Pushing it to the Limit!

The patient is now stable and the bleeding has stopped; however, the hemoglobin count is at a dangerously low level. Your first reflex is to order blood, but the patient has said he wants nonblood treatment. What can you do? How can you make the human body increase the number of circulating red blood cells?

The Early Life of Red Blood Cells

All of the cellular components of blood begin at a common point. This progenitor of white cells, red cells, and platelets, is the pluripotent stem cell. What determines the final product of the individual stem cells? As a foreman directs the workers on a construction site in making a final product, the body has numerous hormones and enzymes that influence the development of stem cells in the bone marrow. One main class of these stimulators is known as cytokines. For red blood cells the major cytokine is a glycoprotein known as erythropoietin.

The environment within the bone marrow is one of continual cellular division, growth, and differentiation. A steady state occurs, where the normal daily needs for new blood cells of all types are cared for. This rate is less than what the bone marrow is capable of.

In the presence of increased levels of [url=http://www.noblood.org/forum/showthread.php?t=943]erythropoietin[/url in the blood stream, more stem cells are committed into the lineage to become red blood cells. Also, burst forming units erythroid (BFU-E) show an increase in reproduction. This heightened state of activity leads to an increased number of red blood cells being produced.

The basic components of these red blood cells are also present in the bone marrow;these components include proteins that are common to all cells. Folic acid and Vitamin B12 are also important basic components for red cell production. Lastly, iron is needed for the hemoglobin within the cells themselves.

Erythropoietin: The Big Player

Once bleeding is under control, the focus shifts to stimulating erythropoiesis to the maximum level possible. Available for this purpose is the recombinantly produced human hormone known as Erythropoietin, or EPO for short. Recombinant Erythropoietin (r-HuEPO) is a synthetic copy of a natural human hormone responsible for stimulation of red blood cell production. It is manufactured using recombinant DNA technology (genetically engineered), and has the same effects as endogenous human erythropoietin, stimulating the bone marrow to produce red blood cells. To a minor extent it affects the other lineages of the pluripotent stem cell. Though the primary target of EPO is the red cell lineage, there is a multitude of other cytokines that affect the growth, production, and maturation of red blood cells. [For more references on erythropoietin, please see our extensive bibliography on this subject

As a general rule, the more r-HuEPO that is administered, the greater the effect on red cell production. This is true across the board when most clinical and patient variables are considered; however, patient response to r-HuEPO can vary.

If the patient is not severely anemic and rapid increase in red cell mass is not required, physicians generally recommend a starting dose of 100-150 Units/kg of body weight, administered subcutaneously three times weekly. Dosage depends to some extent on patient age, coexisting disease, and other factors. After about a week there are noticeable increases in reticulocyte counts. From two to three weeks, there is evidence of increases in hemoglobin and hematocrit levels, with corresponding drops in iron storage. Many clinicians begin with this kind of dosage because it is less expensive and does not rapidly increase circulating red cell mass and corresponding blood viscosity. This is also true of clinicians who use such protocol to cause supranormal red cell counts in preparation for surgery. If reticulocyte counts do not rise after a week, many will begin to increase this dosage to about 300 Units/kg and then 600 Units/kg. This dosing schedule is the most commonly used and in many instances the least expensive.

In the case of the severely anemic critically ill patient there is a need to rapidly increase the red cell count as quickly as possible. Exact protocols in these instances have varied, but some general guidelines still do exist. Many give a dosage of from 300-600 u/kg every other day. The half-life of r-HuEPO is from 12-17 hours, and for this reason, some clinicians have opted to administer the drug in divided doses.

Administration route also varies, with some opting for an IM route while others try the IV approach. Some thought was given to the greater length of time of measurable EPO level increases from IM injections, but total reticulocyte and hemoglobin increases have not differed significantly from either the IM or IV routes. There are early reports of administering EPO in the same mixture used for parenteral nutrition without any decrease in bone marrow response.

Other clinical conditions can also vary the bone marrow’s response to the administration of EPO. Chronic renal failure is a classic example of such. Other conditions include the anemia of chronic disease, SLE, insulin-dependent diabetes, severe rheumatoid arthritis, connective tissue disorders, severe infection, heart surgery, CAD, age of the patient, and many others, all have some degree of bone marrow stunting to the administration of EPO. At times higher than normal EPO dosages may be given to overcome this stunting affect. 1

How Fast?

Many times doctors are under the impression that it will take weeks before EPO can increase the red cell count. In one report a patient with burns had a rapid recovery in her red cell count. In this report, the doctors administered a dosage of 367 U/kg of body weight every day for three days. Her starting hemoglobin count was 5.6 g/dl. On the third day her hemoglobin count had risen to 6.5 g/dl. This was despite debridement surgery which took place during that time. At the end of a week the hemoglobin count had risen to 8.4 g/dl. This is roughly a 3 g/dl of hemoglobin rise in just one week despite surgery being performed. 2

This article shows how high dosages of EPO (367 U/kg/day) are quickly able to increase the red blood cell count by nearly 3 g/dl in one week. During this time the patient’s endogenous EPO levels were extremely elevated. Despite such, the exogenous EPO was still able to significantly increase red cell production. At times doctors may hold back from giving EPO because there is already a high level within the body. But this report shows this is not necessarily the case.

