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Sickle cell disease
This is an inherited multisystem disorder caused by abnormal properties
of RBCs containing HbS.
This results from mutation in the β-globin gene that changes the 6th
amino acid from glutamic acid to valine
Pathophysiology
*Hb S arises from a mutation substituting
thymine for adenine in the sixth codon of
the beta-chain gene, GAG to GTG. This
causes coding of valine instead of
glutamate in position 6 of the Hb beta
chain.
The resulting Hb has the physical properties
of forming polymers under deoxy
conditions. It also exhibits changes in
solubility and molecular stability. These
properties are responsible for the profound
clinical expressions of the sickling
Inheritance--- AR
HbS polymerizes reversibly when deoxygenated forming a
gelatinous network of fibrous polymers that stiffen RBC
membrane, ↑ viscosity, and causes RBC dehydration due
to potassium leakage & calcium influx. These changes
cause the characteristic sickle shape. They lose their
pliability that is needed to pass through the capillaries
circulation. Their cell membrane is sticky & adherent to
endothelium especially the reticulocytes. This leads to
vaso-occlusion & premature RBC destruction (hemolysis).
HbS is also unstable & susceptible to oxidant stress.
Epidemiology
USA prevalence = 8-10% among black newborn.
West Africa
= 25-30%.
USA pregnancy at risk = 4000-5000/year.
Africa = 120000/year born with sickle cell disease
USA = 50000-60000 living patients.
S&S
Asymptomatic (sickle cell trait = Hb-AS)
Sickle cell disease is seen in homozygous
state.
Chronic hemolytic anemia, recurrent painful
episodes, organ dysfunction (sickle cell
disease = Hb-SS)
Anemia
Hemolytic anemia (most).
Mean life span 17 days.
Hct= 15-30% + significant reticulocytosis.
Most severe in Hb-SS & Hb-Sβ˚thalassemia.
Milder in Hb-Sβ+ thalassemia & Hb-SC disease.
---- Low erythropoietin production.
Granulocytosis (has significant relation to mortality rate).
Painful Crises
Acute painful episode is often 1st symptom.
Caused by vaso-occlusion.
Frequent episodes & frequent hospitalization.
Highest frequency in 3rd & 4th decades.
Factors ass with freq pain
1. high Hb level
2. α-thalassemia
3. Low Hb F
4. Sleep apnea.
This can be ↓ by chronic transfusion therapy.
Pptating factors
Cold exposure,
Dehydration,
Infection,
Stress,
Menses,
Alcohol consumption
& most of the times Unknown.
Site
Any area of the body can be affected.
Most commonly the back, chest, extremities & abdomen.
Duration: few days
Severity: varies from mild to agonizing pain.
Ass signs: fever, swelling, tenderness, tachypnea,
hypertension, nausea & vomiting.
Lab. Indicators: ↑ acute phase reactants, ↑ SLDH, IL-1, TNF,
& ↑ serum viscosity.
Other Crises
1) Hemolytic crisis
Sudden exacerbation of anemia,
↑ reticulocytosis, & serum bilirubin level.
--- ass with coexistent G6PD def
2) Aplastic crisis
Transient arrest of erythropoiesis.
-- Abrupt ↓ of Hb, reticulocytes count & RBC
precursors in BM.
-- Duration – a few days.
-- Cause – infection e.g. parvovirus B19
-- BM necrosis.
3) Sequestration crisis
– in the spleen (sometimes in liver).
-- Children < 4 years age, Hb-SC adults, HbSβ+
thalassemia.
-- Sudden exacerbation of anemia,
reticulocytosis, & tender enlarging spleen
(sometimes hypovolemia)
4) Megaloblastic crisis
due to folate def because of hemolysis &
cell turnover.
5) Hepatic crisis
Vaso-occlusion causing ischemia.
Other causes of anemia --- renal failure ass.
Organ Dysfunction
* Auto-splenectomy -- due to repeated splenic
infarcts.
* Growth retardation – Wt affected more than height.
-- Skeletal maturation delayed.
-- Retarded sexual maturation in ♂
due to primary hypogonadism, hypopituitarism &
hypothalamic insufficiency.
* Infection
Major cause of morbidity & mortality.
