Erythropoietin for the Effectiveness of Blood Transfusions

Erythropoietin can be used to enhance the effectiveness of self-blood transfusions both before and after donation of blood. As with perioperative blood transfusions, autologous blood donations should be accompanied by iron supplementation.

1. Bone marrow transplant

Bone marrow transplant from an allogenic donor can suppress the recipient’s bone marrow to synthesize blood cells. The theory behind this is that the donated bone marrow initially responds well to the host’s erythropoietin released by the kidneys, but thereafter, inflammatory cytokines released in response to the foreign tissue transplant start to interfere with erythropoietin release and also suppress the bone marrow’s function, resulting in cytopenia of all blood cells.

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Giving rhErythropoietin has been found to reduce the need for blood transfusions in case of allogenic transplant but such encouraging results have not been obtained after autologous transplant (i.e. tissue transplanted from the host’s own body).

2. Anemia due to non-myeloid cancers.

3. Anemia caused by blood cancers including lymphoma, leukemia, and myeloma etc. as well as non-blood related cancers.

Both these types of cancers may lead to anemia caused by chronic inflammation (causing raised levels of Interferon-γ, TNF & Interleukin-1), occult bleeding, as well as development of erythropoietin resistance. Anemia my also develop in cancer patients in response to radiation therapy and even certain chemotherapeutic agents, the most notorious of which is Cisplatin, (possibly due to its nephrotoxic effects.)

Several studies have shown that erythropoietin not only helps to correct the anemia caused by radiotherapy in cancer patients but may also enhance the effectiveness of radiation therapy, since greater the supply of oxygen to the tumour cell (due to increased Red cell mass), greater will be radiation treatment’s cytotoxic efficacy against it.

The American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) have given the following guidelines regarding the treatment of cancer patients with erythropoietin;

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• Erythropoietin is recommended for use in cancer patients who have anemia in reaction to chemotherapy whose Hb levels have gone down to ≤10g/dL with or without packed cell donation.
• Cancer patients with less threatening anemia (whose Hb levels are <12g/dL but >10g/dL) can have erythropoietin administered should the clinical circumstances dictate so.
• It’s recommended to administer erythropoietin in dose of 150 units/Kg three times a week for a month. If adequate response is not achieved, then the dose may be doubled and given for another 1-2 months.
• If patients still fails to respond to treatment (i.e. Hb rise is <1-2gdL), it may be advisable to discontinue therapy, and other causes for anemia should be looked in to, like iron deficiency.
• When the patient’s Hb level is raised to 12g/dL, dose of erythropoietin should be titrated downwards to a place where such Hb levels can be suitably maintained.
• Monitoring iron levels and giving iron supplements when necessary may help lessen the dose required or even eliminate the need altogether for administering erythropoietin.
• Although there are no high quality clinical trials to support the use of erythropoietin in non-Hodgkin’s lymphoma, myeloma or chronic lymphocytic leukemia, however, if need be, the above-mentioned guidelines can be followed for treating anemia with erythropoietin.

4. In case of blood loss during surgery.

5. To treat hereditary forms of anemia caused by defective Hemoglobin like Thalessemia & Sickle Cell Anemia.

Sickle Cell Anemia is characterized by formation of abnormal hemoglobin, Hb-S as the patient has inherited a faulty gene from one or both of his/her parents. This causes the RBCs to become sickle shaped and prone to lysis while traveling through blood vessels.

The rationale behind using erythropoietin even though such patients of hereditary hemolytic disorders have normal erythropoietin levels is that the former might help augment the production of Fetal Hemoglobin (Hb F) in the new RBCs, which inhibits the production of sickled RBCs containing faulty hemoglobin (Hb S).

Similarly, in thalassemia, there is production of faulty hemoglobin due to the presence of either defective or absent alpha or beta globin gene. Alpha Thalessemia is characterized by an excess of Beta-globin containing hemoglobin while Beta Thalessemia patients have an excess of Alpha-globin containing hemoglobin. Giving rhEpo has been seen to increase the production of Hb-F in such patients as well as possibly rectify the proportion of alpha Vs. beta chains in their hemoglobin.

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However, the use of erythropoietin for hereditary hemolytic disorders still remains investigational.

A downside to treatment with erythropoietin is the slow response to therapy as it takes approximately 3 weeks for a Hematopoietic Stem cell to transform in to a fully mature RBC, and full response doesn’t start to show before 3 months, although the ratio of red blood cells may start going up after about a month of commencing treatment.

