Hereditary hemolytic anemias

Red Cell Membrane Disorders (Overview)

• Presentation: anemia, with or without acute hemolysis. History is negative for poor diet and blood loss, and potentially positive for neonatal jaundice, intermittent jaundice, and family history (anemia, jaundice, transfusion, splenectomy, or cholecystectomy). Exam: scleral icterus, splenomegaly. CBC/retic: MCV variable (often normal in HS), retic elevated. Always review the smear.
• Vertical vs horizontal associations: proteins in vertical associations (link the cytoskeleton to the lipid bilayer) are affected in hereditary spherocytosis; proteins in horizontal associations (link cytoskeletal elements to each other) are affected in hereditary elliptocytosis.

Hereditary Spherocytosis (HS)

• Pathophysiology: the most common hemolytic anemia due to a red cell membrane defect (about 1 in 2000). Reduced vertical association between the cytoskeleton and membrane causes microvesiculation and progressive membrane loss, reducing the surface-area-to-volume ratio to make spherocytes. Spherocytes are less deformable and are phagocytosed by splenic macrophages, giving extravascular hemolysis.
• Inheritance: autosomal dominant in about 75%; the remainder is autosomal recessive or de novo/sporadic dominant.

• Clinical features: anemia, jaundice, and splenomegaly of variable severity; can present at any age (hydrops fetalis to 90 years). Pigment gallstones from chronic hemolysis. Aplastic crisis with parvovirus B19; hemolytic crisis with infection.
• Diagnosis: spherocytes on smear without DAT positivity (distinguishes from AIHA), ↑ MCHC (concentrated, dehydrated cells), reticulocytosis, ↑ indirect bili, ↓ haptoglobin. EMA binding by flow cytometry is a preferred first-line test with high sensitivity (~93%) and specificity; a normal result does not exclude HS (acidified glycerol lysis ~95%; combining assays detects nearly all). Osmotic fragility is the traditional test; genetic testing is an alternative.
• Treatment:
  • Folate supplementation 1 mg/d.
  • Splenectomy for moderate to severe disease (Hb <8 with symptoms, growth failure, severe hemolysis): cures hemolysis (RBCs survive). Vaccinate first (pneumococcal, Hib, meningococcal). Risks: post-splenectomy infection (encapsulated organisms), thrombosis, pulmonary HTN. Generally defer until after age 5 to 6; adolescents may consider splenectomy for mild anemia for quality-of-life reasons (scleral icterus). Transfusion for severe anemia or aplastic crisis.
  • Cholecystectomy for symptomatic gallstones; consider concurrently at splenectomy.
  • Partial or laparoscopic splenectomy increasingly considered. Mild HS may not require splenectomy.
• Spherocytes on smear (board differential): hereditary spherocytosis, immune-mediated hemolytic anemia, cold agglutinin disease, extensive thermal burns, snake bites, scorpion bites, brown recluse spider bites, Clostridium sepsis.

Hereditary Elliptocytosis, HPP, and Stomatocytosis

• Hereditary elliptocytosis (HE): affects proteins in horizontal associations, commonly spectrin (SPTA, SPTB) or protein 4.1. Southeast Asian, African, and Mediterranean backgrounds; protective against malaria; mostly autosomal dominant. Clinically mild with minimal hemolysis; prevalence likely underdetected. Diagnosis primarily by smear (elliptocytes).
• Hereditary pyropoikilocytosis (HPP): on a spectrum with HE, from a spectrin mutation. Variable hemolysis, worse in early childhood; many asymptomatic; smear shows bizarre-shaped RBCs and is typically microcytic. Splenectomy often needed for the severe variant.
• Hereditary stomatocytosis: stomatocytes; overhydrated or dehydrated forms. AVOID splenectomy (↑ thrombosis risk).

Red Cell Enzyme Disorders (Overview)

• Red cells derive energy from glycolysis. Glycolytic defects (eg, PK) impair ATP production and shorten RBC survival. G6PD is in the pentose phosphate pathway and supplies NADPH for antioxidant defense (its deficiency causes oxidant injury); pyrimidine 5'-nucleotidase is in pyrimidine metabolism, not glycolysis. Includes G6PD, pyruvate kinase, pyrimidine 5'-nucleotidase deficiency (autosomal recessive, rare), and glucose phosphate isomerase deficiency (autosomal recessive).

G6PD Deficiency

• Pathophysiology: X-linked. G6PD generates NADPH, which maintains glutathione (GSH) and protects RBCs from oxidative damage. Deficient G6PD lets oxidative stressors damage Hb, forming Heinz bodies, which are pitted by the spleen to give bite/blister cells.
• Clinical history: early or prolonged neonatal jaundice; an exposure (medication or infection) preceding the hemolytic event; background Mediterranean, Middle Eastern, African, or Southeast Asian; family history of acute hemolytic events or transfusion. Presents with an acute hemolytic episode or (less commonly) mild baseline hemolytic anemia.

