Red Cell Disorders

Hemoglobinopathy

Sickle Cell Disease (discussed below)

Thalassemia (discussed below)

Hemoglobin C

• Substitution of lysine for glutamic acid in 6th position of the beta globin chain

• Subtypes:

  • Hb AC (Hb C trait):

    • No symptoms

  • Hb CC (Hb C disease):

    • Causes HbC crystals

    • Symptoms: anemia, mild hemolytic anemia (prone to gallstone), splenomegaly

  • Hb SC:

    • less sickling and vaso-occlusive events compared to Hb SS

    • More retinopathy, priapism and ischemic necrosis of bones

Hemoglobin E

• Substitution of lysine for glutamic acid in 26th position of the beta globin chain

• Common in India, Southeast Asia, Bangladesh

• Heterozygous: No anemia but microcytosis

• Homozygous: microcytic anemia with large target cells

Hemoglobin Lepore

Hemoglobin M

• Genetic cause of methemoglobinemia

  • Can cause cyanosis, otherwise asymptomatic

• Can be due to mutations in alpha, beta or gamma globin genes, but normal methemoglobin reductase level

• Heme iron is locked in ferric state

• Methemoglobin level is 15-30%

• Life expectancy is unaffected

Sickle Cell Disease (SCD)

• Due to 6th amino acid in beta chain changed from glutamate (charged) to valine (hydrophobic)

  • Less soluble in hypoxic conditions → sickling in affected individuals

    • Less common in individuals with Sickle Cell Trait (heterozygous)

      • Electrophoresis for trait: ~40% Hb S, ~60% Hb A2

      • Associated with medullary RCC

• Protects against malaria, hence its geographic distribution

• Other variants:

  • Hgb SC disease

    • Sickle trait with HbC disease

      • Slightly worse phenotype than sickle cell trait alone, less anemic than Hgb S

      • More retinopathy, priapism and ischemic necrosis of bones

    • 50% HgbS, 50% HbC (runs like Hgb A2)

  • Sickle Beta Thalassemia

    • Heterozygous state involving one sickle cell gene (HbS) and one beta thalassemia gene

    • Types:

      • Sickle beta zero thalassemia (S-β⁰):

      • No beta globin production from the thalassemia allele, so no HbA is produced.

      • The clinical presentation is indistinguishable from sickle cell anemia (HbSS).

      • Sickle beta plus thalassemia (S-β⁺):

      • Some beta globin is produced, resulting in variable amounts of HbA.

      • Clinical severity is generally milder than S-β⁰ or HbSS.

        • Electrophoresis: ~60% Hb S, 4-30% Hb A2, <20% Hb A

• Clinical features include:

  • Chronic Pain

  • Pain Crises

  • Infection

    • Encapsulated organisms (due to splenic dysfunction)

      • S. pneumoniae, H. influenzae type b and N. meningitidis

    • Salmonella osteomyelitis

      • Most probably due to Salmonella

  • Long term sequelae affecting multiple organ systems

    • Long term hemolysis → free Hb binds NO → Pulmonary hypertension, leg ulceration, priapism, stroke

      • No role for sildenafil in patients → more pain crises

    • Vaso-occlusion → pain crises, acute chest syndrome, osteonecrosis, retinal vessel occlusion/neovascularization

    • Thrombosis risk (more PE than DVT)

  • Aplastic crisis

    • Associated with parvovirus infection

      • Binds P antigen

  • Hyperhemolysis

    • Almost immediately after transfusion

      • Avoid further transfusions if possible

  • Splenic sequestration crisis

    • Extensive trapping of RBCs in spleen → rapid anemia, hypovolemic shock

    • The size of spleen regress after patient receives blood transfusion

      • Helps to differentiate it from hypersplenism which size of spleen does not regress after blood transfusion.

    • Splenectomy should be considered due to risk of recurrent sequestration

  • Acute chest syndrome

    • Fever, cough, chest pain, hypoxia, infiltrate on XR chest

    • Caused by acute stressors: infection, hypoxia, PEs, etc. 

    • Treated with O2, antibiotics, transfusion (simple vs. exchange), and incentive spirometry

  • Stroke

    • Treat with exchange transfusion in acute setting

    • Recommended to perform chronic transfusion therapy for prevention (goal Hb S <30%)

  • Renal papillary necrosis

    • Can cause hematuria and flank pain

• Vaccination:

  • S. pneumonia, N. meningitides, Haemophilus influenzae

  • Seasonal flu

  • Hepatitis B

• Treatments:

  • Hydroxyurea

    • Decreased vaso-occlusive pain, ACS, transfusion needs, priapism

    • Improved survival and quality of life

    • For all patients regardless of age and history of vaso-occlusive episodes.

      • Can start during infancy

      • Exceptions: pregnancy and time of conception (both males and females)

    • Increases fetal hemoglobin (goal Hb F >20%) and therefore less Hgb S

    • Complications: bone marrow suppression (most common), GI upset

  • L-glutamine (Endari)

    • Oral

    • Amino acid leads to decreased oxidative stress → less acute pain episodes

    • Indication: If patient has ≥2 pain episodes per year despite hydroxyurea

  • Crizanlizumab

    • Monoclonal antibody against p-selectin

    • Reduces frequencies of vaso-occlusive crises

    • IV given at 0, 2, and 4 weeks

    • Indication: If patient has ≥2 pain episodes per year despite hydroxyurea (or if they cannot receive hydroxyurea)

  • Voxelotor

    • Oral 

    • Binds Hb S and stabilizes the oxygenated form → reducing sickling

    • Increases hemoglobin values, reduces hemolysis

    • Can’t be stopped suddenly

  • Transfusions:

    • Simple: 

