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Arch Pediatr 2000 Mar;7(3):249-55
[Prevention of sickle cell crises with multiple phlebotomies].
[Article in French]
Bouchair N, Manigne P, Kanfer A, Raphalen P, de Montalembert M, Hagege I,
Verschuur A, Maier-Redelsperger M, Girot R
Service de pediatrie, CHU, Constantine, Algerie.
OBJECTIVES: Sickle cell disease patients suffering from frequent
painful crises were submitted to phlebotomies in order to reduce
hospitalization days due to pain, through hemoglobin (Hb) level
reduction and iron deficiency in patients with an hemoglobin level
equal to or above 9.5 g/dL. PATIENTS: Seven sickle cell disease
patients (four SC, three SS), aged four to 24 years, were submitted to
sequential phlebotomies during periods from 18 months to four years.
METHODS: The number of hospitalization days for crises was considered.
The volumes and frequencies of phlebotomies were adjusted according to
the patients ages, the hemoglobin concentrations and the serum
ferritin levels. RESULTS: One hundred and forty-four hospitalization
days were recorded in the seven patients in the year preceding the
treatment. During the study period, the annual numbers of
hospitalization days were respectively 20, five, six and one. Mean
hemoglobin concentration was 10.7 g/dL before phlebotomies and 8.8 to
9.2 g/dL during the four years of treatment. Mean corpuscular volume,
mean corpuscular hemoglobin concentration and serum ferritin were also
reduced. The volume of phlebotomies was 116 to 39 mL/kg/year according
to the patients. COMMENTS AND CONCLUSION: The striking decrease of the
number of hospitalization days for all the patients suggests a closed
relationship between therapy and clinical improvement. The mechanism
of this effect is probably multifactorial: a) the concentration of Hb
level is known to influence the blood viscosity and its decrease
always improved rheology in sickle cell disease patients; b) the mean
corpuscular hemoglobin concentration is a critical factor concerning
the HbS molecule polymerization in sickle cell disease, and its slight
reduction may have an important biological effect. We observed these
two biological modifications in our patients and suggest that they
mediate the clinical effects. The iron deficiency induced by
phlebotomies has no evident deleterious consequence either on height
and weight in the children or on intellectual performance in any
patients.
Publication Types:
* Clinical trial
PMID: 10761600, UI: 20224666
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Nutrition 2000 May 1;16(5):330-338
Sickle cell anemia: a potential nutritional approach for a molecular disease.
Ohnishi ST, Ohnishi T, Ogunmola GB
Philadelphia Biomedical Research Institute, King of Prussia,
Pennsylvania, USA
[Record supplied by publisher]
A certain population of red blood cells in patients with sickle cell
anemia has an elevated density and possesses an abnormal membrane.
These "dense cells" have a tendency to adhere to neutrophils,
platelets, and vascular endothelial cells, and, thus, they could
trigger vasoocclusion and the subsequent painful crisis from which
these patients suffer. We developed a laboratory method of preparing
such dense cells and found that nutritional antioxidant supplements,
hydroxyl radical scavengers, and iron-binding agents could inhibit the
formation of dense cells in vitro. The concentrations at which
effective nutritional supplements could inhibit dense cell formation
by 50% were 4.0 mg/mL for aged garlic extract, 0.38 mg/mL for black
tea extract, 0.13 mg/mL for green tea extract, 0.07 mg/mL for
Pycnogenol, 930 muM for alpha-lipoic acid, 270 muM for vitamin E, 45
muM for coenzyme Q(10), and 32 muM for beta-carotene. Both an ex vivo
study and a pilot clinical trial demonstrated that a cocktail
consisting of daily doses of 6 g of aged garlic extract, 4-6 g of
vitamin C, and 800 to 1200 IU of vitamin E may indeed be beneficial to
the patients.
PMID: 10793299
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Int J Biochem 1986;18(10):953-6
Nontransferrin-bound serum iron in thalassemia and sickle cell patients.
Ahmed NK, Hanna M, Wang W
Nontransferrin-bound iron (NTBI) was separated from transferrin bound
iron (TBI) by DEAE-Sephadex-CDS filtration. TBI is eluted with
Tris-NaCl buffer, NTBI that is retained on the column is eluted with
citric acid. NTBI was identified in serum from thalassemia and sickle
cell patients. Normal serum contained less than 6% NTBI as compared
with 15-18% in patient's sera. NTBI levels were decreased
significantly after 8 hr chelation with deferoxamine (DFO).
