Phase 1 Haematology notes Flashcards
Haemopoiesis
- production of blood cells that occurs in the bone marrow
- In embryos (yolk sac)
- In foetus (spleen)
- Bone marrow near end of pregnancy
–>Extensive bone marrow distribution in the skeleton in infants
where are rich sources of bone marrow
Main tissue: pelvis, sternum, skull, ribs and vertebrae
Where we take a trephine biopsy
Bone marrow found in the parietal region (not at proximal or distal ends)
5 major lineage pathways arise from haemopoietic stem cells in bone marrow
Myeloid
1) Erythrocytes
2) Myeloblast: basophiles, neutrophils, eosinophils, monocytes/ macrophages
3) Megakaryocyte-> platelets
Lymphoid
4) B
5)T cells
Hormones
- Erythropoietin- secreted by the kidney stimulates RBC production
- Thrombopoietin- produced by liver and kidney regulates production of platelets
Growth and development of megakaryocytes
- Transcription factors
- Interactions with non-haemopoietic cell types (e.g. endothelial cells)
Reticuloendothelial system (RES)
- Part of the immune system made up of monocytes in the blood and network of tissues which contain phagocytic cells
- Remove damage and dying cells from the circulation
- Main organs:
o Spleen and liver
o TES cells in spleen dispose of blood cells, in particular old red cells
- Back pressure- portal hypertension in liver disease e.g. cirrhosis
- Over work (red or white pulp)
-> Immune problems
-> Have to remove lots of RBC - Expanding as infiltrated by cells
->Cancer cells e.g. Leukaemia
->Other cancer metastases
->TB - Expanding as infiltrated by other material (sarcoidosis (granulomas)
NEVER NORMAL TO HAVE A LARGE SPLEEN
why can hypersplenism cause a low blood count
low blood counts can occur due to pooling of blood in enlarged spleen
- MUST AVOID contact sports and vigorous activity
- Risk of rupture if spleen is enlarged and no longer protected by rib cage
When patients are hypo splenic you can see the lack of function of the spleen ->doesn’t clear RBC properly- will see irregular blood films
Erythrocytes
Function
- Deliver oxygen o tissue
- Carry haemoglobin
- Maintain haemoglobin in its reduced ferrous state
- Main osmotic equilibrium
- Generate energy
- 120 days life
structure of RBC
Biconcave
- Flexible
- Carry lots of oxygen
- No nucleus or mitochondria
Haemoglobin
Haemoglobin
- Tetramer of 2 pairs of globin chains each with own haem group
- Globin gene clusters on Ch 11 and 16
- Different globin chains combine to form diff haemoglobins with diff properties
- Switch from fetal to adult Hb at 3-6 months of age
- Exists in 2 configuration
o Related binding (R state)- oxyhaemoglobin
o Tight binding (T state)- deoxyhaemoglobin
Changes in components in the membrane can make the cell less flexible
Will breakdown easily
- Spleen recognised cell as abnormal and removes from circulation
- RBC turnover increase and anaemia (haemolytic anaemia)
- Can be hereditary or acquired
Degradation of haem
- Stercobilin makes faeces brown
- Urobilin- yellow wee
haemotology terminology
Neutrophils
- First-responder phagocyte
- Most common white cell
- Essential part of innate immune system
- Circulate in bloodstream & invade tissues – live for 1-4 days
maturation of neutrophils
Maturation controlled by hormone G-CSF, a glycoprotein growth factor & cytokine which:
* Increases production of neutrophils
* Speeds up release of mature cells from BM
* Enhances chemotaxis
* Enhances phagocytosis and killing of pathogens
Recombinant G-CSF is routinely administered in cases when more neutrophils are needed e.g. a patient with severe neutropenia and sepsis after chemotherapy
neutrophilia
increase in absolutes no. of circulating neutrophils
Only those cells in circulating pool are actually measured in a blood count (not in tissue). Haemorrhage brings more cells out from marginated pool
Causes:
- Infection
- Tissue damage
- Smoking
- Drugs
- Myeloproliferative disease
- Acute inflammation
- Cancer
- Cytokine s (G-CSF)
- Metabolic disorders
- Endocrine disorders
- Acute haemorrhage
Neutropenia
Neutrophil count <1.5 x 109/L (severe if < 0.5 x 109/L)
Consequences
- Medical emergency
o Bacterial and fungal infections
o Mucosal ulceration e.g. painful mouth ulcers
- Intravenous antibiotics must be given immediately e.g. tazobactam
causes of neutropenia
Monocytes
- Typically largest cell in blood
- Circulate for 1-3 days before migrating into tissues where they differentiate in macrophages or dendritic cells
- Phagocytose microorganisms and breakdown/remove cellular debris
- Antigen presenting role to lymphocytes
- Important in defence against chronic bacterial infections e.g. TB and fungal infections
Monocytosis (increase) causes:
