Presentation on Sickle Cell Disease at Moi University School of Medicine, Eldoret Kenya.

1. SICKLE CELL DISEASE
PRESENTERS: ANTHONY KIBET (MED 4 JNR)
STEVEN AKACH (MED 6)
Facilitator: Dr. Awino

2. DEFINITION
• Sickle cell disease is an inherited structural
haemoglobinopathy that results from a point
mutation of the beta(ß) polypeptide chain of
haemoglobin(Hb), that promotes the polymerization
of deoxygenated hemoglobin, leading to red cell
distortion, hemolytic anemia, microvascular
obstruction, and ischemic tissue damage.
• Haemoglobinopathies are genetic disorders that result
into abnormal production of one of the globin chains
that form haemoglobin.
• It is an autosomal recessive genetic blood disorder
• Is characterized by RBCs which assume a rigid ,sickle
shape

3. • Sickle cell disease occurs in homozygous state and sickle cell
trait in a heterozygous state.

4. AETIOLOGY
• Missense point mutation: substituting
thymine(T) for adenine(A) in the 6th codon of
the beta-globin chain gene that changes coding
of the 6th amino acid from glutamic acid to
valine

5. EPIDEMIOLOGY
• Highest frequency is in tropical regions-Sub-
Saharan Africa, India and the Middle East.
• Over 4.4M people have SCD and over 43M SCT.
• About 300,000 to 400,000 children are born with
SCD each year and over half of these die before
5yrs.
• 3/4 of SCD occur in Africa.
• WHO reports 2% of newborns affected and 6-
15% of all deaths in children under 5.

6. • Recent WHO report estimated Nigeria to have
around 150,000 affected children annually
• In Kenya prevalence of SCD is at 1.6% and a 4.5%
mortality based on a study by Komba et al in Kilifi
District
• Western Kenya study by Foote et al,2013
reported 1.6% and 17.7% prevalence of HbSS and
HbAS.
• Many children die undiagnosed because of lack
of recognition and comprehensive care.

7. PATHOGENESIS
• Hemoglobin consists of a tetramer of globin
polypeptide chains: a pair of α -like chains 141
amino acids long and a pair of ß -like chains 146
amino acids long.
• The major adult hemoglobin, HbA, has the
structure α 2 ß 2.
• HbF (α 2 γ2) predominates during most of gestation
and HbA2 (α 2 δ 2) is minor adult hemoglobin.
• The sickle cell syndromes are caused by a mutation
substituting thymine for adenine in the sixth codon
of the beta-globin chain gene that changes coding
of the 6th amino acid from glutamic acid to valine.

8. PATHOPHYSIOLOGY
• Sickle cell anemia is caused by a point mutation in
the beta-globin chain of Hb.
• Hydrophilic amino acid glutamate is replaced
by hydrophobic amino acid valine at position 6
–chromosome 11.
• Under low O2 conditions, absence of a polar amino
acids at position 6 promotes non-covalent
polymerisation(aggregation) of Hb.
• This distorts RBCs into a sickle shape and
decrease cell’s elasticity.
• In SCD ,low O2 tension promotes RBC sickling and
repeated episodes damage cell membrane.

9. • Repeated and prolonged sickling makes the RBC
assume the characteristic sickle shape and the
membrane damage makes the RBC unable to revert
back to biconcave shape when oxygenated.
• They become . From 5-50% of RBCs permanently
remain in the sickled shape.
• When RBCs sickle, they gain Na+ and lose K+.
Membrane permeability to Ca++ increases due to
impairment in the ATPase dependent Ca++ pump.
• The membrane becomes more rigid, possibly due to
changes in cytoskeletal protein interactions.
• Sickled cells lose the pliability needed to traverse
small capillaries leading to vessel occlusion and
ischemia.

10. • Sickle cells express very late antigen (VLA)-4 on the surface
which interacts with vascular cell adhesive molecule
(VCAM)-1.
• This leads to the adhesion of sickle cells to the vascular
endothelium especially small venules.
• VCAM-1 is up regulated by hypoxia.
• VCAM-1 is inhibited by nitric oxide.
• Hypoxia also decreases nitric oxide production, thereby
adding to the adhesion of sickle cells to the vascular
endothelium.
• Nitric oxide is a vasodilator
• Free Hb is an avid scavenger of nitric oxide.
• Because of the continuing active hemolysis, there is free
Hb in the plasma, and it scavenges nitric oxide.
• This makes it less available and contributes to
vasoconstriction

11. • Neutrophils also take part in the adhesive process
due to expression of increased levels of adhesive
molecules.
• Hemolysis due to : Sickle cells adhering to
macrophages resulting in erythrophagocytosis &
intravascular hemolysis, possibly due to loss of
membrane filaments during oxygenation and
deoxygenation..
• Autoimmune process also implicated in hemolysis
• Bone marrow compensation fails to match rate of
destruction. Sickle cells only survive 10-20 days,
compared to normal RBCs that can last for up to
120 days.