-- Strept pnemoniae is most common cause of
bacteremia.
-- H influenzae type b is the 2nd, affects older
children & less fulminant.
-- G-ve bacteria e.g. E coli in older pts
-- meningitis
--S pn, H infl
--Bact pneumonia causing acute chest
syndrome.
-- Osteomyelitis – Salmonella spp.
CNS
TIA, cerebral infarction, hemorrhage, seizures
& coma.
-- Cerebral thrombosis 70%.
* Pulmonary
Acute chest syndrome – dyspnea, chest pain,
fever, tachypnea, leucocytosis, radiologic
pulmonary infiltrates.
-- usually bacterial (sometimes atypical ).
-- restrictive lung disease
-- pulmonary hypertension
* Hepatobiliary
-- Gall stones (pigmented)
-- Liver dysfunction – vasoocclusion, inf,
iron overload
-- cirrhosis.
* Obst/Gyn
Impaired placental blood flow is the
major concern
-- Spontaneous abortion
-- Intrauterine growth
retardation & death.
-- low birth wt.
-- Preeclampsia
-- Oral contraceptives are safe
& effective
* Renal
-- Decreased urinary conc ability
-- papillary infarct
-- RTA
-- CRF
* Priapism
– sustained unwanted painful erection of
penis.
-- may be recurrent & may
lead to impotence
* Ocular
Retinal artery occlusion,
retinal infarct,
retinal detachment & hemorrhage.
* Bone
Avascular necrosis of femoral head,
hand & foot, vertebrae & other bones.
-- Osteomyelitis.
-- arthritis.
-- BM necrosis.
* Skin – Leg ulcers – ischemic or
traumatic, above malleoli & often
bilateral. Resistant to healing & recur.
-- Myofascial syndrome.
* Cardiac – MI in the absence of CAD.
Dx
CBC – anemia, reticulocytosis,
Granulocytosis.
Blood film – ISCs RBCs, Howell-Jolly bodies
due to asplenia.
Sickling test – now only historical.
Hb- electrophoresis ---- HbS , HbF, ↓ HbA.
Solubility test (Sickledex) – distinguishes HbS
which is not soluble.
PCR – antenatal Dx
SUCB ↑, SLDH ↑, S haptoglobin ↓.
℞
1) Health care maintenance --- routine clinical visits &
lab exam
--- Blood bank file.
--- Counseling regarding dis, genetics,
psychosocial issues.
--- Folic acid 1mg/d orally
--- TCD noninvasive surveillance of
cerebral blood flow to predict impending CVA.
--- Retinal evaluation at school age
regularly.
--- Oral contraception, pelvic exam
--- Immunization using conjugated vaccines
for S pneumoniae & H influenzae type b every 5
years.
2) Infection
---- outpatient ceftriaxone for febrile children.
--- Septicemia needs hospitalization, C&S blood &
CSF
---meningitis – cover S pn & H infl for 2 weeks.
--- Acute chest synd – Cefuroxime & erythromycin
covering Mycop pn & chlamydia.
--- Osteomyelitis – anti salmonella antibiotics for 2-6
weeks + surgical drainage or sequestrectomy.
3) Blood Transfusion
--- For volume replacement, Aplastic
crisis, and to prevent CVA & imminent
complications such as acute chest
syndrome.
---- Not needed for painful
crisis.
--- Preop BlT needed.
--- Exchange BlT – for
emergencies
4) Pain Management
Painful crisis –
-- Hydration – IV fluid.
-- aggressive analgesics e.g. morphine,
NSAID.
--- Local anesthesia.
-- Antidepressant
5) Hydroxyurea
--- induce Hb F production
--- Ribonucleotide reductase inhibitor
--- ↓ painful episodes, acute chest
syndrome
--- ↓ BlT needed
--- improve RBC hydration &
deformability, ↓ endothelial sickle cell
adherence & PMN count.
6) New ttt
--- Clotrimazole, Mg supplements (inhibit
Gardos pathway)
--- Artificial surfactant e.g. poloxamer 188
--- Nitric oxide acute chest synd & painful
episodes.
--- Warfarin & mini dose heparin
--- Methyl prednisolone pain relief but with
rebound
--- Valproic acid
7) BMT
8) Gene therapy •