What is Hemoglobin?
Hemoglobin (Hgb or Hb) is the iron-containing protein in red blood cells that binds and transports oxygen from the lungs to tissues and carries carbon dioxide back to the lungs. It gives blood its red color and is essential for aerobic metabolism.
Structure of Hemoglobin
Each hemoglobin molecule consists of:
- Four globin chains: Two alpha and two beta chains in normal adult hemoglobin (HbA)
- Four heme groups: Each containing an iron atom that binds one oxygen molecule
- Oxygen capacity: One hemoglobin molecule can carry up to four oxygen molecules
- Cooperative binding: Binding of oxygen increases affinity for additional oxygen molecules (sigmoidal dissociation curve)
Types of Hemoglobin
- HbA (Adult Hemoglobin): Comprises ~95-98% of adult hemoglobin; two alpha and two beta chains (α2β2)
- HbA2: Comprises ~2-3% of adult hemoglobin; two alpha and two delta chains (α2δ2); elevated in beta-thalassemia
- HbF (Fetal Hemoglobin): Comprises <1% in adults; two alpha and two gamma chains (α2γ2); higher oxygen affinity than HbA; elevated in some hemoglobinopathies
- HbS (Sickle Hemoglobin): Abnormal hemoglobin causing sickle cell disease; glutamic acid replaced by valine in beta chain
- HbC, HbE: Other variant hemoglobins causing hemolytic anemias
How Does Hemoglobin Work?
Hemoglobin's function depends on its ability to reversibly bind oxygen:
- In the lungs: High oxygen concentration causes hemoglobin to bind oxygen (oxyhemoglobin)
- In tissues: Low oxygen and high CO2 cause hemoglobin to release oxygen (deoxyhemoglobin)
- Bohr effect: Acidic pH and high CO2 promote oxygen release in metabolically active tissues
- 2,3-DPG regulation: 2,3-diphosphoglycerate shifts oxygen dissociation curve right, facilitating oxygen delivery
Hemoglobin normal ranges vary by age, sex, pregnancy status, and altitude. Men have higher hemoglobin than women due to testosterone's stimulatory effect on erythropoiesis and lack of menstrual blood loss.
| Population | Normal Range (g/dL) | SI Units (g/L) |
|---|---|---|
| Adult Men | 13.0-18.0 | 130-180 |
| Adult Women (non-pregnant) | 12.0-16.0 | 120-160 |
| Pregnant Women | 11.0-14.0 | 110-140 |
| Newborns (0-2 weeks) | 14.0-24.0 | 140-240 |
| Infants (2-6 months) | 9.5-14.0 | 95-140 |
| Children (6 months-12 years) | 11.0-16.0 | 110-160 |
| Adolescents (13-18 years) | 12.0-17.0 | 120-170 |
- WHO Anemia Definitions: Men <13.0 g/dL, non-pregnant women <12.0 g/dL, pregnant women <11.0 g/dL
- Altitude adjustment: Hemoglobin increases ~0.5 g/dL per 1000 meters above sea level
- Hydration status: Dehydration falsely elevates hemoglobin (hemoconcentration); overhydration lowers it
- Pregnancy: Physiologic anemia occurs due to plasma volume expansion exceeding RBC mass increase
- Smoking: Chronic smokers have higher hemoglobin (compensation for carbon monoxide binding)
Low Hemoglobin (Anemia)
Anemia is defined as hemoglobin below normal limits for age and sex. Causes are categorized by mechanism and MCV (mean corpuscular volume).
Microcytic Anemia (MCV <80 fL)
- Iron deficiency anemia: Most common worldwide; due to blood loss, inadequate intake, or malabsorption
- Thalassemia: Genetic disorder of globin chain production; common in Mediterranean, Asian, African populations
- Anemia of chronic disease: Can be microcytic or normocytic; iron sequestration by hepcidin
- Lead poisoning: Inhibits heme synthesis
- Sideroblastic anemia: Defective heme synthesis despite adequate iron
Normocytic Anemia (MCV 80-100 fL)
- Acute blood loss: Trauma, GI bleeding, postpartum hemorrhage
- Hemolytic anemia: Increased RBC destruction (autoimmune, hereditary spherocytosis, G6PD deficiency, sickle cell)
- Anemia of chronic disease: Chronic infections, inflammatory disorders, malignancy
- Chronic kidney disease: Decreased erythropoietin production
- Bone marrow failure: Aplastic anemia, myelodysplasia, leukemia infiltration
Macrocytic Anemia (MCV >100 fL)
- Vitamin B12 deficiency: Pernicious anemia, malabsorption, strict veganism
- Folate deficiency: Inadequate intake, malabsorption, increased demand (pregnancy, hemolysis)
- Alcohol use: Direct toxic effect on bone marrow and often folate deficiency
- Hypothyroidism: Decreased metabolic demand
- Liver disease: Impaired folate metabolism and lipid abnormalities affecting RBC membranes
- Medications: Methotrexate, hydroxyurea, azathioprine, antiretrovirals
Elevated Hemoglobin (Polycythemia)
Elevated hemoglobin increases blood viscosity and thrombosis risk. Classified as primary or secondary.
