Doctors Francis and Filipic were thoughtful and appro-
priate in calling their contribution to our attention and to
the attention of the readers of
THE
J
OURNAL
.
JERRY A. SHIELDS, MD
CAROL L. SHIELDS, MD
NOEL PEREZ, MD
Philadelphia, Pennsylvania
The Balance Between Anemia,
Erythropoietin Treatment, and
Elevated Erythrocyte Aggregation in
Patients With Diabetic Retinopathy
and Nephropathy: A Hematologic
Point of View
EDITOR:
IN THEIR ARTICLE ON THE IMPLICATIONS OF ANEMIA AS A
risk factor for the progression of retinopathy and nephrop-
athy in diabetic patients, Sinclair and colleagues (Am J
Ophthalmol 2003;135:740 –743) suggest that treating ane-
mia with erythropoietin is beneficial in preventing the
progression of these complications. However, it is well
known that with the increase in red cell mass during
treatment, a tendency toward a thrombotic state is inevi-
table. Diabetic patients are already prone to thrombosis,
which is implicated in diabetic complications. I would like
to refer to hemorheologic factors in the pathogenesis of
diabetic complications. Blood rheology is complex and
mainly determined by variables such as blood viscosity,
hematocrit, erythrocyte aggregation (EA), and deformabil-
ity.
1,2
Hemorheologic factors, especially elevated EA,
through their effects on microcirculation, have long been
implicated in the pathogenesis of diabetic vascular com-
plications, including retinopathy and nephropathy.
3
The
exact mechanisms of elevated EA in the pathogenesis of
diabetic complications are not known. It was shown that as
EA increases local blood flow and shear rate decrease;
these events cause local acidosis and an increase in platelet
aggregation that lead to endothelial cell damage.
I would like to share our own experience in patients
with diabetic complications. In a preliminary study, we
found that EA was elevated in patients with diabetic
nephropathy compared with healthy control subjects.
4
After this observation, in a larger group of diabetic patients
both with late complications such as retinopathy and
nephropathy and without complications, we assessed EA
rates.
4
We found that EA rates in control subjects and
well-controlled, uncomplicated patients were similar de-
spite slightly higher fasting blood glucose levels in the
latter. In patients who were poorly controlled but without
complications, the EA rates were higher than in control
subjects and well-controlled, uncomplicated patients.
However, hyperglycemia may, at least in part, explain the
relatively higher EA rates in the former group. Conversely,
EA rates were found to be markedly increased in patients
with complications compared with uncomplicated patients
and control subjects despite low plasma glucose levels and
hemoglobin A
1
in well-controlled patients with complica
-
tions. Therefore, the presence of late diabetic complica-
tions seems to be associated with enhanced rates of EA
regardless of the degree of metabolic control. Furthermore,
elevated EA per se might lead to diabetic complications.
In the light of the data that elevated erythrocyte mass
may increase EA rates and that in turn, together with the
contribution of other well-defined and unidentified rea-
sons, prepares a prethrombotic state, we should be very
careful while treating anemia in patients with diabetic
complications. The balance between the beneficial effects
of increasing hemoglobin values should be well established
against the harmful effects of elevated erythrocyte mass.
HALU
ˆ
K DEMIROGLU, MD
Ankara, Turkey
REFERENCES
1. Demiroglu H, Barista I, Dundar S. Erythrocyte aggregability in
patients with coronary heart disease. Clin Hemorheol 1996;
16:313–317.
2. Demiroglu H. The importance of erythrocyte aggregation in
blood rheology: considerations on the pathophysiology of
thrombotic disorders. Blood 1997;89:4236.
3. Demiroglu H. Diabetic nephropathy. Q J Med 1997;90:493.
4. Demiroglu H, Gurlek A. Altered red blood cell rheology as a
predisposing factor for diabetic nephropathy. Nephron 1998;
79:121–122.
5. Demiroglu H, Gurlek A, Barista I. Enhanced erythrocyte
aggregation in type 2 diabetes with late complications. Exp
Clin Endocrinol Diabetes 1999;107:35–39.
AUTHOR REPLY
WE THANK DR. DEMIROGLU FOR HIS VERY APPROPRIATE
letter in response to our editorial on the treatment of
anemia and diabetic retinopathy.
Doctor Demiroglu raises the concern that treatment of
anemia with erythropoietin analogs in the diabetic patient
may potentially cause a worsening of microvascular injury
because of the increased red blood cell mass and potential
increase in erythrocyte aggregability and microvascular
whole blood viscosity. As Dr. Demiroglu points out,
microvascular flow in pathologic conditions is complex,
determined by microvascular viscosity, hematocrit, eryth-
rocyte aggregation, and more recently has been demon-
strated to be altered with leukocyte deformability. Altered
erythrocyte aggregation in the microcirculation of the
diabetic patient appears to be related to altered serum
factors such as elevated fibrinogen. Whatever the cause,
Dr. Demiroglu has discussed his own work, which demon-
strates an association between erythrocyte aggregability
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