---

Congenital Hemolytic Anemias — Enzyme Deficiency Type

Overview: The Two Pathways

Per Harrison's (p. 2985): Prevalence order of enzyme deficiencies causing hemolysis — G6PD > Pyruvate Kinase > G6P Isomerase > others

---

1. Pyruvate Kinase (PK) Deficiency — Glycolysis

Pathophysiology

• PK catalyzes the last step of glycolysis: PEP → Pyruvate + ATP
• Deficiency → ↓ ATP in RBCs → membrane pump failure (Na⁺/K⁺ ATPase) → RBC dehydration & rigidity → extravascular hemolysis (spleen)
• Also: ↑ 2,3-BPG (substrate backs up upstream) — paradoxically shifts O₂ dissociation curve rightward (better O₂ unloading), which is why symptoms are less severe than expected for the degree of anemia

Clinical Features

• Chronic hemolytic anemia from birth/childhood
• Jaundice (intermittent, worsened by infection/febrile illness)
• Splenomegaly (chronic extravascular hemolysis)
• Positive family history — autosomal recessive (parental uncle having splenectomy fits)
• Aplastic crisis precipitated by Parvovirus B19
• Cholelithiasis (pigment stones) — chronic hemolysis → ↑ unconjugated bilirubin

Labs

Confirmatory Test

• Fluorescent spot test (screening) — no fluorescence with PK deficiency
• Enzyme assay — quantitative PK activity (definitive)

Treatment

• Splenectomy — reduces hemolytic rate (spleen is the main site of destruction); indicated in transfusion-dependent cases
• Regular folic acid supplementation
• Blood transfusions for aplastic crises
• Mitapivat (pyruvate kinase activator) — newer drug, activates mutant PK enzyme

---

2. G6PD Deficiency — HMP Shunt

Pathophysiology

• G6PD is the rate-limiting enzyme of the HMP shunt
• Its product (NADPH) regenerates glutathione (GSH), which neutralizes oxidative stress in RBCs
• Deficiency → ↓ NADPH → ↓ GSH → oxidative damage to Hb → Hb denaturation → Heinz bodies → RBC membrane damage → intravascular + extravascular hemolysis

Inheritance

• X-linked recessive → males predominantly affected; females are carriers (lyonization can cause variable expression in females)

Common Triggers (must memorize for NEET PG)

Clinical Variants (NEET PG High Yield)

Clinical Features

• Episodic hemolytic anemia — triggered, not chronic (unlike PK deficiency)
• Neonatal jaundice (can be severe enough to cause kernicterus)
• Back/abdominal pain during acute episode (intravascular hemolysis → hemoglobinuria → dark urine)
• Splenomegaly is NOT prominent (unlike PK deficiency)

Labs

Confirmatory Test

• Fluorescent spot test (screening) — no fluorescence indicates G6PD deficiency
• Quantitative G6PD assay — must be done 4–6 weeks after acute episode (because young RBCs released post-hemolysis have higher G6PD activity and can give false-normal results during attack)
• DNA testing — for heterozygous females

Treatment

• Avoid triggers (educate patient)
• Supportive care during acute hemolytic episode
• Blood transfusion if severe
• No role for splenectomy
• Folic acid supplementation

---

3. Other Glycolytic Enzyme Deficiencies (Lower Yield, but Know for Completeness)

---

4. Key Comparisons — High Yield Table for NEET PG

---

5. Distinguishing from Other Hemolytic Anemias

• Hereditary Spherocytosis (HS): Defect in spectrin/ankyrin/band 3 (membrane, not enzyme); spherocytes on smear; ↑ osmotic fragility; AR/AD
• Sickle Cell Disease: Structural Hb defect; sickle cells; vaso-occlusion
• Thalassemia: Quantitative Hb synthesis defect; microcytic, target cells
• Autoimmune Hemolytic Anemia (AIHA): Coombs POSITIVE — key differentiator from all enzyme deficiencies

---

6. NEET PG Exam Traps & High-Yield Points

1. PK deficiency → ↑ 2,3-BPG → rightward shift of ODC → better O₂ delivery → symptoms milder than anemia degree suggests
2. G6PD assay timing: Do NOT test during acute hemolytic episode — will miss diagnosis (young reticulocytes have higher activity → false negative)
3. Heinz bodies are seen with supravital stains (crystal violet, brilliant cresyl blue), NOT routine Giemsa stain
4. Favism = G6PD deficiency triggered by fava beans — Mediterranean variant
5. Bite cells on smear = macrophages in spleen "bite off" Heinz body-containing portions of RBC
6. Triose phosphate isomerase deficiency = only glycolytic enzyme defect with neurological involvement
7. Neonatal jaundice requiring phototherapy/exchange transfusion in a male infant — think G6PD deficiency
8. In the question stem: "worsened by febrile illness" + "chronic" + "family history/splenectomy" + "AR pattern" = PK deficiency (glycolysis)
9. "Episodic" + "drug/food trigger" + "male" + "dark urine" = G6PD deficiency (HMP shunt)

