What are the possible causes of a decreasing hemoglobin level?

Causes of Hemoglobin Dropping

Hemoglobin drops through three primary mechanisms: decreased red blood cell production, increased destruction (hemolysis), or blood loss—with the reticulocyte index being the critical first test to distinguish between these pathways. 1, 2

Diagnostic Framework: The Reticulocyte Index Approach

The reticulocyte index (RI) immediately separates production defects from destruction/loss 1:

• RI < 1.0-2.0: Indicates decreased RBC production 1, 3
• RI > 2.0: Indicates hemolysis or blood loss with intact marrow response 1, 4

Decreased Red Blood Cell Production (Low Reticulocyte Index)

Bone Marrow Suppression

• Chemotherapy-induced myelosuppression is the most common cause in cancer patients, with anemia rates escalating from 19.5% in cycle 1 to 46.7% by cycle 5 1, 2
• Bone marrow infiltration by cancer cells directly suppresses hematopoiesis 1, 5
• Radiation therapy to marrow-containing areas causes dose-dependent suppression 5

Nutritional Deficiencies

• Iron deficiency causes microcytic anemia with ferritin <30 ng/mL and transferrin saturation <15% 1, 2
• Vitamin B12/folate deficiency impairs DNA synthesis in erythroid precursors, causing macrocytic anemia 1, 2, 5
• Functional iron deficiency occurs when ferritin is <100 mg/dL or transferrin saturation is <20%, particularly in patients receiving erythropoietin therapy 1

Chronic Kidney Disease

• Decreased erythropoietin production by damaged kidneys is the primary mechanism, with anemia prevalence ranging from 24-85% depending on CKD severity 2
• The anemia is typically normochromic and normocytic 2
• Prevalence increases as glomerular filtration rate declines 2

Medication-Induced Suppression

• Certain antibiotics, anticonvulsants, and immunosuppressants cause bone marrow suppression 5
• Immune checkpoint inhibitors can rarely cause aplastic anemia 3

Infectious Causes

• Parvovirus B19, hepatitis viruses, cytomegalovirus, toxoplasmosis, and coxsackie virus can trigger marrow suppression 3

Increased Red Blood Cell Destruction (High Reticulocyte Index)

Hemolysis Mechanisms

Hemolysis occurs through intravascular or extravascular pathways 4, 6:

Laboratory confirmation of hemolysis 1, 4, 6:

• Elevated lactate dehydrogenase (LDH)
• Elevated unconjugated bilirubin
• Decreased haptoglobin
• Hemoglobinemia, hemoglobinuria, and hemosiderinuria (only in severe intravascular hemolysis) 7

Immune-Mediated Hemolysis

• Autoimmune hemolytic anemia from antierythrocyte antibodies, identified by positive direct antiglobulin test (Coombs test) 1, 6
• Secondary to malignancies, autoimmune disorders, drugs, and transfusion reactions 6

Microangiopathic Hemolysis

• Red cell membrane damage in circulation leads to intravascular hemolysis with schistocytes on peripheral smear 6
• Caused by thrombotic microangiopathies and direct mechanical trauma 4

Hereditary Causes

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency leads to hemolysis with oxidative stress 6, 7
• Hereditary spherocytosis characterized by spherocytes, family history, and negative direct antiglobulin test 6
• Sickle cell anemia and thalassemia cause chronic hemolysis from abnormal hemoglobin structure 6, 8

Infectious Hemolysis

• Malaria and babesiosis directly invade red blood cells 6

Blood Loss (High Reticulocyte Index)

Acute Hemorrhage

• Hemoglobin drops within minutes of injury and predicts need for intervention to stop hemorrhage 9
• Hgb ≤10 g/dL within 30 minutes of trauma correctly identifies significant bleeding in 87% of patients 9

Chronic Blood Loss

• Heavy menstrual bleeding causes iron losses of 0.3-0.5 mg/day, representing a leading cause of iron deficiency in reproductive-age women 2
• Gastrointestinal bleeding identified by positive stool guaiac or endoscopy findings 1

Special Populations and Contexts

Cancer Patients

• Multifactorial pathogenesis: bone marrow infiltration, inflammatory cytokines causing iron sequestration, and treatment-related myelosuppression 2, 5
• Myelosuppressive effects accumulate over repeated chemotherapy cycles 1

Hepatitis C Treatment

• Triple therapy with boceprevir or telaprevir increases anemia incidence and severity compared to peginterferon plus ribavirin alone 1
• Ribavirin causes dose-dependent hemolysis combined with interferon-related bone marrow suppression 1

Liver Transplant Recipients

• Higher prevalence of renal insufficiency and myelosuppression from concomitant therapies 1
• 70% develop anemia during treatment, with 22-40% requiring dose reduction or discontinuation 1

Cyanotic Congenital Heart Disease

• Iron deficiency anemia worsens hyperviscosity by producing rigid microcytic red cells with decreased oxygen-carrying capacity 1
• Thrombocytopenia and platelet dysfunction occur secondary to polycythemia and hyperviscosity 1

Critical Pitfalls to Avoid

• Do not assume anemia is normal aging in elderly men—it reflects underlying disease and increased mortality risk 2
• Always review medications as a potentially reversible cause before extensive workup 2, 5
• Do not rely solely on hemoglobin thresholds for transfusion decisions—assess symptoms, comorbidities (especially cardiovascular/pulmonary disease), and clinical stability 1
• Recognize functional iron deficiency in patients receiving erythropoietin therapy, requiring parenteral iron when ferritin <100 mg/dL or transferrin saturation <20% 1
• Peripheral blood smear is mandatory when hemolysis is suspected to identify diagnostic red cell morphologies 1, 4