Sickle cell disease.Therapeutics

Dr. Afzal Haq AsifAssociate Professor

COCP, KFU

Dec 02, 2013 Dr Afzal Haq Asif 1

CaseA 20 years old male reported with history of delayed

puberty, decreased growth, severe joint pain, severe weakness and cough. He also have defective vision

Past history reveals episodes of jaundice, severe body aches and pains, and gall stones

In his childhood he used to have frequently fever swelling of the hands and feet and pain in the chest, abdomen, limbs, and joints and nosebleeds and frequent upper respiratory infections


Case O/E; Decreased growth, delayed signs of

puberty severely anemic, mildly jaundiced, ulcers on right leg, inflamed gums

Enlarged spleen.Temp 39.1°C, diaphoretic, and

uncomfortable. HR of 90, BP 116/84 mm Hg, RR 26 O2 Sat 89% and improved to 94% with 6

L/min via face mask.Family history: similar problem in one of his

cousin who died at the age of 30, who used to receive blood transfusions


CaseWBC of 17 500/μL

62% neutrophils25% lymphocytes9% monocytes2% eosinophils1% basophils1% atypical lymphocytes.

Hb was 8 g/dLreticulocyte 25% platelet 206 000/μL.


CaseWhich lab test you will advise?What is most probable cause of patients

problem?What complications the patient may have?Design therapeutic objectives for this

patient?


Hemoglobin: IntroductionNormal: alpha gene at Chr 16, beta at Chr.11

HbA: 2 Alfa + 2 beta 97-98%Hb A2: 2 Alfa + 2 delta 2-3%Hb F;2 alfa + 2 gamma>1%Hb S: Glutamic acid at 6 in beta chain replaced with ValineHbC:

……………………………………………………………………….Lysine Thalassemia:

Thalassemia describes a group of inherited disorders characterized by reduced or absent amounts of hemoglobin

Alfa: less alfa chain Chr.16Beta: Chr.11: less beta, beta thalassemia minor

or no beta, all alfa chain beta thalassemia major :


An autosomal recessive genetic disease of Hb synthesis

Result of a single–amino acid substitution in the β-globin chain of the Hb molecule, valine for glutamate at position 6

Sickle cell trait: Pt. with hetrozygous genotypeEpidemiology in KSA:

“The prevalence of SCD in Saudi Arabia varies significantly in different parts of the country, with the highest prevalence is in the Eastern province, followed by the southwestern provinces. The reported prevalence for sickle-cell trait ranges from 2% to 27%, and up to 2.6% will have SCD in some areas”

Ann Saudi Med. 2011 May-Jun; 31(3): 289–293.

SICKLE CELL DISEASE

Dec 02, 2013 8Dr Afzal Haq Asif

Comparison with USAAfrican Americans:

SCD: 0.3% Saudia: 2.6%SCT: 8.0% Saudia: 2-27%


PathophysiologyNormal Hemoglobin A: two alpha and two beta chains, 96-97%

Glutamic acid is on the 6th position of the Beta chainHemoglobin S: Chr.11

Due to a one point mutation, glutamic acid is replaced by valine at position 6 in beta chain

HbS: during deoxygenation Polymerize Crystellize

in RBC’s…………………….leading to………………….. Sickling of Cells: RBC cell membrane changes: activate coagulation pathways

Rate of polymerization and sickling augmented by: Hypoxia, deoxygenation Infections, Acidosis, Physical exercise, Vasoocclusion due to cold as well as hypertonic dehydration


Clinical PresentationSickle cell trait (SCT) Carrier, recessive

Rare painless hematuria; normal Hgb level; heavy exercise under extreme conditions may provoke gross hematuria and complications

Sickle cell anemia (SCA) AnemiaChronic hemolytic anemia: jaundice, gall stone,

splenomegalyAcute Pain crises, Microvascular disruption of organs (spleen, liver,

bone marrow, kidney, brain, and lung), gallstone, priapism, leg ulcers, anemia (Hgb 7-10 g/dL)


Clinical PresentationSickle cell hemoglobin C:

Painless hematuria Aseptic necrosis of bone: less commonVaso-occlusive crises less common, occur late in lifePregnancy-related problems; mild anemia (Hb 10–12

g/dL)Sickle cell β-thalassemia

Rare crises; milder severity than sickle cell disease because of production of HbA;

Hb 10–14 g/dL with micro-cytosisSickle cell Alfa-thalassemia or β0 Thalassemia

No HbA production; severity similar to sickle cell anemia; Hb 7–10 g/dL with microcytosis


DiagnosisLaboratory findings

RBC’s: 5-50 % sickledLow hemoglobin; 7-10%; HbA; 0%; HbS 85-

98%Increased reticulocytes: 10-25%, platelet, and

leukocyte counts; and sickle forms on the peripheral smear

Routine neonatal screening programs: DNA from fetal cell for mutation


Goals of TherapyTo reduce

Hospitalizations, Complications, Mortality


TreatmentGENERAL 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 orallytwice daily until 3 years of

age and then 250 mg twice daily, Benzathine penicillin, 600,000 units intramuscularly every 4

weeks.