• Triggers (oxidative stress):
  • Drugs: dapsone, primaquine, nitrofurantoin, methylene blue, rasburicase, henna, nalidixic acid, phenazopyridine. Not on this list: sulfamethoxazole (TMP-SMX) and sulfasalazine are low-to-no risk at standard doses (CPIC).
  • Foods: fava beans (favism, especially the Mediterranean variant).
  • Infection: a common (often unrecognized) trigger. DKA can trigger. Naphthalene (mothballs), especially in neonates.
• Diagnosis: blister cells on smear at the time of the hemolytic event; G6PD activity assay. Pearl: a NORMAL G6PD level during acute hemolysis can be falsely normal (deficient older cells lysed, reticulocytes have higher G6PD); a LOW level still confirms deficiency. Repeat 2 to 3 months after recovery if normal.
• Treatment: supportive (IV fluids, transfusion if severe); identify and remove the trigger; counsel on drug and food avoidance. Most patients do not need long-term hematology follow-up.
• Special, rasburicase is contraindicated in G6PD deficiency (severe oxidative hemolysis). Use allopurinol instead; screen at-risk populations before rasburicase.

Pyruvate Kinase (PK) Deficiency

• Pathophysiology: autosomal recessive (PKLR gene), prevalence about 1 in 20,000, with potential consanguinity and high prevalence in the Amish population. Reduced RBC ATP shortens lifespan and causes splenic destruction. Increased 2,3-DPG results in increased O2 off-loading (a relative benefit).
• Clinical: moderate chronic hemolysis at baseline with episodes of acute worsening (for example, with infection); the smear is often unimpressive (echinocytes may be seen). Splenomegaly, pigment gallstones, iron overload from chronic hemolysis and transfusions.
• Diagnosis: PK enzyme activity assay and sequencing (PKLR).
• Treatment:
  • Supportive (adequate nutrition) and folate.
  • Splenectomy typically indicated for moderate to severe disease; it does not raise Hb as dramatically as in spherocytosis but may add about 1 g. Board pearl: after splenectomy the reticulocyte count rises markedly, because the spleen preferentially sequesters reticulocytes in PK deficiency.
  • Mitapivat (Pyrukynd): allosteric activator of red-cell PK. FDA Feb 2022 for PK deficiency in adults; transformative (ACTIVATE trials). Common side effects: hormonal disturbances, transaminitis; hepatocellular injury warning (monitor LFTs). Also FDA Dec 2025 (as Aqvesme) for anemia in adult alpha- or beta-thalassemia (ENERGIZE, ENERGIZE-T), with a boxed warning for hepatocellular injury and a REMS.
  • Iron chelation if overload develops.

Other Hereditary Hemolytic Anemias

• Pyrimidine 5'-nucleotidase deficiency: autosomal recessive (<10% activity); the most common enzymopathy of nucleotide metabolism. Smear shows basophilic stippling (a lead-poisoning mimicker); diagnosis by screening for ↑ pyrimidine nucleotides in RBCs and molecular testing. Hemolysis with occasional neurologic findings.
• Glucose phosphate isomerase deficiency: autosomal recessive; the second most common glycolytic enzyme defect.
• Hexokinase deficiency: similar to PK; rare.
• Hereditary xerocytosis (PIEZO1): dehydrated stomatocytes; AVOID splenectomy (↑ thrombosis).

High Yield (Hereditary Hemolytic Anemias)

• Spherocytes with a negative DAT support HS in context but are not diagnostic (DAT-negative AIHA exists); a positive DAT indicates immune hemolysis, interpreted by IgG vs C3 (IgG = warm AIHA, C3 = cold agglutinin disease/drug-induced).
• HS proteins: ankyrin (ANK1) most common, then band 3, spectrin, protein 4.2 (vertical associations).
• HS diagnosis: EMA binding (flow cytometry) is a preferred first-line test (normal result does not exclude HS; add AGLT if suspicion persists); osmotic fragility traditional.
• HS treatment: folate plus splenectomy for moderate to severe disease (vaccinate first; defer until after age 5).
• HE: horizontal associations (spectrin, protein 4.1); mild; protective against malaria.
• G6PD A- vs Mediterranean: A- (class III) usually mild self-limited; Mediterranean (class II) severe.
• G6PD level can be FALSELY NORMAL during acute hemolysis (only younger cells with intact G6PD remain); retest 2 to 3 months later.
• Bite/blister cells plus Heinz bodies plus an oxidative trigger = G6PD.
• Rasburicase contraindicated in G6PD.
• PK deficiency: echinocytes; increased 2,3-DPG; reticulocytosis after splenectomy; mitapivat (FDA Feb 2022), the first PK activator.
• Hereditary stomatocytosis/xerocytosis: avoid splenectomy (thrombosis risk).
• Basophilic stippling: pyrimidine 5'-nucleotidase deficiency (or lead poisoning).
• Pigment gallstones classic in chronic hemolysis (HS, SCD, thalassemia, PK).