Sickle cell anemia (Hb SS)

 Autosomal recessive disease characterize by abnormal structure of globin chain (Sickle

cell is the most common Structural hemoglobinopathy).
 It occurs due to mutation in one codon which is in position number six of beta-globin
gene in chromosome number 11.
o The normal codon is CAG (coded for glutamic acid), will mutate into CTG
(coded for Valline).
 The sickle gene is common in Africa, India, Southern Europe ,and middle east. (areas
where malaria is endemic)
 When the both parents are affected, the baby will be homozygous and will suffer from
Sickle Cell disease (Hb SS).
o As the synthesis of Hb F is normal, the disease usually does not manifest itself
until the Hb F decreases to adult levels at about 6 months of age.
 When one of parents is affected where other one is normal, baby will be heterozygous
and so he will has sickle-cell trait (AS).
 When parents are affected and also inherit another genetic abnormality (ex.
Thalassemia, hemoglobin C, ..), the baby will be double-heterozygous .
 The HB AS patients are asymptomatic except in rare cases which may have painless
hematuria, Isosthenuria, or suffer from avascular necrosis of femoral head.
 sickle cell trait give some protection against the severe effects of P. falciparum malaria.
 Sickle cell trait is an example for polymorphism.
 Anoxia can lead to sickling symptoms in Hb AS patients.

 Pathogenesis:
o When Hb S becomes deoxygenated, it become insoluble and polymerized into
a ropelike fiber … this will cause distortion of the biconcave RBCs into a
crescent shape together with a marked decrease in erythrocyte deformability..
o RBCs loss their flexibility and become rigid and sickle in shape. (they unable to
squeeze themselves and pass through microcirculation)
o This process is initially reversible but, with repeated sickling, the cells
eventually lose their membrane flexibility and become irreversibly sickled
(RBCs become dehydrated and dense).
o Sickling process occur due to dehydration and partly due to potassium leakage
from RBCs via gados channels (calcium activated potassium channels).
o Sickling will reduce the life spine of RBCs from 120 days into 10-15 days.
o Sickling increase the liability of RBCs (especially the reticulocytes) to adhere to
the vascular endothelium.
o vascular cell adhesion molecule 1 (VCAM-1) play a causal role in sickling,
particularly for vaso-occlusive crisis by facilitating polymerization of trapped
cells.
 Precipitating
Factors for
sickling
crisis:
o Dehydration.
(could occur with hot
weather)
o Infection.
o fever
o Cold due to vasospasm.
o Hypoxia
o Acidosis
o Physical or psychological stress.
o abrupt changes in temperature.
o hypertonic dyes
o Menses
o Alcohol
o But , Mostly with Unknown factor.

 Manifestation of Sickling will appear after age 6-9 month because before this age Hb is
mostly HbF type (without beta globin chain) which is normal.
 Homozygous (SS) will be suffer from sickle cell anemia and present with numerous
types of crisis: hemolytic, vaso-occlusive, acute sequestration, and megaloblastic crisis.
o hemolytic crisis(drops in haemoglobin level)
 hemolysis is mainly extra-vascular.
 Sickle cell patient get Sever hemolysis, especially when they exposed to
hypoxia, dehydration, fever, and cold.
 Increase the indirect bilirubin
 increase lactate dehydrogenase enzyme.
 Hemoglobin will be low
o The normal hemoglobin is 15-16 grams
o But for these patient 8-10 grams of hemoglobin is the steady state.
o Hb S releases its oxygen to the tissues more easily than does normal
Hb, and patients therefore feel well despite being anaemic (except of
course during crises or complications).
o You can't give them blood transfusion if the hemoglobin is 10 g
because you will cause more harm (if hemoglobin is raised above 10
g/dL, it cause increased viscosity and risk of vaso-occlusive episodes).
o If hemoglobin drops (below 8), you have to treat them. Causes of drop
include spleen sequestration, bone marrow aplasia, and further
hemolysis.
 Reticulocytes are increased
  Haptoglobin is low (haptoglobin is protein molecule that carry serum
hemoglobin to liver).
 Symptoms & signs of anemia:
1- Pallor 2- increase pulse 3- functional heart murmur
4- dizziness 5- insomania 6-palpitation
7- Fatigue 8- increase respiration 9- intermitted claudication

o Vaso-occlusive crisis(ischemic crisis or painful crisis)