12. These abnormalities provoke:
1) unpredictable episodes of microvascular vasoocclusion
(painful vasoocclusive crisis )
2) premature RBC destruction (hemolytic anemia).
3 ) multiple organ damage with microinfarcts, including
heart, skeleton, spleen, and central nervous system - The
rigid adherent cells clog small capillaries and venules,
causing tissue ischemia, acute pain.
• venoocclusive component usually dominates the clinical
course.
• Several sickle syndromes occur as the result of inheritance
of HbS from one parent and another hemoglobinopathy,
such as thalassemia or HbC (α2β2
6 Glu→Lys), from the other
parent.
• sickle cell anemia, is the homozygous state for HbS

13. TYPES OF SCD
 Sickle cell anaemia- homozygous form
(HbS,HbS)
 Severest form
 Sickle cell trait- heterozygous form(HbS,HbA)
 Hemoglobin S-C disease- has no normal
hemoglobin
 Its form is HbS and HbC
 Similar mutation form for HbC except glutamic
acid is substituted by lysine
 2nd most common type of SCD
 Sickle cell thalassemia

14. Factors that promote sickling
• Hypoxia
• Acidosis
• Dehydration
• Increase in temperature.

15. MANAGEMENT OF SICKLE CELL DISEASE
STEVEN AKACH

16. CLINICAL MANIFESTATION
• Clinical signs and symptoms typically develop at an early age
(about 4-6 months of age).
• Earliest presentation is the hand-and-foot syndrome (painful
and swollen hands and/or feet in children).
• Dx in 1st yr of life =10%. Most common age at dx is 1-3 yrs.
Upto 20% are over 10yrs at dx

17. CLINICAL MANIFESTATION
• Height and Weight below average thro’t childhood with little body fat,
long and thin limbs. Height lost due to lordosis
• Bones of the skull show bossing – reversible with long term anti-malarial
prophylactics (Enlargement of medullary cavity of bones due to incr
hemopoietic activity)
• Pallor, Jaundice, enlarged liver and gallstones (10%). Spleen initially large
but shrinks later
• Enlarged heart with displaced apex beat
• Polyuria, polydipsia, enuresis and nocturia due to infarcted renal medulla
• Delayed skeletal maturation – late epiphyseal fusion

18. CLINICAL MANIFESTATION
• Anemia: RBC destruction, Nutritional deficiency, Aplastic crisis, Medication side
effect, sequestration. hemolytic anemia, with hematocrits from 15 to 30%,
reticulocytosis
• Episodes of Pain: Vaso-occlusion, Chronic pain syndrome, dehydration
• Jaundice: RBC destruction, chronic hemolysis
• Frequent infections/Fever: Asplenia, Nutritional deficiencies,defective humoral
immunity
• Priapism: Vaso-occlusion, venous stasis
• Fatigue/weakness: Low Hb, general ill health, lack of proper rest,
depression,stroke if one sided weakness
• Shortness of breath: Low Hb, Possible cardiac complications, Acute chest
syndrome

19. PRECIPITATING FACTORS
• Infections (Covid-19)
• Thirst and dehydration
• Over-exertion
• Over-excitement
• Cold weather and cold drinks and swimming
• Bangs, bumps, bruises and strains
• Stress triggers pain in adults, but does not seem to do so in
children.

20. Precipitating factors
Vaso-occlusive crises
• Cold weather (due to
vasospasm)
• Hypoxia (eg, flying in
unpressurized aircraft)
• Infection
• Dehydration (especially from
exertion or during warm weather)
• Acidosis
• Alcohol intoxication
• Emotional stress
• Pregnancy
Aplastic Crises
• Infection with parvovirus B19
• Folic acid deficiency
• Ingestion of bone marrow toxins
(eg, phenylbutazone)
Acute Chest Syndrome
• Fat embolism
• Infections
• Pain episodes
• Asthma

21. CAUSES OF ANEMIA
• Hemolysis
• Inappropriately low serum erythropoietin (EPO) concentrations
due to progressive renal disease
• Folate and/or iron deficiency resulting from increased
utilization of folate and enhanced urinary losses of iron.
• The net effect is that iron deficiency is present in
approximately 20% percent of patients with sickle cell disease
• Infections e.g. Malaria

22. ACUTE & CHRONIC MANIFESTATION
Acute Manifestations:
• Bacterial Sepsis or meningitis
• Recurrent vasoocclusive pain (dactylitis,
muscoskeletal or abdominal pain)
• Splenic Sequestration
• Aplastic Crisis
• Acute Chest Syndrome
• Stroke
• Priapism
• Hematuria, including papillary necrosis
Chronic Manifestations:
• Anemia
• Jaundice
• Splenomegaly
• Functional asplenia
• Hyposthenuria and enuresis
• Proteinemia
• Cholelithiasis
• Delayed growth and sexual maturation
• Pulmonary Hypertension
• Avascular necrosis
• Proliferative retinopathy
• Leg ulcers

23. Vaso-occlusive(Painful crisis)
• Head to toe pattern
• Occurs when the microcirculation is obstructed by sickled RBCs, causing ischemic injury to
the organ supplied. Recurrent episodes may cause irreversible organ damage.
• Pain is the most frequent complaint during these episodes
• Bones pain (eg, femur, tibia, humerus, lower vertebrae) frequently are involved. Involvement
with the femoral head results in avascular necrosis.
• Joints and soft tissue involvement present as dactylitis or as hand and foot syndrome
• When it involves abdominal organs it can mimic an acute abdomen.
• With repeated episodes, the spleen auto infarcts, rendering it fibrotic and functionless in
most adults with sickle cell anemia. (Autosplenectomy)
• The liver also may infarct and progress to failure with time.

