The Basis of Therapeutic Phlebotomy (TP).
Hereditary hemochromatosis (HH), a common autosomal recessive
disorder of Caucasians, is characterized by iron absorption in
homozygotes wich is inappropriately great for the body iron
content, and, in may subjects, is typified by progressive iron
deposition in the liver, pancreas, heart, and other organs. TP,
the first successful therapy for iron overload due to HH, is used
to reduce body iron stores to minimal levels, and to maintain
this state of iron balance for a lifetime. TP works by removing
red blood cells which are rich in iron (200-250 mg of iron per
unit of blood; 1 unit = 450-500 ml = "1 pint"). With TP,
asymptomatic HH subjects can avoid irreversible tissue injury,
and other patients can minimize the progression of symptomatic
iron overload. Most HH patients are candidates for TP therapy,
regardless of age, although a few, e.g., those with advanced
hepatic cirrhosis and portal hypertension, may not tolerate TP
well enough to permit "de-ironing". Despite attempts to develop
more elegant strategies to remove iron from the body, TP is still
the most effective, economical, and safe treatment known for iron
overload due to HH. The degree of iron overload is assessed by
measurement of the serum ferritin concentrations ([Ftn•)
and by analysis of the liver biopsy specimen for iron. In
practical terms, HH subjects with serum [Ftn] > 50 ng/ml
or with increased liver iron content need TP.
The Rate of TP.
Initial "de-ironing" therapy may require many months in some
cases, a few in others. Regardless of the degree of iron
overload, however, the "de-ironing" must be accomplished as soon
a feasible (preferably within 1 year). Typically, one unit of
blood is removed weekly. Some individuals, especially males and
those with larger body mass, tolerate the removal of two units
per week. Many females, smaller persons, the elderly, and those
with co-existing anemia or heart or pulmonary problems tolerate
the removal of only 0.5 units/week. After a few units of initial
TP, the bone marrow produces new red blood cells at a greater
rate, permitting more blood to be removed more frequently. In
unusual cases, stimulation of the developing red blood cells in
the bone marrow by the hormone erythropoietin (taken by regular
injection) facilitates the recovery of the red blood cells after
TP. However, this is expensive therapy and is unnecessary for
most patients . The red blood cells should be measured
immediately before each TP (hemoglobin concentration =
[Hb]; hematocrit = Hct). As a general rule, subjects
undergoing TP whose values of [Hb] and Hct are less
than 11.0 g/dL and 33%, respectively , are more likely to sustain
undue fatigue and other immediate consequences of excessive blood
removal and anemia. Further, TP is less effective in removing
iron in these patients because of the reduced red blood cell
content of the blood.
Helpful Hints about Blood Removal by TP.
TP should be performed by experienced medical, nurcing, or
laboratory personnel, preferably under the direct supervision of
the responsible physician. Hospitalization is rarely necessary.
Patients should prepare themselves by being well-hydrated prior
to TP, and planning their post-TP schedule to minimize vigorous
psysical activity for 24 hours after TP. Blood should be removed
using a 19- or 21-gauge needle ("butterfly"); a single
venipuncture should suffice for [Hb] and Hct
measurements and TP. Smaller needles are more comfortable for
patients and preserve venous access better than the use of larger
bore needles, and separate venipunctures for these [Hb]
and Hct measurements and TP are unnecessary. Some persons with
smaller veins have fewer problems with clotting in the TP needle
when 1-2 asperin tablets are taken twice weekly. Occasionally,
an indwelling venous access device for TP is necessary because
of insufficient peripheral venous access. A written record of the
[Hb] and the Hct values and volume (or weight) of blood
removed with each TP session should maintained as part of the
medical record. This permits quantification of the total amount
of iron removed by TP.
Measuring and Maintaining Success of TP.
No formula accurately predicts the amount of TP necessary to
achieve iron depletion. The progress of TP is monitored by
periodic assessment of [Hb] and Hct values and their
recovery rate, the size (MCV) of red blood cells, and the serum
[Ftn]. Initial "de-ironing" should reduce the serum
[Ftn]to < 20 ng/ml. Maintenance TP should be performed at
intervals thereafter to maintain the serum [Ftn] < 50 ng/ml.
