvate kinase deficiency
- PKLR-related pyruvate kinase deficiency
- Congenital nonspherocytic hemolytic anemia due to pyruvate kinase deficiency
description: >
  Pyruvate kinase deficiency (PKD) is an autosomal-recessive inborn error of
  erythrocyte glycolysis caused by biallelic loss-of-function variants in PKLR,
  the gene encoding the liver/red-cell (R-type) isozyme of pyruvate kinase. It
  is the most frequent enzyme defect of the glycolytic pathway causing
  hereditary nonspherocytic hemolytic anemia. Pyruvate kinase catalyzes the
  final, ATP-generating step of glycolysis (phosphoenolpyruvate → pyruvate with
  transfer of a phosphate to ADP). Because the mature erythrocyte lacks
  mitochondria and depends entirely on glycolysis for its ATP, reduced pyruvate
  kinase activity depletes red-cell ATP and causes accumulation of the upstream
  intermediate 2,3-diphosphoglycerate; the ATP-starved, metabolically
  compromised erythrocytes are recognized and prematurely destroyed
  (predominantly by splenic macrophages), shortening red-cell lifespan and
  producing chronic hemolysis. The clinical severity is highly variable, ranging
  from fully compensated hemolysis without overt anemia to life-threatening
  neonatal anemia and jaundice requiring exchange transfusion, and even fetal
  hydrops. Long-term sequelae — iron overload (which occurs even in
  non-transfused patients), bilirubin gallstones, splenomegaly, and
  extramedullary hematopoiesis — arise from the chronic hemolytic state and its
  management. Historically treated only supportively (transfusion, splenectomy,
  chelation), PKD is now also targeted by mitapivat, an oral small-molecule
  allosteric activator of pyruvate kinase.
disease_term:
  preferred_term: pyruvate kinase deficiency of red cells
  term:
    id: MONDO:0009950
    label: pyruvate kinase deficiency of red cells
classifications:
  icimd_category:
  - classification_value: glycolysis
    notes: >-
      IEMbase/ICIMD places red-cell pyruvate kinase deficiency under "Disorders
      of glycolysis" within "Disorders of carbohydrate metabolism" (WP-007
      package, classification code 3.3.13.01, gene PKLR). Pyruvate kinase
      catalyzes the terminal ATP-generating step of the glycolytic pathway.
parents:
- Inborn Error of Metabolism
references:
- reference: PMID:15982340
  title: "Red cell pyruvate kinase deficiency: molecular and clinical aspects."
- reference: PMID:26087744
  title: "Erythrocyte pyruvate kinase deficiency: 2015 status report."
- reference: PMID:32702739
  title: "Management of pyruvate kinase deficiency in children and adults."
- reference: PMID:30213831
  title: "Prevalence and management of iron overload in pyruvate kinase deficiency: report from the Pyruvate Kinase Deficiency Natural History Study."
- reference: PMID:35417638
  title: "Mitapivat versus Placebo for Pyruvate Kinase Deficiency."
- reference: PMID:34744776
  title: "Red Blood Cell Metabolism in Pyruvate Kinase Deficient Patients."
pathophysiology:
- name: Erythrocyte Pyruvate Kinase Loss of Function
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Reduced Erythrocyte Integrity"
  description: >
    Biallelic loss-of-function or missense variants in PKLR reduce the activity
    of the red-cell (R-type) pyruvate kinase isozyme, the enzyme catalyzing the
    final, ATP-generating step of glycolysis (phosphoenolpyruvate → pyruvate).
    PKLR is located on chromosome 1, and more than 150 different mutations in it
    have been associated with PK deficiency, giving a wide spectrum of residual
    enzyme activity that underlies the clinical heterogeneity. This is the
    disease-specific lesion that reduces erythrocyte metabolic integrity, the
    generic entry point of the conserved hemolytic-anemia module.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: glycolytic ATP generation
    term:
      id: GO:0006096
      label: glycolytic process
    modifier: DECREASED
  evidence:
  - reference: PMID:15982340
    reference_title: "Red cell pyruvate kinase deficiency: molecular and clinical aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "of the glycolytic pathway causing hereditary non-spherocytic haemolytic anaemia"
    explanation: Establishes red-cell pyruvate kinase deficiency as the most frequent glycolytic enzyme defect causing hereditary nonspherocytic hemolytic anemia.