The response rate also varies from person to person, as well as from disease to disease. Eryhthropoietin has been found to be most effective in treating anemia due to renal dysfunction, with lower rates seen in cancer patients, and the lowest rates observed in patients of myelodisplastic syndrome.

DOSAGE: ⁽¹⁾

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• Starting dose is 100-150 IU/Kg given subcutaneously 2-3 times a week.
• It has mostly been favoured to give the drug IV to dialysis patients especially in the U.S, however clinicians in most European and other countries find the subcutaneous route to be more preferable. Even though the IV route provides greater bioavailability, it was found that the overall response elicited by erythropoietin through both routes was nearly the same. This is because it’s more beneficial to maintain constant, low concentration of erythropoietin in plasma than to administer large IV doses that will be cleared from the plasma rapidly.

Moreover, SQ route requires lesser drug to be administered which is an important consideration since erythropoietin is a considerably expensive drug.

• In case of sub-optimal response, dose may be increased each month by 50 IU/kg of body weight.
• Erythropoetin should be supplemented with Iron administration in order to meet the demand of erythropoiesis. Ascorbic acid can have a help enhance the effectiveness of iron by mobilizing it from its stores inside the body.
• Administration of other supplements such as Vitamin-C, folate, L-Carnitine, Vit-D and cytokines may also have a favourable effect on the response of erythropoietin.
• Patients of HIV infection on Ziduvudine have been treated successfully with doses of 100-200 IU/kg given weekly for 12 weeks.
• Cancer patients who develop anemia respond well to doses of 150 IU/kg thrice week for 12 weeks.
• Premature infants with anemia weighing 1-1.5kg can be optimally treated with doses of 600-700 IU/kg/week.

DRUG INTERACTIONS: ⁽¹⁾

• Concomitant administration of antibiotics such as Cyclosporine or aminophylline has can cause sub-optimal response of erythropoietin.
• Angiotensin Converting Enzyme Inhibitors (ACEIs) have been known to inhibit the endogenous production of erythropoietin and therefore, may affect erythropoietin’s efficacy. One theory postulated to explain this effect states that the active form of the Angiotensinogen enzyme, i.e. Angiotensin-II is a promoter of proliferation in RBC precursor cells. Thus, ACE inhibitors may prevent this effect by inhibiting the activation of angiotensin-II. ACE inhibitors also increase the concentration of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline, a protein which hinders stem cell from advancing to higher growth and division phases. Another possible mechanism may be that ACE inhibitors are known to inhibit Interleukin-2 which is a stimulator of erythropoiesis.

CONTRAINDICATIONS: ⁽¹⁾

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1. In case of uncontrolled hypertension, as it raises risk of developing hypertension.
2. Patients at risk of developing erythrocytosis/polycythemia in response to erythropoietin therapy.

CAUTION: ⁽¹⁾

1. If plasma erythropoietin levels are greater than 500-1000mU/ml, then giving ­erythropoietin endogenously would most probably result in treatment failure.
2. In patients of renal failure, lower doses must be administered.
3. Blood pressure levels should be regularly monitored. In order to avoid rapid rise in B.P, treatment should be started with lower doses of erythropoietin so as to stimulate gradual erythropoiesis.

ADVERSE EFFECTS: ⁽¹⁾

1. Increased erythropoiesis leads to greater number of RBCs making the blood viscous and as a result, such individuals are more susceptible to thrombotic events and even seizures.
2. Another extremely common side effect is heightened blood pressure.
3. Other side effects include extramedullary hematopoiesis, spleenomegaly and flu-like symptoms.
4. Recently, instances of Pure Red Cell Aplasia (PRCA) have also been reported but its definitive relation to erythropoietin has not yet been established. Based on the studies of Castelli et al. in 200, & Casadevall in 2002, it has been theorized that a good majority of patients receiving erythropoietin can develop antibodies to erythropoietin which can couple with the hormone rendering it impotent.
5. Failure of response to erythropoietin treatment has been documented in several cases including that caused by either iron/folate/Vit-B12 deficiency, Al³⁺ toxicity, insufficient dialysis in patients of renal failure, hyperparathyroidism due to secondary reasons, bone marrow dysfunction, conditions of inflammation like infection and cancer, hemolytic blood diseases or other bleeding due to other causes.

