Haematology Flashcards
How is anaemia defined?
Haemoglobin level below the lower limit of normal for age/sex
What are clinical features of anaemia?
- Pallor
- Weakness, fatigue, lethargy, dizziness, headache
- tachycardia
- older patients: HF, angina, claudication
What are the 3 broad groups under the morphological approach to anaemia?
- Hypochromic - reduced MCV and MCH
- Macrocytic - increased MCV
- Normochromic normocytic - normal MCV/MCH
What are examples of hypochromic microcytic anaemia?
- iron deficiency
- anaemia of chronic disease
- thalassaemia
What are Macrocytic anaemia examples?
- megaloblastic - B12/folate
- hypothyroidism
- pregnancy
What are examples of normochormic, normocytic anaemia?
- anaemia of chronic disease
- acute blood loss
- some haemolytic anaemias
What are macro and microcytic anaemias associated with?
Macrocytic - problems in synthesis of RBC
Microcytic - deficiency in Hb production
How are these proteins involved in iron absorption?
- ferritin
- transferrin
- transferrin receptor
- ferroportin
- ferritin - iron storage protein found in serum
- transferrin - transport protein for iron
- transferrin receptor - cells absorb iron through internalisation of transferrin bound to transferrin receptor
- ferroportin - transports iron across cell membrane to plasma
What are the three categories of cause for iron deficiency?
XS blood loss
Decreased absorption
Increased utilisation of iron - pregnancy
What are some clinical features of iron deficiency?
- anaemia
- dietary cravings - pica
- glossitis
- angular stomatitis
- brittle nails
- koilonychia - spoon nails
What would be seen in a FBP of iron deficiency
- reduced Hb, RCC, MCV
Blood film - hypo chromic microcytic red cells + pencil cells
What would be the findings in iron studies of someone with iron deficiency?
- reduced ferritin
- reduced transferrin saturation
- increased transferrin
- reduced serum iron
What is the management of iron deficiency?
- Oral iron - best absorbed as Fe2+ with vitC
- Parenteral iron therapy - non compliant or can’t absorb
- Blood transfusion of iron - for haemodynamically unstable
What is anaemia of chronic disease/inflammation?
Seen in patients with inflammatory or malignant disease - elevation of IL6 which stimulates hepcidin –> causes the internalisation of ferroportin which prevents iron from being absorbed in the GIT - functional iron deficiency because it cannot be accessed
What would a FBP and iron studies of anaemia of chronic disease show?
FBP - mild anaemia, normal or reduced MCV Iron studies: - increased ferritin - reduced transferrin saturation - reduced transferrin - reduced serum iron
What is thalassaemia and what are the types?
Beta-thalassaemia - trait and major
Alpha thalassaemia - trait and major
What is the difference in presentation between beta major and trait thalassaemia?
Major (XS alpha globin)- homozygotes present between 3-12 months of age (transfer from foetal to adult Hb)
Trait - usually asymptomatic
What is megaloblastic anaemia?
Macrocytic anaemia resulting from inhibition of DNA synthesis - causing impaired RBC production
Commonly due to folate or B12 deficiency
What is vitamin B12 involved in and causes the deficiency?
B12 - involved in maintenance of myelin in NS and DNA formation and synthesis/cell division
Cause: malabsorption due to pernicious anaemia, coeliacs, pregnancy
What is pernicious anaemia?
- macrocyclic anaemia caused by B12 deficiency
- due to stomach atrophy and reduced Intrinsic factor secretion
- results in reduced absorption of B12
- Associated with AI diseases
How is the clinical presentation of B12 deficiency unique?
Neurological - peripheral neuropathy and subacute degeneration of posterior columns of spinal cord
What is the treatment for B12 deficiency?
Replacement of B12 via IM injection of 1000ug cyanocobalamin or hydroxocobalamin
What are causes of folate deficiency?
- reduced dietary intake
- reduced absorption
- increased folate use
- increased folate loss
- drugs
What is the treatment for folate deficiency?
Reversing the underlying cause/taking oral supplements
What is haemolysis and what are the clinical features?
Haemolysis - increased RBC destruction and reduced lifespan and leads to compensatory increased EPO and RBC production
Clinical features:
increased RBC destruction - inc bilirubin, lactate hydrogenase, dark urine
Compensatory increased production of RBC - increased reticulocytes, reduced folate stores
What are the causes of RBC haemolysis?
