Hemoglobin/Hematocrit

Acceptance Standards and

Interdonation Interval in
Blood Donors
Introduction
Blood Products Advisory Committee
July 27, 2010

Orieji Illoh, MD
Office of Blood Research and Review
Center for Biologics Evaluation and Research
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Food and Drug Administration E R
 Outline
Introduction
Hemoglobin standards
Regulatory history
Relationship to population norms
Relationship to iron status of donor
International standards
Estimated effect of changes on the blood supply
Interdonation interval
Current US and international requirements
Relationship to iron status of the donor
Effect of changes on the blood supply
Questions for the committee
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 Introduction
Consideration of the balance between
donor safety and blood supply
Donor safety issues
Hemoglobin standards
Interdonation interval

Blood supply issues

Impact of any changes in hemoglobin
standards or interdonation interval on
blood supply C B
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 Why adjust hemoglobin
standards?
Establish ranges within physiologic
norms
Avoid donations from male donors in
anemic range
Allow more donations from female
donors in normal range
~95% of hemoglobin donor deferrals occur in
women
Hemoglobin deferrals have a negative
impact on future blood donations C B
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 Why adjust interdonation
interval?

Improve donor safety

Allow adequate time for iron recovery

Decrease the incidence of iron

deficiency among blood donors
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 Hemoglobin measurement

Current requirement: 21CFR 640.3(b)(3)

Blood hemoglobin level no less than 12.5g/dL
or hematocrit no less than 38% in both male
and female allogeneic donors

Purpose
Ensure collection of a potent product
Ensure donor safety
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Hemoglobin measurement
Test characteristics
Simple, point of care test
Testing methods differ and are affected by
physiologic and operator variables
Quantitative methods reliably measure hemoglobin
within 0.2g/dL to 0.5g/dL
Relationship to donor health
Used as an indirect measurement of iron status
Studies show that hemoglobin is not a good
indicator of iron stores
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 Chronology of FDA
requirements for
hemoglobin standards
There have been discussions about
changing hemoglobin standards and
interdonation interval in the past

The threshold of 12.5g/dL was

established in 1958 and has not changed

The interdonation interval of 8 weeks was

established in 1999 and has not changed
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 Previous public
discussions
Workshop: Maintaining Iron Balance in
Women Blood Donors of Child Bearing Age.
June 8, 2001

Discussed Iron deficiency in female

premenopausal blood donors
Medical issues related to iron replacement
Iron replacement and possible protocols

Recommended implementation of a research

program on iron replacement
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 FDA Proposed Rule
(November 2007)
FDA asked for comments and supporting
data on:
Changing the hemoglobin or hematocrit levels to
12.0g/dL or 36%, as acceptable minimal values for female
allogeneic donors

The possibility of adverse effects if a minimum of

12.0g/dL or hematocrit of 36% is used for females

The possibility of adverse effects if a minimum of

12.5g/dL or hematocrit of 38% is maintained for males

Increasing the interdonation interval C B

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Representative comments to
the Proposed rule
Wait for results of REDS II study on iron status
in blood donors
Agree with proposal to lower hemoglobin
standard in women to 12.0g/dL
Hemoglobin down to 12.0 g/dL is normal for females
Enormous potential to improve the blood supply
Disagree with proposal to lower hemoglobin
standard in women to 12.0 g/dL.
Does not have any positive benefit to the donor
May make women susceptible to iron deficiency or anemia
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 BPAC: September 10, 2008
Topic: Iron Status in Blood Donors
Committee members agreed that iron
depletion in blood donors is a concern
Discussed testing for iron status in the
donor setting
Discussed alternative strategies to
mitigate iron depletion
Iron supplementation, dietary recommendations
Changing Hb/hct acceptance standards
Modification of interdonation interval CB
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 Advisory Committee on Blood
Safety and Availability -
December 2008
Recommendations
FDA should reconsider donor hemoglobin
acceptance values.
Adopt different, gender-appropriate
acceptance values
The current single value (12.5 g/dL) permits
acceptance of a significant number of
"anemic" males while excluding many
normal females.
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 Considerations for
Changing Hemoglobin
Acceptance Standards

