Title:
Adverse Outcomes in Sickle Cell Anemia in Brazil
Heloisa Helena Arantes Gallo da Rocha*
E mail: heloisag@ism.com.br
·
Hematologist from Serviço de Hemoterapia do Hospital dos Servidores do Estado do Rio
de Janeiro
·
Technical Counselor and Foundation of “Associação dos Falcêmicos do
·
Fellow of International Society of
Hematology
·
Member of American Society of Hematology
·
Member of Sociedade Brasileira de Hematologia e
Hemoterapia
·
Member of Colégio Brasileiro de Hematologia
Area: Hematology
Abstract:
The author does an analytical study of the Brazilian patients with sickle
cell disease (SCD). She makes a
comparison between the data with those described by Miller. She concludes that:
1)-The most common bad outcome variable is repetitive painful episode- more
than twice a year needing Medical care
2) - The hemoglobin level of
Brazilian- SCD patients is lower than
those from Miller’s study. (Both obtained from
steady state. patients)
3) There was no difference statistically significant between the levels of
hemoglobin in those SCD patients with or without bad prognosis variants (p=
NS)
4) The survival time was shorter in patients presenting
systematically low levels of hemoglobin (lessen than 7 g/dl).
5) The patients who presented dactylites before their first
anniversary had repetitive painful
crisis in their childhood and adulthood life. If these people are left to their
own natural history the survival time will be shorter than the patients who do not
have these complaints.
5) Children with platelets levels higher than 500 000/mm3 probably will have acute spleen
sequestration syndrome.
6) We noticed that SCD patients who
had strokes had more repetitive painful crises (61%) and Thrombocytosis (38, 4%).
7) The SC P who presented repetitive painful crises probably will have
higher levels of platelets counts or vice- versa.
8) The high reticulocyte counts in SCD patients (> 10%) in steady state
clinical situation is consistent with low survival time.
9) - The worse prognosis variables the sickle cell
patients have the shorter is their survival.
Keywords; sickle cell disease,
prognosis.
Introduction
The sickle cell anemia (SCA)
is a hereditary hemolytic anemia. The
polymerization of hemoglobin S (HbS) in the deoxygenated state in sickle cell
disease (SCD) is the watershed event leading to vase- occlusion, factors that
retard the transit time of sickle erythrocytes in the microcirculation and the
cell’s adhesive properties. The change in shape is responsible for the
enhancing of adhesion in endothelial cells and vase occlusion impeding the
blood flux to tissues (1) .The vascular occlusion is the result of a fall in
oxygen tension in cells presenting a major density (2). The researches in
electronic microscopy had been shown that the irreversible sickle cells does
not have almost anything of polymerized hemoglobin and so still retains the
sickle shape. The sickle shape occurs because the protein fixation in membrane
cytoskeleton and they must not be responsible for the irreversibility shape of
sickle cell. (3). these processes are dependent of sickle hemoglobin concentration.
Thus, the occurrence of dense, dehydrated, take a deleterious effect in sickle
cell process. (4)
In the afro descendant
population of
In the white population we
have 3% of positivity for sickle cell trait (5).
In SCD, besides the chronic
anemia some major complications of the disease itself include acute thoracic
syndrome (AST), stroke, spleen and kidney dysfunction, painful crisis and
priapism. The children with SCD are more susceptible to present bacterial infection
(6).
35% of SCD patients
have coexisting alpha thalassemia, beta thalassemia, hemoglobin C resulting in
clinically significant differences (5).
In order to understand the
pathophysiology of SCD it is necessary to consider the basic information about
the hemoglobin structure and genetic control.
The importance of the intracellular
hemoglobin S (HbS) , cell- cell interactions, high shear rates by red
cell deformability , and the vase-
occlusion and the ischemia effect in tissues(7). Last decade we
had many studies about situations that could influence the prognostic and
survival of patients with SCD. (8,9,10).Garner ( 11) et al (apud Garner) concluded that the variation in the proportion of fetal
cells (FC), leukocytes, platelets and red blood cell are genetically
determined. The combinations of common gens are the causes of bad prognosis
features in SCD. (11)
Miller et al (10) studied
prospectively 392 children with SCD (SS) or S Thalassemia Beta zero before 6
months of age until 10 years of age. He did laboratories and clinical studies
in order to evaluate those symptoms and signs that could be predictive of a bad
outcome.
