3 Myeloma, Lymphoma and Bleeding Flashcards
Risk factors for lymphoma (4)
Age
Immunosuppressed - HIV, organ transplant, autoimmune conditions
Infection - EBV, H.Pylori
Difference in cell types between CLL, ALL, lymphoma and myeloma
CLL - mature cells in peripheral blood/ marrow
ALL - blastic cells in peripheral blood/ marrow
Lymphoma - mature cells in tissues
Myeloma - mature plasma cells in bone marrow
Difference in cell morphology between high and low grade lymphoma
High - Large irregular cells, mitotic bodies (inc proliferation), dispersed chromatin and prominent nucleoli
Low - smaller regular cells, apoptosis rate is low so there is slower accumulation
Difference in presentation and treatment between high and low grade lymphoma
High:
Earlier, localised, stage 1/2 usually as more aggressive
Treatment aim is to cure
Low:
Later, more diffuse, as grows slowly
Treatment aim is for symptoms and to prolong life, but there is no cure
What staining/ immunohistochemistry is done for lymphoma and what are the appearances in low/ high grade?
Ki67 stain = protein produced by cells in S phase (DNA replication)
Low - not much staining as low proliferation rate
High - lots of staining as very high proliferation rate
4 main types of lymphoma
Follicular
Diffuse Large B cell
Burkitt (3 types)
Hodgkins
Treatment and grade (low/high) for Follicular/ DLBCL/ Burkitt lymphoma
Follicular (low) = low dose chemo/radio
DLBCL (high) = aggressive chemo, but some resistance
Burkitt (high) = aggressive chemo, very effective (as high rate of cell death)
3 types of Burkitt lymphoma and patient groups
Endemic = Africa/Papa NG, children, link to malaria and EBV
Sporadic = western europe, older children/ young adults (mean 30)
Immunodeficiency = HIV, organ transplant
Where in the lymph nodes do Follicular/ DLBCL/ Burkitt lymphoma arise?
Follicular = germinal centres DLBCL = lymphoid follicle Burkitt = germinal centres
What mutation is present in Burkitt’s vs follicular lymphoma and what does it cause?
Burkitt: MYC gene translocation 14/8, often next to an immunoglobulin which increases MYC role of increasing cell proliferation, and increasing cell death
Follicular: translocation between chromosome 14/18 -> BCL2/IGH protein (BCL2 is an anti-apoptotic protein) and function increased (decreased apoptosis)
Characteristic feature of Hodgkins lymphoma
What else can it be present in?
Reed sternberg cells - binucleate, prominent nucleolus, large cytoplasm
Some inflammatory conditions - Infective mononucleosis
Types of Hodgkins lymphoma (2)
Classical (94%)
Nodular lymphocyte predominant (6%)
Presentation of follicular vs DLBCL vs Burkitt vs Classical Hodgkins lymphoma
Follicular:
>Painless lymphadenopathy ± BM involvement
DLBCL:
>Rapidly enlarging mass (nodes or Waldeyer’s rings/ GIT/ skin/ bone/ CNS)
Burkitt (mostly extranodal) > All - CNS involvement > Endemic - jaw and face bones > Immuno - BM/lymph nodes > breast/ ovaries/ kidneys
CHL:
>Painless lymphadenopathy
>B symptoms (night sweats/fever/ WL)
>Paraneoplastic phenomenon - sore nodes with alcohol, intractable itch
4 subtypes of Classical Hodgkins lymphoma
Mixed cellularity
Nodular sclerosing
Lymphocyte predominant
Lymphocyte depleted
Surface proteins present/ not present on Reed sternberg cells
CD10 -
CD30 +++
Features of plasma cell myeloma - X-ray/blood/urine
Production of excess immunoglobulin/ fragments (light chains)
X-ray - lytic lesions
Blood - free light chain (fragment), M/para protein (full)
Urine - Bence jones protein (fragment light chains)
Diagnosis criteria of myeloma
Neoplastic cells >10% marrow (+ 1 of: )
CRAB: >hyperCalcemia >Renal failure >Anaemia >Bone lesions - on CT/X-ray
SLiM:
> 60% or more plasma cells in bone marrow
> Light chain ration of >100 (either way, normally 50/50)
> MRI - at least 1 focal bone lesion
Potential cytogenetic abnormalities in myeloma (4)
55-70% IGH rearrangement chr 14
50% - monosomy/ partial deletion chr 13
50% MYC rearrangement
Tp53 mutation/ deletion (in many cancers)
Only treatment of myeloma and gene mutation with poorest outcome
Bone marrow transplant
Tp53
Define smouldering/asymptomatic myeloma
only 10-60% of clonal plasma cells in bone marrow, and none of the SLiM CRAB criteria
Will usually progress to myeloma in around 5 years avg (don’t need treatment til then)
Define Monoclonal Gammopathy of Uncertain Significance
Less than 10% clonal cells in bone marrow, low M-protein in blood, absence of end organ damage
