What is the classification and description of anemia, including its causes, diagnosis, and treatment options, in a patient with impaired oxygen delivery to tissues?

Anemia: Classification and Description

Definition and Diagnostic Criteria

Anemia is defined as a reduction in hemoglobin concentration, red blood cell count, or packed cell volume below normal levels, with standard thresholds being hemoglobin <13.0 g/dL in men and <12.0 g/dL in women, though these values may vary with ethnicity and age. 1, 2

Severity Grading

Anemia severity is classified into distinct categories that guide clinical decision-making:

• Mild anemia: Hemoglobin ≤11.9 g/dL and ≥10 g/dL 1, 3
• Moderate anemia: Hemoglobin ≤9.9 g/dL and ≥8.0 g/dL 1, 3
• Severe anemia: Hemoglobin <8.0 g/dL 1, 3

The National Cancer Institute Common Toxicity Criteria provides an alternative grading system for treatment-related anemia: Grade 0 (within normal limits), Grade 1 (lower normal limit to 10.0 g/dL), Grade 2 (8.0 to <10.0 g/dL), Grade 3 (6.5 to <8.0 g/dL), and Grade 4 (<6.5 g/dL). 1, 3

Pathophysiologic Classification

Primary Mechanisms

The pathophysiologic origins of anemia fall into three fundamental categories that determine the diagnostic and therapeutic approach 1, 4:

1. Decreased production of functional red blood cells

   • Bone marrow infiltration by malignancy directly impairs erythropoiesis 5
   • Nutritional deficiencies (iron, vitamin B12, folate) 1, 5
   • Chronic kidney disease with decreased erythropoietin production (GFR <60 mL/min/1.73 m²) 1, 5
   • Myelosuppressive chemotherapy causing cumulative bone marrow toxicity 5
   • Extensive radiotherapy damaging bone marrow 5
   • Anemia of chronic disease with iron sequestration 1

2. Increased destruction of red blood cells (hemolysis)

   • Autoimmune hemolytic anemia (evaluate with Coombs testing) 5
   • Drug-induced hemolysis 5
   • Inherited hemoglobin disorders (thalassemia, hemoglobinopathies) 5
   • Microangiopathic processes 1

3. Blood loss

   • Acute hemorrhage 1, 4
   • Chronic occult gastrointestinal or genitourinary bleeding 5
   • Menstrual losses (averaging 0.3-0.5 mg/day in reproductive-age women) 5

Morphologic Classification by Mean Corpuscular Volume

Microcytic Anemia (MCV <80 fL)

Iron deficiency is the most common nutritional cause of microcytic anemia, identified by serum ferritin <25-30 ng/mL or transferrin saturation <15-16%. 1, 5

Key diagnostic considerations:

• In cancer patients with chronic inflammatory states, ferritin may be falsely elevated; the lower the ferritin level, the higher the probability of true iron deficiency 1
• Thalassemia and other inherited disorders cause chronic microcytic anemia 5
• Anemia of chronic disease can present with microcytosis 1

Normocytic Anemia (MCV 80-100 fL)

This category includes 6:

• Anemia of inflammation/chronic disease
• Hemolytic anemia (diagnosed by jaundice, hepatosplenomegaly, unconjugated hyperbilirubinemia, increased reticulocyte count, decreased haptoglobin) 6
• Chronic kidney disease anemia
• Acute blood loss anemia
• Aplastic anemia

Macrocytic Anemia (MCV >100 fL)

Primary causes include:

• Vitamin B12 deficiency 5
• Folate deficiency 5
• Myelodysplastic syndromes
• Medication effects (chemotherapy, antiretrovirals)

Clinical Context-Specific Considerations

Cancer-Associated Anemia

Anemia occurs in 40% of patients with non-myeloid malignancies at baseline and increases to 54% during chemotherapy or radiotherapy, with highest incidence in lung (71%) and gynecological (65%) cancers. 1

The etiology is multifactorial 1:

• Direct bone marrow suppression by cancer cells
• Cytokine-mediated iron sequestration
• Chronic blood loss at tumor sites
• Chemotherapy-induced myelosuppression (rates increase from 19.5% in cycle 1 to 46.7% by cycle 5) 5
• Radiation-induced bone marrow damage 1, 5
• Nutritional deficiencies from organ damage 1

Anemia in Chronic Kidney Disease

Anemia prevalence increases as GFR falls below 60 mL/min/1.73 m², with earlier and more severe presentation in diabetic patients compared to non-diabetic patients. 5

The mechanism involves decreased erythropoietin production by damaged kidneys, though other factors may contribute 5.