      • Any acute need for increased O2 carrying capacity

      • Symptomatic anemia

      • Hb goal around 10

      • Beta4 tetramers present

      • Forms Heinz bodies, which cause “bite cells”

      • Acute chest syndrome

      • Prior to/during major surgery (if needed)

    • Exchange: 

      • Goal is to reduce Hb S% quickly: Goal Hb S is 30% (STOP trial)

      • Used for stroke treatment/prevention, life/organ threatening vaso-occlusive event (severe acute chest syndrome), acute severe cholestasis/RUQ syndrome

      • NOT for pain crisis

      • Possibly helps prevent iron accumulation

    • Avoid transfusing blood with C, E, and Kell antigens

    • Transfusion is NOT indicated for:

      • Anemia, uncomplicated pain, infections, minor surgery, avascular necrosis, uncomplicated pregnancies

      • Excess transfusion can lead to alloimmunization and iron overload

  • Gene therapy

    • Casgevy: Exagamglogene autotemcel

    • Lyfgenia: Ovotibeglogene autotemcel

  • ACE inhibitor/ARB

    • Reduce proteinuria

  • Pain management

    • Morphine, hydromorphone and fentanyl

    • Avoid meperidine (increases risk of seizure) and ketorolac 

Thalassemia

• Normal Hgb Electrophoresis: Hb A (95-98%), Hb A2 (2-3%), HbF (~1%)

  • Hgb A: alpha2, beta2

  • Hgb A2: alpha2, delta2

  • Hgb F: alpha2, gamma2

• Also provides protection against malaria, hence its geographic distribution

• Typically we can find full deletions of alpha genes and point mutations in beta genes

Alpha thalassemia

• Hb F and Hb A2 are usually normal

  • Normally 4 alleles (2 on each chromosome)

    • One alpha deletion (silent carrier):

      • Phenotypically silent, normal electrophoresis

    • Two alpha deletions (Alpha thal trait):

      • Microcytic, mild anemia

    • Three alpha deletions (Hemoglobin H):

      • More anemic, variable severity (some transfusion dependent)

      • Beta4 tetramers present

      • Forms Heinz bodies, which cause “bite cells”

    • Four alpha deletions (Hydrops fetalis):

      • Causes gamma tetramers (in utero): Hemoglobin Barts

      • Typically causes intrauterine death

        • Can be treated by in utero exchange transfusions followed by HSCT

    • Constant spring mutation: 

      • “Non-deletional” type of alpha thal mutation (caused by a point mutation)

      • leads to more severe phenotype in Hgb H

      • MCV is near normal 

• Concurrent alpha thalassemia and sickle cell has milder SS phenotype due to unbalanced globin chain synthesis leading to deficiency in Hb per cell (less sickling)

• Also associated with ATRX (alpha thalassemia/mental retardation syndrome)

  • Regulates expression of HBA1 and HBA2 (alpha genes)

  • Craniofacial features, genital anomalies, severe developmental delays, alpha thalassemia

Beta thalassemia

• Multiple types of mutations: 

  • B0 = absent beta globin synthesis for that allele

  • B+ = decreased, but still present beta globin synthesis

• Beta thalassemia major (Cooley’s Anemia): B0, B0

  • Much more severe phenotype

• Beta thalassemia intermedia: contains at least 1 B+ allele

  • Likely not transfusion dependent

    • B+/B+ might require occasional transfusions

  • Associated with osteoporosis 

• Infants are typically okay at birth due to Hb F but starts to become evident around age 1

  • Electrophoresis will show alpha tetramers

• Symptoms:

  • Microcytic anemia

  • Splenomegaly

  • Bony deformities (bossing)

  • Iron overload (due to transfusions, increased absorption from gut)

  • Extramedullary hematopoiesis due to ineffective erythropoiesis/hemolysis

• Treatments:

  • Luspatercept (BELIEVE)

    • Decreases blood transfusion requirement

  • Gene therapy: 

    • Betibeglogene autotemcel

    • Exagamglogene autotemcel (CRISPR/Cas9 gene-edited cell therapy)

  
  

Erythrocytosis/Polycythemia

• Generally defined as:

  • Males: Hb >16.5 and HCT >49

  • Females: Hb >16 and HCT >48

• Work up: First check EPO level

  • If EPO high/inappropriately normal → secondary polycythemia

    • Due to physiological stressor (smoking, obesity, sleep apnea, living in high elevations) or EPO secreting tumor

    • If patient with history of renal transplant, consider post transplant erythrocytosis (PTE)

      • Treat with ACE/ARB

      • If unable to tolerate higher doses, then consider phlebotomy

  • If EPO low → primary polycythemia

    • Consider polycythemia vera (PV) or another myeloproliferative neoplasm (MPN)

      • PV is associated with headache, dizziness, pruritus (after shower), early satiety

      • Related mutations:

        • JAK2 V617F mutation : If positive, consider BMBx

        • MPL, CALR: Also associated with essential thrombocythemia/myelofibrosis

        • BCR/ABL: Associated with Chronic Myeloid Leukemia

        • VHL gene (Chuvash): mutations in EPO receptor

Methemoglobinemia

• Congenital/Acquired

• Due to deficiency of cytochrome b5 reductase

  • Type 1: only affects RBCs

  • Type 2: affects all cells

    • Associated with development abnormalities, most infants die in the first year of life

  • Methemoglobin level:

    • If >20%: patient will develop clinical symptoms (respiratory depression, confusion)

    • If >40%: life threatening

• Prevention:

  • Avoid agents that may induce methemoglobinemia (nitrates, dapsone, benzocaine)

• Treatment: 

  • Methylene blue 1% with dose 1-2 mg/kg IV in 5 min

    • Allows iron in Hb to become ferrous (2+)

  • Ascorbic acid

  • Blood transfusion or exchange transfusion if symptoms are severe