EXTRA-HEMATOPOIETIC FUNCTIONS OF ERYTHROPOIETIN⁽¹⁾

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As opposed to the archaic view that erythropoietin is exclusively involved in the genesis of new erythrocytes, studies in recent years have shown that the hormone exerts several actions on multiple organ-systems outside of erythropoiesis. Some of these functions are discussed below;

1. Angiogenesis:

Erythropoietin stimulates the production of Hemangioblast precursor cells which have the ability to give rise to either erythroid progenitors or endothelial cells. Therefore, erythropoietin can stimulate Angiogenesis by stimulating the proliferation and differentiation of endothelial cells which form the inner lining of blood vessels.

This effect was first reported by Anagnostou et al. in 1990, who discovered that addition of erythropoietin to endothelial cell culture of umbilical vein enhanced the rate of cellular proliferation. They also found that endothelial cells of umbilical cord and placenta were richly supplied with erythropoietin receptors. Ribatti et al. found that erythropoietin’s pro-angiogenesis effect was comparable to that of Fibroblast Growth Factor-2. Ito et al. found that erythropoietin not only induced cellular proliferation of the endothelial cells of blood vessels but also that of their smooth muscles. (2002)

One of the downsides to erythropoietin treatment is increase in blood pressure which according to Carlini ei al. (1993) is directly related to increase in serum endothelin-1 levels caused by erythropoietin. However, other researchers could not replicate the erythropoietin induced increase in serum endothelin-1 levels and have concluded that some other mechanism is involved in mediating the pro-hypertensive effect of erythropoietin.

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Carlini et al. also showed in 1999, that Endothelin-1 may be responsible for propagating not just the hypertensive, but also the angiogenetic effect of endothelin-1 as administration of anti-endothelin-1 antibody also diminished the angiogenetic effect of erythropoietin. They also showed that erythropoietin reduces cell death or apoptosis in endothelial cells. Chong et al. elucidated the possible mechanism behind erythropoietin’s anti-apoptotic effect in 2002. They showed that erythropoietin helps maintain membrane potential of the mitochondria and also that under hypoxic conditions, erythropoietin activated the anti-apoptotic factor, AKT-1

Fodinger showed that erythropoietin also regulates the gene expression of certain factors in the endothelial cells like thrombospondin-1, protein binding transcription factor, NADH Dehydrogenase subunit & protein tyrosine phosphatase G-1)

Haroon et al. in 2003, used an immunoassay to show that erythropoietin enhances granulation tissue synthesis, as well as mobilizes the endothelial progenitor cells. This finding is also supported by the research of Heeschen et al. who found in 2003, that administration of erythropoietin to mice exogenously, had a direct stimulatory effect on the animals’ bone marrow and increased the number of stem cells, progenitor cells and CFUs.

2. Central Nervous System:

The earliest indication that erythropoietin may have a role in the central nervous system was found by Ta et al. in 1992, when they found that hypoxia increased the expression of erythropoietin in not just the liver and kidneys but also in the brain.

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In S1995, Digicaylioglu et al. identified the exact location of the brain where erythropoietin receptors were present as the hippocampus, cortex, mid-brain and the capsula interna region.

Juul et al. found in 1999 that the location and distribution of erythropoietin and its receptors changes during the different phases of fetal and postnatal development, which led them to believe that erythropoietin might play a definitive role in development of the brain.

A clue as to the exact role of erythropoietin in the brain was revealed by Siren et al. in 2001, when they studied the expression of erythropoietin in the normal and the hypoxic brain. Hypoxic brain damage caused an increase in the number and appearance erythropoietin in the vascular endothelial cells of infarcted area, where, they, no doubt helped to promote angiogenesis and augment blood supply to the affected areas. This led the researches to postulate a neuroprotective role of erythropoietin in the brain.

The neuroprotective theory is also supported by the 2002 findings of Yu et al. who found that mice in whom the gene for erythropoietin receptor had been knocked out suffered from excessive apoptosis in the CNS, as well as reduction in the number of neuron precursor cells in the brain during the gestational phase of development. Cell cultures extracted from such embryos showed an increased susceptibility to hypoxia induced brain damage.

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Medusa et al. showed that erythropoietin is principally produced by astrocytes in the brain where they function in a paracrine manner. They also showed in 1993 that when erythropoietin binds to neuronal receptors, it increases intracellular concentration of calcium and certain monoamine transmitters. In 1999, Koshimura et al. studied these specific type of neuronal cells in further detail and not only confirmed these findings but also showed that the erythropoietin mediated Calcium influx was opposed by anti-erythropoietin antibodies. They also found that erythropoietin enhanced the release of dopamine and augmented the synthesis of nitric oxide.

