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Anemia Causes and Treatment
Ernest H. Rosenbaum, MD

Anemia
Causes of Anemia
Treatment of Anemias

Administration of Erythropoietin (Epoetin alfa) Injections Review: Four Types of Anemia
Anemias of Cancer
The Role of Anemia on Prognosis and Survival
Physical Findings

Anemia and Fatigue of Cancer
Summary
References


Anemia
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Anemia is defined as "a pathologic deficiency in the amount of oxygen-carrying hemoglobin in the red blood cells." It is a common problem for cancer patients and often results from the therapies used to suppress or control tumors. Anemia is associated with fatigue - a feeling of weakness or diminished physical and mental capacity unrelieved by rest (fatigue). Additional symptoms include diminished ability to perform daily functions and possibly impaired cognitive function, headache, dizziness, chest pain and shortness of breath, nausea, depression and occasionally pain. These symptoms are often complicated by coexisting disease(s).There are many compromises that are necessary when one has symptomatic anemia. This can affect the tolerability of therapy. Anemia is also associated with a poorer prognosis and increased mortality.


Causes of Anemia
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  1. Blood loss: excessive bleeding such as hemorrhages or abnormal menstrual bleeding
  2. Chronic illness secondary to refractory anemia: inflammatory GI/GU diseases, malignancies (cancer), arthritis, kidney or liver failure, and acute and chronic infections
  3. Cancer therapy: surgery, radiotherapy, chemotherapy and/or immunotherapy
  4. Infiltration (replacement) of bone marrow with cancer
  5. Hemolysis: Breakdown or destruction of red blood cells
  6. Decreased red cell production due to low levels of erythropoietin (a hormone produced by the kidney {90%} and liver {10%}) which promotes red blood cell production

Treatment of Anemias
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First make a diagnosis.
The successful treatment of anemias depends on identifying and treating the underlying cause: blood loss, a nutritional deficiency, cancer, bone marrow infiltration, chronic illness, inflammation, or decreased response to erythropoietin. Through laboratory test results and a physical examination, a physician can determine the cause of your anemia and identify the best approach to treating it.

This may include:
1. Nutritional supplements - Iron, B12 or folic acid
2. Treatment of infections, inflammations or malignancies
3. Erythropoietin
4. Blood transfusions Providing red blood cell transfusions for bleeding and/or severe chronic anemias may be lifesaving. Red cell transfusions are the old mainstay, which offers the quickest relief for anemias. However, there are risks associated with transfusions.
A. Allergic reactions
B. Transmissions of infectious agents (hepatitis, HIV, and Human Leukemia Virus (HTLV)
C. HBV (hepatitis B virus): 1 in 63,000
D. HIV (AIDS) risk: 1 in 675,000 (5,000-1,000,000)
E. HIV 2: <1 in 10,000,000
F. HTLV (Human Leukemia Virus): 1 in 641,000
G. The viral risks of blood transfusions have recently been reduced due to a more accurate blood test called NAT (Nucleic Acid Test). This tests specifically for evidence of HIV and hepatitis C virus (HCV)
H. Immune suppression
I. Iron overload from multiple transfusions (usually over 25-50 units of red cells)

Administration of Erythropoietin (Epoetin alfa) Injections
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Erythropoietin (Epoetin alfa)
is a hormone produced by the kidneys (90%) and liver (10%) in response to hypoxia or low blood oxygen levels. Hypoxia stimulates the kidneys to produce erythropoietin. Erythropoietin selectivity stimulates early red blood cell (erythroid) in the bone marrow to increase bone marrow activity. The increased number of red cells, in turn, help deliver more oxygen to the tissues and resolve some of the symptoms of weakness and fatigue.

A weakened bone marrow due to cancer infiltration (marrow replacement), lymphoma or leukemia may lead to low red cell production. These patients may respond to epoetin alfa (the commercial equivalent to erythropoietin) therapy. Patients who cannot produce adequate erythropoietin due to kidney or liver disease may also be helped by injections of Epoetin alfa.

Erythropoietin injections are generally well tolerated. Some of the uncommon side effects include: hypertension (elevated blood pressure), iron deficiency, occasionally minor allergies, edema, and occasional increased diarrhea. It can cause growth of some tumors, especially myeloid leukemias.

The Effects of Epoetin Alfa on the Central Nervous System
In rodents, who received brain infusions of Erythropoietin, it was noted to help alleviate ischemia due to anemia, which caused learning and navigational disabilities. A decrease in the neuronal (nerve) cell death in those who received Epoetin Alfa before or during the early phase of brain trauma or stroke was noted.

