2.01 - Introduction to Haematology Flashcards
What is haematopoiesis?
Production of mature blood cells from stem cells in the bone marrow:
- red blood cells
- platelets
- white blood cells
Distribution of haematopoiesis in
a) fetal
b) children
c) adults
a) liver and spleen
b) throughout the skeleton
c) axial skeleton
What cell does haematopoiesis begin from?
Multipotent haematopoietic stem cell (HPSC) - haemocytoblast.
Structure of erythrocytes.
- biconcave structure
- enucleated
Structure of haemoglobin.
Globular tetramer protein:
- 2 alpha chains
- 2 beta chains
- 4 haem groups
Deoxyhaemoglobin exists in low affinity (T) state or high affinity (R) state - when oxygen binds, it converts from T to the R state.
Lifespan of erythrocytes.
120 days
Process of erythropoiesis.
- Interstitial peritubular cells in the kidney detect hypoxia.
- Kidney produces EPO in response to hypoxia.
- Common myeloid progenitor (CMP) differentiates, releasing reticulocytes.
- Reticulocytes mature into erythrocytes (RBCs).
- Number of RBCs and Hb increases, allowing more O2 to be delivered to tissues.
How long does it take for reticulocytes to mature into erythrocytes?
2 days.
Process of thrombopoiesis.
- Liver produces TPO in response to thrombocytopenia.
- CMP cells differentiate into megakaryocytes.
- Platelets bud off from the membrane of megakaryocytes.
Process of monocytosis.
- Inflammation (acute or chronic).
- CMP cells differentiate into myeloblast.
- Myeloblast differentiates into monocyte.
- Monocyte leaves the blood circulation after 20 hours, and become tissue macrophages.
Function of
a) monocyte
b) macrophage
a) phagocytosis in the blood
b) phagocytosis in the tissue
Products of granulopoiesis.
- basophils
- neutrophils
- eosinophils
Process of granulopoiesis.
- Microbial infection triggers release of G-CSF.
- CMP cells differentiate into myeloblast.
- Myeloblast differentiates into granulocytes.
Function of:
a) neutrophils
b) eosinophils
c) basophils
a) phagocytose any foreign organisms by releasing reactive oxygen species.
b) actions against parasitic infection; raised in anaphylaxis.
c) release histamine as part of the immune response.
Process of lymphopoiesis.
Common lymphoid progenitor (CLP) cells differentiate into:
- natural killer cells
- B lymphocytes
- T lymphocytes
What organs are part of the reticuloendothelial system?
- kidney
- liver
- spleen
- lymph nodes
- bone marrow
What is the function of the spleen?
White pulp: forms antibodies and removes any bacteria or erythrocytes coated in antibodies; particularly effective against encapsulated bacteria.
Red pulp: removes old RBCs and metabolises haemoglobin.
Role of the spleen in haemorrhage.
In response to bleeding, platelets and RBCs are pooled in the spleen to minimise blood loss.
What are the encapsulated bacteria?
Some Have Pretty Nice Capsules:
Streptococcus pneumoniae
Haemophilus influenzae
Pseudomonas aeruginosa
Neisseria meningitidis
Cryptococcus
Causes of splenomegaly.
- overworking red or white pulp
- backpressure 2° to portal hypertension
- leukaemia
- infection
- accumulation of waste products of metabolism
Infective causes of splenomegaly.
- malaria
- Schistosomiasis
- HIV
- EBV
Causes of hyposplenism.
- splenectomy
- sickle cell disease
- coeliac disease
Indications for splenectomy.
- splenic rupture
- cancer
- hereditary spherocytosis
- ITP
Management of asplenic patients.
- vaccinations
- prophylactic antibiotics
- carry a card notifying medical staff of their condition
Blood film typical of hyposplenic patients.
RBCs with Howell-Jolly bodies (defective).
Normal functioning spleen would remove defective cells as they were filtered through.
Specimen collection errors that may result in abnormal blood results.
- wrong blood in the tube
- wrong bottle used for the test
- pooling of different samples
- poor technique or heavy handling
Delivery of specimen errors that may result in abnormal blood results.
- delay or lost
- delivered at wrong temperature
Specimen analysis errors that may result in abnormal blood results.
- specimen mix up
- wrong test requested or performed
- technical error with the analyser
Responsive action errors that may result in abnormal blood results.
- nothing done in response to abnormal result
- reflex tests not conducted
- right result is applied to the wrong patient
How long after a blood sample is taken must it be processed?