24. Vaso-occlusive(Painful crisis)
• Papillary necrosis is a common renal manifestation of vasoocclusion,
leading to isosthenuria (i.e. inability to concentrate urine).
• This is due to occlusion of vasa recta capillaries in the medulla. The normal
medullary has both a low oxygen tension and high osmolality (osmotically
dehydrating the red cells, thereby increasing the concentration of HbS).
• Painless hematuria,renal colic, focal glomerulosclerosis that can lead to
end-stage renal disease; Renal medullary carcinoma is a recently described
malignancy found almost exclusively in black patients with sickle cell
disease and trait
• Vasoocclusive crises can involve the lungs and cause an acute chest
syndrome. Causes are lower respiratory tract infection, bone marrow fat
embolism, pulmonary Infarction, acute pulmonary sequestration, bone
pain crisis in in thoracic cage; results in respiratory failure

25. Vaso-occlusive(Painful crisis)
• CNS manifestations of vasoocclusive crises include cerebral infarction (children),
cerebral hemorrhage (adults), seizures, TIA, cranial nerve palsies, meningitis,
sensory deficits, acute coma..
• These pts are often maintained on hypertransfusion programs to suppress HbS.
• Risk factors for infarct; prior TIA, low steady state hemoglobin, acute chest
syndrome within past 2 wks, elevated systolic blood pressure
• Skin ulceration, especially over bony prominences (malleoli), Retinal
hemorrhages(ischemia, fragile neovascularisation, hemorrhage, traction retinal
detachments, blindness)
• Occlusion in corpus cavernosum, preventing blood return from the penis and
leading to priapism. occurs in 6-42% of males with SCD. two peak frequencies:
between the ages 5 and 13 and the ages 21 and 29

26. APLASTIC CRISIS
• Xterized by the transient arrest of erythropoiesis, abrupt
reductions in Hb and red cell precursors in the bone marrow,
and without reticulocytes in the PBF.
• Mostly due to human parvovirus B19 which specifically invades
proliferating erythroid progenitors. Other causes include S.
pneumoniae, Salmonella, and Epstein-Barr virus. Also folic acid
deficiency.
• Reticulocytes reappear within 2-14 days after treatment with
transfusion

27. DANGER SIGNS OF A CRISIS
1. Fever
2. Chest pain
3. Shortness of Breath
4. Increasing tiredness
5. Abdominal swelling
6. Unusual headache
7. Any sudden weakness or loss of feeling
8. Pain that will not go away with home
treatment
9. Priapism (painful erection that will not
go down)
10.Sudden vision change

28. SPLENIC SEQUESTRATION CRISIS
• Due to thrombosis of the venous outflow from an organ
• Vaso-occlusion within the spleen and splenic pooling of red cells
produce a marked fall in hemoglobin concentration (2g/dl),high
reticulocyte count and a rapidly enlarging spleen..
• Sequestration can occur as early as a few weeks of age and may
cause death before sickle cell disease is diagnosed
• Sequestration is recurrent in 50 percent of survivors
• In adults the liver may undergo sequestration with severe pain due
to capsular stretching

29. BONE COMPLICATIONS
• The skeletal system is frequently involved in
sickle cell disease due to: accelerated
hematopoiesis and bone infarction
• The extended hematopoietic marrow
resulting from the chronic hemolysis can lead
to chronic tower skull, bossing of the
forehead, and fish-mouth deformity of
vertebrae.
• These effects cause widening of the
medullary space, thinning of the trabeculae
and cortices and osteoporosis.

30. BONE PAIN
• Most common form is hand-and-foot syndrome (dactylitis) due to
infarction of bone trabeculae and marrow cells
• 1st occurs btwn 6months-2yrs
• Symmetrical swelling on dorsum of hand or foot
• If hot, red and flactuant – suspect osteomyelitis
• After 2yrs of age pain shifts to the long bones and pain is localized
around joints, may be in multiple sites and symmetrical
• Usually spontaneous resolution in 5 days
• Pulmonary fat embolism occurs occasionally

31. INFECTIONS
• Affected children are vulnerable to life-threatening infection as
early as four months of age because of splenic dysfunction caused
by sickling of the red cells within the spleen and the inability of the
spleen to filter microorganisms from the blood stream.
• Aetiology is mostly encapsulated organisms, especially
S.pneumoniae, Haemophilus influenzae type B, Neisseria
meningitidis, Salmonella
• Dysfunctional IgG and IgM antibody responses, defects in
alternative pathway fixation of complement, and opsonophagocytic
dysfunction may also play a role in the predisposition to invasive
infection

