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Erythropoietin: Will It Improve Outcome after Subarachnoid Hemorrhage?
Perspectives Commentary on: Erythropoietin for the Treatment of Subarachnoid Hemorrhage: A Review by Turner et al. pp. 500-507.
R. Loch Macdonald, M.D., Ph.D. Keenan Endowed Chair in Surgery Head, Division of Neurosurgery, St. Michael’s Hospital Professor of Surgery, University of Toronto
Erythropoietin: Will It Improve Outcome after Subarachnoid Hemorrhage? R. Loch Macdonald
T
his is an important and timely review of erythropoietin (EPO), its analogues, and subarachnoid hemorrhage (SAH). Now that we at least think we understand some of the regulatory cycles that maintain homeostasis in living organisms, it seems obvious that at least one circulating signaling molecule of some type must regulate the level of hemoglobin in our bloodstream. More than a century ago, Carnot and Deflandre postulated the existence of such a substance in contrast to prevailing opinion that bone marrow hypoxia stimulated erythrogenesis (5). Erslev and Lavietes performed important experiments in the 1950s showing that heat-resistant erythropoietic activity was present in plasma and urine from anemic rabbits (7). It was found to be an ␣2-globulin that was later called erythropoietin by Bonsdorff and Jalavisto (3). EPO is known to be a 30.4-kD glycoprotein with four carbohydrate residues that acts on a receptor composed of two identical polypeptide chains. Early clinical use of EPO was to treat anemia in patients with chronic renal failure on dialysis (8, 14). The optimal hemoglobin concentration in these patients may be about 11 g/dL, with higher doses of EPO that increase the hemoglobin further being associated with thromboembolic complications and hypertension. Since then, other indications have been studied. Among the approximately 6076 records in the Cochrane database of systematic reviews, 20 contain references to EPO. EPO has been used in patients with various malignancies in an attempt to decrease the need for blood transfusion. No benefit, and in some cases, an increase in morbidity and mortality, has been associated with its use (2, 10). Transfusion requirements tend to decrease, but why outcome does not improve is unclear, with theories including that there are side effects of EPO or that it stimulates tumor growth. EPO was not beneficial in preventing transfusion or improving outcome in preterm infants (1). At the risk of raising the ire of EPO advocates, a general summary of much of this literature
Key words 䡲 Cerebral vasospasm 䡲 Erythropoietin 䡲 Subarachnoid hemorrhage
Abbreviations and Acronyms CERA: Continuous EPO receptor activator EPO: Erythropoietin SAH: Subarachnoid hemorrhage
would be that EPO decreases the need for transfusion, increases the risk of thromboembolic complications and hypertension, has little effect on overall morbidity and mortality, and has not been well studied in controlled trials. There are studies of EPO plus preoperative autologous blood donation to reduce the need for blood transfusion mainly in cardiac and orthopedic surgery (4). An emerging area of interest is EPO and its analogues for treatment of heart failure and myocardial ischemia. In addition to stimulating erythropoiesis, other effects of EPO have been discovered that may be of benefit to patients with a variety of central nervous system injuries (18). Normal brain expresses low levels of EPO and EPO receptor but these increase after traumatic brain injury, subarachnoid hemorrhage, and ischemic stroke. EPO and an EPO receptor appear in neurons, glia, neuroprogenitor cells, and cerebrovascular endothelial cells. The pathways are not fully worked out but the EPO receptor activated by these injuries may not be the classic homodimer but a heterodimer consisting of one EPO receptor peptide and a common  chain (6). The signal transduction path activated includes the janus tyrosine kinase-2 pathway that then activates phosphatidylinositol 3 kinase and Akt. These pathways then mediate improvement in outcome after experimental traumatic brain injury, ischemic stroke, and subarachnoid hemorrhage. The mechanisms are unclear but may include neuroprotection, inhibition of apoptosis, decreased inflammation, and enhanced neurogenesis and angiogenesis (9, 18). Clinical trials to test EPO or its variants in head injury, stroke, and subarachnoid hemorrhage are under way. Long-acting analogues of EPO are being developed and include darbepoetin ␣, which is a hyperglycosylated form of EPO and continuous EPO receptor activator (CERA), to name only a few (15). A novel approach, however, has been to try to isolate the neuroprotective from the erythropoietic effects. Carbamylated