PMID: 3792614, UI: 87080986
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Arch Intern Med 1983 May;143(5):1030-2
Iron deficiency and sickle cell anemia.
Rao KR, Patel AR, Honig GR, Vida LN, McGinnis PR
In a patient with sickle cell anemia, iron deficiency was accompanied
by hypochromic, microcytic RBCs, absence of bone marrow iron, and a
low serum ferritin level. The mean corpuscular hemoglobin
concentration (MCHC) was decreased (27.6 g/dL) and was associated with
an extreme scarcity of sickled erythrocytes in blood smears. Iron
therapy resulted in reticulocytosis and an increase in sickled
erythrocytes. In vitro studies demonstrated a decrease in sickling of
erythrocytes as a function of oxygen saturation of the blood when the
patient was iron deficient. The whole blood oxygen dissociation curve
showed a substantial decrease in oxygen pressure necessary to produce
50% saturation of hemoglobin at pH 7.4 and 37 degrees C (P50),
indicating an increased oxygen affinity. These data suggest that a
reduction of the MCHC induced by iron deficiency may ameliorate
sickling.
PMID: 6679216, UI: 84306211
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Arch Intern Med 1982 Sep;142(9):1621-4
Overt iron deficiency in sickle cell disease.
Haddy TB, Castro O
Overt iron deficiency was diagnosed in four patients with sickle cell
disease. Three patients had homozygous SS and one had hemoglobin SC
disease. The cause in each case was proved or suspected blood loss.
Iron repletion was accompanied by increases in the blood hemoglobin
and hematocrit levels, erythrocyte mean corpuscular volume, and mean
corpuscular hemoglobin concentration (MCHC) and by change in the RBC
morphologic characteristics from hypochromic microcytic to
normochromic normocytic. The diagnosis of iron deficiency was
confirmed by the finding of a low serum ferritin level, a high serum
total iron-binding capacity, or both. Two patients who had had no
painful crises while they were iron deficient began having crises
again, and another patient had painful crises for the first time after
the blood values improved. Whether a lowered MCHC is beneficial to
patients with sickle cell diseases is an important but unanswered
question.
PMID: 7114979, UI: 82283023
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Subject: iron status/sickle cell
JPEN J Parenter Enteral Nutr 2001 Jan-Feb;25(1):36-8
Iron status of children with sickle cell disease.
Stettler N, Zemel BS, Kawchak DA, Ohene-Frempong K, Stallings VA
The Children's Hospital of Philadelphia, Department of Pediatrics,
University of Pennsylvania School of Medicine, USA.
nstettle@cceb.med.upenn.edu
[Medline record in process]
BACKGROUND: Dietary iron requirements are unclear in children with
SS-type sickle cell disease. METHODS: Iron status was assessed in 104
nontransfused African American children (aged 0.5 to 17.6 years) with
sickle cell disease who receive no iron supplement. Dietary iron
intake was not measured at the time of this study. RESULTS: Serum
ferritin was normal or high in all children. Other hematologic and
biochemical indicators of iron deficiency were in the normal range in
most children. CONCLUSIONS: Unlike previous studies, this sample of
children and adolescents did not show signs of iron deficiency.
PMID: 11190988, UI: 21029101
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Subject: Ip6/phytic acid/chelator
WHAT DOES IT DO?
IP6 inhibits hemoglobin S, the agent that is responsible for sickle
cell anemia. This is the only known substance which affects the source
of sickle cell anemia.
IP6 is a naturally occurring substance found in grains, especially
corn, and in legumes. It has several special qualities but perhaps the
most dramatic effect of this remarkable substance is that of an
anti-cancer agent.
Inositol is the substance that regulates cell division. It has a
modulation effect which means that although it has no effect on normal
cells, it stops the reproduction of cells which are multiplying too
fast, such as cancer cells. It also forces the cells to mature and
differentiate. Most cancer cells are immature, unspecialized cells
that multiply indefinitely. Inositol stops this. Actually, it is a
phosphorylated Inositol that does the trick. Inositol Phosphate comes
in six varieties from IP1 to IP6 . IP3 is perhaps the most active in
regulating cell division but the exact function of each IP is not
known. Inositol is synergistic with IP6 because as phosphates are
stripped from the hexaphosphate they are taken up by Inositol,
recycling the process.
IP6 is thought to be the substance in fiber that prevents colon
cancer. Also, studies in Finland show that eating a high fat diet
along with a diet rich in this substance yields a much lower incidence
of cancer e.g. breast cancer, than countries such as the USA with less
fat consumption. Inositol Hexaphosphate is among the most powerful
cancer prevention substances known, even more so than Green Tea.
