3. Diagnosis
SCD is suggested by the typical clinical picture of chronic hemolytic anemia and
vaso-occlusive crisis.
Electrophoresis confirms the diagnosis with the presence of homozygous HbS and
can also document other hemoglobinopathies (eg, HbSC, HbS-beta+ thalassemia).
4. the diagnosis of HbSC disease is made with Hb electrophoresis.
The peripheral blood smear may have some sickled cells and a high proportion of target cells. In
addition, microcytic, dehydrated, dense RBCs are seen. These may contain crystal-like
condensations.
5. Laboratory tests used in patients with SCD
include the following:
Mandatory screening for HbS at birth in the United States; prenatal testing can be obtained via chorionic villus
sampling
Hemoglobin electrophoresis
CBC count with differential and reticulocyte count
Serum electrolytes
Hemoglobin solubility testing
Peripheral blood smear
Pulmonary function tests (transcutaneous O 2 saturation)
Renal function (creatine, BUN, urinalysis)
Hepatobiliary function tests, (ALT, fractionated bilirubin)
CSF examination: Consider LP in febrile children who appear toxic and in those with neurologic findings (eg, neck
stiffness, + Brudzinski/Kernig signs, focal deficits); consider CT scanning before performing LP
Blood cultures
ABGs
Secretory phospholipase A2 (sPLA2)
7. people with sickle trait generally are well and
have the following characteristics:
Normal life expectancy
Not at excessive risk for infection
Not subject to painful crisis under normal circumstances
No anemia
8. the differential diagnosis may also include the
following:
Valvular heart disease
Septic arthritis
Sepsis
Upper respiratory tract infection
Aortic arch syndrome
Facioscapulohumeral muscular dystrophy
Incontinentia pigmenti
Familial exudative vitreoretinopathy
Lupus erythematosus
Macroglobulinemia
Polycythemia vera
Talc and cornstarch emboli
Uveitis, including pars planitis
9. recommendations to decrease severity of
complications :
Use of daily oral prophylactic penicillin up to age 5
Annual transcranial Doppler examinations between the ages of 2 and 16 years in
patients with sickle cell anemia
Long-term transfusion therapy to prevent stroke in children with abnormal transcranial
Doppler velocity (≥200 cm/s)
In patients with sickle cell anemia, preoperative transfusion therapy should be used to
increase hemoglobin levels to 10 g/dL
Rapid initiation of opioids for the treatment of severe pain associated with a
vasoocclusive crisis
Use of analgesics and physical therapy for the treatment of avascular necrosis
9
10. Clinical manifestations and complicatons
of sickle cell disease
Acute Complications
Chronic Complications
10
13. Hydroxyurea Therapy
For frequent and severe pain, long-
term hydroxyurea is currently the
accepted treatment.
13
14. Hydroxyurea Therapy
Indications for hydroxyurea include the following:
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
14
15. Hydroxyurea Therapy
Patients receiving hydroxyurea require frequent blood testing and monitoring:
Due to increase the incidence of the development of leukopenia and/or
thrombocytopenia.
15
16. Transfusion
Acute red cell exchange transfusion is indicated in the following situations:
Acute infarctive stroke
Severe acute chest syndrome
Multiorgan failure syndromes
Right upper quadrant syndrome
Priapism that does not resolve after adequate hydration and analgesia
16
18. Treatment of iron overload
Three agents are used for iron chelation:
Deferoxamine
Deferasirox
deferiprone.
18
19. Treatment of iron overload
Deferoxamine is an efficient iron chelator.
It is administered as a prolonged infusion intravenously or subcutaneously for 5-7
days a week.
Although effective, there are significant challenges associated with its use that can
result in non-compliance.
19
20. Treatment of iron overload
Deferasirox:
it is administered orally.
Renal toxicity might be a limiting factor in its use, but it is generally safe.
Deferiprone:
is considered a second-line therapy, due to lack of effectivity comparing to other agents
.
it selectively removes cardiac iron.
is most effective when used in combination with deferoxamine or deferasirox.