  - reference: PMID:15982340
    reference_title: "Red cell pyruvate kinase deficiency: molecular and clinical aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "different mutations in the PK-LR gene have been associated with PK deficiency"
    explanation: More than 150 PKLR mutations underlie the deficiency, accounting for its wide biochemical and clinical spectrum.
  - reference: PMID:32702739
    reference_title: "Management of pyruvate kinase deficiency in children and adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "glycolytic pathway that causes congenital nonspherocytic hemolytic anemia"
    explanation: Confirms PKD is a glycolytic-pathway enzyme defect producing congenital nonspherocytic hemolytic anemia.
  downstream:
  - target: Erythrocyte ATP Depletion and 2,3-DPG Accumulation
    causal_link_type: DIRECT
    description: >
      Reduced pyruvate kinase activity lowers glycolytic ATP output and causes
      the upstream glycolytic intermediate 2,3-diphosphoglycerate to accumulate.
- name: Erythrocyte ATP Depletion and 2,3-DPG Accumulation
  description: >
    Because the mature erythrocyte has no mitochondria and relies entirely on
    glycolysis for ATP, the block at the pyruvate kinase step depletes red-cell
    ATP and leads to accumulation of the upstream intermediates, most
    characteristically 2,3-diphosphoglycerate (2,3-DPG). ATP depletion
    compromises cation-pump-dependent volume and membrane homeostasis, producing
    a rigid, metabolically damaged erythrocyte that is marked for destruction.
    The 2,3-DPG rise shifts the hemoglobin-oxygen dissociation curve, partly
    mitigating the functional impact of anemia.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: reduced erythrocyte ATP generation
    term:
      id: GO:0046034
      label: ATP metabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:34744776
    reference_title: "Red Blood Cell Metabolism in Pyruvate Kinase Deficient Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "red cells depend almost entirely on glycolysis for energy production"
    explanation: Establishes the erythrocyte dependence on glycolysis that makes a pyruvate-kinase block an energy-metabolism lesion.
  - reference: PMID:34744776
    reference_title: "Red Blood Cell Metabolism in Pyruvate Kinase Deficient Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pyruvate kinase is responsible for catalyzing the ATP producing conversion"
    explanation: Directly supports the ATP-producing pyruvate-kinase step modeled in this node.
  downstream:
  - target: Premature Splenic Destruction of Metabolically Damaged Erythrocytes
    causal_link_type: DIRECT
    description: >
      ATP-depleted, metabolically compromised erythrocytes are recognized and
      prematurely removed, mainly by splenic macrophages.
- name: Premature Splenic Destruction of Metabolically Damaged Erythrocytes
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Premature Erythrocyte Destruction"
  description: >
    The metabolically damaged, ATP-depleted erythrocytes are prematurely cleared
    from the circulation, predominantly by macrophages of the spleen
    (extravascular hemolysis). This shortens erythrocyte lifespan and drives the
    chronic hemolytic anemia; the resulting splenic workload and reticuloendothelial
    activity underlie splenomegaly and the therapeutic rationale for splenectomy.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: increased splenic erythrocyte clearance
    term:
      id: GO:0034102
      label: erythrocyte clearance
    modifier: INCREASED
  evidence:
  - reference: PMID:26087744
    reference_title: "Erythrocyte pyruvate kinase deficiency: 2015 status report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "splenectomy to decrease transfusion requirements"
    explanation: Splenectomy reduces transfusion requirements, reflecting that premature red-cell destruction in PKD is predominantly splenic/extravascular.
  downstream:
  - target: Chronic Hemolytic Anemia
    causal_link_type: DIRECT
    description: >
      Shortened erythrocyte lifespan from premature destruction produces the
      chronic hemolytic anemia and its compensatory reticulocytosis.
  - target: Reticulocytosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Compensatory marrow response to shortened red-cell survival.
  - target: Splenomegaly
    causal_link_type: DIRECT
    description: Splenic sequestration and reticuloendothelial workload enlarge the spleen.
  - target: Jaundice
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Heme catabolism from hemolysis elevates unconjugated bilirubin, producing jaundice.
  - target: Hyperbilirubinemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Increased bilirubin turnover from hemolysis.
  - target: Prolonged neonatal jaundice
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Neonatal hemolysis can cause severe/prolonged jaundice requiring phototherapy or exchange transfusion.
  - target: Cholelithiasis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Chronic bilirubin overproduction predisposes to pigment gallstones.
  - target: Secondary iron overload
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Chronic hemolysis with ineffective erythropoiesis drives iron loading even without regular transfusion.