There are now ongoing studies to determine the effectiveness of Epoetin Alfa in protecting the central nervous system for strokes and chemotherapy-induced problems in cognitive thinking. In anemic dialysis patients, Epoetin Alfa has been found to reduce anemia and improve cognitive function.There was both a prolongation of the attention span and improvement in memory skills.

Many studies have been done on recurring chemotherapy patients. Schagn, reported in Cancer, 1999, along with Van Dam and others, studying cognitive function and impairment of brain function along with increased levels of anxiety, depression and fatigue. There was increased brain dysfunction with more intense doses of chemotherapy, such as bone marrow transplantation or higher-dose chemotherapy (CMF or CEF). The estimation is that at least 19% of these patients had cognitive dysfunction or impairment in memory and concentration, which was also correlated with a decrease in hemoglobin.

When one receives surgery, radiation and chemotherapy, the affects can be more severe. In summary, there is a direct correlation between cognitive deficits and anemia. In addition, there are beneficial effects seen experimentally in clinical trials, which are ongoing, to study the beneficial effects of Epoetin Alfa and anemia, as well as the neuroprotective properties in acute stroke patients. Preliminary studies are looking favorable. In patients with cancer, it has been noted that anemia can affect both the young and elderly alike. Cancer treatments can promote anemia with a secondary side effect of cognitive impairment. As the anemia becomes more severe, it can exacerbate cognitive defects.

Epoetin Alfa, thus, can help diminish (at least for six months) cognitive deficits secondary to chemotherapy and can also help reduce the significance of anemia. Multiple studies have shown that it takes somewhere between four and eight weeks for Epoetin Alfa to help raise the hemoglobin between one and two grams. In general, those with hematologic malignancies do better with improved survival versus those with solid tumors. One study 5 showed that those having a greater than 10.5-gm hemoglobin had improved survival compared to those with a less than 10.5-gm hemoglobin.

There are currently two forms of Erythropoietin. One is Epoetin Alfa, which has a shorter half-life, averaging approximately 8.5 hours, versus Darbepoetin Alfa, with a half-life of about 25 hours. Studies have shown that Epoetin Alfa biologic activity has increased several times compared to Darbepoetin. There is a need for a head-to-head trial to compare Darbepoetin to Epotin alfa to see which has the best therapeutic advantage. Based on current studies, Darbepoetin has a higher molecular rate because of added sialic branches with a 3.5 x longer T1/2 half-life but less biologic activity. There is not enough clinical evidence to specify whether one is more effective than the other. The studies on longer- and shorter-acting Erythropoietin agents have yet to be accomplished. Studies are in progress in general, and the head-to-head study has to be set up to compare the 200 mg dose of Darbepoetin versus 40,000 units of Erythropoietin (Procrit®).The consensus is unclear as to which is a superior drug. They are both expensive, and one should find out which is least expensive with an equivalent dose.


Review: Four Types of of Anemias
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1. Iron deficiency due to iron loss. This is usually from a GI site with gastrointestinal bleeding. In the United States, this is rarely from a nutritional deficiency, and in such cases, it usually takes over 10-20 years to develop.
2. Anemia of deficiencies such as:
(a) vitamin B12 deficiency,
(b) folic acid deficiency, and
(c) rarely copper or mineral deficiencies.
3. Production problems with anemia usually secondary to a disease process, as
(a) chronic or acute infections or inflammation,
(b) hematologic problems such as leukemia, lymphoma, usually involving the bone marrow,
(c) cancer, (d) inflammatory diseases such as lupus or arthritis, or (e) chronic illness.
4. Hemoloysis (a shortening of red cell survival), hemolytic anemias as in
(a) non-immune hemolytic anemias such as sickle cell, hemoglobinopathies, spherocytosis, elliptocytosis (oval ) or
(b) autoimmune hemolytic anemias with a positive Coombs test.

Anemias of Cancer
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There are two major causes of the anemia of cancer:

1. Chemotherapy, radiation therapy or surgery.

2. Anemias directly related to the cancer, which produces chemicals, such as cytokines, or anemias due to bone marrow infiltration by lymphomas or cancers. The cancers of anemia are affected by stimulation of the cellular immune system and inflammatory changes, which stimulate the production of chemicals called cytokines and affect both red cell production and survival.Several cytokines, including tumor necrosis factor (TNF), Interferon Gamma and Interleukin-1 (IL-1),can suppress bone marrow production (erythropoiesis) by affecting red cell production.

