What are the causes of a persistent drop in hemoglobin (Hb) levels?

Causes of Persistent Hemoglobin Drop

A persistent drop in hemoglobin requires systematic evaluation across three major categories: patient-related factors (nutritional deficiencies, hemoglobinopathies), disease-related factors (bone marrow infiltration, bleeding, hemolysis, chronic disease), and treatment-related factors (chemotherapy, radiation, drug-induced hemolysis). 1

Patient-Related Causes

Nutritional Deficiencies

• Iron deficiency is the most common nutritional cause, with menstrual losses averaging 0.3-0.5 mg/day in women of reproductive age 1
• Vitamin B12 and folate deficiency should be assessed through serum levels in all patients with persistent anemia 1
• Iron-deficient states are identified by serum ferritin <25 ng/mL or transferrin saturation <16% 1

Hemoglobinopathies

• Thalassemia and other inherited hemoglobin disorders cause chronic hemolysis and persistent anemia 1
• Hemoglobin H disease typically maintains steady-state hemoglobin around 9-10 g/dL but can drop significantly during hemolytic crises triggered by acute infections 2

Disease-Related Causes

Bone Marrow Disorders

• Bone marrow infiltration by malignancy directly impairs erythropoiesis 1, 3
• Chronic kidney disease causes anemia through decreased erythropoietin production, with prevalence increasing as GFR falls below 60 mL/min/1.73 m² 1
• Anemia in CKD is more prevalent, severe, and occurs earlier in patients with diabetes compared to those without 1

Chronic Blood Loss

• Occult gastrointestinal or genitourinary bleeding must be assessed through stool and urine examination 1
• Chronic bleeding leads to iron depletion and progressive anemia over time 1

Hemolytic Processes

• Autoimmune hemolytic anemia should be evaluated with Coombs testing, particularly in patients with chronic lymphocytic leukemia, non-Hodgkin's lymphoma, or autoimmune disease history 1
• Hemolysis is confirmed by reticulocytosis, elevated lactate dehydrogenase, elevated unconjugated bilirubin, and decreased haptoglobin 4, 5
• Intravascular hemolysis causes hemoglobinemia, hemoglobinuria, and hemosiderinuria in severe cases 5

Anemia of Chronic Disease

• Chronic inflammatory states impair iron utilization and erythropoiesis despite adequate iron stores 1
• Elevated C-reactive protein helps identify inflammatory contribution 1

Hypersplenism

• Splenic sequestration causes accelerated red cell destruction and persistent anemia 1

Treatment-Related Causes

Chemotherapy-Induced Anemia

• Myelosuppressive chemotherapy causes cumulative bone marrow toxicity, with anemia rates increasing from 19.5% in cycle 1 to 46.7% by cycle 5 1
• Platinum-based regimens are particularly associated with combined bone marrow and renal toxicity 1

Radiation Therapy

• Extensive radiotherapy damages bone marrow and impairs erythropoiesis 1

Drug-Induced Hemolysis

• Medication-induced hemolysis should be evaluated through detailed medication history and may require discontinuation of offending agents 1

Critical Diagnostic Workup

Essential Laboratory Tests

• Complete blood count with reticulocyte count to assess bone marrow response 1, 3
• Peripheral blood smear for red cell morphology abnormalities, which are present in almost all hemolytic anemias 4, 5
• Iron studies: serum iron, transferrin saturation, and ferritin 1
• Vitamin B12 and folate levels 1
• Renal function assessment to identify CKD contribution 1

Specialized Testing When Indicated

• Direct antiglobulin test (Coombs) for suspected immune-mediated hemolysis 1
• Endogenous erythropoietin levels may predict response in myelodysplasia 1
• Bone marrow examination if infiltrative process or primary marrow disorder suspected 1

Common Pitfalls to Avoid

• Do not assume anemia is normal in elderly patients—it reflects poor health and increased vulnerability to adverse outcomes including hospitalizations, cardiovascular disease, cognitive impairment, and mortality 1
• Do not overlook multiple concurrent causes—anemia is often multifactorial, particularly in cancer patients and elderly populations 1, 6
• Do not delay evaluation—persistent anemia requires thorough investigation as it negatively impacts quality of life and constitutes a negative prognostic factor 1