Another retrospective study was done in Brazilians
sickle cell patients (SS) in order to compare with the Miller data and compare
the results with those of Miller. This study would classify Brazilian patients
with SCD into bad or not bad prognosis. Those with bad prognosis would be
matter of discussion about the medical strategies to be followed with them. So,
the objective of this work is to get to know the clinical or laboratories
variables that would indicate that patients with SCD would have a bad outcome.
Methods:
Characteristics of the patients: patients presenting SCD registered in
Instituto Estadual de Hematologia/
Clinical Events and
Laboratory Methods:
Hemoglobin typing was performed at Instituto de
Hematologia with the use of cellulose acetate and citrate agar electrophoresis
and alkali denaturation (for the measurement of fetal hemoglobin) (12).
Hemoglobin mean levels; platelet counts; reticulocyte counts; acute splenic
sequestration; strokes; dactylitis ;
painful crisis .
Definition of Clinical Events: Stroke was defined as an
acute neurologic syndrome due to vascular occlusion or hemorrhage in which
neurologic symptoms or signs lasted more than 24 hours. Transient ischemic
attacks and silent infarctions were not included. A painful event was defined
as pain in arms and/or legs, back, abdomen, chest or head that lasted at least
two hours, led to request for medical care
and was attributable to sickle cell disease .Dactylitis , the acute
chest syndrome, the right upper quadrant syndrome, osteomyelitis and
apendicitis were not counted as painful crisis.
Dactylitis was defined as pain and tenderness, with or
without swelling, in the hands, feet, or both. Acute splenic sequestration was
defined as a decrease from base line in the hemoglobin level or hematocrit of
at least 20 percent plus a simultaneous increase in the size of spleen to at
least 2 cm below the left costal margin.
Adverse Events:
The adverse events served as proxies for severe sickle
cell disease:
Adverse Event 1: Hemoglobin levels (hb) less than 7g/dL
(in steady – state of the disease)
Adverse Event 2: The steady state platelet count higher
than 5000.000/mm3.
Adverse Event 3: Splenic Sequestration before one year
of age.
Adverse Event 4: Stroke
Adverse Event 5: Dactylitis in patients with less than 2 years age.
Adverse Event 6: Painful crisis two or more times per
year, needing medical care.
Adverse event 7: Reticulocyte count higher than 10% (in
steady state)
Statistical Analysis:
Means or median (for nonnormal sample
distribution) +/- SD were calculated when appropriate.
In order to identify the patients at
highest risk for severe disease, we adopted
the identicators of Miller et al (11)
The paired Student t test was applied
to compare the values of the group with or without bad prognosis (according to
Miller variables of bad prognosis). P values =/< 0.05 where considered
significants.
Comparison between groups was done by
analysis of variance (ANOVA).
Correlation Coefficient.
The steady state hemoglobin level were based on measurements obtained during a
median of three visits, and the steady state platelet count was based on
measurements, obtained during a median of two visits. All means laboratory
values were first examined as continuous covariates to explore potential linear
and nonlinear relations. In order to identify the patients at highest risk for
severe disease, we used the Miller’s indicator’s.
Results:
Characteristics of the Patients:
Of the 279 patients enrolled in the study, 177 (63%) had
adverse outcomes that qualified their disease as severe. In this group the
median duration of follow up was 10.2 +/- 7.6 years. 60% of the patients in the group of severe disease were girls.
