Alternatives to Regular Blood Transfusions
by Dixie Farley

The second genetically engineered blood clotting factor and a new
drug to stem bleeding in heart surgery last year joined other
alternatives to regular "homologous" blood transfusion--blood
transfused into someone other than the donor.
New steps by the Food and Drug Administration are helping to make
the public blood supply as safe as possible. (See "The Real Scoop on
AIDS and Shortages.") Alternatives, too, may increase safety for
some patients, including those with the clotting disorder
hemophilia, who all their lives depend on outside sources for
clotting factors they lack.
       Genetically engineered Kogenate was licensed Feb. 28, 1993, by
the Food and Drug Administration as the second non-blood-derived
alternative for people without clotting factor VIII. FDA licensed
the first non-blood factor VIII, Recombinate, in December 1992.
These products are for patients with hemophilia A. They prevent or
control bleeding and prevent bleeding associated with surgery.
       Previously, factor VIII could only be obtained from products
derived from human plasma, the liquid part of blood. Kogenate and
Recombinate are produced by hamster ovary cells into which the gene
for human factor VIII has been inserted. The resulting factor is
highly purified, eliminating the risk of transmission of viruses
such as hepatitis or HIV, the virus that causes AIDS.
       The new drug Trasylol Injection (aprotinin), approved last Dec.
29, decreases the need for transfusion in patients undergoing
coronary artery bypass surgery. (For more biological and drug
alternatives, see "Approved Alternatives.")
       In addition to drugs and biologics, several medical practices
are available to lessen the already low risk of disease
transmission. These alternatives include using the patient's own
previously donated blood, recycling the patient's blood shed during
surgery, and diluting the patient's blood before surgery.

Your Own Blood
       Patients who are likely to require a transfusion during an
upcoming surgery may decide to donate their own blood for possible
reinfusion. FDA recommends this practice, called "autologous"
transfusion, whenever possible for elective surgery.
       Use of the patient's own blood may reduce the chance of
infection or other adverse reaction. The practice also decreases
demand on the public blood supply. In addition, autologous
transfusion allows blood lost during surgery to be replaced more
quickly because the process of donating blood, in itself, stimulates
the bone marrow to produce new blood cells.
       The disadvantages include: increased cost (about $24 more per
unit), unnecessary donation if surgery doesn't require transfusion,
and sometimes waste of unneeded units. Autologous blood not used by
the donor-patient often cannot be used by another patient.
       Some hospitals have a program for using autologous units in the
public blood supply if the intended patient doesn't use them. These
units must meet all FDA's safety standards for regular  transfusion.
In fact, the agency strongly recommends that all tests routinely
performed on regular donations be performed on all autologous
donations. Uniform testing is less confusing and safer, because it
decreases the chance of releasing for general use an incompletely
tested unit of blood. Labeling of an autologous donation must
clearly indicate the intended recipient. Liquid blood can be stored
refrigerated only 42 days; frozen blood, 10 years.
       Autologous blood is most widely used for surgery on the bones,
blood vessels, urinary tract, and heart. Nevertheless, any medically
stable patient, even a child or pregnant woman, can be a candidate
for autologous donation, according to Joseph Fratantoni, M.D.,
director of hematology at FDA's Center for Biologics Evaluation and
Research.
       Conditions that might prevent someone from donating blood for
others don't necessarily prevent autologous blood donation. For
example, people who have had hepatitis may give blood to themselves.
       Autologous donation may be inadvisable for some patients, such
as those with severe heart and blood vessel disease whose condition
may be worsened by donating a unit or two of blood, says Fratantoni.
"The decision to use autologous donation," he says, "should be made
by the physician and the patient, according to the patient's
condition."
       For an autologous donation, the patient's doctor will make
arrangements with the local blood bank, where the person can give
one unit of blood a week for up to six weeks, as needed. A unit is
just under a pint, about 10 percent of a person's total blood.
       Although the fluid lost from donation replenishes within 24
hours, replacement of red blood cells, with their life-giving
oxygen, can take as long as two months. For patients giving multiple
autologous donations over several weeks, iron supplements may be
prescribed to help increase the red blood cell count.

Recycling Blood During Surgery
       When an operation is expected to involve a large loss of blood,
the surgical team may recover the patient's blood and reinfuse it
during the surgery. This practice, called intraoperative blood
collection, or salvage, has been widely used in open-chest surgery,
says Fratantoni, and may be done using one of two methods.
       One method uses a high-speed centrifuge "specifically designed
to handle blood gently," says Catherine Wentz, a biomedical engineer
who reviews such instruments for FDA's Center for Devices and
Radiological Health. Blood that collects in the surgical cavity is
suctioned into the centrifuge, which separates it into components,
Wentz says. The centrifuge concentrates the red blood cells, washes
them with a saline solution, and pumps the red cell suspension into
an infusion bag for return to the patient.
       Despite the fact that red cell survival in salvaged blood may
be as great as that of regularly transfused blood, the immune
system's white cells and clotting substances such as platelets do
not remain in salvaged blood in useful amounts. To protect against
clotting problems, Wentz says, care  must be taken to limit the
amount of blood reinfused to a patient within a certain time period.
       Another salvage method bypasses the centrifuge and collects the
suctioned blood into a reservoir that filters the blood. After
filtration, the unwashed blood is transferred into a bag for
reinfusion.
       "The choice of blood salvage method, washed or unwashed," Wentz
says, "is usually based on the type of surgery. For example, knee
and hip surgeries tend to 'taint' the suctioned blood with debris
such as bone chips, so the choice may be a washed, or centrifuge,
system."
       Factors that make intraoperative salvage inadvisable include
cancer or infection.
       Scientists are investigating other blood collection practices.

