Sickle cell disease

By: Yara MostafaYasser MostafaYasser Osama

Sickle Cell Disease

• RBCs disorder that causes the sickling of biconcave shaped RBCs.• There are many types:*Sickle cell Anemia.*Sickle cell Trait.

Distribution of Sickle cell Anemia

Brief Medical History

1910 – First Description of Sickle-Shaped Blood Cells by Dr James Herrick.

1917 – Genetic basis for SCD were discovered by Dr. V. Emmel.

1922 – Disease was named “sickle cell anaemia” by Vernon Mason .

1927 – Hahn and Gillespie elaborated on Emmel’s work by demonstrating that the sickling effect was linked to de-oxygenation.

Dr James B. Herrick

Pathophysiology

• Deoxy Hb S polymer forms with low O2, depends on Hgb S concentration, low pH, high temperature, high 2,3-DPG

• Membrane is damaged so RBCs accumulate calcium, lose potassium & water and become rigid & irreversibly sickled

• Sickle cells hemolyze within 10-20 days

•It’s autosomal recessive blood disease.•It’s not contagious “You can’t catch it”.•You inherit it from your parents.

*The gene defect is a known mutation of a single nucleotide.

*The person who receives only one defective gene from either one of his parents will develop Sickle-cell trait.

*The person that receives the defective gene from both his parents will develop Sickle-cell disease.

Genetics

Sickle Cell Trait (AS)*A person has one abnormal allele of the hemoglobin beta gene.

*Those who are heterozygous for the sickle cell allele produce both normal “HbA” and abnormal hemoglobin “HbS” (the two alleles are co-dominant).

*Asymptomatic :Don’t show severe symptoms as in Sickle cell Anemia.

* HbA : 60%, HbS: 40% , HbF:<2%

*They act as carriers and can transmit the disease to their off springs.

*People with sickle cell who exercise heavily, such as athletes and those who are exposed to dehydration or altitude extremes, may sometimes experience sickle cell anemia symptoms.

*It has been suggested that sickle cell trait is linked to two other medical problems that may elicit health and performance concerns. These include:

1) Exercise-related rhabdomyolysis (skeletal muscle breakdown)

2) Exercise-associated sudden death

* Occur in normal, healthy individuals following strenuous exercise.

*Sickle cell trait individuals might be at greater risk for developing the syndrome than those without this trait.* This syndrome can result in renal failure and sudden death.

*Sickle cell trait deaths occurred predominantly in football players.

*Athletes with the trait experienced noninstantaneous collapse with gradual but rapid deterioration, ie, dyspnea, fatigue, weakness, and muscle cramping.

Diagnosis

Sickle testsolubility tests

hemoglobin electrophoresis test

Screening test for newborns DNA Analysis

Sickling TestMethod:1) A sample of venous blood or capillary blood may be collected for this test.*Venous blood from the arm.*Capillary blood from the finger tips or ear lobes and in infants from the heel of the foot.2) Mixing blood with the reducing agent, sodium metabisulphite, will induce sickling in susceptible cells. 3) the results can be viewed under a microscope after 20 minutes.

Normal RBC Sickled RBC

*Positive sickling test associated with a normal haemoglobin is likely to indicate a patient with sickle cell trait.

Positive TestHbS

Negative TestHbA

This test is simple and quick, used to identify the presence of HbS.

Sickle Solubility Test (SST)

Method:

•A rapid and inexpensive technique used to screen for the presence of sickling hemoglobins, can be used at home.•A positive result must be confirmed by another method (HPLC or electrophoresis) to confirm the presence of Hb S and to distinguish Hb AS (carrier state) from Hb SS (sickle cell disease).•Disadvantage: Other insoluble hemoglobins, such as Hb C-Harlem, will also give a positive result.

1) Erythrocytes are lysed by saponin.

Depend on phosphate solubility

2) The released hemoglobin is reduced by sodium hydrosulfite in a phosphate buffer.

3) Reduced HbS is characterized by its very low solubility and the formation of neumatic liquid crystals (tactoids).

The resulting tactoids of HbS causes the solution to remain turbid.

The presence of HbA under these same conditions results in a clear red solution.

Hemoglobin Electrophoresis test

* Haemoglobin electrophoresis will differentiate between homozygous and heterozygous conditions.

* Hemoglobin types have different electrical charges and move at different speeds.

*HbSS: Is less negative by 2 compared to HbA .

Migrates slower than HbA

*HbAS: Has both HbA and HbS.

Shows 2 bands

Newborn screening

•In newborns who carry the sickle cell gene, fetal hemoglobin F will predominate, but a small amount of hemoglobin S will also be present.

• It is performed via the most sensitive Hb isoelectric focusing or HPLC fractionation and identifies the specific types of hemoglobin present.