- Bacterial infection e.g. tuberculosis
- Inflammatory conditions e.g. rheumatoid arthritis, Crohn’s Ulcerative colitis
- Carcinoma
- Myeloproliferative disorders and Leukaemias
Eosinophils
- In circulation for 3-8 hours before migrating into tissues
- Lifespan 8-12 days
- Responsible for immune response against multicellular parasites e.g. Helminths
- Mediator of allergic responses
- Granules contain array of cytotoxic proteins e.g. eosinophil cationic proteins and elastase
- Phagocytosis of antigen-antibody complexes
- Inappropriate activation
- Responsible for tissue damage and inflammation e.g. in asthma
causes of eosinophilia
lymphocytes originate in the
bone marrow
types of lymphocytes
**B cells (humoral immunity). **
Antibody (immunoglobulin) forming cells
T cells (cellular immunity)
* CD4+ helper cells
* CD8+ cells -cytotoxic
**NK cells **
Cell mediated cytotoxicity (innate)
lymphocytosis can be either
reactive or lymphoproliferative
Lymphocytic
Reactive
- Viral infections
- Bacterial infections- esp whooping cough
- Stress related: MI
- Post splenectomy
- Smoking
Lymphoproliferative
i.e. malignant
- Chronic lymphocytic leukaemia
- T or NK cell leukaemia
- Lymphoma
summary of FBC
blood samples
Samples with significant results outside of the normal range, significant change within the normal and abnormal (either immature or unable to identify) cells highlighted by the analyser are identified and a blood film is done.
Biomedical scientists review the blood film and any previous haematological results for that patient. If there are areas of concern, the blood film is then passed on to a haematologist for review and to add any medical comments or additional tests that may be required.
RBC terminology
summary of pathological blood films
Inclusions of erythrocytes
- Howell-Jolly bodies
o DNA/Nuclear fragments - Basophilic stippling
o RNA inclusions in cells - Pappenheimer bodies
o Iron inclusions in cells (Perl’s stain) - Heinz bodies
o Denatured haemoglobin (e.g. G6PD) - Haemoglobin H inclusion
o Gold ball cells; denatured haemoglobin H (brilliant cresyl blue stain)
Anaemia
Haemoglobin concentration lower than the normal range
- Normal range varies with age sex and ethnicity
presentation of anaemia
Symptoms
- Shortness of breath
- Palpitations
- Headaches
- Claudication
- Angina
- Weakness and lethargy
- Confusion
Signs
- Pallor (pale)
- Tachycardia
- Systolic flow murmur
- Tachypnoea
- Hypotension
why may anaemia develop
1) reduced or dysfunctional erythropoiesis
2) a problem with peripheral blood cells (defects in haemoglobin synthesis)
3) increased removal by RES system
Role of erythropoietin in control of erythropoiesis
Low oxygen
1. Low blood oxygen
2. Pericytes in kidney sense hypoxia and produce EPO
3. EPO goes into bloodstream and binds to receptors on erythroblasts in bone marrow and stimulates red cell production
4. Increased number of RBC in blood
High blood oxygen
1. Negative feedback to pericytes
2. Less EPO produced
3. Less RBC produced
Why might develop: (1) Reduced or dysfunctional erythropoiesis
- Anaemia can result from lack of response in the haemostatic loop
o E.g. chronic kidney disease the kidney stops making EPO - Anaemia can result from marrow being unable to respond to EPO
o E,g, after chemotherapy, toxic insult and parvovirus infection - If marrow is infiltrated by cancer cells or fibrous tissue (myelofibrosis) the number of normal HPS cells is reduced
- In anaemia of chronic disease e.g. RA- iron is not made available to marrow for RBC production
- in rare forms of blood cancer called myelodysplastic syndromes abnormal clones of marrow stem cells limit the capacity to make both red and white blood cells
Why might develop: (2) Defects in haemoglobin synthesis
1) Mutations in the genes encoding the globin chain proteins:
* α Thalassaemia
* β Thalassaemia
* Sickle cell disease
2) Defects in haem synthetic pathway -> sideroblastic anaemia
3) Insufficient iron in diet can lead to iron deficiency anaemia (not enough iron to make haem)
- Anaemia of chronic disease can result in functional iron deficiency (sufficient iron in body but not made available for erythropoiesis)
Why might anaemia develop (3): Abnormal structure and mechanical damage can result in haemolytic anaemia
1) Inherited
* Mutations in the genes coding for proteins involved in interactions between the plasma membrane and cytoskeleton
* Cause cells to become less flexible and more easily damaged
* Break up in the circulation or removed more quickly by RES
o E.g. hereditary spherocytosis
2) Acquired damage
* Microangiopathic haemolytic anaemias result from mechanical damage e.g.
