Introduction

Therapeutic phlebotomy—the controlled removal of blood for therapeutic purposes—is a cornerstone of management in Polycythemia Vera (PV) and is used for relieving symptoms in secondary polycythaemias. While the practice of bloodletting has ancient origins, modern therapeutic phlebotomy bears little resemblance to its historical predecessor. Historical bloodletting was rooted in humoral theory and applied indiscriminately across a range of conditions with no physiological rationale. In contrast, contemporary therapeutic phlebotomy is a precisely targeted intervention, supported by trials, with clearly defined mechanisms of action.

This article focuses on the rationale, indications, technique, and complications of therapeutic phlebotomy, with particular emphasis on its role in polycythaemia vera, wh.

1. Physiological Basis: Viscosity and Thrombotic Risk

Hematocrit and Blood Viscosity

Blood viscosity is a critical determinant of flow dynamics, particularly in the microvasculature. The relationship between hematocrit and viscosity is non-linear: viscosity increases exponentially as hematocrit rises. At hematocrit values exceeding 50%, viscosity increases sharply, resulting in:

1. Reduced microvascular perfusion: According to Poiseuille’s law, flow rate is inversely proportional to viscosity. Elevated hematocrit impairs capillary blood flow.
2. Increased cardiac workload: Viscosity increases peripheral resistance increasing the cardiac workload.
3. Elevated wall shear stress: High shear stress induces conformational changes in von Willebrand factor (vWF), promoting platelet adhesion and aggregation at the vessel wall.

Note: Hyperviscosity alone does not fully explain the thrombotic risk in PV. The biology of the JAK2-mutant clone—including platelet hyperreactivity, chronic inflammation, and endothelial activation—contributes significantly. This is discussed in detail in the article on Polycythemia Vera .

2. Mechanisms of Action

Therapeutic phlebotomy exerts its effects through two complementary mechanisms:

A. Acute Reduction of Red Cell Mass

Removal of 450–500 mL of blood by therapeutic phlebotomy immediately reduces circulating red cell volume, lowering hematocrit and improving blood flow within hours.

B. Iron Depletion

Each 500 mL of blood contains approximately 200–250 mg of iron. Repeated phlebotomy depletes body iron stores.

• Hereditary Hemochromatosis: Patients of hereditary hemachromatosis accumulate iron that causes organ damage. The aim of phlebotomy is remove the excess iron.
• Polycythemia vera: Iron deficiency reduces the erythropoiesis by depriving developing erythroid precurssors of a critical component of heme, reducing the need for phlebotomy. (Iron supplementation is contraindicated in patients with PV undergoing phlebotomy. Repleting iron stores would remove this physiological brake and accelerate red cell production by the malignant clone).

3. Indications

The table below gives indications for therapeutic phlebotomy

A. Polycythemia Vera

PV is one of the main indications for therapeutic phlebotomy. The goal is to reduce blood viscosity and thereby mitigate the substantial risk of arterial and venous thrombosis.

The CYTO-PV Trial and the 45% Target

The CYTO-PV trial (Marchioli et al., NEJM 2013) randomised 365 patients with PV to intensive (hematocrit <45%) versus conventional (hematocrit 45–50%) management. The intensive arm demonstrated a four-fold reduction in cardiovascular death and major thrombotic events.[1]

Standard of Care: Target hematocrit <45% in all patients with PV, regardless of sex. Pregnant patinets with PV may be subjected to phlebotomy with a slightly lower (42%) target hematocrit.

Prior to this trial, some practitioners used sex-specific targets; the CYTO-PV data eliminated this distinction.

B. Hereditary (Non-Clonal) Polycythemias

Rare conditions such as VHL mutations, EPO-receptor mutations and high affinity hemoglobins cause elevated red cell mass without a malignant clone.

Key distinction: These patients lack the inflammatory milieu and platelet hyperreactivity of PV. Their baseline thrombotic risk is lower.[2]

Management approach: The strict <45% target derived from CYTO-PV may not apply. Many experts individualise therapy, tolerating hematocrit up to 50–52% in the absence of cardiovascular risk factors, thereby avoiding unnecessary iron deficiency.

C. Secondary Polycythemia

In conditions such as chronic hypoxic lung disease, obstructive sleep apnoea, or cyanotic congenital heart disease, erythrocytosis represents a compensatory physiological response.

The risk of over-treatment: Aggressively reducing hematocrit to 45% in a patient with severe COPD may impair oxygen delivery—these patients require elevated red cell mass to maintain tissue oxygenation.

Indication for intervention: Phlebotomy is considered only if the patient is symptomatic (severe headache, visual disturbance, cognitive impairment) or hematocrit is markedly elevated (typically >55–60%). The goal is symptom relief, not a numerical target.

