ADVANCED MANAGEMENT OF SICKLE CELL DISEASE

BY

NAZIFI MAGAJI

DL/HC/17D/0371

A NON THESIS SEMINAR SUBMITTED TO CENTRE FOR DISTANCE LEARNING, MODIBBO

ADAMA UNIVERSITY, YOLA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE
AWARD OF BACHELOR OF SCIENCE (B.Sc) DEGREE IN COMMUNITY HEALTH

OCTOBER 2021
 TABLE OF CONTENT

Cover page---------------------------------------------------------------------

Table of content---------------------------------------------------------------

CHAPTER ONE
1.0 Etiology and Epidemiology of Sickle cell Disease------------------

CHAPTER TWO
2.0 Pathology of Sickle cell Disease-------------------------------------------------

2.1 Common morbid Complication of Sickle cell Disease----------------------

CHAPTER THREE

3.0 Sickle cell Disease: Pharmacotheraphy (Disease Modifiers and supportive care)

3.1 Disease Modifiers------------------------------------------------------------------------

3.2 Supportive care Agents---------------------------------------------------------------

3.3 Other treatment Moderlities---------------------------------------------------------

3.4 Conclusion---------------------------------------------------------------------------------

Reference------------------------------------------------------------------------------------

CHAPTER ONE
1.0 Etiology and Epidemiology of sickle cell

Sickle cell disease (SCD) it is portentially devastating condition coursed by an

autosomal recessived inherited hemoglobinopathy, results in the hallmark clinical

sequelae of vaso occlusive phenomena and hemolysis. The genetic abnormally is

due to a substitution of the amino acid valine for glutamic acid at the six positions

on the beta globin chain and was first described over one hundred years ago.

Hemoglobin s (Hbs), the hemoglobin that produced as a result of this defect , is a

hemoglobin tetramer (alpha2/beta S2) that is poorly soluble and polimerise

when deoxygenated (American Academy of pediatrics, 2002) overall, the

incidence of sickle cell disease exceeds that most of other serious genetic

disorders, including cystic fibrosis and hemophilia. It is seen worldwide but occurs

most frequently in Africans and less commonly in those Mediterranean, Latino,

East Indian and Arab descent 6 it is estimated that 16% of the population of Africa

has sickle hemoglobinopathy which is the highest proportion worldwide. The

America and east Mediterranean region represent the next highest proportion of

sickle ellhemoglobinopathy as delineated by the world health organization

(National heart, lung, and blood institute, 2002)

SCD result from any combination of the sickle cell gene with any other abnormal

beta globingne and there are many types of SCD the common type include sickle

cell anemia (hb ss), the sickle beta thalassemia, hemoglobin SC diseas (hb Sc) and

sickle cell disease with hereditry persistence of feotal hemoglobin (S/HPFH).

Hbscis the most common form of sickle cell disease.patient with hb SS in general

have the most severe form of SCD including lower hemoglobin level and more

frequent vasooclusive and hemolytic complication. Sickle cell disease C (Hb Sc)

disease is the second most common form of sickle cell disease. Patient with this

type of SCD generally have more benign clinicalcourse then the patient with Hb

SS. Likewise , patient with therlessamia and S/HPFH also general have more

benign clinical course and patient with S/HPFH may actually have hemoglobin

level that are approach normal. Adult with sickle cell who live in united state have

a decreased in life expectancy with the odds of surviving beyond the 7 th decade of

life reported to be lessthan 30%. Historically platt et al reported a large number of

adults with sickle cell disease who died during acute sickle cell related

complication such as pain, acute chest syndrome, and stroke (platt et al 1994). In

this era, the most common cause of death in adults from sickle cell disease

reported are pulmonary hypertension, sudden death of unknown etiology, renal

failureand infection (aliyu et al 2008) with regard to children with SCD, in the
developed world the mortality rate is extimated to beas low as 0.5 to 1.0 per

100,000 children. This is to contrast to high rates in developing countries such as

the republic of benin with recently reported a mortality rate of 15.1 per 1,000

children (or 1550 per 100,000) the most common course of deathin childhood

from SCD are infection , acute chest syndrome and stroke (platt ).

