cber hemoglobin/hematocrit acceptance standards and interdonation interval in blood donors...

CC BBEE RR

Hemoglobin/Hematocrit Acceptance Standards and Interdonation Interval in

Blood DonorsIntroduction

Blood Products Advisory Committee

July 27, 2010

Orieji Illoh, MD

Office of Blood Research and Review

Center for Biologics Evaluation and Research

Food and Drug Administration

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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

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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

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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

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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

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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

NHANES III and Scripts –Kaiser databases

Blood. 2006 Mar 1;107(5):1747-50

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

White men20 -59

13.7

Black men20-59

12.9

White women20-49

12.2

Black women20-49

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Hemoglobin distribution in men

NHANES II data: Hb concentrations in men 18 to 44 years of age. (◆) Caucasian men; (░) African American men.

Transfusion. 2006 Oct;46(10):1667-81.

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Hemoglobin distribution in women

NHANES II data: Hb concentrations in women 18 to 44 years of age. (◆) Caucasian women; (░) African American women.

Transfusion. 2006 Oct;46(10):1667-81.

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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?

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Australian blood donors: Iron storage status of donors with

different predonation thresholds1535 males 1487

females

Dev Biol (Basel). 2007;127:137-46.

Total donor population 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

Females ≥ 12.0g/dL 20.6

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Association of hemoglobin levels with iron status in male blood

donors

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, 2008

Hemoglobin levels

Iron status <12.0(n=57)

12.0-12.4(n=69)

12.5-12.9(n=9)

13.0 – 13.4(n= 20)

>13.5(n= 230)

% Fe deficient 63 46 56 25 19

% Fe depleted 7 12 22 25 18

% Fe replete 30 42 22 50 63

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Association of hemoglobin levels with iron status in female blood

donors Hemoglobin levels (g/dL)

Iron status 11.5(n= 173)

11.5-11.9(n= 215)

12.0-12.4(n=379)

≥ 12.5(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

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International donor Hb levels (g/dL)

Hb-male Hb-female

Council of Europe

13.5 12.5

Australia 13.0 12.0

UK 13.5 12.5

Health Canada

12.5 Both Sexes

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):445–451.

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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

– Røsvik 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

Transfus Apher Sci. 2009 Dec;41(3):165-9

Serum ferritin (μg/L) for both genders at four donations without iron

supplement (red = women, blue = men).

Hb (g/dL) for both genders at four donations without iron supplement

(red = women, blue = men).

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International standards

Country Minimum hemoglobin

Interdonation interval or frequency per year

United States 12.5 56 days

Canada 12.5 56 days

United Kingdom 12.5 for women

13.5 for men

112 days

Australia 12.0 for women

13.0 for men

84 days

Netherlands 12.5 for women

13.5 for men

Women: 18 weeks, 3x/year

Men:10 – 11 weeks, 5x/year

Hong Kong 11.5 for women

13.0 for men

Women: 3x/year

Men: 4x/year

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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