20
21. Erythrocytapheresis
Erythrocytapheresis is an automated red cell exchange procedure that removes
blood that contains HbS from the patient while simultaneously replacing that same
volume with packed red cells free of HbS.
21
22. Management of Ophthalmic Manifestations
Surgical procedures may be performed to treat retinal detachments, nonclearing
vitreous hemorrhage, and epiretinal membranes.
prophylactic preoperative exchange transfusions or erythropheresis is
recommended
patients with sickle cell disease are particularly prone to central retinal artery
occlusion and optic atrophy, even with mildly elevated intraocular pressures,
closely monitor the intraocular pressure. Do not allow it to exceed 25 mm Hg for
longer than 24 hours.
22
23. Vaso-Occlusive Crisis Management
is treated with vigorous intravenous hydration and analgesics.
Intravenous fluids should be of sufficient quantity to correct dehydration and to
replace continuing loss, both insensible and due to fever.
Normal saline and 5% dextrose in saline may be used.
Using hydroxyurea (hydroxycarbamide) significantly reduces the incidence of vaso-
occlusive crisis and dactylitis in very young children
Predictors of admission included the following:
Higher pain score at triage
Older age
Increased systolic blood pressure
23
24. Treatment of Acute Chest Syndrome
Cause : vaso-occlusive episode , neutropenia due to use of hydroxyurea .
Incentive spirometry – In patients with chest or rib pain, to prevent ACS; should be
considered in all patients with ACS
Antibiotics, with cover for atypical organisms, even if blood cultures and sputum
cultures are negative
Anti-viral agents– If there is a clinical suspicion of H1N1 infection
Early simple transfusion should be considered early in patients with hypoxia; however,
exchange transfusion is necessary in patients with severe clinical features or evidence
of progression despite initial simple transfusion
Empiric antibiotics should be initiated and given intravenously, after obtaining
samples for appropriate cultures.
24
25. Treatment of Acute Chest Syndrome
Narcotic agents may be used for more severe pain.
Other supportive therapy as careful hydration.
Volume overload must be avoided, as it may contribute to pulmonary infiltrates
and exacerbate hypoxia.
Intensive care is indicated for patients in severe hypoxia or respiratory distress, as
respiratory decompensation can rapidly require mechanical ventilation.
Treatment should also include oxygen therapy with close monitoring for
hypoxemia with continuous pulse oximetry or frequent assessment of blood gases.
25
26. Management of Chronic Anemia
Women who are menstruating should be checked for coexisting iron deficiency .
Blood transfusion is indicated only in specific situations:
acute chest syndrome
stroke
abnormal findings on transcranial Doppler in children (for stroke prevention)
Pregnancy
general anesthesia
The aim is to decrease the concentration of HbS to 30% or less. Transfusion may
also be required during aplastic crisis.
26
27. Management of Chronic Anemia
For anemic crisis with splenic sequestration
give early red cell transfusions because the process can rapidly progress to shock.
Do not allow hemoglobin (Hb) levels to rise to more than 10 g/dL, since the spleen
may disgorge trapped cells, which can create a relative polycythemia and increased
blood viscosity.
Transfusion is required in an aplastic crisis if the anemia is symptomatic (eg,
dyspnea, signs of hypovolemia). Because aplastic crises are self-limited.
27
28. Prevention and Treatment of Infections
Cause : individuals with SCD are highly susceptible to bacterial and viral infections,
largely due to functional asplenia that develops early in childhood.
immunization for all patients
prophylactic penicillin for all young children (eg, <5 years of age)
28
29. Prevention and Treatment of Infections
Antibiotics are indicated when an infection is suspected :
body temperature is higher than 38° C
recommend the use of broad-spectrum antibiotics in the patient who is systemically ill
or has chest involvement.
parenteral antibiotics for hospitalized patients include cephalosporins (eg,
ceftriaxone, cefuroxime) and macrolides for acute chest syndrome.
For discharged patients oral antibiotics (eg, amoxicillin-clavulanic acid,
clarithromycin, cefixime) are useful in selected cases.
If the patient has localized bone tenderness, the antibiotic selected should provide
coverage for S typhimurium and S aureus.