o Shear stress as cells pass through a defective heart valve (e.g. MAHA in aortic valve stenosis)
o Cells snagging on fibrin strands in small vessels where increased activation of clotting cascade has occurred (e.g. in disseminated intravascular coagulation)
* Heat damage from severe burns
* Osmotic damage (drowning in fresh water
Why might anaemia develop (4): Defects in red cell metabolism
1) G6PDH deficiency
2) Pyruvate kinase deficiency
* Final enzyme in glycolysis
* Genetic defect
* RBC need glycolysis for energy production
* Defective glycolytic pathway causes red cells to rapidly become deficient in ATP and they undergo haemolysis
Why might anaemia develop (5): Excessive bleeding
Acute blood loss
-Injury
-Surgery
-Childbirth
-Ruptured blood vessel
Chronic bleeding
* A small amount of bleeding continuing over a long time may result in signif blood loss
* Heavy menstrual bleeding
* Repeated nosebleeds
* Haemorrhoids
* Occult GI bleeding
e.g.
Chronic NSAID usage- aspirin, ibuprofen, naproxen- inhibits COX)
Ulcers (stomach or small intestine)
Diverticulosis
Polyps in large intestine
Intestinal cancer
Kidney or bladder tumours (blood lost in urine)
Why might anaemia develop (6): Role of reticuloendothelial system (RES)
RES found in
- Liver and spleen
o Remove damaged or defective red cells
* In haemolytic anaemias red cells are destroyed more quickly as they are abnormal or damaged
* Damage can occur within the blood vessels (intravascular haemolysis) or within the RES system (extravascular haemolysis)
* In autoimmune haemolytic anaemias autoantibodies bind to the red cell membrane proteins causing them to be recognised by macrophages in the spleen and destroyed
Why might anaemia develop (7): Often multifactorial
Myelofibrosis
- Proliferation of mutated haematopoietic stem cells results in reactive bone marrow fibrosis
- Fibrotic marrow leaves little space for hemopoiesis
- Mutated progenitor cells from marrow can colonise liver and spleen leading to extramedullary hemopoiesis
- Patients left with enlarged liver and spleen
Thalassaemia
Inherited disorders resulting from decreased or absent alpha or beta globin chain
- Alpha thalassaemia
- Beta thalassaemia
- Imbalance in composition of the haemoglobin alpha2 B2 tetramer-> defective microcytic hypochromic red cells
- Severity depend son type
- Can result in splenomegaly, microcytosis and haemolysis
How to work out the cause of anaemia:
