Disorders of Hemoglobin¶

Chapter 103 | Part 4: Oncology and Hematology · Part 4 – Oncology: Hematologic Malignancies · Chapter 103

Key Clinical Points¶

HbS polymerization is dependent on the 30th power of hemoglobin concentration; small changes in concentration have large effects on polymerization.
Hydroxyurea is the standard of care for all patients with sickle cell anemia and HbS-β0 thalassemia regardless of symptoms; it induces high levels of HbF (30–50% increase).
Transcranial Doppler screening is recommended in children ages 2–16 for stroke prevention in sickle cell disease.
Anemia of aging is multifactorial; prevalence is ~10% at age 65, 25% in people >85 years, and 50% in those with multimorbidity.
The proposed ferritin cutoff for iron deficiency in elderly patients is higher (45–70 μg/L) than in younger patients.
Acute chest syndrome is the second most frequent acute sickle cell–related event; occurs in >50% of patients, often more than once.
BCL11A and ZBTB7A are major repressors of HbF gene expression; mutations in binding sites lead to hereditary persistence of fetal hemoglobin (HPFH).
Sickle cell trait prevalence is 2–15% in emigrant populations; complications include hematuria, papillary necrosis, and increased VTE risk.
Exchange transfusion is the preferred modality for severely ill patients with acute chest syndrome if simple transfusion is insufficient.
In HbSC disease, patients are nearly asymptomatic to disease as severe as HbSS; complications rate is about half that of HbSS.

1. DEFINITION & CLASSIFICATION¶

• Definition: Disorders of hemoglobin are the most common Mendelian genetic diseases and account for most cases of hemolytic anemia. • Key Disorders: • Sickle cell disease • β- and α-thalassemia • Hemoglobin E (HbE)-associated syndromes • Hemoglobin Structure & Function: • Tetramer of two α-globin and two β-like globin chains. • Each contains a heme group for oxygen binding. • Binding influenced by 2,3-bisphosphoglycerate (2,3-BPG). • Functions as a nitrate reductase, releasing NO from nitrite to promote vasodilation. • Classification (Table 1): • I. Hemoglobinopathies: • A. Common variants with unusual properties (HbS: polymerization; HbE: reduced biosynthesis; HbC: hemoglobin-membrane interaction). • B. Altered oxygen affinity (High affinity → erythrocytosis; Low affinity → cyanosis, anemia). • C. Hemoglobins that oxidize readily (Unstable hemoglobins → hemolytic anemia, jaundice; M hemoglobins → methemoglobinemia, cyanosis). • II. Thalassemias: • α, β, and Complex thalassemias. • III. Hereditary persistence of fetal hemoglobin (HbF): • Deletions within the HBB cluster (15–30% HbF in heterozygotes) or mutations in HBG2/1 promoters. • IV. Acquired hemoglobinopathies: • Methemoglobin, Sulfhemoglobin, Carboxyhemoglobin, HbH in erythroleukemia, Elevated HbF in myelodysplasia.

2. EPIDEMIOLOGY¶

• Anemia of Aging: • Prevalence: ~10% at age 65; 25% in people >85 years; 50% in those with multimorbidity. • Causes: Nutritional deficiencies (e.g., iron), inflammation, or unknown causes. • Clinical Note: Adverse effects are seen at lower hemoglobin levels in Black patients compared to White patients. • Sickle Cell Disease (SCD): • Global Prevalence: 2–15% in emigrant populations; ~150,000 annual births with sickle cell anemia in Nigeria. • Genetic Context: HbS originated in Africa due to selection by Plasmodium falciparum. • Mortality: Median age of death in U.S. patients is the fifth or sixth decade.

Sickle Cell Genotype Prevalence¶

• HbS Gene Haplotypes: Correlate with disease severity due to varying HbF levels. • Regional Prevalence: In some regions, nearly half the population has sickle cell trait.