Congenital Hemolytic Anemia — Enzyme Deficiencies (NEET PG Rapid Recap)

---

Glycolysis — Pyruvate Kinase (PK) Deficiency

• AR, most common glycolytic defect
• ↓ ATP → membrane pump failure → extravascular hemolysis (spleen)
• ↑ 2,3-BPG → right shift ODC → anemia better tolerated than expected
• Chronic hemolysis; worsens with infection/fever
• Smear: Echinocytes (burr cells); Coombs negative
• Splenomegaly + pigment gallstones; aplastic crisis with Parvovirus B19
• Rx: Splenectomy helpful; folic acid; Mitapivat (new)

---

HMP Shunt — G6PD Deficiency

• X-linked recessive (males affected; females carriers)
• ↓ NADPH → ↓ GSH → oxidative Hb damage → Heinz bodies → bite cells
• Episodic hemolysis, triggered by: drugs (primaquine, dapsone, sulfonamides), infections, fava beans
• Smear: Bite cells + Heinz bodies (supravital stain only); Coombs negative
• Dark urine (hemoglobinuria); prominent neonatal jaundice
• Enzyme assay: Wait 4–6 weeks post-attack (false normal during attack)
• Rx: Avoid triggers; splenectomy not helpful

---

The One Differentiator

---

• Heinz bodies → supravital stain only (missed on routine smear)
• ↑ 2,3-BPG in PK deficiency = right shift = milder symptoms
• Triose phosphate isomerase deficiency = only glycolytic defect with neuro involvement
• Coombs negative in ALL enzyme deficiencies (positive = AIHA)

• Front = a single question or cue that forces active recall
• Back = the answer, revealed only after you attempt to recall it
• The challenge-response mechanism is what builds memory

---

• e.g., Front: "What is the smear finding in PK deficiency?" → Back: "Echinocytes (burr cells)"
• Best for active recall and spaced repetition

• Everything on one visual sheet
• Best for quick review before an exam

• Front: "Congenital Hemolytic Anemia — Enzyme Deficiencies"
• Back: Concise, well-organized bullet points — not dense paragraphs

Option A — Multiple Anki Cards (one concept per card)

• Your brain is forced to retrieve a specific fact
• You can rate each card (easy/hard) — hard cards come back sooner
• You identify weak spots precisely (e.g., you know G6PD triggers but keep forgetting the enzyme assay timing)

• You flip through cards rapidly
• Easy cards get dismissed quickly
• Only weak cards slow you down
• Total revision of a topic takes 5–10 minutes once cards are mature