CHAPTER TWO
 2.0 Pathophysiology of Sickle cell

There is a large amount hetrogenity in the expression of sickle cell disease

which is not fully explained by the single mutation or different variants of

hemoglobin S. this variability is manifest by a wide spectrum in both frequency

and intensity of painful vaso-occlusive crises as well as highly variable degree of

organ dysfunction. The pathologic process that lead to sickle cell related

complications result from combination of hemolysis and vaso-occlusive hemolysis

occours as result of repeated episodes of hemoglobin

polymerization/depolymerization as sickle red blood cell pick up and release

oxygen in the circulation (Quinn 2004). Red blood cell cell membranebecome

abnormal from this process and red blood cell have shortened lifespan.

Hemolysis can occour both chronically and acute painful vaso-occlusive crises and

also result in release of substantial quantities of free hemoglobin into vasculature.

This resultant free ferrous hemoglobin likely consumes significant quantity of

nitric oxide (NO), which in turn lead to abnormal regulation in vascular

hemostasis (Quinn 2004).

2
 In addition to hemolysis intermittent episode of vascular occlusion cause

tissue ischemia , a major morbid component of the disorder which result in acute

and chronic multi organ dysfunction, and which is characterized by chronic

inflation and ischemia reperfusion injury. Data suggest that neutrophils play a

key role in the tissue damage which occurs as both neutrophils numbers are

increase and evidence suggest that they are abnormal activated adherent.

Likewise, recent data suggest that sickle red cell induce adhesion of lymphocytes

and monocytes to the endothelium such that these may contribute to the

pathogenesis of vascular occlusion (Quinn 2004).

2.1 Commo morbid complication s of sickle cell Disease

2.1.1 Vaso-occlusion

Vaso-occlusive painful event are the most common morbidity seen in patients

( both children and adults) with sickle cell diseasevaso-occlusion not only result in

recurrent of painful episodes, but also a verity of serious organs system

complication that lead to life long disabilities and/or early death. For examples ,

based on data from cooperative study of sickle cell disease (CSSCD), in which the

circumstances of death were examine in 209 patients who were over 20 year of

age when they died 22% of death occured during a painepisode. Acute chest
episodes were temporarily related to hospitalization for pain in 77% of patients

who had them, and individuals older than 20 years of age with a higher of painful

episodes had an increased risk of pasture when compared to those with a lower

rate of pain (vichinsky 2000).

Painful events are unpredictable and severe resulting in repeated

hospitilisations, missed days of schools or work and very poor health related

quality as well as an increase of mortality rate . further more recent data suggest

that nearly every day, children adolescence and adult with sickle cell all are suffer

from the pain that is intense to distrupt day to day functioning. Despite how

common and witdspread this complication is, there are few treatment option to

prevent the development of this event and most are prevent with traditional

supportive caremaesure that have markedly changed in decades. The pain which

occur can be acute or chronic, it varies amongs individuals in its frequency and

intensity, and it is the primary cause of hospitalization inpatients with SCD.

Common triggers for vaso-occlusive crises include dehydration,extreme

temperature, and emotional stress. However often no identifiable cause is found

and pain often occur without warning ( Vichinsky 2000).

2.1.2 Bacteremia/sepsis

Children with sickle cell disease are at risk for bacteremia that can lead to

sepsis and adult death: due in large part to functional asplenia that developed

over a time in these children . in developing countriesand recently in Africa the

most common organism involve include : Streptococcus pneuomiae, salmonella

species, and haemophilus influenza ( Brandow 2009)

2.2.3 Acute chest syndrome

The specific definition of what constitue acute chest syndrome (ACS) varies but

refers to a new pulmonary infiltrate accompanied by fever and/ or symptom or

sign of respiratory disease in a patient with sickle cell disease (SCD). It is relative

common cause of frequent hospitalization and death , and it’s a common

indication for transfusion and treatmen with hydroxyurea. several studies suggest

that the case fatilit rate is lower in children (1.5%) than in adult (3-9%), but ACS

account for a significant proportion of mortality in both groups. Over half of the

patients whos developed ACS were hospitalize for other reasons prior to

developing ACS , usually a vaso-occlusive pinful crises (Brandow 2009)

The etiology of ACS is multi factorial and not completely understood. Previous

studies have shown that infection ,fat emboli , and pulmonary infection are all
commonly associated with ACS many episode of ACS develop without any obious

cause. Treatment usually involve microbials to cover both common cause of

pneumonia such as streptococcus pneumonia and chlamydia pneumoniae as

well as typical pathogens such as mycoplasma. If there is a history of asthma,

bronchodilator ACS. r and corticosteroids may be use during the event however

used of corticosteroids may prolong hospitalization or readmission. In addition of

this measures, red blood cell transfusion is often used as supportive treatment

during an ACS event.

