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(BETA) Blood Cell Deficiencies - Part 1




 

Many people with HIV disease develop blood cell deficiencies at some point in the course of their illness. This article will discuss the different types of blood cells, the various deficiencies associated with each, and how to manage them.

Blood Cell Production

Blood contains various different types of cells circulating within the body suspended in a fluid called plasma. These include red blood cells, which carry oxygen to the body's tissues; several types of white blood cells, which are an important part of the immune system; and platelets, which are involved in blood clotting.

The production of blood cells is known as hematopoiesis. In the fetus, blood cells are produced in the liver, spleen and thymus. By the time of birth and throughout life, blood cells are manufactured in the bone marrow. Bone marrow is the spongy tissue inside certain bones including the ribs, vertebrae, pelvis, and the long bones of the arms and legs. The bone marrow contains pluripotent stem cells (CD34 cells) that develop into all the various types of blood cells. These cells are few in number but can proliferate rapidly. Stem cells differentiate into precursor cells called colony-forming units that go on to produce red blood cells, white blood cells and platelets.

Stem cells and later precursor cells are stimulated by various chemical messengers called cytokines. These messengers are released, for example, when the level of oxygen reaching the tissues is too low or when invading microorganisms are encountered. Erythropoietin stimulates the production of red blood cells. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor stimulate the production of different types of white blood cells. Cytokines called interleukins also influence the production of blood cells. For example, interleukin-3 (IL-3) stimulates stem cells and promotes proliferation of all types of blood cells, IL-2 stimulates production of helper T-cells, IL-4 stimulates the growth of B-cells and IL-11 stimulates the production of platelets.

Blood Cell Growth Factors


Factor Cell Type(s) Affected Action
Stem cell factor (SCF) stem cells, mast cells proliferation
Erythropoietin (EPO) red blood cells production  
Thrombopoietin (TPO) megakaryocytes proliferation and division into platelets
Granulocyte colony- stimulating factor (G-CSF) neutrophils production and activation
Granolocyte-macrophage colony- stimulating factor (GM-CSF) neutrophils, monocytes, eosinophils production and activation
Macrophage colony- stimulatng factor (M-CSF) monocytes production and activation
Interleukin 1 (IL-1) B-cells, T-cells proliferation
Interleukin 2 (IL-2) a.k.a. T-cell growth factor T-cells, B-cells

NK cells

proliferation, growth

activation

Interleukin 3 (IL-3) a.k.a. multi-colony-stimulating factor stem cells (precursor of all blood cell types) proliferation, differentiation
Interleukin 4 (IL-4) a.k.a. B-cell growth factor B-cells, mast cells, T-cells proliferation
Interleukin 5 (IL-5) a.k.a. eosinophil colony- stimulating factor eosinophils, B-cells proliferation
Interleukin 6 (IL-6) a.k.a. B-cell stimulatory factor B-cells, T-cells growth, differentiation
Interleukin 7 (IL-7) a.k.a. lymphopoietin B-cells, T-cells proliferation
Interleukin 8 (IL-8) neutrophils activation
Interleukin 9 (IL-9) T-cells
mast cells
proliferation
activation
Interleukin 10 (IL-10) macrophages inhibition
Interleukin 11 (IL-11) stem cells proliferation
Interleukin 12 (IL-12) T-cells, stem cells
NK cells
proliferation
activation
Interleukin 13 (IL-13) macrophages inhibition

General Causes of Blood Cell Deficiencies

Low blood cell levels can have a variety of causes. These can be broken down into deficiencies due to inadequate blood cell production and those due to excessive blood cell destruction or loss. These causes will be discussed below in relation to specific deficiencies.

Conditions that involve low blood cell levels are usually designated by the suffix "-penia." For example, leukopenia is a lack of white blood cells and neutropenia is a low level of neutrophils. Pancytopenia refers to low levels of all types of blood cells.

Blood cell deficiencies may be the result of an autoimmune response in which a person's immune system attacks the blood-producing cells in the bone marrow. Deficiencies may also be caused by drugs -- including many of the drugs used to treat HIV, opportunistic infections and cancer -- or exposure to toxic chemicals (e.g., arsenic, benzene). These agents damage the blood-producing cells, a condition known as bone marrow suppression or aplasia. Stem cells are particularly vulnerable to toxic drugs because they reproduce so rapidly. Drugs that are toxic to the bone marrow include AZT, TMP-SMX (Bactrim, Septra), hydroxyurea and many cancer chemotherapy regimens. Radiation (both radiation therapy and exposure to nuclear fallout) can also damage the bone marrow. In fact, some chemotherapy and radiation therapy is potent enough to kill all stem cells; this may be done to prepare a person for a bone marrow transfer. Damage to the bone marrow can lead to deficiencies of all types of blood cells.

