Haematology Flashcards
How much Iron is there in the body?
4g
Where is dietary iron absorbed and briefly describe how.
Duodenum and jejunum
Stomach acid causes Ferrous (Fe2+) iron to be made, which is more soluble and so more readily absorbed than ferric (Fe3+)
What are some complications of iron overload?
Cirrhosis, HF, arrhythmia, diabetes, bronzing of skin
(e.g. Hereditary haemachromatosis)
Due to deficiency of hepcidin due to mutation in HFE gene
What are the side effects of oral ferrous sulphate or ferrous fumarate?
Constipation, black coloured stool
What is haemolytic anaemia?
Anaemia related to a reduced RBC lifespan, increased destruction of red cells. < 20 days
Reduced Hb
Increased Reticulocytes, unconjugated bilirubin
splenomegaly
What is the complication of hyposplenism?
Increased risk of infection from encapsulated organism
SNKHSCP
Strep. pne, Nesseria meningitis, klebiella pne, H. infulenz
Long-term penicillin V
Target cells and Howel jolly bodies
Give an example of abnormal red cell enzymes and how it causes intravascular haemolytic anaemia?
Glucose 6 phosphate deficiency. X-linked recessive
No protection against oxidative stress
Stress causes lysis in the blood - free Hb - bind to haptoglobin in the blood - haemaglobinuria.
Give an example of abnormal red cell enzymes and how it causes extravascular haemolytic anaemia?
Pyruvate kinase AR
ATP deficiency
RES recognises it as abnormal and so engulfs it - IC haemoglobin - biliverdin - bilirubin in haptocytes
Splenomegaly and hepatomegaly due to increased RBC destruction
What are the AI causes of haemolytic anaemia?
Cold type - IgM - Agglutinate in cold parts of the body- acrocyanosis. Intravascular. Myocplasma infection, EBV or idiopathic
Warm type - IgG - IgG bind to RBC and damages membrane. Agglutinates EV. CLL/NHL, Hapten (drug)
Give some examples of intravascular haemolysis?
Breakdown by defective mechanical heart valve, malaria, ABO incompatibility, transfusion, cold IgM
What are findings in IV haemolysis?
Haemoglobinuria, haemoglobinaemia, haemosiderinuria, acrocyanosis, anaemia (reticulocytes and unconj Bili)
Where is B12 absorbed?
Terminal ileum
2-3mg in the body sufficient for 3 years
What type of anaemia is from B12 deficiency?
Megaloblastic microcytic anaemia. With Hypersegmented neutrophils.
B12 is required for DNA synthesis and neurological functioning
What is pernicious anaemia?
A form of B12 deficiency
AI disease to parietal cell - loss of intrinsic factor needed for B12 absorption in the terminal ileum
Atrophic gastritis
What blood results are in B12 deficiency anaemia?
LDH increased
Homocysteine increased
Fe stores increased
Leucopenia and thrombocytopenia
How do you treat B12 deficiency?
1mg Hydroxocobalamin IM every 2-3months
folic acid PO 5mg daily for4 months
Where is folate absorbed?
Proximal jejunum
What is anaemia of chronic disease?
Failure of iron utilisation, Iron trapped in RES
Inflammatory mediated reduction in RBC production
normocytic normochromic or microcytic hypochromic
What is Talassaemia?
Inadequate production/ decreased synthesis of normal globulin genes. Relative lack of globulin genes.
What are the different types of alpha thalassaemia? (1 gene missing, 2 genes missing etc)
AR
1 missing - asymptomatic carrier
2 missing - mild anaemia
3 missing - HbH disease, severe anaemia, hepatosplenomegaly, jaundice, infection - need transfusion in times of stress. Hb 65-75g/L
4 missing - Hb Barts hydrops fetalis- incompatible with life
What chromosomes are the alpha and beta globulin genes on?
Alpha - 16
Beta - 11
What would thalassaemia look like on a blood smear?
Microcytosis, hypochromic, target cells, nucleated red cells, increased reticulocytes
What treatment is available for alpha thalassaemia?
Folic acid. May need transfusion
What type of beta thalassaemia is there?