Approximately one-third of cancers have anemia, although, it is higher in lymphomas, genitourinary cancers and ovarian cancer - up to 50-60%.Hypoxia (low oxygen concentration) is associated with anemia, and this is regulated by erythropoietin production from the renal cortex. Erythropoietin is also produced in the liver under stress, and astrocytes in the brain can also produce some erythropoietin, which is protective against brain injury.In cancer-related anemias, there is also the shortening of the red cell life span, which is usually 120 days, to between 60 and 90 days.

The lifespan is also shortened in transfused red cells (hemolysis). Of note is that in anemia of cancer, there are similarities to the anemia of chronic diseases with a low serum iron and a low transferrin saturation and normal or elevated ferritin level and a low reticulocyte count. The red cells are normochromic.

Thus, in summary, anemia of cancer is due to several causes:
1. A shortened red cell survival (hemolysis).
2. The activated immune system and macrophages, which produce cytokines, Interferon Gamma, IL-1 and tumor necrosis factor, which can affect and impair iron utilization, suppress bone marrow production of red cells, as well as reduce erythropoietin production, which results in a decreased marrow stimulation for production of red cells.

Hypoxia (a decrease in oxygen concentration) stimulates erythropoietin production. There is a factor HIF-1 alfa and HIF-1 beta, which are hypoxia-inducible factors from hypoxic cells. Recent reviews have developed new concepts in the role of hypoxia, which can potentially increase angiogenesis and, thus, tumor growth.


The Role of Anemia on Prognosis and Survival
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Anemia can have a direct effect on prognosis and survival, and so, it may be very important to keep the hemoglobin at a higher level to decrease the effects of hypoxia, especially during treatment. There is a direct correlation between the hemoglobin level and the median P02 at the primary tumor site. There has also been a well-known effect of tissue hypoxia in radiation therapy and anemia relating to the efficacy of radiation therapy. This has been well-evaluated in head and neck cancers, and it has been shown that tissue hypoxia has a negative impact on local control and survival in cervical cancer as well.The radiation therapy damages DNA through its production of hydroxyl radicals. Thus, under hypoxic conditions, there is a smaller amount of oxygen available to produce DNA damage from free radicals, and so, radiation therapy may be less effective.

In a paper by Jeffrey Crawford, David Cella and Charles Cleeland, et. al., entitled Relationship Between Changes in Hemoglobin Level and Quality of Life During Chemotherapy in Anemic Cancer Patients Receiving Erythropoietin Therapy, they concluded that there was a direct relationship between the hemoglobin increases during Epoetin alfa therapy and corresponding quality of life improvements in cancer patients receiving chemotherapy across the clinically-relevant range of 8-14 grams per deciliter. It was felt that maximal incremental gain in quality of life occurs when the hemoglobin range is 11-13 gm/dl. (Cancer 2002: 95:888-95)

The tests usually done to access anemia include:
(1) Hemoglobin and hematocrit
(2) Reticulocyte count - counts number of early red cells being produced and released from bonemarrow.
(3) A Coombs antibody test, direct and indirect antibodies
(4) Serum haptoglobins detect hemoloysis
(5) Enzymatic deficiencies with secondary drug sensitivity (allergy), such as G6PD, pyruvate kinase enzyme deficiencies.

Physical Findings
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Iron deficiency is a common anemia worldwide, and in severe cases, there is spooning of the nails kylonychia, a smooth tongue and a pallor of the skin.

In a physical examination, one needs to check for enlarged lymph nodes, which could reflect lymphoma, leukemia or an inflammation or infection, enlarged liver or spleen, which could reflect many different disease processes, and edema. There is often a murmur due to the decrease in red cells (hemoglobin), causing a flow sound on examination of the heart.

An examination of the peripheral blood smear is important, as in iron deficiency, it can show smaller red cells that have a poor hemoglobin concentration versus in hemolysis, larger cells that are often early cells called reticulocytes - red cells that have lost their nuclei and have just entered the blood stream from the bone marrow. One also looks for fragmented cells or bizarre cell shapes (schiztocytes) that may often reflect hemolytic anemia and nucleated red cells, which are red cells that still have a nucleus. This reflects many different disease processes as an example of bone marrow distress or cancer involvement, hemolysis, bleeding or some hereditary anemias.