Medicinal iron supplements should be avoided, but major dietary
changes intended to minimize or avoid ingested iron are not
usually necessary. Many patients and physicians monitor the serum
iron concentration and transferrin saturation values after the
the diagnosis of HH is established. These are not helpful
indices of remaining iron stores, although the serum iron
concentrations become normal and transferrin saturation values
fall < 60% in many patients adequately treated with TP.
Sustaining overt iron deficiency by excessive TP is not
warrented.
The Benefits of TP.
The benefits of TP appear at various times in different subjects.
Many patients with weakness and fatigue notice almost immediate
alleviation of their symptoms early in the treatment course. Others
do not regain their normal energy levels and sense of well-being
for many weeks after "de-ironing" therapy is complete. Elevated
hepatic enzymes levels, hepatomegaly, and right upper quadrant
pain often take many months after "de-ironing" to resolve.
Failure for this to occur should prompt an investigation for
alternative explanations for the abnormal clinical findings. In
patients with hepatic cirrhosis, TP has no apparent effect on the
risk of developing primary liver cancer. Patients with
arthralgias and minimal findings of arthropathy often improve
with TP. The pain and progression of more severe arthropathy may
be slowed by TP, but significant improvement in join function and
deformity is uncommon. Occasional patients have exacerbation of
joint pain during TP which resolves with iron depletion. Diabetes
mellitus and other endocrinopathies are unlikely to improve
greatly with TP, although hypogonadism of relatively recent onset
sometimes abates with TP. Cardiac complications due to iron
deposition in heart muskle or in the cardiac conducting systen
often improve dramatically with aggressive TP. However, coronary
artery disease is a common accompaniment of cardiac abnormalities
in older patients and is unaffected by TP. The dark skin
discoloration of iron overload gradually fades as "de-ironing"
with TP nears completion. TP is never a substitute for
appropriate management of hepatic cirrhosis or other liver
disease, diabetes mellitus and other endocrine abnormalities,
arthropathy, and cardiac abnormalities. Altogether, patients
without hepatic cirrhosis or diabetes mellitus who undergo and
maintain iron depletion by TP have a statistically normal life
expectancy. Recent evidence suggests that HH subjects diagnosed
early in life and treated with TP for health maintenance could
experience a decreased rate and/or severity of coronary artery
atherosclerosis and/or malignancy, although this is unproven.
Even in patients with hepatic cirrhosis or diabetes mellitus, TP
significantly improves the quality of life in many patients, and
may yield some longevity benefits.
Disposal of TP blood
The disposal of blood removed by TP concerns many HH patients and
health care personnel, and many believe that most, if not all,
of this blood is suitable for transfusion. Because approximately
1 in 200 apparently healthy individuals who volunteer as blood
donors (unknowingly) have HH, it is known that blood from HH
subjects is being used for transfusion on a regular basis.
Further, blood banking statutes and practice sometimes coincide
with HH experts such that selected HH patients can donate their
TP blood to the community blood supply. However, maintaining a
high quality of blood for transfusion causes the rejection of
many donors: those beyond certain age limits (usually < 18 years
and > 60 years), those with diabetes mellitus, elevated hepatic
enzyme concentrations, cardiac disorders, excess ethanol intake,
or viral hepatitis, those using certain medications, and those
who have donated blood (or been treated by TP) within 6 weeks.
Some HH patients are geographically situated such that
utilization of their TP blood for transfusion is not possible.
Most blood procurement organisations do not deliver therapy (TP,
in this case), and do not have adequate resources to monitor TP
(and other) treatments required by many HH patients). Thus,
diverse factors commonly encountered in HH exclude many patients
from being transfusion donors. Alternatively, HH blood obtained
by TP can sometimes be used for medical research projects.
However, it is mandatory that approval of such projects be
obtained through institutional review boards for human use, that
donors be adequately informed of the anticipated use of their
blood and the possible consequences of the research, and that the
research outcomes not be prejudiced by possible differences in
the blood of HH subjects and otherwise normal individuals
(especially with regard to studies involving human leukocyte
antigen (HLA) immunophenotypes of DNA). TP blood not suitable for
the above purposes must be discarded according to current
regulations for body fluids and other medical waste.