 In Sickle cell disease, RBCs will have sickle-shape and will be rigid
(inflexible) and so will be trapped in microcirculation (especially small
venules) resulting in destruction of red cells and occlusion that will result
in: ischemia of tissue and infraction.
 There will be severe pain result from the occlusion.
 When crises multi time attack tissue such as spleen, the spleen going to
degenerated and become a fibrous tissue, patient will lose spleen
(autosplenoectomy) result in immune-compromising state.
o These occur in patient who inherited Hb SS or double-heterozygous
(βo-Thalassemia + Sickle cell)
 Crisis may affect other area other than spleen
o pain in the hands and feet (dactylitis), { this is the earliest
presentation in first few year of life}
o Brain result in stroke, especially in children.
 Commonest affected artery is distal intracranial internal
carotid or proximal middle cerebral artery.
 10% of sickler patient have no neurological signs and
symptoms, but they have significant cerebral artery stenosis …
So they have high risk to develop stroke … stroke can prevent
(90%) in such patient by regular blood transfusion (by making
Hb S less than 30%).
 Stroke in adult is less common, and it is often hemorrhagic.
o Retina result in proliferative retinitis, or retinal detachment.
o Kidney result in papillary necrosis
o Bones result in avascular necrosis of femoral head
o Joints especially hip and shoulder.
o Lung result in pulmonary hypertension.
o Acute abdominal pain.
 Sickle cell crisis is often associated with periarticular pain and joint
effusions. (joint effusion is non-inflammatory)
 Vaso-occlusive attacks vary in frequency from daily to perhaps only once a
year. Fever often accompanies the pain.

o Acute splenic sequestration crisis (Acute venous obstruction of the spleen)

 Occur commonly in children, who have their spleen intact.
  The blood suddenly start pooling in the spleen, so circulation will shifted to
supply spleen and spleen become very large and very painful, may result in
shock (circulatory collapse) and so death may occur.
 It is life threating condition, should treated as emergency by transfusion
and \ or splenectomy.
o Aplastic crisis
 Patient with chronic hemolytic anemia are susceptible to viral infection
(Parvovirus B19).
 Parvovirus B19 will infect progenitor cells in bone marrow resulting in
erythroblastpenia (aplastic crisis)
 Usually it is self-limiting, resolved within 1-2 weeks.
 Aplastic crisis characterize by absence of reticulocytosis.

o Megaloblastic crisis
 In Sickle cell patient, bone marrow try to compensate and will be very
active, and so increase its demand to folate.
 Megaloblastic crisis happen when patient doesn't get folic acid
supplementation.
 So they will develop megaloblastic anemia in top of sickle cell anemia.

