BLOOD PRODUCTS ADVISORY COMMITTEE

92st Meeting, September 10-11, 2008

Rockville, MD

 

Issue Summary

 

 

Topic II:  Iron Status in Blood Donors

 

 

Issue:   FDA seeks advice from the Committtee on the impact of blood donation   on donor iron stores and donor health and, if needed, on possible        strategies to mitigate iron depletion in the donor setting.

 

 

Background:

 

Iron is found in all cells and functions as a major component of hemoglobin

About 70% of body iron is in the form of red cell hemoglobin.  Most of the remainder is in a storage compartment, while smaller amounts are in myoglobin and still smaller amounts in labile pools, intracellular respiratory enzymes, and associated with transport glycoproteins.  Men generally have a total of  ~3.8 g and women ~2.3 g of iron.  The amount of iron in the body is determined by intake through diet or iron supplementation and losses from the gastrointestinal tract, menses, pregnancy, breast feeding, and intravascular hemolysis.  The primary reasons for iron deficiency in healthy women of child bearing age are menstruation, pregnancy, breast feeding and inadequate diet.

 

Deficiency of iron is one of the most common nutritional deficiencies.  Iron deficiency ranges from iron depletion with limited or no physiological consequences to iron deficiency anemia which can affect multiple organs.  Iron is primarily used for erythropoiesis with the vast majority of iron recovered from senescent erythrocytes (the iron cycle).  Transferrin transports iron to the bone marrow for use in erythrocyte production.  Iron is mainly stored in a water soluble form as ferritin (9 mg/kg in men, 4mg/kg in women), but some is stored in a water insoluble form as hemosiderin (4 mg/kg in men and 1 mg/kg in women).  As iron stores become depleted, iron is mobilized as measured by serum ferritin.  There may not be physiologic consequences of iron depletion in the early stages.  However, as iron depletion progresses, storage iron is exhausted and transport iron is reduced as measured by a diminished transferrin saturation.   Iron-deficient erythropoiesis may result.  In children, normal growth or development of cognitive function may be impacted.  With the depletion of iron, production of red blood cells is impaired and free erythrocyte protoporhyrin concentration increases.  In iron deficiency anemia there is underproduction of needed iron containing compounds including hemoglobin.  Red blood cells (RBC) from these anemic individuals are microcytic and hypochromic.

 

In infants and young children, iron deficiency anemia can result in developmental delays, low birth weight, and malnutrition.   In adults, iron deficiency anemia has been reported to impact work capacity in the developing world.  In pregnant women, iron deficiency anemia during the first two trimesters is associated with an increased risk for preterm delivery and a three-fold increase in low birthweight.  Other symptoms that may be associated with lower iron levels include fatigue, restless leg syndrome and pica.  In contrast, a limited number of recent studies have suggested a potential cardiac benefit with reduced iron levels. 

 

The NHANES (1999-2000) survey found that 12% of women 16-49 years of age were iron deficient and about 3-4 % had iron deficiency anemia.  For women 50 years or older about 9% were iron deficient and 3 % had iron defiency anemia.  In contrast, for men 16-69 years old about 2% were iron deficient and 1% had iron deficiency anemia.    However, iron deficiency was greater in certain racial or ethnic groups.  CDC defined iron deficiency as abnormal value for at least two of three indicators: serum ferritin, transferrin saturation, and free erythrocyte protoporhoryin.  Individuals with iron deficiency and low hemogoblin were considered to have iron deficiency anemia. 

 

Normal Hemoglobin

 

The NHANES III survey (1994-1998) found that 95% of men over 18 years had a hemoglobin concentration that was greater than 13.5g/dl or 39.9% hematocrit, while 95% of women greater than 18 years had hemoglobin levels of 12.0g/dl or 35.7% hematocrit.  These levels were established as the defining levels for iron deficiency anemia and are consistent with other population based studies.  However, hemoglobin and hematocrit levels can vary by race.  African-Americans have slightly lower hemoglobin or hematocrit levels (about 0.8g/dl or 2% for adults) while some studies suggest even lower levels for African-American females.   Some of this difference can be accounted for by the relatively high prevalence of alpha-thalassemia in African-Americans.  Other conditions can also have an impact on hemoglobin or hematocrit levels include high altitude residence, seasonal variation in temperature, and smoking.  

 

In the blood bank setting, hemoglobin or hematocrit measurements are used to determine donor eligibility.  The FDA standard for the lower level for hemoglobin is 12.5 g/dL or 38% hematocrit for both men and women.   The standards for hemoglobin/hematocrit vary and some countries have different standards for men and women.  The FDA standard allows men who are below the “normal level” for hemoglobin based on population levels to donate. 

 

Previous studies have found that about 40-75% of all deferrals are due to low hemoglobin value and 95% of these deferrals occur in women.  These deferrals also discourage female donors from subsequent donations and result in a long term loss of donors.   The use of iron supplements to increase the number of younger female donors who would meet hemoglobin/hematocrit standards was discussed at an NIH workshop in 2001, however, few blood establishments and transfusion services have piloted studies on the use of iron supplements in blood donors.  