Inositol and the phosphate form also combine to defeat cancer that has
already occurred. Malignant cells instantly absorb these nutrients
where it persuades them to convert to normal cells. Tumors given these
nutrients tend to shrink and disappear. Regular chemotherapy destroys
cancer cells and adds a toxic load onto the body as it attempts to
clear cellular debris. Inositol and IP6 do not do this. Chemotherapy
wrecks the immune system. IP6 boosts the immune system, especially the
Natural Killer (NK) cells that attack cancer. Cancer cells become
resistant to chemotherapy drugs. They cannot become resistant to the
Inositol derivatives. IP6 increases the activity of the tumor
suppressor gene, P53 by seventeen fold. The P53 gene is reponsible for
inhibiting the pathway that allows normal cells to become cancerous.
Chemotherapy is in itself, carcinogenic.
It has been used against a wide variety of cancers. Naturally, blood
based cancers such as leukemia are the most sensitive, with solid
tumors needing a larger dose. Most studies at this point have used
either animals or human cancer cells in vitro, i.e. in a test tube. As
an example, adding IP6 to human liver cancer cells resulted in
complete inhibition of tumors. Human liver cancer cells injected into
mice resulted in 71% tumors. Cells pretreated with IP6 resulted in no
tumors. Pre-existing liver cancers regressed. In another study with
Rhabdomyosarcoma, tumors were suppressed from 25 to 49 fold!
IP6 and Inositol have other properties, too. They are strong
antioxidants. IP6 is also strongly anti-inflammatory. Asbestos given
to rats resulted in lung inflammation and fibrosis. IP6 reduced this
by from 6 to 30 fold!
IP6 reduces the incidence of kidney stones in those prone to them.
It is also useful in cardiovascular disease. IP6 inhibited platelet
aggregation (stickiness) by 45% in rats. Platelet aggregation causes
blood clots which cause heart attacks and stroke. Other studies with
animals showed cholesterol lowered by 19% and triglycerides by 65%
when IP6 was added to their chow.
Inositol prevents fatty liver, prevents and treats the neural
complications of diabetes, is an antidepressant (at high doses,) and
helps obsessive-compulsive disorder and panic attacks (also at high
doses.)
CAUTIONS
InosoPhate 6 is nontoxic and its use is not associated with any
significant side-effects. Previous concerns that it would bind
minerals and cause mineral deficiencies have been shown to be
unfounded.
Most of the studies done using a combination of Inositol and IP6 were
done using a different ratio than the ratio in this product. It is not
known whether that makes a difference.
See Disclaimer.
DOSE
The effects of InosoPhate 6 are dose dependent. In other words, the
more you take, the better then result. For daily prevention, from 2 to
4 capsules per day in two divided doses is sufficient. Those at high
risk for cancer, fatty liver, kidney stones, etc should take from 4 to
8 per day in two divided doses. Anyone with an active case of cancer
should take from 10 to 16 capsules per day in two divided doses. All
doses should be taken on an empty stomach.
Subject: iron/sickle cell
Biochem J 1986 Jul 1;237(1):265-9
Sickle cell membranes and oxidative damage.
Rice-Evans C, Omorphos SC, Baysal E
Sickle erythrocytes and their membranes are susceptible to endogenous
free-radical-mediated oxidative damage which correlates with the
proportion of irreversibly sickled cells. The suppression of
incubation-induced oxidative stress by antioxidants, free radical
scavengers and an iron chelator suggest that oxidation products of
membrane-bound haemoglobin contribute towards the pathology of the
disease.
PMID: 3800879, UI: 87099822
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Subject: sickle cell/free radicals/
J Clin Invest 1982 Dec;70(6):1253-9
Spontaneous oxygen radical generation by sickle erythrocytes.
Hebbel RP, Eaton JW, Balasingam M, Steinberg MH
Since the various membrane abnormalities of sickle erythrocytes might
result from excessive accumulation of oxidant damage, we have measured
the generation of superoxide, peroxide, and hydroxyl radical by normal
and sickle erythrocytes using assays involving reduction of cytochrome
c, aminotriazole inhibition of catalase, and methane evolution from
dimethyl sulfoxide, respectively. Compared with normal erythrocytes,
sickle erythrocytes spontaneously generate approximately twice as much
superoxide, peroxide, and hydroxyl radical. One possible source of
hydroxyl radical generation was identified as hemichrome, excessive
amounts of which are bound to sickle erythrocyte membranes. Hemichrome
did not generate hydroxyl radical when exposed to superoxide alone or
peroxide alone. However, in the presence of both superoxide and
peroxide, hemichrome greatly facilitated hydroxyl radical generation.
