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8 Haematology
Fig 8.
https://t.me/med1917
3
Acanthocytosis.
Fig 8.
5
Burr cells: the cause may be kidney or
liver failure, or an
Fig 8.
(short arrow), acanthocyte (long arrow), and a
Howell– Jolly body (arrow head).
From the New England Journal of Medicine, Bain,
B, ‘Diagnosis from the blood smear’,
Copyright ©
Reprinted with permission from Massachusetts
EDTA
7
Film in hyposplenism: target cell
2005
Massachusetts Medical Society.
© Dr N Medeiros.
storage artefact.
© Prof. Christine Lawrence.
353(5
),
498
Medical Society.
Fig 8.
4
Basophilic stippling.
From the New England Journal of Medicine,
Bain, B, ‘Diagnosis from the blood smear’,
353(5
),
498
Medical Society. Reprinted with permission from
Fig 8.
.
Fig 8.
phils in the blood. See
. Copyright ©
6
A Cabot ring.
8
Left shift: presence of immature neutro-
2005
Massachusetts
Massachusetts Medical Society.
2
© Crookston Collection.
p
324
.
© Prof. Krzysztof Lewandowski.
321
Fig 8.
9
Pappenheimer bodies.
Top image © Prof. Christine Lawrence, bottom
image © Crookston Collection.
Fig 8.
10
Reticulocytes.
staining (azure
Fig 8.
11
Rouleaux formation.
RNA
B
; cresyl blue) is needed.
© Dr N Medeiros.
in
© Dr N Medeiros.
RBC
S; supravital
8 Haematology
The dierential white cell count
HES
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322
Neutrophils (figs
values are more meaningful than percentages).
Increased in (ie neutrophilia)
• Bacterial infections.
• Inflammation, eg myocardial infarction, polyarteritis nodosa.
• Myeloproliferative disorders.
• Drugs (steroids).
• Disseminated malignancy.
• Stress, eg trauma, surgery, burns, haemorrhage, seizure.
Decreased in (ie neutropenia— see p
• Viral infections.
• Drugs: post- chemotherapy, cytotoxic agents, carbimazole, sulfonamides.
• Severe sepsis.
• Neutrophil antibodies (
• Hypersplenism (p
• Bone marrow failure— production (p
8.12, 8.13) 2– 7.5
369
Other neutrophil responses to infection These include: • Vacuoles in the cytoplasm
(the most specific sign of bacterial infection).
areas of cytoplasm (residual ribosomes). Up to
a drumstick- shaped Barr body (arrow,
Lymphocytes (fig
8.14) 1.5– 4.5
Increased in (ie lymphocytosis)
• Acute viral infections.
• Chronic infections, eg TB, brucellosis, hepatitis, syphilis.
• Leukaemias and lymphomas, especially chronic lymphocytic leukaemia (
Large numbers of abnormal (‘atypical’) lymphocytes are characteristically seen
EBV
infection: these are T cells reacting against
with
a large amount of clearish cytoplasm with a blue rim that flows around neigh-
RBC
bouring
Decreased in (ie lymphopenia)
• Steroid therapy;
T- lymphocyte subset reference values:
tion).
Eosinophils (fig
S. Other causes of ‘atypical’ lymphocytes: see p
SLE
tion; post chemotherapy or radiotherapy.
CD8
count:
235– 753
8.15) 0.04– 0.4
Increased in (ie eosinophilia)
• Drug reactions, eg with erythema multiforme, p
• Allergies: asthma, atopy.
• Parasitic infections (especially invasive helminths).
• Skin disease: especially pemphigus, eczema, psoriasis, dermatitis herpetiformis.
Also seen in malignancy (eg lymphomas),
Löer syndrome (
Strauss) (
The hypereosinophilic syndrome (
tained for >
p
p
686
), and during the convalescent phase of any infection.
6
weeks leading to end- organ damage (endomyocardial fibrosis and restrictive cardiomyopathy, skin lesions, thromboembolic disease, lung disease, neuropathy,
and hepatosplenomegaly). The cause is often unknown, though if
diagnose myeloproliferative
(anti- interleukin-
Monocytes (fig
5
monoclonal antibody). Imatinib is 1st choice for myeloproliferative
8.16) 0.2– 0.8
aftermath of chemo- or radiotherapy, chronic infections (eg malaria,
protozoa), malignant disease (including
and Hodgkin’s disease), myelodysplasia.