2.1.4 pulmonary hypertension

The prevalence of pulmonary hypertention in adult with sickle cell disease is 25-

32% in both united state and Africa. The used of echocardiogram to detect the

high velocity as a marker of increase systolic pulmonary artery pressure that has

been increasingly used over the last five years leading the recognition that

pulmonary hypertension is common in sickle cell disease and is associated with

an increase risk of death ( panepinto et,al 2005),

2.1.5 Central nervour system disease

Central nervous system disease is common in sickle cell disease and usually

manifest as stroke and /or vasculopathy in those with the disease . overt stroke
occurs in 10% of children with the disease and usually involve large cerebral

vessels that affect large regions of the brain. 38% without treatment, there is a

high risk of resource. With transfusion therapy, this risk remains substantial at

22% . 39 silent stroke , define as an infarct on imaging studies with a normal

neurological examination, occur in atleast 22% of those with sickle cell disease .

40 over the last decade much has been learned about cerebral vasculopathy

given the advent of newer imaging modalities panepinto et al 2005)

2.1.6 Priapism

Priapism is another vaso-occlusive event that occurs in patient with sickle

cell disease. Priapism is not uncommon for male with SCD with a probability of

having one episode by age 20 of 89% and an average of age 12 years for the first

episode. The frequency in adul with SCD range from 30-45% 43 -45 treatmens

varies and consist largely of supportive measure with intravenous fluids, non

steroidal anti inflammatory medication and opiods. A urological consultation for

aspiration and irrigation of the corpora is warranted for persisting priapism and

has been effective. There are few randomized trails comparing treatment options

and preventive measures especially in pediatric patient (panepinto et, al 2005).

2.1.7 Renal effects

 Microalbuminuria and albuminuria are common in the more severe

genotypes of SCD and can occur in up to 80% of patients resulting in a

glumerulopathy. Approximately 15% of patients will advanced to end stage renal

disease by their third decade of life. About 25% of patient with hemoglobin SS

disease have renal insufficiency define as a reduce creatinine clearance less than

90ml/min. 49 currently , there are no identified treaments that have been shown

to be effective in preventing the development of disease in patients with SCD

who show evidence of kidney disease early on. However treatment with an

angiotensin converting enzymes inhibitor may decrease microalbuminuria and

proteinuria (Field and Debaun, 2010)\

2.1.8 Avascular Necrosis

Avascular necrosis is one of the few complications that is more common

with Hb SC than HbSS and its prevalence has been reported to e as high as 41%

of adults with SCD. With advent of newer imaging such as magnetic resonance

imaging , however , trues prevalence remain unknown. Surgical treatment with

coring osteotomy and joint replacement have both been used for severe disease

(Field and debaun, 2010).

 CHAPTER THREE

3.0Sickle cell disease : pharmacotheraphy ( disease modifiers and supportive

care agent )

3.1.0 disease measures

3.1.1 Hydroxyur Hydroxyurea represent the only major break througin

pharmacotheraphy of sickle cell disease within the past 20 years and is the only

drug that is approved by the U.S, FOOD DRUG ADMINISTRATION (FDA) for

treatment of adult with SCD. For treatment of adults with sickle cell disease. It is

also represents the only currently available agent that is capable of modifying

disease pathogenesis and its use to ransform the treatment of sickle cell disease

( field and Debaun, 2010)

Treatment with hydroxyurea has not only been shown to significantly decrease

the incidence of painful crises but also, to be effective in the treatment of acute

chest syndrome , priapism, and in reducing overall mortality in adults patients.

Hydroxyurea has also been shown to be cost in effective in the treatment of

adults with sickle cell disease and to be of value for treatment of SCD.