Supporting this, normal erythrocyte membranes induced to acquire
sickle hemichrome concomitantly acquired an enhanced ability to
mediate hydroxyl radical generation. Finally, sickle erythrocyte
membranes greatly enhanced superoxide/peroxide-driven hydroxyl radical
generation as compared with normal erythrocyte membranes. These data
suggest that an excessive accumulation of oxidant damage in sickle
erythrocyte membranes might contribute to the accelerated membrane
senescence of these cells. They further indicate that accumulation of
oxidant damage could be a determinant of normal erythrocyte membrane
senescence.
PMID: 6294138, UI: 83083186
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Subject: cyanate/sickle cell/iron
Blood 1975 Oct;46(4):583-90
Iron metabolism, sickle cell disease, and response to cyanate.
Peterson CM, Graziano JH, de Ciutiis A, Grady RW, Cerami A, Worwood M,
Jacobs A
In an attempt to understand the variability of the hematologic
response to oral sodium cyanate, iron metabolism was studied in a
group of 39 patients with sickel cell disease. Eleven of the 39
patients were found to have no stainable iron in the marrow despite
the fact that patients with sickle cell disease are generally
considered to have hemosiderosis. The mean per cent saturation and
total iron-binding capacity were in the low-normal range in sickle
cell patients whether or not stainable iron was present in the bone
marrow aspirate. Serum ferritin concentrations, on the other hand,
were found to be high in both groups (greater than 500 mu g/liter)
when compared to controls (60 mu g/liter). The high serum ferritin
levels denoted significant total-body iron deposition which may be
unavailable for normal metabolic processes. One patient with no
stainable iron in the bone marrow aspirate did respond to iron therapy
alone with an increase in hemoglobin concentration. Serum
ceruloplasmin levels were also found to be high in sickle cell disease
patients. The ability to respond to oral cyanate therapy was
correlated with the amount of stainable iron in the bone marrow
aspirate. These studies emphasize the necessity of a reevaluation of
iron metabolism in the pathophysiology and treatment of sickle cell
disease.
PMID: 1174692, UI: 76019476
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Subject: sickle cell/serum ferritin
Arch Dis Child 1978 Apr;53(4):319-21
Value of serum ferritin estimation in sickle cell anaemia.
Hussain MA, Davis LR, Laulicht M, Hoffbrand AV
In a group of 35 children with sickle cell anaemia serum ferritin
concentration ranged from 70 to 2460 microgram/l (mean 367, median 180
microgram/l). This was significantly higher than the ferritin levels
(range 8-101, mean 34, median 30 microgram/l) in a group of 63 normal
control children of the same age group. 30 (86%) of the sickle cell
children showed serum ferritin levels greater than 101 microgram/l,
and 2 (6%) levels greater than 1000 microgram/l. 7 of the patients had
not been transfused before this study. Their serum ferritin levels
were all raised and showed a significant correlation with age but not
with haemoglobin level. In the remainder of the patients the serum
ferritin bore no significant correlation with age, haemoglobin level,
or number of units of blood transfused. 2 children with HbSC disease
had levels within the control range. Since patients with sickle cell
anaemia have an increasing chance of long survival, we suggest that
serial estimations of their iron status be made by means of serum
ferritin assay in order to determine which patients are accumulating
excessive iron.
PMID: 646443, UI: 78164857
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Subject: sickle/leg ulcers
Trop Geogr Med 1987 Oct;39(4):354-6
Haematological factors associated with leg ulcer in sickle cell disease.
Adedeji MO, Ukoli FA
Department of Haematology and Blood Transfusion, College of Medical
Sciences, University of Benin, Nigeria.
Haematological factors in 42 Nigerian patients with homozygous sickle
cell disease (SS) and leg ulcers was the subject of this study. The
results suggest that this complication is associated with high
haemoglobin and low fetal haemoglobin levels. The role of the
significantly higher mean platelet count (P less than 0.05) in male
patients than in controls is not clear.
PMID: 3451412, UI: 88236670
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Subject: hyroxyurea/sickle/chelator
Blood 1999 Nov 1;94(9):3022-6
Hydroxyurea as an alternative to blood transfusions for the prevention of
recurrent stroke in children with sickle cell disease.