32. INFECTIONS
• Bacteremia – mostly due to S. pneumoniae. Bacteremia typically presents
with leukocytosis, a left shift, aplastic crisis and sometimes DIC
• Bacterial pneumonia – Causes include M. pneumoniae, C.pneumoniae,
Legionella and respiratory viruses. Presentation: dyspnea, cough, chest
pain, fever, tachypnea and leukocytosis and may develop the acute chest
syndrome
• Osteomyelitis: The most common offending organisms in US & Europe(S.
aureus 25%). S.typhi (50%) & E.coli. Others - Serratia, Enterobacter cloacae,
Enterococcus faecium, and Pseudomonas aeruginosa.
• In Sub-Saharan Africa – S. aureus 80% & S. typhi (20%)
• Articular infection is less common and is often due to S. pneumoniae

33. INVESTIGATIONS

34. PRE-NATAL TESTING
• DNA-based testing for sickle cell can be performed during the first
trimester of pregnancy on villi obtained by chorionic villus sampling
(typically performed at 10 to 12 weeks of gestation), or
• on cultured amniotic fluid cells obtained by amniocentesis
(typically performed after 15 weeks of gestation)
WHO TO TEST- AT RISK COUPLES
• Parent history — Parents may have a history of anemia
• History of a relative with a hemoglobinopathy
• Couples from extended families living in endemic areas
• Parents ethnic background

35. NEWBORN SCREENING
• Infants with SCD generally are healthy at birth and develop symptoms only
when fetal hemoglobin levels decline later in infancy or early childhood.
Goals :
• Early recognition of affected infants
• Early medical intervention to reduce morbidity and mortality, particularly
from bacterial infections
• Institution of regular and ongoing comprehensive care
• Access for families of children with SCD to accurate information about the
diagnosis, clinical manifestations, treatment options, and age-appropriate
anticipatory guidance toward the management of these emerging issues.

36. OLDER CHILDREN AND ADULTS
• The purpose of correct diagnosis in this age group is to identify patients
who need therapy for sickle cell disease and counseling for the disease or
the trait.
Methodology
• High performance liquid chromatography (HPLC)-is a highly precise
technique. This automated technique is able to detect most hemoglobin
variants by their different retention times.
• It is highly sensitive and specific and provides both quantitative and
qualitative interpretation
• Cellulose acetate electrophoresis at pH 8.4 is a standard method of
separating Hb S from other hemoglobin variants. However, Hb S, G, and D
have the same electrophoretic mobility with this method

37. OLDER CHILDREN AND ADULTS
• Thin layer isoelectric focusing is a highly accurate and cost
effective.The bands on isoelectric focusing are sharper than
those on electrophoresis and can distinguish some
hemoglobins not seen on standard electrophoresis.
• Citrate agar electrophoresis at pH 6.2 separates Hb S from Hb
D and G, which co-migrate with Hb A in this system.
• A solubility test such as the Sickledex® also distinguishes Hb D
and G from Hb S as only Hb S precipitates using this test

38. OTHER RELEVANT INVESTIGATIONS
• Complete blood count: the level of Hb is in the range 6-8g/dl with a high
reticulocyte count(3-15%), hematocrit 20-30%.
• **Blood films: features of hyposplenism (howell-jolly bodies),
polychromasia indicative of reticulocytosis and sickling(sickle-shaped cells).
• Sickle solubility test: a mixture of hbs in a reducing soln e.g Na dithionate
gives a turbid appearance coz of precipitation of hbs , whereas normal hb
gives a clear soln.
 Sickledex- for rapid screening of presence of Hbs. A solubility test that
distinguishes Hb D and G from Hb S as only Hb S precipitates using this
test.
• **Hb electrophoresis: is needed to confirm the dx. (there is no Hb A, 80-
90% Hb SS & 2-20% Hb F).

39. OTHER RELEVANT INVESTIGATIONS
• Liver function tests – Unconjugated hyperbilirubinemia
• BUN, creatinine, and serum electrolytes
• Fetal hemoglobin
• Lactic dehydrogenase and haptoglobin
• Elevated levels of LDH show hemolysis
• Decreased levels of haptoglobin confirm the presence of
hemolysis.

40. IMAGING
• Radiograph to demonstrate areas of infarction for painful
bones.
• CT/MRI to demonstrate areas of avascular necrosis for the
femoral and humeral heads and may distinguish between
osteomyelitis and bony infarction for painful bones
• Abdominal sonogram is useful to document spleen size and
the presence of biliary stones
• Adults should be tested for evidence of pulmonary
hypertension with Doppler echocardiography

41. TREATMENT
STEVEN AKACH

42. Principles of Treatment
Goals of Therapy
To reduce:
• Hospitalizations
• Complications
• Mortality
Interventional Approaches
Primary
• Public Health Education
• Awareness of one’s carrier state
• Reproductive choices
• Prevent birth of sicklers
Secondary
• New Born Screening
• Prevention of the complications
Tertiary
• Management of the complications

43. Principles of Treatment
 GENERAL PRINCIPLES
• No Treatment for the primary disease
• Lifelong multidisciplinary care
• general measures,
• preventive strategies,
• treatment of complications and acute crises.
 Routine immunizations plus influenza,
meningococcal, and pneumococcal vaccinations.
 Prophylactic penicillin for children with sickle
cell disease until they are 5 years old.
• Penicillin V potassium, 125 mg orally twice daily
until 3 years of age and then 250 mg twice daily,
• Benzathine penicillin, 600,000 units (Children)
1.2M (adults) intramuscularly every 4 weeks
• Amoxil 40mg/kg for 10 days.
• Folic acid, 1 mg daily, is recommended in adult
patients, pregnant women, and patients of all
ages with chronic hemolysis.