Sugawa et al. found that exogenously administered erythropoietin helped stimulate cellular differentiation and proliferation of oligodendrocytes in the brains of murine embryos.

Medusa et al. were also the ones to show that erythropoietin is produced in the rats of brain in inverse proportion to the oxygen tension. Bernaudin et al. showed in the year 2000, that erythropoietin is produced by both neurons as well as astrocytes in response to stimuli such as hypoxia, Cobalt and desferrioxamine.

Studer et al. found in the year 2000, that hypoxia not only promotes generation and proliferation of neuronal precursor cells but also increases the percentage of dopaminergic neurons. This latter effect induced by hypoxia was replicated with administration of erythropoietin.

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Chin et al. described the transcription of erythropoietin receptor gene in the CNS in the year 2000, and found that it was slightly differently transcribed as compared to RBC precursor cells.  Nagai et al. discovered in 2001, that transcription of the erythropoietin gene and that of the erythropoietin receptor gene was adversely affected in the neurons by different inflammatory cytokines like IL-1, IL-6 & TNF-α; whereas, in the astrocytes, expression of EpoR was augmented by the action of TNF-α.

Morishita et al. demonstrated in 1997, the neuroprotective effect of erythropoietin by using rat models of glutamate induced toxicity. Glutamatic acid, being the central nervous system’s primary excitatory neurotransmitter, binds to its receptor (NMDA receptor) and causes opening of ion channels to promote Na⁺ & Ca²⁺ influx. Extreme elevation of cytosolic calcium concentrations can lead to cell death. This neuronal cell death was found to be opposed by erythropoietin. This neuroprotective effect of erythropoietin was further solidified when the scientists observed that addition of soluble erythropoietin receptor prevented erythropoietin from exerting its neuroprotective effect by binding to it.

Digicaylioglu & Lipton also conducted an experiment in 2001 to demonstrate the neuroprotective effect of erythropoietin by introducing proinflammatory cytokines in to rat brain cultures which caused apoptosis in the neuronal cells. However, pretreating the culture with erythropoietin helped reduce neuronal cell death by half. Their findings also suggest that activation of JAK Kinase-2 and nuclear translocation of NF κB may be the mechanisms involved in propagating the neuroprotective effects of erythropoietin.

In 2002, Ruscher & colleagues used murine brain to study the role of erythropoietin in cerebral ischemia. They discovered that erythropoietin protected against Oxygen Glucose Deprivation or OGD which lasted for up to 2 days. Proof of this neuroprotective effect was fortified when the authors saw that addition of soluble erythropoietin receptor (EpoR) or erythropoietin antibody prevented the hormone from exerting its neuroprotective effect due to these moieties binding to it.

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Weber et al. showed in 2002, that erythropoietin also has an effect on neuronal transmission when they found that introduction of erythropoietin to murine brain cultures actually augmented action potential transmission which appears to be mediated via JAK2 kinase pathway as erythropoietin’s effect on neurotransmission was antagonized by treatment with JAK2 inhibitors.

Sadamoto et al. also reported producing cerebral ischemia in 1998, in murine specimens by causing indefinite obstruction of the cerebral arteries and found that erythropoietin hindered degeneration and improved survival of neurons. Sakanaka & colleagues produced similar ischemia the same year via blockage of carotid artery but in gerbils as test subjects and found that treatment with erythropoietin deterred neuronal degeneration and learning impairment due to cerebral ischemia in addition to boosting the number of neuronal synapses. Proof that erythropoietin was responsible for these effects was demonstrated when introduction of soluble erythropoietin receptor prevented erythropoietin from carrying out these effects, while inoculation of soluble EpoR that had been denatured/deactivated by heat helped restore erythropoietin’s  neuroprotective function.

In 1999, Bernaudin & co-workers studied how the expression of erythropoietin in infarcted brain tissue evolves over time in mice. They saw that erythropoietin receptors were expressed first followed by expression of erythropoietin itself first in the endothelial cells of the cerebral arteries (post 1 day), followed by cerebral immune cells (microglia) by day 3, and finally in the astrocytes by day 7. They observed that administration of erythropoietin 24 hours prior to inducing cerebral ischemia helped to decrease the size of infarcted area. A year later, similar results were also attained by Brines et al. when they discovered that erythropoietin pre-administration helps to shrink the size of infarction to half and even up to one fourth.