For all of the reasons, hydroxyurea is available to be a part of standard of care for

the patients with severe sickle cell SS disease in the united states. Studies have
also shown, however that patint with sickle cell disease have a variable response

to hydroxyurea, which in some instance, may limits its utility. The mechanisms

responsible for this variability remain unknown and may include adherence to

therapy as the medication is dosed on a daily basis and treatment requires regular

follow up (Steinberg et,al 2003)

Hydroxyurea increases Hbf in sickle cell anaemia through its cytotoxics effects

which course erythroid regeneration. Its also cause myelosupression which leads

to decreased leukocyte counts and less inflammation which is likely results in

decrease in both hemolysis and vaso occlusion. Although the clinical

improvement observed following treatment with hydroxyurea has been attribute

to increase levels of HbF, hydroxyurea also reduces the number of poorly

deformable dense sickle cells, highly adhesive sickle reticulocytes, and leukocytes,

and improve hemolyglobin level any one of which may also alter disease severity.

And while hydroxyurea is portentially mutagenic and carcinogenic, there are no

definitive data suggest that the incidence of malignancy is increased in patiens

who receive hydroxyurea for therapy related to sickle cell disease ( Steinberg,

barton ,castro 2003)

Given that the death from the complication of adults sickle cell disease appears to

be substantially greater than the potential forhydroxyurea induced leukemia, the

risk benefit ratio of treatment appears to favor treating patiens with SCD. Despite

the fact that hydroxyurea is a well known drug with proven efficacy for SCD. Its

utilization in the united state and elsewuise is limited. Despite lack of FDA

approval for use in children, hydroxyurea is also utilized for treatment of children

who exhibits signs of severe disease. Therapeutic studies of hydroxyurea have

been performed in children including investigation that documented hematologic

response and lack of significant toxicity, decrease in vaso occlusive episode and

possible prevention of secondary sroke. An additional study in children has also

shown that hydroxyurea decrease resting energy expenditure may cutail the

hyper metabolic state observed in sickle cell disease. Importantly recent data also

suggest that administration of hydroxyurea in children with sickle cell disease is

feasible, well tolerated , demonstrate, efficacy as measured by hematologic and

biochemical parameters and may delay functional asplenia. In longer term studies

of hydroxyurea in children, the treatment effects sustained in some patients for

more than 5 years without any clinical important toxicity. Interestingly pediatric

patients appear to exhibit a more robust hemoglobin F response than adults. The

reason for this phenomenon (e.g., age associated difference in pharmarcokinetics,

concentration effects response as pertain to increasing NO availability) remain

unknown (Steinberg et al 2003).

3.2.0 supportive care agent

3.2.1 Analgesi

There are evidence based guidelines for the treatment of SCD associated to acute

pain episodes, either in the hospital or at home. Only small number of high

quality studies of analgesics have been performed with small number of patients

suffering from acute SCD related pain and there are no studies performed which

address the management of chronic pain. Reasonable strategies for patients care

addressing management of can be employed based on established principles of

pain management of cancer related pain (aliyu el at 2008). Rational and effective

management of SCD related pain relies on through assessment and

individualization of therapy couple with the used of both non pharmacologic

approaches. Nonpharmacologic approaches include the used of heat or ice packs,

relaxation, distruction , muisic, massage, prayer therapeutic exercise, menthol

cream rub, transcutenous electrical nerves stimulation , while there are few

controlled trails whichvalue the efficacy of these modalities, anecdotal reports

from patients and and providers that these approaches are also releaving mild
pain and decreasing the amount of opioid consumption for more severe pain

(manci et ai, 2003)

Unfortunately, multiple studies shows that a large number of patients with SCD in

many countries including united states do not seek medical attention for the

treatment of the pain and, insteed cope with pain at home or imn the community.

Mild pain can be treatedat home and usually adqetly treated with general

nonsteroidal anti inflammatory drugs (NSAID) such as ibupropen and ketorolac or

other non opiod analgesics like paracetamol. However , given the compromise of

renal blood flow in patients with SCD and the risk of acute renal failure ,NSAIDs

should be utilized based on a case by case basis, should be avoided in those with

renal involvement , and probably should not be used beyond fives days (manci et

al, 2003)