3. ETIOLOGY & PATHOPHYSIOLOGY¶

• Sickle Cell Disease Mechanism: • HbS polymerization upon deoxygenation → erythrocyte sickling → vasoocclusion. • Polymerization Dynamics: • Dependent on the 30th power of hemoglobin concentration. • Small changes in concentration or cell hydration → large effects on polymerization. • Process begins seconds to minutes after deoxygenation. • Cellular Damage: • Irreversibly sickled cells (ISCs) develop from repeated sickling events; membrane is permanently damaged. • Sickle erythrocytes live <20 days (normal ~120 days). • Hemolysis & Inflammation: • Intravascular hemolysis → release of DAMPs, depletion of haptoglobin and hemopexin. • Consequence: Scavenging of nitric oxide (NO), activation of platelets and endothelium, reduced antioxidant activity, and pro-inflammatory state. • Genetic Regulation: • Repressors: BCL11A and ZBTB7A are major repressors of HbF gene expression. • Therapeutic Target: Mutations in binding sites lead to HPFH; CRISPR/Cas9 disruption of these regulators can induce 30–50% HbF.

Molecular Basis¶

• HbS Mutation: Glutamic acid (E7) → Valine (V7) (GAG → GTG).

4. CLINICAL FEATURES¶

• Primary Symptoms: • Pain: Most common acute event; occurs 1–2 times/year in most patients. • Presentation: Hand-foot syndrome (children) or acute vasoocclusive episodes (adults). • Chronic Pain: From osteonecrosis or leg ulcers; note that opioids can cause hyperalgesia. • Acute Chest Syndrome (ACS): • Prevalence: >50% of SCD patients; often occurs more than once. • Etiology: In situ thrombosis, emboli, infection, or hypoventilation. • Presentation: Chest pain, fever, hypoxia, and pulmonary infiltrates.

Chronic Complications (Table 3)¶

• Priapism: ~30% of males; can be episodic/short or severe (impotence risk); associated with markers of hemolysis. • Stroke: 10–15% of all cases; infarction in early childhood into adulthood; associated with markers of hemolysis. • Gallstones: ~40% of patients; related to UGT1A polymorphisms; surgery requires pre-op transfusion to Hb ≥ 10 g/dL. • Nephropathy: ~30% of adults age >30 years; early albuminuria, later nephrotic-range proteinuria; associated with markers of hemolysis. • Retinopathy: 30% in HbSC disease; 3% in HbSS-α; requires annual screening starting at age 10. • Multiorgan Failure: Can accompany severe ACS; often confused with sepsis; can involve CNS, liver, muscle, lung, or kidney.

5. DIFFERENTIAL DIAGNOSIS¶

• Distinguishing Hemoglobinopathies (Table 2): • Sickle Cell Trait (HbAS): • Clinical: Hematuria, papillary necrosis, hyposthenuria; increased VTE risk (2–4x); stroke/splenic infarction at altitude. • Lab: HbA 60–70%, HbS 30–40%; Normal MCV. • Sickle Cell Anemia (HbSS): • Clinical: Vasoocclusion (pain, ACS, osteonecrosis), hemolysis (stroke, pulmonary/systemic vasculopathy). • Lab: HbS >75%, HbF 2–25%; Hb 70–100 g/L; MCV 80–100 fL. • HbS-β0 Thalassemia: • Clinical: Rate of complications similar to HbSS. • Lab: HbS >75%, HbF 2–15%, HbA 5–6%; Hb 80–100 g/L; MCV 60–85 fL. • HbS-β+ Thalassemia: • Clinical: Symptoms delayed; often Asian/Indian ancestry; complications ≈ half of HbSS. • Lab: HbS 60–90%, HbA 5–40%; Hb 100–140 g/L; MCV 70–80 fL. • HbSC Disease: • Clinical: Nearly asymptomatic compared to HbSS; half the complication rate of HbSS; increased risk of retinopathy. • Lab: HbS 50%, HbC 50%; Hb 100–140 g/L; MCV 70–100 fL. • HbSE: • Clinical: Resembles HbS-β+ thalassemia; symptoms delayed; often Asian/Indian ancestry. • Lab: HbS 65%, HbE 35%; Hb 90–130 g/L; MCV 65–75 fL. • HbSS-α Thalassemia: • Clinical: Phenocopies HbS-β0 due to microcytosis and high HbA; fewer strokes/leg ulcers. • Lab: HbS >75%, HbF 2–15%, HbA 4–5%; Hb 80–100 g/L; MCV 60–85 fL. • HbC & HbE (Table 7): • HbC Trait: Target cells, no disease; HbC 30–40%, HbA 2–3%. • HbE Trait: No hemolysis, 20–80% target cells; HbE 27–31%, HbF 1%, HbA 3%. • High O Affinity Hemoglobins: • Isolated erythrocytosis (no JAK2V617F mutation); Hb 150–200 g/L. • Unstable Hemoglobins: • Pigmenturia, hemolysis, reticulocytosis; 20–35% variant.

