Sickle cell Anemia

What is Anemia
Definition: Anemia is a pathological condition characterized by lowering of the circulating red cell mass ( or Hb concentration or both together) below normal levels. normal adult levels males= 13-17 gm/dl Females= 12-16 gm/dl Anemia : Males= <13gm/dl Females=<12gm/dl Pregnant=<11gm/dl Normal RBC count= 4.5-5.5 million/l This ultimatley leads to a decrease in the O2 carrying capacity of the blood.

Classification
Anemia may be classified in one of the following 2 ways: according to the cause or red cell size and Hb content a) According to the cause 1. Hemorrhagic Anemia: This is anemia caused by acute or chronic blood loss Eg. Bleeding peptic ulcer or piles, or bilharziasis

2.Hemolytic anemia: Excessive hemolysis of RBC may occur due to either Intracapsular (congenital) causes Eg. Abnormalities in red cell membrane ( as in congenital spherocytosis) Or in Hb as in thalasemia and sickle cell anemia ( which we will discuss) Or deficiency in G6PD enzyme

 Extracapsular (acquired) causes= Eg. Chemicals and toxins ( as some snake venoms) Certain infections as malaria Hypersplenism Incompatible blood transfusion Autoimmunity

3. Apalastic anemia: This is anemia caused by damage to bone marrow due to Exposure to x rays or gamma rays Certain drugs such as antineoplastic drugs Leukemia

4. Nutritional ( deficiency) anemia: Anemia caused by deficiency of nutritional factors required for erythropoiesis eg. Fe deficiency anemia ( most common type) Pernicious anemia ( vitamin b12 deficiency) Macrocytic anemia ( folic acid defeciency)

b) Classification according to red cell size and Hb concentration 1. Normochromic normocytic anemia: In this anemia the size of RBC and their Hb content are normal but their count is less than normal It occurs in Hemorrhagic anemia Hemolytic anemia Apalastic anemia Hepatorenal disease

2.Hypochromic microcytic anemia: Anemia in which red cell size and their Hb are decreased but their count is normal it occurs in Fe deficiency anemia Thalasemia Pb intoxification hypothyroidism

3.Macrocytic anemia in this anemia, both red cell volume and its Hb content are increased but the mean Hb concentraion is normal. There are 2 types of this anemia Megaloblastic anemia= this occurs in pernicious anemia and in cases of folic acid defeciency Non-megaloblastic anemia= this occurs after recent hemorrhage or hemolysis and in some cases of apalastic anemia

Definition of sickle cell anemia

Sickle cell anemia (SCA) is a hereditary disorder caused by mutation of globin chain that creates sickle hemoglobin (HbS). leading to destruction of the RBC. The synthesis of normal HbF is normal, so the disease does not manifest itself until HbF decreases to adult levels at about 6 months of age

Incidence
Approximately 8% of American blacks are heterozygous for HbS. In parts of Africa where malaria is endemic the gene frequency approaches 30%, as a result of small but significant protective effect of HbS against plasmodium falciparum malaria In the USA SCA affects I every 600 blacks. Worldwide SCA is the most common form of familial hemolytic anemia

Etiology and pathogenesis

Etiology: HbS arises from a mutation substituting thymine
for adenine in the sixth codon of the beta-chain gene, GAG to GTG This causes coding of valine instead of glutamate in position 6 of the Hb beta chain

 The resulting Hb has the physical properties of forming polymers under deoxy conditions It also exhibits changes in solubility and molecular stability These properties are responsible for the profound clinical expressions of the sickling syndromes

 Pathogenesis: Upon deoxygenation , HbS molecules undergo polymerization. These polymers distort the red cell, which assumes an elongated crescent ( sickle) shape. Sickling is reversible upon reoxygenation.

 However, membrane damage occurs with each episode of sickling Eventually the cells accumulate Ca, lose K and H2O and become irreversibly sickled The affected RBC becomes liable to hemolysis As well as very liable for adhession to the endothelium leading to vascular occlussion

Inherited types ( or forms)

SCA denotes all genotypes containing at least 1 sickle cell gene, in which HbS makes up at least half of the hemoglobin present. Major sickle genotypes include: HbSS disease or sickle cell disease ( the most common form) - Homozygote for the S globin with usually a severe or moderately severe phenotype and with the shortest survival

 Presence of hemoglobin other than than HbS In heterozygotes aproximatley 40% HbS; the ramainder is HbA HbA interacts only with weakly deoxygenated HbS. Presence of HbA slows polymerization greatly As a result red cells of heterozygotes have little tendency to sickle in vivo. Such individuals are said to have sickle cell trait

Other combinations of HbS with other genetic defects

HbS/ thalassemia - Double heterozygote for HbS and thalassemia; MCH and MCV are lower than homozygous HbSS clinically indistinguishable from sickle cell anemia. Splenomaegaly is common.