The RBC size
- Macrocytic
- Microcytic
- Normocytic
**The presence or absence of reticulocytosis **( has the marrow responded normally?)
- Would expect increase in reticulocyte if marrow was working normally
Reticulocytes
- Immature red blood cells (those which just been released from marrow into blood)
o Slightly LARGER than mature RBC so increase reticulocyte number will increase MCV - No nucleus, some RNA
- 1% of all RBC
o Take 1 day to mature
Macrocytic anaemia
Anaemias where the average red cell size is greater than normal (increased MCV)
- Megaloblastic anaemia
- Macronormoblastic erythropoiesis
- Stress erythropoiesis
megaloblastic anaemia
think low B12/folate
think chemotherapy
think leukaemia
Macronormoblastic erythropoiesis
stress erythropoiesis
Folate deficiency
Causes
- Dietary deficiency (poor diet)
- Increased requirements
o Pregnancy
o Increased erythropoiesis e.g. haemolytic anaemia
o Severe skin disease e.g. psoriasis
- Disease of duodenum and jejunum (e.g. coeliac disease and crohns disease)
- Drugs which inhibit dihydrofolate reductase e.g. methotrexate
- Alcoholism
- Urinary loss of folate in liver disease and heart failure
Symptoms
- Anaemia related
- Reduced sense of taste
- Diarrhoea
- Numbness and tingling in feet and hands
- Muscle weakness
- Depression
Key clinical point:
Folic acid taken before conception and during first 12 weeks of pregnancy prevent neural tube defects in babies e.g. spina bifida
vitamin B12 def (cyanobalamin)
Causes
- Dietary deficiency
- Lack of intrinsic factor (Pernicious anaemia)
- Disease of the ileum (Crohns disease, ileal resection, tropical sprue)
- Lack of transcobalamin (congenital defect)
- Chemical inactivation of B12 e.g. frequent use of anaesthetic gas nitrous oxide
- Parasitic infestation (tapeworm can trap b12)
- Some drugs can chelate intrinsic factor (e.g. hypercholesterolaemia drug cholestyramine)
Symptoms
- Anaemia related
- Glossitis and mouth ulcers
- Diarrhoea
- Paraesthesia
- Disturbed vision
- irritability
what is a presentation of B12/folate deficiency
Subacute combined degeneration of the cord
- B12/folate deficiency can also affect NS
o Folate deficiency in pregnancy can cause neural tube defects
o Vitamin B12 deficiency associated with focal demyelination - B12 deficiency more often results in a reversible peripheral neuropathy
- However, can also result in a serious condition called subacute combined degeneration (irreversible) of the cord- involving degeneration of posterior and lateral columns of the spinal cord
Symptoms
- Gradual onset weakness, numbness and tingling in arms, legs and trunk which progressively worsens
- Changes in mental state
Key clinical point
Always seek urgent advice from a haematologist if neurological involvement is suspected in a patient with vitamin B12 deficiency
Why do B12 and folate deficiency cause a megaloblastic anaemia?
- Both folate and B12 deficiency lead to thymidine deficiency
- In absence of thymidine, uracil is incorporated into DNA instead
- DNA repair enzymes detect these errors and constantly repair excision
- Results in asynchronous maturation between nucleus and cytoplasm
o Nucleus doesn’t fully mature
o Cytoplasm matures at the normal rate
o Large nuclei and open chromatin
o Mature red cells also large leading to macrocytic anaemia
Treatment of vitamin and folate deficiency
- Folate
- Vitamin B12
o For pernicious anaemia- Hydroxocobalamin intramuscular (NOT oral) - Other causes of B12 deficiency: oral cyanocobalamine
o Blood transfusion in patients with severe anaemia caused by vitamin B12 deficiency can cause high output cardiac failure- if absolutely required transfuse smaller volume
Microcytic anaemias pathophysiology
- Reduced rate of haemoglobin synthesis
- Erythrocytes smaller than normal (microcytic)
- Cells often paler than normal (hypochromic)
o Less haemoglobin
causes of microcytic anaemia
1) Reduced haemo synthesis
- Iron deficiency
Insufficient iron for ahem synthesis
- Lead poisoning (rare)
Acquired defect
Lead inhibits enzymes involved in haem synthesis
- Anaemia of chronic disease
Hepcidin results in functional iron deficiency
- Sideroblastic anaemia
Inherited defect in haem synthesis
2) Reduced globin chain synthesis
- Alpha thalassaemia
Deletion or loss of function of one or more of the 4 alpha globin genes
- Beta thalassaemia
Mutation in B globin genes leading to reduction or absence of the B globin
