Working Problem 9- Anaemia

Question 1

What causes and sickle cell anemia?What are the complications of sickle cell anemia

Answer 1

It is due to a single nucleotide mutation that leads replacement of glutamic acid with

Question 2

What is the pathogenesis of GP6D deficiency anemia?

Answer 2

To put it simply basically it involves the destruction of Red blood cells by oxidants(free radicals) as there deficiency of GP6D prevents formation of glutathione which is anti oxidant
The signs of oxidative damage is Heinz bodies

Question 3

What are 3 major type of anaemia classified according to their morphology?

Answer 3

Microcytic hypochromic anemia
Macrocytic anemia
Normocytic anemia

Question 4

Explain Hemolytic disease of newborn

Answer 4

The Rh D antigen is the most immunogenic of the red cell antigens after the ABO system and is the commonest cause of haemolytic disease of the newborn whereby an Rh D negative mother with an Rh D positive foetus produces anti D antibodies in response to the immunogenic stimulus of Rh D positive foetal red cells crossing into the maternal circulation - the anti D antibodies can cross back into the foetal circulation and cause immune destruction (haemolysis) of foetal red cells resulting in anaemia and jaundice in the foetus which in the most severe cases may be fatal “hydrops foetalis”

Question 5

What are the complications of ABO and Rh D incompatibility?

Answer 5

ABO incompatibility causes acute intravascular hemolysis due to activation of complement by anti A and anti B antibodies in the patients which may destroy transfused group A and group B red cells

Group O blood tyoes are at the greatest risk

70% of RhD negative individuals who receive Rh D positive red cells will develop anti D antibodies are which are IgG type and cause extravascular haemolysis by destruction of the anti D coated red cells by macrophages in RE system which may cause jaundice and anemia post transfusion
RH antibodies not cause in complement activation and intravascular hemolysis

Question 6

What are the incompatible transfusion reactions?

Answer 6

Immediate - intravascular haemolysis usually caused by ABO incompatibility characterised by -acute onset within a short time and may occur after only a small volume of blood has been transfused - symptoms of chills, fever, nausea, vomiting, back pain, headache, pain along the line of transfusion - signs of tachycardia, hypotension, passing of red urine, bleeding (DIC), renal failure may develop

Delayed - extravascular haemolysis - delayed onset at a variable time but always greater than 24 hours post transfusion usually 7 -10 days - fevers, chills, malaise, jaundice, progressive anaemia

Question 7

What is Red cell concentrates used for and what are storage life?

Answer 7

prepared from whole blood by removing plasma followed by the addition of a preservative solution containing adenine, dextrose, phosphate and mannitol which are required for red cell metabolism and extend the shelf life to 42 days ( compared with 35 days for whole blood ) - haemoglobin is the oxygen carrier of blood - indications for transfusion include acute blood loss and anaemia - under normal stable conditions 1 unit of packed cells will increase the haemoglobin of an adult patient by approximately 10 gm/L - once transfused the red cells have a circulating half life of about 57 days

Question 8

What is fresh frozen plasma and what are their indications?

Answer 8

is prepared from whole blood donation by centrifuging and removing from the red cells then snap frozen and stored at minus 30 degrees C with a shelf life of 12 months - contains all the labile coagulation factors - does not contain platelets - indication for use is coagulation factor deficiency eg. acute blood loss, warfarin anticoagulant overdose, liver disease

Question 9

What are platelet concentrates and what are their indications?

Answer 9

• prepared by separating platelets from red cells and plasma and stored at room temperature in specialised plastic bags giving a shelf life of 5 days - indicated specifically for thrombocytopenia induced by bone marrow failure eg. chemotherapy or consumption of platelets eg massive blood loss or platelet dysfunction induced by aspirin

this is the most prone to infections

Question 10

What is the biggest risk of transfusion?

Answer 10

TRIM. Transfusion related immunomodulation causing increased infection and ischaemia in patients who are transfused. Not well studied or understood but clearly the greatest risk to patients.

Question 11

What do the most heavily transfused patients die from?

Answer 11

MDS Patients often become transfusion dependent
Those that become transfusion dependent die at a faster rate than those not transfused. This is thought to be due to disease severity or iron overload.
Autopsy series show that these patients die of Infection and Myocardial infarction.
Transformation to leukaemia 18% of all cases. Presumed cause

Question 12

What should think as the cause of anaemia in elderly and post menopausal women?

Answer 12

In all elderly males and post menopausal females you should think bowel cancer as the cause of anemia unless proven otherwise

Question 13

When thinking of giving RBC transfusion what should be considered?

Answer 13

RBC transfusion should not be dictated by a Hb concentration alone,but should be based on assessment of the patient’s clinical picture

where indicated transfusion of single unit of RBC,followed by clinical reassessment to determine the need for further transfusion is appropriate.This reassessment also guides the decision on whether to retest Hb level

Question 14

How do you differentiate between hypoproliferative anemia(due to bone marrow dysfunction) and hemolytic anemia

Answer 14

The reticulocyte count is a good indicator

Increased in the hemolytic anemia and decreased in hypoproliferative anemia

Question 15

what is hypoproliferative anemia and what causes it?

