Haemolytic Anaemias And Haemoglobinopathies Flashcards
What are Haemoglobinopathies
Haemoglobinopathies are inherited disorders where expression of one or more of the glob in chains of haemoglobin is abnormal. There are two main categories:
- Abnormal haemoglobin variants: Result from mutations in the genes for the alpha or beta globin chains that alter the stability or function of haemoglobin (sickle cell disease)
- Thalassaemias: Results from reduced or absent expression of normal alpha or beta globin chains. This leads to a reduced level of haemoglobin rather than the presence of an abnormal haemoglobin.
Explain the significance of sickle cell anaemia and appreciate the clinical manifestations of the disease
The most common haemoglobin variant of clinical significance is haemoglobin S (HbS). This variant is fount mainly in people of black African descent. Heterozygous develop resistance to malaria as the change makes in difficult for Falciparum parasites to grow. Homozygotes develop sickle cell disease.
The HbS variant has an uncharged valine instead of a charged glutamic acid at position 6 of beta globin making haemoglobin S more prone to polymerise at low oxygen tension. This leads to formation of long twisted haemoglobin polymers that can result in the deformation of the red blood cell membrane causing the cell to have a sickle shape. After repeated suckling damage occurs to the membrane causing it to lose elasticity. These damaged cells fail to return back to a normal shape.
What are the consequences of sickle cell formation.
- Vaso-occlusive episodes due to occlusion of small capillaries from sickle cells getting trapped. Leads to recurrent acute pain and syndromes such as stroke or acute chest syndrome
- Anaemia due to sickle cells undergoing haemolytic resulting in a shortened erythrocyte lifespan from 120 day to 20-30 days
- Jaundice and gallstones due to increased bilirubin resulting from chronic haemolysis
- Splenic atrophy due to splenic infarction with an associated susceptibility to infection by encapsulated bacteria such as Streptococcus pneumonia e and Streptococcus meningitidis
Explain the haematological abnormalities of patients with alpha thalassaemia
Alpha thalassaemia results from deletion or loss of function of one or more of the 4 alpha globin genes. The severity of the condition depends on how many genes are malfunction along ranging from normal with mild microcytosis (1 or 2 genes affected), to death in utero (all 4 genes affected leading to absence of alpha globin chain). Lack of function in 3 of 4 alpha globin genes leads to haemoglobin H disease which is characterised by severe microcytosis, anaemia, haemolysis and splenomegaly
Explain the haematological abnormalities of patients with beta thalassaemia
Beta thalassaemia results from mutation of 1 or both beta globin genes leading to reduction in amount of beta globin polypeptide chains.
Heterozygous (1 mutated genes) are mutated in rate of beta globin production resulting in microcytosis. Although size decreases, number remains the same so anaemia only develops in times of increased demand such as pregnancy.
Homozygous (both mutated genes) results in a life threatening condition called beta thalassaemia major. Synthesis of beta globin totally absent and they are dependent on blood transfusions for their whole life since the synthesis of haemoglobin A cannot replace haemoglobin F due to lack of beta globin
Explain the underlying causes of acquired haemolytic anaemias
Acquired Haemolytic anaemias are due to damage to cells and include:
- Mechanical damage e.g., Microangiopathic anaemia
- Antibody damage e.g., Autoimmune haemolytic anaemia
- Oxidant damage e.g., Exposure to chemicals or oxidants
- Heat damage e.g., severe burns
- Enzymatic damage e.g., snake venom
Explain the underlying causes of Inherited haemolytic anaemia
Inherited haemolytic anaemia is due to a defective gene. This includes:
- Glycolysis defect e.e., pyruvate kinad=we deficiency limits ATP production
- Pentose-P pathway e.g., G6PDH deficiency leads to oxidative damage
- Membrane protein e.g., hereditary spherocytosis
- Haemoglobin defect e.g., sickle cell
What are the 4 major types of myeloproliferative neoplasm
Myeloproliferative neoplasms (MPNs) are a group of diseases of the bone marrow where excess cells are produced. These arise from genetic mutations in the precursors of myeloid lineage in the bone marrow. These include:
- Polycythaemia Vera (excess erythrocytes)
- Esential thrombocytopenia (overproduction of megakaryocytes leading to excess platelets)
- Primary myelofibrosis (initial proliferative phase followed by replacement of haematopoietic tissue by connective tissue leading to impairment of the generation of all blood types (pancyopenia))
- Chronic myeloid leukaemia (excess granulocytes)
Explain polycythaemia Vera
Polycythaemia is a disease state where the volume percent of erythrocytes in the blood exceed 52% (male) or 48% (female). Polycythaemia Vera is a specific form resulting in an overproduction of erythrocytes. 95% of cases are caused in a mutation of the gene coding for Janus Kinase 2 (JAK2). Multipotent stem cells harbouring the JAK2 mutation survive longer and proliferate continuously..