- name: Chronic Hemolytic Anemia
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Hemolytic Anemia"
  description: >
    The net result is a lifelong hemolytic anemia of highly variable severity,
    from fully compensated hemolysis without apparent anemia to life-threatening
    neonatal anemia and jaundice necessitating exchange transfusion, and, at the
    extreme, fetal hydrops. This is the disease-specific terminal state of the
    conserved hemolytic-anemia module.
  biological_processes:
  - preferred_term: abnormal erythrocyte homeostasis
    term:
      id: GO:0034101
      label: erythrocyte homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:15982340
    reference_title: "Red cell pyruvate kinase deficiency: molecular and clinical aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The degree of haemolysis varies widely, ranging from very mild or fully"
    explanation: Documents the wide severity spectrum of the hemolysis, from compensated to life-threatening.
  - reference: PMID:32702739
    reference_title: "Management of pyruvate kinase deficiency in children and adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ranging from fetal hydrops and symptomatic anemia requiring"
    explanation: Confirms the severity range from fetal hydrops and transfusion-dependent anemia to compensated hemolysis.
phenotypes:
- name: Chronic hemolytic anemia
  description: >
    Lifelong hemolytic anemia is the defining clinical feature; PKD is the most
    common red-cell glycolytic enzyme defect causing hereditary nonspherocytic
    hemolytic anemia.
  phenotype_term:
    preferred_term: Chronic hemolytic anemia
    term:
      id: HP:0004870
      label: Chronic hemolytic anemia
    temporality: CHRONIC
  evidence:
  - reference: PMID:30213831
    reference_title: "Prevalence and management of iron overload in pyruvate kinase deficiency: report from the Pyruvate Kinase Deficiency Natural History Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pyruvate kinase (PK) deficiency is the most common"
    explanation: Establishes PKD as the most common red-cell glycolytic enzyme defect causing hereditary nonspherocytic hemolytic anemia.
- name: Reticulocytosis
  description: >
    Compensatory reticulocytosis reflects increased marrow erythropoiesis in
    response to the shortened erythrocyte lifespan; reticulocyte counts are often
    markedly elevated and rise further after splenectomy.
  phenotype_term:
    preferred_term: Reticulocytosis
    term:
      id: HP:0001923
      label: Reticulocytosis
  evidence:
  - reference: PMID:34744776
    reference_title: "Red Blood Cell Metabolism in Pyruvate Kinase Deficient Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high reticulocyte counts (20–40%)"
    explanation: Reports high reticulocyte counts in PKD patients with compensated hemolytic anemia.
- name: Splenomegaly
  description: >
    Splenomegaly results from splenic sequestration and reticuloendothelial
    activity against the metabolically abnormal erythrocytes; splenectomy is used
    to reduce transfusion requirements and hemolysis.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:26087744
    reference_title: "Erythrocyte pyruvate kinase deficiency: 2015 status report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "splenectomy to decrease transfusion requirements"
    explanation: The role of splenectomy reflects the splenic sequestration/enlargement caused by chronic hemolysis in PKD.
- name: Jaundice
  description: >
    Jaundice results from elevated unconjugated bilirubin generated by ongoing
    hemolysis.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:15982340
    reference_title: "Red cell pyruvate kinase deficiency: molecular and clinical aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "compensated forms, to life-threatening neonatal anaemia and jaundice"
    explanation: Documents jaundice (with neonatal anemia) as part of the clinical spectrum of PKD.
- name: Hyperbilirubinemia
  description: >
    Increased bilirubin turnover from chronic hemolysis produces unconjugated
    hyperbilirubinemia, which contributes to jaundice and pigment gallstone
    formation.
  phenotype_term:
    preferred_term: Hyperbilirubinemia
    term:
      id: HP:0002904
      label: Hyperbilirubinemia
  evidence:
  - reference: PMID:30213831
    reference_title: "Prevalence and management of iron overload in pyruvate kinase deficiency: report from the Pyruvate Kinase Deficiency Natural History Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "had a higher median total bilirubin"
    explanation: Reports elevated total bilirubin in PKD patients, reflecting hemolytic hyperbilirubinemia.
- name: Prolonged neonatal jaundice
  description: >
    Neonatal presentation can include severe anemia and jaundice; management may
    require phototherapy and/or exchange transfusion in the newborn period.
  phenotype_term:
    preferred_term: Neonatal jaundice
    term:
      id: HP:0006579
      label: Prolonged neonatal jaundice
    onset:
      onset_category: NEONATAL
  evidence:
  - reference: PMID:26087744
    reference_title: "Erythrocyte pyruvate kinase deficiency: 2015 status report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment remains supportive with phototherapy and/or exchange transfusion in"
    explanation: Phototherapy and exchange transfusion in the newborn period address the severe neonatal jaundice of PKD.
