Anemia

Overview

Anemia is an inadequate supply of red blood cells, resulting in a decrease in the oxygen-carrying capacity of the blood. A common reason that cancer patients experience anemia is as a side effect of chemotherapy. Anemia is important because it may cause unwanted symptoms, such as fatigue, tiredness or shortness of breath, and may exacerbate or cause other medical problems, such as a heart condition. Fortunately, administration of the blood growth factor erythropoietin can increase the production of red blood cells and constitutes an effective treatment for anemia that is less risky than blood transfusions.[1] Currently, there are two commercially available forms of erythropoietin for use in patients, epoetin alfa (Epogen® or Procrit®) and darbepoetin alfa (Aranesp®), a longer acting form of erythropoietin.

• What is anemia?
• Why is anemia important?
• How is anemia diagnosed?
• How is anemia treated?

What is anemia?

Anemia is an inadequate supply of red blood cells, resulting in a decrease in the oxygen carrying capacity of the blood. Red blood cells contain the protein hemoglobin, which carries oxygen to all parts of the body. Low levels of red blood cells, and thus hemoglobin, cause a reduction in the amount of oxygen that can be carried to the body. The decreased delivery of oxygen causes the following symptoms:

• Fatigue or tiredness
• Trouble breathing
• Rapid heartbeat
• Dizziness, light-headedness, inability to concentrate, or headache
• Chest pain
• Difficulty staying warm
• Loss of sex drive
• Pale skin

Fortunately, there are treatments available to improve anemia and its symptoms.

Anemia commonly occurs in cancer patients, either as a direct result of the cancer or as a side effect of cancer treatment. Chemotherapy, radiation therapy and blood loss during surgery are all common causes of anemia in cancer patients. Chemotherapy drugs kill rapidly dividing cells in the body, including cancer cells and normal cells, such as cells in the bone marrow responsible for red blood cell production. Over 60% of patients treated with chemotherapy develop anemia.[2]

The production of red blood cells in the bone marrow is called erythropoiesis. Erythropoiesis is controlled by red blood cell growth factors. Erythropoietin is the major blood cell growth factor that increases red blood cell production in the bone marrow. Erythropoietin is produced by cells in the kidney. When kidney cells detect a decrease in tissue oxygen, erythropoietin is released into the circulation. The end result is increased red blood cell production in the bone marrow.

Anemia occurs because patients can't produce enough red blood cells or because red blood cells are lost through bleeding or destroyed faster than they can be produced. Many different causes of anemia exist. A careful evaluation is necessary to determine the cause of anemia so that the most appropriate treatment is administered.

Why is Anemia Important?

There are three main reasons that anemia is important:

1. Patients with anemia experience unwanted symptoms such as fatigue, tiredness, shortness of breath and a reduced tolerance to activity. All of these symptoms contribute to a decreased feeling of overall well-being and treatment of anemia can alleviate these symptoms.[3][4][5]
2. Anemia may exacerbate or cause other medical problems. For example, anemia requires the heart to work harder and this additional stress to the heart could cause a heart attack in patients with preexisting heart disease.
3. Delivery of chemotherapy according to the planned dose and schedule of treatment is important to achieve the best treatment results. Anemia as a side effect of chemotherapy may prevent patients from receiving their treatment at the appropriate dose and time.

How is Anemia Diagnosed?

A simple laboratory test known as a CBC, or complete blood count, measures the different types of cells in the blood. The results of a CBC indicate the amount of hemoglobin in the red blood cells. The hemoglobin count is the most useful indicator of anemia because it determines the oxygen-carrying capacity of the blood. The normal hemoglobin count is 12 g/dl - 16 g/dl for women and 14 g/dl - 18 g/dl for men. Patients with a hemoglobin count that falls below the normal range have anemia. In order to better understand the interpretation of a CBC, a sample is provided below.

Measurement of Blood Counts

A test called the complete blood count (CBC) is used to determine whether your red blood cells are low. The CBC measures the levels of the three basic blood cells: red, white, and platelets.