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Definitions of anemia
Group Hemoglobin levels below
which 5% of the normal
subjects in the population
will be found (g/dL)

White men 13.7

20 -59
Black men 12.9
20-59
White women 12.2
20-49
Black women 11.5
20-49

NHANES III and Scripts Kaiser databases C B

Blood. 2006 Mar 1;107(5):1747-50 E R
 Hemoglobin distribution in
men

NHANES II data: Hb concentrations in men 18 to 44 years of

age. () Caucasian men; () African American men. C B
Transfusion. 2006 Oct;46(10):1667-81. E R
 Hemoglobin distribution in
women

NHANES II data: Hb concentrations in women 18 to 44 years of

age. () Caucasian women; () African American women. C B
E R
Transfusion. 2006 Oct;46(10):1667-81.
 Adverse effects
Are there adverse effects of maintaining a
minimum hemoglobin of 12.5g/dL (hct 38%)
for males?
Underlying medical conditions may not be
addressed
Promotes iron deficiency?

Are there adverse effects of lowering

hemoglobin to 12.0g/dL (hct 36%) for
females?
Promotes iron deficiency? C B
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 Australian blood donors: Iron
storage status of donors with
different predonation thresholds
Total donor 1535 males
population 1487
females
iron deficient (%)
ARCBS Hb threshold
from 1/1/04
Males 12.6g/dL 6.2
Females 11.8g/dL 22.0
ARCBS Hb threshold
from 1/1/05
Males 13.0g/dL 6.0 Dev Biol (Basel).
2007;127:137-46.

Females 12.0g/dL 20.6

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 Association of hemoglobin levels
with iron status in male blood
donors
Hemoglobin levels
Iron status <12.0 12.0-12.4 12.5-12.9 13.0 >13.5
(n=57 (n=69) (n=9) 13.4 (n=
) (n= 20) 230)
% Fe deficient 63 46 56 25 19
% Fe depleted 7 12 22 25 18
% Fe replete 30 42 22 50 63
Fe deficient: ferritin < 18 mcg/L
Fe depleted: ferritin 18-29 mcg/L
Fe replete: ferritin 30 mcg/L

From BPAC presentation by Dr Barbara Bryant Sept, 2008C B

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 Association of hemoglobin levels
with iron status in female blood
donors
Hemoglobin levels (g/dL)

Iron status 11.5 11.5-11.9 12.0-12.4 12.5

(n= 173) (n= 215) (n=379) (n=145)
% Fe deficient 40 23 14 10
% Fe depleted 27 29 35 30
% Fe replete 33 48 51 60
Fe deficient: ferritin < 9 mcg/L
Fe depleted: ferritin 9-19mcg/L
Fe replete: ferritin 20 mcg/L

From BPAC presentation by Dr Barbara Bryant Sept, 2008 C B

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 International donor Hb
levels (g/dL)
Hb-male Hb-female
Council of 13.5 12.5
Europe
Australia 13.0 12.0
UK 13.5 12.5
Health 12.5 Both Sexes
Canada
FDA 12.5 Both sexes

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 Effect on blood availability -
Males
There will be a loss of male blood
donors if the hemoglobin threshold is
raised

Loss of male African American donors

special phenotypes RBCs required for
sickle cell patients

May impact availability of male plasma

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 Effect on blood availability -
Males
If standard is changed to 13.5g/dL there may be
a loss of about 3% Caucasian donors and as
many as 21% African American donors
(Transfusion; 2006 Oct;46(10):1667-81)

Assuming a 4% loss of about 4,000,000 male

whole blood donors with an average donation
rate of 1.5, there would be an approximate loss
of about 240,000 units/year

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 Effect on blood availability -
Females
If the standard is dropped to
12.0g/dL, there may be gain of
about 9% Caucasian female
donors. (Transfusion; 2006
Oct;46(10):1667-81)

Assuming 4,000,000 female

donors with an average
donation rate of 1.5/yr, there
would be an approximate gain
of 540,000 units/yr.
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Interdonation interval

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 Interdonation interval
An appropriate interdonation interval
should ensure donor safety by allowing
time for adequate red blood cell recovery.

