Anaemias Flashcards
Haemolytic Anaemia
Haemolytic anaemia is where there is destruction of red blood cells (haemolysis) leading to anaemia. There are a number of inherited conditions that cause the red blood cells to be more fragile and break down faster than normal leading to chronic haemolytic anaemia. There are also a number of acquired conditions that lead to increased breakdown of red blood cells and haemolytic anaemia.
Inherited Haemolytic Anaemias
Hereditary Spherocytosis
Hereditary Elliptocytosis
Thalassaemia
Sickle Cell Anaemia
G6PD Deficiency
Acquired Haemolytic Anaemias
Autoimmune haemolytic anaemia
Alloimmune haemolytic anaemia (transfusions reactions and haemolytic disease of newborn)
Paroxysmal nocturnal haemoglobinuria
Microangiopathic haemolytic anaemia
Prosthetic valve related haemolysis
Features
The features are a result of the destruction of red blood cells:
Anaemia due to the reduction in circulating red blood cells
Splenomegaly as the spleen becomes filled with destroyed red blood cells
Jaundice as bilirubin is released during the destruction of red blood cells
Investigations
Full blood count shows a normocytic anaemia
Blood film shows schistocytes (fragments of red blood cells)
Direct Coombs test is positive in autoimmune haemolytic anaemia
Hereditary Spherocytosis
Hereditary spherocytosis is the most common inherited haemolytic anaemia in northern Europeans. It is an autosomal dominant condition. It causes sphere shaped red blood cells that are fragile and easily break down when passing through the spleen.
It presents with jaundice, gallstones, splenomegaly and notably aplastic crisis in the presence of the parvovirus. It is diagnosed by family history and clinical features with spherocytes on the blood film. The mean corpuscular haemoglobin concentration (MCHC) is raised on a full blood count. Reticulocytes will be raised due to rapid turnover of red blood cells.
Treatment is with folate supplementation and splenectomy. Removal of the gallbladder (cholecystectomy) may be required if gallstones are a problem.
Hereditary Elliptocytosis
Hereditary elliptocytosis is very similar to hereditary spherocytosis except that the red blood cells are ellipse shaped. It is also autosomal dominant. Presentation and management are the same.
G6PD Deficiency
G6PD deficiency is a condition where there is a defect in the red blood cell enzyme G6PD. It is more common in Mediterranean and African patients and is X linked recessive. It causes crises that are triggered by infections, medications or fava beans (broad beans).
It presents with jaundice (usually in the neonatal period), gallstones, anaemia, splenomegaly and Heinz bodies on blood film. Diagnosis can be made by doing a G6PD enzyme assay.
Medications that trigger haemolysis include primaquine (an antimalarial), ciprofloxacin, sulfonylureas, sulfasalazine and other sulphonamide drugs.
TOM TIP: The key piece of knowledge for G6PD deficiency relates to triggers. In your exam look out for a patient that turns jaundice and becomes anaemic after eating broad beans, developing an infection or being treated with antimalarials. The underlying diagnosis might be G6PD deficiency.
Autoimmune Haemolytic Anaemia (AIHA)
Autoimmune haemolytic anaemia occurs when antibodies are created against the patient’s red blood cells. These antibodies lead to destruction of the red blood cells. There are two types based on the temperature at which the auto-antibodies function to cause the destruction of red blood cells.
Warm Type Autoimmune Haemolytic Anaemia
Warm type autoimmune haemolytic anaemia is the more common type. Haemolysis occurs at normal or above normal temperatures. It is usually idiopathic, meaning that it arises without a clear cause.
Cold Type Autoimmune Haemolytic Anaemia
This is also called cold agglutinin disease. At lower temperatures (e.g. less than 10ºC) the antibodies against red blood cells attach themselves to the red blood cells and cause them to clump together. This is called agglutination. This agglutination results in the destruction of the red blood cells as the immune system is activated against them and they get filtered and destroyed in the spleen. Cold type AIHA is often secondary to other conditions such as lymphoma, leukaemia, systemic lupus erythematosus and infections such as mycoplasma, EBV, CMV and HIV.