Anemia of Aging vs. Inflammation¶

• Anemia of Aging: • Unexplained anemia accounts for ~33% of cases. • Treatment: IV iron (target ferritin 200–700 μg/L) and prolyl hydroxylase inhibitors.

6. INVESTIGATIONS & DIAGNOSIS¶

Initial Screening: • Reticulocyte count: >2% indicates hemolytic anemia. • Hemoglobin electrophoresis/HPLC: To identify specific hemoglobin fractions (e.g., HbS, HbF, HbC).
Phenotyping & Genotyping: • Use HPLC to determine percentages of HbA, HbS, and HbF. • DNA sequencing: Required for genetic counseling and identifying specific mutations (e.g., β-globin cluster deletions).
Clinical Correlation: • Compare hemoglobin levels and MCV against Table 2 criteria to differentiate between HbSS, HbSC, and thalassemias. • Identify target cells or sickle cells on peripheral blood smear (Figure 4 & 5).

Laboratory Criteria for Sickle Hemoglobinopathies¶

• HbSS: HbS >75% and HbF 2–25%. • HbS-β0: HbS >75%, HbF 2–15%, HbA 5–6%. • HbSC: HbS 50%, HbC 50%. • HbSE: HbS 65%, HbE 35%.

7. MANAGEMENT & TREATMENT¶

Pharmacologic Management: • Hydroxyurea: Standard of care for SCD and HbS-β0 thalassemia; induces HbF (30–50% increase). • Opioids: Used for acute pain; utilize patient-controlled analgesia or fixed doses with rescue for breakthrough.
Acute Complications Management: • Acute Chest Syndrome (ACS): • Immediate: Supplemental oxygen (if SpO2 <95%), antibiotics (even without culture confirmation). • Setting: ICU admission if hypoxia or fever is present. • Severe Acute Chest Syndrome: • If simple transfusion is insufficient → Exchange transfusion (preferred modality).
Chronic Management: • Thromboembolism Prophylaxis: For vasoocclusive events. • Iron Chelation: Required for patients with thalassemia and iron overload.

Specialized Interventions¶

• Splenectomy: Indicated when transfusion requirements to maintain ideal hemoglobin increase due to splenomegaly. • Transfusion Strategy: For surgery with general anesthesia, simple pre-operative transfusion to Hb ≥ 10 g/dL is recommended.

8. COMPLICATIONS & PROGNOSIS¶

• Prognosis: • Long-term outcomes depend on genotype and treatment adherence. • SCD patients in high-income countries have a median survival into the fifth or sixth decade. • Systemic Complications: • Stroke, pulmonary hypertension, renal failure, and retinopathy.

Thalassemia Specific Complications (Table 5)¶

• Growth Retardation: Often due to delayed/inadequate transfusions. • Splenomegaly: Can trap 1–40% of RBC volume; increases plasma volume → worsens heart failure. Splenectomy indicated when transfusion requirement to maintain ideal hemoglobin increases. Prophylactic penicillin after splenectomy. • Lung Disease: Fibrosis, chronic thromboembolic disease, and reduced nitric oxide bioavailability. • Endocrinopathies: Diabetes, hypothyroidism, hypoparathyroidism, adrenal insufficiency; hypogonadism (sensitive to iron).