MICROCYTIC ANAEMIA
AR mutation to Chr 11
Beta thalassaemia minor - asymptomatic - MCV too low for Hb*. no tx required
Beta thalassaemia major (Cooley’s anaemia) -
Sx present at ~3-6month -
Anaemia (SoB, fatigue, Pallor), Hepatosplenomegaly (jaundice, distended abdo), Growth retardation, chipmunk face, hair-on-end skull Xray, failure to thrive
Transfusion dependent
What treatment ins available for beta thalassaemia major?
Lifelong blood transfusions - 2-4 wks
Iron chelation therapy
What is aplastic anaemia?
A gross reduction or absence in the haemopoietic precursors of all 3 lineages in the bone marrow causing pancytopenia in the peripheral blood.
What are some causes of aplastic anaemia?
Chemotherapy, BM failure, hepatitis A, B, C, CMV, EBV, Falconi anaemia (10-20% cases), drugs (NSAIDs, gold, carbamazepine)
What clinical signs indicate aplastic anaemia?
Pancytopenia, purpura, ecchymosis, bleeding from mucosal surface, infections, anaemia
What is Fanconi anaemia?
A rare genetic syndrome, AR, impaired response to DNA damage. Bone marrow failure. FANCA-G gene
What are some symptoms if falconi anaemia?
Microphthalmia, hydrocephalus, short stature, GU and GI malformations, Increased risk of malignancy, Hypopigmentation of freckles, hearing loss, mental retardation
What is gold standard treatment in fanconi anaemia?
Allogenic stem cell transplant
What patients are likely to get neutropenic fever?
85-95% acute leukaemia patients receiving induction chemotherapy
What is neutropenic sepsis?
Neutrophil count <0.5 or < 1 x 10^9/L
PLUS
Fever/hypothermia, or SIRS or sepsis/septic shock
What is the most common cause of neutropenia?
Chemo
What is neutropenic fever?
A single oral temperature of >. 38.3 or a temperature of >38 sustained for over an hour in a neutropenic patient.
What treatment would you use for standard, high and critical risk neutropenic sepsis?
Standard: IV piperacillin/ Tazobactam 4.5g/6hr ± IV vancomycin
High: IV Pip/tazo 4.5g/6hr + IV vancomycin + IV gentamicin
Critical: IV meropenam 1g/8hr + amikacin + Vancomycin
What is sickle cell anaemia?
Abnormal Hb and shape of red blood cells, sickling causes them to be destroyed more easily (10-20days)
AR
Single aa substitution in the beta chain at position 6
Glutamine to lysine Hb C
glutamine to valine Hb S
What are the complications of sickle cell anaemia?
Veno-occulsion - tissue hypoxia/ infarction
Haemolysis
Sickling causes acidosis, hypoxia and dehydration
What does a low haptoglobin indicate?
Intravascular haemolysis
each haptoglobin takes 3Hb
e.g. sickle cell anaemia, cold IgM, G6PD
What organ systems are affected in sickle cell anaemia?
Rep - acute chest syndrome / pulmonary HTN Brain - stroke/ moya moya Kidney - loss of concentration / infarction GU - priapism Eye - vascular retinopathy Placental - IUGR, foetal loss Bones - osteonecrosis Spleen - hyposplenic
In myelodysplastic syndrome there is a chance it will progress to AML, how can u assess this risk?
IPSS score
% blasts in BM, Karytotype, cytopenia
(>20% blasts = AML)
What is essential thrombocytosis or primary thrombocythaemia?
A chronic, sustained increased in megakaryocyte proliferation, leads to an increase in the number of circulating platelet
>600 x10^9/L
50% JAK2 mutation 50% calreticulin
In essential thrombocytosis, what might you treat a high risk person with?
1st line - Hydroxycarbamide + aspirin
2nd line - Anagrelide + aspirin
if JAK2 mutation - JAK 2 inhibitor - Ruxolitnib
What is myeloproliferative disease?
Effective haematopoiesis
Thrombocythaemia
Myloefibrosis (increased platelets, WBC)
Polycythaemia vera
What gives normocytic normochromic anaemia?
