Sickle Cell Anaemia1. Describe the inheritance of clinical and haematological features of sickle cells anaemia (SS)Population Genetics of SS: Up to 10% of Caribbean’s, and 25% of sub-Saharan Africans carry the sickle cell gene Distribution of the gene matches that of malaria 200,000 births affected worldwide annually Commonest inherited disease in the UK – neonatal screening 10,000 patients in the UK Only adult Hb is affected so problems start at around 6 months when levels of HbF fall and HbA increase

SS results from a single amino acid change in the Hb molecule: A point mutation at codon 6 of the gene for β-globin Glutamin acid is replaced by valine Glutamic acid is polar and soluble Valine is non-polar and insoluble

Sickle haemoglobin (HbS) differs therefore from HbA by a single amino acid As a result of molecule polymerisation due to this change it causes red cells to distort and undergo the characteristic shape change to become sickle shaped

Changes in red cells: Distortion – polymerisation initially reversible with formation of oxyHbS Polymerisation is subsequently irreversible Dehydration of red cells Increased adherence to vascular epithelium due to membrane changes Cells become – rigid, adherent and dehydrated

SS anaemia refers to a condition where there are two βs genes and no normal β genes – therefore there is no production of normal β chains and so no HbA produced SS disease is a more general term that covers other conditions that lead to the formation of sickle cells such as co-inheritance of HbS and either HbC (another β chain variant) or the β thalassaemia trait

Condition β genes

Haemoglobins present (in addition to A2

and F)

Sickle Cell Disease

Sickle Cell Anaemia ΒS βS SSickle Cell/HbC

Disease ΒS βC S and C

Sickle Cell Trait ΒS βA A and S

Normal ΒA βA A

Only adult Hb is affected because HbF does not have any beta chains. The problems therefore start at 4-6 months or oler, after the HbF level decreases and the adult Hb level increases.

Pathogenesis: Shortened red cell life – haemolysis :

Gall stones – by 25 years prevalence = 50% Anaemia Aplastic crisis (parovirus B19)

Cells become trapped in the circulation leading to blocked micovasculature ( vaso-occlusion ) and damage to multiple organs:

Tissue damage and necrosis (infarct) Pain Dysfrunction

Consequences of tissue infarction: Hyposplenism (infection) Ulceration of the skin

Bones: Dactylitis – inflammation of the digits from bone infarction Osteomyelitis Avascular necrosis of the hip Hand-foot syndrome in children – pain and shortening of small bones of hands and feet

Lungs : “chest crisis” – hypoxia resulting from death of lung tissue Chronic damage leading to pulmonary hypertension

Kidneys Haematuria Failure to concentrate urine, Papillary necrosis

Brain – stroke (affects 8%, most common in 2-9yr olds), cognitive impairment Eyes – Proliferative retinopathy Spleen

Splenic sequestration – pooling of large numbers of red cells in the spleen Hyposplenism – reduced function of the spleen (in this case, as a result of recurrent interruption of the blood supply leading to death of splenic tissue)

Skin – skin ulcers

The affinity of HbS for oxygen is lower than that of HbA so it gives up oxygen more readily at tissues – therefore anaemia is often well tolerated In an attempt to compensate for the shortened red cell life span there is an increased turnover of red cells and the body’s supply of folic acid can become low. The shortened life span of red cells makes patients particular susceptible to parovirus B19 infection – infects red cell precursors and can stop red cell production for up to a week

In the setting of a short red cell life span, if red blood cell production stops for even short period of time the Hb level can fall dramatically – aplastic crisis.

An aplastic crisis is a sudden, dramatic fall in Hb levels due to stoppage of red cell production Children are at risk of a splenic sequestration crisis – abdominal pain, pallor and shock together with a large spleen and low Hb are common

The reticulocyte count is raised in sequestration crisis but in an aplastic crisis it is much lower than normal.

In one large survey the median life expectancy for men was 42 and women 48 with homozygous sickle cell anaemia Causes of death (no need to memorise):

21% associated with painful crisis 14% associated with chest crisis (hypoxia as a result of death of lung tissue) 9% associated with renal failure 7% associated with infection 6% asscoted with perioperative complications

The clinical course of SS can be varied an unpredictable even within the same family: Features first seen at 3-6 months when HbA takes over from HbF as principle Hb First features seen – dactylitis, splenic sequestration, infection

Laboratory Features and Diagnosis:1. Blood count shows low Hb and raised reticulocyte levels2. Blood film shows sickled cells, signs of hyposplenism (Howell-Jolly bodies – nuclear remnant

usually removed by the spleen) and target cells3. Simple screening tests

These tests depend on the decreased solubility of haemoglobin S when the oxygen tension is low.

Sickle solubility test in which a reducing agent is added to a diluted blood sample which leads to the formation of many sickle cells (in sickle trait as well as disease) – blood becomes turbid A positive result must be confirmed by Hb electrophoresis.

4. Definitive diagnosis requires haemoglobin electrophoresis Electrophoresis separates proteins according to their charge; this varies according to the pH at which it is carried out. In SS there is no HbA, variable (5-15%) of HbF and small amounts of HbA2, patients with the sickle trait have HbA and HbS (and small amounts of HbA2 and HbF)

2. Outline the principles of managementManagement of SS: Painful crisis: A painful crisis is triggered by – infection, exertion, dehydration, hypoxia, psychological stress

Avoid precipitating factors Fast pain relief with Opioids Rehydration Warmth

Additional oxygen if hypoxic Exclude infection – chest x-ray, urine and blood cultures – give antibiotics if necessary

General: Folic acid 5mg/day Prophylactic penicillin to prevent infection caused by hyposplenism Vaccination to prevent against pneumococcal infection Monitor spleen size Blood transfusion for aplastic or sequestration crisis (top up transfusion), full exchange blood transfusion, aiming to reduce HbS to 20% in a stoke or chest crisis

NOTE top-up blood transfusion is NOT a treatment for painful crisis; it will increase blood viscosity and may make the painful crisis worse.

Care in pregnancy Children with severe disease – consider stem cell transplant – 90-95% survival, and 85-90% cure

3. Explain the inheritance, clinical significance and diagnosis of the sickle cell trait

Sickle Cell Trait: The carrier state for sickle cell disease - HbAS Normal life expectancy Normal blood film Clinically silent Needs to identified as certain situations can provoke sickling – e.g. anaesthesia, high altitude, air travel in unpressurised planes All patient from ethnic groups in which SS occurs are screened before surgery Must be identified in pregnant women so partners can be tested and appropriate counselling given if necessary