summary about Sickle cell anemia from different resources

1. Sickle cell anemia
Mohammed AlHinai

2. Sickle cell anemia
• Autosomal recessive disorders occur by point mutation in beta globin
gene results in the production of sickle hemoglobin.
Pathophysiology
Point mutation in chromosome 11 in the beta-chain gene lead to change glutamate to valine in
position 6 of the Hb beta chain.

3. Classification
Sickle cell trait Hb AS :
• Mutation only in one allele of
beta-chain gene (heterozygous
state).
• Usually no serious clinical
consequences.
Sickle cell disease:
• Occur as mutation in two allele of
beta-chain gene (homozygous
state) as Hb SS.
• Or occur as mutation in two
different location of beta chain
but one of them should be in
sickle mutation include :
- Hb S/Bthal
- Hb SC
- Hb SO
- Hb SE

4. Clinical manifestation
Usually present with complication of sickle cell disease which start at age of 4 to
6 months
Common
presentation

6. Diagnosis
The goals and methods of diagnosis of sickle cell disease (SCD) vary with the age
of the patient and need at least two confirmatory test to diagnose.
Prenatal testing :
• using specific
molecular methods
for detecting the
HbS gene by taking
fetal DNA samples
obtained by
chorionic villus
sampling at 8 to 10
weeks gestation.
Older children and adult:
• Sickledex
• HPLC
• Hb electrophoresis
• Molecular testing
Newborn :
• in the fetal and newborn
periods can be difficult to
detect HbS because of the
predominance of hemoglobin F
(HbF), which confounds
detection of hemoglobin S
(HbS) by solubility testing.
• Use newborn screening
including :
- Hb Electrophoresis
- HPLC
- Molecular testing

7. Diagnostic approach :
 Detailed history taking and physical examination.
 Laboratory test including :
• CBC with finding of :
- Low Hb
- Finding of chronic hemolysis including high or normal MCV, high retics.
• Peripheral blood smear :
- Sickled red cells.
- Polychromasia indicative of reticulocytosis.
- Howell-Jolly bodies reflecting hyposplenia.

8.  Confirmatory tests:
• Sickledex :
- By taking blood sample and putting under stress lead to polymerize and precipitate.
- Detect the presence of HbS but doesn’t differentiate between sickle cell disease or
trait.
• Hb eletrophoresis :
- Analyze different type of Hb based on charge and size.
- In SCD the HbSS or other type will be predominate.
• HPLC ( high performance liquid chromatography) :
- Give the percentage of Hb types.
• Molecular test based on genetic sequences.
Sickledex test

10. HPLC show predominate HbSS with normal A2 and low A0

12. General management
General measure :
• Educate the patient and family
about SCD.
• Obtaining steady state laboratory
value as baseline for comparison
during exacerbation.
• Infection prevention by :
- Immunization for all patient (PCV,
Hib, influenza, meningococcal)
- Prophylactic penicillin for all young
children (<5 yrs old).
• Nutrition :
- Folic acid 1 mg oral supplement
daily and multi-vitamin.
- Screening of iron for those non-
tranfused.
• Routine evaluation for any
complication
Cure of SCD :
• Bone marrow
transplantation.
Management of
complication:
• Depend on present of
complication (as
explain next pages).

13. Indication for blood transfusion
Simple transfusion :
• Symptomatic anemia
• Spleen sequestration
• Aplastic crisis
• Pregnancy
Exchange transfusion :
• Acute stroke
• Acute chest syndrome
• Multi-organ failure
• Hepatic sequestration
• Recurrent VOC not controlled
• Pre-OP

14. Hydroxyurea
The mechanism of hydroxyurea
• Inhibition of
ribonucleotide reductase
to inhibit DNA synthesis.
• As affect cell devision,
cause global
myelosuppression
including neutropenia,
anemia and
thrombocytopenia.
Other mechanism include :
- Increase production of
NO by endothelial cell.
- Reduce WBC count
and/or neutrophil
adhesivity to the
vascular endothelium.
• Increased HbF production
which lead to :
- Reduce sickling by reduce
Hb polymerization.
- RBC lifespan increased
- Improved RBC hydration
- Reduce hemolysis
- Reduce the adhesion of
cell to vascular
endothelium.
Which in general :
• Reduce frequency/quality of pain
• Reduce recurrence of ACS
• Reduce hospitalization and need to transfusion
• Reduce hemolysis

15. Indication and contra-indication
Indication :
• 4 or more severe episodes of
painful crisis.
• ACS
• Stroke
• Priapism
• Renal disease
• Severe anemia
Contra-indication:
• Pregnancy
• Breastfeeding
• Severe anemia
• Severe decreased WBC
• Severe decreased Plt
• Reduction in kidney function
Prediction for response and compliance :
• Higher HbF
• High MCV
• Reduce WBC, Plt and retics

