Haem Flashcards
What’s the pattern of inherited of haemophilia?
X Linked recessive
What are the 4T s in HIT pretest probability?
Thrombocytopenia (>50% decrease or platelet ~20)
Timing of thrombocytopenia (5-14 days)
Thrombosis (or skin necrosis)
OTher causes excluded
What test for the extrinsic pathway?
PT
What factors are in the intrinsic pathway?
TENET
(twelve-eleven-nine-eight-ten)
What is bound in HIT?
Platelet Factor 4
(Autoantibodies)
What receptor on platelets binds to vwf?
GP1B-V-IX (reversible adhesion to exposed extracellular matrix)
What does platelet adhesion to ECM trigger?
GPIIb-IIIa activation (irreversybinding to matrix ligand and platelet activation)
What does GPIIb-IIIa do?
Mediates platelet aggregation + binds fibrin to form fibrin clot
What does clopidogrel and ticagrelor work on?
P2Y receptor antagonists
PT-N, APTT-long, TT-N Fibr-N, Plt- N, diagnosis?
Factor VIII, IX XI, XII deficiency, vwf def
What is dilute Russel venom viper test used for?
Detecting presence of antiphospholipids, (prolonged test), esp b2gp.
Is also prolonged if DOAC present.
What hormonal state is the most risky for clots?
Post-partum
How does VITT doffer from HIT?
No heparin exposure
What is the bleeding pattern with platelet type bleeding disorders
Skin, mucosal membranes, vaginal, petichiae common, prolonged bleeding from skin cutes, bleeding immediately
What is the bleeding pattern with clotting factor disorders?
Deep soft tissue bleeds, muscles, joints, minimal bleeding from skin cuts as primary haemostasis intact, bleeding delayed 1-2 days and often severe (e.g post op day2)
What clotting factor deficiency has no clinical significance?
XII
What is inheritance of haemophilia?
X-Linked recessive, 1/3 if cases have no apparent family history
What is emicizumab?
MAB used in Haemophilia A to act as factor 8 and bond X to IX
What is type 1 VWF disease?
Partial quantitative deficiency. most common , 70-80%
What is VWD 2B?
Increased affinity of VWF for GP1B, selective deficiency of high molecular weight multimeters
What is VWD type 3?
Complete deficiency VWF
How to treat VWD?
Replace VWF, dvavp in acute bleeding if required (releases stores from wible plaby bodies)
What is the reversal agent for heparin?
Protamine
What does PFA100 test?
Primary haemostasis - used in assessment of VWD
How is iron absorbed?
In the gut through DMT1 receptors on enterocytes
What is the action of feroportin?
Allows iron to exit the cell into the circulation and become bound to transferrin in the blood
What is the role of hepcidin?
Inactivates feroportin receptors on macropophages and enterocytes - traps iron in the cell.
What are the iron studies in iron deficiency anaemia?
Transferrin - High
Trabsferrin saturation - low
Ferritin - low
What is the pathogenesis/ autoimmune target in ITP?
Autoantibodies towards Glycoprotein IIb/IIa complex
What is the outcome of reduced G6PD?
Reduced NADPH - making red cells more susceptible to damage by oxidative stress
BCR-ABL mutation
t(9;22)
What are the driver mutations in ET/PMF?
JAK2V617F
CALR (CALR 1 deletion mutation ass with mylofribrosis transformation)
MPL (test these two if JAK2 negative)
What is the treatment criteria fo ET?
CVD risk factors present
JA2 mutation
Age >60
History of thrommbosis
What is treatment for intermediate and high risk ET?
Hydroxyurea + aspirin
Add warfarin if VENOUS thrombosis
What is the treatment target for HCT in PV?
<45% Hct
What is the hb level required for dx of PV
160 women, 165 men
What are risk indicators for cytoreductive therapy in PV?
High risk ( Age >60, previous thrombotic event)
Poor tolerance of phlebotomy
WCC >15
Uncontrolled myeloproliferation
- Increasing splenomegaly
Uncontrolled symptoms ( HTN, blurred vision sx of hyperviscosity)
What is ruxolitinib?
JAK inhibitor - used to treat PV, superior at HCT control than hydrocycarbamide (hydroxyurea)
What are the bone marrow findings in PV?
Hypercellular, panmyelosis, pleomorphic megalokaryocytes
What are contraindications for aspirin therapy in ET?
Extreme thromocytosis, aquired VFD, low risk CALR positive
What are toxicities associated with CAR-T cells?
