SICKLE CELL ANAEMIA

nt. Dr. Yalman Eyin

Hb is a conjugated protein molecule consist of two pairs of polypeptide chain. (alpha & beta) Each globin chain bears a haem group whose central iron atom is the site to which O2 attaches to haemoglobin.

Hb A1- 97% of adult haemoglobin, consists of 2 alpha & 2 beta chains. Hb A2- Consists of 2 alpha & 2 delta chains. Hb F - 70 90% at birth, 25% by 1 month and 5% by 6months of age, consists of 2 alpha & 2 gamma chains. Hb Gower 1-Confined to embryonic stage, consists of 2 alpha & 2 epsilon chains. Hb Gower 2-Consists of 2 alpha & 2 zeta chains. Hb Portland- Found in trace in neonates and intrauterine life. Hb Barts Found in small amount in cord blood of neonates with thalasseamia.

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Sickle Cell Traits (HbAS) Adequate amount of normal haemoglobin is present, they are carriers, do not have symptoms of sickle cell disorder. Sickle Cell Anemia (HbSS) Most severe form of disease Haemoglobin C (HbSC) Haemoglobin E (HbSE) Haemoglobin S beta Thalasseamia-This is a mild form of sickle disorder.

In the year 1904 cardiologist and professor of medicine James B Herrick found peculiar elongated cells in blood of a 20 years old dental student who was suffering from anemia. Veron Mason in 1922 named SICKLE CELL ANAEMIA. Linus Pauling("father of molecular biology")in Pauling( 1940 demonstrated that sickling occurs as a result of abnormality in haemoglobin molecule. Sickle cell disease is the first genetic disorder whose molecular basis was known. June 19th is celebrated as World Sickle Cell Day

Sickle cell anemia is a autosomal recessive genetic disease that results from the substitution of Valine from Glutamic acid in position 6 of beta globin gene leading to production of defective form of haemoglobin.(Hb S) Hb S is a structurally defective haemoglobin.

Deoxygenation leads to hydrophobic interaction between adjacent Hb S molecules. Distortion of RBC into sickle form cells Rapid haemolysis Decreased elasticity of cell wall of RBC Decreased life span 10 20 days. Clogging of RBC in microcirculation.

Vasooclusive crisis Haematological crisis Aplastic crisis Sequestration crisis Infectious crisis

The hallmark of sickle cell disease is the vasoocclusive pain crisis. It is the most common clinical manifestation but can occur with varying frequency in different individuals. It results from the complex interplay between sickled red cells, neutrophils, endothelium, and plasma factors as outlined in the section on pathophysiology. The end result is that of tissue hypoxia leading to tissue death and accompanying pain

Crisis may affect any tissue, but patients typically complain of pain in the chest, lower back, and extremities. Abdominal pain occurs and may mimic acute abdomen from other causes. Fever is often present, even in the absence of infection. Episodes may be precipitated by dehydration, infection, and cold weather, although in about half of the cases no precipitating factor is found. Repeated splenic infarctions in childhood typically result in "autosplenectomy" and loss of splenic function by age 6 to 8 years

These include a prodromal phase characterized by low intensity pain, paresthesias, decreased red cell deformability, and an increase in irreversibly sickled cells; followed by an initial, evolving phase characterized by increasing pain and worsening of hematologic parameters. This is then followed by an established (inflammatory) phase with steady, severe pain, increased hemolysis, increased neutrophils, and increased acute phase reactants, at which time patients typically seek medical care. Physical signs may include fever, joint swelling, and effusion.

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Obstructed microcirculation leading to ischemic injury to organ Avascular necrosis Acute chest syndrome Acquired asplenia Splenic sequestration Hand foot syndrome Papillary necrosis in kidneys Hyposthenuria and enuresis Cerebral infarction Skin ulceration Retinal hemorrhage and retinopathy Priaprism

Vasoocclusion resulting in infarction of articular surfaces of long bone occurs most commonly in the femur followed by the humerus. It is a complication more prevalent than previously believed as more sensitive imaging studies have been used. It was previously thought to occur with increased frequency in Hb SC disease as opposed to Hb SS. However, with increased longevity of Hb SS patients, its prevalence is greatest in patients with Hb SS As per CSSCD estimates, 50 percent of patients by age 33 years will have avascular necrosis of the femoral head

Avascular necrosis of the right hip in a 31-year-old female with SCD depicting a patchy lucency and sclerosis and irregular contour of the femoral head and loss of the joint space.