Within 2 hours.
Why are blood films fixed with methanol?
Protects the practitioner from from any infectious diseases in the blood.
What are the three key stages where anaemia may occur.
- Abnormalities during production.
- Abnormalities during circulation.
- Abnormalities during removal.
Anaemia - abnormalities during production.
- defective RBC production
- defective Hb production
Anaemia - abnormalities during circulation.
- haemolytic anaemia
- excessive bleeding
Causes of haemolytic anaemia.
- aortic stenosis (MAHA)
- heat damage
- hereditary spherocytosis
- G6PD deficiency
- PKU deficiency
- autoimmune (e.g. SLE, lymphoma, EBV)
Anaemia - abnormalities during removal.
- hypersplenism
Normal reticulocyte count in response to anaemia.
Reticulocytosis should be observed on blood film, demonstrating active bone marrow trying to replace RBCs rapidly.
If reticulocyte count is low / normal, this suggests the bone marrow is not functioning as normal.
Causes of reticulocytosis.
Anaemia with normal bone marrow function:
- excessive bleeding
- splenic sequestration of RBCs
- haemolysis
Causes of microcytic anaemia.
Causes of normocytic anaemia.
Causes of macrocytic anaemia.
Symptoms of anaemia.
- fatigue
- headache
- SOB
- palpitations
- dizziness
- syncope
Signs of anaemia.
- pallor
- bounding pulse
- postural hypotension
- tachycardia
Treatment of anaemia.
Identify the cause and treat that!
What is the role of vitamin B12?
Required for DNA synthesis and essential for the production of reticulocytes.
Storage of vitamin B12.
Stored in the liver that are able to sustain the body for 3 to 5 years - symptoms of deficiency will not present for a long time.
Causes of B12 deficiency.
- insufficient intake (vegan diet)
- lack of intrinsic factor
- disease of the ileum
- use of PPIs
- abuse of nitrous oxide
- methotrexate
What are the causes of lack of intrinsic factor?
Parietal cells of the stomach produce intrinsic factor:
- gastrectomy
- autoimmune destruction (pernicious anaemia) (#1 cause in UK)
Complications of B12 deficiency.
Associated with neurological disease - subacute combined degeneration of the cord
Symptoms of subacute combined degeneration of the cord.
Loss of vibration and proprioception in the hands and feet.
Sensory gait ataxia.
Distal muscle weakness.
Features of dementia.
Function of folate (B9).
DNA synthesis and reticulocyte production.
Causes of folate deficiency.
- insufficient intake
- excessive demand (e.g. pregnancy, increased erythropoiesis)
- Crohn’s disease
Complications of folate deficiency in pregnancy.
Neural tube defects in the unborn fetus.
Dietary sources of iron.
- red meat
- raisins
- oats
- spinach
- fortified cereal
Foods that inhibit iron absorption.
- tannins in tea
- red wine
- phytates in chapattis
Foods that promote iron absorption.
Citrus fruits (ie. orange juice)
Storage of iron.
Macrophages phagocytose erythrocytes:
- return iron to blood via transferrin
- store in the macrophage as ferritin
What protein regulates absorption of iron?
Hepcidin - degrades ferroportin, so prevents iron entering blood.
Hepcidin levels fall to promote erythropoiesis.
Causes of excess iron.
- hereditary haemochromatosis
- transfusion associated haemosiderosis
Pathophysiology of hereditary haemochromatotsis.
Autosomal recessive mutation of HFE protein reduces the affinity of transferrin receptors.
This means more iron is stored in cells, leading to the skin looking tanned and secondary conditions such as cardiomyopathy and diabetes.
Causes of iron deficiency.
- insufficient intake of iron
- lack of absorption of iron
- increased requirements for iron (ie. puberty, pregnancy)
- bleeding
- anaemia of chronic disease
Signs of iron deficiency.
Blood film findings of iron deficiency anaemia.
- reduced RBC count
- microcytic cells
- hypochromic cells
- irregularly sized and shaped cells
What is given as an oral replacement for iron?
Ferrous sulphate
In which state is iron able to be transported across the cell membrane into enterocytes?
Fe2+ via the DMT1 transporter.
What is a haemoglobinopathy?
Genetic disorders that alter the structure of haemoglobin, resulting in deformed structures of reduced production of globin chains.
This results in reduced oxygen carrying capacity, and produces symptoms of anaemia.
Inheritance pattern of haemoglobinopathies.