Siren et al. also showed in 2001 that erythropoietin administration to rats with induced cerebral ischemia helped avert neuronal cell death.

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Junk & colleagues discovered in 2002, that erythropoietin also exerts its neuroprotective effect in other areas as well like the eyes where it helped to prevent retinal damage due to elevated IOP (intraocular pressure) and sped up recovery.

The same year, while studying the effectiveness of erythropoietin against spinal cord damage, Gorio & colleagues observed that erythropoietin helped make full recovery from compression injury in rodents whereas, in contusion trauma, erythropoietin helped decrease inflammation.

Interestingly, Erbayraktar discovered in 2003, that the neuroprotective efficacy of erythropoietin is still preserved in mice after being enzymatically denatured by desialylation, even though its pre-erythropoietic action is lost. This led the scientists to speculate that denatured erythropoietin may be useful in treatment of patients with neurological injuries in whom augmentation of RBC count is not required/useful.

Clinical trials are now underway to take advantage of erythropoietin’s neuroprotectve potential. One such trial conducted in 2002, by Ehrenreich & colleagues showed that rherythropoietin helped to diminish size of infarction in stroke patients as compared to placebo.

3. Reproductive System:

In 1998, Yasuda et al. studie the presence and effects of erythropoietin in murine uteri, whereby, they discovered that estrogen stimulates the production of erythropoietin in the uterus where the latter functions to stimulate synthesis of new blood vessels. A couple of years later, the researchers discovered the presence of erythropoietin in human reproductive organs like the cervix, endometrium and the ovaries.

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In 2000, Masuda et al. studied erythropoietin’s production in other areas of the reproductive tract such as the ovaries and the oviduct, and found that both areas do indeed contain erythropoietin. Moreover, its production was found to be stimulated by both estrogen and hypoxia in the oviduct.

In 2002, while studying the expression of erythropoietin in the endometrium, Yokomizo et al. found that erythropoietin production varies in various phases of the menstrual cycle with maximum levels recorded during the secretory phase of the endometrium. This led the scientists to speculate that erythropoietin may be involved in the cellular differentiation and proliferation of the endometrium.

This endometrial proliferative effect of erythropoietin was confirmed by Matsuzaki in 2003, who found its presence in endometriosis.

Presence of erythropoietin receptor has also been reported in the human placenta by Sawyer et al. in 1989, & later by Fairchild, Benyo & Conrad in …..

Erythropoietin’s presence in the male reproductive organ, specifically the testes was detected by Magnanti & coworkers in 2001; they also reported that its synthesis was positively stimulated by FSH and Cobalt and negatively affected by Testosterone.

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Erythropoietin’s potential usefulness in treatment of male reproductive disorders was reported by Cortes et al. the same year who noticed that erythropoietin treatment of renal failure patients with undescended testes resulted in increased rate of spermatogenesis.

4. Cardiovascular System:

In 2003, Stukman & colleagues found that erythropoietin indirectly stimulated the growth and proliferation of cardiac muscle cells and that this growth was adversely affected by erythropoietin’s blockade.

Furthermore, Calvillio et al. also found in 2003, that erythropoietin exerts a cardioprotective effect by protecting against hypoxia-induced infarction, and also reduced cell apoptosis in cardiac muscles if they were pre-treated with erythropoietin before inducing hypoxia.

Erythropoietin’s role in protecting cardiomyocytes gainst hypoxic damage was further solidified the same year when Cai et al. demonstrated loss of this cardioprotective effect inHIF-1α knockout mice.

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Not only does erythropoietin help protect the heart against hypoxic induced apoptosis, but according to Sterin Borda & coworkers, it also prevents hypoxia induced reduced cardiac contractility. This effect was lost by administration of anti-erythropoietin antibody.

All of these studies suggest that erythropoietin may be a viable future option for treatment of myocardial ischemia and related conditions.

5. Gastrointestinal System:

Juul et al. discovered that erythropoietin is present in the GI tract of human fetuses, which led them to study their presence and function postnatally. The researchers found that it helps speed up the migration of enterocytes in the murine intestinal cells, and that it helps promote their growth.

Juul also observed in the year 2000, that when erythropoietin was administered to premature babies to treat anemia, it also protected against necrotizing enterocolitis.