---

The Ideal Card Structure for This Topic

---

---

🔴 GLYCOLYSIS — Pyruvate Kinase Deficiency

---

---

---

---

---

---

---

---

---

---

🔵 HMP SHUNT — G6PD Deficiency

---

---

---

---

---

---

---

---

---

---

⚡ EXAM TRAP CARDS

---

---

---

---

---

---

PK deficiency — which metabolic pathway and inheritance?;Glycolysis | Autosomal Recessive
PK deficiency — exact enzyme defect and its normal function?;Pyruvate Kinase | Catalyzes last step of glycolysis: PEP → Pyruvate + ATP
PK deficiency — mechanism of hemolysis?;↓ATP → Na⁺/K⁺ ATPase pump failure → RBC dehydration + rigidity → extravascular hemolysis in spleen
Why is anemia in PK deficiency better tolerated than expected?;Metabolic block → ↑2,3-BPG → right shift of O₂ dissociation curve → better O₂ delivery to tissues
PK deficiency — type of hemolysis and triggers?;CHRONIC hemolysis | Worsens with fever/infection | Aplastic crisis triggered by Parvovirus B19
PK deficiency — peripheral smear finding?;Echinocytes (burr cells) | Coombs NEGATIVE
PK deficiency — complications?;Splenomegaly | Pigment gallstones | Aplastic crisis (Parvovirus B19)
PK deficiency — confirmatory test?;Quantitative PK enzyme assay | Fluorescent spot test (screening — no fluorescence = deficient)
PK deficiency — treatment?;Splenectomy (beneficial) | Folic acid | Mitapivat (activates mutant PK) | Transfusion for aplastic crisis
G6PD deficiency — which pathway and inheritance?;HMP Shunt (Pentose Phosphate Pathway) | X-linked Recessive — males affected, females carriers
G6PD deficiency — mechanism of hemolysis?;↓G6PD → ↓NADPH → ↓GSH → oxidative Hb damage → Heinz bodies → RBC membrane damage → hemolysis
G6PD deficiency — type of hemolysis and triggers?;EPISODIC | Drugs (primaquine, dapsone, nitrofurantoin, sulfonamides) | Infections (most common globally) | Fava beans | Naphthalene
G6PD deficiency — peripheral smear findings and how are Heinz bodies visualized?;Bite cells + Blister cells + Heinz bodies | Heinz bodies: supravital stain ONLY (crystal violet/brilliant cresyl blue) — NOT on routine Giemsa
What are bite cells and how do they form?;Splenic macrophages bite off Heinz body-containing portions of RBC → bite cells (degmacytes)
G6PD deficiency — clinical features?;Episodic hemolytic anemia | Dark urine (hemoglobinuria) | Back/abdominal pain | Neonatal jaundice (kernicterus risk) | Minimal splenomegaly
G6PD deficiency — when to perform enzyme assay and why?;Wait 4–6 weeks after acute attack | During attack young reticulocytes have higher G6PD activity → false normal result
G6PD deficiency — variants, ethnicity, severity?;A- (African) mild self-limiting | Mediterranean severe favism all RBCs affected | Canton (SE Asian) moderate-severe
G6PD deficiency — treatment?;Avoid triggers | Supportive care | Transfusion if severe | Folic acid | Splenectomy NOT indicated
Which glycolytic enzyme deficiency causes neurological involvement plus hemolysis?;Triose Phosphate Isomerase (TPI) deficiency — rarest and most lethal
How to differentiate enzyme deficiency hemolytic anemias from AIHA on one test?;Coombs test — NEGATIVE in all enzyme deficiencies | POSITIVE in AIHA
Prevalence order of RBC enzyme deficiencies causing hemolysis?;G6PD > Pyruvate Kinase > G6P Isomerase > others
PK deficiency vs G6PD deficiency — splenectomy useful in which?;PK deficiency — YES (extravascular hemolysis in spleen) | G6PD deficiency — NO

---

1. Save the above as hemolytic_anemia.txt
2. Open Anki → File → Import
3. Select the file
4. Set Field separator: Semicolon
5. Map Field 1 → Front, Field 2 → Back
6. Import — you will get exactly 22 cards

---

What are reticulocytes?;Non-nucleated red cell precursors | Have blue-red polychromatophilic cytoplasm due to residual ribosomal RNA (mesh-like reticular network)
How are reticulocytes visualized on smear?;Supravital stains — methylene blue or brilliant cresyl blue | Stain the ribosomal RNA | NOT seen on routine Giemsa stain
What is the normal reticulocyte count?;0.5–1.5% of total red cells
What does reticulocytosis indicate?;Effective erythropoiesis — good bone marrow response to anemia | Seen in: Hemolytic anemias | Acute blood loss
What does reticulocytopenia indicate?;Ineffective erythropoiesis — poor bone marrow response | Seen in: Aplastic anemia | Chemotherapy | Bone marrow malignancy | Anemia of chronic disease | Iron deficiency anemia | Vitamin B12/Folate deficiency
Why is reticulocyte count HIGH in hemolytic anemias like PK and G6PD deficiency?;Increased RBC destruction → bone marrow compensates → releases more reticulocytes into circulation (effective erythropoiesis)
What is the corrected reticulocyte count formula and why is it used?;Corrected count = Reticulocyte% × (Patient Hb/Normal Hb i.e. 15) | Raw % is falsely high in anemia because fewer total RBCs; correction adjusts for this
What is Reticulocyte Production Index (RPI) and its interpretation?;RPI = Corrected reticulocyte count ÷ Maturation factor | RPI >3 = Hemolytic anemia or acute blood loss (hyperproliferative) | RPI <2 = Hypoproliferative anemia (iron deficiency, aplastic, B12/folate deficiency)
What is polychromasia on routine smear and what does it represent?;Blue-tinged RBCs on Giemsa stain = reticulocytes released early from marrow | Indicates stress erythropoiesis / active hemolysis
PK deficiency — which metabolic pathway and inheritance?;Glycolysis | Autosomal Recessive
PK deficiency — exact enzyme defect and its normal function?;Pyruvate Kinase | Catalyzes last step of glycolysis: PEP → Pyruvate + ATP
PK deficiency — mechanism of hemolysis?;↓ATP → Na⁺/K⁺ ATPase pump failure → RBC dehydration + rigidity → extravascular hemolysis in spleen
Why is anemia in PK deficiency better tolerated than expected?;Metabolic block → ↑2,3-BPG → right shift of O₂ dissociation curve → better O₂ delivery to tissues
PK deficiency — type of hemolysis and triggers?;CHRONIC hemolysis | Worsens with fever/infection | Aplastic crisis triggered by Parvovirus B19
PK deficiency — peripheral smear finding?;Echinocytes (burr cells) | Coombs NEGATIVE | HIGH reticulocyte count
PK deficiency — complications?;Splenomegaly | Pigment gallstones | Aplastic crisis (Parvovirus B19)
PK deficiency — confirmatory test?;Quantitative PK enzyme assay | Fluorescent spot test (screening — no fluorescence = deficient)
PK deficiency — treatment?;Splenectomy (beneficial) | Folic acid | Mitapivat (activates mutant PK) | Transfusion for aplastic crisis
G6PD deficiency — which pathway and inheritance?;HMP Shunt (Pentose Phosphate Pathway) | X-linked Recessive — males affected, females carriers
G6PD deficiency — mechanism of hemolysis?;↓G6PD → ↓NADPH → ↓GSH → oxidative Hb damage → Heinz bodies → RBC membrane damage → hemolysis
G6PD deficiency — type of hemolysis and triggers?;EPISODIC | Drugs (primaquine, dapsone, nitrofurantoin, sulfonamides) | Infections (most common globally) | Fava beans | Naphthalene
G6PD deficiency — peripheral smear findings and how are Heinz bodies visualized?;Bite cells + Blister cells + Heinz bodies | Heinz bodies: supravital stain ONLY (crystal violet/brilliant cresyl blue) — NOT on routine Giemsa
What are bite cells and how do they form?;Splenic macrophages bite off Heinz body-containing portions of RBC → bite cells (degmacytes)
G6PD deficiency — clinical features?;Episodic hemolytic anemia | Dark urine (hemoglobinuria) | Back/abdominal pain | Neonatal jaundice (kernicterus risk) | Minimal splenomegaly | HIGH reticulocytes post-attack
G6PD deficiency — when to perform enzyme assay and why?;Wait 4–6 weeks after acute attack | During attack young reticulocytes have higher G6PD activity → false normal result
G6PD deficiency — variants, ethnicity, severity?;A- (African) mild self-limiting | Mediterranean severe favism all RBCs affected | Canton (SE Asian) moderate-severe
G6PD deficiency — treatment?;Avoid triggers | Supportive care | Transfusion if severe | Folic acid | Splenectomy NOT indicated
Which glycolytic enzyme deficiency causes neurological involvement plus hemolysis?;Triose Phosphate Isomerase (TPI) deficiency — rarest and most lethal
How to differentiate enzyme deficiency hemolytic anemias from AIHA on one test?;Coombs test — NEGATIVE in all enzyme deficiencies | POSITIVE in AIHA
Prevalence order of RBC enzyme deficiencies causing hemolysis?;G6PD > Pyruvate Kinase > G6P Isomerase > others
PK deficiency vs G6PD deficiency — splenectomy useful in which?;PK deficiency — YES (extravascular hemolysis in spleen) | G6PD deficiency — NO

