Patients
with SCA/SCD exhibit an array of clinical syndromes[17,27,38]. Many patients
experience frequent bouts of debilitating painful episodes[31]. SCD is
associated with significant morbidity and mortality[31]. These painful
crises entail frequent and extended hospitalization periods[39]. As a result,
many have a generally poor quality of life. Still, while some patients can incur
fatal episodes in early childhood or adolescence, with the advent of better
treatment and/or therapies, many more individuals do survive to adulthood.
A
number of well-defined sickling syndromes have been described that involve
general patterns of expression in children and adults and/or specific tissue and
damage to organ systems. The episodic painful vaso-occlusive crisis is the
leading cause of SCD morbidity for all patients[27]. Young SCD patients display
splenomegaly (splenic sequestration)[40]. Adolescents with SCD typically suffer
from skin lesions and bone infarcts due to RBC trapping[28,29]. Cerebrovascular
accidents (CVAs) occur in children and adolescents due to ischemia or hypoxia
and result in significant neuropsychological impairment[41]. Many adults with
the disease suffer from chronic tissue and major organ damage presumably due to
obstruction by sickled cells, which accounts for most of the SCD-related
deaths[42].
Individuals
with SCD are at increased risk of death at all stages of life. During infancy,
without prophylactic intervention, infection is the primary cause of SCD
death[43-45]. Young children tend
to lose splenic function due to infarction[45], which is a major cause of
febrile (infectious) crises. The acute chest syndrome (ACS) is the major cause
of death in adolescents[44]. Pulmonary infection resulting from trapping of
sickled cells in the lung plays a major role in ACS[44]. Fatal CVAs occur in ~8%
of children[44]. Conversely, the major cause (~33%) of death in adults is
attributed to acute crises (painful vaso-occlusive episode(VOE)s
and ACS)[44]. Many of these latter ACS cases result from loss of
pulmonary functioning due to infarcts and include heart failure due to
myocardial ischemia[44]. In ~18% of adults organ (kidney) failure is the cause
of death[44]. As a consequence of these abnormalities, the mean lifespan of
treated SCD patients is markedly reduced[31,44],with the actual lifespan of the
patient varying according to the degree of severity of anemia, organ damage and
sickle cell-related complications.
The major risk factor for early SCD fatality is a high intracellular level of Hb S (and low level of HbF) in RBCs[44]. Besides the cellular Hb S level, other important factors or variables include the frequency of VOEs, and presence of renal insufficiency, ACS, CVAs, and/or high white blood cell (WBC) counts[43,44].