The acute chest syndrome (ACS) is a constellation of signs and symptoms in patients with SCD that includes a new infiltrate on chest radiograph defined by alveolar consolidation but not atelectasis, chest pain, fever, tachypnea, wheezing, or cough, and hypoxia It is the leading cause of mortality in patients with SCD. Infections with viruses and bacteria were found to be the leading cause in the pediatric age-group A large number of adults developed ACS as a result of pulmonary fat microembolization, derived from marrow necrosis, usually during the course of a vasoocclusive crisis.

Regardless of the triggering factor, the pathogenesis of ACS involves increased intrapulmonary sickling, intrapulmonary inflammation with increased microvascular permeability, and alveolar consolidation. The treatment of acute chest syndrome includes oxygenation, incentive spirometry, adequate pain control to avoid chest splinting, antimicrobial therapy that covers atypical bacteria, avoidance of overhydration, application of bronchodilators and red cell transfusion to decrease intrapulmonary sickling.

Anteroposterior view of chest radiograph depicting bilateral, patchy, lung infiltrates in a 30-year-old female with SCD and evolving acute chest syndrome.

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Obstructed microcirculation leading to ischemic injury to organ Avascular necrosis Acute chest syndrome Acquired asplenia Splenic sequestration Hand foot syndrome Papillary necrosis in kidneys Hyposthenuria and enuresis Cerebral infarction Skin ulceration Retinal hemorrhage and retinopathy Priaprism

This type of crisis is characterized by sudden, massive pooling of red cells, especially in the spleen, which may result in hypovolemic shock and cardiovascular collapse. It is typically seen in infants and children (usually <5 years of age) prior to autoinfarction of the spleen A minor sequestration episode is usually accompanied by a hemoglobin of more than 7 g/dL, and a major episode usually is one in which the hemoglobin is less than 7 g/dL or the hemoglobin has decreased by 3 g/dL from baseline.

Acute splenic sequestration crisis and hepatic sequestration crisis can present with rapidly enlarging spleen or liver, pain, hypoxemia, and hypovolemic shock. Treatment consists of either red cell transfusion or exchange transfusion. Transfusion carries the risk of hyperviscosity when the sequestration crisis resolves and the sequestered red cells are returned to the general circulation. Acute splenic sequestration crisis can be recurrent, especially in children. Splenectomy is recommended for those with life-threatening splenic sequestration crisis or chronic hypersplenism. Partial splenectomy is probably best avoided in most cases.

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Obstructed microcirculation leading to ischemic injury to organ Avascular necrosis Acute chest syndrome Acquired asplenia Splenic sequestration Hand foot syndrome Papillary necrosis in kidneys Hyposthenuria and enuresis Cerebral infarction Skin ulceration Retinal hemorrhage and retinopathy Priaprism

Dactylitis is a term used to describe painful swelling of digits of hands and feet. It occurs early in infancy as hematopoietic marrow is still present in these bones at this age. Most episodes resolve within 2 weeks. Epiphyseal infarction can result in joint pain and swelling mimicking septic arthritis Vertebral body infarctions with subsequent collapse causes the classic "fish mouth" appearance on plain radiographs.

The acidic, hypoxic, and hypertonic environment of the renal medulla promotes sickling of Hb SS erythrocytes, leading to ischemia of the renal microcirculation The incidence of renal failure varies between 4 and 20 percent. Angiotensin-converting enzyme inhibitors decrease proteinuria and may reverse pathologic changes such as focal segmental glomerulosclerosis. Effective blood pressure control, avoidance of nephrotoxic agents, and treatment of urinary tract infection are the cornerstones of treatment In patients with SCD, 5-18% develop renal failure.[12] In one study cohort, the median age at the time of renal failure in patients with SCD was 23.1 years.