9. SPECIAL CONSIDERATIONS¶

• Pregnancy: • Requires close monitoring for vasoocclusive crises and fetal growth restriction. • Family Planning: Screening both patients for hemoglobin disorders with risk counseling is critical. • Anemia of Inflammation/CKD: • Management: Erythropoietin (ESA) to target Hb <11.5 g/dL. • Iron Supplementation: IV preferred in advanced CKD.

Elderly Patients¶

• Iron Deficiency: Use higher ferritin cutoffs (45–70 μg/L) compared to younger patients.

10. KEY PEARLS & HIGH-YIELD POINTS¶

• HbF Induction: A primary therapeutic goal for both SCD and β-thalassemia. • Acute Chest Syndrome: Requires ICU admission if hypoxia or fever is present; use exchange transfusion if simple transfusion fails. • SCD Screening: Transcranial Doppler screening in children ages 2–16 for stroke prevention. • HbSC Distinction: Nearly asymptomatic compared to HbSS; complications occur at roughly half the rate of HbSS.

Reference Tables¶

TABLE 103-1 Disorders of Hemoglobin I. Hemoglobinopathies —hemoglobin variants with amino acid sequence¶

Harrison's 22e, p.770

I. Hemoglobinopathies—hemoglobin variants with amino acid sequence
variants that alter the physical, chemical, or functional properties of
hemoglobin
A. Common variants with unusual properties
1. HbS—polymerization
2. HbE—reduced biosynthesis
3. HbC—hemoglobin-membrane interaction
B. Altered oxygen affinity
1. High affinity—erythrocytosis
2. Low affinity—cyanosis, anemia
C. Hemoglobins that oxidize readily
1. Unstable hemoglobins—hemolytic anemia, jaundice
2. M hemoglobins—methemoglobinemia, cyanosis
II. Thalassemias—defective biosynthesis of globin chains
A. α Thalassemias
B. β Thalassemias
C. Complex thalassemias
III. Hereditary persistence of fetal hemoglobin—persistence of higher than
normal levels of HbF into adult life
A. Deletions within the HBB cluster—15–30% HbF in heterozygotes,
pancellular HbF
B. Point mutations in HBG2/1 promoters—5–30% HbF in heterozygotes;
pancellular or heterocellular HbF
IV. Acquired hemoglobinopathies
A. Methemoglobin due to toxic exposures
B. Sulfhemoglobin due to toxic exposures
C. Carboxyhemoglobin
D. HbH in erythroleukemia
E. Elevated HbF in myelodysplasia
Liver
Bone marrow
HBG1
HBB
HBG2
HBE1
HBD

TABLE 103-2 Common Sickle Hemoglobinopathies GENOTYPE Sickle cell trait (HbAS)¶

Harrison's 22e, p.772

GENOTYPE	CLINICAL ABNORMALITIES	HEMOGLOBIN LEVEL, g/L (g/dL)/MCV, fL	HEMOGLOBIN FRACTIONS (%)
Sickle cell trait (HbAS)	8% of African Americans; hematuria, papillary necrosis, hyposthenuria, increased incidence of chronic kidney disease; 2–4 times increased VTE risk;? stroke; splenic infarction at altitude; rhabdomyolysis	Normal	HbA: 60–70 HbS: 30–40 Percent HbS dependent on presence or absence of α thalassemia
	Vasoocclusion related: pain, acute chest syndrome, osteonecrosis, splenic infarction Hemolysis related: stroke, pulmonary and systemic vasculopathy, nephropathy, leg ulceration gallstones, priapism	70–100 (7–10)/80–100
HbS-β0 thalassemia	Rate of complications similar to HbSS	80–100 (8–11)/60–85	HbS: >75 HbF: 2–15 HbA: 5–6 2
	Rate of complications about half the rate of HbSS depending on percent HbA	100–140 (10–14)/70–80
Hemoglobin SC disease (HbSC)	Nearly asymptomatic to disease as severe as HbSS; about half the rate of complications as HbSS. Increased risk of retinopathy	100–140 (10–14)/70–100	HbS: 50 HbC: 50
	Resembles clinically HbS-β+ thalassemia; symptoms delayed; often Asian/Indian ancestry	90–130 (9–13)/65–75
HbSS-α thalassemia	Present in 30% of HbSS; phenocopies HbS-β0 thalassemia because of microcytosis and high HbA; like HbSS but with fewer strokes and leg ulcers 2 and less pulmonary vascular and renal disease	80–100 (8–11)/60–85	HbS: >75 HbF: 2–15 HbA: 4–5 2