Folic acid, 1 mg daily, is recommended in adult patients, pregnant women, and patients of all ages with chronic hemolysis.


Fetal hemoglobin stimulators and other strategiesHydroxyurea, 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.

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


Stem Cells in the Treatment of SCD

Skin stem cells cure mice of sickle cell anemia

Success is proof that technique has potential to cure diseasehttp://www.msnbc.msn.com/id/22136029/


ComplicationsAcute Chest Syndrome SepticemiaStroke or CVAAcute splenic sequestration crisis (ASSC)Aplastic CrisisVasoOcclusive pain: Sickle cell crisis

Severe pain is an emergency called acute sickle cell crisis

Osteomyelitis


Sickle Cell CrisisRapid diagnosis and treatment are necessary to

minimize morbidity and mortality.


Case 1

A 16-year-old boy with a history of SCD presented to the ED with a 3-day history of fever, cough, and SOB.

Five days prior, he had been evaluated and treated for severe pain in his legs and arms.

He complained of persistent and worsening pain in both his lower extremities and pain in his chest, in spite of oral narcotic therapy.


His medical history included multiple, vasoocclusive, painful crises, including an episode of priapism, and he had received multiple blood transfusions over his lifetime.

Case 1


Case -1On examinationTemp 39.1°C, diaphoretic, and

uncomfortable. HR of 80, BP 116/84 mm Hg, RR 26 O2 Sat 89% and improved to 94% with 6

L/min via face mask.Conjunctivae were icteric Mucous membranes were moist


Cardiovascular II/VI systolic ejection murmur.

labored respiration with suprasternal and intercostal retractions.

decreased breath sounds in the right midzone and lower zone, and scattered crepitations on the right side.

no lower extremity edema Abdominal examination NormalCNS Normal

Case 1


WBC of 17 500/μL 62% neutrophils25% lymphocytes9% monocytes2% eosinophils1% basophils1% atypical lymphocytes.

Hb was 8 g/dLreticulocyte 25% platelet 206 000/μL.

ABG on room air •PO2 59 mm Hg•PCO2 29 mm Hg•pH 7.32•HCO3 13 mmol

A chest x-ray right lower-lobe consolidation with a moderate right pleural effusion.

Case 1


In the ED, he received antipyreticssupplemental oxygen cefotaxime 2 g IVpacked red blood cell transfusion was initiated after 20

mL/kg of normal saline was infusedOver the next hour, while waiting for a bed to

become available in the intensive care unit, the nurse noticed that the patient's oxygen saturation continued to worsen, and he was hypoxic even on supplemental oxygen of 12 L/min via nonrebreather mask.

He underwent emergency intubationA diagnostic pleural tap was performed which

demonstrated an exudative fluid. The resulting Gram stain and culture were negative.

Case-1


Case 1What is it


1.Acute Chest Syndrome 1 of the most serious and life-

threatening complications of SCDLeading 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


New infiltrate on chest radiograph in combination with at least 1 clinical sign or symptomChest painCoughWheezingTachypneaFever

•Fever and cough are the most common in children •chest pain, sob, and chills are common in adults.

1.Acute Chest Syndrome Dx


Common causesPulmonary infection: Mycoplasma pneumoniae more commonly associated with acute chest syndrome

ThromboemboliFat emboliRib infarction

Infection and fat emboli were the most common identifiable causes.

Vichinsky EP, Neumayr LD, Earles AN, et al. Causesand outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group [published erratum appears in N Engl J Med 2000; 343:824]. N Engl J Med 2000;342:1855–65.

1.Acute Chest Syndrome

Possible causesIatrogenic: excessive hydration or narcotic use


Therapeutic ModalitiesSupportive measures

Oxygen for hypoxia Appropriate hydration Appropriate pain control

Antibiotics: third-generation cephalosporin + macrolides

Transfusion therapy: Reports of dramatic improvement in clinical

condition after initiation of transfusion Simple transfusion Exchange transfusion

Experimental therapyNitric oxideCorticosteroids

1.Acute Chest Syndrome


Bodo I, Khoury H, Blinder M. Rapid resolution of the acute chest syndrome of sickle cell disease after automated red cell exchange. Blood 1997;90 Suppl 1:23b

2.SepticemiaSCD 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

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


3.Stroke or CVAMajor complication of SCDIs 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. 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


Treatment: Stroke or CVAInitial 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.


A 44-year-old diabetic presented to the ED complaining of nonexertional dyspnea and severe back pain for 12 hours before presentation. The patient reported malaise, fatigue, weakness that started 3 days before, chronic blurred vision, insomnia, and anxiety. The remainder of the review of systems was unremarkable.


O/E

HR 101 bpmRR 31/minTemp 37CBP 148/62 mm Hgo2 sat 99%. The patient was awake, alert, and orientedHe was motionless to avoid back pain.

Case 2


Normal S1 and S2 Chest Normal Strength was 4/5 in all 4 extremities. Deep tendon reflexes were normoactive. Normal flexor plantar response was obtained,

and no meningismus

Case 2O/E


WBC 11.2 × 109/L (with no abnormalities in differential count)

Hg of 9.4 g/dLHCT of 26.3%MCVof 76.7 Femtoliters (fL)MCH 27.3 pgPlatelets of 144 × 109/L.