How Much Can Be Given

There may be times when doctors fear that they may give to much EPO and harm the patient. Much of this concern is based on the original studies done on EPO, which were in patients who had chronic renal failure. The sudden rise in red cell counts would increase the viscosity of the blood; however, this rise in blood pressure has not been seen in the vast majority of patients who are suffering from acute anemia. Of note, in many of these acutely anemic patients there is a problem of a lack of blood pressure. Efforts are put forth to increase this pressure by the treating clinician.

In one study doctors gave high-doses of EPO to children who had congenital hypoplastic anemia or Diamond-Blackfan syndrome. In this study, EPO was not significantly effective in treating this disease; however, the doctors did give extremely high doses of EPO. On page 277 of this article, under the heading "Patients, Material and Methods," paragraph two, sentence five, it is noted that in two of the patients, the dose was increased to 2,000 U/kg/day. This particular dosage schedule was carried out so that the patients received 14,000 U/kg/week. Despite these high dosages of EPO there were no side effects experienced in these children. 3

Nutritional Components

Once adequate bone marrow stimulation is achieved, there is a need to have all of the basic components of red blood cells. Some initial studies have shown that adequate amount of nutrition, and especially proteins, can greatly affect the bone marrow response to EPO administration. Folic acid and Vitamin B-12 also can make a significant difference. If any of these agents are lacking then the overall effect of EPO injections will be stunted. 4, 5, 6

The Strength of Iron

Iron is a main ingredient of red cell production. Under normal conditions, the body stores an adequate supply of iron in the body in a bound form. It is able to transport it to the bone marrow for assimilation into the hemoglobin of red blood cells. This storage is important since the body is only able to absorb a very small amount of iron each day. But is this enough to sustain a large degree of hematopoiesis (red blood cell production)?

The answer to this question depends on many factors. First and foremost is how rapid the rate of reproduction is. At mild to moderate levels of red cell production there is normally enough iron available in storage to keep up. If this mild to moderate level is maintained for weeks, or if there is an abnormally low level of stored iron in the body to start with, there may be a lack of iron available from internal stores. At this point, oral iron therapy can be administered with the idea that it should be adequate to keep up with this modest demand under normal conditions.

Oral iron therapy may not be enough if red cell production is pushed to a high level. If such is the case a clinician may see an inappropriately stunted effect to the EPO administration or there may be red blood cells that are hypochromic and microcytic. At this point, the doctor may wish to use a more bioavailable version of iron. This can include iron dextran and other similar medications.

Some forms of injectable iron have a known history of causing allergic reactions, such as iron dextran. Some clinicians try to avoid this by giving a total dose infusion or an "all at once" dosing schedule instead of a daily smaller dose over several days. Recent formulation changes of some of these iron products have changed their level of reactivity. Standard anaphylaxis prevention seems to work well in such instances.

One can give to much iron with these injectable forms. Careful monitoring of the serum iron, total iron binding capacity, and serum ferritin levels can highlight the internal iron status of the patient. Hemosiderosis is the term given to the condition when overdosing of iron occurs. This can lead to damage to the liver, heart, and other vital organs. 7, 8, 9, 10, 11, 12, 13

Measuring the Success

If all has gone well, you should expect to see immediate improvement. At first this may be a decrease in the rate of decline of the hemoglobin count as fluid shifts from the intracellular to the extracellular compartment. But how can you know if the bone marrow is responding?

The simplest test would be a reticulocyte count. A reticulocyte is defined as an immature red blood cell that contains a network of basophilic filaments. These immature cells are normally almost nonexistent in the blood stream. This changes as the bone marrow increases red cell production beyond normal levels. Reticulocyte counts from 5-10% are normally indicative of a good bone marrow response. Levels below 3% after a week of therapy is indicative of a poor response, which may necessitate an increase in EPO dosing schedules, switching to an intravenous iron dextran, and perhaps reviewing the clinical condition to see if there are other conditions that may be stunting the bone marrow. This knowledge can help to make the proper adjustments to the therapy given.

Conclusion

Increasing red cell production in a case of extreme anemia is very important. By careful use of EPO and other hematinic agents one can expect to see significant improvements in red cell counts. It is important to be aggressive with these agents and apply them quickly to the case. In instances involving Jehovah’s Witnesses, who will not take a blood transfusion, there are no other options available. At that point, any concerns over reactions to these drugs are not at issue since there are no other options. Many clinicians have found that even in the presence of severe anemia as low as 3 g/dl, a patient can recover if careful management is used.

We have now considered initial management, bleeding control, and increasing red cell production. But what else needs to be considered? There are the issues of augmenting oxygen management in the acutely anemic patient. These issues will be considered next.

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