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Flashcards in Haematology Deck (33)
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1
Q

What are the Porphyrias?

A

Definition:
Porphyria = PURPLE
Group of disorders that result from defect in normal processing or porphyrins.
Porphyrins are synethesised in the manufacturing process to produce heme
Some of this occurs in liver, some in bonemarrow and kidney.
Defects of enzymatic processing at one of 8 steps gives rise to a specific porphyria
Defect is never great enough to cause anaemia
Defects cause build up of a specific porphyrin at the respective level of processing
Pophyria may never present as an acute episode.

More common in women - cyclical oestrogen variability and association of attacks with oestrous spikes

Types: Define based on attack of site of porphyrin defect

ACUTE PORPHYRIAS - 2 specific + 2 variable

  • Build-up of ALA and PBG
  • aminolevulinic acid and porphobilinogen
  • Damage the nerves - can mimic GBS in presentation

AIP = acute intermittent porphyria (high ALA/PBG)
ADP =ALA dehydrogenetase porphyria - rare

VP - variegate porphyria (strong assoc HCC)
CP - hereditary copoporphyria

CUTANEOUS - 1 specific - 3 with manifestations
ight-sensitive porphyrins build up (A, B and E respectively),
which cause the skin problems, but they do not
cause acute attacks.

(hepatic cutaenous - secondary to iron overload)
PCT - porphyria cutanea tarda - uroporphyrinogen decarboxylase COMMONEST

(erythropoeitic porphyria)
EPP - erythropoietic porphyria (BM and renal processing)
CEP - congenital erythropoietic porphyria

MIXED - ACUTE AND CHRONIC FEATURES

VP - variegate porphyria (varied - variegate :) )
HC - hereditary copopophyria

Pathogenesis
e.g. Deficiency of URO-PORPHYRINOGEN -
DECARBOXYLASE - cutanea tarda (skin)
7 types of porphyrias - 7 enzymes affected
Each has a defect in one of the processing steps for heme leading to a different porphyrin accumulating.

Inheritance:
autosomal dominant,
autosomal recessive,
X-linked traits,
exception of the most common porphyria, porphyria cutanea tarda (PCT), which usually is sporadic.
-inherited or triggered by alcohol / drugs / COCP

Presentation: - dependent on type
Severe abdominal pain
Neurological symptoms
Light sensitive dermatitis (epidermal deposition of porphyrins)
Urine left to stand is coloured due to reaction of porphyrin with light
–>purple / brown / orange

Diagnosis:
raised urinary porphobilinogen

2
Q

What are the acute porphyrias?

A
Acute porphyrias
Symptoms of acute porphyria can vary. 
-abdominal pain. 
-muscle weakness 
-numbness i
-agitation
-mania
-depression 
-hallucinations.
-hyponatraemia and HTN may increase seizure risk

Acute intermittent porphyria AIP
-COMMONEST

Aminolaevulinic acid dehydratase porphyria ADP (rare)
-plumboporphyria

3
Q

What are the cutaenous porphyrias?

A
Cutaneous porphyrias
This type of porphyria mainly affects the skin. 
-hyperpigmentation
-hypopigmentation
-blistering
-skin fragility
-scarring
-hypertrichosis over cheeks

Porphyria cutanea tarda. PCT

  • Uro-porphyrinogen decarboxylase mutation
  • SKIN BLISTERING

Erythropoietic protoporphyria. EPP

  • NO BLISTERING
  • porphyrins also deposited in TEETH / NAIL BED = teeth flouresce

Congenital erythropoietic porphyria CEP
-Günther’s disease

PCT is the most common, as it is the only
porphyria which can be caused by something
other than a “porphyria” gene. It can be triggered
later in life, by heavy drinking, iron supplements
or certain drugs including COCP and by liver infections.

EPP causes pain in the skin on sun exposure,
and there is no blistering and often no redness
with it, so it can be puzzling for doctors.

CEP is very rare. It can cause severe scarring.

4
Q

What are the mixed porphyrias?

A

Mixed porphyrias
This type of porphyria can lead to symptoms of both acute porphyria and cutaneous porphyria. They can therefore cause abdominal pain, affect the skin and the nervous system and may also cause psychiatric problems. The mixed porphyrias include:

Variegate porphyria - hepatic porphyria
NEUROVASCULAR COMPLICATOINS
36-61% increased risk of HCC
Hereditary coproporphyria.

5
Q

How is porphyria managed?

A
IX:
IRON STORES
URINE PORPHYRINS 
URINE - flouresces under WOODS LIGHT
LIVER SCREEN - other causes deranged LFTs
\+ AFP to exclude HCC
Skin biopsy - will scar badly

Acute:
Removal of trigger
-COCP
-Alcohol
-carbemazepine / clonazepam / metoclopramide
- IV HAEM ARGINATE replaces haem and reduces prophyrin production

Chronic:
sun avoidance
Therapeutic phlebotomy 
- iron inhibits uroporphyrobilinogen decarboxylase (UROD) therefore bloodletting encourages RBC prodction and use of hepatic iron stores raising UROD activity
CHRLOROQUINE
6
Q

What is the pathogenic mechanism in AIP

A

The acute attacks result from the hepatic production of a neurotoxic substance, presumably ALA (a γ-aminobutyric acid analog) and/or PBG that may interact with γ-aminobutyric acid or glutamate receptors.