Autosomal recessive
What is alpha thalassaemia?
Deletion mutations of the HBA allele (x4), results in abnormal globular protein production:
- HBA1 allele (x2)
- HBA2 alelle (x2)
Name of disease with ONE HBA allele deletion.
Silent carrier state - asymptomatic.
Name of disease with TWO HBA allele deletion.
a-thalassaemia trait / minor.
Results in a mild anaemia and microcytosis.
Name of disease with THREE HBA allele deletion.
HbH disease.
Too few alpha chains to bind with beta chains, forming SOME tetramers of beta chains (HbH).
Results in moderately severe anaemia.
Name of disease with FOUR HBA allele deletion.
Alpha thalassaemia major (Hydrops fetalis).
Not compatible with life as Hb molecules have an extremely high affinity for oxygen, with almost no oxygen delivery to tissues.
What is beta thalassaemia?
Autosomal recessive mutation of the HBB alleles (x2), leading to the inability to construct beta chains.
This leads to microcytic anaemia.
Name of disease with ONE HBB allele deletion.
Thalassaemia minor - patient doesn’t exhibit severe symptoms, but will have mild microcytic anaemia.
Thalassaemia intermedia - patient presents with mild to severe anaemia, but are not transfusion dependent.
Name of disease with TWO HBB allele deletion.
Thalassaemia major.
Massively reduced ability to produce HbA, causing a severe microcytic and hypochromic anaemia.
The patient is transfusion and chelaton dependant.
Signs of thalassaemia major.
- abnormal skull bones (secondary to extramedullary haemopoiesis; hair on end appearance)
- hepatosplenomegaly (secondary to increased action of red pulp)
What is sickle cell disease?
Autosomal recessive mutation of HBB gene means at least one of the beta chains are replaced with an abnormal version (HbS).
In the deoxygenated state, HbS polymerises and causes the cell to become sickle shaped.
What is sickle cell anaemia?
A severe type of sickle cell disease where both beta chains in HbA are replaced with HbS.
These cells are fragile and are removed by the spleen readily, causing a pronounced anaemia.
Symptoms of sickle cell disease.
- dyspnoea
- fatigue
- jaundice
- pain
Symptoms begin in childhood.
What is the cause of pain in sickle cell disease?
Sickle cells get stuck in blood vessels, causing vaso-occlusive crisis.
This occurs when tissues and organs are deprived of oxygen and become ischaemic.
Complications of sickle cell disease.
- sickle cell anaemia
- vaso-occlusive crisis
- stroke
- acute chest syndrome
- hyposplenism (2° to infarcts)
Most common sites for vaso-occlusive crisis in sickle cell anaemia.
Fingers - as the blood vessels are smallest there.
Causes extreme pain, for which large amounts of opioids may be required.
Presentation of acute chest syndrome.
- acute fever
- cough
- wheezing
- tachypnoea
- chest pain
Treatment of acute chest syndrome.
- broad spectrum antibiotics
- bronchodilators
- oxygen
- ventilation
Management of sickle cell disease.
Only curative treatment is bone marrow transplant.
Management is available to alleviate symptoms.
Management of hyposplenism secondary to sickle cell disease.
Multiple splenic infarcts cause hyposplenism.
Prophylactic antibiotics and immunisation against encapsulated bacteria should be given:
- Streptococcus pneumoniae
- Haemophilus infleunzae
- Neisseria meningitidis
Life expectancy of sickle cell disease.
Greatly reduced (67 years in UK).
Most common causes of death:
- stroke
- multi-organ failure
- acute chest syndrome
What disease can sickle cell trait be protective against?
The plasmodium falciparum which causes malaria cannot enter the sickle cell, so those with a sickle cell trait have some resistance against malaria.
Sickle cell trait can be found in up to 30% of the West African population, as it has a survival advantage here.
What are the causes of overproduction of blood cells?
- abnormalities in hormonal signalling
- myeloproliferative neoplasms (genetic mutation of CMP cells; leukaemia).
Define polycythaemia.
a) absolute polycythaemia
b) relative polycythaemia.
Raised haematocrit.
a) increased erythrocytes
b) decrease in plasma volume
Causes of absolute polcythaemia.
Primary: polycythaemia vera
Secondary: increased levels of EPO (ie. high altitude, secreting tumour, self-administered EPO).
Causes of relative polycythaemia.
Dehydration - resolved by replenishing fluids.
What is polycythaemia vera?