From the Division of Neurosurgery, St. Michael’s Hospital; Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s Hospital; Department of Surgery, University of Toronto, Toronto, Ontario, Canada To whom correspondence should be addressed: R. Loch Macdonald, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2010) 73, 5:463-464. DOI: 10.1016/j.wneu.2010.03.041
WORLD NEUROSURGERY 73 [5]: 463-464, MAY 2010
www.WORLDNEUROSURGERY.org
463
PERSPECTIVES
EPO is one such product that is otherwise similar to EPO apart from lacking erythropoietic effects (17). An 11–amino acid peptide that mimics the aqueous surface of helix B of EPO and is devoid of hematopoietic effects that may increase the complications has also been investigated experimentally (6). A number of other similar peptides are being developed. EPO does not cross the blood– brain barrier well, which is another theoretical advantage at this point, and high doses are required. Many of the biologic effects of EPO could be beneficial to patients with SAH, even the side effect of hypertension. Stimulation of erythropoiesis might be beneficial in patients with SAH. Transfusion may be detrimental and there is some evidence to suggest maintaining a low-normal hematocrit is beneficial (12). In addition to neuroprotective effects, prevention of vasospasm in rabbits by EPO was reported and is an important action of EPO that may be mediated by activation of endothelial nitric oxide synthase (11). Thus far, however, much work needs to be done regarding EPO and SAH. The two clinical trials conducted so far are small and
REFERENCES 1. Aher SM, Ohlsson A: Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 3:CD004865, 2006. 2. Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, Trelle S, Weingart O, Bayliss S, Brunskill S, Djulbegovic B, Benett CL, Langensiepen S, Hyde C, Engert E: Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev 3:CD003407, 2006. 3. Bonsdorff E, Jalavisto E: A humoral mechanism in anoxic erythrocytosis. Acta Physiol Scand 16:150170, 1948. 4. Cardone D, Klein AA: Perioperative blood conservation. Eur J Anaesthesiol 26:722-729, 2009. 5. Carnot P, Deflandre Cl: About the hematopoietic activity of the serum during the regeneration of blood. C R Acad Sci Paris 143:384-386, 1906. 6. Dumont F, Bischoff P: Non-erythropoietic tissueprotective peptides derived from erythropoietin: WO2009094172. Expert Opin Ther Pat 20(5):715723, 2010. 7. Erslev AJ, Lavietes PH: Observations on the nature of the erythropoietic serum factor. Blood 9:1055-1061, 1954. 8. Fried W: Erythropoietin and erythropoiesis. Exp Hematol 37:1007-1015, 2009.
464
www.SCIENCEDIRECT.com
provide safety data that would support conducting larger clinical trials (13, 16). The first trial randomized 73 patients (13). The primary endpoint was the dichotomous Glasgow outcome score but the number of patients was too small to show any effect on this. In terms of safety, no comment was made about venous thromboembolic or other events, although no side effects of EPO were reported. Interestingly, blood pressure was significantly higher in the EPO-treated patients. The second trial randomized 80 patients and did demonstrate significant reductions in transcranial Doppler ultrasound vasospasm, which was the primary outcome measure (16). In addition, there was a significant decrease in delayed neurologic deterioration and a trend toward better outcome. There were no side effects like hypertension or thromboembolic events. For future trials, design issues include dose, duration, and type of EPO to administer; outcome measures to employ that would be sensitive to EPO effects; and patient populations to study. Nevertheless, the work so far suggests EPO for SAH should be pursued.
9. Jerndal M, Forsberg K, Sena ES, Macleod MR, O’Collins VE, Linden T, Nilsson M, Howells DW: A systematic review and meta-analysis of erythropoietin in experimental stroke. J Cereb Blood Flow Metab 30(5):961-968, 2010. 10. Lambin P, Ramaekers BL, van Mastrigt GA, Van den Ende P, de JJ, De Ruysscher DK, Pijls-Johannesma M: Erythropoietin as an adjuvant treatment with (chemo) radiation therapy for head and neck cancer. Cochrane Database Syst Rev 3:CD006158, 2009. 11. Santhanam AV, Smith LA, Akiyama M, Rosales AG, Bailey KR, Katusic ZS: Role of endothelial NO synthase phosphorylation in cerebrovascular protective effect of recombinant erythropoietin during subarachnoid hemorrhage-induced cerebral vasospasm. Stroke 36:2731-2737, 2005. 12. Smith MJ, Le Roux PD, Elliott JP, Winn HR: Blood transfusion and increased risk for vasospasm and poor outcome after subarachnoid hemorrhage. J Neurosurg 101:1-7, 2004. 13. Springborg JB, Moller C, Gideon P, Jorgensen OS, Juhler M, Olsen NV: Erythropoietin in patients with aneurysmal subarachnoid haemorrhage: a double blind randomised clinical trial. Acta Neurochir (Wien) 149:1089-1101, 2007.