Doesn’t need treatment, risk of progression to myeloma is low
Plasmacytoma definition and treatment
Single localised bone tumour, may have M-protein, but with no other signs of plasma myeloma
Tx = local radiation, no chemo
Population of incidence of Classical hodgkin’s lymphoma
2 age peaks:
Young adults (15-30)
Elderly/ older adults
Mostly males
What does lymphadenopathy in lymphoma feel like compared to other caners/ inflammation
Painless and rubbery
Cancer - craggy
Reactive/ inflammation - sore
General lymphoma presentation
Splenomegaly
Anaemia
Painless lymphadenopathy - rubbery
B symptoms
Investigations ofr lymphoma/ myeloma
Bloods: FBC, ESR (HL, ACD, myeloma), Calcium (severe lymph/myel), LDH (NHL), U+Es/LFT’s (function pre Tx)
Imaging: CT, PET/CT
Bone marrow biopsy: aspirate, trephine
Other: Echo, pulmonary function test (function pre Tx) - lymp
Myeloma only:
Urine, Serum free light chain, serum electrophoresis (M protein/band)
What is the staging classification for lymphoma
Ann-Arbor: 1 - one node group 2 - >1 node group, same side diaphragm 3 - >1 node group, different side diaphragm 4 - extranodal
A - no B symptoms
B - B symptoms
What surface antigen is present on most B cell lymphomas and targeted for treatment (and name of treatment)
CD20 - treated with Rituximab monoclonal Ab
What are the RCHOP (RCAVP) chemo drugs for lymphoma
R - rituximab C - cyclophosphamide H/A - adriamycin O/V - vincristine P - prednisolone
What is being tested for in myeloma with: Serum electrophoresis Blood film Immunocytochemistry Imaging
Serum electrophoresis - M band
Blood film - blue background, rouleaux, inc plasma cells
Immunocytochemistry - light chain restriction
Imaging - lytic bone lesions (pepper pot skull)/ fractures
What are the ABVD chemo drugs for Hodgkins lymphoma
A - ariamycin
B - bleomycin
V - vinblastine
D - dacarbamizine
Describe the extrinsic/ activation part of coagulation cascade
TF(3a) + 7a > 10a
Describe the intrinsic/ propagation part of coagulation cascade
12a > 11a > 9a (+8a) > 10a
Describe the regulation part of coagulation cascade (3)
1) Thrombin stimulates antithrombin which down regulates factors
2) protein C + thrombomodulin > APC (+ protein S) > down regulates factors 5 & 8
3) Factor 10 feedback to TPFI > down regulates factor 7
Describe the fibrinolysis part of coagulation cascade and its regulation
(Plasminogen>) Plasmin - breaks don fibrin clot
Inhibited by:
PAI 1/2 (plasminogen activation inhibitors)
TAFI - also inhibits plasminogen activators)
alpha2 antiplasmin - inhibits plasmin
Requirements for the initiation and propagation steps of coagulation cascade (2)
Calcium
Phosphates
Analysis of coagulation 1y haemostasis (3)
In vivo - bleeding time
Ex vivo:
>FBC (platelets)
> Light Transmission Aggregometry - agonists added to plasma and aggregation measure by light transmission
Analysis of coagulation 2y haemostasis (4)
Prothrombin time - extrinsic
Activated partial thromboplastin time - intrinsic
Thrombin clotting time - fibrinogen
Individual coagulation factor assays
What is added to patient plasma in PT, APTT, TCT?
PT - thromboplastin (TF + phospholipids)
APTT - contact factor (12) + phospholipids
TCT - bovine thrombin
What would cause prolonged PT, APTT, TCT (@ normal time)?
PT (10-13) - extrinsic problems: factor 7
APTT (26-38) - intrinsic problems: F 12,11,9,8; lupus anticoagulant/ some antibodies
TCT - fibrinogen problems; fibrin inhibitors, thrombin inhibitors (heparin/ dibagatran)
PT and APTT - common problems: F 10,5,2(thrombin), 1 (fibrinogen)
Describe the pathway of coagulation cascade
10a (+5a) > 2a (thrombin) > (fibrinogen (1a)>) fibrin
Benefits of LMWH vs UFH
Less side effect frequency
Longer half life
More bioavailability and less protein binding
Doesnt require monitoring
Uses of heparins (4)
> Tx of acute DVT/ PE (LMWH)
Px of acute VTE in obstetrics, cancer, post op (LMWH)
*Cardiac bypass surgery (UFH)
*Acute coronary syndrome (+ antiplts)
Target INR for warfarin
2-3
Uses of warfarin evidence (3)
> PE/VTE - recurrence prevention
*AF - stroke prevention
*Prosthetic heart valve - stroke/ valve thrombosis prevention
Uses of DOACs
> DVT/PE
*AF
*Total hip/knee replacement
Route of administration of: Heparins Warfarin DOACs Fibrinolytics
Heparins - parenteral
Warfarin - oral
DOACs - oral
Fibrinolytics - oral/ parenterally/ catheter
Uses of tissue plasminogen activators
Acute MI (12 hrs of symptoms onset) - 30 day mortality dec.
Ischemic stroke (4.5 hrs of symptoms onset) - 90 day disability dec.