The most common adverse event that resulted in the classification of the
disease as severe was the repetitive painful crisis (37%) (Table I)
Table I – characteristics of bad outcome registered in 279 patients (some with more
than one characteristics)
Group |
No of Patients |
Percentage |
N
=
304 |
100
% |
|
Platelets
count > 500 (x 10- 3 /
mmm 3) |
46 |
15% |
Stroke |
15 |
5% |
Dactylitis
in patients with less than 2 years of
ages |
26 |
8.5% |
Acute
splenic sequestration |
26 |
8.5% |
Painful
events >2/yr |
112 |
37% |
Hemoglobin
level <7 g/dl |
31 |
10% |
Reticulocytes
>10 % |
48 |
16% |
Variable I:
Hemoglobin levels < 7 g/dl
The mean steady state hemoglobin level for the
entire cohort was 7,5 g/dl. The steady state hemoglobin level was the mean
value obtained during 3 routine visits.
The multivariate analysis included three variables that were significantly
associated with na adverse clinical course: early dactylitis, repetitive
painful crisis and stroke, there were no significant interactions between them when we talk about hemoglobin
levels less than 7 g/dl. (table II)
Table II: Mean
Hemoglobin Levels in Patients with Miller’s Severe Sickle Cell Disease.
Group |
No of patients |
Mean
hemoglobin Level |
|
Stroke |
15 |
7,13 |
|
Repetitive
painful crisis |
58 |
7,74 |
|
Dactylitis
presenting in SC patients with less than two years of age. |
17 |
7,35 |
|
P Value |
|
||
0,2563 NS |
|
||
Age at death in patients with mean hemoglobin levels
< 7g/dl was 17, 6 years
Age of death in patients with mean hemoglobin levels
> 7g/dl was 34 years. One tail p: 0, 05 (significant)
Variable 2-
Thrombocytosis:
The statistic analysis of the patients with sickle cell
disease who presented platelets counts higher than 500.000/mm3 with
or without repetitive painful crisis did not showed any difference. (Pair T
analysis –P value=NS. So, the higher number of platelet did not influence the
painful events .in our population. (Table I)
The higher platelet counts is a risk factor for the
occurrence of acute splenic sequestration.
Variable 3:
Acute splenic sequestration :
The SC patients
that presents acute splenic sequestration have higher platelets count than
those who did not presented the acute splenic sequestration ( p≤0.05 ).
Variable 4
Stroke:
15 patients had stroke. From these 15 patients we just
could study 13 patients.
These 13 patients age, varied from
9/13 patients (70%) presented stroke with less or equal
12 years old (mean: 6, 5 yrs).Still in this group, 5 patients (55%) died with
an average age of 16, 6 years. From 13 patients who presented stroke, 5 died
(38%)
Four (4) patients presented stroke with ages higher than
28 years (average: 38, 2 years) .None died. (Table III).
The patients who presented stroke presented repetitive
painful crisis and dactylitis before two years of age (Table IV)
Table III: Prevalence of stroke in different ages:
Age ≤ 6years |
38% |
Age ≤ 15years |
69% |
Age ≥ 40 years |
23% |
Table IV: Univariate
analysis of the Risk of Severe Sickle Cell Disease:
Dactylitis: |
30,7% (4/13) |
Repetitive Painful
Crisis |
61,5% (8/13) |
Hemoglobin levels < 7 g/dl |
15,3% (2/13) |
Count Platelets
> 500( X 10 -3 /mm3) |
38,4% (5/13) |
VARIABLE 5:
Dactylitis:
The patients who presented dactylitis before the age of
two years old also presented hemoglobin level (g/dl) < 7 when compared with
the group of patients with SCD who did not presented dactylitis (p = 0,03).
The patients with repetitive painful crisis (> two
times /yr, with admittance in Unit Emergency), had also dactylitis before the
age of two years)- p value: 0,04.
The patients who presented early dactylitis had a
survival age minor (16 years old) than the people that did not presented dactylitis
(26years old) (p: 0, 05).
The patients, who presented dactylitis before the age of
one year, came to the first medical consultation and admittance at hospital
early than the group that did not presented this event. (p = 0, 05).
In the group of patients who presented stroke, 30% also
presented early dactylitis.