44. HbF STIMULATORS/ALTERNATIVE STRATEGIES
Hydroxyurea, a chemotherapeutic agent
• Stimulate HbF by stimulating erythropoiesis
• In patients with frequent painful episodes, severe symptomatic anemia,
acute chest syndrome, or other severe vasoocclusive complications.
Butyrate and 5-aza-2-deoxycytidine.
Chronic transfusion every 3 to 4 weeks The optimal duration is unknown
• to prevent stroke and stroke recurrence in children.
• Maintain HbS of less than 30% of total hemoglobin..
• Risks include, hyperviscosity, viral transmission (requiring hepatitis A and B
vaccination), volume and iron overload, and transfusion reactions.

45. HbF STIMULATORS/ALTERNATIVE STRATEGIES
Allogeneic hematopoietic stem cell transplantation
• The only therapy that is curative.
• Best candidates are
• younger than 16 years of age,
• With severe complications,
• Have HLA Matched donors
• Risks: mortality, graft rejection, and secondary malignancies
NOTE:
 Skin stem cells cure mice of sickle cell anemia
 Success is proof that technique has potential to cure disease

46. COMPLICATIONS
• Acute Chest Syndrome
• Septicemia
• Stroke or CVA
• Acute splenic sequestration crisis (ASSC)
• Aplastic Crisis
• VasoOcclusive pain: Sickle cell crisis
 Severe pain is an emergency called acute sickle cell crisis
• Osteomyelitis
Also known as sickle cell crises: Rapid diagnosis and treatment are
necessary to minimize morbidity and mortality.

47. Acute Chest Syndrome
• One of the most serious and life-
threatening complications of SCD
• Leading cause of mortality and
morbidity in affected patients, since
the impact of more effective
antimicrobials and the
pneumococcal vaccine
• Caused by a vasoocclusive crisis
involving the pulmonary
vasculature.
• Not distinguishable from
pneumonia
Diagnosis
• New infiltrate on chest radiograph
in combination with at least 1
clinical sign or symptom
Sx: Chest pain, cough, tachypnea,
fever, wheezing.
• Fever and cough are the most
common in children
• Chest pain, sob, and chills are
common in adults.

48. Acute Chest Syndrome
Common causes
• Pulmonary infection:
• Mycoplasma pneumoniae more
commonly associated with acute
chest syndrome
• Thromboemboli Fat emboli
• Rib infarction
Possible causes
• Iatrogenic: excessive hydration
&
• narcotic use
• Note: Infection and fat emboli
were the most common
identifiable causes.

49. Acute Chest Syndrome - Management
Supportive
• Oxygen for hypoxia
• Appropriate hydration
• Appropriate pain control
Medical
3rd Generation Cephalosporins (Ceftriaxone) + Macrolides (Azithromycin)
Transfusion therapy:
• Reports of dramatic improvement in clinical condition after initiation of transfusion
• Simple transfusion
• Exchange transfusion
Experimental therapy
• Nitric oxide
• Corticosteroids

50. SEPTICEMIA
• SCD pts have impaired immunologic function that is caused by splenic
dysfunction.
• Impairment of splenic function can occur in infants as young as 3 months.
• High risk for encapsulated organisms such as S pneumoniae and H influenzae.
Recommended antibiotic
• Third-generation cephalosporin; ceftriaxone, or cefotaxime
• Vancomycin should be added to protect against penicillin- resistant strains of S
pneumoniae if suspected until culture results become available
Note: All SCD patients with fever must be managed with extreme caution because
of the risk of overwhelming bacteremia which can rapidly lead to septic shock.

51. STROKE/CVA
• Major SCD complication.
• Is a leading cause of death in both and disability children and
adults
• The most common is blockage of the intracranial internal carotid
and middle cerebral arteries. (Ischemic stroke)
• Patients with stroke usually present with obvious signs such as
acute hemiparesis, aphasia or dysphasia, seizures, severe
headaches, cranial nerve palsy, altered mental status, or coma.
• The most common tends to be hemiparesis.
• Can be very subtle, such as a slight limp

52. STROKE/CVA - Management
• Patients should be rehydrated immediately
• Stroke: Transcranial Doppler prior, Exchange transfusion
• Exchange transfusion advocated – but should be individualized
• Recurrent transfusions aimed at reducing HbSS to less than 30% largely prevent recurrent
strokes
Initial therapy is
• exchange transfusion in an ICU setting to reduce Hb S to less than 30% of total Hb.
• After acute clearance of symptoms should be started on a long-term transfusion therapy.
• If not on a long-term transfusion program have an 80% chance of recurrent stroke within 3
years of the initial event
• Long-term transfusion involves regularly scheduled blood transfusions aimed at reducing
the percentage of Hb S and not at normalizing the Hb level.

