Causes of Very Low Hemoglobin and Hematocrit Levels

Major Pathophysiologic Categories

• The National Comprehensive Cancer Network recommends that very low hemoglobin and hematocrit levels are primarily caused by decreased production of red blood cells, increased destruction of red blood cells, or blood loss, with specific etiologies requiring systematic evaluation to determine appropriate treatment 1, 2
• Chronic Kidney Disease is associated with a progressive decline in kidney function, leading to reduced erythropoietin production, with anemia becoming nearly universal in CKD stage 5, as stated by the American Journal of Kidney Diseases 3
• Iron deficiency is the most common nutritional cause of anemia, according to the MMWR Recommendations and Reports 4, 5
• Vitamin B12 deficiency can cause anemia, as noted by the Journal of the National Comprehensive Cancer Network and Kidney International Supplements 1, 6
• Folate deficiency can also cause anemia, as stated by the Journal of the National Comprehensive Cancer Network and MMWR Recommendations and Reports 1, 7
• Myelodysplastic syndromes can cause anemia, as noted by the Journal of the National Comprehensive Cancer Network 1
• Bone marrow infiltration by cancer cells can cause anemia, as stated by the Journal of the National Comprehensive Cancer Network 1
• Anemia of Chronic Disease/Inflammation is caused by cytokine-mediated iron sequestration, decreasing RBC production, as noted by the Journal of the National Comprehensive Cancer Network 1, 2
• Chemotherapy-induced myelosuppression can cause anemia, as stated by the Journal of the National Comprehensive Cancer Network 1, 2
• Radiation-induced myelosuppression can cause anemia, as noted by the Journal of the National Comprehensive Cancer Network 1

Diagnostic Approach for Very Low Hb/Hct

• The Kidney International Supplements recommends a complete blood count with peripheral smear examination for initial laboratory evaluation 6
• Reticulocyte count can assess bone marrow response, as noted by the Kidney International Supplements 6
• Iron studies, including serum iron, ferritin, total iron binding capacity, and transferrin saturation, are recommended by the Journal of the National Comprehensive Cancer Network and Kidney International Supplements 1, 6
• Kidney function tests, including GFR and creatinine, are recommended by the American Journal of Kidney Diseases 3, 8
• Vitamin B12 and folate levels should be checked, as stated by the Journal of the National Comprehensive Cancer Network 1

Special Considerations

• The Journal of the National Comprehensive Cancer Network notes that multiple mechanisms often contribute simultaneously to cancer-related anemia, including direct bone marrow infiltration by cancer cells, cytokine-mediated iron sequestration, chronic blood loss from tumor sites, nutritional deficiencies, and chemotherapy-induced myelosuppression 1, 2
• The American Journal of Kidney Diseases states that anemia in CKD correlates with declining GFR and becomes more prevalent at GFR <60 mL/min/1.73m² 3
• Normal Hb/Hct values vary by sex, with lower thresholds for anemia of <13.5 g/dL in men and <12.0 g/dL in women, as noted by the American Journal of Kidney Diseases 3
• The MMWR Recommendations and Reports states that normal Hb/Hct values also vary by race, with potentially lower normal values in Black individuals 5
• The MMWR Recommendations and Reports notes that smoking status can affect normal Hb/Hct values, with higher normal values in smokers 7
• The American Journal of Kidney Diseases states that altitude can affect Hb levels, with an increase of ~0.6 g/dL in women and ~0.9 g/dL in men per 1000m above sea level 9
• The Journal of the National Comprehensive Cancer Network recommends considering multiple concurrent causes of anemia, especially in patients with complex medical conditions 1, 2
• The Journal of the National Comprehensive Cancer Network notes that ferritin may be falsely elevated despite true iron deficiency in chronic inflammatory states 1