- name: Cholelithiasis
  description: >
    Chronic bilirubin overproduction predisposes to pigment (bilirubin)
    gallstones, a recognized complication of the chronic hemolytic state in PKD.
  phenotype_term:
    preferred_term: Bilirubin gallstones
    term:
      id: HP:0001081
      label: Cholelithiasis
  evidence:
  - reference: PMID:32702739
    reference_title: "Management of pyruvate kinase deficiency in children and adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complications, including iron overload, bilirubin gallstones, extramedullary"
    explanation: Lists bilirubin gallstones among the complications of the chronic hemolytic anemia of PKD.
- name: Secondary iron overload
  description: >
    Iron overload is common in PKD and occurs even in patients who are not
    regularly transfused, driven by chronic hemolysis and ineffective
    erythropoiesis; in a natural-history cohort, 38% of non-regularly transfused
    patients had iron overload defined by ferritin.
  phenotype_term:
    preferred_term: Increased circulating ferritin concentration
    term:
      id: HP:0003281
      label: Increased circulating ferritin concentration
  evidence:
  - reference: PMID:30213831
    reference_title: "Prevalence and management of iron overload in pyruvate kinase deficiency: report from the Pyruvate Kinase Deficiency Natural History Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "iron overload as defined by ferritin"
    explanation: Documents ferritin-defined iron overload in a substantial fraction of non-regularly-transfused PKD patients.
  - reference: PMID:30213831
    reference_title: "Prevalence and management of iron overload in pyruvate kinase deficiency: report from the Pyruvate Kinase Deficiency Natural History Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regular red cell transfusions are known to"
    explanation: Contextualizes that while transfusion causes iron overload, PKD patients develop it even without regular transfusion.
biochemical:
- name: 2,3-diphosphoglycerate (2,3-DPG)
  presence: Increased
  notes: >
    The block at the pyruvate kinase step causes accumulation of the upstream
    glycolytic intermediate 2,3-DPG in the erythrocyte, which shifts the
    hemoglobin-oxygen dissociation curve rightward and partially compensates for
    the reduced oxygen-carrying capacity. Erythrocyte ATP is correspondingly
    reduced. (Curated from the described mechanism; no citable exact-quote
    snippet retained for the metabolite level.)
- name: Erythrocyte pyruvate kinase activity
  presence: Decreased
  evidence:
  - reference: PMID:35417638
    reference_title: "Mitapivat versus Placebo for Pyruvate Kinase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "oral, first-in-class activator of erythrocyte pyruvate kinase, increased the"
    explanation: A pharmacologic activator of erythrocyte pyruvate kinase raises hemoglobin, confirming the reduced red-cell enzyme activity central to the disease.
genetic:
- name: PKLR pathogenic variants
  gene_term:
    preferred_term: PKLR
    term:
      id: hgnc:9020
      label: PKLR
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:32702739
      reference_title: "Management of pyruvate kinase deficiency in children and adults."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Pyruvate kinase deficiency (PKD) is an autosomal-recessive enzyme defect of the"
      explanation: PKD is described as an autosomal-recessive glycolytic enzyme defect causing congenital nonspherocytic hemolytic anemia.
  features: >
    Biallelic (homozygous or compound-heterozygous) PKLR variants cause red-cell
    pyruvate kinase deficiency. PKLR is on chromosome 1 and encodes the R-type
    (erythrocyte) and L-type (liver) pyruvate kinase isozymes via
    tissue-specific promoters; more than 150 pathogenic variants have been
    reported, spanning missense, nonsense, splicing, and small
    insertion/deletion changes, and this allelic heterogeneity contributes to
    the wide clinical spectrum. Confirmatory diagnosis requires demonstrating
    two pathogenic PKLR variants (a criterion used to define cases in the
    Natural History Study).
  evidence:
  - reference: PMID:15982340
    reference_title: "Red cell pyruvate kinase deficiency: molecular and clinical aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "different mutations in the PK-LR gene have been associated with PK deficiency"
    explanation: More than 150 PKLR mutations have been associated with PK deficiency, establishing broad allelic heterogeneity.