Drugs That Can Cause Bone Marrow Suppression

This list shows some of the drugs that commonly cause bone marrow suppression and blood cell deficiencies. Many other drugs may also cause these conditions.

Drug   Resulting deficiencies    
  anemia leukopenia neutropenia thrombocytopenia
amphotericin B X     X
AZT X X X  
cidofovir X   X  
chloramphenicol X X X X
cyclophosphamide X X X  
dapsone X   X  
dexamethasone     X X
doxorubicin X X X  
doxycycline X   X X
delavirdine     X  
foscarnet X X X  
ganciclovir   X X X
hydroxyurea X X   X
ibuprofen   X    
indinavir X      
interferon-alpha X      
isoniazid X   X  
methotraxate X X   X
paclitaxel     X  
penicillins X X   X
pentamidine X X    
phenytoin X   X  
pyrimethamine X X   X
rifabutin   X X X
rifampin     X X
sulfonamides X X X X
TMP-SMX X   X X
trimetrexate X X X  
vinblastine   X    
vincristine   X    

Diagnosing Deficiencies

A normal adult has 4-5 million red blood cells, 5,000-10,000 white blood cells and 150,000-300,000 platelets per cubic millimeter (mm3) of blood. Of the white blood cells, about 60% are neutrophils, about 30% are lymphocytes (T-cells and B-cells), about 6% are monocytes and macrophages, about 3% are eosinophils and 1% or less are basophils. These types of blood cells are described below.

Healthcare providers perform various tests to determine if blood cell numbers are normal and if the cells are functioning properly. A complete blood count is an inventory of all of the different types of cells in the blood. A peripheral smear involves looking at a blood sample under a microscope to determine cell size and shape. The hematocrit and hemoglobin tests indicate the oxygen-carrying capacity of red blood cells. For more information, see the article Blood Tests in the December 1996 BETA. In some cases, a bone marrow biopsy is done to look for stem cells and precursor blood cells.

Anemia

The Basics

Red blood cells, also known as erythrocytes, are the most abundant type of blood cell. Anemia refers to a low hemoglobin level or a low number of properly functioning red blood cells.

Red blood cells are responsible for picking up oxygen in the lungs and transporting it to the body's tissues. These cells contain hemoglobin, a red pigment that gives blood its color and enables the cells to carry oxygen. If the level of oxygen reaching body tissues is too low (a condition known as hypoxia), the kidneys release erythropoietin (EPO), a cytokine hormone that stimulates the production of new red blood cells. The heart also works harder to circulate more blood and thus more oxygen. When this happens, the heart has little reserve capacity to handle exertion, and people with anemia may feel short of breath when exercising. When the hemoglobin level is severely reduced, people may experience shortness of breath even while at rest.

Other symptoms of anemia include fatigue, mental lethargy, weakness, mouth sores, headache, dizziness and in some cases chest pain (angina) due to insufficient oxygen reaching the heart muscle. Men may develop impotence and women may experience menstrual irregularities. People with anemia may show pallor (paleness), especially apparent in the nail beds and the mucous membranes. People with hemolytic anemia may have jaundice (yellowing of the skin and whites of the eyes) due to the increased release of bilirubin when red blood cells are broken down.

Blood tests that measure the oxygen-carrying capacity of red blood cells can detect anemia that is not severe enough to result in symptoms. Hematocrit is the percentage of whole blood that is made up of cells (all but about 1% of blood cells are erythrocytes). A normal adult hematocrit is 37-45% cells. A hematocrit below 36% for women or 38% for men indicates anemia. A normal blood hemoglobin concentration is 14-18 grams/deciliter (g/dL) for men and 12-16 g/dL for women. Another measure sometimes used is mean corpuscular volume (MCV), a measure of red blood cell size.

Types of Anemia

As with all blood cell deficiencies, anemia is due either to inadequate cell production or excessive cell loss or destruction. There are many different types of anemia, all with different causes; the most common are described here.

Aplastic anemia is due to the inability of damaged stem cells in the bone marrow to manufacture new red blood cells. The condition may be due to an autoimmune reaction in which a person's antibodies attack red blood cell precursors. Aplastic anemia may also result from chemotherapy or radiation that damages stem cells. Aplastic anemia can be detected by looking at a sample of blood, which may show a lack of immature red cells called reticulocytes, or a sample of bone marrow, which may show an absence of red blood cell precursors.