 Complication
~ In adults, nearly every organ is involved eventually~
o Venous thromboembolism.
o Black Pigmented (calcium bilirubinate) stone (due to chronic hemolysis that cause
chronic increase in bilirubin concentration of bile).
o Leg ulcer (commonly over medial and lateral Malleolus).
 These ulcers caused by vaso-occlusive or trauma.
 They are spontaneous, and often become infected.
 They resistance to treatment, but blood transfusion may facilitate healing.
o Liver sequestration, hepatomegaly, or liver dysfunction.
o Hypopituitarism resulting from pituitary apoplexy.
o Delay sexual maturation.
o Male hypogonadism.
o testicular atrophy present in 1\3 of patient.
o Priapism (unwanted painful erection), occur in 35% of male cases (usually before
25 y age) and treated by α-adrenergic blocking drug, analgesia and hydration.
o Mild zinc deficiency cause stunted growth in children, decreased taste
sensation (hypogeusia), and impaired immune function.
o Cardiomegaly, arrhythmia, MI, iron overload cardiomyopathy, Pulmonary
hypertension, and cor pulmonale.
o Splenomegaly (in childhood), Spleen atrophy, or autosplenism,.
o proliferative retinopathy, Hyphema, vitreous haemorrhages (due to
neovascularization) , and retinal detachments.
o Avascular necrosis of hip and shoulder, compression of vertebra and shortening of
hand & foot bones. (Occasionally hip joint replacement may be required.)
o Joint pain (seen in young black Africans)
o Haemarthrosis of the knee.
o Arthritis in children.
o gouty arthritis (uncommon even 40% of patient are hyperuremic).
o Secondary Osteoarthritis
o Avascular necrosis of femoral head (in 5% of cases) and humeral head.
o osteonecrosis (ischemic necrosis of bone) .
o extracellular volume depletion.
o Jaundice.
o Bone marrow hyperplasia result in widening of the medullary cavities, thinning of
the cortices, and coarse trabeculations and central cupping of the vertebral
bodies.
o bone malformations due to extra-medullary haematopiosis.
o Hyperuricemia due to increase red cell turnover.
o Sickle cell nephropathy:
 Chronic tubulo-interstitial nephritis.
 Papillary sclerosis or necrosis (due to sickling of RBCs which occur because
the renal medulla is hypotonic, relatively hypoxic, and the blood flow to it
is slow).
 Urinary tract obstruction by sloughed papilla. (can occur also in Hb AS)
 Isosthenuria (inability of the kidney to concentrate urine), occur due to
papillary necrosis.
 Cortical infract that will cause persistent hematuria, and perinephric
hematomas.
 partial ischemic injury to the renal tubules.
 distal renal tubular acidosis (Type I RTA).
 Hyperkalemia risk of arrhythmia.
 In young patient, renal hyperperfusion, glomerular hypertrophy, and
hyperfiltration occur….And So result in glomerulopathy that may cause
protienuria, or even nephrotic syndrome. (double heterozygosity sickling
with thalassemia protect against Sickle-cell nephropathy).
 Mild azotemia (secondary to ischemic injury that cause nephron loss)
 Hyperuricemia.
 Renal failure and uremia (occur in 10% of cases), it is a common late
cause of death.
 Nephrogenic diabetes insipidus (due to tubulointerstitial nephritis),it
occur with Hb SS and Hb AS.
o CNS complication occur in 25% of sickler patient
 Cerebral infarction.
 Cerebral hemorrhage.
 Transient ischemic attack (mini stroke)
 fits
  Stroke (occur in 11% of sickler patient under 20 year age)
o Acute chest syndrome
 Occur in up to 30% of sicklers.
 Triggers: 1)infection. 2) unknown
 Onset : sudden (could be gradual)
 Mechanism:
1)Pulmonary infection 2) pulmonary infarction
3)Pulmonary Embolism (fat or clot) 4)sudden hypoxemia
5)pulmonary edema (hypervalemia), which occur due:
a)overhydration (ex. Excessive I.V fluid)
b) drugs (ex, morphine)
 Symptoms & sign:
1- shortness of breath 2- chest pain 3- hypoxia
4- consolidation (it will cause X-ray changes "new infiltration")
5- fever 6- tachypnea 7- cough
8- arterial oxygen desaturation sickling painful crisis
 Treatment: 1) pain relief 2) inspired oxygen 3) antibiotics
4) blood exchange (to reduce Hb S to less than 20%)

o Infections
 Infections are common in tissues susceptible to vasoocclusion, e.g. bones,
lungs, kidneys.
 Patient who loss his spleen will have impaired opsonization and
complement pathway activation, also they have lower serum IgM
 Sickler patients are susceptible to many organism including:
o M Meningococcus , and mycobacterium.
o E E.coli and EBV
o S strept. , staph. , and sallmenolla
o H H.influnza, heptits C, hepatitis B, and HIV
o R respiratory syncytial virus (RSV)
o P Parvovirus B19
 Osteomyelitis caused by staph. aureus, strept. pneumoniae, salmonella,
and H. influenzae. (most commonly by salmonella typhimurium)
 Septic arthritis caused by staph aureus, streptococcus, E.coli, and
salmonella.
 Pneumonia caused by Chlamydia, mycoplasma, and strept pneumoniae.
 M.pnemoniae cause upper & lower respiratory infection.
o It can cause digital necrosis, if sickler patient have very high titers
of cold agglutinins.
 Urinary tract infection.
 Intra-abdominal infection by non-typhoidal salmonella, especially as
splenic abscess.
 Hepatitis by HBV or HCV.
 Sickling and pregnancy
o Impaired placental blood flow, it will causes
 spontaneous abortion
 intrauterine growth retardation
 Pre-eclampsia
 fetal death.
o Mother may get severe anemia, painful episodes, and infections.
o Note: 1) Prophylactic blood transfusion does not improve fetal outcome.
2)Oral contraceptives with low-dose estrogens are safe.

 Factors associated with increased morbidity and reduced survival

o more than three crises requiring hospitalization per year
o chronic neutrophilia
o a history of splenic sequestration or hand-foot syndrome
o second episodes of acute chest syndrome.

