1. health and fitness
2. disease

Anemia To Blood Doping: What’s
The Latest
Thomas M. Best, MD, PhD,
FACSM
February 22, 2014
I have no commercial, financial, or
research relationships or interests within
the past 12 months that affect my ability to
provide a fair and balanced presentation
for the proposed CME activity.
OUTLINE
 Laboratory Evaluation of Anemia
 Sports Anemia (Dilutional Pseudoanemia)
 Iron Deficiency Anemia
 Foot Strike Hemolysis
 Sickle Cell Trait
 Blood Doping/EPO
What Is Ideal Hematocrit?
 ~ 40% for a long life?
 ~ 50% to win the big
marathon?
 ~ 60% to climb Mt.
Everest without an
oxygen tank?
 ~ 60% to die from blood
doping?
Sports Medicine
Who Gets Anemia?
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Heavy menses
Vegetarian
Calorie cutter
Breakfast skipper
Sky-high carb diet
Sports Medicine
Work up for Anemia - Principles
 Detailed history
– Symptoms of: fatigue, sob, decreasing
performance, palpitations, tachycardia, pica
– GI, urinary bleeding
– Menstrual history
– Nutritional practices
– Training
– Use of medications and
supplements
Sports Medicine
Physical Exam
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Resting bp, pulse, orthostatics
Skin – pallor, jaundice
Cardiopulmonary
Abdominal
Possibly rectal exam
Sports Medicine
Laboratory Studies
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Hemoglobin/Hct including MCV, MCH
Reticulocyte count
Peripheral smear
Serum iron, ferritin
Total iron-binding capacity/transferrin
LDH, bilirubin, haptoglobin
Possibly further GI/GU evaluation
Consider CRP, ESR, TSH, electrophoresis if
ruling out other disease
Sports Medicine
Exercise-Induced Iron Loss
 Gastrointestinal bleeding – decrease in visceral
blood flow with possible ischemia
 Hematuria – mechanical trauma to the glomerulus,
bladder motion during running
 Sweating – some iron loss, particularly during
periods of extreme heat
 Hemolysis – foot-strike hemolysis
Sports Medicine
Sports Anemia
 Also called “Dilutional Pseudoanemia”
 Not true anemia
 Increased plasma volume in response to
exercise
–
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–
–
Increase in aldosterone, renin, ANF, vasopressin
increased renal retention of water and salts
Increase in plasma proteins
Increased hydration
Sports Medicine
Sports Anemia
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Endurance athletes mainly
Expanded plasma volume
Dilutes Hgb down 1.0-1.5 g/dl
In men, most common “anemia”
Waxes and wanes with training
Benefit, not a detriment
Shaskey & Green, “Sports Haematology,” Journal
Sports Medicine 29 (1):27-38, 2000
Sports Medicine
Iron Deficiency Anemia
 #1 Nutritional Deficiency in U.S.
– Iron Deficiency ~ 11% of women
– Iron Deficiency Anemia 1-2% adults
 #1 cause of Anemia in Athletes
– Up to 12.5% of athletes
  Dietary intake
 Menstruation
  Loss from other sources (GI, GU, hemolysis,
sweating)
  Absorption
Sports Medicine
Iron Deficiency Anemia
 Hg <12g/dL (36 Hct) Female
 Hg < 14 g/dL (42 Hct) Male
 MCV < 75
–
(if < 60 consider hemoglobinopathy)
 Ferritin <12
 Low Serum Iron w/ High TIBC
 High Hg – think doping/steroids
Sports Medicine
Iron Deficiency Anemia
 Stage 1- “prelatent anemia”
– Depleted Iron Stores
– Ferritin NL-TIBC/Iron NL-HCT
 Stage 2- “iron-deficient erythropoeisis”
– above plus Ferritin TIBC IRON, Mild HCT
– Normocytic to mildly microcytic, mild Hypochromic
 Stage 3- overt Microcytic and Hypochromic anemia
–  Ferritin TIBC IRON HCT
Sports Medicine
Gastrointestinal Hemorrhage in Athletes
 Particularly in distance runners, triathletes
 Following endurance events stool occult
positive 13-85%
– Overt hematochezia was reported in 6%
 Increased blood loss with increased intensity
