Case 4- anaemia Flashcards
Sickle cell anaemia (HBSS)
Homozygous sickle cell disease, geontype is HbSS. Most common and severe type, occurs when the child has two sickle cell genes, inheriting one from each parent. Is a haemoglobinopathy, the red blood cells become sickle shaped instead of a biconcave disk
Sickle Haemoglobin C disease (HBSC)
Has a mutation in their beta globin genes that produces both haemoglobin C and haemoglobin S which are both abnormal haemoglobin. Causes similar symptoms to sickle cell anemia but less severe anemia. When you inherit one sickle genes from one parent and a ‘C’ gene from another parent.
Sickle beta Thalassemia (HbSβ+ / HbSβ0)
Have mutations in both beta globin genes. One mutation is resulting in HbS and another is Beta Thalassemia. The severity of the disease varies according to the amount of normal beta globin produced. The sickle genes creates crescent shaped red blood cells that break down while thalassemia produces smaller RBCs. There are two types of beta thalassemias, sickle beta plus which is mild, whilst sickle beta zero is more severe
Sickle cell trait (HbAS)
Not a disease but means the person has one copy of the sickle cell gene. They are carriers and can pass it on to their children
Haemoglobinopathies
Genetic disorders affecting the structure or production of the haemoglobin molecule. Mutations in the genes encoding the globin chain. The haem portion of the molecules is normal. These Globin abnormalities can be quantitive or qualitive.
Quantitative Hb disorders
When there is a quantitive decrease in the production of alpha or beta globin chains but the chains are structurally normal. Known as Thalassemia
Qualitative Hb disorders
Causes a change in the structure of the Hb molecules. There are several hundred variants, they were originally classified by a letter in the alphabet (HbS, HbC). Majority are benign and discovered incidenty, only a few Hb variants can cause severe disease. Includes haemoglobin S which is found in sickle cell anaemia.
Epidemiology of sickle cell anaemia
Commonly affects people from African, Caribean, middle Eastern and Indian ancestory.
Mutation which causes sickle cell anaemia
It is autosomal recessive. A single base substitution of adenine to Thymine in the sixth codon of the beta-chain gene, changing from GAG to GTG. This causes coding of valine instead of glutamate which makes the body produce abnormal hemoglobin called HbS.
GAG –> GTG
Val –> Glut
Sickle cell crisis
HbS (sickle cell haemoglobin) forms polymers under deoxygenated conditions which distort the erythrocyte into a sickle shape. This can be triggered by cold, infection, dehydration, hypoxia and exercise. The sickle cells are stickier and less flexible than normal red blood cells. They can form clusters which block and damage blood vessels. Sickling can cause pain and other symptoms. When it happens suddenly it’s a sickle cell crisis.
Between sickling events
Between sickling events the RBC’s retain their normal shape. After recurrent episodes of sickling the membranes damage and RBC’s are unable to resume their biconcave disk when they reoxygenate. They are irreversibly sickled cells. The cells are also quite fragile and easily broken down or removed by the spleen leading to haemolytic anaemia. RBCs will have a shorter life span. However, haemoglobin S releases oxygen to tissues more readily than haemoglobin A (normal), and this may reduce the drive to erythropoiesis.
What can sickle cell anaemia lead to
Haematuria, blindness, and heart failure. Can lead to ischaemia (necrosis, organ dysfunction, acute pain, oxidative reperfusion stress) and Haemolysis (fatigue, anaemia, cholelithiasis, endothelial dysfunction).
Clinical manifestations of sickle cell anaemia
Evident after the first 6 months of life, variable severity. A minority have few complications and their disease is unapparent, a majority have an intermediate form and some have severe complications. Most people have a few episodes of sickle cell crisis each year. Can lead to infections, anemia and accute vaso-occlusion crisis in acute manifestations. In chronic manifestations it is mostly related to chronic organ ischaemia and infarction due to obstruction of the blood vessels by sickle cells.
How are most cases of sickle cell anaemia diagnosed
Most are diagnosed in the neonatal bloodspot screening program
Tests done on sickle cell anaemia
- FBC and blood film: the hemoglobin level is in the range 6-8 g/dL with a high reticulocyte count (immature red blood cells); the blood films may show sickled RBCs.