53. ACUTE SPLENIC SEQUESTRATION CRISIS (ASSC)
Clinical Presentation:
• Sudden impounding of red blood cells by the spleen
• Characterized by the rapid fall in hemoglobin concentration, rise in reticulocyte count, and
splenomegaly
• Requires prompt recognition and treatment.
• In the adult patient, ASSC is extremely rare.
• Hypotension caused by large volumes of blood (mainly sickled cells) entrapped in the
spleen.
• Hb levels may fall acutely more than 2 g/dL less than the patient's normal value, causing
circulatory compromise
Treatment
• Prompt diagnosis and therapy with RBC transfusions
• Surgical splenectomy may be indicated in certain patients to prevent recurrences

54. APLASTIC CRISIS
• Temporary cessation of red cell production with a corresponding decrease in the
reticulocyte count.
• Approximately 80%, are thought to be caused by human parvovirus B19
infection
• Diagnosis is made by comparing baseline blood and reticulocyte counts to those
obtained during the acute illness.
• Sign Symptoms: , tachypnea, tachycardia, or hypoxia
Treatment:
• Simple blood transfusion to raise serum Hb back to the patient's baseline and to
prevent heart failure secondary to severe anemia.
• Parvovirus B19 is contagious, affected persons should be isolated from
pregnant women, who are at risk for miscarriage with infection, and from
immuno-compromised patients and those

55. OSTEOMYELITIS
• Most commonly caused by Salmonella species or Staphylococcus aureus
• Bone pain or joint pain with localized swelling and decreased range of
motion, along with fever, should alert the physician to the possibility of
osteomyelitis.
• Increased white blood cell count and elevated ESR
• Broad-spectrum antibiotic:
 Ceftriaxone: Covers s.typhi and staph
After culture:
Specific therapy for gram +ve staph, s. typhi.
Vancomycin for MRSA

56. PRIAPISM
• Painful prolonged erection of the penis
• Caused by sickling of the red blood cells producing venous stasis in the erectile tissue of the penis.
• The resulting stasis causes ischemia, hypoxia, and pain.
Treatment:
• Initial treatment involves intravenous hydration and analgesia.*
• Antianxiety agents
• Vasoconstrictors to force blood out of corpus cavernosum:
 Phenyl ephedrine
 Epinephrine
• Vasodilators: to relax smooth muscles:
 Terbutaline
 Hydrallazine
• Episodes refractory to this initial management include direct irrigation of the corporeal bodies of the
penis

57. VASO-OCCLUSIVE PAIN CRISES: SUMMARY
• Most common symptoms of SCD
• Severe pain
• Caused by sickle-shaped red blood cells trapped in small blood vessels causing localized
ischemia.
Triggered by
• Dehydration, fever, cold exposure, and emotional stress
Therapy
• Intravenous/Oral hydration
• Pain management
• It is useful to assess pain in a standard manner using pain measurement scales (see next)
Causal Treatment: (treatment of the cause)
• Poloxamer 188 (Flocor) a surfactant - returns RBCs to a non adhesive state and blocks RBC
aggregation to enhance blood flow in ischemic

58. NUMERICAL PAIN PAIN SCALE
• 0- Pain free
• Mild Pain – Nagging, annoying, but doesn't really interfere with daily living activities.
1 Pain is very mild, barely noticeable. Most of the time you don't think about it.
2 Minor pain. Annoying and may have occasional stronger twinges.
3 Pain is noticeable and distracting, however, you can get used to it and adapt.
Moderate– Interferes significantly with daily living activities.
4-Moderate pain. If you are deeply involved in an activity, it can be ignored for a period
of time, but is still distracting.
5 - Moderately strong pain. It can't be ignored for more than a few minutes, but with effort
you still can manage to work or participate in some social activities.
6- Moderately strong pain that interferes with normal daily activities. Difficulty
concentrating.

59. PAIN SCALE
• Severe Pain – Disabling; unable to perform daily living activities.
• 7 – Severe pain that dominates your senses and significantly
limits your ability to perform normal daily activities or maintain
social relationships. Interferes with sleep.
• 8 – Intense pain. Physical activity is severely limited.
• Conversing requires great effort.
• 9-Excruciating pain. Unable to converse. Crying out and/or
moaning uncontrollably.
• 10 – Unspeakable pain. Bedridden and possibly delirious. Very
few people will ever experience this level of pain

60. PAIN SCALE
 Mild to moderate pain - NSAID’s or acetaminophen.
 Moderate pain - Weak opioid, such as codeine or hydrocodone.
 Severe pain
• IV opioid morphine, hydro-morphone, fentanyl, and methadone.
• Titrate to pain relief and then administer on a scheduled basis with as-needed dosing for
breakthrough pain.
• Patient-controlled analgesia can be used
Avoid
• Meperidine should be avoided because accumulation of the normeperidine metabolite can cause
neurotoxicity, especially in patients with impaired renal function
• Minimize dependence /addiction by :
• Aggressive pain control,
• Frequent monitoring,
• Tapering medication according to response

61. PRINCIPLES OF PAIN MANAGEMENT
 Morphine is the preferred agent in treatment of sickle cell pain.
 Start by the mouth
 By the Clock:
• Regular analgesia (4-6 hourly) with breakthrough doses when needed
 By the ladder:
• Patients move up the ladder or may also move down the ladder if pain
decreases.
 Individualized Therapy:
• Start with higher step for Patients presenting with moderate to severe pain.
• Some don’t tolerate oral medication, plan for alternative route.
• Consider non drug therapies. as well
• No standard dose of opioid - morphine from 5mg to 1000mg every four
hours.
 With attention to detail:
• Total analgesia usage should be monitored every 24 hours,
• Breakthrough doses should be adjusted in line with changes to regular
medication.
• New pain should be assessed promptly
• Patients should be informed of possible adverse drug effects.