 Mixed results on increased blood loss with
concurrent use of NSAIDs
 Blood loss can be trivial to severe
Sports Medicine
Gastrointestinal Hemorrhage in Athletes
 Visceral ischemia due to decreased
splanchinc perfusion
 Gastritis and espohagitis most frequently
noted abnormalities on endoscopy – but also
cases of small bowel and colonic ischemia
– Exercising at 70% of VO2 max reduces blood flow
to the gastrointestinal tract by 60-70%; more
intense exercise may cause reductions in excess
of 80% - worsened by dehydration
– Up and down motion of running appears to be risk
factor - ? Direct trauma to viscera
Sports Medicine
Genitourinary System Losses
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Exercise-induced hematuria
Typically microscopic
Usually resolves within a few days of event
Renal causes
– Renal vasoconstriction
– decreased renal plasma flow with damage to
nephron
– direct trauma to GU system
 Intravascular hemolysis causing
hemoglobinuria
Sports Medicine
Iron Deficiency Anemia - Impact on
Performance
 Reduction in aerobic capacity, endurance and
energetic efficiency due to decreased oxygen
delivery
 Correction of anemia with iron
supplementation improves performance
 ? No improvement in performance shown
with iron supplementation in nonanemic, irondeficient athletes
Sports Medicine
Iron Deficiency Anemia - Treatment
 Discuss Dietary Consumption
– Males require 10mg/day, female 15mg/day
– Heme iron (meats) more bioavailable (10-35%) vs non-hem
iron (2-5%)
– Handouts/Websites - www.fwhc.org/health/iron.htm
 Consider Iron Replacement
– Stage 1&2?, Stage 3 yes
Sports Medicine
Iron Replacement
need 150-200mg/day
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Ferrous vs Ferric
Ferrous is absorbed better
sulfate 325mg (65mg)
gluconate 325mg (36mg)
Replace w/ palatable forms
Increased absorption w/
Vitamin C (Ascorbic Acid)
 GI side effects
– Take w/ food (but can absorptio
up to 65%)
 Do not use enteric coated
forms (do not dissolve in
stomach)
 Drug Interactions (H2 blockers
PPI, tea and coffee tannates,
caffeinated drinks)
Sports Medicine
Iron Deficiency Anemia - Treatment
 Re-evaluate
– CBC in 1 month
– Reticulocytes and MCV increase first
– If HCT not up despite therapy – consider further evaluation
 Replaced Iron stores complete when Ferritin
= 50
 Can take 4-6 months to treat then
maintenance therapy
Sports Medicine
To Prevent Anemia
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Lean red meat
No coffee at meals
OJ with breakfast
Iron cookware
Mixed meals
Supplements
Eichner ER, Curr Sports Med Rep 9:122-23, 2010
Sports Medicine
Intravascular Hemolysis
• Also called “Foot Strike Hemolysis”
 Caused by RBC destruction from repeated
trauma
• Elevated temperature in muscle, turbulence
and acidosis may also be involved
Robinson et al, MSSE 38:480-83, 2006
Sports Medicine
Foot Strike Hemolysis
Diagnosis
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 Bilirubin
 Haptoglobin
 Schistocytes
Slight  MCV & Reticulocytes
– Preferential breakdown of older rbcs
 Hemoglobinuria
 Anemia resolves w/ d/c exercise
Telford RD et al, J Appl Physiol 94:38-42, 2003
Sports Medicine
Foot Strike Hemolysis
Treatment
 Change Shoes
 Change Running Surfaces
 Modification of Training Program
• Search for other causes of hemolysis
- Drugs (ABX, INH)
- Acute Illnesses (Mycoplasma, Mono, Sepsis, Viral)
- Chronic Illnesses (Autoimmune)
- Heredity (G6PD, Thalassemia, Sickle Cell)
Sports Medicine
Intravascular hemolysis in non-foot strike
sports
 Swimmers
– Compression from contracting
muscles
 Cyclists, other sports
- ? Increase in body temperature may
increase red cell turnover
- oxidative and osmotic stress
Sports Medicine
Sports Anemia – Fact or Fiction?