Unexplained Anemia in Elderly

In approximately one-third of elderly patients, anemia cannot be attributed to nutritional deficiency, chronic disease, or specific pathological processes 2. This "unexplained anemia" may result from:

• Progressive resistance of bone marrow erythroid progenitors to erythropoietin 2
• Chronic subclinical pro-inflammatory state 2

A critical pitfall is assuming anemia is normal in elderly patients; it actually reflects poor health and predicts adverse outcomes including hospitalizations, cardiovascular disease, cognitive impairment, and mortality. 5

Comprehensive Diagnostic Evaluation

Essential Initial Workup

Before initiating any treatment, all potential causes must be systematically evaluated through a structured diagnostic approach. 1, 3, 5

Mandatory Laboratory Assessment

• Complete blood count with reticulocyte count to assess bone marrow response 5
• Iron studies: serum iron, total iron binding capacity, ferritin, transferrin saturation 1, 5
  • Absolute iron deficiency: ferritin <30 ng/mL and transferrin saturation <15% 1
  • Note laboratory-specific variations in ferritin thresholds 1
• Vitamin B12 and folate levels in all patients with persistent anemia 5
• Renal function assessment (GFR) to identify chronic kidney disease contribution 1, 5
• Peripheral blood smear examination for morphologic abnormalities 1, 5

Targeted Investigations Based on Clinical Suspicion

• Hemorrhage evaluation: stool guaiac, endoscopy for gastrointestinal bleeding 1
• Hemolysis assessment: Direct antiglobulin test (Coombs), DIC panel, haptoglobin, unconjugated bilirubin 1, 5, 6
  • Coombs testing specifically indicated in chronic lymphocytic leukemia, non-Hodgkin lymphoma, or autoimmune disease history 1, 3, 5
• Bone marrow examination when indicated by clinical context 1
• Endogenous erythropoietin levels may predict response in myelodysplastic patients 1

Critical Diagnostic Pitfalls to Avoid

Do not overlook multiple concurrent causes of anemia, as it is frequently multifactorial, particularly in cancer patients and elderly populations. 5

Do not delay comprehensive evaluation of persistent anemia, as it negatively impacts quality of life and constitutes a negative prognostic factor for overall survival in most cancer types. 1, 5

Do not assume single-cause anemia in complex patients; systematically exclude hemorrhage, hemolysis, nutritional deficiencies, inherited disorders, renal insufficiency, and treatment-related factors before concluding the evaluation. 1

Physiologic Consequences and Oxygen Delivery

Compensatory Mechanisms

When oxygen-carrying capacity decreases, multiple physiologic responses occur 1:

• Carotid body chemoreceptors sense decreased PaO2 and stimulate increased ventilation 1
• Cardiac output increases within seconds to enhance oxygen delivery to tissues 1
• Renal erythropoietin production increases over days to weeks to stimulate red blood cell production 1
• Hypoxic pulmonary vasoconstriction diverts blood flow to better-ventilated lung areas 1

Limitations of Oxygen Therapy

Oxygen therapy is less effective in anemia-induced tissue hypoxia because oxygen availability is not the limiting factor; the problem is reduced carrying capacity. 1

This contrasts with hypoxemia from ventilation-perfusion mismatch (e.g., pneumonia), where supplemental oxygen is highly effective 1. Similarly, carbon monoxide poisoning blocks oxygen binding to hemoglobin despite normal oxygen levels in lungs and blood 1.

Treatment Principles and Thresholds

General Approach

All causes of anemia must be identified and corrected before considering erythropoiesis-stimulating agents or other specific interventions. 1, 3

Specific Treatment Thresholds

Iron Deficiency

When absolute iron deficiency is confirmed (ferritin <30 ng/mL, transferrin saturation <15%), initiate intravenous or oral iron supplementation and reassess hemoglobin after 4 weeks 1.

Chemotherapy-Induced Anemia

• Hemoglobin ≤10 g/dL: Erythropoiesis-stimulating agents may be considered to increase hemoglobin to <12 g/dL or prevent further decline 1, 3
• Hemoglobin 10-12 g/dL: ESAs could be considered only if symptomatic or to prevent further decline (off-label indication) 1
• Target hemoglobin: Never exceed 12 g/dL; aim for increase <2 g/dL 3

Patients Not Receiving Chemotherapy

ESAs are contraindicated in cancer patients not receiving chemotherapy, as targeting hemoglobin 12-14 g/dL increases mortality risk. 1, 3

Chronic Kidney Disease

ESAs should not be initiated in asymptomatic patients until hemoglobin falls below 10 g/dL 6.

Acute Blood Loss

• Initial management: Crystalloid fluid resuscitation for hypovolemia 6
• Severe ongoing bleeding with hemodynamic instability: Initiate mass transfusion protocol 6
• Primary focus: Cessation of bleeding source 6

Transfusion Considerations

Red blood cell transfusions should be limited to patients with severe symptomatic anemia to avoid complications including iron overload, infection transmission, and immune suppression. 1, 6

Clinical Impact and Prognostic Significance

Anemia has negative impact on quality of life, is a major contributor to cancer-related fatigue, and constitutes a negative prognostic factor for overall survival in most cancer types. 1

The clinical presentation differs between acute and chronic anemia 7:

• Acute anemia: Symptoms from acute blood loss with hemodynamic compromise
• Chronic anemia: Progressive fatigue, dyspnea, lightheadedness, chest pain

Most patients with chronic anemia who are hemodynamically stable may be managed as outpatients with appropriate follow-up 7.