62. When and how IV
• REASSESS before starting IV opioids and ADJUST dose frequently,
but not before 8 hours
• Scheduled IV Narcotic Dosing for 24 hours, round the clock
• Morphine sulfate: 0.1 mg/kg, 5 - 10mg, IV scheduled every 3-4
hours.
• Hydromorphone: 0.015 mg/kg, 0.75 - 2mg, IV scheduled every 3-4
hours.
• Monitor vital signs and pain level, using the pain scale, before and
after every dose

63. IV Dosing Cares
• Doses should be based on level of tolerance to opioids. Most
SCD patients have some opioid tolerance.
• Maximum analgesic effect within 10-15 minutes and will
usually last 2-3 hours.
• Consider around-the –clock (ATC) (patient may refuse) to
ensure the patient is offered the medication consistently at
the preferred interval.

64. Scheduled IV Narcotic Dosing - Opiate Tolerant
patients
 Convert the patients usual oral dose to IV:
 Morphine IV/PO ratio: 1:3
 Hydromorphone IV/PO ratio: 1:5
• Example: Patient is taking morphine SR 60mg PO q12h and is now in pain crisis,
requiring an additional 10mg PO q4 hours. 10mg X 6 = 60 mg + (60 mg x 2) =
180 mg PO morphine/day.
• Convert PO to IV: 180mg PO / 3 = 60mg IV over 24h = 10mg IV q4h
• Start with 50-75% of the calculated equianalgesic dose if changing / converting
to a different opioid to allow for incomplete cross-tolerance between opioids.
 Dose adjustment for taper
• Decrease dose by 25% per day once the patient’s pain is under control for 24
hours

65. Monitoring the Patient
• Chest X-ray: Order for any patient with cardiopulmonary complaints,
hypoxia, know chronic lung disease, fever, tachycardia, or tachypnea.
• Complete blood count q24 hours
• Comprehensive metabolic panel, magnesium, phosphorous q48 hours
 Keep magnesium level > 2 mg/dL:
 Magnesium < 1.8 mg/dL, replace with IV magnesium
 May need to follow with daily oral supplementation
 Magnesium > 1.8 mg/dL, replace with oral product
• Lactic dehydrogenase (LDH) q72 hours

66. Converting IV to Oral Pain Management
• Once the IV dose has been tapered to 50% of the initial dose, start
oral morphine or hydromorphone:
• Morphine & Hydromorphone: Add total daily dose of IV morphine
received; multiply by 2-3 to determine total daily dose.
• Immediate release formulations should be administered on a
scheduled basis, every 4 hours.
• Sustained release formulations should be administered every 12
hours.
• Morphine to oral Oxycodone:
Convert morphine 10mg IV q4h to oxycodone 30 mg PO q6h.

67. Adjunct therapies
• Bowel regimen: All patients on opioids must also be on a bowel
regimen of stool softener and a cathartic.
• May administer Hydroxyzine 25-50 mg PO with each narcotic dose.
• Itching:
Diphenhydramine 50mg IV/PO can be given with the initial dose of
morphine and PRN
Diphenhydramine may be given in conjunction with opiates for
additive effect.
• Nausea: administer prochlorperazine 10mg PO PRN nausea.

68. MANAGEMENT OF OTHER CRISES
ANAEMIC CRISIS
• Folic acid supplementation (1g OD)
• An adequate overall diet is essential
• Transfuse as needed. Target Hb between 7-9g/dl
• Blood transfusions is given in three situations:
i. To improve oxygen carrying capacity (Hb<6g/dl) and as volume
replacement during an aplastic or splenic sequestration crisis.
ii. To provide protection from imminent danger during acute chest syndrome
or septicemia.
iii. To improve properties of blood and prevent initial or recurrent cerebral
thrombosis, to prevent recurrent priapism, and to reduce perioperative
complications

69. ANAEMIC CRISIS
• Transfusion therapy for individuals with SCD can be categorized
as therapeutic or prophylactic. Accepted indications include:
• Therapeutic — Used in acute stroke, acute chest syndrome,
acute multi-organ failure, acute symptomatic anemia, aplastic
crisis, reticulocytopenia (most commonly associated with
Parvovirus B19 infection, but can occur with any infection),
pre-operative settings, hepatic or splenic sequestration.
• Prophylactic — Used for primary or secondary stroke
prevention.