Haemorrhage, chronic kidney disease, anaemia of chronic disease, fanconi anaemia
What give hypo chromic microcytic anaemia?
Anaemia of chronic disease, IDA, thalassaemia, sideroblastic anaemia
What gives megaloblastic macrocytic anaemia?
B12/ folate def
What gives Non-megaloblastic macrocytic anaemia?
Liver disease, alcohol damage, drug induced
What gives anaemia with increased reticulocytes?
Major haemorrhage, haemolytic anaemia
Describe the Ann Arbour staging.
I - One lymph node group
II - One or more lymph node groups on the SAME side of the diaphragm
III - LN groups involving both sides of the diaphragm (included spleen)
IV - Extra-nodal involvement - Liver, bone marrow
A and B - Absence (A) and presence of B symptoms
X - >10cm widened mediastinum
E - single extra node group contiguous or proximal to known nodal sites
What is alcohol induced pain a rare feature of?
Hodgkins lymphoma (B-cell lymphoma)
What causes 40% of classical Hodgkins lymphomas?
Epstein barr virus
What are some cellular features of HL?
Strong expression of CD30 and loss of some B-cell antigens (CD3, CD20, CD45)
Neoplastic cells resemble atypical activated B cells seen in EBV infection
Reed Sternberg cells
What are the 4 major grades of HL?
Nodular sclerosisng (80%) - good prognosis Mixed cellular - intermediate prognosis Lymphocyte depleted - common in HIV patients. poor prognosis Lymphocyte predominant - favourable prognosis
What chemotherapy is used in HL?
ABVD Adriamycin Bleomycin Vinblastine Darcarbazine
What is the most common presentation in lymphoma?
Painless lymphadenopathy
What are useful prognostic markers in NHL (CD20)?
Beta2-microglobin and LDH, both raised
Give an example of an indolent NHL and its mutation.
Follicular t(14,18), to BCL-2 over expressed = reduced Apoptosis rate
How would you treat a high grade follicular NHL?
R-CHOP
Rituximab, Cyclophosphamide, doxorubicin/adriamycin, vincristine, prednisolone
How would diffuse large B cell lymphoma present?
NHL, Resemble activated B cells (immunoblasts and centroblasts)
Can present with pyrexia of unknown origin (PUO)
Ascites and pleural effusion are common end-stage Sx
Requires aggressive chemo with intention to cure
Early(1A) R-CHOP x 3 + RT
All other R-CHOP x6
What cancer involves over expression of the MYC gene?
Burkitts lymphoma
Cells resemble proliferating germinal centre cells
EBV, HIV, Malaria
Most cases have extra nodal disease *Ileoceacal region often primary site. Jaw and facial bones
What is tumour lysis syndrome and what cancer is it in>
Burkitts lymphoma and Leukaemia
Tumour cell release their contents into the blood stream spontaneously or in response to therapy
- High uric acid, K, PO4, low Ca
AKI, seizure, arrhythmias
What is myeloma?
Cancer of the plasma cells - CRAB Hypercalcaemia Renal failure Anaemia Bone lesions/ pain (punched out/ lytic lesions)
Give an example of a premalignant myeloma.
Smouldering myeloma - is a progressed monoclonal gammopathy of undetermined significance. There are more antibodies
How might myeloma present?
Back pain or rib pain
Sx of hypercalcaemia
Fatigue, recurrent infections, renal impairment
What is the triad the typifies myeloma?
- Increased plasma cells in the bone marrow
- Clonal Ig or paraprotein
- Lytic bone lesions
How would you diagnose Myeloma?
BLIP Bence jones protein Serum free light chain assay Serum Igs Serum protein electrophoresis
Bone marrow biopsy
Imaging whole body MRI then WB CT, skeletal survey
What is the myeloma diagnostic criteria?
Neoplastic plasma cells >/=10% of bone marrow total cells + at least 1 of:
1. Evidence of end-organ damage attributable to plasma cell proliferation (anaemia, renal failure, hypercalcaemia, bone lesions >/= 1 lytic)
2. Markers of malignancy
Clonal plasma cell >60%
Serum free light chain >100
>1 focal lesion on MRI
Give some features of acute leukaemia.
