What causes a drop in hemoglobin levels?

Why Hemoglobin Drops: Causes and Mechanisms

Hemoglobin drops occur through three primary mechanisms: blood loss (acute hemorrhage or chronic bleeding), decreased red blood cell production (from nutritional deficiencies, bone marrow disorders, inflammation, or kidney disease), and increased red blood cell destruction (hemolysis). 1, 2

Blood Loss Mechanisms

Acute Hemorrhage

• Overt bleeding with hemoglobin drop ≥2 g/dL or requiring ≥2 units of packed RBCs is associated with significantly increased mortality risk, particularly in patients with cardiovascular disease 1
• Critical site bleeds (intracranial, pericardial, intra-abdominal, retroperitoneal) cause rapid hemoglobin decline with life-threatening consequences 1
• Pre-resuscitation hemoglobin may be artificially elevated due to hemoconcentration, masking the true severity of blood loss 1

Chronic Blood Loss

• Gastrointestinal bleeding (from ulcers, malignancy, or inflammatory bowel disease) is the most common cause of iron deficiency in adults, leading to progressive hemoglobin decline 1, 3, 4
• Menstrual blood loss causes iron deficiency in approximately 38% of nonpregnant reproductive-age women and 13% develop iron-deficiency anemia 3
• Excessive phlebotomy for diagnostic laboratory testing contributes to anemia in critically ill patients 1
• Ongoing blood loss from renal replacement therapy in dialysis patients causes progressive anemia 1

Decreased Red Blood Cell Production

Nutritional Deficiencies

• Iron deficiency is the most common nutritional cause of anemia worldwide, affecting approximately 2 billion people 3
• Iron deficiency progresses from depleted iron stores (ferritin <30 ng/mL or transferrin saturation <20%) to iron-deficiency anemia with decreased hemoglobin 1, 3
• Vitamin B12 and folate deficiencies impair DNA synthesis in erythroblasts, causing ineffective erythropoiesis and macrocytic anemia 1, 2
• Protein-energy malnutrition (requiring minimum 1700 kcal/day and 1.7 g/kg/day protein) stimulates cytokine production, inducing inflammation and anemia 5

Impaired Erythropoiesis in Critical Illness

• Anemia of critical illness is characterized by blunted erythropoietin production and abnormal iron metabolism identical to anemia of chronic disease 1
• Inflammatory cytokines (TNF-α, IL-1, IL-6) suppress erythropoietic response of red cell precursors 1, 2
• Increased hepcidin synthesis leads to iron sequestration in macrophages, reducing iron availability for erythropoiesis despite adequate total body iron stores 1, 2
• Shortened red blood cell lifespan and hemodilution from fluid resuscitation contribute to declining hemoglobin in critically ill patients 1

Chronic Kidney Disease

• Erythropoietin deficiency from damaged kidney cells is the primary cause of anemia in CKD, with nearly universal prevalence in stage 5 CKD 1, 2
• Specialized interstitial cells in the kidney cortex sense tissue hypoxia and produce erythropoietin; kidney disease impairs this production 2
• The most common reason for inadequate reticulocyte response in CKD patients replete with iron, folate, and vitamin B12 is insufficient erythropoietin production or inflammation 1
• Uremic toxins suppress erythropoiesis and shorten red cell survival 2

Bone Marrow Disorders

• Direct bone marrow infiltration by cancer cells reduces red blood cell production 1, 2
• Chemotherapy and radiation-induced myelosuppression cause treatment-related anemia 1, 2
• Myelodysplastic syndromes cause ineffective erythropoiesis with declining hemoglobin 1

Malabsorption Conditions

• Atrophic gastritis, celiac disease, and bariatric surgical procedures impair iron absorption, leading to progressive iron deficiency and hemoglobin decline 1, 3, 4
• Celiac disease screening with transglutaminase antibody (IgA type) should be performed in patients with unexplained iron deficiency 4

Increased Red Blood Cell Destruction

Hemolytic Anemias

• Autoimmune hemolytic anemia (particularly in chronic lymphocytic leukemia and non-Hodgkin's lymphoma) causes accelerated red cell destruction 1
• Drug-induced hemolysis from medications causes acute hemoglobin drops 1
• Coombs testing should be conducted in patients with chronic lymphocytic leukemia, non-Hodgkin's lymphoma, or history of autoimmune disease 1

Special Populations and Contexts

Cancer Patients

• Multiple simultaneous mechanisms contribute to anemia in cancer patients: bone marrow infiltration, cytokine-mediated inflammation, chemotherapy/radiation myelosuppression, nutritional deficiencies, and chronic blood loss from tumor sites 1, 2
• Anemia affects 18-82% of cancer patients depending on cancer type and treatment 3

Pregnancy

• Iron deficiency affects up to 84% of pregnant women during the third trimester in high-income countries due to increased iron requirements 3
• Intravenous iron is indicated during the second and third trimesters of pregnancy for iron deficiency 3

Elderly Patients

• In elderly patients, one-third of anemia cases are due to nutritional deficiency (iron, folate, vitamin B12), one-third to chronic disease, and one-third remains "unexplained" 6
• Unexplained anemia in elderly may result from progressive bone marrow resistance to erythropoietin and chronic subclinical pro-inflammatory state 6

Critical Diagnostic Pitfalls

• Ferritin may be falsely elevated despite true iron deficiency in chronic inflammatory states because ferritin acts as an acute-phase reactant 1, 2
• In hemodilution states, hemoglobin concentration decreases without actual red cell mass loss; postdialysis hemoglobin increases 3-4 g/dL for every liter of volume ultrafiltered 1
• Transferrin saturation is more reliable than ferritin for assessing iron sufficiency in CKD patients because it is less affected by inflammation 1
• Normal hemoglobin values vary by sex (men <13 g/dL, women <12 g/dL), race, smoking status, and altitude (increase of 0.6-0.9 g/dL per 1000 meters elevation) 1, 2