Answer 15

ineffective erythropoiesis(megaloblastic anemia)

lack of nutrients(b12 and iron)

Bone marrow disorder(aplastic anemia)

Bone marrow suppression(chemotherapy)

low levels of trophic hormone which stimulate RBC production such as erythropoietin (renal failure)

Anaemia of chronic disease (inflammation or infection or malignant disorders

In Children anaemia is always due to diet unless proven otherwise(iron deficiency due to diet)
In Adult it is blood loss unless proven otherwise(iron deficiency due to blood loss)

Question 16

What is hemolytic anaemia?

Answer 16

Defined as an RBC lifespan of less than 100 days
In the lab – often see elevated LDH, increased bilirubin, positive DAT (if autoimmune), elevated reticulocyte count

Examples:
Inherited haemolytic anaemias (eg, hereditary spherocytosis, sickle cell disease, thalassemia major)
Acquired haemolytic anaemias (eg, Coombs-positive autoimmune haemolytic anaemia,)
Increased destruction of normal red cells by an enlarged spleen (ie, hypersplenism)
Intravascular haemolysis
MAHA, clostridium sepsis, etc

Question 17

When do you transfuse blood?

Answer 17

If the Hb is less than 70 red cell transfusion may reduce mortality
in some cases it may be well compensated, that the patient might not required or when other specific therapy is available
Clinical scenario very important (usually below 70 and symptomatic have to be transfused)

Hb concentration between 70-100g/L is dependent on the clinical signs and symptoms and patient’s response to previous transfusion

transfusion when Hb concentration more than 100 not advisable

Question 18

Why is excessive transfusion a problem?

Answer 18

Each transfusion increases the risk of nosocomial infection and increases other morbidities

The higher the number of transfused RBC, the higher the number of clinical complications

Transfusion associated circulatory overload (TACO) is among the high risk adverse effects of red cell transfusion (up to 1 in 100 per unit transfused).

Therefor the correct approach is transfuse one unit,reassess the patient and don’t increase the risk if no benefit

Question 19

If you cannot give transfusion what do you do instead?

Answer 19

If cannot give blood restore the deficiency

Question 20

What is the main thing you look for when assess iron deficiency?

Answer 20

Ferritin(most important parameter you have to look at if you are assessing someone for iron deficiency)

Question 21

What are few special considerations when it comes to transfusion?

Answer 21

Acute coronary syndrome-No reason for HB levels above 100 g/L as it increases risk of mortality

Heart failure-circulatory overload can occur

For GIT-give iron instead of transfusion

chronic kidney disease -give EPO

Question 22

When is cryoprecipitate given?

Answer 22

Cryoprecipitate is a fraction of fresh frozen plasma produced when plasma is thawed between 1ºC and 6 ºC.
The precipitate formed is removed, and refrozen.
Contains Fibrinogen
Contains most of the factor VIII, VWF and Factor XIII
Indicated for the treatment of:
Fibrinogen deficiency (based on laboratory results and clinical condition)
Dysfibrinogenaemia when there is clinical bleeding
Invasive procedures
Trauma or disseminated intravascular coagulation (DIC)

Question 23

Low Hb ,high MCV,high reticulocyte counts-what is the diagnosis?

Answer 23

hemolytic anemia

Question 24

Low haemoglobin,normal to high MCV,low reticulocyte count,what is the ddx?

Answer 24

Megaloblastic anaemia
Aplastic anaemia
MDS
Hypothyroidism

Question 25

Low Haemoglobin,normal to mildly low MCV,moderate reticulocyte?

Answer 25

Iron deficiency-early stages

anaemia of chronic disease

Question 26

What is the pathophysiology of sickle cell anaemia?

Answer 26

• Normal adults red cell contains 96% HbA (α2β2), 3% HbA2 (α2δ2), and 1% fetal Hb (HbF, α2γ2).
• HbS is produced by the substitution of valine for glutamic acid at the sixth amino acid residue of β-globin.
• In homozygotes all Hb A is replaced by HbS, whereas in heterozygotes only about half is replaced

Deoxygenation causes HbS to sickle(by distortion) which is initially reversible but on repeated sickling causes membrane to be damaged and eventually result in irreversible sickling and cause hemolysis

Question 27

What are the clinical features of sickle cell anaemia

Answer 27

Severe chronic haemolytic anaemia
The increased breakdown of heme to bilirubin
Microvascular obstruction which provoke tissue ischemia and infarction

There is a compensatory hyperplasia of erythroid progenitors in the BM
Cellular proliferation→ bone resorption and secondary bone formation→prominent cheek bones and changes in skull resembling crewcut in radiographs

Splenomegaly and auto splenomegaly(where spleen becomes fibrotic due to hypoxic damage from chronic splenic erythrostasis) and this leads to more likelihood of infection

vasoocclusive pain crisis

Question 28

What are the investigations done for sickle cell anaemia?

Answer 28

• Blood count-Level of Hb is in the range from 60-80g/L with a high reticulocyte count (10-20%)
• Blood films- features of hyposplenism and sickling
• Sickle solubility test-Hb S presence gives the solution a turbid appearance
• Hb electrophoresis-always needed to confirm diagnosis

Question 29

What are the management for sickel cell anemia?