Management of autoimmune haemolytic anaemia:
Blood transfusions
Prednisolone (steroids)
Rituximab (a monoclonal antibody against B cells)
Splenectomy
Alloimmune Haemolytic Anaemia
Alloimmune haemolytic anaemia occurs where an there is either foreign red blood cells circulating in the patients blood causing an immune reaction that destroys those red blood cells or there is a foreign antibody circulating in their blood that acts against their own red blood cells and causes haemolysis. The two scenarios where this occurs are transfusion reactions and haemolytic disease of the newborn.
In hemolytic transfusion reactions red blood cells are transfused into the patient. The immune system produces antibodies against antigens on those foreign red blood cells. This creates an immune response that leads to the destruction of those red blood cells.
In haemolytic disease of the newborn there are antibodies that cross the placenta from the mother to the fetus. These maternal antibodies target antigens on the red blood cells of the fetus. This causes destruction of the red blood cells in the fetus and neonate.
Paroxysmal Nocturnal Haemoglobinuria
Paroxysmal nocturnal haemoglobinuria is a rare condition that occurs when a specific genetic mutation in the haematopoietic stem cells in the bone marrow occurs during the patients lifetime. The specific mutation results in a loss of the proteins on the surface of red blood cells that inhibit the complement cascade. The loss of protection against the complement system results in activation of the complement cascade on the surface of red blood cells and destruction of the red blood cells.
The characteristic presentation is red urine in the morning containing haemoglobin and haemosiderin. The patient becomes anaemic due to the haemolysis. They are also predisposed to thrombosis (e.g. DVT, PE and hepatic vein thrombosis) and smooth muscle dystonia (e.g. oesophageal spasm and erectile dysfunction).
Management is with eculizumab or bone marrow transplantation. Eculizumab is a monoclonal antibody that targets complement component 5 (C5) causing suppression of the complement system. Bone marrow transplantation can be curative.
Microangiopathic Haemolytic Anaemia (MAHA)
Microangiopathic haemolytic anaemia (MAHA) is where the small blood vessels have structural abnormalities that cause haemolysis of the blood cells travelling through them. Imagine a mesh inside the small blood vessels shredding the red blood cells. This is usually secondary to an underlying condition:
Haemolytic Uraemic Syndrome (HUS)
Disseminated Intravascular Coagulation (DIC)
Thrombotic Thrombocytopenia Purpura (TTP)
Systemic Lupus Erythematosus (SLE)
Cancer
Prosthetic Valve Haemolysis
Haemolytic anaemia is a key complication of prosthetic heart valves. It occurs in both bioprosthetic and metallic valve replacement. It is caused by turbulence around the valve and collision of red blood cells with the implanted valve. Basically the valve churns up the cells and they break down.
Management involves:
Monitoring
Oral iron
Blood transfusion if severe
Revision surgery may be required in severe cases
Pernicious Anaemia
Pernicious anaemia is a cause of B12 deficiency anaemia. B12 deficiency can be caused by insufficient dietary intake of vitamin B12 or pernicious anaemia.
Pathophysiology
The parietal cells of the stomach produce a protein called intrinsic factor. Intrinsic factor is essential for the absorption of vitamin B12 in the ileum.
Pernicious anaemia is an autoimmune condition where antibodies form against the parietal cells or intrinsic factor. A lack of intrinsic factor prevents the absorption of vitamin B12 and the patient becomes vitamin B12 deficient.
Vitamin B12 deficiency can cause neurological symptoms:
Peripheral neuropathy with numbness or paraesthesia (pins and needles)
Loss of vibration sense or proprioception
Visual changes
Mood or cognitive changes
TOM TIP: For your exams remember testing for vitamin B12 deficiency and pernicious anaemia in patients presenting with peripheral neuropathy, particularly with pins and needles.
Antibodies
Testing for auto-antibodies is used to diagnose pernicious anaemia.
Intrinsic factor antibody is the first line investigation
Gastric parietal cell antibody can also be tested but is less helpful
Management
Dietary deficiency can be treated with oral replacement with cyanocobalamin unless the deficiency is severe.
In pernicious anaemia oral replacement is inadequate because the problem is with absorption rather than intake. They can be treated with 1mg of intramuscular hydroxycobalamin 3 times weekly for 2 weeks, then every 3 months. More intense regimens are used where there are neurological symptoms (e.g. 1mg every other day until the symptoms improve).