Table VII
Comparison between patients with or without
early dactylitis presenting count platelets> 500 (X 10-3/mm
3) (T test paired) : |
|||
|
Platelets<500(x10-3/mm3) |
Platelets>500(x10-3/mm3)
|
|
Average |
442,583 |
545,483 |
|
P(T<=t) bi-tailoredl |
0,389122 |
|
|
Critical T bi-tailored |
3,182449 |
P= NS |
|
The platelets count higher 500(x10-3/mm3) did not influenced the
occurrence of dactylitis.
Variable: 6
Repetitive Painful Crisis:
When one compares the
group of patients who presented
repetitive painful crisis with the group of patients who did not
presented it and make a correlation of both group, with the platelet counts
higher than 500(x10-3/mm3
)the T test of Student results in a p
value significant in one tail, showing that there is a bias
When one compares the group that presented repetitive painful crisis with the group that
did not presented it there is a bias the firs group to have a shorter survival
time( 24,2 years old) . P=NS
The patients with hemoglobin levels < 7 g/dl
compared with the group with hemoglobin levels > 7g/dl, when analyzed
with the variable dactylitis before the
age of one year, the statistical study
was not significant ( p value= NS)
Variable
7:
Reticulocytes count > 10 %:
The Regression Curve (regression
analysis) demonstrated a relationship between the higher number of reticulocytes
and shorter survival time.
When we compared
the age of death in the group of patients that presented reticulocyte higher
than 10% with the patients who presented reticulocyte counts less than 10% percent, we observed that both statistical analysis: T paired
study and Regression Analysis showed us
a linear enhancement in death occurrence according to reticulocyte
count elevation. (p= 0, 01)
It was done a comparative study of death occurrence in SC patients that presented more bad outcome
variables ( 1, 2, 3, 4 e 5 ); The age of death was lower in SC patients with
two bad outcome variables in comparison
with those patients that presented only one bad outcome variable, but in T student test it was not statistically
significant.
When we compared SC patients presenting one or three bad
outcome variables the p value was 0, 08, putting altogether there are a bias
.The age group average was different between these patients. The age at death
in those patients that presented one bad outcome variable was 21 years of age;
the age at death in those patients that presented two bad outcome variables
was: 19 years; the age at death in those patients that presented three
variables was 13 years old. With a bigger number of patients we think that it
will be statistically significant, meaning that:
The more the numbers of bad outcome variables, earlier
will be the death.
Also, according to Graphic Regression II, the more the
number of bad outcome variables in patients with SCD the greater probability of
early death
From 13 patients that presented stroke, 5 died. (38%)
Table VIII- Deaths and ages of whole group of SC patients:
Group |
Number (%) |
Average (yrs) |
death<10 years |
8 (8.5%) |
6,8 |
death>10 years |
16(16%) |
14,8 |
death>20 years |
72(75.5%) |
38,3 |
Discussion:
In this observational study of patients with sickle cell
anemia, we found that repetitive painful crisis as the most common of bad
outcome variables (37%).
There was association between early dactylites and
repetitive painful crisis. So there is a correlation of early dactylites
(before one year of age) and sever disease, in accordance with the Miller’s
population. The clinical importance of this fact is that when we, hematologists
meet a child with SC anemia with early dactylites we must go on and become worry
about the future of this child for he probably will present painful crisis in
infancy and adolescence. At the moment we have this insight, we are oblige to
act in order to give a better life quality for him/her. We will have to use
Hidroxiurea or EACA inhibitors or what else appear not to permit the pain to
become a constant in him/her life. We know that in
Hydroxyurea stimulates the production of fetal cells
within the red blood cells.
The intracellular
polymerization of sickle hemoglobin is the most important determinant of
clinical and biological manifestations of sickle cell anemia. The fetal
hemoglobin at this point has the most important role. (2). When there is fetal hemoglobin there is
no production of S polymers and its intracellular expression in sickle cells
inhibit the polymerization.