RBC abnormalities:
- membrane abnormalities - hereditary spherocytosis or eliptocytosis
- enzyme deficiencies - G6PD
- Hb abnormalities
Extrinsic to RBC
- AI haemolytic anaemia
- infection
- mechanical trauma
What is Autoimmune haemolytic anaemia? How is it diagnosed?
Auto-antibodies produced against RBC’s causing agglutination and haemolysis
Diagnosis:
-normocytic/macrocytic anaemia
- increased RCC
- increased bilirubin
+ve direct antiglobulin test (DAT)/Coomb’s
What are the subtypes of AIHA?
IgG - warm antibody AIHA
- antibodies more active in body temp
- therapy - steroid, rituximab, splenectomy, immunosuppressant
C3d - cold antibody AIHA
- more active at room temp
- therapy - rituximab
What happens after disruption to the vascular endothelium?
- platelets bind and form unstable clot
- TF n sub endothelium activates FVII
- Clotting cascade - thrombin production
- large scale thrombin production
- Fibrinolysis is activated to localise the clot
What are the causes of accelerated bleeding?
- abnormalities of vasculature
- defects of primary haemostats - platelet disorders
- defects of secondary haemostats - procoagulant protein deficiency
- accelerated breakdown of clot
What are disorders of primary homeostasis?
- abnormal platelet number - thrombocytopenia
- impaired BM
- Hypersplenism
- increased destruction - infection/ITP
- drug induced - Abnormal platelet function
- congenital - bernard solider, glanzmanns, VWD
- Acquired - drugs
What is the normal function of platelets?
Involves adhesion, shape change causing platelet activation, granule release and recruitment of more platelets - aggregation and platelet plug!
What is Von Willebrand’s disease?
Defective or missing VWF
Autosomal disease affecting primary haemostasis as VWF is needed for platelet binding AND it is also a carrier protein for FVIII - secondary haemostasis
What are the types of VWD?
Type 1 - decreased quantity VWF
Type 2 - decreased function VWF
Type 3 - rare, severe deficiency of VWF due to 2 defective genes
What is the laboratory diagnosis of VWD?
Potentially prolonged APTT - due to FVII and VWF
VW screen for VWF antigen, function and FVII levels
What is the management of VWD?
Desmopressin (DDAVP) - releases endogenous stores of VWF
Tranexamix acid tablets - stop clot breakdown
Biostate - for severe VWD or non-responders to DDAVP
How does vitamin K deficiency effect bleeding? How is it diagnosed?
VitK is essential for clotting and activation of FII, VII, IX, X.
Diagnosis - prolonged INR, normal fibrinogen and normal/prolonged APTT that corrects on mixing with normal plasma
How does liver disease affect coagulation?
- reduced synthetic function
- reduced vitK absorption
- reduced clearance of clotting factors
- hyprfibrinolysis
- thrombocytopenia
- acquired platelet dysfunction
What is a massive transfusion and the clotting problems associated with it?
Transfusion of >50% of blood volume within 24 hours. Packed cells contain diluted amount of clotting factors and platelets
What is disseminated intravascular coagulation?
When blood is exposed to pro-coagulant factor (TF e.g.) causing massive thrombin generation, widespread coagulation and then fibrinolysis and depletion of clotting factors
In DIC what is the most common presentation and how is it confirmed?
Feature: bleeding - acute spontaneous from cannula site
Confirmation:
- prolonged INR and APTT that correct on mixing
- low fibrinogen, platelets
- RBC fragmentation, raised D-dimers
What are the bleeding symptoms in platelet disorders?
- Mucocutaneous bleeding, oral, GI etc
- bleeding after minor cuts
- petechia common
- immediate bleeding in procedures
What are the bleeding symptoms in clotting factor deficiencies?
- deep tissue bleeding, joints, muscles
- may develop hematomes
- delayed bleeding
What are acquired, inherited and other risk factors for VTE?
Acquired - previous VTE, trauma, surgery, cancer, nephrotic syndrome, immobility
Inherited - antithrombin deficiency, protein S/C deficiency, prothrombin gene mutation
Other - elevated FVIII
What is antiphospholipid syndrome?
Acquired thrombophilic syndrome
- evidence of antiphospholipid antibodies
- venous or arterial thrombosis
What does thrombophilia screen involve?
