H e m a t o lo g y E d u c a t io n - European Hematology Association

protein, cytokines, and soluble adhesion molecules like
ICAM-1, VCAM-1, and E-selectin. 30-31 Taken together, it
is clear that SCA features widespread and chronic
inflammation that affects circulating cellular elements,
cellular-derived microparticles, and soluble plasma factors
that collectively promote vaso-occlusion and
endothelial damage.
An additional characteristic feature of SCA that is
likely important in vaso-occlusion and organ damage,
but relatively poorly understood at this time, is the
hypercoagulable state. 32 A variety of factors could contributes
to hypercoagulability in SCA, including functional
asplenia, reticulocytes and erythrocytes that
express adhesion molecules and exposed surface phosphatidylserine,
increased numbers of WBC that express
increased adhesion markers, activated platelets, 30,33
chronic inflammation, and elevated levels of plasma
clotting proteins. 34-35 Owing to a combination of these
abnormalities, the coagulation system in SCA is clearly
tilted toward the procoagulant state. Whether or not
this hypercoagulability initiates cell-endothelial contacts
remains unclear, but almost certainly it promotes
and propagates the pathophysiology of vaso-occlusion.
It should be noted, however, that patients with SCA do
not develop deep venous thrombosis or other common
manifestations of a hypercoagulable state.
Finally, the contributions of products of hemolysis
toward vaso-occlusion must be considered in the unique
setting of SCA. Sickled erythrocytes are fragile, and
about one-third of the overall hemolysis in SCA occurs
in the intravascular compartment. 36 Considerable effort
has been directed toward promoting the hypothesis that
this intravascular hemolysis, measured specifically by
elevated levels of plasma hemoglobin but more often by
lactate dehydrogenase (LDH), is itself a direct and critical
etiologic factor of vascular endothelial damage in SCA
through consumption of nitric oxide, with substantial
clinical consequences, including stroke, leg ulcers, pulmonary
hypertension, and early mortality. 37-38 However,
the merits of these arguments have been recently questioned
with regard to their scientific rigor and accuracy. 39-
40 Indeed, many other hematological disorders include
intravascular hemolysis with similarly elevated levels of
LDH (or higher), yet none features the clinical spectrum
of SCA. The most likely answer to this apparent paradox
is that no other medical condition features intravascular
hemolysis so prominently in the setting of generalized
inflammation, hypercoagulability, and endothelial dysfunction;
39 hence hemolysis per se is not the etiology of
the vasculopathy in SCA but merely a participant.
Another alternative explanation regarding hemolysisbased
pathophysiology warranting further experimental
testing is the possibility that some elevated serum LDH
in SCA actually derives from damaged and/or circulating
endothelial cells rather than just from erythrocytes; if
proven, this observation would suggest that elevated
LDH reflects an “effect” rather than a “cause” of the
endothelial damage in SCA. Additional possibilities
should be explored as well, including the recent proposal
that hemolysis-derived pathophysiological characteristics
of SCA, such as excessive plasma heme, also contribute
to blood cell and endothelial damage. 40-41
In this complex environment, the process of small
vessel vaso-occlusion in SCA thus begins initially with
repeated erythrocyte sickling and adhesion-mediated
vessel blockage, but over time develops into a unique
vasculopathy characterized by activated circulating
blood cells, including erythrocytes, reticulocytes, neutrophils,
monocytes, platelets, and even endothelial
cells. These sticky cells are then coupled with soluble
plasma mediators of inflammation, coagulation, and
hemolysis, which lead to further adhesion that alters
the normal integrity of the endothelium. Perhaps in this
setting of such widespread cellular adhesion, damage,
and inflammation, the question should not be “Why do
patients with SCA have acute vaso-occlusive events?”
but instead “Why do patients with SCA not have vasoocclusive
events all the time?” since the microvascular
processes are both widespread and continuous. It
should be emphasized that vaso-occlusion is ongoing
even when not clinically recognizable.
Epidemiology
London, United Kingdom, June 9-12, 2011
Most of the data regarding the types and frequency of
acute vaso-occlusive events in SCA derive from two
large prospective studies, the Jamaican cohort and the
US multicenter Cooperative Study of Sickle Cell
Disease (CSSCD). These studies have documented that
painful events, acute chest syndrome, and stroke are frequent
clinical manifestations that lead to substantial
morbidity and mortality. 42-44 However, there is considerable
phenotypic diversity with regard to vaso-occlusive
events; most patients are affected occasionally, but a
small percentage of patients suffer from frequent and
repeated events.
In the first decade of life, pain occurs at a surprisingly
low average frequency of events per year, based on
recall of pain severe enough to warrant medical evaluation.
7 Hand-foot syndrome (dactylitis) occurs primarily
under age 2 years, while long-bone pain is more common
among older children and adults. 43,45 Acute chest
syndrome in young patients can have an infectious
component but becomes exacerbated by intrapulmonary
sickling and vaso-occlusion. 46 Stroke is perhaps
the most severe form of acute vaso-occlusion in children
with SCA, 47 featuring abrupt interruption of cerebral
blood flow, with consequent damage to both grey and
white matter.
Among teens and adults with SCA, pain remains a
serious and occasionally debilitating part of their disease.
A recent multicenter study has documented that
sickle-related pain, both acute and chronic, is typically
under-reported and diminishes quality of life. 45,48 Acute
chest syndrome from acute vaso-occlusion becomes
more frequent and more dangerous, often escalating
into a life-threatening process characterized by respiratory
distress with hypoxia, acute pulmonary hypertension,
multi-organ failure, and death. 46 Stroke occurs in
adults but is more often hemorrhagic than vaso-occlusive
in etiology. 47 In adulthood, chronic vaso-occlusion
(or repeated acute events) becomes equally as important
as the acute clinical events, with progressive damage to
the kidneys, brain, eyes, bones, and other organs that
ultimately leads to early mortality. 44
Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 325 |