Anemia and Fatigue of Cancer
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Case History A 52-year-old female recently diagnosed with stage II breast cancer had a 4 cm left breast mass and two positive sentinel lymph nodes removed. She was placed on neoadjuvant chemotherapy with CEF (Cytoxan, Epirubicin, 5-Florouracil) with a good response and a 66% reduction in the mass.

She complained that she was tired all the time, even after she had a good night's rest, she still felt tired. As she puts it, "I don't have any energy - I can hardly get up in the morning. I feel exhausted", and wonders what she can do. She is suffering from fatigue, which is the most common symptom endured by patients with cancer.

Over 70-90% of cancer patients suffer from fatigue at some time, yet it is poorly understood 1

Epoetin alfa for chemotherapy- or radiotherapy-induced anemia has been evaluated by many investigators. 2,3,4 They all show that with breast cancer, there is a rise in the hemoglobin with Epoetin alfa approximately 1.6 to 2.1 gm with an overall improvement in quality of life between 23 and 26%.

Fatigue is also related to cancer therapy, such as surgery, radiotherapy, chemotherapy and/or immunotherapy. It's often cumulative and frequently peaks a few days after therapy and can persist for weeks or months or a year and rarely two years.

In addition, fatigue is a universal problem with biologic therapies, such as Interferon or Interleukin, and can be quite severe and persistent.

There are other symptoms that are of importance, including diarrhea, nausea and vomiting, weight loss, constipation, dyspnea, pain and depression.

Fatigue has many signs and symptoms related to:
1) Decrease in patient's performance status (either Karnofsky or ECOG scores) is associated with a decreased quality of life.
2) The greater degree of anemia directly correlates with symptoms of weakness.
3) One needs to rule out other diseases, such as hypothyroid, decreased potassium and magnesium.
4) Muscle loss (atrophy) results in weakness due to disuse (lack of exercise).
5) May relate to emotional depression and distress.
6) Sleep hygiene problems - insomnia.
7) Uncontrolled pain.
8) Poor nutrition.

As disease progresses, anemia will usually become more severe. Using a pain-type rating, one can grade the severity of fatigue, usually between one and ten. (Analog Scale)

One can also use proven tools, which have been standardized, to screen and measure fatigue, such as the LASA (Linear Analog Scale Analysis) pre-fatigue or the Piper scale, which involves a 41-item questionnaire.


Summary
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Fatigue decreases one's performance status and reduces quality of life. It can also affect the response to therapy and the relationship between family, friends and community. The symptoms are often hard to solve, and the solutions don't always resolve the fatigue problem.

With correction of fatigue, one's appetite often improves along with weight gain and improved body strength, bowel habits and self image. What often helps is a structured aerobic series of exercises. If one would take a brisk ten-minute walk away from home with ten minutes back, this would yield a twenty-minute exercise program that can be very effective.

Set realistic goals: This involves motivation to use support services (nutrition, exercises) to achieve benefits, along with using methods of energy conservation. The use of occupational therapy techniques to help save energy is often very helpful, as well as selecting the best time to do activities. Getting an afternoon nap is helpful for many people. Doing tasks when one feels more energetic in the morning is a good strategy.

In addition to the use of Erythropoietin agents, antidepressants, such as paroxetine (Paxil) 10-20 mg per day, or psychostimulants such as methylphenidate (Ritalin) 5-20 mg per day can help lessen fatigue; although there are no good randomized trials.

In addition, one should maintain good nutrition to help sustain the body, as well as joining exercise classes.(See sections on Nutrition and Exercise)

To help control/reduce fatigue:
1. Do exercises - bed, sitting, standing and walking.
2. Strategize methods to help save energy.
3. Taking naps often improves the sleep pattern.
4. Exercises such as Yoga, Qi gong and Feldenkreis, and massage and visual imagery can be of help.
5. For many, spirituality and religion can give peace of mind and emotional strength.
6. One needs to reduce stress, control depression and sadness and participate in relaxation and recreational activities, which can help improve quality of life. Using diversions such as card games, enjoying music and movies can be of help in relieving stress and tension.

References
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1. Stone, et al., entitled Cancer Related Fatigue: Inevitable, Unimportant and Untreatable? in Annals of Oncology, 2000; 11:971-975.
2. Glaspy, J., et al., published in the Journal of Clinical Oncology, 1997
3. Demetri, G.D., et al., Journal of Clinical Oncology, 1998
4. Gabilove, J.L. et. al., Journal of Clinical Oncology, 20015. Bokemeyer, C., et al., British Journal of Cancer, 2002




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