Massive PE with haemodynaic instability - dec thrombus size and cardiac strain
DOAC contraindications (3)
Pregnancy/ breast feeding
Liver disease/cirrhosis (± coagulopathy)
Certain drugs
Define catheter directed thrombolysis and uses (3)
Drug injected directly into clot via catheter
Reduces systemic effect, but not bleeding risk
Uses:
>Acute limb schema
>Massive DVT - proximal and high/ pelvis
>Blocked CVC (Hickman line)
Antiplatelet drug names: ADP R ax GPIIb/IIIa R ax COX1 inhibitor Phosphodiesterase 3 inhibitor Thromboxane synthetase / Receptor inhibitors
> ADP R ax - clopidogrel/ ticagrelor, ticlodipine
GPIIb/IIIa R ax - abciximab, tirofiban
COX1 inhibitor - aspirin
Phosphodiesterase 3 inhibitor - dypyradimole
Thromboxane synthetase / Receptor inhibitors - picotamide/ ifetroban
Uses of antiplatelets in:
CVD - acute MI, 2y prevention
Cerebrovascular: acute stroke/TIA/ 2y prevention, PVD
CVD:
>acute MI: aspirin (+ ticagrelor/clop 12 months) (±tirofiban)
>2y prevention: aspirin
Cerebrovascular:
> acute stroke/TIA/ 2y prevention: clopidogrel (2nd- aspirin + dipyramidole)
>PVD: clopidogrel (2nd aspirin)
Antiplatelet drug mechanisms of action: ADP R ax GPIIb/IIIa R ax COX1 inhibitor Phosphodiesterase 3 inhibitor Thromboxane synthetase / Receptor inhibitors
ADP R ax: irreversibly block ADPR, > prevents expression of GPIIb/IIIa R > no fibrinogen binding
GPIIb/IIIa R ax: prevents fibrinogen binding
COX1 inhibitor: prevents arachidonic acid >thromboxane a2
Phosphodiesterase 3 inhibitor: prevent cAMP> AMP, so increase cAMP > reduced platelet aggregation
Thromboxane synthetase / Receptor inhibitors: reduced platelet aggregation
Fibrinolytic drug names:
Kinases
tPAs
Kinases - streptokinase, urokinase
tPAs - telecteplase, alteplase, reteplase
Define process of DIC and causes (5)
Causes: major trauma, sepsis, malignancy, major haemorrhage, pregnancy complications
Inappropriate coagulation > micro thrombi > exhaustion of cascade > excess bleeding
Lab tests for DIC
> Coagulation tests: APTT, PT, fibrinogen (PT) - raised
D-Dimer
FBC + film platelets - anaemia, thrombocytopenia, RBC fragmentation
Look for underlying cause
Treatment of DIC
Treat underlying cause
FFP ± platelets (if at high bleeding risk)
Management of severe bleed caused by warfarin (3)
Stop warfarin
IV vitamin K1, 5mg
IV factor concentrate - Beriplex, Octaplex
How does liver disease affect coagulation?
> Reduced production coagulation factors
Poor clearance of activated coagulation factors
Reduced thrombopoietin synthesis (low platelets)
Hypersplenism - inc removal WBC/platelets
> DIC
Vit K deficiency - dietary deficiency, malabsorption?
Describe haemophilia A and inheritance pattern
X linked
Deficiency of factor 8, causing prolonged APTT
Severe - <1% F8
Moderate - 2-5%
Mild 6-40%
Treatment of haemophilia A (4)
Desmopressin
Replacement factor therapy
Gene therapy
Education for patient/doctor
What does von willebrand disease have an effect on (2) and what are the 3 classifications?
Platelet aggregation
Binds and increases half life of F8
Type 1 - reduced production (partial quantitative)
Type 2 - produce enough but faulty (qualitative)
Type 3 - complete deficiency (quantitative)
2 main severe inherited platelet disorders and their defect
Glansmanns Thromboasthenia: Defect/absent GP 2b/3a but normal platelet numbers
Bernard Soulier Syndrome: Defect/absent GP 1b/5/9 and macrothrombocytopenia
Characteristics of platelet disorders
Mucosal bleeding pattern
Autosomal dominant - parents may be related (asian)
Petechiae
Can have normal numbers in haematology blood test
Treatment of severe platelet disorders (5)
Platelet transfusion - severe
Pressure - mild
Desmopressin - increase VWF
Tranexamic acid - inhibit fibrinolysis
Recombinant factor 7a - increase thrombin production
How does lupus anticoagulant affect coagulation process and tests
Phospholipid dependent antibody, if persistent, is prothrombotic
Increases APTT as interferes with phospholipid dependent tests
Define antiphospholipid syndrome and its clinical scenarios
Persistent lupus anticoagulant (or other phos. dept. Ab)
+ thrombosis/ or recurrent metal loss
Clinical:
Recurrent miscarriage
Young, recurrent thrombosis (arterial/venous)
Causes of inherited thrombophilia (5)
> Antithrombin deficiency (most common)
Protein S deficiency
Protein C deficiency
> Mutation F5 - factor 5 leiden (resistance to inactivation by APC
Mutation prothrombin gene - increase prothrombin