The homozygous state of SC
anemia from Saudi Arabian is clinically
milder for they have higher levels of fetal because there is a gene mutation in
globinic beta chain in 11 chromosome.(5)
Hereditary persistence of
fetal hemoglobin (HPFH) is the name given to a group of conditions
characterized by persistence of fetal hemoglobin synthesis into adult life in
the absence of significant hematological manifestations. This state has much in
common with b and d b thalassemias.
There are different forms of HPFH. When the heterozygous state combines with
hemoglobin S, there are usually no anemia and little evidence of because of the
uniformly high level of HbF per cell that renders the interaction with HPFH and
HbS so mild. This is an important observation because it provides valuable
insights into the level of HbF in each red cell that would be required to
control sickle cell anemia by pharmacological stimulation of HbF synthesis (9).
The level of HbF varies between 15 and 42%. The mean level of HbF is about 29%.
A high level of HbF in SCD
correlates with increased life expectancy and a decrease in the incidence of vase-
occlusive crises. HbF levels at birth vary between 60 and 80 per cent and are
similar in newborns with SS disease and in matched AA controls. The rate of
fall in HbF after birth is slower in SS disease compared to AA controls. As the
HbF falls start the symptoms of the disease fatigue, pallor, jaundice and
dactylitis (13) .An analysis of 105 patients with SCD found that the average in
HbF in each group is higher than in general population. The age group
correspondent to 0 to 5 years old the levels of HbF are the highest (mean: 13, 8%
and 12, 3%). At older ages the levels fell. In those patients with ages between
30 and 40 years old HbF increased up (mean: 8, 45%). Over the age of 40 years
no trends was apparent with a HbF mean of 3, 13.
The leukocytes levels, mainly if there are also a
monocytosis must be considered in ambulatory patients because they are related
to a severe disease. The monocytes must be respected because of their action in
conjunction with endothelial cells playing an important role in stroke and in
painful crises (3).
As Miller, we did not observed correlation in the
platelet number and painful crises.
We could not compare the clinical and laboratorial
features of acute chest syndrome in Brazilian SCD patients, but they are very
common and sometimes worse or even began with the use of Tramadol, and the
author related three cases of patients that began with painful crises, went to
Emergency Room and the medical in charge prescribed Tramadol and all of them
developed an acute chest syndrome, one of the patients died.
CONCLUSION:
The hemoglobin level of our population was 7.5 g/dl, while
in the Miller’s was 8.1g/dl
We found correlation
between the platelet counts higher than 500 000 /mm3 and acute
spleen sequestration P< 0, 05.
70% of SC patients had stroke at ages equal or
less than 12years. 55% of SC patients who presented stroke died (mean age: 16
years). 23% of SC patients presented stroke after 40 years old. None died.
The patients who
presented early dactylitis had a decrease in survival time. (16 years old was the average death age of this
group).
It was not found correlation
between platelets count higher than 500 000/mm3 and dactylitis p: NS
In the patients who presented
repetitive painful crises, we observed a positive correlation with higher
platelet counts in one tail. (Miller compared with platelet counts higher than
400 000/mm3)
It was not observed that the patients who presented repetitive painful
crises had a lower survival time. This fact is in accordance with Miller’s
study.
The regression graphic and the T
paired test were consistent with: the
higher the reticulocyte counts is, the decreased is, the survival time. This
statement is discordant with Miller’s wok.
Miller described that the
probability of interactions of more than one bad outcome variables is important
for us to begin a therapeutic strategy for in those cases the survival time is
decreased. The regression curve of our patients also showed in agreement with
this statement.
According Miller the most
important bad outcome variables were: dactylitis before the first birthday; Hb<7g/dl; acute spleen sequestration;
leukocytes counts constantly elevated; STA.
In the Brazilian patients the most important bad outcomes variables were:
stroke; dactylitis before the first birthday and the percentile of reticulocyte
constantly higher than 10%. The platelet count higher than 500 000 /mm3
was correlated with the acute splenic sequestration event.
The bad outcome variables leukocytes
counts high and acute chest syndrome was not available for us to study.
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