 Sickling and organ transplantation

o Hb SS Patient that get organ transplantation (such as kidney transplantation) will
suffer of increase frequency and severity of painful crisis as result from increase
liability of infection because they will given immunosuppressive drugs to manage
transplantation.
 Cause of death
o The commonest causes of death is due to respiratory complication, i.e. acute
chest syndrome, pulmonary hypertension, and chronic lung disease.
o (According to Kochar's 5th edition) Most common causes of death are infection
(48%), stroke (10%), complications from transfusion reactions (7%), splenic
sequestration (7%), thromboembolism (5%), renal failure (4%), and
pulmonary hypertension (3%).
 Clinical presentation of Sickle cells anemia
o Patient present with painful crisis in ER (emergency room) at middle of night or
early morning and they are crying especially children
 You will give them analgesic (Pethidine), which may became addicted to it.
 investigations
o Low hemoglobin level (HB range from 6-8 g/dl) & reticulocyte count 10-20%.
o hematocrits = 15–30%
o The mean corpuscular volume(MCV) is high (=80-100 fL) due to increase
reticulocytosis. (If it is within normal limits, the possibility of another
hemoglobinopathy or iron deficiency must be excluded).
o Granulocytosis is common
o Peripheral blood smear show
 Sickle-shaped red cells
  Howell-Jolly bodies (which are remnant of nucleus), it indicate
hyposplenism.
 Polychromasia (immature red cells without nucleus and have bluish color)
 Reticulocytosis
o Sickle solubility test:
 Incubate blood with reducing solution such as sodium dithionite, Hb S will
precipitate and give a turbid appearance, where normal Hb give clear
solution.
 This is screening test can done by using commercial kits such as Sickledex.
 This test can't distinguish between Hb SS, Hb AS.
o Electrophoresis
 In case of sickle cell disease: Hb SS is 80-95%, Hb F is 2-20%, Hb A 0%.
 Hb D move identical to Hb S in alkaline pH (PH 8.5) in cellulose acetate. But
HbD can be distinguished from Hb S by its normal solubility as well as different
mobility from Hb S on citrate agar electrophoresis at pH 6.2.
o isoelectric focusing or HPLC fractionation
 Screening test to infant less than 6 months aged.
o DNA analysis.

 Management of sickle cell disease

o I.V fluid or oral hydration.
o Antibiotic
 Penicillin as prophylaxis
o Analgesic
 Morphine (its side effect : bronchospasm and pulmonary edema)
o Oxygen
o Folic acid
o Hydroxycarbamide (INN) or hydroxyurea (used to reduce episodes of pain by
increase Hb F production, and decrease reticulocyte and granulocyte counts)
o Pulsed admission of Butyrates (it stimulate HbF production).
o Blood transfusion (to increase the oxygen-carrying capacity), given in case of
 Severe anemia (if Hb less than 6 mg/dl)
 heart failure
 TIAs (Transient ischemic attack)
 Strokes
 acute chest syndrome
 acute splenic sequestration
 aplastic crises
o blood exchange (to improve viscosity and reduce the risk of iron overload), given
in case of:
 severe or recurrent crises
 before emergency surgery
 o Vaccination
 polyvalent pneumococcal vaccine
 Haemophilus influenzae type B vaccine
 Meningococcal quadrivalent vaccine
o Bone marrow transplantation

 common surgeries in sicklers:

o splenectomy (due to acute splenic sequestration)
o cholecystectomy (due to gallstones)

Sickle cell haplotype

 There are two main haplotypes: African type and Asian type.
 Asian haplotype called Indian/Arabian type.
 African haplotype : Senegal type, Benin type, Bantu type, Cameroon type
 Here in saudia, we have Indian/Arabian type in eastern region, and African type in
western and north.
 The most severe haplotype is Bentu type which present in south Africa.
 Mildest haplotype is Senegal type
 Indian/Arabian haplotype is mild to moderate in severity.

Sickle cell and Double Heterozygous

 HB SC disease :
o Clinical course is same as Hb SS , but have lesser degree of hemolytic anemia.
o Presence of Hb C will increase likelihood of thrombosis.
o It is associated with more retinopathy, aseptic necrosis of bones, and life-
threatening episodes of thrombosis during pregnancy.

Drugs contraindicated for sicklers

 Alprostadil (espically intracavernosally) due to risk of priapism.