- Sickle solubility test / the sickling test: when you expose RBCs to a deoxygenated agent, they will turn cloudy because the HbS precipitates, normally it will be a clear solution. It is observed against a white background with black lines.
- Haemoglobin analysis- by electrophoresis or high performance liquid chromatography is needed to confirm a diagnosis.
- May use DNA analysis
Sickle cell anaemia management
Lifelong treatment and monitoring are needed. You can have treatment to prevent sickling episodes or prevent related problems such as infection. The only curative treatment is a bone marrow transplant.
Spherocytosis
Red blood cells are spherical instead of a bi-concave disk. It can be hereditary or caused be immunologically mediated haemolytic anaemia. The immunological cause can be further split into autoimmune hemolytic anaemia, the haemolytic disease of newborne and hemolytic transfusion reaction. However, hereditary spherocytes (HS) is the most common.
Where is HS (hereditary spherocytosis) common
More common in northern European ancestry, about 75% of cases are autosomal dominant, the rest are recessive
Pathophysiology of Spheroctosis
Caused by a molecular defect in some of the proteins of the red blood cell cytoskeleton. This mutation in the membrane proteins leads to separation of the lipid membrane from the cytoskeleton and weakening of the vertical connections between them. Areas of the membrane not connected to the cytoskeleton are released from the cell as microvesicles and RBCs become sphere shaped. Less surface for oxygen and CO2 to be exchanged. They are also less flexible and get caught in the microcirculation of the spleen and promote phagocytosis by the macrophages in the spleen leading to hemolysis, shortening RBC lifespan and causing anaemia.
Clinical features of Spherocytosis
Presents at any age, normally a known family history. Neonates may require an exchange transfusion. Individuals with severe hemolysis may develop additional complications such as jaundice, splenomegaly, pigment gallstones and nutrient deficiencies – such as folate, vitamin B12, or iron deficiency.
Tests for Spherocytosis
- FBC and red cell indices: raised MCHC (an MCHC ≥36 g/dL is consistent with spherocytes), increased red cell distribution width.
- Blood film: Spherocytes and reticulocytosis
- Haemolysis testing: Increased reticulocytes count, increased unconjugated bilirubin and lactate dehydrogenase
- Direct antiglobulin test/ Coombs testing- usually done to eliminate the possibility of immune-mediated haemolysis. Direct antiglobulin test is usually negative in HS but is positive in autoimmune haemolytic anaemia.
Whats the most important thing to look out for in Spherocytosis
Hemolytic anaemia and spherocytes on the peripheral blood smear.
How is is Thalassemia classified
According to what chain of the globin molecule is affected and the number of genes deleted
Alpha Thalessemia
A reduction or absence in alpha globin chain production. Its highly prevailent in Southern China, South east asia (Malaysia, Thailand), Africa and India. Associated with gene deletions on chromosome 16.
Alpha Thalessemia- single gene deletion (silent carrier)
Deletion of a single α-globin genes causes a barely detectable reduction in α-globin chain synthesis. These individuals are completely asymptomatic.
Alpha Thalessemia- two gene deletion (alpha thalassemia minor/trait)
Caused by the deletion of two α-globin genes from a single chromosome (–/αα) or the deletion of one α-globin gene from each of the two chromosomes (-α/-α). Asymptomatic but may have mild hypochromic anaemia.
Alpha Thalessemia- three gene deletion (haemoglobin H disease)
In HbH there is only one normal alpha-globin gene, so the synthesis of chains is markedly reduced. Excess beta globin chains form Hb H (beta chain tetramers - β4) which has a high affinity for oxygen and therefore is not useful for oxygen delivery, leading to tissue hypoxia. HbH is prone to oxidation which causes it to precipotate and form intracellular inclusions that promote hemolysis in the spleen leading to moderately severe anemia, marked microcytosis, splenomegaly and bone marrow erythroid hyperplasia.
Alpha Thalessemia- four gene deletion (Hydrops fetalis/ Hb Barts)
All 4 alpha-globin genes on both alleles of chromosome 16 are deleted. Leads to a lack of HbF which is the major source of haemoglobin in gestation. γ chains takes the place and form gamma chain tetramers (γ 4) known as Hb Barts which cannot deliver oxygen to the tissues because its affinity for oxygen is too high. The baby is then stillborm.