 Miller et al Int J Sports Med 1988 – force dependent
relationship between heel strike and degree of hemolysis
 Lippi and Guidi Blood Trans 2012 – 15 ultramarathon runners
– no change in Hb, hematocrit, RBC count, potassium
 Post exercise decrease in haptoglobin, reduction in MCV
 ? Compensatory shift of intracellular water outside the RBC to
counterbalance loss of fluid
 Conclusions
- No evidence that iron supplementation improves athletic
performance
Ottomano and Franchini Blood Transf 2012
Sports Medicine
Sports Anemia – Fact or Fiction?
 Athletes with low serum ferritin without anemia – iron
supplementation might be useful
 Serum ferritin should be monitored in conditioned athletes
 Most studies have NOT shown benefit of iron supplementation
on performance, “the uncontrolled use of iron should be
avoided”
 Risk factors for iron deficiency include; adolescence, female
sex, vegetarian diet, Helicobacter pylori infection
Ottomano and Franchini Blood Transf 2012
Sports Medicine
Sickle Cell
 Inherited disease of abnormal hemoglobin S
– Polymerizes under physiologic stress = destruction of rbcs
 Sickle disease – usually incompatible with
participation in intense physical activity
 Sickle Trait - Heterozygous state where Hgb S is
present with Normal Hgb A in RBC
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< 50% Hgb is Hgb S
Usually Asymptomatic w/ no anemia
Up to 8% of African Americans
1/10,000 Whites
Sports Medicine
Sickle Cell Risks
 Gross hematuria
 Splenic infarction
 Exertional heat illness
– Rhabdomyolysis
– heat stroke
– renal failure
 Idiopathic sudden death
 Physiologic changes associated with exercise
– (regional hypoxemia, acidosis, dehydration,
hyperthermia) – all increase risk of sickling
Sports Medicine
Adverse Events Associated With SCT
 Renal
Hyposthenuria, hematuria. papillary necrosis
 Spleen
Splenic infarction
 Pregnancy
Fetal loss, low birth weight, preeclampsia, premature
delivery
 Hyphema
 Venous thromboembolic events
Sports Medicine
Sickle Cell Trait
SPLENIC INFARCTION
 Pathophysiology of SCT events not entirely clear
 Cascade of events leading to microvascular sickling,
vascular occlusion, endothelial damage, decreased
blood flow to muscles, rhabdomyolysis, DIC
 Rare in sickle cell trait – 47 reported cases
 Likely due to microvascular occlusion
 Severe hypoxia - elevations > 10,000 feet
 Descend to lower height, O2, hydration
Sports Medicine
Sickle Cell Trait And Sudden Death
In Athletes
 Kark et al NEJM 1987 – military recruits
 2010 – NCAA mandated screening for D1
 Harmon et al Br J Sport Med 2012 – SCT associated with a
relative risk of death of 37 times in NCAA football athletes
 Harris et al Am J Cardiol 2012 – Minneapolis Heart Institute
Foundation database
- 31 yr injury registry, 2462 athlete deaths
- 23 deaths in association with SCT, college
football highest risk (7% of 271 AA football
players, 8% of players estimated to carry the trait in this
population)
- distinctive clinical picture of gradual
deterioration over several mins, early in training season,
conditioning drills, temp > 80F
Sports Medicine
Sickle Cell – Treatment/Prevention
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Train wisely
Stay hydrated
Avoid heat and elevation
Rest when sick
Report hematuria
Respect pain – abdominal, muscles, cardiac
Screen or not screen?