70. ANAEMIC CRISIS
• Chronic red cell transfusion lowers the percent of sickle hemoglobin (HbS)
in subjects with sickle cell disease by three mechanisms:
Dilution;
Suppression of erythropoietin release secondary to the rise in hematocrit,
thereby reducing the production of new sickle erythrocytes;
Longer circulating lifespan of normal compared to sickle erythrocytes.
Complications of chronic transfusion
• Iron overload
• Infection

71. INFARCTIVE CRISIS
Principles include:
• Control of Pain
• Acid-base balance and Hydration
• Treatment of infection
Mild pain – paracetamol; Moderate pain – dihydrocodein tartrate; Severe
pain – Opiates such as morphine 10mg stat.
Chronic pain is managed with long-acting oral morphine preparations and
acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs)
Non-pharmacologic pain mgt includes physical therapy, heat and cold
application, acupuncture.
Normal saline and 5% dextrose in saline may be used to correct dehydration

72. PRIAPISM
• Aim of Rx: relieving pain and preventing fibrosis of the Cavernosa
• Mild priapism – relieved by micturition, walking around, avoiding
sexual arousal, and bathing in cold water
• Moderately severe priapism responds within 24 hrs to bed rest,
Sedation, Analgesics, IV hydration and cyproterone or stilbesterol
• Severe Priapism – Opiate analgesics, Rehydration, Under General
or Spinal Anaesthesia a wide bore needle is inserted into the lateral
side of the base of penis and viscous blood aspirated then irrigate
with adrenaline 1:106 in saline and aspiration until fresh blood is
obtained.
• Impotence is the common outcome with sexually mature males.

73. LEG ULCERATION
• Small and clean ulcers – daily antiseptic washing and dressing
• Large Ulcers – bed rest, Antibiotic therapy, H2O2 and
Antitetanus injection.
• Grafting
NOTE
• Patients with SCD should be counseled to:
– To avoid high altitudes
– To maintain an adequate fluid intake
– Treat infections promptly when they occur.

74. PREVENTION OF COMPLICATIONS
• New Born Screening
• Follow up and provide prophylactic management.
• All standard vaccines
Other special vaccines
Pneumococcal vaccine ( PCV 7 and PCV 23 )
Typhoid vaccine
Haematinic Supplementation
Iron - Unnecessary
Folate: start during infancy

75. HYDROXYUREA
INDICATIONS
• Frequent painful episodes (six or more per
year)
• History of acute chest syndrome
• History of other severe vaso-occlusive
events
• Severe symptomatic anemia
• Severe unremitting chronic pain that
cannot be controlled with conservative
measures
• History of stroke or a high risk for stroke
DOSING
• Oral dose started at 500mg (10-15mg/kg)
per day.
• If tolerated, the dosage is increased to
1000mg per day after 6-8 wks; the dose
can be increased further to 2000mg (20-
30mg/kg) per day.
MONITORING
• CBC, HbF, Renal fxn, and hepatic fxn
monitoring required
• Short term toxicity is minimal.
• Long term toxicity is Includes induction of
leukaemias in patients with
myeloproliferative disorders.

76. Hydroxyurea MoA (UpToDate)
• Inhibition of ribonucleotide reductase
• Increased HbF production
• Other proposed mechanisms
Increases Nitric oxide production
RBC rheology (shift to more mature RBCs)
Reduced WBC- Reduced white blood cell (WBC) counts and/or
neutrophil adhesivity to the vascular endothelium may also
contribute to reduced vaso-occlusion.

77. Infection Prophylaxis
• Antibiotic prophylaxis
 Penicillin V or Erythromycin: start at age 2 months
 Dose - 125mg BD if <5 years
 250 mg BD if > 5 years
Benzathine penicillin - I.M 600,000 units every 4 weeks.
• Malaria Prophylaxis
 Proguanil / Paludrine
• 100 mg ( 2- 6 yrs ) , 150 mg ( 7 – 10 yrs )
• 200 mg ( > 10 yrs )
 Mefloquine
• 62.5 mg ( 15 -19 kg ) , 125 mg ( 20 – 30 kg)
• 187.5 mg ( 31 – 45 kg ) 250 mg ( > 45 kg )

78. PRIMARY PREVENTION (prevent birth of sicklers)
• Public Health Education
• Awareness of one’s carrier status
• Pre- conception genetic counseling
• Reproductive choices
• Screening to recognize couples at risk
• Prenatal dx and termination of homozygous or heterozygous
fetuses.

79. • Who should receive counseling?
-Parents of newborns with sickle disorders or traits
-Pregnant women/ prenatal counseling
• What is the purpose of counseling?
-Education
-Informed decision-making
• Content should include:
-Genetic basis, chances of disease or trait (potential pregnancy outcome),
disease-related health problems, variability/unpredictability of disease,
family planning, average life span

80. SCREENING OF COMPLICATIONS
1)Regular blood work up
 CBC
 Reticulocytes
 UECs
 LFTs
2)Transcranial doppler us:annually until 6 years old
3)Retinal exams: anually from 8 years
4)Echocardiography: every 2years from 10 years
old(screen for pulmonary hypertension)
5) urinalysis

81. Other modalities
• Bone marrow transplantation
• Gene transfer therapy

82. PROGNOSIS
• In Africa few children with SCA survive to adult life without
medical attention.
• 15% die by 20 yrs and 50% by 40 yrs (even with std medical
care)
• Three significant predictors of an adverse outcome include:
 Dactylitis before 1yr
 Hb<7 g/dL.
 Leukocytosis in the absence of infection.