TABLE 103-3 Complications of Sickle Cell Disease COMPLICATION Priapism Stroke and silent infarction Gallstones/surgery¶

Harrison's 22e, p.774

COMPLICATION	INCIDENCE, DIAGNOSIS, AND FEATURES	TREATMENT
Priapism	~30% of males; can be episodic and short duration (stuttering); severe episodes can cause impotence; associated with markers of hemolysis	Many therapies including α-adrenergic agonists, stilbesterol; consult urology for treatment, which is time-critical
	10–15% of all cases; infarction in early childhood into adulthood; hemorrhagic in adults; neurocognitive abnormalities in adults even without apparent stroke; associated with markers of hemolysis
Gallstones/surgery	~40% of patients; bilirubin levels and stones related to polymorphisms of UGT1A; in surgery requiring general anesthesia, simple preoperative transfusion to a hemoglobin of 10 g/dL is recommended	If asymptomatic, usually let be; otherwise, laparoscopic cholecystectomy
	>80% of patients have hepatomegaly; intrahepatic cholestasis can have bilirubin ~100 mg/dL; viral hepatitis, iron overload, RBC sequestration, extrahepatic cholestasis also contribute
Nephropathy	~30% of adults age >30 years; hyperfiltration in children, renal failure in adults; early albuminuria, later nephrotic-range proteinuria; associated with markers of hemolysis	Screen for microalbuminuria by age 10 years; avoid NSAIDs; use ACE inhibitors or receptor antagonists for albuminuria; erythropoietin for symptomatic anemia; dialysis or transplant for renal failure
	Restrictive disease; asthma common; 5–10% have pulmonary hypertension by right heart catheterization; 30% have increased TRV that portends poor prognosis; associated with markers of hemolysis
Retinopathy	30% in HbSC disease, 3% in HbSSa; develops in peripheral retina; vitreous hemorrhage and retinal detachment can cause blindness	Screen annually starting at age 10 tears with fluorescein angiography; laser photocoagulation for proliferative disease
	B19 parvovirus infection, folic acid deficiency, splenic sequestration, delayed hemolytic transfusion reaction with destruction of transfused and sometimes autologous red cells
Multiorgan failure	Can accompany severe acute chest syndrome; often confused with sepsis and can coexist with sepsis; CNS liver, muscle, lung, kidney affected	Exchange transfusion, ICU support
	Screening both partners for hemoglobin disorders with risk counseling is critical component of family planning

TABLE 103-4 β Thalassemias CLASSIFICATION β -Thalassemia trait¶

Harrison's 22e, p.777

CLASSIFICATION	HEMOGLOBIN (g/dL)/MCV (fL)	HEMOGLOBIN FRACTIONS (%)	CLINICAL FEATURES
β-Thalassemia trait	100–140 (10–14)/60–80	HbA: 94 HbF:1–2 HbA: 4–6 2	Heterozygosity for β+ or β0 thalassemia mutations; “silent” carriers can have normal HbA 2 and red cell indices.
	70–120 (7–12)/65–80	HbA: 60–90 HbF: 10–40 HbA: 4–6 2
Transfusion-dependent β thalassemia (Thalassemia major)	20–40 (2–4)/50–80	HbA: 0–5 HbF: 90–100 HbA: 2–5 2	Caused by many different genotypes including homozygosity and compound heterozygosity for β0 and β+ mutations, combinations of β and α thalassemia; transplantation curative; iron chelation required.
	50–80 (5–8)/60–70	HbE: 50–70 HbF: 30–50
δβ Thalassemia and Hb Lepore	110–120 (11–12)/65–75	HbA: 70 HbF: 7–13 HbA: 2 2	Rare; deletions removing the δ- and β-globin genes cause δβ thalassemia; Lepore hemoglobins are fusion globin chains; values are for heterozygotes; homozygotes have 100% HbF with hemoglobin 10–11 g/dL.
	120–140 (12–14)/75–85	HbA: 70 HbF: 15–30 HbA: 2 2