6. Other Cells:

Even though the primary source of erythropoietin in adults is kidney, the presence of its receptors in different renal areas poses questions regarding it function/role in the kidneys.

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Erythropoietin was also discovered in immature muscle cells where they were observed to play a role in cellular proliferation and differentiation.

Erythropoietin receptors have also been found in human pancreas where they are proposed to protect against cellular apoptosis.

A study conducted by Suzuki et al. raises some pertinent questions regarding the absolute need for erythropoietin in extra-hematopoietic tissue. They used genetically mutated models of mice in which erythropoietin receptors were expressed only in the hematopoietic tissue, and the mice grew up with no apparent defect or disorder, even though detailed analysis of each organ in which erythropoietin receptor is expressed was not furnished.

ERYTHROPOIETIN AS AN ABUSED HORMONE⁽¹⁾

The role of hypoxia in inducing enhanced athletic performance became evident during the 1968 Olympics which were held in Mexico, a city which is located at a comparatively higher altitude. Those athletes originating from other countries situated at higher altitude locations (such as those from Kenya and Ethiopia) excelled in their events. The theory behind this is that hypoxia induces increased production of erythropoietin which in turn stimulates increased production of RBCs and hemoglobin, thereby providing increased blood supply to various body areas including skeletal muscles.

A randomized trial was conducted by Levine & Stray-Gundersen in 1997 where they randomly assigned atheletes to one of three groups of subjects; 1) Those who lived at high altitude and trained at high altitude, 2) Those who lived at high altitude and trained at low altitude, and 3) Those who lived at low altitude and trained at low altitude. Those athletes who lived at high altitudes experienced a substantial increase in their maximum Oxygen carrying capacity, due to increase in RBC production, but athletic performance was enhanced only in the group that lived at high altitude and trained at low altitude. However, there was no change observed in the group that lived and trained at low altitude.

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Conversely, a separate study conducted by Chapman et al. in 1997, revealed that athletes don’t always respond the same to this “Live-High, train-low” strategy as witnessed in a group of 39 athletes, all of whom experienced a rise in their serum erythropoietin levels as a result of this strategy, but not all of these athletes had a marked improvement in their performance. Upon detailed inspection it was revealed that the group of athletes who had a corresponding increase in their RBC count and maximum Oxygen carrying capacity (VO₂) were the ones whose performance improved, whereas the athletes whose RBC count rise did not correspond to the rise in their serum erythropoietin levels, suffered a loss or no change in their athletic level. The reason for this variation in response is unknown.

The author speculates that longer the duration of exposure to hypoxia, greater the corresponding rise in serum levels of erythropoietin. This knowledge has been exploited by athletes worldwide, with illicit practices such as “blood doping” becoming a norm. Blood doping involves both autologous and allogenic blood transfusion to raise the serum RBC count and subsequently, increase the VO₂ (Maximum Oxygen Carrying Capacity) of athletes. The most famous or rather infamous cases of blood doping were reported in the 1980 Moscow Olympics, in which a runner won medals after receiving blood transfusion, and the subsequent, 1984, LA Olympics, in which 4 of 7 American cyclists who received blood transfusions, won medals in the ensuing race.

With the availability of recombinant erythropoietin products, their abuse by athletes quickly spread. This even led to incidents of inexplicable deaths among Belgian and Dutch cyclists. However according to Catlin et al. (2003), there have been no structured studies to investigate the potential adverse effect of doping with erythropoietin. There has only ever been a single documented case of sinus thrombosis found to occur with the use of recombinant erythropoietin, however, this cannot be solely attributed to erythropoietin as the subject was also taking other drugs at the time.

The first international scandal to come to light regarding the illicit use of rEpo, was in the 1998 Tour De France, when the director for the French Cyclists team admitted to providing doping products to his athletes which included rEPO.

Following this incident, IOC (International Olympics Committee) sought to establish the WADA (World Anti-Doping Agency) in 1999, a regulatory body to examine and restrict the use of banned products by competing athletes.

Biochemical Testing of Recombinant Erythropoietin: ⁽¹⁾

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Presence of exogenously administered erythropoietin in the body can be detected either by directly measuring the serum levels of recombinant human erythropoietin or indirectly by assessing levels of different biological markers. Of special interest are the hematocrit or serum hemoglobin values.

