Pocket Oncology (Pocket Notebook Series), 1st Ed.

HEMOGLOBINOPATHIES

Alexander N. Shoushtari and Rekha Parameswaran

Physiology

• Hb = 2 pairs of 2 globin chains, eg, NL adult has majority HbA = α2β2; also HbA2 = α2Δ2; HbF = α2γ2

• Globin Mt → α ≠ β or shape change → RBC changes → clinical manifestations; protect against malaria (Nature 1986;321:744)

• Nomenclature: α° or β° = sev. Mt; α+ or β+ = milder Mt

• Dx: Periph smear, Hb electrophoresis (if not recently transfused), genetic testing

Alpha Thalassemia

• Genetics: 2 loci on each Chr 16; αα/αα = NL. Mt: α–/α– = trans, αα/– = cis

• Epidemiology: S. & SE Asia (cis deletion), Sub-Saharan Africa (trans deletion), Mediterranean, Middle East. Incr incidence in US from immigration.

• Alpha Thal (0), Homozygous = –/– = Hb Bart’s (γ4 tetramers) → hydrops fetalis, incompatible w/extrauterine life. Incidence ↑ in Asians due to ↑ cis deletion.

• Alpha Thal major = α–/– → HbH disease = neonatal jaundice b/c no HbF; HSM, hemolytic anemia, chronic leg ulcers.

• Alpha Thal Trait = α–/α– or αα/– → mild microcytic anemia, reduced MCH

• Alpha Thal Minima = αα/α– → Silent carrier, no hematologic manifestations

Beta Thalassemia

• Genetics: 1 locus on Chr 11; β/β = NL. Autosomal recessive inheritance.

• Epidemiology: Highest in Mediterranean, N Africa, Middle East, W Asia

• Beta Thal Major, eg, β°/β° = Cooley Anemia. Jaundice > 6 mo after ↓ HbF, ineffective hematopoiesis → sev. skeletal abnl, poor growth; extravascular hemolysis → HSM, biliary stones. Transfusion dep→ allo-Abs & iron overload. Suscept to Yersinia infxn; Parvo B19 → aplastic crisis. Chronic hypoxia → pulm HTN, cardiac tox.

• Beta Thal Minor/Trait, eg, β/β+ or β/β° – mild anemia w/sev. hypochromia & microcytosis. MCV/RBC ratio <13. RDW NL (contrast w/iron-def anemia). Typically free of sev. sx.

• Beta Thal Intermedia, eg, β°/β+ – varying degrees of anemia & transfusion dependence, growth, HSM.

• Tx: Splenectomy, chronic transfusion, iron chelation, folate supplementation. Only curative option is allogeneic SCT.

Hemoglobin C Disease

• Genetics: β-globin gene: 6th AA Glu→Lys. Autosomal recessive.

• Epidemiology: ↑ freq in African-Americans (2% carrier, 1:6000 homozygous)

• Dx: Mild hemolytic anemia w/↑bili.; smear w/microcytes, target cells, & RBCs w/inclusions of HbC crystals

Sickle Cell Disease

• Genetics: Beta globin – 6th AA: Glutamine → Valine = HbS. Autosomal Recessive. If coinherited w/other hemoglobinopathies, generally ↓ sx severity if ↑ HbF (eg, HbSC, HbS/β+)

• Epidemiology: African-Americans: 1:400–600 S/S disease. 8% Carrier rate (A/S) = Sickle cell trait → Asymptomatic

Vasoocclusive Crisis (VOC)

• Triggers: Triggered by infxn, trauma, other stress

• Pain – tx w/O2, IVFs, analgesia

• Acute Chest Syndrome: Major source of mortality

Dx by new infiltrate, often w/pain, tachypnea, hypoxia, confusion, fever

Triggers: Recent or current VOC, infxn, fat embolism

Tx: Exchange or simple transfusion (HbS < 30%), O2, euvolemia, broad abx

Acute Anemia

• Exacerbation of Hemoglobinopathy: Hemolytic anemia → ↑ LDH, ↑ unconj bili., ↓ hapto, ↑ retic. DAT–. Often occurs w/VOC as above.

• Delayed Hemolytic Transfusion Reaction (DHTR): 5–15 d after transfusion, due to alloimmunization; up to 50% have Ab against minor blood Ag (Blood 2012;120:528). Dx w/DAT (+) Ab in elution. Prev: Minimize transfusions, perform extended-Ag matching (Rh, Kell, Duffy, Kidd, MNS groups).

• Hyperhemolytic Crisis—↑↑hemolysis due to DHTR against pt’s own RBCs. ↑ retic (contrast w/aplastic crisis).

• Splenic Sequestration: Esp in younger pts; sev. HSM, life-threatening rapid drop in Hb may → shock

• Aplastic Crisis: Retic <1% despite brisk hemolysis; often Parvo B19 trigger

Clinical Sequelae and Chronic Complications

• Cardiopulmonary: Cardiomegaly, pulm HTN (major cause of mortality)

• Endocrine: Delayed puberty, growth delay, short stature

• GU: Priapism → impotence; tx intracavernous aspiration, phenylephrine

• Hematologic: Anemia; Chronic transfusions → alloimmunization & Fe-overload → multiorgan dysfxn (esp liver, endocrine, cardiac)

• Hepatobiliary: Pigment gallstones; frequently require CCY

• ID: Functional asplenia →↑↑ risk encapsulated bacterial infxn (S pneumo, H fluNeisseria; Salmonella, & S. aureus osteo)

• Musculoskeletal: Dactylitis in infancy (sausage digits), AVN of femur/humerus, osteomyelitis

• Neuro: ↑↑risk of CVA; screen w/transcranial Doppler in children (NEJM 1992;326:605); if abnl → simple transfusion to ↓ HbS <30% (STOP, NEJM 1998;339:5) ↓ risk by >90%. Acute tx: Exchange transfusion; chronic tx: Simple transfusion & chelation superior to hydroxyurea (SWiTCH, Blood 2012;119:3925)

• Ophtho: Proliferative retinopathy → detachment, ↑↑ risk for Hb SC disease.

• Renal: Hematuria, papillary necrosis, CKD, RTA, nephrogenic DI

• Skin: Chronic leg ulcers, poor wound healing

Chronic Management

• Vaccinations—CDC rec: pneumococcal 13-valent × 1, pneumococcal polysaccharide q5y × 2 (>8 wk s/p 13-valent), meningococcal, influenza; consider HAV, HBV; H. flu if not given as child

• Maintenance Meds: Hydroxyurea ↑ HbF, ↓ VOC risk (NEJM 1995;332:1317); poss mortality benefit (JAMA 2003;289:1645). Folate supp given ↑ RBC turnover; Fe chelation for chronic Fe overload (eg, deferoxamine, deferasirox)

• Simple Transfusion: Adding HbA → dilutes HbS. Minimize use; avoid “goal” Hb unless CVA, acute chest, or sev. organ dysfunction. Extended-Ag matching preferred when available to ↓ alloimmunization risk.

• Exchange Transfusion: Adding donor HbA removes HbS (goal < 30%); often requires apheresis catheter, ICU-level care. Indicated for CVA, sev. acute chest, refractory priapism, end-organ dysfunction

• Curative Tx: Nonmyeloablative-matched related donor Allo-SCT (NEJM 2009;361:2309)