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Vasooclusive crisis Haematological crisis Aplastic crisis Sequestration crisis Infectious crisis

Acute splenic sequestration, pooling of blood in the engorged spleen Aplastic crisis Seen in patients with parovrus B-19 infection or folic acid deficiency leading to decreased marrow erythropoiesis Anemia Pigmented gallstone Jaundice Delayed growth

Infectious crisis is due to functional asplenia and decreased level of serum immunoglobulin M (IGM) increasing susceptibility to infections. Haemophilius influenzae, streptococcus pneumoniae, mycoplasma pneumoniae, salmonella typhimurium, staphylococcus aureus, and escherichia coli are the common causative microbes. Common infections include pneumonia, bronchitis, pyelonephritis, cystitis, osteomyelitis, meningitis, and sepsis

CVS-Anemia and vasooclusive phenomena causing myocardial ischemia and myocardial infarction, repeated blood transfusion leading to restrictive cardiomyopathy. Pulmonary-Acute chest syndrome CNS-25% patient have TIA, strokes, cerebral hemorrhage Hepato biliary system-Gall stone recurrent abdominal pain, autosplenectomy Urinary system- Haematuria, hyposthenurea and renal failure Ocular complication- Proliferative retinopathy, vitreous hemorrhage and retinal detachment Orthopedic Hand foot syndrome, avascular necrosis of hip, osteomyelitis

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Young infants have recurrent edema of the dorsum of hands and feet. Infarction of cortex of long bones lead to prominent signs of local inflammation. Repeated infarction in the joints of large and small bones lead to abnormal angled digits, malformed and frozen joints, particularly at the knee and ankle. Chronic leg ulcer is common in adolescent patients. Abdominal examination may reveal splenomegaly if sequestration is occurring otherwise the spleen is small in size due to autoinfarction Evidence of cholilethiasis is seen in patients as young as 3 years old. By mid childhood most patients are underweight as compared to children of their same age and height.

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There is a higher rate of spontaneous abortion. A miscarriage may happen up to 25% of the time. There is ahigher rate of babies not surviving to birth or being stillborn. 8-10% . Birth weight is lower than average. Infection is more common in women with sickle cell disease during pregnancy, especially bladder infection. Increased chance of PIH and preeclampsia Increased incidence of PPH.

Hb-6-8gm% Reticulocytes high Peripheral smear may show sickle cells Features of hyposplenism :Target cells and HowellJolley bodies seen Sickle solubility test Sickling test with reducing agent Sodium metabisulphide Hb electrophoresis High performance liquid chromatography(HPCL) WBC may be elevated Bilirubin may be elevated Urinarary cast may be seen or trace of RBC in urine

Pattern of hemoglobin electrophoresis from several different individuals. Lanes 1 and 5 are hemoglobin standards. Lane 2 is a normal adult. Lane 3 is a normal neonate. Lane 4 is a homozygous HbS individual. Lanes 6 and 8 are heterozygous sickle individuals. Lane 7 is a SC disease individual.

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Oxygenation Pain Management (NSAID, OPIODS) Hydroxyurea, Folic acid Hydration Blood Transfusion Antibiotics (Penicillin group) Steroids Bone marrow transplantation Gene therapy

The MSH study included patients and investigators from 22 sickle cell anemia treatment centers in the U.S. and Canada. The study included over 290 patients in the in the placebo-controlled, double-blind investigation The Independent Oversight Committee, charged by the National Heart, Lung, and Blood Institute (NHLBI) to guard the welfare of the patients, terminated the study on January 31, 1995 because the patients on the hydroxyurea (HU) arm had significantly fewer episodes of vaso-occlusive painful crises, fewer hospitalizations, and fewer episodes of acute chest syndrome. The initial results were reported in the New England Journal of Medicine, May 18, 1995. Hydroxyurea is the first agent that can prevent above-mentioned complications of sickle cell anemia.