- antithrombin
- protein C and S
- prothrombin gene mutation
What is antithrombin involved in and what causes deficiency?
Majori inhibitor of thrombin and and factor Xa
Deficiency - autosomal dominant condition, results in 10x increase in thrombosis risk (can also be an acquired condition)
How is protein C involved in coagulation?
VitK dependent Anticoagulant protein that is enhanced by protein S, has anti-inflammatory actions, protects endothelial barrier function and enhances fibrinolysis
- autosomal dominant disorder = deficiency
What is Factor V leiden mutation?
Point mutation that prevents protein C from inactivating factor V = constantly high Va levels
What are clinical features of DVT?
- swelling, redness, tenderness, pitting edema
How can d-dimer be used in the diagnosis of DVT?
D-dimer not a specific test for VTE because elevated in infectionn, DIC, malignancy
Negative d-dimer can exclude CVT
Positive d-dimer - cannot confirm DVT
Clinical features of PE
- Chest pain
- SOB
- Cough/haemoptysis
- Palpitations/syncope
What are the treatment aims of VTE?
- relieve symptoms
- prevent PE
- prevent death
- prevent recurrence
- prevent complications
Complication of DVT
Post-phlebitic syndrome - chronic edema, pain and swelling in the leg causing ulceration and increased susceptibility to infection
Complication of PE
Pulmonary HTN - will affect heart and lung function
What are treatment options in DVT/PE?
- Parenteral anticoagulants:
- unfractionated heparin (inpatient)
- low molec weight heparin (outpatient)
- fondaparinux - Oral anticoagulants:
- warfarin
- new oral agents: dabigatran, rivaroxaban - Aspirin
What are the steps prior to blood transfusion to find a compatible donor?
Group, screen, crossmatch
What is involved in grouping?
Tube agglutination - antiserum added to patient RBC and check for agglutination
Column agglutination - pre made cartridge of serums, add drop of RBC to each one (faster)
What does screening involve?
Screen patient’s plasma for antibodies: patient plasma mixed with O RBC’s with antigens (Rh, Kel, Duffy etc)
What is involved in the crossmatch?
Donor RBC mixed with patient plasma
When should packed cells be tranfused?
When Hb <70 always transfuse, if 70-100 transfuse if symptomatic (normal
What does fresh frozen plasma contain? does it need to be grouped?
Clotting factors fibrinogen, vWF - indicated for reduced factor production, XS factor consumption
- needs to be ABO grouped but not RhD grouped (AB suitable for all groups as there are no a/b)
Which blood groups are the universal donor and recipient?
Universal donor - type O RhD -v
Universal recipient - type AB RhD +ve
What are the immune complications of blood transfusion?
- febrile non-haemolytic transfusion reaction: cytokines a/b to donor WBC
- Acute haemolytic transfusion reaction: ABO/RhD incompatible blood
- Delayed haemolytic transfusion - a/b from previous alloimmunisation
- Allergic reaction: hypersensitivity to plasma proteins from donor
What are less common but serious immune reactions to blood transfusion?
- TRALI - lung neutrophils activated by donor a/b - fever + resp distress
- Transfusion associated graft vs host disease
What are non immune complications with blood transfusion?
- transfusion associated circulatory overload
- transmitted bacterial infection
- transmitted viral infection
What percentage of blasts in the blood and bone marrow is normal?
blood - none
BM - 2-5%
What are -ve and +ve symptoms in haematology?
Negative - no WBC - frequent infection - no RBC - anaemic - no platelets - bleeding, petechiae Positive - Type B symptoms - weight loss, fever, night sweats seen in lymphoma and acute leukaemia
What is left shift?
increase in the number of immature neutrophils in the peripheral blood, usually in the form of band neutrophils
- myeloblasts only in blood of those with cancer
What are myeloproliferative disorders?
Examples
Hyperplasia disorders where there is an over-production of blood cells usually along one lineage due to acquired KINASE MUTATIONS
- polycythaemia rubra vera
- essential thrombocythaemia
- myelofibrosis
- chronic myeloid leukaemia
What is polycythaemia rubra vera?
Myeloprolif: High haematocrit (too many RBC)
JAK2 kinase mutation in 95%
What is essential thrombocythaemia?