17. Acute complication of SCD

18. Vaso-occlusive crisis (VOC)
• A 24 yrs old lady from Nizwa known case of SCD, presented with two days history of increasing
pain involving the right leg and both arms which not relieved by oral analegsia. She gave history
of repeated admission to peripheral hospital with painful episodes. On examination, she was
mildly pale and afebrile. Chest was clear. Liver was palpable at 2 cm below the right costal margin
and spleen was palpable at 3cm below the left costal margin.
According from case, patient present with
painful crisis in different sites which
caused by VOC
CSSCD defined painful episodes (painful crisis) as pain related to SCD
in the extremities, back, abdomen, chest, or head lasting at least two
hours and leading to a clinic visit or hospitalization. But this
underestimates the true degree of pain because many individuals
have pain that is treated at home. The painful crisis precipitate by :
• Exposure to cold.
• Dehydration
• Excessive exercise or stress
• Hypoxia or infection
Quick HIT :
• the patient had
splenomegaly and
hepatomegaly which
might associated with
spleen sequestration.
But that can’t be
confirmed as we don’t
have the baseline of
spleen and liver.
Investigation :
CBC , Blood smear, LFT and RFT

19. Management:
Depend on the severity and if associated with other serious complication
(IV)

20. • Adjuvant therapy like anti-convulsant (gabapentine), anti-depressant (amitryptyline), bisphophanate
(zoledronic acid), physiotherapy (TENS)

21. Acute chest syndrome
• Khalid 19 yrs old known case of SCD, came to the A&E with SOB, productive cough and fever. He
looked sick. Physical examination revealed T 38.8C, HR 112, BP 100/50 mmHg and RR 28 with
oxygen saturation of 88% on room air. Chest examination revealed bilateral basal crackles.
ACS Defined as a NEW radio-density on chest radiograph (consolidation or infiltration) accompanied by
fever and/or respiratory symptoms including chest pain, SOB and cough, wheeze desaturation caused by :
Bone marrow fragment and/or fat
emboli :
• More common in adult compared to
children.
• Could associated with lipemia retinalis,
petechiae and neurological symptoms
(but less common).
• Test to confirm (not performed
routinely):
- need bronchoalveolar lavage for the
presence of fat-containing alveolar
macrophages.
- Bone marrow aspiration and biopsy show
necrosis and infraction of bone marrow.
Other causes :
• Pulmonary infection.
• Pulmonary thrombosis.
VOC and lung
sequestration :
• More common in
children.

22. Pathophysiology of ACS

23. Investigation :
• CBC, blood smear, ECG, AP and lateral X-ray, blood and
sputum culture.
• Other test in some cases including chest CT scan for
pulmonary emboli, serum troponin for myocardial
damage, bone marrow aspiration and biopsy,
Bronchoscopy with bronchoalveolar lavage for fat
embloi.
Quick HIT :
• the differential diagnosis of ACS
are pulmonary embolus, acute
coronary syndrome and
pneumonia.
• But even the patient present with
one of previous differential, still
consider ACS otherwise excluded
as different management require
for ACS.
Management :
• Adequate and immediate pain control as same guideline of VOC.
• Supplemental oxygen.
• Hydration to prevent hypovolemia by typical regimen is 1.5 times maintenance fluids of D5 in one-
half normal saline for the first 24 to 48 hours.
• Exchange transfusion :
- if the Hb >8 g/dL to reduce hemoglobin S percentage <30 percent
- if Hb < 8g/dL give first simple transfusion to achieve Hb >8 g/dL and then apply exchange transfusion.
• Bronchodilator.
• Antibiotic with a third generation cephalosporin along with a macrolide, or a fourth generation
fluoroquinolone are typical regimens including :
- cefotaxime 1 to 2 grams IV every eight hours plus azithromycin 500 mg orally or IV once daily for seven
days
- moxifloxacin 400 mg orally or IV for seven days.
- ceftriaxone should be used with caution as drug-induced immune hemolysis

24. • Incentive spirometry : to prevent ACS episodes in children with SCD who were admitted to the hospital
for a painful crisis by Performing incentive spirometry using 10 maximal breaths every two hours while
awake was associated with a significantly reduced rate of developing ACS.
•
Prevention :
• Consider hydroxuria if not started before.
• Chronic transfusion therapy might use in some cases.
• Bone marrow transplantation.
Quick HIT :
• type of antibiotic given depend
on presence of spleen or its
function :
- In case of splenectomized patient
will give antibiotic for
encapsulated bacterial including
tazocin and azithromycin
- If not splenectomized will give
cefuroxime and azithromycin.