Case 2


Total bilirubin level of 2.3 mg/dl

Direct bilirubin level of 0.8 mg/dL

ESR 54 mm/h C-reactive protein level of 2.3 mg/dL.ECG NormalMRI of the lumbar spine was Normal

• Blood glucose 267 mg/dL

• AST 79 U/L• ALT 30 of U/L• ALK Ph 475 U/L

Case 2


Despite aggressive narcotic treatment of back pain, the pain continued to increase

CT abdomen: an enlarged spleen1 hour later hypotension of 90/50 mm Hg. The new CT scan of the abdomen revealed

an increasing splenomegaly compared with the previous one

Case 2


Despite transfusion therapy, the patient's Hb progressively dropped to a level of less than 4 mg/dL over the course of 3 hours, with thrombocytopenia (<50 × 109/L).

immediately transferred to an ICU. altered mental status. Airway protection with intubation and

mechanical ventilation were initiated.As the patient was rapidly deteriorating, an

emergent splenectomy was performed The patient recovered every organ function and,

6 months later, has resumed his normal activities

Case 2


4.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


5.Aplastic CrisisTemporary cessation of red cell production with a

corresponding decrease in the reticulocyte count. Approximately 80%, are thought to be caused by

human parvovirus B19 infectionDiagnosis is made by comparing baseline blood and

reticulocyte counts to those obtained during the acute illness.

Sign Symptoms: , tachypnea, tachycardia, or hypoxiaTreatment:

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 with chronic illness


6.OsteomyelitisMost commonly caused by Salmonella

species or Staphylococcus aureusBone 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:


7.PriapismPainful prolonged erection of the penisCaused 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 agentsVasoconstrictors 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


8.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 nextCausal 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 areas


Pain scale0 – 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.

– 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.


Pain ScaleSevere 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


Pain ManagementMild 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


Principles of pain management (WHO guidelines) 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.


When and how IVREASSESS 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


IV dosing: caresDoses 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.


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 Dec 02, 2013 Dr Afzal Haq Asif 58

Monitoring the patientChest 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 magnesiumMay need to follow with daily oral supplementation Magnesium > 1.8 mg/dL, replace with oral product

Lactic dehydrogenase (LDH) q72 hours


PCA

Patient-controlled analgesia (PCA) is a method of pain control that gives patients the power to control their pain. In PCA, a computerized pump called the patient-controlled analgesia pump, which contains a syringe of pain medication as prescribed by a doctor, is connected directly to a patient's intravenous (IV) line.


Patient Controlled Analgesia (PCA)For setting where scheduled IV dosing is not controlling the patient’s pain. There is no “PCA protocol.” Continuous opioid infusion

should not be used in opioid naive patients until assessed the needs over a given period of time (i.e. after 12 hrs of demand/bolus doses)

Only use a in patients with a known opioid requirement. Those patients taking daily opioids: calculate an equianalgesic dose of

currently used opioids over past 24 hrs and then convert to an equianalgesic basal rate

Example: Patient taking 120 mg extended release morphine Q 12 hrs now in crisis taking an additional 15 mg immediate release morphine q 4 hrs. 15 mg X 6 = 90 mg + (120 mg X 2)= 330 mg PO morphine/day. Convert to IV equivalent 330/3= 110 mg IV morphine/24 hrs = 4-5 mg/hr.

If changing/converting to a different opioid, start with 50-75% of the calculated equianalgesic dose to allow for incomplete cross-tolerance between opioids.


Titration of DoseBasal infusions will take at least 8 hours to reach steady state.

Do not titrate the basal rate more frequently than every 8 hours.

Never increase basal rate by more than 100% at any one time.

Demand Doses: Adjust demand dose size every 30-60 minutes to quickly reach adequate analgesia. For mild-moderate pain increase dose by 25-50%. For moderate-severe pain increase dose by 50-100%.


Converting IV to Oral Pain ManagementOnce 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. Dec 02, 2013 Dr Afzal Haq Asif 63

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.Dec 02, 2013 Dr Afzal Haq Asif 64

Evaluation of Therapeutic outcomesAll patients should be evaluated regularly to

establish change in baseline, parametersLaboratory evaluations

complete blood cell and reticulocyte counts HbF level. Kidney and Liver function tests and pulmonary

functionPatients should be screened for retinopathy.The efficacy of hydroxyurea can be assessed by

monitoring the number, severity, and duration of sickle cell crises.


References and further readingPharmacotherapy: pathophysiologic approachhttp://www.nejm.org/doi/full/10.1056/

NEJM19940603302303http://www.ncbi.nlm.nih.gov/pubmed/11694150

Vaso-occlusive disordersFuture prospects: Stem cell therapy:

http://newsroom.ucla.edu/portal/ucla/ucla-stem-cell-gene-therapy-for-246937.aspx

For some references please visit: https://www.facebook.com/COCP.Therapeutics?ref=hl


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Sickle cell disease.Therapeutics

Health & Medicine

Transcript of Sickle cell disease.Therapeutics