A myeloproliferative neoplasm caused by mutations in the JAK2 gene, making the bone marrow hypersensitive to EPO and stimulating their proliferation.
Symptoms of polycythaemia vera.
- headaches
- tinnitus
- dizziness
- itching after a bath
- burning sensation in fingers and toes
Treatment of polycythaemia vera.
Ruxolitinib - JAK2 inhibitor.
Phlebotomy - reduces haematocrit levels.
Causes of thrombocytosis.
Primary: essential thrombocythaemia.
Secondary: chronic inflammation, acute infection and cancer.
What is essential thrombocythaemia?
Myeloproliferative neoplasm caused by mutations in the JAK2 gene or TPO receptor.
This results in increased thrombopoiesis, causing thrombocytosis.
Symptoms of essential thrombocythaemia.
- thrombosis
- numbness in extremeties
- easy bruising
What are the causes of thrombocytopenia?
Primary thrombocytopenia: Alport syndrome
Secondary thrombocytopenia:
- lack of vitamin B12 or folate
- liver failure (no TPO)
- massive haemorrhage
- DIC
- TTP
- ITP
- hypersplenism
- drug induced
Symptoms of thrombocytopenia.
- bleeding gums
- nosebleeds
- petechiea
- heavier and longer menstrual periods
What is thrombotic thrombocytopenic purpura (TTP)?
Fragmentation of vWF causes thromboses to form in small blood vessels throughout the body, causing excessive consumption of platelets.
When consumption exceeds supply, thrombocytopenia occurs.
Triggers of TTP.
- bacterial infection
- autoimmune (e.g. SLE, HIV)
- pregnancy
- congenital
- chemotherapy
- cancer (e.g. lymphoma, gastric cancer, lung cancer)
Presentation of TTP.
- fever
- changes in mental status
- thrombocytopenia
- reduced kidney function
- haemolytic anaemia
Treatment of TTP.
Exchange transfusion.
Steroids.
What is disseminated intravascular coagulopathy (DIC)?
Excess thrombin causing dysregulation of coagulation and fibrinolysis, results in widespread clotting, and resultant bleeding.
Triggers for DIC.
- head trauma
- sepsis
- transfusion reaction
- cancer
- pre-eclampsia
How to differentiate TTP and DIC?
TTP: associated with drugs and chemotherapy; schistocytes DEFINITELY present.
DIC: associated with head trauma and sepsis; schistocytes MAY be present.
What is immune thrombocytopenic purpura (ITP)?
A decrease in platelets caused by an autoimmune reaction.
Acute thrombocytopenic purpura.
Acute ITP starts suddenly and the symptoms usually disappear within 6 onths; treatment is not needed.
Usually affects young children following a viral illness.
Chronic thrombocytopenic purpura.
Onset occurs at any age and symptoms last a minimum of 6 months.
Chronic ITP can recur often.
Causes of chronic ITP.
- AIDS
- pregnancy
- autoimmune conditions (e.g. RA or SLE)
- low grade lymphoma
- low grade leukaemia
Symptoms of ITP.
- easy bruising
- widespread purpura
- nosebleeds
- gum bleeding
- menorrhagia
- blood in vomit, urine or stool
- intracranial bleed
Treatment of ITP.
- prednisolone (1mg/kg)
- intravenous gamma globulin (IVGG)
Platelet transfusion, splenectomy and biologics may be considered.
What are myelodysplastic syndromes?
A group of cancers that causes immature blood cells to be destroyed soon after being released.
It usually affects a single cell lineage.
Symptoms of myelodysplastic syndrome.
Depends on the myeloid cell affected:
Erythrocytes: anaemia; fatigue; dizziness; SOB; postural hypotension.
Thrombocytes: bleeding; bruising;
Granulocytes: recurrent or atypical infection;
Risks of myelodysplastic syndromes.
50% eventually develop AML (acute myeloid leukaemia).
50% of deaths occur as a result of bleeding or infection.
What is aplastic anaemia?
Autoimmune condition where the body stops producing new blood cells of all three types, as a result of bone marrow damage.
Aplastic anaemia vs myelodysplastic syndromes.
Aplastic anaemias cause a pancytopenia.
Myelodysplastic syndromes effect one cell lineage.
Triggers of aplastic anaemia.
- immune disorder
- exposure to chemicals
- radiation
- certain drugs
- idiopathic (~50%)
Management of aplastic anaemia.
- steroids
- bone marrow transplant.