Cytokine storm - fro mCARTcell expansion
ICANS: immune effector cell associated neurotoxicity syndrome
How do you manage cytokine release storm after CART cells?
Anti IL-6 - tocilizumab and corticosteroids.
Supportive care
What is ICANS?
Immune effector cell associated neurotoxicity syndrome
- Disturbed blood brain barrier in the setting of severe systemic inflammation.
Confusion, headache, attention deficits, word finding difficulties, focal neurological deficits, or encephalopathy to life threatening cerebral oedema, transient coma, or seizures
Pathogenesis not well understood.
How to treat ICANS?
Corticosteroids, neurology review, seizure prophylaxis, supportive care
Presence of basophils on blood film is indicative of what?
CML
How do you treat CML?
Imatinib
Nilotinib - quicker and deeper responses
Dasatinib
What are side effects of imatinib?
Fluid retention, muscle pain, GI issues, fatigue
What mutation causes resistance to usual treatment for CML?
T315l - use ponatinib instead
Can TKIs be used in pregnancy?
No they are teratogenic
Can you get GVHD in BMT in the aplastic phase?
No- the graft hasnt started to function - pre-engraftment
What is sinusoidal obstructive syndrome?
Microthrombi in the hepatic venles causing occlusion of liver flow - cholestatic liver pattern.
Enlarged, tender liver, ascites, pulomonary infiltrates, oedema. This is an early complication of BMT
How do you treat Hepatic veno-occlusive disease?
Defibrotide - antithrombotic/anti inflammatory effect to dissolve microthrombi.
Ursodeoxycolic acid - billiary acid suppression
What cell has CD34?
Stem cell
What cell has CD3?
T lymphocytes
What are haematological indications for BMT?
AML, ALL, myelodysplasia, severe aplatic anaemia , NHL, myeloma, CML
Thallasaemia, sickle cell
Whn does engraftment happen after BMT?
12-21 days
How long does it take for immune reconstitution?
Up to 2 years
What is the most important mismatch in BMT?
HLA (A B OR C)
What are early BMT complications?
transplant related mortality 100 days - 5-15%
Infection/neutropenic sepsis in 85%
Acute GVHD - 40-60%
What is the pathophys of GVHD?
Damage to mucosa from chemoconditioning causes cytokines and bacterial invasion.
Donor T cells become activated and expand - T cells effector phase - attack host tissue.
What are risk factors for GVHD?
HLA compatibility, sex mismatch, alloimmunity, source of stem cells CMV seropositivity
What are late BMT complications?
Relapse - usually in first 5 years
Chronic GVHD
Infection
Infertility
Cardioresp disease
What are the greatest causes of mortality in early and late BMT?
Early: GVHD, infection
Late: Relapse
What doe the bone marrow show in ET?
Normocellular with proliferation of enlaged megalokaryocytes
Which cells are myeloid?
(Monocyte), Macrophage, neutrophil, platelet, RBC, eosinophil, basophil
What are the symptoms of myelodysplastic syndrome?
Anaemia - fatigue
Febrile neutropenia
Thrombocytopenia - bleeding
What is management of myelodysplastic syndrome?
Depends on ECOG
- If high risk + low ECOG - allogeneic stem cell is cure
- Azacitidine - hypomethylating agent
- Low risk. - supportive with RBC/EPO/GCSF
- Luspatercept, sotatercept - fusion protein that blocks tranfroming growth factor beta inhibitors of erythropoiesis (i.e helps blasts to mature)
Diagnosis of AML requires?
Pancytopenia on film, blasts in peripheral blood
Bone marrow aspirate shows >20% blasts
What are cells with Auer rods?
Myeloblasts - if seen in the peripheral blood - AML
What are adverse genetic markers in AML?
t(6;9), BCR-ABL, -5 or Del(5q) -7, -17, Mutated TP53, FLT3-ITD mutation without NPM1
What are favirable genetic markers in AML?
NPM1 mutation, RUNX`, t(8;21)
How do you treat AML?
Fit patient: 7+3 - 3 days anthracycline, 7 days cytarabine + allogeneic BMT
Unfit: Azacitidine and venetoclax
What are targeted therapies for AML?
FLT3 inhibitors: Midostaurin, gilteritinib, gemtuzumab
What defines complete remission in AML?
<5% bone marrow blasts, no circulating blasts or blasts with auer rods, no extramedullary disease, neut >1, Plt >100
What are the CD for B lineage?
CD19, CD20, CD79a
What are the CD for T cells
CD1, 2, 3, 5, 7
What are blasts in the peripheral blood that don’t have auer rods?