 HbSC disease (hemoglobin C disease) - Double heterozygote for HbS and HbC (another mutant -globin) characterized by moderate clinical severity caused by substitution of lysine for glutamic acid HbC tends to from rhomboidal crystals in the homozygous state there is mild hemolytic anemia with marked target cell formation ( rhomboidal crystals and microspherocytes) The spleen is enlarged Carriers show few target cells HbS/hereditary persistence of fetal Hb (S/HPHP) - Very mild or asymptomatic phenotype

 HbS/HbD- this is the same group of variants with the same electropheric mobility Heterozygotes shows no hematological abnormality Homozygotes show mild hemolytic anemia HbS/HbE syndrome - Very rare with a phenotype usually similar to HbS/b+ thalassemia. Homozygous state there is mild microcytic , hemolytic anemia

Clinical presentation/complications
1.Features of anemia and hemolysis such as: Symptoms of anemia Hemolytic jaundice Chronic leg ulcer Hemolytic crises

 Vaso-occlusive crises ( organ failure or pain crises): Vascular congestion, thrombosis and infarction dactylitis Acute abdomen Liver, splenic and renal infarction Mycardial infarction Hemiplagia Retinal detachment Bone pain Priapism CNS stroke

 Visceral sequestration crisis: Suseptibility to infections eg. Pneumococci and salmonella. Chronic leg ulcer Gall stones ( pigment stone) Aseptic necrosis of bone Blindness Acute sickle chest syndrome ( presents with dyspnea and falling arterial pO2) Moderate splenomegaly in children

 Aplastic crises: These result from infection from prvovirus or from folate deficiency and are characterised by Sudden fall in hemoglobin and reticulocytes

How to diagnose
Laboratory findings Hemoglobin is usually 6g/dl low in comparison to symptoms of anemia sickle cells and target cells occur in blood (rhomboidal crystals and microspherocytes) High serum bilirubin ( indirect)

Hemoglobin electrophoresis
HbS is high In HbSS, no HbA is detected The amount of HbF is variable, larger amounts are usually associated with milder disorder. This slide shows the results of haemoglobin electrophoresis of the blood from a normal adult a patient with sickle cell anaemia (SS) people with sickle cell trait (AS) haemoglobin C trait (AC)

 Sickling test= ( blood + Na bisulphate) Test is positive when blood is deoxygenated as in SS and SA In sickle C disease: 50% HbS+HbC in Mild to moderate anemia Spleen and retinal detachment Nearly normal life span Sickle thalassemia: 70% HbS+ 30% HbF, there is also splenomegaly

Other investigations
Transcranial ultrasonography detects abnormal blood flow indicative of arterial stenosis ( this predicts strokes in children) Chest x-ray can reveal pulmonary infiltrate indicating acute sickle chest syndrome. Pulmonary hypertension can be detected by doppler and ECG

Treatment
Prophylactic- avoid factors that are known to precipitate vaso-occlusive crises such dehydration, hypoxia, infections, stasis of blood circulation and cooling of skin surface. Folic acid (eg. 5 mg weekly) Good hygiene and nutrition( espcially red meat, liver and green vegetables which are rich in Fe)

 Pneumococcal , meningicoccal and hemophillus vaccination. Oral penicillin should start at diagnosis and continue at least until puberty. Crises- treat by rest, warmth, rehydration by oral fluids or intravenous saline ( 3L in 24 h) Analgesia at the appropriate level should be given. NSAIDs (eg. Subcutaneous diamorphine) Hydroxyurea ( 15-20 mg) can increase HbF and has been shown to improve clinical course in children (should not be used during pregnancy)

 Gene therapy Research into other drugs (eg. Butyrates) to enhance HbF synthesis or increase solubility of HbS is taking place. Bone marrow transplantaion Has proved to be succesfull in treating SCD with survival rate of 70-90% if the donor is a matched sibling 36-65% if the donor is unrelated Transplantation is only indicated in serious cases whose life expectancy is impaired.

Blood Transfussion
The two primary goals of transfusion are to correct the low oxygen-carrying capacity caused by severe anemia to improve microvascular perfusion by decreasing the proportion of sickle red cells in the circulation. In the clinical setting, transfusions are often used to address both indications

 Indications: Management of severe anemia simple transfusions should be used without taking any blood from the patient. Acute splenic sequestration Severe acute splenic sequestration produces hypovolemia and cardiovascular decompensation Patients require immediate transfusion to prevent cardiovascular collapse

 transfusions are indicated when the hemoglobin drops by more than 2 gm/dl from the steady state. The rise in hemoglobin following transfusion is usually greater than expected reflecting release of sequestered red cells Consequently, excessive initial transfusion should be avoided.

 Transient red cell aplasia (caused by parvovirus b19) Severe anemia develops over a few days secondary to shortened red cell survival without compensatory production of new red cells While many patients recover spontaneously, red cell transfusions are indicated for those who become symptomatic or whose hemoglobin value falls 2 gm/dl below baseline.

 Acute chest syndrome When acute chest syndrome is associated with hypoxia and a falling hemoglobin, transfusions are indicated. Studies suggest that early transfusion may prevent the progression of acute pulmonary disease

 Stroke Chronic transfusion therapy reduces the rate of recurrent vaso-occlusive stroke and is indicated for all victims of this complication of sickle cell disease. Some studies have suggested that transfusions may improve perfusion and oxygenation to brain tissue, thus limiting damage.

 Management of multi-organ failure Acute multi-organ failure is a devastating complication of sickle cell disease. classically associated with falling hemoglobin and platelet count, as well as progressive multi-organ failure. Limited studies indicate that aggressive transfusion may improve survival and recovery of organ function.