If there is also folate deficiency it is important to treat the B12 deficiency first before correcting the folate deficiency. Treating patients with folic acid when they have a B12 deficiency can lead to subacute combined degeneration of the cord.
Iron Deficiency Anaemia
The bone marrow requires iron to produce haemoglobin. There are several scenarios where iron stores can be used up and the patient can become iron deficient:
Insufficient dietary iron
Iron requirements increase (for example in pregnancy)
Iron is being lost (for example slow bleeding from a colon cancer)
Inadequate iron absorption
Iron is mainly absorbed in the duodenum and jejunum. It requires the acid from the stomach to keep the iron in the soluble ferrous (Fe2+) form. When the acid drops it changes to the insoluble ferric (Fe3+) form. Therefore, medications that reduce the stomach acid such as proton pump inhibitors (lansoprazole and omeprazole) can interfere with iron absorption. Conditions that result in inflammation of the duodenum or jejunum such as coeliac disease or Crohn’s disease can also cause inadequate iron absorption.
Causes
Blood loss is the most common cause in adults
Dietary Insufficiency is the most common cause in growing children
Poor iron absorption
Increased requirements during pregnancy
Whilst growing the dietary requirements of children often exceed their dietary intake, particularly if their diet is low in red meat.
The most common cause in adults in blood loss. In menstruating women, particularly in women with heavy periods (menorrhagia) there is a clear source of blood loss. In women that are not menstruating or men the most common source of blood loss is the gastrointestinal tract. It is important to be suspicious of a GI tract cancer. Oesophagitis and gastritis are the most common causes of GI tract bleeding. Inflammatory bowel disease (Crohn’s and ulcerative colitis) should also be considered.
Understanding Tests for Iron Deficiency
Iron travels around the blood as ferric ions (Fe3+) bound to a carrier protein called transferrin. Total iron binding capacity (TIBC) basically means the total space on the transferrin molecules for the iron to bind. Therefore, total iron binding capacity is directly related to the amount of transferrin in the blood. If you measure iron in the blood and then measure the total iron binding capacity of that blood, you can calculate the proportion of the transferrin molecules that are bound to iron. This is called the transferrin saturation. It is expressed as a percentage. The formula is:
Transferrin Saturation = Serum Iron / Total Iron Binding Capacity
Ferritin is the form that iron takes when it is deposited and stored in cells. Extra ferritin is released from cells in inflammation, such as with infection or cancer. If ferritin in the blood is low it is highly suggestive of iron deficiency. If ferritin is high then this is difficult to interpret and is likely to be related to inflammation rather than iron overload. A patient with a normal ferritin can still have iron deficiency anaemia, particularly if they have reasons to have a raised ferritin such as infection.
Serum iron varies significantly throughout the day with higher levels in the morning and after eating iron containing meals. On its own serum iron is not a very useful measure.
Total iron binding capacity can be used as a marker for how much transferrin is in the blood. It is an easier test to perform than measuring transferrin. Both TIBC and transferrin levels increase in iron deficiency and decrease in iron overload.
Transferrin saturation gives a good indication of the total iron in the body. In normal adults it is around 30%, however if there is less iron in the body transferrin will be less saturated and if iron levels go up transferrin will be more saturated. It can temporarily increase after eating a meal rich in iron or taking iron supplements so a fasting sample gives the most accurate results.
Blood Test
Normal Range
Serum Ferritin
41 – 400 ug/L
Serum Iron
12 – 30 μmol/L
Total Iron Binding Capacity
45 – 80 μmol/L
Transferrin Saturation
15 – 50%
Two things can increase the values of all of these results (except TIBC, which will be low), giving the impression of iron overload:
Supplementation with iron
Acute liver damage (lots of iron is stored in the liver)
Management
New iron deficiency in an adult without a clear underlying cause (for example heavy menstruation or pregnancy) should be investigated with suspicion. This involves doing a oesophago-gastroduodenoscopy (OGD) and a colonoscopy to look for cancer of the gastrointestinal tract.
Management involves treating the underlying cause and correcting the anaemia. The anaemia can be treated depending on the severity and symptoms with three methods, that range from fastest to slowest and most invasive to least invasive:
Blood transfusion. This will immediately correct the anaemia but not the underlying iron deficiency and also carries risks.