29
30. Prevention and Treatment of Infections
Penicillin prophylaxis and vaccination :
Begin at age 2 months with 125 mg bid of penicillin V or G
at 3 years, increase the dose to 250 mg bid. Prophylaxis should continue until age 5
years or the early teens.
Protein-conjugated pneumococcal vaccines (PCVs) , The 7-serotype PCV (PCV7) in
combination with penicillin prophylaxis and PPV23 booster vaccination .
prevention against S pneumoniae infection. The vaccine is given at age 2 years,
with a booster dose at age 5 years.
Meningococcal prophylaxis is administered as a single quadrivalent vaccine when
the child is older than 2 years.
30
31. Treatment of Gallstones
Cause : gallstones are produced from excess bilirubin, which is caused by the constant
breakdown of red blood cells. Biliary sludge (formed when excess bile settles in the duct)
can also lead to gallstones.
For patient with acute cholecystitis :
Can receive antibiotics and general supportive care and may consider elective
cholecystectomy several weeks after the acute episode subsides.
Elective laparoscopic cholecystectomy for symptomatic disease.
supportive care for cholecystitis if stones are visualized.
Elective cholecystectomy has been used for asymptomatic patients with cholelithiasis, to
avoid the possible future need for an emergent procedure.
But still controversial
31
32. Treatment of Gallstones
supportive care for cholecystitis if stones are visualized:
Prophylactic antibiotic coverage with levofloxacin (Levaquin, 500 mg PO qd) and
metronidazole (500 mg PO bid), which should provide coverage against the most
common organisms
Antiemetics, such as oral/rectal promethazine (Phenergan) or prochlorperazine
(Compazine), to control nausea and to prevent fluid and electrolyte disorders
Analgesics, such as oral oxycodone/acetaminophen (Percocet) or
hydrocodone/acetaminophen (Vicodin)
32
34. Control acute pain
Initiate analgesic therapy within 30 minutes of triage, or 60 minutes of registration
In patients with mild to moderate pain, continue treatment with NSAIDs in those who
report relief with these agents, unless contraindicated
In patients with severe pain, rapidly initiate treatment with parenteral opioids
Reassess pain every 15-30 minutes until the patient reports that pain is under control;
readminister opioids if necessary for continued severe pain
The drug should be given intravenously, hourly at first. Once the effective dose is
established, it should be administered every 3 hours.
Meperidine is not recommended , due to CNS toxicity .
34
35. Control chronic pain
The weak opiates (eg,codeine and hydrocodone) are commonly used first.
Sustained-release long-acting oral morphine is reserved for more severe cases.
Hydroxyurea and tCAs may decrease the frequency and severity of pain episodes.
Nonpharmacological approaches to pain management may have a substantial
impact. These include physical therapy, heat and cold application, acupuncture and
acupressure, hypnosis, and transcutaneous electric nerve stimulation (TENS).
35
36. Medications
Oxycodone and aspirin
Aspirin inhibits platelet aggregation; has analgesic and anti-inflammatory properties.
Methadone
Morphine sulfate
Oxycodone and acetaminophen
It is the drug of choice for patients who are hypersensitive to aspirin.
for patients who are hypersensitive to aspirin.
Fentanyl
fentanyl is not commonly associated with histamine release.
Nalbuphine
Codeine
pathways, altering perception and response to pain.
Codeine/acetaminophen
36
38. Stroke Prevention
Adults with SCD should be managed according to the
2014 AHA/ASA primary stroke prevention guidelines.
Secondary stroke prevention guidelines include
recommendations for controlling risk factors and the use
of antiplatelet agents.
Regular blood transfusions (to reduce HbS to < 30%-50%
total hemoglobin), hydroxyurea, bone marrow
transplantation , bypass surgery for advanced occlusive
disease.
39. Stroke Prevention
Transfusion therapy, aimed at keeping the proportion of HbS below 30%.
Erythrocytapheresis , This procedure allows rapid reduction of HbS
concentrations to be less than 30% without significantly increasing total
hemoglobin concentration post transfusion.
hydoxyurea or bone marrow transplantation might be an option for children at
high risk for stroke in whom RBC transfusion is contraindicated.
hydroxyurea/phlebotomy can be use as second line , but transufusion and
exchange is the first line .