Primary Polycythemia
- Polycythemia vera: Myeloproliferative neoplasm with JAK2 mutation; autonomous RBC overproduction
Secondary Polycythemia
- Chronic hypoxia: COPD, sleep apnea, high altitude living, cyanotic heart disease
- Renal disease: Renal cell carcinoma, polycystic kidney disease (excess EPO production)
- EPO-secreting tumors: Hepatocellular carcinoma, cerebellar hemangioblastoma
- Exogenous EPO: Erythropoietin therapy, athletic doping
- Testosterone therapy: Stimulates erythropoiesis
Relative Polycythemia
- Dehydration: Hemoconcentration from volume depletion
- Gaisböck syndrome: Apparent polycythemia in obese, hypertensive individuals
Anemia Severity Classification
| Severity | Hemoglobin (g/dL) | Clinical Features |
|---|---|---|
| Mild Anemia | 10.0-12.0 (women) 10.0-13.0 (men) |
Often asymptomatic or mild fatigue |
| Moderate Anemia | 8.0-10.0 | Fatigue, dyspnea on exertion, tachycardia |
| Severe Anemia | 6.5-8.0 | Marked symptoms, possible angina in CAD patients |
| Life-Threatening | <6.5 | High-output heart failure, shock risk; urgent transfusion often needed |
Approach to Low Hemoglobin
Step 1: Confirm anemia and assess severity
Step 2: Classify by MCV (microcytic, normocytic, macrocytic)
Step 3: Check reticulocyte count:
- Elevated reticulocytes: Suggests appropriate bone marrow response (blood loss or hemolysis)
- Low reticulocytes: Suggests production problem (nutritional deficiency, bone marrow failure, renal disease)
Step 4: Order targeted testing based on MCV:
- Microcytic: Iron studies (ferritin, TIBC, serum iron), hemoglobin electrophoresis for thalassemia
- Normocytic: Hemolysis labs (LDH, haptoglobin, indirect bilirubin), renal function, bone marrow biopsy if indicated
- Macrocytic: B12, folate, TSH, liver function tests
Transfusion Guidelines
- Threshold: Transfuse if Hgb <7.0 g/dL in hemodynamically stable patients
- Target: Hgb 7.0-9.0 g/dL post-transfusion
- Acute coronary syndrome: Transfuse if Hgb <8.0 g/dL
- Symptomatic anemia: Consider transfusion if Hgb <8.0 g/dL with symptoms (dyspnea, chest pain, tachycardia)
- Massive hemorrhage: Transfuse to maintain Hgb >7.0-8.0 g/dL during active bleeding
Factors That Increase Hemoglobin
- Dehydration: Hemoconcentration from volume depletion (most common cause of falsely elevated Hgb)
- Altitude: Chronic high altitude causes true elevation (physiologic adaptation)
- Smoking: Carbon monoxide binding reduces oxygen delivery, stimulating EPO
- Medications: Erythropoietin (EPO), testosterone, anabolic steroids
- COPD: Chronic hypoxia stimulates RBC production
Factors That Decrease Hemoglobin
- Overhydration: IV fluids, SIADH (hemodilution)
- Pregnancy: Physiologic hemodilution (plasma volume increases 40-50%)
- Recent transfusion: May mask underlying anemia
- Blood donation: Temporary decrease post-donation
- Supine position: Hemoglobin ~0.5 g/dL lower when supine versus standing
Pre-analytical Errors
- Clotted sample: Falsely low hemoglobin; redraw required
- Lipemia: Severe hypertriglyceridemia can falsely elevate hemoglobin
- Leukocytosis: Extreme WBC elevation (>100,000) can falsely elevate hemoglobin
- Prolonged tourniquet time: Hemoconcentration causes falsely high hemoglobin
Hemoglobin Variants
- Carboxyhemoglobin: CO poisoning; hemoglobin bound to carbon monoxide
- Methemoglobin: Oxidized hemoglobin unable to carry oxygen; caused by certain drugs or toxins
- Sulfhemoglobin: Rare; caused by certain drugs (sulfonamides, phenacetin)
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