Myeloprolif: too many platelets causing risk of bleeding and thrombosis
What is myelofibrosis?
Fibrosis of the bone marrow
- overgrowth of stromal cells
- haematopoesis shifted to spleen - splenomegaly
What is CML?
- features
- cause
- treatment
Myeloprolif: high neutrophil count
- raised WCC with left shift
- weight loss, fatigue, headache
- massive splenomegaly
Cause: mutation on BCR-ABL gene of philadelphia chromosome
Treatment: Imatinib - competitively binds kinase domain of abnormal BCR-ABL, preventing further proliferation
What are the types of acute leukaemia?
Neoplasia of BM stem cell
- acute myeloid leukaemia
- acute promyelocytic L is a subtype where there is abnormal accumulation of immature granulocytes (promyelocytes) - acute lymphoblastic leukaemia
What is lymphoma and what are the common features?
Cancer of the immune system
- almost always present with lump anywhere on the body
- symptoms can mimic infection - B symptoms
What proportion of lymphomas are B and T cell origin?
B cell - 80%
T cell - 20% and more chemo resistant
Which lymphoma incidence doubled between 1980 and 2010? suggesting modern lifestyle is stressing our immune system
Non-hodgkin lymphoma
What are causes of non-hodgkin lymphoma?
Chemo/radiation Immunosuppression AI disease Infections Environmental
Which chromosomal translocations are commonly associated with lymphoma? and what do they encode?
Encode: immunoglobulin Chromosomes - 2, 14, 22 •2p12 -> light chain gene (IgK) •14q32.3 -> heavy chain gene (IgH) •22q11 -> light chain gene (IgG)
How is the germinal centre involved in lymphoma?
Germinal centres: mature B cells proliferate, differentiate and produce antibodies using Kappa, gamma, heavy chain. Immune system then determines if they have favourable binding, if not they apoptose.
- sometimes this goes wrong and during rapid proliferation, B cell picks up another gene resulting in lymphoma
What were problems with the international working formulation in classifying lymphomas?
- site of disease
- B vs T cell origin
- defining low grade NHL
- new entities
How did WHO/REAL classify B-cell neoplasms?
- precursor B cell neoplasm
- mature B cell neoplasm
- - follicular lymphoma (35%)
- - diffuse large B cell lymphomas (25%)
What are the stages of lymphoma?
I - one lymph node region/lymphoid structure
II - 2+ lymph node regions on same side of diaphragm
III - lymph nodes on both sides of diaphragm
IV - involvement of extra nodal sites
What investigations are done in lymphoma to determine staging?
- open biopsy
- blood tests
- imaging PET
- bone marrow biopsy
What is the clinical spectrum of NHL? (0,2,6,10)
0 - small lymphocytic lymphoma (CLL)
2 - Follicular B cell NHL
6 - Diffuse large cell NHL
10 - Burkitt’s lymphoma
What is the commonest type of lymphoma?
Follicular B cell NHL
- incurable (7-15 year prognosis)
- symptoms uncommon
What is diffuse large B-cell lymphoma? and what does the international prognostic index measure to assess severity?
Commonest aggressive lymphoma (many subtypes) IPI: A - age P - performance status L - LDH (raised) E - extra nodal disease (2+ sites) S - stage (II, IV)
What is the translocation causing Burkitt’s lymphoma and where does it commonly present?
Treatment?
t (8, 14) - associated with EBV
Rapidly growing mass in head, neck , abdomen in young adults
Treatment: intensive chemo = 80% cure
How does mucosal associated lymphoid tissue lymphoma develop?
Chronic pylori infection causes lymphocytes to accumulate and they start to grow independently of H. pylori stimulation –> turns into MALT lymphoma
What is the treatment for NHL?
Rituximab is a humanised antibody that binds CD20, which is expressed on B cells at most of their stages of development
What is hodgkin lymphoma?
B cell lymphoma not expressing B cell surface antigens, presents with itch and large mediastinal mass
- large inflammatory response with Reed-Sternberg cells
For HL and NHL, which is common, who is affected, and what % is nodal disease?
HL - uncommon, reed-sternberg cells, young and elderly, 90% nodal
NHL - common, elderly, varied cells, 60% nodal
How does HL and NHL spread?
HL - contiguously
NHL - haematogenously
What is the cure rate for HL?
> 80%
What is multiple myeloma?