- NCAA D1 (?D2, D3)
- American Society of Hematology
(www.hematology.org/news/2012/7703.aspx)
Sports Medicine
Blood Doping
Sports Medicine
Erythropoietin (EPO)
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Glycoprotein hormone regulating RBC production
Produced by renal cortex (90%), brain, lung & uterus
Binds to CFU erythroid stem cells in bone marrow
EPO regulation controlled by gene on chromosome 7
with hypoxic inducible factor
 New circulating erythrocytes seen 1-2 days after EPO
levels rise
Sports Medicine
Blood Doping
 Increasing the number of red blood cells in the
body to increase the oxygen carried to muscle
– Administration of blood, red blood cells, or related blood
products
– Erythropoietin (EPO) or rHuEPO
o Stimulates bone marrow to produce red blood cells
Sports Medicine
Blood Doping
 1968 Mexico City Olympics (Alt. 7300 ft)
– Most endurance race winners from highlands
– Athletes from high altitude had “thick blood”
 Elblom et al (1972)*
– 3 men, 800ml autologous transfusion (4 weeks)
o 13% increase in Hg
o 9% increase in VO2max
o Run time to exhaustion increase 23%
 1976 Blood Transfusions Banned by IOC
 1987 rHuEPO first available in Europe
 1990 – IOC prohibited use of EPO
*Eichner, ER. Sports Med (2007)
Sports Medicine
Blood Doping - Does It Work?
 Performance Studies- (Williams and
Branch summarized study findings)
– 7% increase in Hgb
– 5% increase in VO2 max
– 34% increase in time to exhaustion at 95% VO2
max
– 44 second improvement in 5 mile treadmill run
time
– 69sec decrease in 10K time
Blood Doping - Side Effects
 Infections with transfusions
 Inhibit endogenous EPO production
 Increased viscosity of blood
– Stroke, MI, venous thromboses. PE
– HTN (direct relation to dose), CHF
Recombinant Human Erythopeietin
(rHuEPO)
 rHuEPO isolated from chineese hampster ovaries
– SQ administration, 50-300 u/kg, 2-3/week
– Hct increases noted after 2-6 weeks
 Clinical Applications:
– treatment of anemias related to renal failure,
chemotherapy, HIV infection, prematurity,
hemoglobinopathies, autoimmune disease and
malignancy
 Adverse Effects:
– headache, fever, nausea, anxiety, lethargy
– hypertension & hyperkalemia in dialysis population
– hyperviscosity syndromes
– seizures and hyperkalemia (rare)
Sports Medicine
rHuEPO
 1987-1991, 20 top European cyclists died
unexpectedly, suspected EPO use
 1998-2000, 18 more cyclists with suspected EPO use
died of thromboembolic complications (PE, CVA, MI)
 Ergogenic Effectiveness*
– Birkeland et al (1999) EPO vs placebo, 20 athletes
o Hct increase from 43% to 51%
o 7% increase VO2max
o 9% increase in run time to exhaustion
o Effects lasted up to 3 weeks after EPO stopped
*Eichner, ER. Sports Med (2007)
Sports Medicine
Detection of rHuEPO Misuse
 1990 rHuEPO banned by IOC, later USOC & NCAA
 Nearly identical in structure and metabolism to endogenous
EPO form, rapid half life (24 hours)
– Cleared from body within 2-3 days
 1997 International Cycling Union created Hct cutoffs
– Males (50%), Females (47%)
 2000 Mathematical Model
– measuring indirect blood markers associated with rHuEPO
– Hb, EPO level, reticulocyte %, soluble transferrin
 2000 Isoelectric Focusing & Immunoblotting
– possible to separate rHuEPO and endogenous EPO based
on differences in charge status of glycosylated side chains
– rHuEPO slightly more acidic than EPO
– Also able to detect Darbopoietin (rHuEPO analogue)
Sports Medicine
Detection of Blood Transfusion
 Advancement of rHuEPO testing, indirectly leads to
a return to older practices of blood transfusion
– Autologous transfusions currently undetectable
– Homologous transfusions can be detected by flow
cytometry after labeling RBC membrane proteins
o Multiple RBC populations
o Enhanced production of RBC line
Additional Blood-Boosting Methods
 High Altitude Training / Altitude Tents
– In low pO2, Hg binds O2 more efficiently
– Natural stimulus for erythropoiesis, over 3-4
weeks
 Artificial Oxygen Carriers
– Hemoblobin Oxygen Carriers (ex. Hemopure)
o No positive effect on endurance or VO2max*
o Hypertension, GI hypertonicity, renal toxicity
– Perfluorocarbons Emulsions
o Synthetic liquid dissolves oxygen 100x greater
than plasma, requires oxygen supplementation
o Flu-like symptoms, thrombocytopenia, allergic
reactions, hepatosplenomegaly,
organ failure
*Aschenden MJ. Int J Sports Med (2007)
Sports Medicine
Gene Engineering And Gene Screening
 HERITAGE and GENATHLETE – genes responsible for
endurance capacity in humans
 Angiotensin-converting enzyme (ACE) coding gene, (185-bp)
gene code of the EPO receptor, gene code of α2 adrenergic
receptor all correlated with increased endurance capacity in
runners – Wolfarth et al Med Sci Sports Exer 2000
 Currently up to 214 autosomal dominant gene entries and trait
loci identified that are connected with endurance, muscle
strength, training response, exercise tolerance (Rankinen T et al
Med Sci Sports Exer 2010)
 PPARα and ACTN3 – potential risk for genetic screening abuse
given location on a single gene and important role in endurance
training and speed performance, respectively?