25. Acute stroke
• Khalid 19 yrs old known case of SCD, came to the A&E with headache and right sided hemiplegia
started recently. He had some episodes of seizure.
ACS Defined as a NEW onset of neurological defect including hemiparesis, aphasia, seizure, sensory
deficit, altered consciousness, intellectual decline and other depend on site of lesion:

26. Age (years)
Hazardfunction
0.0010
0.0015
0.0020
0.0025
0.0030
0.0035
0.0040
10 20 30 40 50
Haemorrhagic stroke
Ischemic stroke
• Ischemic stroke (common)
– 54% of CVAs
– highest in 1st decade and
after 30 years
– peak at 2–5 years
• Hemorrhagic stroke (rare)
– during 2nd decade
Stroke subtype by age

27. Investigation :
important to differentiate between ischemic and hemorrhagic stroke as different management
• CBC, cross-match for transfusion, coagulation profile, electrolyte, RFT and blood glucose.
• Neuroimaging :
- Head CT scan done first which might detect hemorrhagic stroke but less sensitivity for ischemic stroke.
- If head CT not clear, do head MRI which more sensitive for ischemic stroke.
• EEG might done in some cases for seizure.
Management :
Immediate management for all patient with ischemic or hemorrhagic stroke include:
• Stabilize the patient with ABC.
• Airway protection from aspiration
• Intravenous access and hydration with isotonic fluids, typically at 1.25 to 1.5 times the normal
maintenance rate
• Simple transfusion to raise the hemoglobin concentration to not more than 10 g/dL to prevent hyper-
viscosity.
• Attention to identification and treatment of concurrent infection; including antipyretics if needed.
• Management of seizures if present.

28. Ischemic stroke :
• For patients with SCD who have a
radiologically confirmed acute ischemic
stroke include :
- Urgent Exchange transfusion to reduce
sickle hemoglobin to ≤30 percent of total
hemoglobin.
- Thrombolytic/antithrombotic use only
for patients with a greater likelihood of
another cause of ischemic stroke such as
embolism.
Additional management depend on type
of stroke
Hemorrhagic stroke :
• for treat the bleeding :
- Discontinue all anticoagulants and antiplatelet
agents, unless their benefits are thought to
outweigh their risks for that patient.
- For patients with thrombocytopenia, administer
platelet transfusions as necessary to maintain the
platelet count over 100,000/microL
- Obtain neurosurgical consultation if an
intervention may be required (eg, to reduce
intracranial pressure or to treat a bleeding
aneurysm).
Prevent the recurrence:
• Consider hydroxuria if not started before.
• BMT if there is donor.
• Chronic exchange transfusion especially for those with higher risk.

29. Acute anemia
• 21 yrs old man with SCD was admitted with LUQ pain of 6 hrs duration. He had repeated admission in the past
with acute painful episodes and was on daily hydroxyuria and folic acid as well as mefenamic acid as needed.
He had one brother and two sisters with SCD. On examination, he was pale and jaundiced. His HR 110, BP
90/50, RR24, O 94% on room air, T 37.8C. Chest was clear. He had tender splenomegaly with being palpable at 8
cm below costal margin. CBC showed Hb 6g/dl, WBC 3.1 and Plt 110.
Sudden decline in Hb below than the baseline of patient which commonly caused by :
Splenic sequestration crisis :
• acute drop in hemoglobin
level caused by vaso-
occlusion within the spleen
and splenic pooling of RBCs.
• Present with :
- pallor.
- Rapidly enlarging spleen
which cause LUQ pain.
Hyperhemolytic crisis :
• sudden exacerbation of
hemolysis with worsening
anemia despite ongoing
reticulocyte production.
• Might associated by VOC,
infection or drug exposure.
• Present with :
- pallor.
- Jaundice
- Dark urine
Aplastic crisis :
• characterized by an acute drop
in hemoglobin level caused by
a transient arrest of
erythropoiesis, leading to
abrupt reductions in red cell
precursors in the bone
marrow commonly caused by
human parvovirus B19
infection.
• restoration of erythropoiesis
and reappearance of
reticulocytes in the peripheral
blood within 2 to 14 days.

30. Investigation :
Splenic sequestration crisis :
• CBC :
- Low Hb, might associated with
low plt or WBC.
- Normal or high retics.
• Blood smear show high retics
• Other test might be ordered
as LFT, U&E.
Hyperhemolytic crisis :
• CBC :
- Low Hb and might high
MCV.
- High retics
• Blood smear with high
retics.
• High unconjugated
hyperbilirubinemia.
• elevated serum lactate
dehydrogenase (LDH)
• low serum haptoglobin
Aplastic crisis :
• CBC :
- Low Hb.
- Low reticulocytes in the
peripheral blood (typically,
reticulocytes <1.0 percent,
absolute reticulocyte count
<10,000 per microL).
• Serology test for virus antigen.
• Blood smear show low retics
• Other test might be ordered as
LFT, U&E.• Give simple transfusion but
until return Hb to baseline or
being asymptomatic.
• Prevent to give high blood as
may worse the sequestration
and lead to rupture.
• Advise to splenectomy.
• Hydration
• Pain management if
associated with pain.
• Give simple transfusion but
until return Hb to baseline or
being asymptomatic.
• Hydration
• Pain management if
associated with pain.
• Give simple transfusion
but until return Hb to
baseline or being
asymptomatic.
• Hydration
• Pain management if
associated with pain.