---

• 9 reticulocyte cards (from your image + extra NEET PG high-yield points)
• 9 PK deficiency cards
• 9 G6PD deficiency cards
• 4 exam trap/comparison cards

1. Save as hemolytic_reticulocyte.txt
2. Anki → File → Import
3. Separator: Semicolon
4. Field 1 → Front, Field 2 → Back
5. Import → exactly 31 cards

---

What are reticulocytes?;Non-nucleated red cell precursors | Have blue-red polychromatophilic cytoplasm due to residual ribosomal RNA (mesh-like reticular network)
How are reticulocytes visualized on smear?;Supravital stains — methylene blue or brilliant cresyl blue | Stain the ribosomal RNA | NOT seen on routine Giemsa stain
What is the normal reticulocyte count?;0.5–1.5% of total red cells
What does reticulocytosis indicate?;Effective erythropoiesis — good bone marrow response to anemia | Seen in: Hemolytic anemias | Acute blood loss
What does reticulocytopenia indicate?;Ineffective erythropoiesis — poor bone marrow response | Seen in: Aplastic anemia | Chemotherapy | Bone marrow malignancy | Anemia of chronic disease | Iron deficiency anemia | Vitamin B12/Folate deficiency
Why is reticulocyte count HIGH in hemolytic anemias like PK and G6PD deficiency?;Increased RBC destruction → bone marrow compensates → releases more reticulocytes into circulation (effective erythropoiesis)
What is the corrected reticulocyte count formula and why is it used?;Corrected count = Reticulocyte% × (Patient Hb ÷ 15) | Raw % is falsely high in anemia because fewer total RBCs — correction adjusts for the dilution effect
What is Reticulocyte Production Index (RPI) and its interpretation?;RPI = Corrected reticulocyte count ÷ Maturation factor | RPI >3 = Hemolytic anemia or acute blood loss (hyperproliferative) | RPI <2 = Hypoproliferative anemia (iron deficiency, aplastic, B12/folate deficiency)
What is polychromasia on routine smear and what does it represent?;Blue-tinged RBCs on Giemsa stain = reticulocytes released early from marrow | Indicates stress erythropoiesis or active hemolysis

---