For more severe pain, oral opioids should be consider as first line treatment in

acute pain crisis unless there is clinical evidence that the patientscannot take or

absorb oral medication. For children, sustained release oral opioids, coupled with

readily available rescure analgesia to be an effective alternative to parental

opioids. Codeine in combination with other analgesics appears to be most

common first line oral opioids treatment and play an essential role in home pain
management regimens. Howerver , there are a multitude of alternative opioids

drugs that commonly used to treat patients with SCD related pain that include

hydrocodone/acetaminophen combinationsoxycodone, morphine, and

hydromorphone,(manci et al,2003)

The choice of an opioids , its dose, and route of administration should be

individualized based on past history and experience and severity of pain. No one

opioids constitute an effective treatmentfor all patients or even a given patient at

difference times. The general trent currently to avoid the use of meperidine and t

administer opioids orally for mild pain and intravenously or subcutaneously for

drug metabolizing enzymes polymorphisms(e.g CYP2D6, UGT2B7) and drug

interactions must be taken in to account ( kaul and hebbel, 2000)

In addition to analgesic drugs treatment, acute pain episodes may also be treated

with hydration ( oral or intravenous ) as increased plasma osmolarity from a

reduced plasma volume can worsen as vaso occlusive crisis by coursing

intracellular dehydration hemoglobin polimerisation and further sickling. Patients

with SCD also have isosthenuria that lead to difficulty in excreting a sodium load.

Therefore, fluids should be administer in a quantity sufficiency to correction

existing deficite and replace ongoing losses to maintain euvolemic state (kaul and

hebbel, 2000)

3.2.2 vaccines

Due to the increase risk of bacteremia with streptococcus pneumonia, it is

recommended that children with sickle cell disease receive pneumococul

vaccines with both the recent 13- valent pneumococcal conjugate vaccine and

the pneumococcal polyscharide vaccine. In united states and other developed

countries, this lead to significant reduction in the incidence of infection from this

organism. Infact, used of 7 valent pneumococcal conjugate vaccine over the last

nine years is likely the reason why the mortality rate for childrenless than four

years of age has decreased so significantly(kaul and hebbel,2000)

3.3 treatment modalities

3.3.1 Red blood cell transfusion

Chronic red blood cell transfusion is utilized to suppress hemoglobin S production

and is the mainstay of secondary prevention of over stroke in patient with SCD.

For the first three years after an over stroke, the goal of red blood cell transfusion

is to suppress hemoglobin S levels to 30% or less. After 3 years, the global

maintain hemoglobin S levels to 50% or less.for those with high TCD velocity ,

chronic red blood cell transfusion are recommended to to decrease the risk of

overt stroke occurring, 41 treatmentto suppress hemoglobin S is recommended

indefinitely. There is currently no recommended standard treatment for

prevention of silent stroke. An ongoing multi centre trails is presently underway

to determine if chronic red blood cell transfusion are effective in preventing

recurrent silent stroke. In addition, a multi center trail is determine the efficacy of

hydroxyurea compared t chronic red blood cell transfusion is preventing

reoccuringovert stroke was recently underway but stop prematurely (stroke with

transfusion changing to hydroxyurea.) further data on findingsfrom this study will

help inform future therapy of stroke. Many centres also perform pre operative

transfution with the aim of reducing the complications of surgery and anesthesia

( Aliyu gordeur, sacheder, 2008).

3.4. conclusion

Sickle cell disease is a chronic, disorder with a myriad of symptoms that

make disease challenge. While there is need for new treatments for sickle

cell disease, especially for disease modifying agents there is also s need to

explore new approaches for improving treatment with existing modalities

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 Panepinto,JA, O’Mahar, KM, DeBaun, MR, Loberiz FR, scott, JP.(2005).
Health related quality of life in children with SCD: child and perception.
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 Platt, OS brambilla DJ, Rosse WF(1994). Mortality in SCD. Life expectancy
and risk factor for early death. N Engl J Med 330:1639:44
 Quinn CT, Rogers ZR Buchanan, GR,(2004). Survival of children with sickle
cell disease. Blood 103:4023-7
 Steinberg, M,FB, Castro Med,O,(2003). Effect of hydroxyurea on mortality
and morbidity in adult sickle cell anaemia. Risk and benefits up to 9years
of treatment 289:1645.
 Vichinsky,Ep, Neumayr, LD, Earles, AN, (200). Causes and outcomes of the
acute chestsyndrome in sickle cell disease. National acute chest syndrome
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