Neoplastic proliferation of plasma cells involving >10% of bone marrow with lytic bone lesions, hypercalcemia and renal failure
Usually presents as tumours masses spread throughout the skeletal system
What do malignant plasma cells secrete? (in 95% of cases hence absence does not exclude diagnosis)
Monoclonal immunoglobulin called M protein
What do the factors secreted by neoplastic plasma cells mediate?
- bone destruction/resorption
2. leads to hypercalcaemia
What are the clinical features of MM?
- Leukopenia, anaemia, thrombocytopenia (prolif. of plasma cells interferes with other cell production)
- aberrant antibodies lead to impaired humeral immunity
What is the CRAB presentation of MM?
hyperCalcaemia
Renal failure
Anaemia
Bone lesions
Clinical scenario in which to consider MM?
- unexplained normocytic anaemia
- unexplained renal impairment
- low trauma fracture
- lytic bone lesion
- unexplained hypercalcaemia
How does MM affect neurological processes?
- muscle weakness and pain
- vertebral fracture - radiculopathy
- spinal cord compression
What are general processes in MM that affect the body?
- Amyloidosis - accumulation of free light chains that infiltrate any system
- Hyperviscocity - headaches, stroke, angina
- Weight loss
How is the diagnosis of MM made?
- serum or urinary monoclonal protein
- presence of clonal plasma cells in BM or plasmacytoma
- Presence of end-organ damage related to plasma cell abnormalities
What is the treatment for MM?
Its non-curative
- improve quality of life, slow progression and complications
- autologous stem cell transplant
Which patients with MM are transplant eligible? and what do they receive?
patients if <70 yrs and no major comorbidities
- chemotherapy, proteasome inhibitor and autologous transplant
What is chronic lymphoblastic leukaemia?
Indolent disease with clonal malignancy of mature B-cells (>5000 lymphocytes per mm3)
What is the difference between CLL and small lymphocytic lymphoma (SLL)?
CLL - blood and bone marrow involved
SLL - lymph nodes involved, minimal blood or bone marrow involvement
What are the clinical features of CLL?
- 25% asymptomatic
- Lymphadenopathy, hepatomegaly and splenomegaly common
- 5-10% have B symptoms
- immune disregulation
- bone marrow failure
What would CLL investigations show?
FBC - clinical ppn of CLL lymphocytes >5x10^9/L
Blood film - small lymphocytes
Bone marrow aspirate - >30% nucleated cells are lymphocytes
What is the diagnostic criteria for CLL, SLL and monoclonal B cell lymphocytosis?
CLL: B cell >5x10^9/L in peripheral blood
SLL: B cell <5x10^9/L in peripheral blood + lymphadenopathy + splenomegaly
Monocloncal B cell lymphocytosis: B cell < 5x10^9/L in peripheral blood, no lymphadeno. or splenomegaly + no disease related symptoms
What is the prognosis of CLL determined by?
Rai staging
Cytogenetic status
Low risk -> lymphocytosis in blood and bone marrow only
Intermediate risk -> lymphocytosis with enlarged nodes in any site or splenomegaly, hepatomegaly
High risk -> lymphocytosis with disease-related anaemia (<110 g/L) or thrombocytopenia (<100 x 109/L)
What are the complications of CLL
- impaired cell mediated and humeral immunity
- Autoimmune cytopenias
- Transformation to high grade lymphoma
Treatment for CLL
- most don’t require treatment
Indications for treatment: disease related symptoms, progressive marrow failure/lymphadenopathy/splenomegaly - although incurable, symptomatic patients treated with chemo, immunotherapy with antibodies against proteins on CLL cells
Young/fit: FCR fludarabine + cyclophosphamide + rituximab
Old/unfit: BR bendamustine + rituximab
Blood film and bone marrow findings in macrocytic anaemia
Blood film - low RCC, Macrocytosis, hyperhsegmented neutrophils
Bone marrow - giant pronormoblasts and metamyelocytes
Which leukaemia is more common in children and adults?
Children - ALL
Adults - AML
Role of JAK-2 and which conditions it is often mutated in
Pathway signalling, EPO binding, stem cell differentiation Hyperplasia/myeloproliferative disorders - PRV - ET - MF
What is pathognomonic to CLL/SLL
Activated lymphocytes gather in loose aggregates called proliferation centres
