What medications can decrease hemoglobin (Hb) and hematocrit (Hct) levels?

Medications That Decrease Hemoglobin and Hematocrit

Thiazolidinediones (TZDs)

Thiazolidinediones (rosiglitazone and pioglitazone) consistently decrease hemoglobin by 0.8-1.1 g/dL and hematocrit by 2.3-3.6% through hemodilution from increased plasma volume, not through effects on erythropoiesis. 1

Mechanism and Clinical Impact

• TZDs cause hemodilution by increasing plasma volume by approximately 1.8 mL/kg, which mechanistically explains the decrease in hemoglobin and hematocrit values 1
• The decreases occur within the first weeks of therapy and plateau thereafter, with no clinically significant changes in other cellular blood components 1
• No increase in red blood cell turnover has been demonstrated, confirming TZDs have no direct effect on erythropoiesis 1
• These hematologic changes occur whether TZDs are used as monotherapy or in combination with metformin, sulfonylureas, or insulin 1

Dose-Related Effects

• The hemoglobin and hematocrit decreases appear dose-dependent across the therapeutic ranges: rosiglitazone 2-8 mg/day and pioglitazone 15-45 mg/day 1
• Similar magnitude of effect is seen with both agents at equivalent doses 1

Trimethoprim-Sulfamethoxazole

Trimethoprim-sulfamethoxazole can cause significant reductions in hemoglobin and hematocrit through bone marrow suppression, requiring frequent complete blood count monitoring during therapy. 2

Monitoring Requirements

• Complete blood counts should be performed frequently in patients receiving trimethoprim-sulfamethoxazole 2
• If a significant reduction in the count of any formed blood element is noted, the drug should be discontinued immediately 2
• Elderly patients face increased risk of generalized bone marrow suppression and specific decreases in platelets 2

Mechanism

• The drug can cause hematological changes indicative of folic acid deficiency, particularly in elderly patients 2
• These effects are reversible with folinic acid therapy 2
• Megaloblastic anemia may develop when used concomitantly with pyrimethamine at doses exceeding 25 mg weekly 2

Chemotherapeutic Agents

Multiple chemotherapeutic agents decrease hemoglobin and hematocrit through direct myelosuppression, with thresholds for intervention typically set at hemoglobin <10 g/dL. 1

Clinical Management Thresholds

• Erythropoiesis-stimulating agents (ESAs) are recommended as treatment options when hemoglobin decreases to less than 10 g/dL in patients receiving chemotherapy 1
• For hemoglobin between 10-12 g/dL, the decision to initiate ESA therapy should be determined by clinical judgment, considering risks and benefits 1
• Red blood cell transfusion remains an alternative option depending on severity of anemia or clinical circumstances 1

Evaluation Before Treatment

• A thorough drug exposure history must be obtained, and peripheral blood smear carefully reviewed before initiating therapy for chemotherapy-induced anemia 1
• Iron, folate, and B12 deficiency should be assessed where indicated 1
• Occult blood loss and renal insufficiency must be evaluated 1

Azathioprine

Azathioprine causes red blood cell macrocytosis and can lead to selective erythroid hypoplasia, resulting in decreased hemoglobin levels that typically resolve with drug discontinuation. 3

Clinical Presentation

• Red blood cell macrocytosis is a well-known complication, with mean corpuscular volume substantially higher than normal population 3
• Selective erythroid hypoplasia is a less frequent but serious complication 3
• Recovery occurs when drug therapy is discontinued, though smaller doses may be tolerated without anemia recurrence 3

Metformin

Metformin may cause vitamin B12 deficiency, which can subsequently lead to decreased hemoglobin and hematocrit levels. 1

• This effect develops through interference with B12 absorption rather than direct bone marrow suppression 1
• Monitoring of B12 levels should be considered in patients on long-term metformin therapy 1

Common Pitfalls and Monitoring

• Do not assume hematocrit is simply three times hemoglobin value—this relationship is age-dependent and non-linear, with significant variations that can lead to misclassification of anemia severity 4
• The crude relationship between hematocrit and hemoglobin significantly differs from the commonly assumed factor of 3, particularly in pediatric populations 4
• Hemoglobin measurement is more accurate than hematocrit for assessing anemia, with less variability in laboratory assessment 5