In the United States, the CBC is typically reported in the format shown below. If your blood counts fall outside of the normal range, which is shown in the “Reference interval” column, their values will be reported in the “Flag” column with an ‘L’ for low and an ‘H’ for high. The example CBC below shows that red blood cells are low.

Result: The result column shows counts that fall within the normal range.

Flag: Counts that are above or below the reference range are recorded in the flag column, and marked with an ‘L’ for low or ‘H’ for high.

Reference interval (or reference range): The reference interval shows the normal range for each measurement for the lab performing the test. Different labs may use different reference intervals.

White blood cells: White blood cells help protect individuals from infections. The above CBC report shows that the patient’s total white cell count is 7.2, which is within the normal range of 4.0-10.5.

Red blood cells: Red blood cells carry oxygen from the lungs to the rest of the body. The above CBC report indicates that the patient has a red cell count of 3.5. This count is lower than the normal range of 4.7-6.1, and is therefore recorded in the flag column and marked with an ‘L’ for low.

Hemoglobin (Hb or Hgb): Hemoglobin is a protein in the red cell that carries oxygen. The above CBC report indicates that the patient's Hb count is 10.8, which is below the normal range of 14.0-18.0. The hematocrit (HCT) is another way of measuring the amount of Hb, and it is also low. This means that the patient has mild anemia and may be starting to notice symptoms. The reference ranges for hemoglobin and hematocrit will vary depending on age and gender. For women, they will be lower than those shown here. For example, the hemoglobin reference interval for a woman is 12.0-16.0.

Platelets: Platelets are the cells that form blood clots that stop bleeding. The above CBC report indicates that the platelet count for this patient is normal.

Differential: This portion of the CBC shows the counts for the 5 main kinds of white cells, either as percentages (the first 5 counts), or as the absolute number of cells (the second 5 counts).

Absolute neutrophil count: Neutrophils are the main white blood cell for fighting or preventing bacterial or fungal infections. In the CBC report, neutrophils may be referred to as polymorphonuclear cells (polys or PMNs) or neutrophils. The absolute neutrophil count (ANC) is a measure of the total number of neutrophils present in the blood. When the ANC is less than 1,000, the risk of infection increases. The ANC can be calculated by multiplying the total WBC by the percent of polymorphonuclear cells. For example, this patient's ANC is 3.10, which equals the white blood cell count (7.2) times 43%.

How is Anemia Treated?

Anemia can be treated by increasing the hemoglobin level with blood transfusions or with erythropoietin (epoetin alfa or darbepoetin alfa), a blood cell growth factor that increases red blood cell production. The two objectives for treating anemia are to first correct the underlying cause of the anemia and second treat the symptoms of the anemia. Successful management of anemia may require erythropoietin, transfusions or both.

Erythropoietin: Erythropoietin is a blood cell growth factor that selectively increases production of red blood cells. The body produces erythropoietin to increase red blood cell production.

Clinical trials have demonstrated that erythropoietin is safe and effective in reversing anemia in cancer patients. Erythropoietin has been proven to effectively:

• Increase hematocrit
• Decrease the need for blood transfusions
• Reverse fatigue
• Improve overall sense of well-being

Erythropoietin is FDA-approved for the treatment of anemia in patients with nonmyeloid cancers whose anemia is a result of chemotherapy.

Treatment with erythropoietin causes a gradual increase in red blood cell production. The body uses iron in red blood cell production. Thus, supplemental iron may be required to adequately support erythropoietin-stimulated erythropoiesis. Virtually all patients receiving erythropoietin therapy will eventually require supplemental iron therapy.

Currently, there are two commercially available forms of erythropoietin for use in patients, epoetin alfa (Epogen® or Procrit®) and darbepoetin alfa (Aranesp®). Both are manufactured in the same facility in the same manner. Epogen® or Procrit® have been in use for many years. Aranesp® is a unique, longer-acting form of erythropoietin and is more convenient because it allows patients to receive fewer injections than with Epogen® or Procrit®.[6][7] The most common side effects seen in clinical trials with Aranesp® were fatigue, edema, nausea, vomiting, diarrhea, fever and shortness of breath. No important differences in side effects were seen between groups treated with Aranesp® and groups treated with the existing anemia treatment, Epogen®.