Serum Hemoglobin & Hematocrit values: ⁽¹⁾

The International Ski Federation banned athletes from competing with Hb levels greater than 185gm/L (for men), and 165gm/L (for women)

Similarly, in 1997, the International Cycling Union established a general rule regarding erythropoietin doping that any athlete with blood hematocrit levels greater than the upper normal limit (>50% for men & >47% for women) would be disqualified from participating in the competition, however this test does not take in to account exceptional cases where an athlete naturally has high hematocrit values.

Serum Ferritin & Soluble Transferrin Receptor Levels: ⁽¹⁾

A direct consequence of increased stimulation of erythropoiesis is increased iron uptake and upregulation of soluble transferrin receptors or sTfR. Conversely, serum ferritin levels (i.e. levels of the transport protein responsible for carrying iron in blood) are reduced due to increased iron consumption. This augmented ratio of soluble transferrin receptor to serum ferritin can be used as an indirect biomarker for use of erythropoietin.

These findings were reiterated by Parisotto et al. in 2001, who found that 5 serum biomarkers including hematocrit, reticulocyte hematocrit, % macrocytes, soluble transferrin receptor and serum erythropoietin concentrations were all good indicators of recent erythropoietin use. This led to their development of a couple of statistical methods called ON Recombinant Erythropoietin & OFF Recombinant erythropoietin to detect current and recent use of erythropoietin respectively. This ON test was even used during the 2000 Sydney Olympic Games, where if an athlete’s blood levels of specific markers exceeded the permitted limit, he or she would be subjected to a urine erythropoietin detection and measurement test.

Direct Measurement of Erythropoietin Levels: ⁽¹⁾

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The first group of researchers to show that erythropoietin levels could be detected and measured from both urine and blood samples using electrophoresis was Wide et al. in 1995. This is because recombinant erythropoietin shows different electrophoretic behavior than the endogenous erythropoietin.

Lasne & De Ceaurriz used anti-erythropoietin antibodies to detect and measure levels of rherythropoietin in urine in 2002. They did so by separating the different glycoprotein components of recombinant erythropoietin obtained from urinary source by applying isoelectric focusing technique. The reason they were able to do so is that the isoelectric focusing pattern of glycoprotein components obtained from recombinant erythropoietin differs from that of endogenous human erythropoietin.

Another form of erythropoietin whose abuse by athletes has surfaced during the past years is Darbepoetin-alpha, a mutant form of recombinant erythropoietin, which due to extensive glycosylation has a longer half-life than regular erythropoietin. Reports of its abuse first appeared during the 2002, Salt Lake City winter games, as it can be detected in human urine for up to 12 days after last use. Even after stopping the use of exogenous erythropoietin, serum hematocrit levels remain elevated for nearly two to three weeks. Ergo, analyzing urinary levels of recombinant erythropoietin is not sufficient to establish recent doping by athletes, and should thus, be coupled with measuring blood hematocrit values which remain elevated for weeks after doping has ceased.

LATEST DEVELOPMENTS ⁽¹⁾

Researchers around the world are working on improving the existing formulations of erythropoietin available. For instance Morlock et al. developed a novel formulation of erythropoietin in 1998 that was contained inside microspheres of a specific kind of polymer. However, a major problem seen with this type of formulation was development of erythropoietin sedimentations. Similar problems were encountered by Pistel et al. in 1999, when developing a microsphere formulation of recombinant erythropoietin from polymer.

In 2003, Qui et al. developed a hydrogel preparation of erythropoietin that had a prolonged half-life and allowed sustained release for 2-4 weeks. They used a polymer containing polyethylene glycol with thiol cross linked, that precluded the need for using an organic solvent or increased temperature to formulate.

Different researchers have also published papers describing a hydrogel preparation of erythropoietin using cross-linked hyaluronic acid including Motoka et al. & Sei Kwang Hahn & colleagues.

However, on a commercial level, no sustained release preparation of erythropoietin has been made available to date.

Oral formulations have met with even lesser success due to degradation of the glycoprotein in the G.I.

Glycosylated & Non-glycosylated Preparations: ⁽¹⁾

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Darbepoetin-Alpha is a mutated version of rheruthropoietin that has been approved by the FDA. It contains added number of oligosaccharides especially sialic acid at terminal position, which helps to augment its half-life approximately two-to-four times more than that of regular rerythropoietin; thereby reducing its need for frequent administration.