In some cases anemia is caused by low levels of EPO. Since this cytokine is produced by the kidneys, the condition commonly occurs in people with chronic kidney failure.

In other cases the body lacks the necessary "ingredients" to manufacture normally functioning red blood cells. Iron is an essential component of hemoglobin. Iron deficiency results in the production of small red blood cells that contain a reduced amount of hemoglobin, a condition known as microcytic hypochromic anemia. Loss of blood, inadequate iron in the diet, inability to absorb iron properly or inability to transport iron to the bone marrow can lead to iron deficiency anemia, the most common type. Iron deficiency anemia occurs more often in women than in men because women must produce more red blood cells to make up for blood lost through menstruation. The inherited disease thalassemia is characterized by small, short-lived red blood cells due to the inability to properly incorporate hemoglobin into newly forming cells.

Both vitamin B12 (cobalamin) and folic acid are necessary for red blood cell production. Deficiencies of these nutrients are common in people with HIV. Usually the amount of vitamin B12 in the diet is adequate and low blood levels are due to the inability of the body to absorb it. Pernicious anemia is a condition in which the lining in part of the intestine (the ileum) fails to produce a substance called intrinsic factor that enables the absorption of vitamin B12.

Deficiencies in folic acid may be due to either low levels in the diet or poor absorption. Poor absorption may occur in people who have intestinal diseases (e.g., Crohn's disease, sprue) or who have had part of their intestine removed. Lack of vitamin B12 and folic acid causes red blood cells to fail to mature properly, leading to the production of large, oddly shaped, short-lived red blood cells, a condition known as macrocytic or megaloblastic anemia.

Blood loss anemia is caused by excessive loss of blood cells due to bleeding. After a severe injury, it may take 3-4 weeks for the number of red blood cells to return to normal. This type of anemia may also be a sign of chronic internal bleeding (e.g., an ulcer).

Hemolytic anemia refers to conditions in which red blood cells are destroyed (a process known as hemolysis) at a faster rate than they can be replenished. In this type of anemia, red blood cell membranes are fragile and less able to bend when the cells pass through tiny vessels in the spleen, an immune system organ in the abdomen; this causes the cells to burst. Hemolytic anemia can be detected by looking at blood cells under a microscope. The presence of reticulocytes indicates that the bone marrow is attempting to rapidly produce new blood cells to replace those lost.

There are various types of hemolytic anemia, including several hereditary disorders. In some cases, the immune system produces antibodies that destroy red blood cells. This may happen following an immune response to an infection such as mononucleosis. In a condition known as erythroblastosis fetalis, antibodies from a Rh negative mother attack the blood cells of a Rh positive fetus. In sickle cell anemia, a change in the hemoglobin molecule leads to the formation of crystals inside red blood cells. These crystals give the cells an elongated shape that makes them get stuck in small blood vessels, and the sharp crystals may puncture the cells. Hemolytic anemia may also be caused by enzyme deficiencies (e.g., G6PD deficiency), some infections (e.g., malaria) and certain drugs. Merck and Company added a warning to the product insert for their protease inhibitor indinavir (Crixivan) after 20 cases of hemolytic anemia were reported in people taking the drug. Finally, this type of anemia may be caused by an enlarged spleen that removes too many red blood cells from circulation, a condition known as hypersplenism.

In addition to the above causes, anemia may also occur in pregnant women due to an inability to make enough new red blood cells to supply the developing fetus, and in premature infants whose blood production system is immature. Some people with chronic illnesses (e.g., cancer, AIDS, rheumatoid arthritis) experience anemia of chronic disease. This generally mild to moderate condition is due to a combination of a shortened red blood cell life span, inadequate production of EPO and the inability of the bone marrow to compensate for increased cell destruction.

Anemia is very common in people with HIV and AIDS. A recent epidemiological study of over 27,000 HIV positive men showed that 28% of men with HIV but not AIDS, 55% of HIV positive men with fewer than 200 CD4 T-cells/mm3, and 87% of men with clinically-defined AIDS had hemoglobin levels below 14 g/dl; results were similar in 5,000 women studied (31%, 52% and 77%, respectively, had hemoglobin levels below 12 g/dl).

Managing Anemia

Proper treatment of anemia first requires a determination of the cause. Anemia is really a symptom, not a disease in itself, and different types of anemia have different optimal treatments. Underlying causes -- such as a bleeding ulcer or malaria -- must be treated in addition to the anemia itself.