15. Testa U: Erythropoietic stimulating agents. Expert Opin Emerg Drugs 15:119-138, 2010. 16. Tseng MY, Hutchinson PJ, Richards HK, Czosnyka M, Pickard JD, Erber WN, Brown S, Kirkpatrick PJ: Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a phase II randomized, double-blind, placebo-controlled trial. Clinical article. J Neurosurg 111:171-180, 2009. 17. Vogiatzi G, Briasoulis A, Tousoulis D, Papageorgiou N, Stefanadis C: Is there a role for erythropoietin in cardiovascular disease? Expert Opin Biol Ther 10: 251-264, 2010. 18. Xiong Y, Mahmood A, Chopp M: Emerging treatments for traumatic brain injury. Expert Opin Emerg Drugs 14:67-84, 2009.
Conflict of Interest Statement: Dr. Macdonald is a consultant for Actelion Pharmaceuticals. He has grant support from Physicians Services Incorporated Foundation. He is Chief Scientific Officer of Edge Therapeutics. Citation: World Neurosurg. (2010) 73, 5:463-464. DOI: 10.1016/j.wneu.2010.03.041 Journal homepage: www.WORLDNEUROSURGERY.org
14. Strippoli GF, Navaneethan SD, Craig JC: Haemoglobin and haematocrit targets for the anaemia of chronic kidney disease. Cochrane Database Syst Rev 4:CD003967, 2006.
Available online: www.sciencedirect.com 1878-8750/$ - see front matter © 2010 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, DOI:10.1016/j.wneu.2010.03.041
R. Loch Macdonald, M.D., Ph.D. Keenan Endowed Chair in Surgery Head, Division of Neurosurgery, St. Michael’s Hospital Professor of Surgery, University of Toronto
Erythropoietin: Will It Improve Outcome after Subarachnoid Hemorrhage? R. Loch Macdonald
T
his is an important and timely review of erythropoietin (EPO), its analogues, and subarachnoid hemorrhage (SAH). Now that we at least think we understand some of the regulatory cycles that maintain homeostasis in living organisms, it seems obvious that at least one circulating signaling molecule of some type must regulate the level of hemoglobin in our bloodstream. More than a century ago, Carnot and Deflandre postulated the existence of such a substance in contrast to prevailing opinion that bone marrow hypoxia stimulated erythrogenesis (5). Erslev and Lavietes performed important experiments in the 1950s showing that heat-resistant erythropoietic activity was present in plasma and urine from anemic rabbits (7). It was found to be an ␣2-globulin that was later called erythropoietin by Bonsdorff and Jalavisto (3). EPO is known to be a 30.4-kD glycoprotein with four carbohydrate residues that acts on a receptor composed of two identical polypeptide chains. Early clinical use of EPO was to treat anemia in patients with chronic renal failure on dialysis (8, 14). The optimal hemoglobin concentration in these patients may be about 11 g/dL, with higher doses of EPO that increase the hemoglobin further being associated with thromboembolic complications and hypertension. Since then, other indications have been studied. Among the approximately 6076 records in the Cochrane database of systematic reviews, 20 contain references to EPO. EPO has been used in patients with various malignancies in an attempt to decrease the need for blood transfusion. No benefit, and in some cases, an increase in morbidity and mortality, has been associated with its use (2, 10). Transfusion requirements tend to decrease, but why outcome does not improve is unclear, with theories including that there are side effects of EPO or that it stimulates tumor growth. EPO was not beneficial in preventing transfusion or improving outcome in preterm infants (1). At the risk of raising the ire of EPO advocates, a general summary of much of this literature
Key words 䡲 Cerebral vasospasm 䡲 Erythropoietin 䡲 Subarachnoid hemorrhage
Abbreviations and Acronyms CERA: Continuous EPO receptor activator EPO: Erythropoietin SAH: Subarachnoid hemorrhage