TAILS
Thalassaemia
Anaemia of chronic disease
Iron deficiency
Lead poisoning
Siderblastic anaemia
Iron
- Essential element in all living cells
- Free iron potentially very toxic
- Complex regulatory systems to ensure the safe absorption, transportation and utilisation
- Body has no mechanism for excreting iron- important concept
Required for:
1) Oxygen carriers
- Hb in red cells
- Myoglobin in myocytes
2) Co-factor in many enzymes
- Cytochrome (oxidative phos)
- Kreb cycle enzymes
- Cytochrome P450 enzymes (detoxification
- Catalase
Ferrous vs ferric iron
- Iron can exist in a range of oxidation states
- Ferrous iron (Fe2+) and ferric iron (Fe3+) most common
- Fe2+ is the reduced form, Fe3+ is the oxidised form
- Dietary iron consists of haem iron (Fe2+) and non-haem (mixture of Fe2+ and Fe3+)
o Ferric iron must be reduced to ferrous Fe2+ before it can be absorbed from the diet
Haem vs non-haem iron
- Need 10-15 mg/day iron in diet
- Absorption occurs in duodenum and upper jejunum
- Haem iron (Fe2+)best source
- Some foods fortified with iron e.g. breakfast cereals
examples of sources of haem vs non-haem iron
Dietary absorption of iron
- In the upper duodenum region that absorption occurs
- Haem iron (Fe2+ ferrous) can be absorbed without transporters
- Non haem iron needs transporter
o Fe3+ Fe2+
o Reductase uses vitamin C to reduce ferric to ferrous
o Fe2+ can then be absorbed via DMT1 (divalent (meaning 2- fe2+) metal transporter 1) cotransporter - Haem is degraded within the enterocyte to release Fe2+ (haem oxygenase)
o Iron can be stored as ferritin (Fe3+)
o Iron can be transported into the blood via ferroportin - To transport iron around the body it is bound to a protein called Transferrin (binds 2 ferric Irons – Fe3+)
o Hephaestin converts Fe2+ to Fe3+ - Hepcidin inhibits the function of ferroportin
Factors affecting absorption of non-Haem iron from food
Negative influence
- Tannins (tea)
- Phytates (e.g. chapattis, pulses)
- Fibres
- Antacids (e.g. Gaviscon)
Positive influence
- Vitamin C and citrate
- Prevent formation of insoluble iron compound
- Vit C also help reduce ferric to ferrous irons
o E.g. take iron tablets with orange juice
Cellular iron uptake
1) Fe3+ bound transferrin binds transferrin receptor and enters the cytosol receptor-mediated endocytosis
2) Fe3+ within endosome released by acidic microenvironment and reduced to Fe2+
3) The Fe2+ transported to the cytosol via DMT1.
4) Once in the cytosol, Fe2+ can be stored in ferritin, exported by ferroportin (FPN1), or taken up by mitochondria for use in cytochrome enzymes
Hepcidin
- A key negative regulator of iron absorption
- During iron overload hepcidin synthesis is increased
o Induced internalisation and degradation of ferroportin - Hepcidin synthesis is decreased by high erythropoietic activity
Anaemia of chronic disease (functional iron deficiency)
- Main mechanism: cytokine IL-6 released by immune cell due to inflammatory condition such as arthritis
- IL-6 increases the production of Hepcidin by liver
o Inhibition of ferroprotein
o Decreased iron released from retinoendothelial system
o Decreased iron absorption in the gut
Plasma iron reduced
Inhibition of erythropoiesis in bone marrow - IL-6 also inhibits erythropoietin, further inhibiting erythropoiesis
Iron deficiency
- Most common nutritional disorder worldwide
- 1/3rd of world population are anaemic with at least half of these due to iron deficiency
- Iron deficiency is a sign not a diagnosis
o Need to seek underlying reason why patient is iron deficient
causes of iron deficiency
- Insufficient intake/ poor absorption
e.g. Vegan and vegetarian diets - Physiological reasons e.g. pregnancy and rapid growth (increased requirement)
- Pathological reasons e.g. bleeding
e.g. Menstruation
e.g. Gastric bleeding due to chronic NSAID usage - Anaemia of chronic disease e.g. IBD
presentation of iron deficiency
Physiological effects of anaemia
* Tiredness
* Pallor
* Reduced exercise tolerance (due to reduced oxygen carrying capacity)
* Cardiac- angina, palpitations, development of heart failure)
* Increased respiratory rate
* Headache, dizziness, light-headedness
Pica – unusual cravings for non-nutritive substances e.g. dirt and ice
Cold hands and feet
Epithelial changes
Testing for iron deficiency
- Plasma ferritin commonly used as indirect marker of total iron status