Certain groups of patients with sickle syndromes who might benefit from treatment with hydroxyurea were excluded from the MSH study to reduce the baseline variability in the patient population. Among the excluded patients were compound heterozygotes with sickle -thalassemia, as well as patients with hemoglobin SC disease. Patients under 18 years of age were excluded, as well as people on chronic transfusion therapy for any reason. Hydroxyurea is a chemotherapy agent with potent effects on the bone marrow. The agent was used for many years to treat people with certain malignancies before being used for sickle cell disease The primary side-effect of hydroxyurea is suppression of blood counts, particularly the white blood cells (neutropenia) and platelets (thrombocytopenia). Neutropenia and thrombocytopenia respectively place patients at risk for infection and bleeding

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Recurrent painful vaso-occlusive crises (Patients who are hospitalized more than 4 or 5 times per year with painful vaso-occlusive crises are good candidates for hydroxyurea therapy) Acute Chest Syndrome (Patients who survive the syndrome
are more likely to suffer a recurrent episode than are people who have never been affected. Hydroxyurea reduced by half the number of episodes of ACS in the patients in the treatment arm. Given the life-threatening nature of this condition, patients who survive acute chest syndrome should be considered for hydroxyureatherapy.)

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Other complications of SCD (stroke,priapism,chronical transfusion need, leg ulcers, aseptic necrosis of bone..)

Baseline measurements- At least two months of baseline information on the hematologic status of patients with sickle cell disease should be available before starting treatment. Starting dose- hydroxyurea can be started at a dose of 10 mg/kg orally, on a daily basis. The patient's hematologic status should be monitored to rule-out falls in the neutrophil count to less than 2,500 per cubic millimeter or platelet count to less than 80,000 per cubic millimeter. Dose escalation- The dose of hydroxyurea can be increased at a rate of 5 mg/kg/wk as long as the hematologic values remain in an acceptable range, and the patient shows no other evidence of side-effect from the HU.

Maximum dose- At BWH, the maximum dose of hydroxyurea used in most patients is 25 mg/kg/day. Patients at some institutions receive doses of hydroxyurea as high as 35 mg/kg/day. Limiting effects platelet count of less than 80,000. neutrophil count (not white count) of less that 2,500 hemoglobin of less than 6 g/dl. hair loss, GI upset, rash

Hydroxyurea blood levels- Blood levels of hydroxyurea are difficult to interpret because of fluctations that reflect, among other things, the pattern of drug use (e.g., once a day versus twice a day) and the timing of the blood test relative to ingestion of the HU. MCV- The MCV rises in many patients treated with hydroxyurea. The response varies significantly between patients, making it unreliable as a measure of hydroxyurea efficacy or patient compliance with the drug. Fetal hemoglobin levels- Fetal hemoglobin levels rise in many patients treated with hydroxyurea, but the response is variable. A correlation between patient clinical response and a rise in fetal hemoglobin levels has not been demonstrated.

Blood transfusion is currently the most effective and proven treatment for severe anemia of SCD, it significantly reduces crisis. Blood transfusion reduces pain by increasing the number of functioning RBC and by increasing the oxygen caring capacity of blood

Bone marrow transplant is the closest thing possible to the cure of SCA. Helps in production of healthy RBC from transplanted bone marrow The success rate is 90 95%

Gene therapy is a relatively new idea of inserting genes into the cells of an individual in order to treat hereditary disease such as SCA, in which a defective mutants alleles is replaced with a functional one. Gene therapy would be the best cure for SCA in future, as of now it is on its experimental stage.

Dialysis or kidney transplant for renal failure. Cholecystectomy for pigmented cholelitheasis. Hip replacement for avascular necrosis. Surgery for eye problem. Irrigation surgery for Priapism. Wound care for leg ulcer.

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Genetic counseling Pre implantation genetic diagnosis Perenatal testing -amniocentesis (16 18 wks) and chorius villus sampling ( 9 -10 wks)

Regular health check up & good hydration. 2. Vaccination for pneumonia, meningitis, influenza, and hepatitis 3. Preventing infection daily dose of penicillin 4. Preventing strokes Transcranial doppler ultrasound every 3 months. 5. Preventing eye damage Fundus examination every 3 months. 6. Avoid alcohol, smoking, cold climate, high altitude exposure. THERE ARE 4 MILLION SICKLE CELL DISEASED PATIENTS WORLDWIDE
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