Other alternatives to glycosylation include PEGylation or adding Polyethylene Glycol to erythropoietin to help increase the size of the molecule and consequently, prolong its half-life. A Methoxy polyethylene glycol-epoitin Beta preparation has been developed and marketed by Hoffman-LaRoche whereby they have avoided suing recombinant form of erythropoietin and instead have linked methoxy PEG to the lysine amino terminal. It has been approved for use in  alsReceptor Activator) or MIRCERA. It has lesser affinity for binding to the erythropoietin receptor than it recombinant counterpart but has a longer half-life of approximately 135 hours.

Total Chemical Synthesis: ⁽¹⁾

Kochendoerfer et al. were the first to report a total chemically synthetic form of erythropoietin that was shown to have a longer half-life than its recombinant versions.

In 2012, Danishefsky et al. also reported successful total chemical synthesis of erythropoietin; however, it had a smaller molecular size and lower biological activity as compared to natural erythropoietin. Even improved version of this original product failed to retain absolute purity and did not show Mass Spectrometry results comparable to that of natural erythropoietin.⁽³⁾

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Erythropoietin Fusion Proteins:

Sytowski et al. started working on the hypothesis that augmenting the molecular size of rherythrorpietin by dimerization and trimerization would enhance receptor binding and boost the biological half-life of the product. They did so by simply cross-linking the monomers and it did, indeed help to expand both the biological activity and half-life of the drug considerably. This formed the basis for their team to develop a fusion coding protein in 1999, that they named, “EPO-EPO,” in which they incorporated two erythropoietin coding sequences. It was found to have 3 times greater in vitro activity that erythropoietin monomer and more extended half-life than recombinant erythropoietin.

Other types of fusion protein such as those made by combining GM-Colony Stimulating Factor with erythropoietin (GM-CSF/Epo) by Coscarelia et al. in 1998, or by combining interlukin-3 with erythropoietin (IL-3/Epo) as done by Weich et al. in 1993, also exhibited superior activity as compared to simple recombinant erythropoietin.

Another type of fusion protein was developed by fusing erythropoietin together with the Fragment Crystallizable (Fc) part of immunoglobulin, which gain results in amplification of erythropoietin’s half-life. An advantage of this sort of formulation is its possible administration via inhalation route as described by Spiekermann et al. in 2002. This is because the epithelial cells lining the human airways are richly supplied with Fc receptors for binding of immunoglobulins.

Non-erythropoietin type Erythropoietic Agents:

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The first non-erythropoietic receptor agonist of erythropoietin was described by Elliot et al. in 1996, whereby they developed specific antibodies that could target and bind to the erythropoietin receptor and mediates its biological activity.

The same year, Wrighton et al. reported isolating a 14 amino acid peptide with amino acid sequence different than that of erythropoietin that could act as a potential agonist at erythropoietin receptor. A year later, they also developed a dimer that they named Erythropoietin Mimetic Peptide (EMP 1) that had increased binding capacity and ergo greater potency. However, EMP1 has a relatively short half-life and Kuai et al. decided to improve upon this formulation by devising a fusion protein consisting of erythropoietin with TPA inhibitor i.e. Tissue Plasminogen Activator Inhibitor, however, it could not be administered orally.

In an attempt to synthesize a non-protein and orally administrable compound, Qureshi et al. first developed an erythropoietin receptor antagonist in the year 2000, which they named, Compound-1. They then combined together 8 molecules of this compound-1 to make another compound that they termed, Compound-5 which in turn, exhibited partial agonist activity at the erythropoietin receptors.

Goldberg et al. (2002) & Connolly et al. (2000) also worked along these lines to develop non-protein based agonists and partial agonists of erythropoietin.

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Gene Therapy:

Several different approaches have been developed to carry out gene therapy with erythropoietin including inserting the gene for erythropoietin in to the extra ring of DNA found in bacterial cells (Plasmid) and then injecting that mutated plasmid into the liver or muscles of subjects/ introducing the erythropoietin gene into viral cell and then using them as vectors to deliver the erythropoietin synthesis stimulating gene into the cells of subjects/ using capsules containing erythropoietin gene expressing cells, which can be implanted directly beneath the skin. However, none of these tactics have advanced beyond animal lab testing.

REFERENCES

1. Sytkowski, A. J. (2004). Erythropoietin; blood, brain & beyond, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
2. H. Franklin Bunn. (2013) Erythropoietin. Cold Spring Harbor Perspectives in Medicine.Vol. 3 (3).
3. 3. Wang, P. et al. (2012). Angew. Chem. Int. Edn 51, 11576–11584