- Ferritin predominantly a cytosolic protein but small amounts are secreted into the blood where it functions as an iron carrier
- Reduced plasma ferritin definitively indicates iron deficiency
- BUT.. Normal or increased ferritin does not exclude iron deficiency
- Ferrtitin levels can also increase considerably in cancer, infection, inflammation, liver disease and alcoholism
- CHr (reticulocyte haemoglobin content) recommended by NICE to test for functional iron deficiency
- CHr remains low during inflammatory responses etc. (also low in those with thalassaemia)
Treatment of iron deficiency
- Dietary advice
- Oral iron supplements
o Safest, first-line therapy for most patients but many experience GI side effects and compliance with treatment - Intramuscular iron injections
- Intravenous iron
- Blood transfusion- only used if severe anaemia with imminent cardiac compromise
Response
- Improvement in symptoms
- 20g/l in Hb in 3 weeks
Iron excess is dangerous
- Excess iron can exceed binding capacity to transferrin
- Excess iron deposited in organs as haemosiderin
- Iron promotes free radical formation and organ damage
o E.g. plays a role in the fenton reaction which creates free radicals
Causes:
- Transfusion associated hemosiderosis
- Hereditary hemochromatosis (HH)
Transfusion associated hemosiderosis
- Repeated blood transfusions give gradual accumulation of iron
- 400ml blood = 200mg iron
- Problem with transfusion dependent anaemias such as thalassaemia & sickle cell anaemia
- Iron chelating agents such as desferrioxamine can delay but do not stop inevitable effects of iron overload
Accumulation of iron (hemosiderin) in the liver, heart and endocrine organs:
- Liver cirrhosis
- Diabetes mellitus
- Hypogonadism
- Cardiomyopathy
- Arthropathy
- Slate great colour skin
Hereditary hemochromatosis
- Autosomal recessive disease caused by mutation in HFE gene (on Chr 6)
- HFE protein normally interacts with transferrin receptor reducing its affinity for iron-bound transferrin
- HFE also promotes hepcidin expression through activation of signalling pathways in liver
- Mutated HFE therefore results in loss of negative influences on iron uptake and absorption
- Too much iron enters cells and accumulates in end organs causing damage
- Treat with venesection
Causes:
* Liver cirrhosis
* Diabetes mellitus
* Hypogonadism
* Cardiomyopathy
* Arthropathy
* Increased skin pigmentation
Myeloproliferative disorders
- clinical features
- Overproduction of one or several blood elements with dominance of a transformed clone
- Hypercellular marrow (marrow fibrosis)
- Cytogenetic abnormalities
- Thrombotic/ haemorrhagic diatheses
- Extramedullary hemopoiesis (liver/spleen)
- Potential to transform to acute leukaemia
- Overlapping clinical features
Essential thrombocythemia
“too many platelets”
A rare chronic blood cancer (myeloproliferative neoplasm) characterised by the overproduction of platelets (thrombocytes) by megakaryocytes in the bone marrow. - Can develop into acute myeloid leukaemia or myelofibrosis.
Characterised by
- Excess platelets in blood
- Large and excess megakaryocytes in bone marrow
- thrombotic event
Management
- Any cardiovascular risk factors should be aggressively managed
- Aspirin
High risk patients
- >60 year
- Platelet count >1500 or disease- related thrombosis/haemorrhage
- Return the platelet count into the normal range with drug such as hydroxycarbamide
Screen for JAK2 and CALR mutations
Polycythaemia vera (PV)
High red blood cells
- Diagnostic criteria= high haematocrit or raised red cell mass
- JAK2 mutation present in 95% of PRV patients
- No reactive cause found
- Some patients also have high platelets and neutrophils
- Median age 60
- Male= female
Clinical features
- Significant cause of arterial thrombosis
- Venous thrombosis
- Haemorrhage into skin or GI tract
- Pruritis- itchiness
- Splenic discomfort, splenomegaly
- Gout- due to excess cell breakdown
- In some transformation to myelofibrosis or acute leukaemia
Management
- Venesection to maintain Hct to <0.45
- Aspirin 75mg unless contraindicated
- Manage CVS risk factors e.g. cholesterol and BP
- Sometimes drug to reduce the overproduction of cells should be considered
Myelofibrosis
Myelofibrosis is an uncommon type of bone marrow cancer that disrupts your body’s normal production of blood cells. Myelofibrosis causes extensive scarring in your bone marrow, leading to severe anaemia that can cause weakness and fatigue.
