Brief Medical History1910 – First Description of Sickle-ShapedBlood Cells by Dr James Herrick.1917 – Genetic basis for SCD were discoveredby Dr. V. Emmel.1922 – Disease was named “sickle cellanaemia” by Vernon Mason .1927 – Hahn and Gillespie elaborated onEmmel’s work by demonstrating that thesickling 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
Genetics •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 asingle nucleotide.*The person that receives the defectivegene from both his parents will developSickle-cell disease.*The person who receives only onedefective gene from either one of hisparents will develop Sickle-cell trait.
Sickle Cell Trait (AS)*A person has one abnormal allele of the hemoglobinbeta gene.*Those who are heterozygous for the sickle cell alleleproduce both normal “HbA” and abnormal hemoglobin“HbS” (the two alleles are co-dominant).* HbA : 60%, HbS: 40% , HbF:<2%*Asymptomatic :Don’t show severe symptoms as in Sicklecell Anemia.*People with sickle cell who exercise heavily, such asathletes and those who are exposed to dehydration oraltitude extremes, may sometimes experience sickle cellanemia symptoms.*They act as carriers and can transmit the disease to theiroff springs.
*It has been suggested that sickle cell trait is linked to two othermedical problems that may elicit health and performance concerns.These include: 1) Exercise-related rhabdomyolysis 2) Exercise-associated sudden death (skeletal muscle breakdown) * Occur in normal, healthy individuals *Sickle cell trait deaths occurred following strenuous exercise. predominantly in football players. *Sickle cell trait individuals might be at *Athletes with the trait experienced greater risk for developing the syndrome noninstantaneous collapse with than those without this trait. gradual but rapid deterioration, ie, * This syndrome can result in renal dyspnea, fatigue, weakness, and failure and sudden death. muscle cramping.
Diagnosis Sickle test solubility 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 ininfants 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. Negative Test This test is simple and quick, used Positive Test HbA to identify the presence of HbS. HbS Normal RBC Sickled RBC *Positive sickling test associated with a normal haemoglobin is likely to indicate a patient with sickle cell trait.
Sickle Solubility Test (SST)•A rapid and inexpensive technique used to screen for the presence of sicklinghemoglobins, can be used at home.•A positive result must be confirmed by another method (HPLC or electrophoresis) toconfirm 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 apositive result.Method: Depend on phosphate solubility1) Erythrocytes are lysed by saponin.2) The released hemoglobin is reduced bysodium hydrosulfite in a phosphate buffer. The presence of HbA under The resulting tactoids of HbS3) Reduced HbS is characterized by its very these same conditions results causes the solution to remainlow solubility andred solution. of in a clear the formation turbid.neumatic liquid crystals (tactoids).
Hemoglobin Electrophoresis test* Haemoglobin electrophoresis will differentiate between homozygous andheterozygous conditions. * Hemoglobin types have different electrical charges and move at different speeds. *HbAS: Has both HbA and HbS. Shows 2 bands *HbSS: Is less negative by 2 compared to HbA . Migrates slower than HbA
Newborn screening• It is performed via the most sensitive Hb isoelectricfocusing or HPLC fractionation and identifies thespecific types of hemoglobin present.•In newborns who carry the sickle cell gene, fetalhemoglobin F will predominate, but a smallamount of hemoglobin S will also be present.•There also may be a small amount of hemoglobinA if they have sickle cell trait. 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”.
Globin Gene Family Chromosome 16 1 Zeta Alpha Family 2 Alpha Globin Gene 1 Epsilon Family 2 Gamma Beta Family 1 Beta Chromosome 11 1 Delta
HbF*If fetal hemoglobin remains the predominant form of hemoglobin after birth, thenumber of painful episodes decreases in patients with sickle-cell disease.*The fetal hemoglobins reduction in the severity of the disease comes from its ability toinhibit the formation of hemoglobin aggregates within the red blood cells also containinghemoglobin 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.
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 transfusionsHemolytic crisis • Common in patients with G6PD deficiency
Complications*Priapism Damge to the Penis andImpotence.*Retinopathy Blindness.* Sickle cell nephropathy Chronicrenal failure.*Pulmonary hypertension Fatigue,Shortness of breath.*In pregnancy spontaneous abortion.*Aseptic bone necrosis.
Management• Blood transfusions: – Acute chest crisis OH O – Decreases the risk for strokes – Defrasirox: iron chelator• Folic acid daily intake N N• Penicillin N *• Malaria chemoprophylaxis OH * * HO 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 andimproving its quality.*Recently as 1973, the average lifespan forpeople with sickle cell disease was only 14years.*Currently, life expectancy for thesepatients can reach 50 years and over.*Women with sickle cell live longer thantheir 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 medicalproblems 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 HO-1 and with sickle blood brain cells barrier