Rapid onset and can lead to death in days to weeks if not treated.
Blastic cell proliferation in BM (>20%) (maturity arrest)
CD34 antigen
Gum swelling, skin rash, bleeing and bruising, bone pain
What are some features of AML.
M3 t(15,17) M2 t(8,21) most common in adults High % of myeloblasts in BM (on blood film and BM aspirate) and Aeur rods in the cytoplasm. Tx. - intense chemo (anthracycline and cytarabine bases ) ± allogenic SC transplant
What is the most common childhood malignancy?
Acute lymphoblastic leukaemia
B-cells. Associated with Downs syndrome
Limping child - stays off legs - bone and joint pain
Purpuric rash, SoB, infections, epitaxis
What causes CML?
BCR-ABL t(9,22)
Granulocyte hyperplasia
Tx - imatinib
Splenomegaly - LUQ pain and abdominal fullness, sternal tenderness, B symptoms, infections, SoB
What are the phases of CML?
- Chronic phase (~5 years, asymptomatic, picked up incidentally as raised WCC)
- Accelerated phase (~6-9 months, symptoms of bone marrow failure, 10-20% of BM blast cells)
- Blast phase (>30% blast cells in BM, severe symptoms)
Define the criteria for a blast crisis
- Blast cells > 20% peripheral blood WCC, or of nucleated cells in the BM
- Extramedullary blast cell proliferation
- Large foci or clusters of blast cells in BM biopsy
What is Chronic Lymphocytic leukaemia?
Progressive accumulation of mature appearing, functionally incompetent B-lymphocytes in the blood, BM, LN, liver, spleen etc.
CD5, CD19, CD23
>30% BM has mature LYMPHOCYTES
Tx - steroids (only symptomatic)
What are some immune complications of CLL?
Warm type AI haemolytic anaemia
AI thrombocytopenia
What are some infections in CLL?
Acquired Hypogammaglobulinaemia due to immuneparesis
Neutropenia
Defects in complement activation
Pulmonary infection
What is Richter’s transformation?
CLL transforms into the fast growing diffuse large B cell lymphoma
What can cause increased homocyteine level?
B12 or folate deficiency, renal disease
B6 deficiency
What are the different patterns of bleeding?
Vascular and platelets disorders lead to prolonged bleeding from cuts, bleeding into the skin and from mucous membrane
Coagulation disorders cause delayed bleeding into joints and muscles
What is Haemophilia A?
Deficiency of factor VIII. X-linked recessive
Increased aPTT
Bleeding into joints (haemiarthrosis) and muscle
What is Disseminated intravascular coagulation?
Raised D-dimer
Pathological process characterised by activation of the clotting cascade causing small thrombi, and so eventually reduced platelets and so - bleeding. ISTH scoring system
Leads to organ failure, usually caused by sepsis
Small thrombi cause schistocytes - Microangiopathic haemolytic anaemia
What will happen if platelets <50 x 10^9/L (thrombocytopenia)?
Easy or spontaneous bruising and prolonged bleeding.
Bleeding gums, nose bleeds, menorrhagia, haematuria
What is immune thrombocytopenic purpura?
Antibodies are created against platelets (IgG) causing destruction of them and so low platelet count
What is thrombotic thrombocytopenic purpura?
Tiny clots form in tiny blood vessels using up the platelets.
Deficiency in ADAMTS 13 which usually breaks down von willie brand factor and reduced platelets adhesion.
What is Heparin induced thrombocytopenia?
Heparin induced antibodies against platelets - Specifically anti-Platelet factor 4 which activates clotting mechanisms - hypercoagulable state. And also destroys the plts
The pt has low platelets and unexpected blood clots
What are some inherited causes of thrombophillia?
Activated protein C resistance due to a single point mutation in factor V
Protein S and C deficiency
Prothrombin gene mutation - down regulation of fibrinolysis due to thrombin activated fibrinolysis inhibitor.
