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Sickle Cell Vascular Disease Section
Gregory J. Kato, MD, Staff
Clinician
Our section investigates mechanisms of vascular occlusion in sickle cell disease, an inherited disorder of
red blood cells occurring predominantly in people of African descent, and less frequently in people of Arabic
or Indian descent. We are particularly focused on disease of the blood vessel wall occurring in sickle cell
disease, producing pulmonary hypertension, linked to early mortality in these patients. Research from our
group and others has strongly suggested that this sickle cell vasculopathy is associated with pulmonary
hypertension, cutaneous leg ulceration, and priapism, a painful, persistent penile erection. Ongoing
research is investigating whether chronic renal disease, ischemic stroke and other chronic complications
of sickle cell disease are also consequences of sickle cell vasculopathy. Our branch has been integral
in developing a scientific model to explain the development of this vasculopathy. Sickle cells are prone
to become rigid and elongated and occlude capillaries episodically, termed vaso-occlusive crisis. However,
they are also prone to prematurely break down, called hemolysis.
The breakdown products of blood cells appear to be the principal cause of sickle cell vasculopathy.
Hemoglobin released into blood plasma from red blood cells inactivates nitric oxide, a key regulator of
blood vessel health. Arginase is also released from hemolyzed red cells into blood plasma, where it
depletes the level of the amino acid L-arginine, the required substrate for nitric oxide production by
the nitric oxide synthase family of enzymes. In this way, hemolysis both reduces nitric oxide production
and accelerates its destruction. Other groups have also indicated that nitric oxide destruction may be
further hastened by high levels of reactive oxygen species in patients with sickle cell disease. All of
these and other aspects of hemolysis, including abnormalities of the red cell membrane, also may induce
excessive activation of the blood clotting system in patients with sickle cell disease.
Our group is focused on clinical investigation in patients with sickle cell disease. This research is
conducted in three major pathways. The first involves measurement of blood flow patterns in the forearm
of patients and healthy volunteers, using a technique called venous occlusion strain gauge plethysmography.
The second involves measurement of blood metabolites in patients with sickle cell disease, at steady state,
during vaso-occlusive crisis, and during forearm blood flow studies, to gather information regarding the
biochemical correlates of sickle cell vasculopathy. We also study blood proteins using proteomic techniques,
particularly high throughput mass spectroscopy, in order to discover new pathways and markers of sickle cell
vasculopathy. This has already been successful in identifying apolipoproteins dysregulated in sickle cell
pulmonary hypertension. Our third pathway involves clinical trial of drugs are promising for improving blood
flow in patients with sickle cell disease.
Similar patterns of vasculopathy occur in other diseases featuring high levels of intravascular hemolysis,
particularly thalassemia intermedia and major, hereditary spherocytosis and paroxysmal nocturnal
hemoglobinuria (PNH). Our group is working with other collaborators to determine whether the nitric oxide
pathway is disturbed as it is in sickle cell disease.
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