What are the indications for therapeutic phlebotomy?

Indications for Therapeutic Phlebotomy

Therapeutic phlebotomy is indicated for hereditary hemochromatosis with evidence of iron overload (elevated ferritin and transferrin saturation), polycythemia vera, porphyria cutanea tarda, secondary iron overload from transfusions, sickle cell disease, and nonalcoholic fatty liver disease with hyperferritinemia. 1, 2

Primary Indication: Hereditary Hemochromatosis

Initiate therapeutic phlebotomy in all patients with confirmed hereditary hemochromatosis who have elevated serum ferritin above the normal range, regardless of symptoms. 1

Specific Thresholds for Treatment Initiation:

• Men: Start phlebotomy when serum ferritin ≥300 μg/L 3
• Women: Start phlebotomy when serum ferritin ≥200 μg/L 3
• Any patient with end-organ damage (liver disease, cardiomyopathy, arthropathy, diabetes, hypogonadism): Initiate immediately regardless of ferritin level 1

The decision becomes straightforward when liver disease or other organ manifestations are present. 1 The more challenging scenario is the C282Y homozygote with moderately elevated ferritin (e.g., 800 μg/L), normal liver tests, and no symptoms—yet treatment should still be initiated because it is safe, inexpensive, prevents progression, and there are no reliable predictors of who will develop complications. 1

Treatment Protocol:

• Induction phase: Remove 500 mL blood weekly or biweekly until ferritin reaches 50-100 μg/L 1, 4
• Each unit removes approximately 200-250 mg iron 1, 5
• Check hemoglobin/hematocrit before every session; do not allow decline >20% from baseline 1, 4, 5
• Monitor ferritin every 10-12 phlebotomies (approximately every 3 months) initially, then more frequently as target approaches 1, 4
• Maintenance phase: Continue lifelong phlebotomy at individualized intervals (monthly to 1-2 units yearly) to maintain ferritin 50-100 μg/L 1, 4

Secondary Iron Overload from Transfusions

Therapeutic phlebotomy is effective and safe for reducing transfusional iron overload in long-term survivors of acute leukemia and other multiply-transfused patients who have achieved disease remission and adequate hematopoiesis. 6

• Initiate when serum ferritin is significantly elevated (typically >1000 μg/L) and transferrin saturation is high 6
• Weekly phlebotomy reduces ferritin effectively from mean 1727 μg/L to 93 μg/L over approximately 37 units 6
• Well tolerated with no significant adverse events in this population 6

Polycythemia Vera

Phlebotomy is first-line therapy for polycythemia vera to reduce red cell mass and prevent thrombotic complications. 2

Porphyria Cutanea Tarda

Therapeutic phlebotomy effectively treats porphyria cutanea tarda by reducing hepatic iron stores, which decreases porphyrin production. 2

Sickle Cell Disease

Phlebotomy may be indicated in select sickle cell patients with secondary iron overload from chronic transfusions. 2

Nonalcoholic Fatty Liver Disease with Hyperferritinemia

Therapeutic phlebotomy is indicated for NAFLD patients with elevated ferritin and evidence of iron overload. 2

Critical Safety Considerations

In patients with cardiac arrhythmias or cardiomyopathy, rapid iron mobilization carries increased risk of sudden death—consider slower phlebotomy schedules or alternative iron chelation therapy. 1, 4

Avoid supplemental vitamin C during active iron depletion, as it accelerates iron mobilization to potentially toxic levels that can saturate transferrin and increase oxidative stress. 1, 4, 5

Alternative When Phlebotomy Is Not Feasible

Erythrocytapheresis is the preferred alternative to standard phlebotomy, removing up to 1000 mL red cells per session (versus 250 mL with phlebotomy), reducing treatment duration by approximately 70% while maintaining the same ferritin targets. 1, 4, 7, 8

Iron chelation therapy (deferoxamine 20-40 mg/kg/day subcutaneously or oral deferasirox) should be reserved as second-line only when neither phlebotomy nor erythrocytapheresis is possible, after careful risk-benefit assessment. 1, 4, 5 Deferasirox is not approved for hemochromatosis by the European Medicines Agency and should not be used in advanced liver disease. 1

Common Pitfalls to Avoid

• Do not delay treatment waiting for symptoms in confirmed hemochromatosis with elevated ferritin—organ damage may be irreversible once it develops 1
• Do not over-treat: Stop at ferritin 50-100 μg/L to avoid iron deficiency, which can persist for months and cause significant symptoms 1, 4
• Do not recommend dietary iron restriction as primary therapy—dietary changes remove only 2-4 mg/day versus 200-250 mg/week with phlebotomy 1, 5
• Do not give iron supplements or iron-fortified foods 1, 4, 5
• Warn patients to avoid raw or undercooked shellfish due to risk of Vibrio vulnificus infection in iron-overloaded states 1, 4, 9