Blood Transfusion: Blood transfusions rapidly replace the oxygen-carrying capacity of the blood. The goal of a blood transfusion is to increase oxygen and carbon dioxide exchange between the tissues and reduce the symptoms of anemia. However, transfusions are associated with complications. Patients should carefully consider whether to undergo a transfusion and the benefits should outweigh the risk or complications of the procedure.

Although improvements have lowered the risk of transfusion-transmitted complications, the only way to effectively eliminate the risk is to avoid exposure to allogeneic or "banked" blood. Despite the risks, red blood cell transfusions are common treatments for the severe anemia associated with cancer and chemotherapy. Transfusions only temporarily correct anemia. Iron supplements alone, although commonly administered to patients, have little therapeutic benefit in these patients.

Complications of Blood Transfusion

Patients receiving red blood cell transfusions are at risk for several noninfectious reactions that range from mild allergic reactions to life-threatening anaphylaxis. Clinically, the most significant complications involve impact on the immune system. However, these conditions are rare.

Infectious Complications: Patients receiving allogeneic blood are at risk for bacterial, parasitic and viral infections. Bacterial infections are estimated to occur in 1 of every 2500 blood transfusions and viral infections occur in approximately 1 in every 3000. Fear of infection with the human immunodeficiency virus (HIV) has caused the most concern, although the risk per unit of blood transfused is relatively low (1 in 225,000 transfusions). All blood components are tested for HIV antibodies; however, there is a period of time after HIV exposure before antibodies can be detected in the blood. To address this issue, intense donor screening is being used and more sensitive tests are being developed.

Patients receiving an allogeneic transfusion are at greater risk for lethal infection with the hepatitis viruses than from HIV. It is estimated that hepatitis results from approximately 1 in every 3000 transfusions.

Other Alternatives to Allogeneic Blood Transfusions

Autologous blood transfusion: A transfusion in which the patient is used as both donor and recipient is called an autologous blood transfusion. For the patient, autologous blood transfusion has no risk of infection, alloimmunization, allergic reaction or graft-versus-host disease. Autologous blood is obtained from the recipient before it is needed, which means that collection must be preplanned (e.g., before surgery or bone marrow harvest). Usually autologous blood is not collected more than once per week and no closer than 72 hours before the procedure. The autologous blood is then mixed with an anticoagulant solution and either stored for up to 42 days or frozen.

Directed donors: Directed blood donations are collected from designated donors, usually friends and family of the recipient. However, no evidence exists that directed donor blood is safer than allogeneic blood.

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References

[1] Dunphy FR, Harrison BR, Dunleavy TL, et al. Erythropoietin reduces anemia and transfusions: a randomized trial with or without erythropoietin during chemotherapy. Cancer.1999;86:1362-1367.

[2] Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. JNatl Cancer Inst. 1999;91:1616-1634.

[3] Curt GA. Impact of fatigue on quality of life in oncology patients. Semin Hematol. 2000;37:14-17.

[4] Cella D. Factors influencing quality of life in cancer patients: anemia and fatigue. Semin Oncol. 1998;25:43-46.

[5] Vogelzang NJ, Breitbart W, Cella D, et al, for the Fatigue Coalition. Patient, caregiver, and oncologist perceptions of cancer-related fatigue: results of a tripart assessment survey. Semin Hematol. 1997;34(suppl 2):4-12.

[6] Glaspy JA, Jadeja J, Justice G. Optimizing the management of anemia in patients with cancer: a randomized, active-controlled study investigating the dosing of darbepoetin alfa [abstract]. Proceedings of the American Society of Clinical Oncology 38th annual meeting;May 18-21, 2002. Abstract 1446.

[7] Kotasek D, Albertson M, Mackey J. Randomized, double-blind, placebo-controlled, dose-finding study of darbepoetin alfa administered once every 3 (Q3W) or 4 (Q4W) weeks in patients with solid tumors [abstract]. Proceedings of the American Society of Clinical Oncology 38th annual meeting; May 18-21, 2002. Abstract 1421.