  - reference: PMID:15982340
    reference_title: "Red cell pyruvate kinase deficiency: molecular and clinical aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "control of the PK-LR gene located on chromosome 1"
    explanation: Localizes erythrocyte pyruvate kinase synthesis to the PKLR gene on chromosome 1.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:32702739
    reference_title: "Management of pyruvate kinase deficiency in children and adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pyruvate kinase deficiency (PKD) is an autosomal-recessive enzyme defect of the"
    explanation: States explicitly that PKD is inherited as an autosomal-recessive enzyme defect.
treatments:
- name: Red Cell Transfusion
  description: >
    Regular or intermittent red-cell transfusions treat symptomatic anemia,
    especially in severe or transfusion-dependent disease and in the newborn
    period; they contribute to iron overload requiring monitoring and chelation.
  treatment_term:
    preferred_term: red blood cell transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  evidence:
  - reference: PMID:32702739
    reference_title: "Management of pyruvate kinase deficiency in children and adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "approaches are supportive and include transfusions, splenectomy, and chelation"
    explanation: Transfusion is a core supportive treatment for PKD.
- name: Splenectomy
  description: >
    Splenectomy reduces the rate of extravascular (splenic) hemolysis, decreasing
    transfusion requirements and anemia-related symptoms; it typically raises
    hemoglobin and reticulocyte counts.
  treatment_term:
    preferred_term: splenectomy
    term:
      id: NCIT:C15328
      label: Splenectomy
  evidence:
  - reference: PMID:26087744
    reference_title: "Erythrocyte pyruvate kinase deficiency: 2015 status report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "splenectomy to decrease transfusion requirements"
    explanation: Splenectomy is used to decrease transfusion requirements and hemolysis-related symptoms in PKD.
- name: Iron Chelation Therapy
  description: >
    Iron chelation (e.g., deferasirox, deferiprone, or deferoxamine) manages the
    iron overload that arises from chronic hemolysis and transfusion, including
    in non-regularly transfused patients.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: iron chelator (e.g., deferasirox)
      term:
        id: CHEBI:49005
        label: deferasirox
  evidence:
  - reference: PMID:32702739
    reference_title: "Management of pyruvate kinase deficiency in children and adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "approaches are supportive and include transfusions, splenectomy, and chelation"
    explanation: Chelation is part of the supportive management of PKD-associated iron overload.
- name: Mitapivat
  description: >
    Mitapivat is an oral, first-in-class small-molecule allosteric activator of
    erythrocyte pyruvate kinase. In a phase 3, randomized, placebo-controlled
    trial (ACTIVATE) in adults with PKD not receiving regular transfusions, it
    significantly increased hemoglobin and decreased markers of hemolysis, a
    disease-modifying rather than purely supportive approach.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mitapivat
      term:
        id: NCIT:C157039
        label: Mitapivat
  target_mechanisms:
  - target: Erythrocyte Pyruvate Kinase Loss of Function
    treatment_effect: ACTIVATES
    description: >
      Mitapivat allosterically activates residual erythrocyte pyruvate kinase,
      partially restoring glycolytic ATP output and reducing hemolysis.
  evidence:
  - reference: PMID:35417638
    reference_title: "Mitapivat versus Placebo for Pyruvate Kinase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "oral, first-in-class activator of erythrocyte pyruvate kinase, increased the"
    explanation: Defines mitapivat as an oral activator of erythrocyte pyruvate kinase that increases hemoglobin.
  - reference: PMID:35417638
    reference_title: "Mitapivat versus Placebo for Pyruvate Kinase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "significantly increased the hemoglobin level, decreased hemolysis, and improved"
    explanation: Phase 3 trial shows mitapivat significantly increases hemoglobin and decreases hemolysis in PKD.
📚

References & Deep Research

References

6
PMID:15982340
Red cell pyruvate kinase deficiency: molecular and clinical aspects.
No top-level findings curated for this source.
PMID:26087744
Erythrocyte pyruvate kinase deficiency: 2015 status report.
No top-level findings curated for this source.
PMID:32702739
Management of pyruvate kinase deficiency in children and adults.
No top-level findings curated for this source.
PMID:30213831
Prevalence and management of iron overload in pyruvate kinase deficiency: report from the Pyruvate Kinase Deficiency Natural History Study.
No top-level findings curated for this source.
PMID:35417638
Mitapivat versus Placebo for Pyruvate Kinase Deficiency.
No top-level findings curated for this source.
PMID:34744776
Red Blood Cell Metabolism in Pyruvate Kinase Deficient Patients.
No top-level findings curated for this source.