Ware RE, Zimmerman SA, Schultz WH
Duke Pediatric Sickle Cell Program and the Division of
Hematology-Oncology, Department of Pediatrics, Duke University Medical
Center, Durham, NC 27710, USA. ware0005@mc.duke.edu
Children with sickle cell disease (SCD) and stroke receive chronic
transfusions to prevent stroke recurrence. Transfusion risks including
infection, erythrocyte allosensitization, and iron overload suggest a
need for alternative therapies. We previously used hydroxyurea (HU)
and phlebotomy in two young adults with SCD and stroke as an
alternative to transfusions. We have now prospectively discontinued
transfusions in 16 pediatric patients with SCD and stroke. Reasons to
discontinue transfusions included erythrocyte alloantibodies or
autoantibodies, recurrent stroke on transfusions, iron overload,
noncompliance, and deferoxamine allergy. HU was started at 15 mg/kg/d
and escalated to 30 mg/kg/d based on hematologic toxicity. Patients
with iron overload underwent phlebotomy. The children have been off
transfusions 22 months, (range, 3 to 52 months). Their average HU dose
is 24.9 +/- 4.2 mg/kg/d, hemoglobin concentration is 9.4 +/- 1.3 g/dL,
and mean corpuscular volume (MCV) is 112 +/- 9 fL. Maximum percentage
fetal hemoglobin (%HbF) is 20.6% +/- 8.0% and percentage
HbF-containing erythrocytes (%F cells) is 79.3% +/- 14.7%. Fourteen
patients underwent phlebotomy with an average of 8,993 mL (267 mL/kg)
removed. Serum ferritin has decreased from 2,630 to 424 ng/mL, and 4
children have normal ferritin values. Three patients (19%) had
neurological events considered recurrent stroke, each 3 to 4 months
after discontinuing transfusions, but before maximal HU effects. These
preliminary data suggest some children with SCD and stroke may
discontinue chronic transfusions and use HU therapy to prevent stroke
recurrence. Phlebotomy is well-tolerated and significantly reduces
iron overload. Modifications in HU therapy to raise HbF more rapidly
might increase protection against stroke recurrence.
PMID: 10556185, UI: 20028282
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Subject: iron/sickle
Blood 1988 Oct;72(4):1278-85
Nonheme iron in sickle erythrocyte membranes: association with phospholipids
and potential role in lipid peroxidation.
Kuross SA, Hebbel RP
Department of Medicine, University of Minnesota Medical School,
Minneapolis.
Previous studies documented the abnormal association of heme and heme
proteins with the sickle RBC membrane. We have now examined RBC ghosts
and inside-out membranes (IOM) for the presence of nonheme iron as
detected by its formation of a colored complex with ferrozine. Sickle
ghosts have 33.8 +/- 18.2 nmol nonheme iron/mg membrane protein, and
sickle IOM have 4.3 +/- 3.0 nmol/mg. In contrast, normal RBC ghosts
and IOM have no detectable nonheme iron. The combination of heme and
nonheme iron in sickle IOM averages nine times the amount of
membrane-associated iron in normal IOM. Kinetics of the ferrozine
reaction show that some of this nonheme iron on IOM reacts slowly and
is probably in the form of ferritin, but most (72% +/- 18%) reacts
rapidly and is in the form of some other biologic chelate. The latter
iron compartment is removed by deferoxamine and by treatment of IOM
with phospholipase D, which suggests that it represents an abnormal
association of iron with polar head groups of aminophospholipids. The
biologic feasibility of such a chelate was demonstrated by using an
admixture of iron with model liposomes. Even in the presence of
tenfold excess adenosine diphosphate, iron partitions readily into
phosphatidylserine liposomes; there is no detectable association with
phosphatidylcholine liposomes. To examine the bioavailability of
membrane iron, we admixed membranes and t-butylhydroperoxide and found
that sickle membranes show a tenfold greater peroxidation response
than do normal membranes. This is not due simply to a deficiency of
vitamin E, and this is profoundly inhibited by deferoxamine. Thus,
while thiol oxidation in sickle membranes previously was shown to
correlate with heme iron, the present data suggest that lipid
peroxidation is related to nonheme iron. In control studies, we did
not find this pathologic association of nonferritin, nonheme iron with
IOM prepared from sickle trait, high-reticulocyte, postsplenectomy, or
iron-overloaded individuals. These data provide additional support for
the concept that iron decompartmentalization is a characteristic of
sickle RBCs.
PMID: 3167208, UI: 89001187
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