Answer 29

• Give intravenous fluids and adequate analgesia to treat acute pain crisis
• In extremely painful situations give morphine
• Milder pain can sometimes be relieved by codeine, paracetamol and NSAIDS
• Manage other symptoms such as constipation with laxatives ,vomiting with antiemetic, pruritus with anti-pruritic
• Folic acid given to patients with haemolysis
• Vaccination given against pneumococcal and Haemophilus influenzae type B vaccine
Treating anaemia

• Hydroxcarbamide (hydroxyurea)-: the first drug that has been used widely as therapy for sickle cell anaemia.
- Acts by increasing HbF concentration→takeover the HbS role and reduce the episodes of pain, the acute chest syndrome and the need for blood transfusions
• Stem cell transplantation: has been used to tx sickle cell anaemia in fewer cases then thalassemia.
- Children and adolescents younger than 16 years of age who have severe complications(recurrent chest syndrome or refractory pain) and have HLA-matched donor are the best candidate for transplantation

Question 30

What is the pathogenesis of thalassemia?

Answer 30

• Hb A is a tetramer composed of two α chains and two β chains.
• The α chains are encoded by two α-globin genes, which lie in tandem on chromosome 16,
• While the β chains are encoded by a single β-globin gene located on chromosome 11.
• Clinical features vary according to the specific mutant alleles that are inherited by parents
Beta Thalassemia
• In beta thalassemia it is important to note that the HbA2 will increase to make up for the defect in HbA due to decreased B globin production, globin replaced by delta globin in Hb A2
• The mutations associated with β-thalassemia fall into two categories: (1) β 0, in which no β-globin chains are produced; and (2) β + , in which there is reduced (but detectable) β-globin synthesis.

Alpha Thalassemia
• Unlike B thalassemia, A thalassemia is caused mainly by deletion involving one or more of the alpha globin genes
• The severity is dependent on the number of genes missing
• Single gene loss→silent carrier
• Deletion of all 4 gene→lethal and life non-compatible as virtually no oxygen delivering capacity

Question 31

What are the clinical manifestation of Beta thalassemia

Answer 31

• B thalassemia minor and alpha thalassemia trait(2 genes deletion),abnormalities confined to peripheral blood
• In smears cells are microcytic and hypochromic
• Target cells are seen=Cell with ↑ area to volume ratio that allows the cytoplasm to collect in a central dark red puddle
• In B thalassemia major there is microcytosis,hypochromia,poikilocytosis(variation in size and anisocytosis(variation in shape) in peripheral smear
• B thalassemia intemedia→findings lie b/n the 2 spectrums
• Anatomical changes in B thalassemia major=skeletal deformities(due to hyperplasia of erythroid progenitor),
• splenomegaly ,hepatomegaly and lymphadenopathy(extramedullary haematopoiesis and hyperplasia of mononuclear phagocytes in them)
• Cachexia and Hemosiderosis(↑ consumption of nutrient by erythropoeitic precursors and ↑Fe accumulation)

Question 32

What is the management of thalassemia?

Answer 32

Aim is to suppress ineffective erythropoiesis, prevent bony deformities and allow normal activity and development

• Long term folic acid
• Regular transfusions should be given to keep the Hb above 100g/L
• Blood transfusions may be required every 4-6 weeks
• Transfusion requirements increase splenectomy would help but must delay till age of 6 as there is a risk of infection and prophylaxis is required for those undergoing splenectomy
• Iron overload(due to repeated transfusions)which can damage the heart, liver and pancreas →Desferrioxamine should be given(iron chelating agent)+ascorbic acid should be given to increase urinary excretion of iron
• Bone marrow transplantation
• Prenatal dx and gene therapy
• Patient’s partner should be tested if both partners have β-thalassaemia trait, there is a one in four chance of such pregnancy resulting in a child having β-thalassaemia major. Therefore, couples in this situation must be offered prenatal diagnosis

Question 33

What is HBH disease?

Answer 33

It is due to deletion of 3 alpha globin alleles(remember there is 2 genes for alpha and one for beta)

The excess β chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains) which have abnormal oxygen dissociation curves

Unstable hemoglobin have a higher affinity for oxygen than normal hemoglobin, resulting in poor oxygen delivery to tissues.
There is a microcytic hypochromic anemias with target cells and Heinz bodies (precipitated HbH) on the peripheral blood smear, as well as hepatosplenomegaly.
The disease may first be noticed in childhood or in early adult life, when the anemias and hepatosplenomegaly are noted.

Heinz bodies are inclusions within the
red blood cells composed of denatured hemoglobin

Question 34

Who is bigger the red cell or the reticulocyte?

Answer 34

It is the reticulocyte which is 10- 20% bigger than normal red blood cells(super big misconception)reticulocytes are called that because they contain residual strands of ribosomal material called “reticulum” that remains following the extrusion of the nucleus from the bone marrow normoblasts.
They persist in the circulation 1-2 days after they are made in the bone marrow