Conserving Red Cells
       Blood dilution (hemodilution) is a practice to prevent loss of
red blood cells. The patient has blood drawn before surgery and is
immediately given intravenous fluids to make up for the drawn blood,
which is saved to be reinfused after the operation.
       "The idea," Fratantoni says, "is that during the operation any
blood the patient loses will have been diluted, and therefore fewer
red cells are lost. Following surgery, reinfusion of the removed
blood provides a supply of normally concentrated red cells."

Directed Donations Safer?
       In directed donations, friends or family donate blood for a
specific patient. Such donors must go through all the standard donor
screening and testing procedures. Several states have passed laws
establishing directed donation as a procedure that must be followed
when requested, except in an emergency.
       Some people may feel it's always safer to receive blood from a
relative or friend than from the general blood supply, but experts
say this is not necessarily the case.
       "In fact, the track record on directed donations is mixed,"
Fratantoni says. "Studies have shown that relatives or friends,
feeling pressured to donate, sometimes hide information during
screening that they wouldn't under other circumstances, so that they
give blood when they shouldn't." (Since the blood is tested the same
as all other donations, blood that tests positive for infection or
other problems will not be used.)
       While matching a patient's blood type may be easier when the
donor is a relative rather than someone else, such patients have a
high risk of developing graft-versus-host disease, a complication
due to the donor and recipient's sharing certain tissue-type
substances. In this disease, lymphocyte white blood cells from the
transfused blood multiply and react against the recipient's tissues.
       When the donor and recipient are both from the general U.S.
population, the probability of their sharing a tissue-type substance
is very low. Not zero, Fratantoni says, but "somewhere between rare
and extremely uncommon."
       In the United States, the risk of graft-versus-host disease 
with blood from a blood relative is about 1 in 7,000 (or higher,
depending on the data used). The closer the relatedness, the greater
the risk. In a parent-child relationship, the risk is double that in
a relationship between grandparent, uncle or aunt.
       To reduce the risk, the American Association of Blood Banks
recommends irradiating blood derived from all donors who are blood
relatives of the recipient. Irradiation suppresses proliferation of
lymphocytes contained in the transfused blood. Blood treated this
way must meet special FDA licensing requirements, such as permanent
labeling that it has been irradiated.

For the Future
       A look to the future may envision the ultimate alternative to
homologous transfusion to be artificial blood. As blood is extremely
complex, however, the dream of a true substitute may never be
realized.
       Even so, one important blood function has been reproduced
artificially: bloodstream transport of life-giving oxygen, the
substance all tissues need to survive.
       The ideal artificial blood oxygen carrier would pick up oxygen
in the lungs and deliver it to all tissues, have a long shelf life
with stability at room temperature, be compatible with all blood
types, and present no risk of infection, immune reaction, or other
health problem.
       In 1989, FDA licensed the first artificial oxygen carrier,
Fluosol, which used substances called "perfluorochemicals" to
temporarily transport oxygen to the heart during coronary artery
balloon angioplasty. But the product carried limited amounts of
oxygen and had other drawbacks. The manufacturer recently stopped
production.
       Fratantoni says that two new investigational perfluorochemicals
have advantages over Fluosol, including greater oxygen solubility
and the capability to be stored at room temperature without being
reconstituted before infusion.
       Researchers are also experimenting with modifying normal red
blood cells so that the cells can be freeze-dried, stored at room
temperature, and then reconstituted and infused without concern for
blood type.
       One modification, by a process called "polymerization," permits
high concentration and increases circulation time. Using another
technique that encapsulates red cells with a fatty membrane,
researchers have supported oxygen requirements in animals with too
few red cells to sustain life.
       But a major problem with perfluorochemical and red cell oxygen
carriers is that the bloodstream retains them only six to 36 hours.
Normal red cells survive 100 to 120 days.
       There also is an ethical consideration to testing artificial
oxygen carriers in human studies in which some participants would
get the real biologic while others receive a placebo (dummy)
infusion.
       According to Thomas Zuck, M.D., director and professor of
Hoxworth Blood Center of the University of Cincinnati Medical
Center, in Transfusion Medicine in the 1990's: "If whole blood or 
red cells that are known to be effective are available, it would be
difficult to contend that participating in blood substitute clinical
trials for acute hemorrhage would benefit recipients."
       At a meeting in March 1990, members of FDA's Blood Products
Advisory Committee expressed concerns about reports of severe,
unexplained toxicity of artificial red cell oxygen carriers in
patients in clinical trials.
       Fratantoni and other CBER experts evaluated the committee's
recommendations, as well as animal and human studies of the
preparations. In the May 1991 issue of Transfusion, FDA published
"points to consider" for researchers investigating red cell oxygen
carriers. In evaluating risks and benefits of the carriers, the
agency recommended "consideration of, and comparison with, the
safety profile of approved oxygen carriers, such as red cells
[derived from the public blood supply]."
       No one knows for sure whether researchers will ever develop an
"ideal" artificial oxygen carrier as an alternative to homologous
transfusion. But promising possibilities are on the drawing board,
and FDA is monitoring those possibilities.
       Meanwhile, working alternatives continue in the operating room
and the pharmacy. n