TABLE 103-5 Complications of a Thalassemia COMPLICATION Growth retardation Delayed puberty; secondary amenorrhea…¶

Harrison's 22e, p.778

COMPLICATION	INCIDENCE, DIAGNOSIS, AND FEATURES
Growth retardation	Most often a feature of delayed or inadequate transfusions but can occur in well-transfused children.
Splenomegaly	Can trap 1–40% of red blood cell volume; increases plasma volume, worsening heart failure. Splenectomy indicated when transfusion requirement to maintain ideal hemoglobin increases. Prophylactic penicillin after splenectomy.
Leg ulcers	Common in thalassemia intermedia.
Lung disease/ pulmonary hypertension	Fibrosis, chronic thromboembolic disease, restrictive pathophysiology, intravascular hemolysis, and reduced nitric oxide bioavailability.
Endocrinopathies	Diabetes, hypothyroidism, hypoparathyroidism, adrenal insufficiency; hypogonadism; hypothalamic-pituitary axis might be especially sensitive to iron.
Infections	Transfusion associated; linked to iron overload (Yersinia); malaria.

TABLE 103-6 ` Thalassemias CLASSIFICATION α -Thalassemia trait¶

Harrison's 22e, p.778

CLASSIFICATION	`-GLOBIN GENE ARRANGEMENT	HEMOGLOBIN LEVEL, g/L (g/dL)/MCV (fL)	CLINICAL FEATURES
α-Thalassemia trait	−α/αα −α/−α − −/αα αTα/αα	120–150 (12–15)/65–80	The chromosome with one deleted α gene (—α/) is called α+ thalassemia (α thalassemia-2); the chromosome with both deleted α genes is α0 thalassemia (α thalassemia-1); non–gene deletion α thalassemias (αT) often have a more severe phenotype.
	− −/−α αTα/− − αTα/αTα	50–120 (5–12)/60–70
Hb Bart’s hydrops fetalis	−−/−−		Fatal in utero or at birth with rare survivors. Hydrops can also result from combinations of gene deletion and non–gene deletion α thalassemia.
	− −/αα or − −/−α in ATR-16 αα/αα in ATR-X
α Thalassemia with myelodysplasia (ATMDS)	αα/αα		Mutations in ATRX; striking male predominance. Hematologic findings of HbH disease.

TABLE 103-7 HbC, HbE, and Rare Hemoglobinopathies CLASSIFICATION HbC trait HbC disease¶

Harrison's 22e, p.779

CLASSIFICATION	CLINICAL ABNORMALITIES	HEMOGLOBIN LEVEL, g/L (g/dL)/MCV, fL	HEMOGLOBIN FRACTIONS (%)
HbC trait	2% of African Americans; target cells; no disease	Normal	HbC: 30–40 HbA: 2–3 2
	Target cells; HbC crystals; mild reticulocytosis; splenomegaly	100–130 (10–13)/60–70
HbE trait	50% incidence in some Asian populations; a few target cells; clinically normal	120–140 (12–14)/80–90	HbE: 27–31 HbF: 1 HbA: 3 2
	No hemolysis; 20–80% target cells; no splenomegaly	100–120 (10–12)/65–75
High O affinity hemoglobins 2	Isolated erythrocytosis; often familial; no splenomegaly; no JAK2V617F mutation	150–200 (15–20)	Variants in α- and β-globin genes; patients are heterozygotes; ~25–50% variant
	Asymptomatic mild anemia; cyanosis	100–140 (10–14)
Unstable hemoglobins	Pigmenturia; hemolysis; reticulocytosis; splenomegaly	90–140 (9–14)/70–90	20–35% variant; rare hyperunstable variants can be undetectable and have the phenotype of thalassemia
	Some have mild hemolysis; few symptoms	100–140 (10–14)/80–90