would be that EPO decreases the need for transfusion, increases the risk of thromboembolic complications and hypertension, has little effect on overall morbidity and mortality, and has not been well studied in controlled trials. There are studies of EPO plus preoperative autologous blood donation to reduce the need for blood transfusion mainly in cardiac and orthopedic surgery (4). An emerging area of interest is EPO and its analogues for treatment of heart failure and myocardial ischemia. In addition to stimulating erythropoiesis, other effects of EPO have been discovered that may be of benefit to patients with a variety of central nervous system injuries (18). Normal brain expresses low levels of EPO and EPO receptor but these increase after traumatic brain injury, subarachnoid hemorrhage, and ischemic stroke. EPO and an EPO receptor appear in neurons, glia, neuroprogenitor cells, and cerebrovascular endothelial cells. The pathways are not fully worked out but the EPO receptor activated by these injuries may not be the classic homodimer but a heterodimer consisting of one EPO receptor peptide and a common  chain (6). The signal transduction path activated includes the janus tyrosine kinase-2 pathway that then activates phosphatidylinositol 3 kinase and Akt. These pathways then mediate improvement in outcome after experimental traumatic brain injury, ischemic stroke, and subarachnoid hemorrhage. The mechanisms are unclear but may include neuroprotection, inhibition of apoptosis, decreased inflammation, and enhanced neurogenesis and angiogenesis (9, 18). Clinical trials to test EPO or its variants in head injury, stroke, and subarachnoid hemorrhage are under way. Long-acting analogues of EPO are being developed and include darbepoetin ␣, which is a hyperglycosylated form of EPO and continuous EPO receptor activator (CERA), to name only a few (15). A novel approach, however, has been to try to isolate the neuroprotective from the erythropoietic effects. Carbamylated
From the Division of Neurosurgery, St. Michael’s Hospital; Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s Hospital; Department of Surgery, University of Toronto, Toronto, Ontario, Canada To whom correspondence should be addressed: R. Loch Macdonald, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2010) 73, 5:463-464. DOI: 10.1016/j.wneu.2010.03.041
WORLD NEUROSURGERY 73 [5]: 463-464, MAY 2010
www.WORLDNEUROSURGERY.org
463
PERSPECTIVES
EPO is one such product that is otherwise similar to EPO apart from lacking erythropoietic effects (17). An 11–amino acid peptide that mimics the aqueous surface of helix B of EPO and is devoid of hematopoietic effects that may increase the complications has also been investigated experimentally (6). A number of other similar peptides are being developed. EPO does not cross the blood– brain barrier well, which is another theoretical advantage at this point, and high doses are required. Many of the biologic effects of EPO could be beneficial to patients with SAH, even the side effect of hypertension. Stimulation of erythropoiesis might be beneficial in patients with SAH. Transfusion may be detrimental and there is some evidence to suggest maintaining a low-normal hematocrit is beneficial (12). In addition to neuroprotective effects, prevention of vasospasm in rabbits by EPO was reported and is an important action of EPO that may be mediated by activation of endothelial nitric oxide synthase (11). Thus far, however, much work needs to be done regarding EPO and SAH. The two clinical trials conducted so far are small and
REFERENCES 1. Aher SM, Ohlsson A: Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 3:CD004865, 2006. 2. Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, Trelle S, Weingart O, Bayliss S, Brunskill S, Djulbegovic B, Benett CL, Langensiepen S, Hyde C, Engert E: Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev 3:CD003407, 2006. 3. Bonsdorff E, Jalavisto E: A humoral mechanism in anoxic erythrocytosis. Acta Physiol Scand 16:150170, 1948. 4. Cardone D, Klein AA: Perioperative blood conservation. Eur J Anaesthesiol 26:722-729, 2009. 5. Carnot P, Deflandre Cl: About the hematopoietic activity of the serum during the regeneration of blood. C R Acad Sci Paris 143:384-386, 1906. 6. Dumont F, Bischoff P: Non-erythropoietic tissueprotective peptides derived from erythropoietin: WO2009094172. Expert Opin Ther Pat 20(5):715723, 2010. 7. Erslev AJ, Lavietes PH: Observations on the nature of the erythropoietic serum factor. Blood 9:1055-1061, 1954. 8. Fried W: Erythropoietin and erythropoiesis. Exp Hematol 37:1007-1015, 2009.