Lymphoblasts
ALL diagosis?
> 20% blasts in bone marrow (no aur rods), pancytopenia, blasts in peripheral blood
CLL diagnisis?
Isolated lymphocytisis - >5 for >3 months, + cytopenias
Generally small mature monomorphic lymphocytosis on blood film
What does CD5 on a B cell mean?
CD5 normally a T cell marker, expressed on B cells in CLL
What CD do you see in CLL?
CD5 ( on B cells), CD19, overexpression of either kappa or lambda
What are good and bad prognostic markers of CLL?
Good: 13q deletion
Bad: 11q, 17p, TP53 (less likely to respond to chemo)
When do you treat CLL?
if symptomatic
Evidence of bone marrow failure - cytopenia
>50% increase in lymphocyts over 2 months or doubled in <6
Diseasse related symptoms ( abdo pain from splenomegaly, night sweats, weight loss)
What is venetoclax?
BCL-2 inhibitor, which is an anti-apoptotic protein, used in CLL
What is ibrutinib?
Brutons tyrosine kinase inhibitor
What is POEMS syndrome?
Polyneuropathy
Organomegaly
Endocrinopathy
Monoclonal plasma cell proliferative disorder
Skin changes
What is AL amyloidosis?
MGUS + extracellular deposition of fibrils composed of fragments of monoclonal light chains can cause kdiney, cardiac, GI and skin problems
What is the stain for amyloidosis?
Congo red stain with possitive/ apple green birefringence
Diagnosis of MM?
Clonal bone marow plasma cells >10% AND evidence of end organ disease
(CRAB)
What are myeloma defining events?
Features that gurantee progression to myeloma
- > 60% clonal plasma cell on bone marrow
- Free light chain ratio >100
- More than one focal lesion on MI that is at least 5mm or more.
Treat these as if they have myeloma
How do you treat multiple myeloma?
Induction chemo-immunotherapy + BMT if fit
8-12 cycle chemoimmunotherapy if not fit for BMT.
Triplet: Bortezomib (proteasone inihibitor), Lenalidomide (IMiDs), Dexamethasone
What sites of DLBCL are associated with higher risk of CNS disease?
Kidneys and adrenals
What is used in DLBCL for CNS prophylaxis?
High dose methotrexate
What is the starry sky appearance?
Burkitts lymphoma:
Large histiocytes with abundant clear cytoplasm ingested apoptotic tumour cells in background of basophilic tumour cells.
MYC onc ogene is translocated in what disease?
Burkitts lymphoma - MYC found on Chr 8
t(8;14), t(2;8), t(8;22) can be implicated
What is t(14;18) found in ?
Follicular lymphoma
What is Waldestrom macroglobulinaemia?
Lymphookasmacytic lymphoma in the bone marrow and IgM monoclonal gammopathy
How do people present with waldenstroms?
IgM autoantibody sx - peripheral neuropathy
Cryoglobulinaemia
Hyperviscosity syndrome
Malabsorption and diarrhoea
If haematopoietic tissue infiltrated - cytopenia, hepatosplenomegaly
What gene is found in >90% of WM?
MYD88L265P mutation
What is required for WM diagnosis?
IgM paraprotein, >10% bone marrow infiltrate of small lymphocytes
How do you treat hyperviscosity syndrome from WM?
Plasma exchange
What is the driver mutation in hairy cell lymphoma?
BFARv600E
How to diagnose tumour lysis syndrome?
Uric acid >0.46
K + >6
Phos - >1.45
Ca <1.75
What is the MoA of rasburicase?
It is exogenous urate oxidase which breaks down excess uric acid produced from excess purines released in tumour lysis.
Allopurinol is a xanthine oxidase inhibitor which pevents formation of uric acid
CD30 + cells are seen in ?
Reed-sternberg cells/ hodgekin lymphoma
What is used for Hodgekins?
ABVD - Doxorubicin, bleomycin, vinblastine, dacabazine
What is Brentuximab?
Anti-CD30
What is used in relapsed/refractory hodgekin lymphoma?
Brentuximab, pembrolizumab, allogeneic stem cell transplant
T(8:14)
Burkitts ly,phoma
T(11;14)
Mantle cell lymphoma
T(15;17)
Acute promyelocytic leukaeia
t(4;14), t(14;16), t(14;20)
Myeloma - high risk genetic abnormalities.
Including Del 17p, p53 myration
what is TP53?
Tumour suppressor gene - deletion of this confers worse prognosis
What is 17p?