Dixie Farley is a staff writer for FDA Consumer.
The Real Scoop on AIDS and Shortages
       Two concerns about blood transfusion get a lot of news
coverage: AIDS and shortages.
       The American blood supply is reasonably safe, and patients who
need blood can accept it with confidence, according to Food and Drug
Administration experts. But this doesn't mean that blood is entirely
risk-free. Blood is human tissue, a biological product, so it
carries a degree of risk.
       Estimates of the risk of infection with HIV, the virus
responsible for AIDS, range from 1 in 61,000 to 1 in 225,000
transfused units--or potentially 90 to 300 infections among some 18
million blood products used each year. The risk from transfusion,
however, is far less than the risk of not getting blood when it's
needed.
       FDA's job is to enforce safeguards, such as questioning
potential donors about risk behaviors, testing their blood for
infection, quarantining donated blood until tests show it to be
safe, and monitoring the blood banking system. Recent steps by FDA
to help make the blood supply safer include:
œ      informing firms making computer software intended for blood
product manufacture that the software programs are medical devices
œ      obtaining a consent degree placing the American Red Cross under
court supervision to strengthen its quality control procedures
œ      proposing guidelines to help prevent recurrent blood center
problems by eliminating causes of errors, ensuring integrity of test
results, establishing effective controls for manufacture and
recordkeeping, and ensuring adequate employee training
œ      proposing a rule, in conjunction with a Health Care Financing
Administration rule, calling for blood centers to provide donor test
results to hospitals so that patients who receive units can be
notified if the donors later test positive for HIV antibodies.
       In other words, FDA regulates blood banking much as it does
manufacturers. Blood banks must meet quality control requirements
comparable to those of the pharmaceutical industry and must ensure
the safety of their commodities.
       As for shortages, the blood supply has its ups and downs, like
any commodity, but this fluctuation does not mean there's not enough
blood for transfusions, says Joseph Fratantoni, M.D., director of
hematology at FDA's Center for Biologics Evaluation and Research,
which regulates blood banks and blood products. "It's a relative
shortage," he says. Last winter, for instance, some 40 U.S. cities
reported blood shortages. Contributing circumstances included the
Los Angeles earthquake, a severe influenza season, and extremely
cold weather over an extended period.
       At any one time, Fratantoni says, only 4 to 5 percent of the
U.S. population is donating all the blood, with 8 million volunteers
donating 12 million units each year. About 20 to 25 percent of
Americans, when interviewed, say they want no part of giving blood,
he says. Of the rest, a significant percentage are unable to donate
because they're anemic--mostly reproductive-age women--leaving about
40 to 50 percent of the total population eligible to donate. n
 
--D.F.
Approved Alternatives
       A number of approved drugs and biologicals can lessen the need
for or serve as alternatives to blood transfusion:
œ      Kogenate and Recombinate (recombinant factor VIII)--prevent or
control bleeding in patients with hemophilia A and prevent bleeding
associated with surgery.
œ      Amicar (aminocaproic acid)--stabilizes clotting to control
urinary tract bleeding and bleeding related to heart surgery, lung
or cervical cancer, and other conditions.
œ      Cyklokapron (tranexamic acid)--controls bleeding in hemophilia
and reduces the need for factor VIII replacement after tooth
extraction; it is for short-term use (two to eight days).
œ      DDAVP Injection (desmopressin)--increases clotting factor VIII
to control bleeding in patients with mild to moderate von Willebrand
disease (a bleeding disorder) or hemophilia A, and prevents bleeding
associated with surgery.
œ      Trasylol Injection (aprotinin)--decreases the need for
transfusion in patients undergoing coronary artery bypass surgery.
œ      Epogen and Procrit (epoetin alfa)--stimulate red blood cell
production in patients with anemia related to chronic kidney
failure, taking Retrovir (zidovudine) for HIV infection, or
receiving cancer chemotherapy.
œ      Leukine and Prokine (sargramostim)--stimulate the bone marrow,
where blood cells form, to produce white blood cells; they are used
in patients with non-Hodgkin's lymphoma, Hodgkin's disease, and
acute lymphoblastic leukemia.
œ      Neupogen (filgrastim)--stimulates white blood cell production
in cancer patients undergoing chemotherapy. 
--D.F.