Iron infusion e.g. “cosmofer”. There is a very small risk of anaphylaxis but it quickly corrects the iron deficiency. It should be avoided during sepsis as iron “feeds” bacteria.
Oral iron e.g. ferrous sulfate 200mg three times daily. This slowly corrects the iron deficiency. Oral iron causes constipation and black coloured stools. It is unsuitable where malabsorption is the cause of the anaemia.
When correcting iron deficiency anaemia with iron you can expect the haemoglobin to rise by around 10 grams/litre per week.
Components of Blood
Blood is made up of plasma (the liquid of the blood) that contains red blood cells, white blood cells and platelets. The plasma also contains lots of clotting factors such as fibrinogen.
Once the clotting factors are removed from the blood what is left is called the serum. Serum contains:
Glucose
Electrolytes such as sodium and potassium
Proteins such as immunoglobulins and hormones
Blood Cells
Blood cells develop in the bone marrow. Bone marrow is mostly found in the pelvis, vertebrae, ribs and sternum. It is important to understand the different cell lines to understand the conditions where things go wrong with these cells. I strongly suggest watching the Zero to Finals video on “understanding the cells of the immune system” to get your head around the development of blood cells in the bone marrow.
Pluripotent Haematopoietic Stem Cell
These are undifferentiated cells that have the potential to transform into a variety of blood cells. They initially become:
Myeloid Stem Cells
Lymphoid Stem Cells
Dendritic Cells (via various intermediate stages)
Red Blood Cells
Red blood cells (RBCs) develop from reticulocytes that comes from the myeloid stem cells. Reticulocytes are immature red blood cells. Red blood cells survive about 4 months (120 days).
Platelets
Platelets are made by megakaryocytes. Their lifespan is 10 days. The normal count is 150000 – 450000 /mm3. Their role is to clump together (platelet aggregation) and plug gaps where blood clots need to form.
White Blood Cells
Myeloid stem cells become promyelocytes that can become:
Monocytes then macrophages
Neutrophils
Eosinophils
Mast Cells
Basophils
Lymphocytes come from the lymphoid stem cells and become B cells or T cells.
B lymphocytes (B cells) (mature in the bone marrow) and differentiate into:
Plasma Cells
Memory B Cells
T lymphocytes (T cells) (mature in the thymus gland) and differentiate into:
CD4 cells (T helper cells)
CD8 cells (Cytotoxic T Cells)
Natural Killer Cells
Blood Film Findings
A blood film involves a specialist examining the blood using a microscope to manually check for abnormal shapes, sizes and contents of the cells and note abnormal inclusions in the blood. Exam questions will often say “… was seen on a blood film” to give you a clue about the diagnosis. There are a lot of possible findings on a blood film but the key ones worth knowing for your exams are included below.
Anisocytosis refers to a variation in size of the red blood cells. These can be seen in myelodysplasic syndrome as well as some forms of anaemia.
Target cells have a central pigmented area, surrounded by a pale area, surrounded by a ring of thicker cytoplasm on the outside. This makes it look like a bull’s eye target. These can be seen in iron deficiency anaemia and post-splenectomy.
Heinz Bodies are individual blobs seen inside red blood cells caused by denatured globin. They can be seen in G6PD and alpha-thalassaemia.
Howell-Jolly bodies are individual blobs of DNA material seen inside red blood cells. Normally this DNA material is removed by the spleen during circulation of red blood cells. They can be seen in post-splenectomy and in patients with severe anaemia where the body is regenerating red blood cells quickly.
Reticulocytes are immature red blood cells that are slightly larger than standard erythrocytes (RBCs) and still have RNA material in them. The RNA has a reticular (“mesh like”) appearance inside the cell. It is normal to have about 1% of red blood cells as reticulocytes. This percentage goes up where there is rapid turnover of red blood cells, such as haemolytic anaemia. They demonstrate that the bone marrow is active in replacing lost cells.
Schistocytes are fragments of red blood cells. They indicate the red blood cells are being physically damaged by trauma during their journey through the blood vessels. They may indicate networks of clots in small blood vessels caused by haemolytic uraemic syndrome, disseminated intravascular coagulation (DIC) or thrombotic thrombocytopenia purpura. They can also be present in replacement metallic heart valves and haemolytic anaemia.