DNA analysis• This test is used to investigate alterations and mutations in the genes that produce hemoglobin components.

•It may be performed to determine whether someone has one or two copies of the Hb S mutation or has two different gene mutations.•Genetic testing is most often used for prenatal testing: The usual tests offered are chorionic villus sampling (CVS) or amniocentesis “14 to 16 weeks”.

•There also may be a small amount of hemoglobin A if they have sickle cell trait.

Globin Gene Family

Alpha Family

1 Zeta

2 Alpha

Beta Family

1 Epsilon

2 Gamma

1 Beta

1 Delta

Chromosome 16

Chromosome 11

Globin Gene Family

HbF

*If fetal hemoglobin remains the predominant form of hemoglobin after birth, the number of painful episodes decreases in patients with sickle-cell disease.

*The fetal hemoglobin's reduction in the severity of the disease comes from its ability to inhibit the formation of hemoglobin aggregates within the red blood cells also containing hemoglobin S.

*A form of treatment of Sickle cell anemia is hydroxyurea that promotes the production of fetal hemoglobin

Signs and Symptoms

• Infection, dehydration, and acidosis act as triggers but in most instances no predisposing cause is identified.

• They usually appear after 4 months of age.• Most common signs are linked to Anemia and

Pain.

Signs and Symptoms

• Vaso-occlusive crisis.• Aplastic crisis• Splenic sequestration crisis.• Hemolytic crisis

Vaso-oclusive crisis

• Ischemia• Pain• Necrosis• Often leads to organ damage• Management

– Severe: analgesics, Opioid– Mild: NSAIDs– New treatment involving

*Adenosine A2a receptor agonists. These medicines may reduce pain-related complications.

Splenic squestration crisis

• Acute, painful enlargements of the spleen, caused by intrasplenic trapping of red cells

• Caused by intrasplenic trapping of red cells• Die within 1-2 hours due to circulatory failure• Autosplenectomy

Aplastic crisis

• Paravirus B19– Divides in RBCs precursors and destroys them– Stops erythropoiesis for two or three days– Causes reticulocytopenia– Disappears within one week with management and

blood transfusions

Hemolytic crisis• Common in patients with G6PD deficiency

Complications

*Hand-Foot syndrome Pain, Fever, Swelling.

*Overwhelming post-splenectomy infection (OPSI) treated with antibiotics and supportive care.

*Acute chest Syndrome Chest pain, Shortness of breath, Fever.

*Stroke Learning problems, Long term disability, Brain damage, Paralysis, Death.

*cholelithiasis (gall stones) & Cholecytitis Nausea, Vomiting, Jaundice, Sweating, Clay-coloured stool.

Complications

*Retinopathy Blindness.

* Sickle cell nephropathy Chronic renal failure.

*Pulmonary hypertension Fatigue, Shortness of breath.

*In pregnancy spontaneous abortion.

*Aseptic bone necrosis.

*Priapism Damge to the Penis and Impotence.

Management

• Blood transfusions:– Acute chest crisis– Decreases the risk for strokes– Defrasirox: iron chelator

• Folic acid daily intake• Penicillin• Malaria chemoprophylaxis

O

OH

HOOH

N N

N

Fe

*

* *

Treatment

• Hydroxyurea.– Reactivates fetal Hb production– Decreases severity of attacks– Increases life span– More effective with Erythropoietin.

• Bone marrow transplant during childhood.• 5-HMF. This natural compound binds to red blood cells and

increases their oxygen. This helps prevent the red blood cells from sickling.

Prevention

• You can’t prevent sickle cell anemia, because it’s an inherited disease.

• If a person is born with it, steps should be taken to reduce complications.

• Genetic Counseling should be considered.

• A counselor can explain the risk of having a child who has the disease and can help explain the choices that are available.

Prognosis

*New and aggressive treatments for sickle cell disease are prolonging life and improving its quality.

*Recently as 1973, the average lifespan for people with sickle cell disease was only 14 years.

*Currently, life expectancy for these patients can reach 50 years and over.

*Women with sickle cell live longer than their male counterparts.

*The median age at death :-Males : 53years-Females: 58 years

*As children with sickle cell disease live longer, older patients are now facing medical problems related to the long-term adverse effects of the disease process.

Malaria

• Parasitic infection: Plasmodium falciparum• Two stages in the human body:– Exoerythrocytic stage in liver (8 to 30 days)– Erythrocytic stage

Sickle cell gene and malaria

• Heterozygous individuals are tolerant to malaria

• Homozygous individuals are less tolerant to malaria because of the common functional asplenia

Why?

Direct contact with sickle

cells

HO-1 and blood brain

barrier

Heme oxygenase-1

Refrences

• Harper’s illustrated Biochemistry• Lippincott’s illustrated reviews of Biochemistry• Robbins basic Pathology• American society of hematology

Thank You