CM lect 5: Hemolytic Anemia Hemoglobinopathies 2026

heme

made of iron and protoporphyrin

globin

protein that binds/transports o2

Hb A

Adult hemoglobin

-Alpha chain: chromosome 16, 2 genes each (FOUR total), disrupted by DELETION

-Beta chain: chromosome 11, 1 copy each (TWO total), usually disrupted by POINT mutation

Hb A2

2 alpha chains, 2 delta chains

Hb F

2 alpha chains, 2 gamma chains

-At birth, newborn has 60-80% HbF

-Eventually (around 6 mos, by 1 yoa), switch in production from HbF -> HbA

-Gamma replaced by beta

thalassemias

What disorder:

Problems w/ synthesis of GLOBIN chains

-Thought to protect carries from plasmodium falciparum MALARIA

• Def in alpha chains = alpha thalassemia

• Def in beta chains = beta thalassemia

-Severity depends on how many chains are absent

-RBC will be MICROCYTIC and can appear target-like

alpha thalassemia

What disorder:

-Etiology: gene DELETION

-asian and african descent

-Manifests in BOTH fetal and adult, b/c alpha chains are common among HbF and HbA

• ¼ genes: carrier state, asymptomatic

• 2/4 genes: trait/minor, mild symptoms

• ¾ genes: moderate to severe, HbH disease

• 4/4 genes: HYDROPS FETALIS -> incompatible w/ life

Hb H disease

What disorder:

-alpha thalassemia with ¾ genes deleted

-HbH = tetramer of BETA chains

-May require episodic transfusion

-May have EXTRAMEDULLARY HEMATOPOIESIS

hydrops fetalis

What disorder:

-Complete LACK of alpha chains -> severe anemia -> hydrops fetalis

-Hb BARTS: tetramers of GAMMA globin

-Fetus develops: anemia, organomegaly, hypoalbuminemia, heart failure, ASCITES, effusions, etc.

-often fatal in utero

-Confirm diagnosis: chorionic villus sampling, amniocentesis, fetal blood sampling

-management/tx: intrauterine infusion therapy, chronic transfusions, phototherapy

beta thalassemia

What disorder:

-More common in MEDITERRANEAN ancestry

-Caused by gene MUTATIONS

-Will manifest in first year of life as gamma chains in HbF are replaced by beta in HbA

-Two genes:

• ½ mutated: minor, mild, carrier ‘trait’

• 2/2 w/ SOME being made: intermedia

• 2/2 w/ NO production: major, COOLEY anemia

-erythroid hyperplasia

beta thalassemia trait

What disorder:

½ mutated beta genes: minor, mild, carrier

-May have mild anemia w/ microcytosis -> may be mistaken for IRON def anemia

monitor and observe, folic acid, transfusions as needed

management of beta thalassemia minor/intermedia

beta thalassemia intermedia

What disorder:

2/2 mutated beta genes with some beta globin production

-varying degrees of anemia, transfusion requirements

beta thalassemia major (cooley’s anemia)

What disorder:

2/2 mutated beta genes w/ NO production of beta chains/HbA

-Symptoms occur 6-12 mos after birth

-Clinical manifestation: severe anemia, jaundice, hepatosplenomegaly, EXTRAMEDULLARY HEMATOPOIESIS

protein electrophoresis, high performance liquid chromatography, genetic testing

dx of beta thalassemias

scheduled RBC infusions, increased risk of HEMOCHROMATOSIS (may need iron CHELATION therapy), splenectomy, stem cell transplant, induction of Hb F, gene therapy

management of beta thalassemia major

erythroid hyperplasia

what symptom:

-Erythroid hyperplasia: thickened bone marrow, FACIAL bone changes, increased fracture risk, and ectopic hematopoiesis

sickle cell trait

What disorder:

HETEROZYGOUS; inherited one HbS gene from one parent and a normal HbA gene from the other

-Do not have clinical symptoms, unless subject to severe STRESS

• Dehydration, hypoxia, strenuous athletic training

• Most pts have NORMAL life expectancy

-Rare: splenic infarction, strokes, or sudden death

-At risk for sickling of the RENAL MEDULLA -> painless HEMATURIA from medullary infarction

-Selective advantage for malaria

sickle cell disease

What disorder:

Point mutation in beta globin gene -> chronic hemolytic anemia w/ vaso-occlusion episodes and vasculopathy

-Can cause chronic organ damage and cause premature mortality

-Etiology: AR; intra- and extravascular hemolysis

• HbS: VALINE instead of normal GLUTAMIC ACID on position 6 on chromosome 11

• HbS under LOW O2 -> polymerizes and distorts -> sickle shape -> risk of vaso-occlusion and hemolysis

• Clinical severity of disease depends on the amount of HbF, as HbF as HIGH AFFINITY for O2 and does NOT sickle

• HYDROXYUREA increases HbF production

MSK pain, swollen digits, fatigue, SOB, weakness, chest and abdominal pain

scleral icterus, pale conjunctiva, jaundice, lethargy, fever, splenomegaly, hematuria

presentation of sickle cell disease

sickled cells seen on peripheral smear

labs of sickle cell disease

dactylitis, bone deformities, SPLENIC enlargement/splenic infarction, vaso-occlusive crisis, ACUTE CHEST syndrome, stroke, pulmonary HTN, priapism

complications of sickle cell disease

osteonecrosis, hemosiderosis, infarctions, marrow hyperplasia, osteomyelitis (SALMONELLA)

bone effects of sickle cell disease

RBC sequestration, infarction, INVOLUTION, loss of immune function against encapsulated bacteria (AUTOSPLENECTOMY)

spleen effects of sickle cell disease

supplemental O2, IV fluids, pain management

tx for vaso-occlusive crisis

acute chest syndrome

What disorder:

Pulmonary vaso-occlusive crisis

-Triad: chest pain, pulmonary infiltrates, arterial hypoxemia

-Often very difficult to distinguish b/w this and PNEUMONIA -> so tx w/ antibiotics

-If necessary, exchange transfusion to replace at least HALF of pt’s HbSS blood w/ normal HbAA blood

acute chest syndrome

Most COMMON cause of death in children and adults w/ HbSS

newborn screen, HPLC, hgb electrophoresis

diagnosis of sickle cell disease

Prophylactic and chronic: folic acid, vaccinations, HYDROXYUREA, daily penicillin until 5 yoa

management of sickle cell disease

Higher level of care: hospital for IV fluids, Abx, O2, blood transfusion, exchange transfusion, HSC transplant

acute tx of sickle cell disease

hydroxyurea

only drug approved for sickle cell disease

-Increase in NO -> increase in cGMP -> increase in globin synthesis -> HbF

-decreased transfusions, painful crisis, mortality, and hospitalizations