7
Q

What is Haem Arginate and when can it be used

A

Definition
Haem coupled with arginine

When:
Any acute attack of porphyria not improving after 24 hours

Any attack complicated by severe symptoms, hyponatraemia, convulsions, indicators of incipient neuropathy (including loss of reflexes or complaints of pain in the muscles of the back, thighs and upper arms).

MOA:
Effect of haem arginate to reduce porphyrin synthesis

Replenishing haem stores within the body.
By negative feedback, this inhibits the initial rate-limiting enzyme of the haem synthetic pathway, ALA synthase,
The formation of porphyrins and the precursors ALA and PBG is almost immediately reduced to low levels, and the symptoms improve.
Haem arginate is safe.

8
Q

What is the pathophysiology behind Sideroblastic anaemia

A

Failure to incorporate iron into heme.

Congenital or secondary to myelodysplasia

9
Q

When do SMUDGE cells arise

A

CLL

  • remnant of WCC
  • no csm or nucleus hence a smudge
  • CLL = old lymphocytyes

Smudge cells arise in any condition where the white ells are old or fragile or renewal is delayed

10
Q

What are the features of leuco-erythroblastic anaemia

A

Immature WCC and RBC
Typically see RBC with nuclei
Lots of myelocytes Vs mature WC
Raised RDW

associations:

  • myelofibrosis - fibrosis of BM - no maturation of T and B before ascension to secondary lymphoid tissues
  • malignant marrow infiltration
  • CML
  • POLYCYTHAEMIA RUBRA VERA
11
Q

What is polycythaemia rubra vera?

A

Primary polycythaemia i.e. myeloid line cancer
Primary therefore not EPO dependent - EPO suppressed
Drive is primarily from BM

Neoplastic proliferation and maturation of erythroid, megakaryocytic and granulocytic elements
= panmyelosis.

In contrast to secondary polycythemias, PCV is associated with a low serum level of the hormone erythropoietin (EPO).

Instead, PCV cells often carry activating mutation in the tyrosine kinase (JAK2) gene, which acts in signaling pathways of the EPO-receptor, making those cells proliferate independent from EPO

Diagnosis:
JAK-2 mutation
low serum EPO
BM biopsy

polycythaemia
high RDW
High platelets

Signs:
Erythromyelgia
Due to polycthaemia and thrombocythaemia get intermittent microvascular occulsions
repeated iscahemiac-reperfusion injury
Characteristic purpura
characteristic hyperaemic swollen and deformed arms and fingers

12
Q

What malignancy is associated with Auer rods

A

AML

13
Q

What information is prognostically useful in AML

A

Myeloblast malginancy
Prognostic depends heavily on cytogenetics

AML is curable in about 35% of people under 60 years old and 10% over 60 years old.
Older people who are not healthy enough to receive intensive chemotherapy have a typical survival of 5–10 months

  1. Deletion of chr 5q or 7 poorer
  2. t(8:21) better prognosis - 5-12%
  3. older age of onset poor
  4. previous leukaemia poor
14
Q

What is the philadelphia chromosomal translocation

A
Typically CML
t(9:22)
Produces fusion protein BCR-ABL
B cell receptor-ABL
Tyr Kinase - uncontrolled division of myeloblast or myeloid precursor.

also found in CLL
AML rarely
ALL 25–30% of adult cases

15
Q

How is CML treated?

A

Chr 9:22 = tyr kinase const activation

Tyr Kinase inihibitors -
imatinib = 76% remission rate - not curative

Cure = transplant

Leukophoresis if symptomatic hyperviscosity

16
Q

What is seen on blood film in CLL

A

mature small volume quiescent lymphoctyes

WCC> 30 typically

17
Q

How is CLL treated

A

Very slow progressive
Fludarabine based regimens - purine analogue
Alemtuzumab - anti CD52 if fails
chlorambucil / ofatumumab (same as ritux)

18
Q

What is seen on blood film in ALL

A

Typically Hb<5

High blast count seen on blood film
very few mature cells

19
Q

What is typical of AML on blood film?

A

auer rods

azurophilic granular material that form elongated needles seen in the cytoplasm of myeloid leukemic blasts.