21CFR 640.3(b)
A person may not serve as a source of
Whole Blood more than once every 8 weeks
~ 6 donations/year
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 Iron loss following blood
donation
Iron loss following blood donation ~
200mg
Premenopausal women have lower iron
stores than men
Frequent blood donations deplete iron
stores
Replacement of lost iron is dependent on
exogenous sources
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 Effects of iron deficiency
Adverse effects include anemia, fatigue,
restless leg syndrome, possible cognitive
impairment, depression, and anxiety.

There are reports suggesting a beneficial

effect of low iron stores in males undergoing
repeated phlebotomy
Favorable lipoprotein profile compared to non
blood donors
Lower risk of cardiovascular disease
Possible reduction of iron-induced oxidative stress
van Jaarsveld et al. Atherosclerosis. 2002 Apr;161(2):395-402.
Salonen et al. Am. J. Epidemiol. 148 (1998):445451.
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 Studies of iron stores and
donation frequency
High prevalence of iron deficiency in frequent
blood donors
REDS II donor iron study
Repeat donations lead to decreased serum
ferritin in male and female donors
Rsvik AS, et al. Transfus Apher Sci. 2009 Dec;41(3):165-9
Clear correlation of iron deficiency with
frequency of donation
Page EA et al. Transfus Med. 2010 Feb;20(1):22-9
Depletion of iron stores occurs gradually with
increased frequency of blood donation
Simon TL et al. JAMA. 1981 May 22-29;245(20):2038-43.
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 Effect of donation frequency on
hemoglobin and iron status

Serum ferritin (g/L) for both genders

Hb (g/dL) for both genders at
at four donations without iron
four donations without iron supplement
supplement
(red = women, blue = men).
(red = women, blue = men).
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Transfus Apher Sci. 2009 Dec;41(3):165-9 E R
 International standards
Country Minimum Interdonation interval or
hemoglobin frequency per year
United States 12.5 56 days

Canada 12.5 56 days

United Kingdom 12.5 for women 112 days
13.5 for men
Australia 12.0 for women 84 days
13.0 for men
Netherlands 12.5 for women Women: 18 weeks,
13.5 for men 3x/year
Men:10 11 weeks,
5x/year
Hong Kong 11.5 for women Women: 3x/year C B
13.0 for men Men: 4x/year E R
Increasing the interdonation
interval
May decrease the risk of iron deficiency

May allow more time for iron recovery.

May decrease future donor deferral for
low hemoglobin

Will adversely affect the blood supply

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 Effect on blood availability
Increasing the interdonation interval may
negatively affect the supply of the
following:
Red blood cells especially O negative RBCs
and other rare phenotypes
Collections obtained by apheresis
Other blood components
Double red blood cells
Blood components other than red blood cells
Availability of donors for reagent
manufacturers.
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 Key points
Donor safety issues
Blood collection from anemic males with
current hemoglobin standard

Iron deficiency due to frequent donations

Blood availability issues

Potential gain of female blood donors
Potential loss of male blood donors
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 Questions for the
Committee
1. Does available scientific evidence support
changing the donor hemoglobin acceptance
standard for males?
a) If yes, what hemoglobin acceptance standards
does the committee recommend?

2. Does available scientific evidence support

changing the donor hemoglobin acceptance
standard for females?
a) If yes, what hemoglobin acceptance standards
does the committee recommend?
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 Questions for the
Committee
3. Please comment on the risks and benefits of
extending interdonation intervals as a
strategy to prevent iron deficiency in male
donors.
4. Please comment on the risks and benefits of
extending interdonation intervals as a
strategy to prevent iron deficiency in female
donors.
5. If any changes to the hemoglobin standard or
interdonation interval were to be made, what
mitigations can be considered to lessen
possible adverse effects on the blood supply?
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 Speakers
Ritchard Cable, MD American Red Cross,
Framingham, CT
REDS II donor iron study

Barbara Bryant, MD University of Texas

Medical Branch, Galveston, TX
NIH study on Iron stores in blood donors

Anne Eder, MD - American Red Cross,

Washington, DC
Impact of changes in hemoglobin standards or
interdonation interval on blood availability
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