Sports Medicine
Gene Treatment And Gene Manipulation
 Gene therapy – congenital or acquired muscular dystrophies,
diabetes, primary/secondary forms of anemia, cardiovascular
disease, growth deficiency
 Differentiation of key molecules produced from gene doping
from their ‘natural counterparts’ is a real challenge
 Delivery of genetic material
- direct transplant
- transfection - use of non-viral transporters (liposomes,
plasmids, plain DNA) for local injection
- transduction – with inactive viral vectors (adenovirus,
adeno-associated virus)
- other techniques – microinjection, bioballistics
Sports Medicine
IGF-1 and Myostatin Effects on Skeletal Muscle
Sports Medicine
IGF-1 And Myostatin –
Local Growth Factors And Effects On Skeletal Muscle
 Glucocorticoids inhibit production
of IGF-1 (in vitro and in vivo)
 Glucocorticoids stimulate
production of myostatin (growth
factor that inhibits muscle mass
development by downregulating
satellite cells and protein
synthesis)
 Myostatin – gene, when mutated,
is responsible for ‘double
muscling’ in certain breeds of
cattle
Sports Medicine
Growth Factors And Doping – Where Is The Line?
 Goldspink et al 2008 “This fact that MGF ‘kick starts’
the hypertrophy process clearly has potential for
abuse and has already attracted the attention of body
builders”
 MGF (derived from IGF-1) – expressed as pulse dose
for 2 days following injury resulting in longer lasting
expression of IGF-I
 WADA – continues to update and fine tune its
antidoping rules
OSU Sports Medicine
Summary
 Sports Anemia – dilutional due to increase plasma
volume
– Rule out other causes
– No treatment needed
 Iron Deficiency Anemia
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–
–
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Order appropriate labs
Evaluate nutritional intake
Evaluate for possible losses including GI, GU
Training adaptations
 Hemolytic Anemia
– Order appropriate labs
– Training adaptations
 Sickle Cell Trait
– Higher risk for sickling crisis with heat, exertion, dehydration,
altitude
Sports Medicine
References
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Ashenden MJ, Schumacher YO, Sharpe K et al. Effects of Hemopure on
Maximal Oxygen Uptake and Endurance Performance in Healthy Humans. Int J
Sports Med (2007) 28(5): 381-385.
Buzzini SR. Abuse of Growth Hormone Among Young Athletes. Pediatr Clin N
Am (2007) 54: 823-843.
Casavant MJ. Consequences of Use of Anabolic Androgenic Steroids. Pediatr
Clin N Am (2007) 54: 677-690.
Eichner ER. Blood Doping: Infusions, Erythropoietin and Artificial Blood. Sports
Med (2007) 37(4-5): 389-391.
Kerr JM, Congeni JA. Anabolic-Androgenic Steroids: Use and Abuse in
Pediatric Patients. Pediatr Clin N Am (2007) 54: 771-785.
Pommering TL. Erythropoietin and Other Blood-Boosting Methods. Pediatr Clin
N Am (2007) 54: 691-699.
Robinson N, et al. Erythropoietin and Blood Doping. Br J Sports Med (2006) 40:
30-34.
Saugy M, et al. Human Growth Hormone Doping in Sport. Br J Sports Med
(2006) 40: 35-40
Smurawa, TM. Testosterone Precursors: Use and Abuse in Pediatric Athletes.
Pediatr Clin N Am (2007) 54: 787-796
Sports Medicine