- Causes a massive splenomegaly due to extramedullary haematopoiesis
- Heavily fibrotic marrow-> little space for hemopoiesis
- Blood vessels get squeezed out of the bone due to reduced space—blood film shows red cells looking like tear drops
- - Clonal haemopoietic stem cell proliferation
- May be end result of Polycythaemia vera or Essential thrombocythemia
- Primary disease= PMF
- PMF starts with proliferative phase when all counts may be high, then in all cases progressive pancytopenia (all blood cells low) due to marrow fibrosis and hyperspenism
Treatment
- Bone marrow failure requiring transfusions of blood products
Results in
- Transformation to leukaemia
- Early death
CML (Chronic myeloid leukaemia)
Chronic myeloid leukaemia
- Usually presents with very high WCC
- Patients may present with symptomatic splenomegaly, hyperviscosity (sticky blood) or bone pain
- Disease of adults, very rare in children
Symptoms: due to hyperviscous blood
- Headache
- Blurred vision
- Lung problems
- Kidney failure
Causes
- Reciprocal switch of genetic material between chr 9 and 22
- Switches on receptor tyrosine kinase
Pancytopenia
Reduction in white cells, red cells and platelets
Why may someone become pancytopenia
1. Reduced production (most common)
2. Increase removal
o Splenic pooling
o Hypersplenism in massive splenomegaly
o Immune destruction
o Haemophagocytosis- chewing up of the cells in the bone marrow v v rare
What can cause reduced production
- B12/folate deficiency
- Bone marrow infiltration by malignancy (blood cancers of other cancers)
- Marrow fibrosis
- Radiation
- Drugs – chemotherapy, antibiotics, anticonvulsants, psychotropic drugs, DMARDs
- Viruses – EBV, viral hepatitis ,HIV, CMV
- Idiopathic aplastic anaemia
- Congenital bone marrow failure eg Fanconi’s anaemia, dyskeratosis congenital – present in childhood
Aplastic anaemia
- Pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate with no increase in reticulin (fibrosis)
- Mortality is high as cure is difficult – immune treatments and bone marrow transplantation
- Deaths often due to neutropenic infection or bleeding
causes of thrombocytopenia
Decreased platelet production
* B12 of folate deficiency
* Acute leukaemia or aplastic anaemia
* Liver failure
* Sepsis
* Cytotoxic chemotherapy
Increased platelet consumption
* Massive haemorrhage
* Disseminated intravascular coagulation
* Thrombotic thrombocytopenic purpura
Increased platelet destruction
* Autoimmune thrombocytopenic purpura
* Drug induced e.g. heparin
* Hyperspenism resulting in increased destruction and splenic pooling of platelets
Consequences of severe thrombocytopenia
* Patients generally not symptomatic until the platelet count < 30
* Easy bruising
* Petechiae, purpura (blood spots or skin hemorrhages)
* Mucosal bleeding
* Severe bleeding after trauma
* Intracranial haemorrhage
Immune destruction of platelets
Immune thrombocytopenic purpura most common cause- autoantibodies against glycoprotein (GP) IIb/ IIIa and GPIb/IX
- Can be secondary to autoimmune disease e.g SLE and lymphoproliferative disorders e.g. lymphoma CLL
- Treated with immunosuppression (corticosteorids or IV immunoglobulin first line)
- Platelet transfusions do not work – transfuse platelets get destroyed too
Haematological changes associated with
- Anaemia of chronic disease and anaemia of renal disease
- Rheumatoid arthritis
- Liver disease / alcohol excess
- Post-operative state and infection
- Cancer
Changes to the blood is systemic disease are often multi-factorial due to…
- Physiological causes e.g. inflammatory cytokines (IL-6)
- Complications of the disease
o e.g. UC loss of blood and unable to absorb nutrients - Treatment- adverse effects e.g. methotrexate
Anaemia results due to
- Lack of response from haemostatic loop
- E.g. in chronic kidney disease the kidney stops making EPO
- Bone marrow unable to respond to EPO
- E.g. after chemotherapy, toxic insult or infections (parvovirus)
- In anaemia of chronic disease e.g. rheumatoid arthritis, iron is not made available to marrow for RBC production
Physiological life cycle of blood cells