464
www.SCIENCEDIRECT.com
provide safety data that would support conducting larger clinical trials (13, 16). The first trial randomized 73 patients (13). The primary endpoint was the dichotomous Glasgow outcome score but the number of patients was too small to show any effect on this. In terms of safety, no comment was made about venous thromboembolic or other events, although no side effects of EPO were reported. Interestingly, blood pressure was significantly higher in the EPO-treated patients. The second trial randomized 80 patients and did demonstrate significant reductions in transcranial Doppler ultrasound vasospasm, which was the primary outcome measure (16). In addition, there was a significant decrease in delayed neurologic deterioration and a trend toward better outcome. There were no side effects like hypertension or thromboembolic events. For future trials, design issues include dose, duration, and type of EPO to administer; outcome measures to employ that would be sensitive to EPO effects; and patient populations to study. Nevertheless, the work so far suggests EPO for SAH should be pursued.
9. Jerndal M, Forsberg K, Sena ES, Macleod MR, O’Collins VE, Linden T, Nilsson M, Howells DW: A systematic review and meta-analysis of erythropoietin in experimental stroke. J Cereb Blood Flow Metab 30(5):961-968, 2010. 10. Lambin P, Ramaekers BL, van Mastrigt GA, Van den Ende P, de JJ, De Ruysscher DK, Pijls-Johannesma M: Erythropoietin as an adjuvant treatment with (chemo) radiation therapy for head and neck cancer. Cochrane Database Syst Rev 3:CD006158, 2009. 11. Santhanam AV, Smith LA, Akiyama M, Rosales AG, Bailey KR, Katusic ZS: Role of endothelial NO synthase phosphorylation in cerebrovascular protective effect of recombinant erythropoietin during subarachnoid hemorrhage-induced cerebral vasospasm. Stroke 36:2731-2737, 2005. 12. Smith MJ, Le Roux PD, Elliott JP, Winn HR: Blood transfusion and increased risk for vasospasm and poor outcome after subarachnoid hemorrhage. J Neurosurg 101:1-7, 2004. 13. Springborg JB, Moller C, Gideon P, Jorgensen OS, Juhler M, Olsen NV: Erythropoietin in patients with aneurysmal subarachnoid haemorrhage: a double blind randomised clinical trial. Acta Neurochir (Wien) 149:1089-1101, 2007.
15. Testa U: Erythropoietic stimulating agents. Expert Opin Emerg Drugs 15:119-138, 2010. 16. Tseng MY, Hutchinson PJ, Richards HK, Czosnyka M, Pickard JD, Erber WN, Brown S, Kirkpatrick PJ: Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a phase II randomized, double-blind, placebo-controlled trial. Clinical article. J Neurosurg 111:171-180, 2009. 17. Vogiatzi G, Briasoulis A, Tousoulis D, Papageorgiou N, Stefanadis C: Is there a role for erythropoietin in cardiovascular disease? Expert Opin Biol Ther 10: 251-264, 2010. 18. Xiong Y, Mahmood A, Chopp M: Emerging treatments for traumatic brain injury. Expert Opin Emerg Drugs 14:67-84, 2009.
Conflict of Interest Statement: Dr. Macdonald is a consultant for Actelion Pharmaceuticals. He has grant support from Physicians Services Incorporated Foundation. He is Chief Scientific Officer of Edge Therapeutics. Citation: World Neurosurg. (2010) 73, 5:463-464. DOI: 10.1016/j.wneu.2010.03.041 Journal homepage: www.WORLDNEUROSURGERY.org
14. Strippoli GF, Navaneethan SD, Craig JC: Haemoglobin and haematocrit targets for the anaemia of chronic kidney disease. Cochrane Database Syst Rev 4:CD003967, 2006.
Available online: www.sciencedirect.com 1878-8750/$ - see front matter © 2010 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, DOI:10.1016/j.wneu.2010.03.041