For a healthy person -- whether HIV positive or HIV negative -- the key to preventing anemia is good nutrition. It is important to get adequate amounts of iron, vitamin B12 and folic acid in the diet. If a person is unable to get enough nutrients through regular meals, supplements can be used; consult a healthcare provider, since overdoses can be harmful. Pregnant women should take folic acid supplements to support the increased blood production required by the developing fetus. The drug leucovorin (folinic acid) may be used to prevent anemia when a person is taking certain bone marrow-suppressing drugs.

If poor absorption rather than inadequate intake is the problem, other steps must be taken. Vitamin B12 is often given by injection to people who cannot absorb it through the gastrointestinal tract.

Selected Dietary Sources of Nutrients Important for Blood Cell Production

Iron (red blood cells)

  • Beans
  • Beef liver
  • Cabbage
  • Dried fruit (apricots, prunes, raisins)
  • Green vegetables (broccoli, peas, spinach)
  • Fish
  • Meat (beef, chicken, lamb, pork)
  • Molasses
  • Oatmeal
  • Peanuts
  • Shellfish (oysters, shrimp)
  • Whole grain products (bread, muffins)

Folic Acid/Folate (red blood cells)

  • Beans
  • Beef liver
  • Beets
  • Brewer's yeast
  • Egg yolks
  • Some fruits (cantaloupe, banana)
  • Green vegetables (asparagus, broccoli, spinach)
  • Orange juice
  • Peanuts
  • Potato
  • Sunflower seeds

Vitamin B12 (red blood cells)

  • Beef liver
  • Dairy products (milk, cheese)
  • Eggs
  • Fish
  • Meat (beef, chicken, lamb, pork)
  • Shellfish (oysters, shrimp)

Zinc (lymphocytes)

  • Beef liver
  • Bran cereal
  • Dairy products (milk, cheese)
  • Eggs
  • Meat (beef, chicken, lamb, pork)
  • Oysters
  • Wheat germ

Injections of genetically engineered EPO (epoietin alfa), which stimulates the bone marrow to produce more red blood cells, are used to treat anemia due to inadequate cell production. Brand names are Epogen and Procrit (see Epoietin alfa (EPO) for Anemia, this issue). Epoietin alfa is approved for the treatment of anemia in people with chronic kidney failure and bone marrow suppression due to anti-HIV drugs or cancer chemotherapy. The typical dose is 50-150 units per kilogram of body weight, injected 3 times per week. Side effects may include increased blood pressure, headache, fatigue, rash and joint pain. After beginning treatment, it usually takes about 4 weeks before the number of functional red blood cells begins to increase. Epoietin alfa can effectively treat anemia due to reduced red blood cell production, but should not be used to treat hemolytic anemia or anemia due to blood loss or nutritional deficiencies.

In cases where red blood cells are destroyed by an autoimmune reaction, immunosuppressive drugs such as prednisone may be effective. Another treatment that may be used is immunoglobulin plasmapheresis, a procedure in which harmful antibodies are removed from the blood.

In some cases, blood transfusion may be necessary. Healthcare providers prefer transfusions of packed red blood cells rather than whole blood. If anemia is due to a temporary cause, such as blood loss due to injury, a transfusion can maintain a person until the cause is addressed and their own blood production system compensates for the loss. Potential detrimental effects of transfusions include hypersensitivity reactions and blood-borne infections.

In severe cases of hemolytic anemia, removal of the spleen (splenectomy) may be done. This is effective because the spleen is the primary site of red blood cell destruction.

In persistent cases of aplastic anemia, a bone marrow transfer may be necessary to enable an individual to produce his or her own new red blood cells. Bone marrow transfers should come from a closely matched donor, preferably a sibling. The newly transplanted bone marrow will produce white blood cells that attack the tissues of the recipient (a condition called graft-versus-host disease), so immunosuppressive drugs must usually be given to the person receiving the transplant. A relatively new procedure, transplantation of stem cells from the umbilical cords of newborns, reduces some of the difficulties associated with bone marrow transfer.


NEXT: Blood Cell Deficiencies Part 2




 


Copyright © 1998 -BETA, Publisher. All rights reserved to the San Francisco AIDS Foundation. Reproduced by permission. Reproduction of this article (other than one copy for personal reference) must be cleared through BETA: PO Box 426182, San Francisco, CA 94142-6182. Tel: 415 487 8060 Fax: 415 487 8069 San Francisco AIDS Foundation, Mail SFAF..

Information in this article was accurate in July 1, 1998. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.