39
40. Treatment of Priapism
Cause : Sickle cells can block the blood vessels in the penis.
At the onset of priapism, patients should be advised to drink extra fluids, use oral
analgesics, and attempt to urinate.
A nightly dose of pseudoephedrine (30 mg orally) may prevent priapism in some
cases.
For episodes that last more than 2 hours, patients should go to the emergency
department to receive intravenous hydration and parenteral analgesia.
If detumescence does not occur within 1 hour after arrival in the emergency
department, penile aspiration followed by irrigation .
if early intervention with irrigation fails, red cell exchange transfusions to reduce
the HbS level to less than 30% .
to prevent recurrent priapism use phosphodiesterase type 5 inhibitors (eg,
sildenafil, tadalafil).
40
41. Sickle cell nephropathy
Cause : hypoxia and ischemia.
More distal tubular dysfunction may impair renal acidification and potassium secretion,
leading to an incomplete form of distal renal tubular acidosis and hyperkalemia.
Risk factors associated with progression of chronic kidney disease (CKD) to end-stage
renal disease (ESRD) include the following [5] :
Hypertension
Nephrotic range proteinuria
Severe anemia
Vasoocclusive crisis
Acute chest syndrome
Stroke
βS-gene haplotype
Pulmonary hypertension
Parvovirus B19 infection
41
42. Sickle cell nephropathy
The recommended hemoglobin (Hb) target should be an Hb concentration of no
greater than 10-10.5 g/dL.
Blood transfusions or erythrocyte-stimulating agents (ESA), such
as erythropoietin or darbepoetin alfa .
But transfusion and exchange is superior , as it provide patient with a higher
amount of Hb A , compare to patient own blood .
ESA dosing may be higher in individuals receiving hydroxyurea due to its inherent
bone marrow suppressive effect.
42
43. Treatment of Leg Ulcers
Cause : Leg ulcers may result from venous stasis and chronic hypoxia and may
become infected.
Leg ulcers are treated with debridement and antibiotics.
Zinc oxide occlusive dressing (Unna boot) and leg elevation .
Transfusion may accelerate healing.
Skin grafting may be necessary in recalcitrant cases.
43
44. Treatment of Pulmonary Hypertension
Cause : chronic intravascular hemolysis, older age, renal insufficiency,
cardiovascular disease, cholestatic hepatopathy, systolic hypertension, high
hemolytic markers, iron overload, and a history of priapism.
Treatment : hydroxyurea and chronic transfusion have been used.
Enothelin-1 receptor antagonists (eg, bosentan)
phosphodiesterase inhibitors (eg, sildenafil).
Cor pulmonale treat as patient with right side heart failure .
44
45. Stem Cell Transplantation
allogeneic marrow transplantation
who qualify for stem cell transplantation ?
First, donors must be human leukocyte antigen (HLA) compatible and full siblings
(those with sickle trait are acceptable)
45
46. second, candidates should be limited to patients younger than 16 years with HbSS
or HbS–β-0 thalassemia who have evidence of disease severity demonstrated by
the following:
Stroke
Recurrent acute chest syndrome
Recurrent severe crisis pain (>2 episodes/y for several years)
Recurrent priapism
Impaired neuropsychological function with evidence of cerebral infarction
Sickle cell nephropathy
Bilateral proliferative retinopathy and major visual impairment in at least one eye
Osteonecrosis of multiple joints
Red cell alloimmunization with more than 2 antibodies during long-term transfusion
therapy
46
Stem Cell Transplantation
47. Investigational Treatments
Nitric oxide inhalation has been investigated in the treatment of pulmonary
hypertension.
Topical GM-CSF has been reported to hasten the healing of leg ulcers.
topical granulocyte-macrophage colony-stimulating factor
Butyrate was studied to decrease vaso-occlusive crisis.
Arginine has been proposed to use as a precursor of nitric oxide production.