Blood cells made in bone marrow—> sent out to the periphery and then removed by the spleen (reticulocytes-endothelial system)
anaemia of chronic disease
Examples: Rheumatoid arthritis, IBD, chronic infections e.g. TB
At least three contributors all caused by inflammatory cytokines
* Functional iron deficiency – available iron not released for use in bone marrow
* Marrow shows lack of response to EPO
* Reduced lifespan of red cells
Functional iron deficiency
Sufficient iron in the body but not available to develop erythropoiesis cells
–> due to hepcidin
Anaemia of chronic kidney disease
- Kidney becomes damaged and less functional throughout disease
- Will need renal replacement therapy e.g. dialysis or intraperitoneal dialysis
- Underlying cause of CKD often associated with raised cytokines
- Reduced clearance of hepcidin and increase hepcidin production due to inflammatory cytokines
- Dialysis- damages red blood cells- shear stress e.g. of the dialysis tubing
- Reduced lifespan of RBC as a direct effect of uraemia - high levels of urea
- Ureamia also inhibits megakaryocytes- leading to low platelet count
Treatment of anaemia of chronic disease
- Treat underlying condition
- Associated with renal failure
- Give recombinant human EPO
- Ensure Vit B12 folate and iron stores are adequate
- Transfuse red cells- only if all else fails and patient symptomatic
- Absorption given in IV form due to absorption being impaired
Possible haematological abnormalities in kidney disease
anaemia in RA
- Anaemia is multifactorial
o ACD
o GI blood loss due to NSAIDS and steroids
o Risk of autoimmune haemolytic anaemia - High platelets and neutrophils when disease is active (CRP will also be up)
- Low platelets and neutrophils may occur due to treatment, autoimmune reactions or to hypersplenism (splenomegaly can occur in this condition)
o Feltys syndrome
Felty’s syndrome
Triad: Rheumatoid arthritis, splenomegaly and neutropenia
- Neutropenia due to splenomegaly contributing to peripheral destruction of neutrophils and failure of bone marrow to respond to GCSF (myeloid cell stimulator)
Liver disease
Chronic liver disease will cause portal
hypertension which causes splenomegaly
which leads to:
* Splenic sequestration of cells
* Overactive removal of cells
* Low blood count
Portal hypertension also leads to oesophageal and gastric varices (dilated veins prone to bleeding due to higher than normal pressure)
- Most clotting factors are made by the liver, synthesis of some dependent on vitamin k- patients will become quickly deficiency in clotting factors
Other haematological features of liver disease are depending on the underlying cause
Alcohol excess
- Directly toxic to bone marrow cells- pancytopenia
- Secondary malnutrition – folic acid deficiency
Viral hepatitis
- Bone marrow failure (hypoplastic/aplastic marrow) can develop after hepatitis
Autoimmune liver disease
- Immune mediated anaemia, thrombocytopenia or neutropenia
haematological changes in cancer
anaemia
neutropenia
thrombocytopenia
Post operative reactive changes
which cells are affected by infection
1) RBC
2) Neutrophils
3) Thrombocytes/ platelets
Haematological changes with infection: Red blood cells
chronic infection can cause anaemia of chronic disease e.g. malaria can cause haemolytic anaemia
Haematological changes with infection: Neutrophils
Bacterial
- Neutrophilia- associated with bacterial infections
- Neutropenia- associated with severe bacterial infection/sepsis
Parasitic- eosinophilia
Viral- lymphocytosis and neutropenia
Haematological changes with infection: thrombocytes
- Infection can cause reactive thrombocytosis
- Severe infection can cause thrombocytopenia
- Thrombocytopenia may be associated with with disseminated intravascular coagulation (DIC) in severe sepsis
Sepsis can lead to clotting abnormalities- disseminated intravascular coagulation (DIC)
- Pathological activation of coagulation
- Numerous microthrombi are formed in the circulation
- Consumption of clotting factors and platelets and a consequence microangiopathic haemolytic anaemias (MAHA)
- Clotting tests
o Clotting time ling
o Low fibrinogen
o Raised D-dimers - Risk of both bleeding and thrombosis