Risks of bone marrow transplant.
Graft-vs-host disease - newly created WBCs may attack the rest of the body.
Prognosis of aplastic anaemia (5 year survival).
45%
What is myelofibrosis?
A myeloproliferative neoplasm, where excessive multiplication of abnormal HPSC causes fibrosis of the bone marrow.
This causes a decrease in functioning tissue, eventually leading to pancytopenia.
Genetic mutation associated with myelofibrosis.
JAK2 mutation
Can be secondary to polycythaemia vera or essential thrombocythaemia.
Cause of hepatosplenomegaly in myelofibrosis.
Fibrosis of the bone marrow results in HPSC to colonise the liver and spleen, leading to extramedullary haematopoiesis.
Presentation of myelofibrosis.
- easy bruising
- increased fatigue
- atypical infection
- increased sweating
- weight loss
Causes of anaemia of chronic disease.
- rheumatoid arthritis
- SLE
- tuberculosis
- malignancy
Pathophysiology of anaemia of chronic disease.
- Inflammation results in release of cytokines.
- Cytokines stimulate hepcidin production in the liver, inhibiting ferroportin (less iron absorbed; less iron released from macrophages).
- Cytokines inhibit EPO production by the kidney, so less erythropoiesis.
- Cytokines increase activity of macrophages in the reticuloendothelial system, shortening the lives on the erythrocytes.
How does chronic kidney disease (CKD) cause anaemia?
- decreased clearance of hepcidin = less ferroportin
- decreased EPO production
- uraemia (toxic to erythrocytes)
- dialysis (damages erythrocytes)
Causes of polycythaemia in patients with CKD.
- EPO secreting renal tumour
Causes of neutropenia in patients with CKD.
- immunosuppression medication after kidney transplant
- bone marrow inflammation
Causes of neutrophilia in patients with CKD.
- inflammation leading to white cell activation
- steroids (enhance neutrophil survival)
- infection of the kidney
Causes of thrombocytopenia in patients with CKD.
- uraemia (directly toxic to megakaryocytes)
- medications
Causes of thrombocytosis in patients with CKD.
- iron deficiency
Causes of anaemia in patients with rheumatoid arthritis.
- anaemia of chronic disease
- long term NSAID use (?peptic ulceration)
- methotrexate compromises folic acid pathway
Causes of neutrophilia in patients with rheumatoid arthritis.
- corticosteroids (enhance lifespan of neutrophils)
- infection 2° to immunosuppression
Causes of thrombocytopenia in patients with rheumatoid arthritis.
- immune dysfunction (ITP)
- splenomegaly
Causes of thrombocytosis in patients with rheumatoid arthritis.
- NSAID related peptic bleed
What is Felty’s syndrome?
Triad of:
1. RA
2. Splenomegaly
3. Neutropenia
Puts people at very high risk of life-threatening infection.
Why are patients with chronic liver disease at increased risk of bleeding?
Vitamin K dependent clotting factors (II, VII, IX and X) are produced in the liver - cirrhosis = deficiency.
The liver also produced TPO so there is less thrombopoiesis in cirrhosis.
This puts the patient at high risk of bleeding exacerbated by impaired clotting.
What is Zieve’s syndrome?
Liver disease results in alteration to erythrocyte membrane, leading to abnormally shaped erythrocytes.
This abnormal shape is more prone to damage in circulation, so contributes to a haemolytic anaemia (MAHA).
What is the direct effect of alcohol on the blood?
Excess alcohol is directly toxic to the bone marrow, suppressing haematopoiesis and thrombopoiesis.
What is the indirect effect of alcohol on the blood?
Acetaldehyde binds with erythrocyte membranes and flags the erythrocyte as ‘foreign’, resulting in a subsequent autoimmune anaemia.
What are the causes of anaemia post-operatively?
- blood loss during surgery
- large amounts of fluids given (dilutional)
What are the causes of polycythaemia post-operatively?
- dehydration (relative polycythaemia)
What are the causes of neutropenia post-operatively?
Neutropenic sepsis
What are the causes of neutrophilia post-operatively?
Infection post-surgery triggering a leukocytosis.
What are the causes of thrombocytopenia post-operatively?
- medications such as LMWH
- DIC / TTP
What are the causes of thrombocytosis post-operatively?
Platelets are raised to prevent any further bleeding (physiological).
Effects of chemotherapy on blood.
- anaemia
- neutropenia
- thrombocytopenia