D. Hereditary Hemachromatosis

Phlebotomy in hereditary haemochromatosis serves a fundamentally different purpose than in polycythemia: the goal is iron depletion, not hematocrit control. Patients with haemochromatosis accumulate iron progressively, leading to hepatic, cardiac, pancreatic, and endocrine damage. Phlebotomy remains the mainstay of treatment and can prevent further organ damage; early intervention may reverse some manifestations, though established cirrhosis is irreversible.

Induction phase: Phlebotomy (450–500 mL per session, removing approximately 200–250 mg of iron) is performed weekly until the serum ferritin falls below 50 ng/mL. Haemoglobin should be monitored before each session; phlebotomy is typically deferred if haemoglobin falls below 11 g/dL. In patients who tolerate the procedure well and maintain adequate haemoglobin, some centres perform phlebotomy twice weekly to accelerate iron depletion.

Maintenance phase: Once the target ferritin is achieved, phlebotomy frequency is reduced—typically to every 2–4 months—to maintain serum ferritin in the range of 50–100 ng/mL. Lifelong monitoring is required, as iron will re-accumulate without ongoing venesection.

4. Setting

For the majority of patients, day care or OPD-based phlebotomy is standard practice. Admission is reserved for high-risk situations.

Pre-Procedure Assessment

• Verify current hematocrit
• Assess blood pressure and volume status
• Confirm adequate hydration status

Hydration

Adequate hydration is essential to prevent hypovolaemia and to optimise haemodilution following blood removal.

Volume

Usually the volume of blood drawn in one session of therapeutic phlebotomy is 450-500ml. The amount may be less in those not likely to tolerate volume depletion like the elderly, those with cardiac disease and those who are hemodynamically unstable. The volumes drawn per therapeutic phlebotomy may be 200-250ml or one may even perform a daily phlebotomy of 50-100ml.

• Polycythemia Vera: Therapeutic Phlebotomy may be performed every 2-3 days till the hematocrit falls to below 45%.
• Secondary Polycythemia: The goal in secondary polycythemia is relief of symptoms. Too aggressive a therapeutic phlebotomy is harmful as polycythemia is a compensatory mechanism.
• Hereditary Hemochromatosis: The goal is a serum ferritin level of 50ng/mL during induction and a ferritin in the range of 50-150ng/mL during the maintainance phase.

The frequency of maintainance therapeutic phlebotomy needs to be individualized and depends on the rate of rise of hematocrit, rate of rise of ferritin or recurrance of symptoms.

Post-Procedure Observation

Patients should be observed for 15–30 minutes following the therapeutic phlebotomy to monitor for:

• Vasovagal reactions
• Orthostatic hypotension
• Symptoms of hypovolaemia

Post-procedure instructions: The patient should be instructed to:

• Remain well-hydrated for the remainder of the day
• Avoid strenuous physical activity for 24 hours
• Avoid alcohol for 24 hours
• Report symptoms of dizziness, chest pain, or unusual bleeding

5. Complications

6. Disposal of Phlebotomised Blood

A common question from students and patients: Can this blood be donated? The answer depends on the regulations prevailing where one is practicing. The table below is a summary of the usually practices. Blood not used needs to be discarded in keeping with local guidelines.

7. Summary Points

4. Target of Phlebotolmy: PV hematocrit <45% in PV (CYTO-PV trial); consider <42% in pregnancy, Secondary Polycythemia: Symptoms relief, Hereditary hemachromatosis : Freriting < 50ng/ml (induction), 50-150ng/mL (maintainance).
5. Do not over-phlebotomize secondary polycythemia—these patients require compensatory erythrocytosis for adequate tissue oxygenation.
6. Never give iron to patients with PV undergoing phlebotomy—it fuels the malignant clone.
7. Hydration is essential: Oral pre-hydration for all patients; IV crystalloid in day care for high-risk patients or during induction.
8. Phlebotomy is typically an outpatient/day care procedure; observe for 15–30 minutes post-procedure.
9. Blood from PV patients cannot be donated—it must be discarded as clinical waste.

References

1. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22-33. doi.org/10.1056/NEJMoa1208500

2. McMullin MF, Mead AJ, Ali S, et al. A guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis: A British Society for Haematology Guideline. Br J Haematol. 2019;184(2):161-175. doi.org/10.1111/bjh.15647.

3. Tefferi A, Barbui T. Polycythemia vera: 2024 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023;98(9):1465-1487. doi:10.1002doi:10.1002/ajh.27002

4. Barbui T, Tefferi A, Vannucchi AM, et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia. 2018;32(5):1057-1069. doi:10.1038/s41375-018-0077-1

5. Spivak JL. Polycythemia vera. Curr Treat Options Oncol. 2018;19(2):12. doi:10.1007/s11864-018-0529-x