20
Q

What are the stages of multiple myeloma

A

MM = spectrum of monoclonal gamopathies
IgG
IgA
IgM

MM is always preceeded by
MGUS - blast <10% and no protein or CRAB

-Monoclonal Gammopathy of Unknown Significance
Can be quiescent for 20+ years -
chance of progression to MM is 25% at 20 years
1% cumulative risk per year

SMM follows - blasts >10 % +/- >3g protein - no CRAB

  • Smouldering Multiple Myeloma
    Chance of progression to MM is 73% at 15 years
    5% cumulative risk of progression for 5 years
    3% each year up to 10 years
    1% after 10 years

MM - blasts / protein / CRAB
- symptomatic multiple myeloma characterised by CRAB end organ damage
HYPERCALCAEMIA - moans / bones/ stones/ thrones
RENAL INSUFFICIENCY
ANAEMIA (RENAL AND BM)
BONE LYTIC LESIONS

21
Q

How are the stages of MM classified

A

Stages blasts circulating protein CRAB
MGUS <10% <3g/dl no
SMM >10% 3g/dl no
MM >10 >3g/dl yes

CRAB = hypercalcaemia - renal insuff - anaemia - bone lytic lesions

22
Q

What the risk factors for quicker progression from MGUS to SMM and MM

A
IgA subtype
Reduction in polyclonal globulins
bence jones proteinurea
any lesion on MRI
circulating plasma cells
23
Q

When should MM be treated?

A

Current guidance suggests treatment only when CRAB arises i.e. progression into End Organ Damage.

FIRST LINE
High Dose Chemo and Transplant (TDV)
-Thalidomide / dex/ bortezumib (TDV) + Autologous SC trans

Low dose chemo (>75) (MPV) NO TRANSPLANT
-Mephalan / pred / thalidomide OR bortezumib (>75)
MP superior in survival and progression free survival in over 75 group to TD
MPV = 75% RESPONSE RATE
treatment free interval 18 months
3 year survival 68 % Vs 54% MP alone

SE bortezomib - peripheral neuropathy

New = LM
lenalidomide and dex
May improve progression free survival

TARGETS:
4 CYCLES BORTZUMIB - REDUCE PROTEIN BY 50%

RELAPSE
BORTEZUMIB IF previously achieved 50% response reduction
Repeat autologous stem cell transplant provided response from first >24 months

24
Q

How is MGUS or MM diagnosed

A

Serum protein electrophoresis + serum‑free light‑chain
- confirm paraprotein

Urinary Bence Jones - active or risk of progression to MM

Bone Marrow biopsy
- microscopy and Flow Cytometry
(estimate blast % (micro) and morphology (flow))

Perform fluorescence in‑situ hybridisation (FISH) on CD138‑selected bone marrow plasma cells
- Risk abnormalities t(4;14), t(14;16), 1q gain, del(1p) and del(17p)(TP53 deletion).
Use these abnormalities alongside International Staging System (ISS) scores to identify people with high‑risk myeloma.
IgA / low polyclonal count / bence jones /

Consider performing immunophenotyping of bone marrow to identify plasma cell phenotype, and to inform subsequent monitoring.

Consider performing immunohistochemistry (including Ki‑67 staining and p53 expression) on the trephine biopsy to identify plasma cell phenotype and give an indication of cell proliferation, to provide further prognostic information.

Imaging:
Whole body CT / MRI

PET CT

25
Q

What are the complications of myeloma

A

renal disease

  • epo - ensure ferritin >200
  • calcitonin for tertiary hyperparathyrodism
  • phosphate binders

bone disease

  • bisphosphonates - zoledronic acid or pamidronate
  • calcium and vit D

vertebral fractures

  • spinal stabilisation
  • radiotherapy

neuropathy on bortezumib

  • reduce dose
  • increase time between doses
  • neuroapathic pain medication

prophylatic LMWH

26
Q

What is the likely cause behind a rapid drop in Hb in a patient with CLL?

A

Auto immune haemolytic anaemia
COMMENCE PRED 1MG/KG
RITUXIMAB 2nd line
failure to respond = splenectomy.

Rapid course implies a much worse prognosis

think outside the box - cold agglutination disease

27
Q

How is AML / ALL / lymphoma treated

A

FLAG regimen
fludarabine - anti-purine
cytarabine - anti metabolite
GCSF - maturation of lymphoblasts = correct neutropenia

28
Q

What is typical treatment for B cell lymphoma?

A
R-CHOP
Rituximab
cyclophosphamde
hydroxydanorubicin
vincristine
Prednisolone
29
Q

What side effects are associated with flourouracil?

A

renal tubular acidosis
Cardiomyopathy and cardiac failure
same as doxorubicin

30
Q

What side effects are associated with trastuzumab (tamoxifen)?

A

HER2 inhibitor
Biventricular cardiac failure
Pulmonary fibrosis

31
Q

What side effect is associated with cyclophosphamide?

A

hemorrhagic cystitis

bladder TCC

32
Q

What are the typical patterns of HIT presentation?

A
1 - 4-10 days post heparin
switch to non heparin based regimen and monitor
IVIg may be needed
- rivaroxaban
- bivalirudin
33
Q

What is bivalrudin

A

A direct thombin inhibitor = II

useful in management of HIT in DVT / PE