Sideroblasts are immature red blood cells that contain blobs of iron. They occur when the bone marrow is unable to incorporate iron into the haemoglobin molecules. They can indicate a myelodysplasic syndrome.
Smudge cells are ruptured white blood cells that occur during the process of preparing the blood film due to aged or fragile white blood cells. They can indicate chronic lymphocytic leukaemia.
Spherocytes are spherical red blood cells without the normal bi-concave disk space. They can indicated autoimmune haemolytic anaemia or hereditary spherocytosis.
Anaemia
Anaemia is defined as a low level of haemoglobin in the blood. This is the result of an underlying disease and is not a disease itself. The prefix an- means without and the suffix –aemia refers to blood.
Haemoglobin is a protein found in red blood cells. It is responsible for picking up oxygen in the lungs and transporting it to the cells of the body. Iron is an essential ingredient in creating haemoglobin and forms part of the structure of the molecule. When a patient has a low level of haemoglobin they have a condition called anaemia.
You can diagnose a patient with anaemia when they have a low haemoglobin. When you find an anaemic patient you should check the mean cell volume (MCV). This is the size of the red blood cells. The normal ranges are:
Haemoglobin
Mean Cell Volume (MCV)
Women
120 – 165 grams/litre
80-100 femtolitres
Men
130 -180 grams/litre
80-100 femtolitres
Anaemia is initially subdivided into three main categories based on the size of the red blood cell (the MCV). These have different underlying causes:
Microcytic anaemia (low MCV indicating small RBCs)
Normocytic anaemia (normal MCV indicating normal sized RBCs)
Macrocytic anaemia (large MCV indicating large RBCs)
Microcytic Anaemia Causes
A helpful mnemonic for understanding the causes of microcytic anaemia is TAILS.
T – Thalassaemia
A – Anaemia of chronic disease
I – Iron deficiency anaemia
L – Lead poisoning
S – Sideroblastic anaemia
Normocytic Anaemia Causes
There are 3 As and 2 Hs for normocytic anaemia:
A – Acute blood loss
A – Anaemia of Chronic Disease
A – Aplastic Anaemia
H – Haemolytic Anaemia
H – Hypothyroidism
Macrocytic Anaemia Causes
Macrocytic anaemia can be megaloblastic or normoblastic. Megaloblastic anaemia is the result of impaired DNA synthesis preventing the cell from dividing normally. Rather than dividing it keeps growing into a larger, abnormal cell. This is caused by a vitamin deficiency.
Megaloblastic anaemia is caused by:
B12 deficiency
Folate deficiency
Normoblastic macrocytic anaemia is caused by:
Alcohol
Reticulocytosis (usually from haemolytic anaemia or blood loss)
Hypothyroidism
Liver disease
Drugs such as azathioprine
Symptoms of Anaemia
There are many generic symptoms of anaemia:
Tiredness
Shortness of breath
Headaches
Dizziness
Palpitations
Worsening of other conditions such as angina, heart failure or peripheral vascular disease
There are symptoms specific to iron deficiency anaemia:
Pica describes dietary cravings for abnormal things such as dirt and can signify iron deficiency
Hair loss can indicate iron deficiency anaemia
Signs of Anaemia
Generic signs of anaemia:
Pale skin
Conjunctival pallor
Tachycardia
Raised respiratory rate
Signs of specific causes of anaemia:
Koilonychia is spoon shaped nails and can indicate iron deficiency
Angular chelitis can indicate iron deficiency
Atrophic glossitis is a smooth tongue due to atrophy of the papillae and can indicate iron deficiency
Brittle hair and nails can indicate iron deficiency
Jaundice occurs in haemolytic anaemia
Bone deformities occur in thalassaemia
Oedema, hypertension and excoriations on the skin can indicate chronic kidney disease
Investigating Anaemia
Initial Investigations:
Haemoglobin
Mean Cell Volume (MCV)
B12
Folate
Ferritin
Blood film
Further Investigations:
Oesophago-gastroduodenoscopy (OGD) and colonoscopy to investigate for a gastrointestinal cause of unexplained iron deficiency anaemia. This is done on an urgent cancer referral for suspected gastrointestinal cancer.
Bone marrow biopsy may be required if the cause is unclear