 

Although measuring hemoglobin levels by a gravimetric test using copper sulfate is a relatively easy and widely used method for determining donor eligibility in the blood bank setting, there are other methods that provide a more precise measure of iron status.  These methods include Mean Corpuscular Volume (MCV - the average volume of red blood cells); Red Blood Cell Distribution Width (RDW); Erythrocyte Protoporhyrin Concentration; Serum Ferritin Concentration; and Transferrin saturation.   However, measurements of iron status such as serum ferritin and transferrin saturation, are not routinely used in this country for donors and may not be practical for blood bank screening . 

 

 

Donor Safety 

 

A number of studies have shown that iron stores may be depleted in donors with normal hemoglobin values.  A healthy male blood donor loses about 200-250 mg of iron per donation. The loss is made up by mobilizing iron stores in the form of ferritin. By contrast, a double RBC donation, permitted every 16 weeks, results in the loss of 500 mg of iron per donation.   However, there are few reports documenting adverse events due to the loss of iron in blood donors.  The reported adverse effects include fatigue, restless leg syndrome (RLS), and pica. 

 

Screening techniques can detect iron depletion in blood donors. 

Mean ferritin levels are significantly lower in blood donors than in non donors.  Men usually have the most dramatic drop in ferritin levels because of higher iron stores before donation.  Studies have shown that iron stores decline with repeated blood donation.  After 6-8 phlebotomies the ferritin level is about 40 % lower than at baseline.  The proportion of male donors with decreased iron stores went from 8 to 19 % with an increase from 5 to 6 donations per year.

 

In one study in Australia, it was found that about 19% of female blood donors were iron deficient at a hemoglobin level of 12.5 g/dL, while about 5% of male donors were iron deficient at a level of 13.5 g/dL .  Other countries have different standards for hemoglobin levels and a longer interval between donations presumably to reduce the risk of iron depletion in blood donors

 

Ongoing Clinical Research Initiative

 

The NHLBI REDS-II Donor Iron Status Evaluation Study aims to evaluate the effects of blood donation intensity on iron and hemoglobin status in first time and frequent blood donors and determine changes using baseline measures as well as demographic, reproductive, and behavioral factors.  The study will also identify optimal laboratory procedures that predict the development of iron depletion and hemoglobin deferral in blood donors.  Additionally, the study will help formulate optimal blood donation guidelines by establishing a model that predicts the development of iron depletion and hemoglobin deferral in individual blood donors.

 

 

Summary:

 

The committee will hear presentations on (1) population based studies on normal levels of hemoglobin; (2) the impact of blood donation on blood donor iron stores; (3) studies that are in progress on the iron status of blood donors; (4) potentially harmful or beneficial effects of blood donation related to iron depletion; (5) experience of U.S. programs that provide iron replacement to donors; and (6) the European experience and perspective on iron management in donors.  

 

 

 

Questions to the Committee:

 

1.      Is iron depletion in blood donors a concern?

 

2.      If so, are there tests for iron status that would be practical and appropriate in the donor setting?

 

3.  Please discuss the risks and benefits of alternative strategies to mitigate iron depletion in donors including:

a) iron supplementation;

b) dietary recommendations;

            c) modification of the inter-donation interval;

            d) changing the acceptance standard for donor hemoglobin/hematocrit.      

 

References:

 

Centers for Disease Control and Prevention. Recommendations to prevent and control iron deficiency in the United States. Morb Mortal Wkly Rep. 1998;47(RR-3):1-36.

 

Looker AC, Cogswell ME, Gunter EW. Iron deficiency, United States, 1999–2000. Morb Mortal Wkly Rep. 2002;51:897-9.

 

Iron-Status Indicators in National Report on Biochemical Indicators of Diet and Nutrition in the U.S. Population 1999-2002

http://www.cdc.gov/nutritionreport/pdf/nr_ch3.pdf

 

Beutler E. and Wallen, J. The definition of aneria: What is the lower limit of normal of the blood hemoglobin concentration ?  Blood 2006: 107(5) pag 1747-1750.

 

Bianco C. et.al. Maintaining iron balance in women blood donors of childbearing age: summary of a workshop.  Transfusion 2002;42 798-805.

 

Farrugia  A, Iron and Blood Donation-An UnderRecognized Safety Issue.  Advances in Transfusion Safety-(IV) Dev. Biol., Basel, Karger, 2007, 127; 137-146.

 

Newman, B. Iron depletion by whole-blood donation harms menstruating females: The current whole-blood-collcttion paradigm needs to be changed.. Transfusion 2006;46: 1667-1681

 

Brittenham, GM. Iron balance in the red blood cell donor. Advances in Transfusion Safety Dev Biol (Basel), Karger, 2005, vol 120, 77-82

 

 

Magnussen  K, Bork N, Asmussen L. The effect of a standardized protocol for iron supplementation to blood donors low in hemoglobin concentration Transfusion 2008;48:749-754