How might TTP cause microangiopathic haemolytic anaemia?
Deficiency of ADAMTS13 (due to IgG?, malignancy?)
This usually breaks down then large Von Williebrand multimers, If not broken down its like see grass on the endothelium. Shearing forces causes Schistocytes** - haemolytic anaemia
What is microangiopathic haemolytic anaemia and what features does it have?
IV haemolysis.
Damaged endothelium - platelet aggregation and fibrin deposition - these in the endothelium cause shearing forces to the RBC as they pass- SCHISTOCYTES (a true red cell fragment)- IV haemolysis
Anaemia, jaundice, elevated LDH and reticulocytes
Causes:
HUS, TTP, DIC, malignancy, artificial heart valves, malignant HTN, drugs (tacrolimus), vasculitis
What is pancytopenia and what are some Sx?
Failure in the ability to produce enough differentiated cells in the peripheral blood. Deficiency in all blood cells.
Due to consumptive process (splenomagly), increase in 1 cell type (e.g. immature blasts in leukaemia), or failure in production (haemotinic deficiency, virus, aplastic anaemia)
Ax - Anaemia - pallor, chest pain, SoB, fatigue, Neutropenia - frequent infections. Thrombocytopenia - epistaxis, bleeding, bruising
When might Wet purpura in the oropharynx be observed?
Severe haemostatic defect - Platelets <30
All-trans retinoid acid can be used to treat AML M3, how does it work?
Binds to PML- RARA fusion protein and degrades it.
This releases the block that was on differentiation of cells.
Also causes apoptosis of malignancy cells
Usually combined with anthracycline or arsenic trioxide
In platelet disorders there can be prolonged bleeding from cuts and bleeding into the skin and from mucous membranes. What are some causes of platelets disorders?
Decreased marrow production - Aplastic anaemia, megaloblastic anaemia, marrow suppression
Excess destruction - immune (ITP, SLE, CLL, heparin), non-immune (TTP, DIC, HUS)
Poorly functioning platelets - myeloproliferative diseases, NSAIDs
What are some signs of haemophilia A?
Excessive bleeding in response to minor trauma and spontaneous bleeding with no trauma
Neonates may present with IC haemorrhage, Haematoma or cord bleeding
Spontaneous bleeding into joints and muscles
Bleeding from gums, GI tract, urinary tract, IC
How might you treat a mild and severe bleed in a patient with haemophilia?
Mild - Compression and elevate
Mod-severe - Tranexamic acid ± desmopressin ± recombinant factor VII infusion
What causes Von Williebrand disease?
AD, 3 types, deficiency, absence or malfunctioning VWB
Affects primary and secondary haemostasis
(1 due to reduced platelet adhesion and so increases bleeding time, 2 due to reducing VIII activity as VWB binds VIII - increasing APTT)
What are some clinical features of VWB disease?
Menorrhagia, unusual easy, prolonged or heavy bleeding, epistaxis, bleeding and bruised gums, heavy bleeding during ops
What are some causes of Fe deficiency anaemia?
Dietary insufficiency - children, elderly, vegans
Loss of iron - heavy period, bleeding
Malabsorption - inadequate absorption - atrophic gastritis, coeliac, crohns
What might be seen on a blood film in Fe deficiency anaemia?
Pencil cells - elongated ellipsoid cells with a central pallor
Why should you NEVER treat megaloblastic anaemia with folic acid alone?
If they are also deficient in B12 then folic acid on its own can precipitate subacute combined degeneration of the spinal cord.
Give hydroxocobalamin + Folic acid
What clinical features might be seen in acute leukaemia?
Sx due to inc blasts - lymphadenopathy, hepatosplenomegaly
Sx due to BM failure -
Anaemia - SoB, tiredness, palpitations, lethargy, weakness
Infections - esp chest
Haemorrhage - menorrhagia, epistaxis, retinal haemorrhage, purpura, bleeding gums
Gum hypertrophy, fever, malaise, night sweats
What triad is seen in plummers Vinson syndrome?
IDA, glossitis (beefy red tongue), dysphagia (oesophageal webs)