47
48. Avascular necrosis
treatmeant : not bearing weight at the site.
need to make career and lifestyle adjustments. Occupational retraining and
physical therapy.
surgical intervention with hip replacement or other orthopedic procedures are
needed.
Cause : result from chronic hypoxia in weight-bearing joints, commonly the femoral
head.
48
49. Treatment of Other Complications
Avascular necrosis of the femoral and humeral heads:
May result from chronic hypoxia in weight-bearing joints, commonly the femoral
head
Treat by:
1. Not bearing weight at the site.
2. make career and lifestyle adjustments.
3. Occupational retraining and physical therapy may be needed.
4. Surgical intervention with hip replacement or other orthopedic procedures may be
needed.
Psychological problems, such as depression, anxiety, and chronic pain
behavior. Ensure an appropriate physician-patient relationship. Anxiolytics
and amitriptyline may be used
50. Long-Term Monitoring
For patients with minimal symptoms, a visit with blood work every 3-4 months is
reasonable. Others may need much more frequent observation.
proliferative sickle retinopathy (PSR); once stabilized, visits every 3-6 months may
be adequate. When intraocular pressures are stabilized, the patient can be
monitored every 6 months.
Pneumococcal and influenza vaccination is safe in patients with functioning kidney
transplants.
The use of live vaccines is contraindicated due to the immunosuppressive therapy
that these patients require.
50
Symptoms of HbSC disease are similar to SCD but less frequent and less severe.
Splenomegaly often persists well into adult life.
Aseptic necrosis of the femoral head is not more common than in SCD.
A proliferative retinopathy may lead to progressive loss of vision.
Imaging studies
Imaging studies that aid in the diagnosis of sickle cell anemia in patients in whom the disease is suggested clinically include the following:
Radiography: Chest x-rays should be performed in patients with respiratory symptoms
MRI: Useful for early detection of bone marrow changes due to acute and chronic bone marrow infarction, marrow hyperplasia, osteomyelitis, and osteonecrosis
CT scanning: May demonstrate subtle regions of osteonecrosis not apparent on plain radiographs in patients who are unable to have an MRI [3] and to exclude renal medullary carcinoma in patients presenting with hematuria
Nuclear medicine scanning:99m Tc bone scanning detects early stages of osteonecrosis;111 In WBC scanning is used for diagnosing osteomyelitis
Transcranial Doppler ultrasonography: Can identify children with SCD at high risk for stroke
Abdominal ultrasonography: May be used to rule out cholecystitis, cholelithiasis, or an ectopic pregnancy and to measure spleen and liver size
Echocardiography: Identifies patients with pulmonary hypertension
Transcranial near-infrared spectroscopy or cerebral oximetry: Can be used as a screening tool for low cerebral venous oxygen saturation in children with SCD
Hydroxyurea increases total and fetal hemoglobin in children with SCD. [55] The increase in fetal hemoglobin retards gelation and sickling of RBCs. Hydroxyurea also reduces levels of circulating leukocytes, which decreases the adherence of neutrophils to the vascular endothelium (see image below.) In turn, these effects reduce the incidence of pain episodes [55] and acute chest syndrome episodes.
Increased HbF production — Hydroxyurea causes a shift in gene expression at the beta globin locus, such that expression from the gamma globin locus is increased relative to that from the beta globin locus. This results in increased production of fetal hemoglobin (HbF; α2γ2) and decreased production of adult hemoglobin (HbA; α2β2), the reverse of the normal fetal switch. Since the gamma globin chain is not affected by the sickle mutation, the overall effect in patients with SCD is to reduce the relative concentration of hemoglobin S (HbS; α2βS2).
but it is well tolerated and causes no clinical problems. Hydroxyurea causes HbF production to be increased at least twofold above baseline, often much more
Transfusions are not needed for the usual anemia or episodes of pain associated with SCD. Urgent replacement of blood is often required for sudden, severe anemia due to acute splenic sequestration, parvovirus B19 infection, or hyperhemolytic crises. Transfusions are helpful in acute chest syndrome, perioperatively, and during pregnancy.