The clinical conditions associated with Polycythaemia Vera result from the blood being thicker and include:
- Thrombosis (venous and arterial)
- Haemorrhage (skin or GI tract)
- Headache and dizziness
- Plethora
Explain Essential thrombocythaemia
Thrombocytosis is an increase in the platelet count compared to the normal range of a person of same gender and age. It can result from an MPN where it is then called an essential thrombocytopenia. This is a fair chronic blood cancer characterised by the overproduction of platelets by megakaryocytes in the bone marrow. Around half the cases are caused by the same JAK2 mutation found in Polycythaemia Vera. Mutations in the thrombophlebitis receptor can also cause the disease. The most common symptoms include:
- Numbness in the extremities
- Thrombosis (most often arterial e.g., stroke or peripheral gangrene)
- Disturbances in hearing and vision
- Headaches
- Burning pain in hands or feet
Explain Primary myelofibrosis
Primary myelofibrosis is a MPN where the proliferation of the mutated hamatopoietic stem cells result in reactive bone marrow fibrosis leading to the replacement of bone marrow with scar tissue (collagen deposition). Mobilisation of mutated progenitor cells can occur and these can colonise the liver and spleen leading to extramedullary haemopoiesis. The is why patients with primary myelofibrosis show an enlarged liver and spleen. Mutations in the JAK2 gene are often associated with the disease. Secondary myelofibrosis is when the disease has developed as a consequence of Polycythaemia Vera or essential thrombocythaemia. Symptoms include:
- Hepatosplenomegaly
- Bruising
- Fatigue
- Weight loss
Explain Chronic myeloid leukaemia
Acute leukaemia rapidly cause bone marrow failure due to large numbers of immature blast cells overwhelming the ability of the tissue to produce mature blood cells.
Chronic leukaemia are more often saw it cause symptoms and may even be picked up as a chance finding on a blood count.
Chronic myeloid leukaemia (CML), is characterised by the unregulated growth of myeloid cells in the bone marrow leading to the accumulation of mature granulocytes (mainly neutrophils), as well as myelocytes in the blood.
How does acquired thrombocytopenia arise
Thrombocytopenia is a low level of platelets. it can arise for a number of reasons and can be acquired or inherited.
Inherited - Number of inherited syndromes are associated with a decrease in platelet number.
Acquired thrombocytopenia is much more common and is typically detected from a full blood count. Some individuals with a low blood count may experience bleeding gums, nosebleeds. Spontaneous bleeding under the skin may sometimes also be visible as bruising and petechaie (red spots) are usually seen on the feet, shins and forearms. Acquired thrombocytosis can result from a decrease in platelet production, increased consumption of platelets or an increased destruction of platelets.
Explain immune thrombocytopenic purpura (ITP)
ITP is a autoimmune disease characterised by isolated thrombocytopenia which can take an acute (short lived) or chronic course. It presents due to symptoms if the platelet count is very low or as an incidental finding on a blood count. It is mainly due to anti-platelet auto-antibodies but T-cell activity against the platelets and megakaryocytes are contributory. Sometimes there is an obvious trigger e.g., acute infection. Other causes are associated autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus.