Tumour supressor gene - deletion = bad
What is MoA of bortezomib?
Proteasome inhibitor
What is amyloidosis?
Extracellular tissue deposition of highly ordered fibrils resulting in a wide range of clinical manifestations depending on location and amount of deposition
What is AL amyloidosis?
Caused by a plasma cell dyscrasia, is due to deposition of protein derived from immunoglobulin light chain fragments. Think L is for light chain. Can get AH if amyloid is derived from heavy chain
What is AA amyloid?
A potential complication of chronic diseases in which there is ongoing or recurring inflammation that results in sustained high-level production of serum amyloid A protein
What is transthyretin?
Wild type TTR can be deposited into sites such as myocardium causing amyloidosis. This is old people Amyloid
Mutatsnt/variant TTR deposition = hereditary amyloid.
What organ is most comonly affected by AA Amyloidosis?
Kidneys (80% of patients) leading to nephrotic syndrome
What is depositied in herediatary amyloidosis?
Transtheretin (TTR), also referred to as prealbumin
How do you treat AL amyloidosis?
Treat the underlying plasma cell dyscrasia
What protein is implicated in dialysis realted amyloidosis?
beta2-microglobulin amyloid
What is Bence jones protein?
Fragments of free light chain found in the urine - indicator of monoclonal expalnsion and Myeloma
How do you treat vTTR/hTTR amyloidosis?
Liver transplant
Gene therapy
TTR stabilisation: Diflunisal, tafamidis, inotersen
What are the fundoscopy findings expected in hyperviscosity from myeloma?
Flame haemorrhages
In myeloma, B2 microglobulin levels >5.5mg/l are assoaited with what?
Higher stage ( III) and worse 5 year survival
What is the pathophysiology of myeloma cast nephropathy?
Paraprotiens and Free light chains are filtered through the glomerulus, travel to the tubule and complexes with Tamm-Horsfall proteins and form casts that block the tubule. These are endocytosed into lysozomes which break down the proteins and trigger a toxic inflammatory cascade causing damage to the cell. This replies on the action of NF-kappa-B
How does Borteznib work in myeloma cast nephropathy?
It is an NF-kappa-B antagonist - to inflammatory cytokines are not recruited - lead to rapid reversal of acute renal failue
What are pathopneumonic findings of myeloma on BM biopsy?
Dutcher bodies, flaming cells
What is daratumumab?
Anti-38 MAB - used in MM
What is BCMA?
only expressed on B cells and myeloma - target for Bi-specific T cell engaging monoclonal antibody, and CAR-T cells
What do promyelocytes look like?
Heavily granulated with auer rods, can have multiple rods per cell
How do you treat APML?
ATRA (all trans retinoic acid) - a differentiating agents that helps promyelocytes differentiate into their mature cells then die by apoptosis
What is defferentiation syndrome?
Secondary to ARTA use in APML, also ass with arsenic use. Myeloid cell maturation leads to systemic inflammatory response and cytokine expression (IL1, IL6, IL8, TNF-A).
- 7-12 days post induction
- Dyspoea, fever, peripheral oedema, hypotension, pleural-pericardial effusion, AKI, Pain, hyperbili.
What is sweet syndrome?
Acute febrile neutriohilic sermatosis
What is the treatment of differentiation syndrome?
- Stop atra or arsenic
- Give dexamethasone
What are the common driver mutations in AML?
FLT3, DNMT3a, NPM1
What cell surface proteins are common on myeloblasts?
CD13, CD33
What agents is used in induction if there is FLT3 mutation in AML?
Midostaurin
FLT3 is a tyosine kinase ITD mut is juxtamembranous
What PCR test is used to diagnose APML?
PML-RARA
What us 5q minus syndrome?
Indolent MDS.
- Hypoplastic anaemia, normal plt, atypical marrow megalokaryocytes.
Interstitial deletion of 5q.
Clinical response ++ to Lenalidomide
ELISA antibodies to evoplakin or periplakin is indicative of what?
Paraneoplastic pemphigus (PNP) - a rare autoimmune blistering disorder that may occur in the setting of lymphoproliferative disorders and malignancies ( non-Hodgkin lymphoma, chronic lymphocytic leukemia, and Castleman’s disease.)
What are causes of prolonged reptilase time?
Inherited dysfibrinogenaemia, DIC, paraproteinaemia
What does reptilase do?
Used when thrombin time prolonged - it replaces thrombin to try create a clot - abnormalities in this suggest fibrinogen/fibrin problem