Right upper quadrant syndrome : pain, fever, jaundice, elevated AST/ALT and hepatic enlargement
In general, raising the hemoglobin concentration to between 10 g/dL and 12 g/dL provides the patient with approximately 20-30% hemoglobin A. The presence of this fraction of normal hemoglobin may provide some protection from complications. Many anesthesiologists require a hemoglobin concentration of more than 10 g/dL prior to the procedure. [60]
When the patient’ baseline hemoglobin level is above 10 g/dL, the approach is less certain. If the complexity of the surgical procedure or the duration and risk of anesthesia is considerable, exchange transfusion or erythrocytapheresis can reduce the hemoglobin S concentration to 30%, while keeping the total hemoglobin level below 12 g/dL.
In patients undergoing retinal surgery, the HbS concentration or combined concentration of HbS and HbC needs to be reduced to less than 30% (increase the hemoglobin A concentration to 70%).
With continued transfusion, iron overload inevitably develops and can result in heart and liver failure, and multiple other complications. Serum ferritin is an inaccurate means of estimating the iron burden;
liver iron evaluation, or perhaps MRI, is a more accurate means of determining tissue iron concentration and the response to chelation.
Deferoxamine :
Although effective, there are significant challenges associated with its use that can result in non-compliance.
has a capacity similar to deferoxamine in chelating iron,
The ocular manifestations of sickle cell disease (SCD) result from vascular occlusion, which may occur in the conjunctiva, iris, retina, and choroid.
it is important to rule out other causes of occlusion, including central retinal vein occlusion, Eales disease, and retinopathy secondary to diabetes and other disorders. [1] Other causes of ocular changes that should also be considered include familial exudative vitreoretinopathy, polycythemia vera, talc and cornstarch emboli, and uveitis
Dactylitis is inflammation in fingers and swelling , as it cause leukopenia , it can decrease inflammation
Predictors of admission included the following:
Higher pain score at triage
Older age
Increased systolic blood pressure
Factors associated with longer length of hospital stay included the following:
Higher pain score at triage
Older age
Increased polymorphonuclear count
Homozygous SCD type
The antibiotics chosen should be active against Streptococcus pneumoniae, Mycoplasma pneumoniae, and Chlamydia; for the latter two, a macrolide may be appropriate. Antibiotic changes are based on response to therapy and results of cultures and sensitivities.
chest pain, cough, fever, hypoxia (low oxygen level) and lung infiltrates
and, if it is found, given iron supplements. An adequate overall diet is essential.
temporary cessation of red cell production.
ndividuals with SCD are highly susceptible to bacterial and viral infections, largely due to functional asplenia that develops early in childhood.
Neonatal screening, penicillin prophylaxis, appropriate immunizations (particularly against Streptococcus pneumoniae), and parental teaching have remarkably minimized infection-related morbidity and mortality.
Trivalent : Trivalent vaccines include an influenza A (H1N1) virus, an influenza A (H3N2) virus and one influenza B virus.
An opioid analgesic, morphine interacts with endorphin receptors in the CNS, inhibiting the pain pathways, altering pain response and perception.
During the transfusion period, most of the TCD studies reverted to or toward normal. Once the transfusion program was stopped, however, there was an unacceptably high rate of TCD reversion to high risk, as well as to actual strokes.[44]
if detumescence does not occur within 1 hour after arrival in the emergency department, penile aspiration followed by irrigation of the corpora with a 1:1,000,000 solution of epinephrine in saline is initiated. [71] (The procedure should be performed within 4-6 h of priapism onset.)
Higher Hb levels and more rapid correction of anemia may precipitate a vasoocclusive crisis.
Recent intensive investigations are centered on the application of GM-CSF as an immune adjuvant for its ability to increase dendritic cell (DC) maturation and function as well as macrophage activity. It is used clinically to treat neutropenia in cancer patients undergoing chemotherapy, in AIDS patients during therapy, and in patients after bone marrow transplantation.
Even modestly increased pulmonary artery pressures are associated with severe reduction in exercise capacity, as assessed by both the 6-minute walk and cardiopulmonary exercise testing, and herald a poor prognosis. Both pulmonary hypertension and cardiac sequelae, such as diastolic dysfunction, have been associated with accelerated mortality