Basophils (fig
8.17) 0– 0.1
ferative disease, viral infections,
caria, hypothyroidism), and inflammatory disorders (eg
×
109/ L (40– 75% of white blood cells: but absolute
350–1
)
SLE,
haemolytic anaemia)— destruction.
), eg Felty’s syndrome (p
348
688
).
).
• Döhle bodies: inconspicuous grey- blue
17
% of neutrophils from females show
fig
8.13d
×
109/ L (20– 45%).
; uraemia; Legionnaire’s disease;
/ mm3;
CD4/ CD8
×
109/ L (1– 6%).
692
), eosinophilic granulomatosis with polyangiitis (Churg–
HES
or eosinophilic leukaemia. : PO steroids ± mepolizumab
×
109/ L (2– 10%). Increased in (ie monocytosis) the
×
109/ L (0– 1%). Increased in (ie basophilia) myeloproli-
IgE
). It is the inactivated X chromosome.
CLL
EBV
- infected B cells. They have
401
.
HIV
infection; marrow infiltra-
CD4
count:
537– 1571
/ mm3 (low in
HIV
ratio: 1.2– 3.8.
560
.
PAN
, adrenal insuciency, irradiation,
) occurs when eosinophilia >1.5 ×
M4
and M5 acute myeloid leukaemia (p
FIP1L1- PDFRA
TB
109/ L is sus-
genotype,
, brucellosis,
- mediated hypersensitivity reactions (eg urti-
UC
, rheumatoid arthritis).
).
infec-
HES.
354
),
8 Haematology
Fig 8.
(a) (b)
https://t.me/med1917
12
Neutrophil. These ingest and kill bac-
teria, fungi, and damaged cells.
Courtesy of Prof. Krzysztof Lewandowski.
Fig 8.
14
Lymphocyte: divided into T & B types,
which have important roles in cell- mediated immunity and antibody production.
Courtesy of Prof. Krzysztof Lewandowski.
(c) (d)
Fig 8.
13
Neutrophils: (a) ‘toxic granulation’
seen in infection or pregnancy; (b) normal appearances; (c) ‘left shift’: immature forms are
released with few lobes to their nuclei, seen in
infection; (d) Barr body (arrow, see text).
Courtesy of Prof. Tangün and Dr Köroğlu.
Fig 8.
15
Eosinophil: these mediate allergic re-
actions and defend against parasites.
Courtesy of Prof. Krzysztof Lewandowski.
323
Fig 8.
16
Monocyte: precursors of tissue
macrophages.
Courtesy of Prof. Krzysztof Lewandowski.
Fig 8.
17
Basophil. The cytoplasm is filled
with dark- staining granules, containing histamine, myeloperoxidase, and other enzymes.
IgE
On binding
basophil.
, histamine is released from the
Courtesy of Prof. Krzysztof Lewandowski.
8 Haematology
Anaemia
MCV
MCV
MCV
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324
Anaemia is defined as a low haemoglobin (Hb) concentration, and may be due
either to a low red cell mass or increased plasma volume (dilutional as in pregnancy). A low Hb is <
may reflect reduced production or increased loss of
These will often be distinguishable by history, examination, and inspection of the
blood film (
fig
8.2
, p
319
Symptoms Of ten a combination of underlyi ng cause and anaemia per se: fatigue,
dyspnoea, light- headness, palpitation, headache, tinnitus, anorexia— and angina
if there is pre- existing coronary artery disease. Are there symptoms suggestive
of malignancy (eg weight loss, fever/ night sweats) or chronic conditions (eg
CKD
)?
Signs May be absent even in severe anaemia. There may be pallor (eg of the
conjunctivae, see
80
g/ L), there may be signs of a hyperdynamic circulation, eg tachycardia, flow
<
fig
murmurs (ejection- systolic loudest over apex), and cardiac enlargement; or retinal
haemorrhages (rarely). Later, heart failure may occur: here, rapid blood transfusion
can be fatal.
Types of anaemia The first step in diagnosis is to look at the mean cell volume
MCV).
Normal
MCV
(
Low
1
Iron- deficiency anaemia (
2
Thalassaemia (suspect if the
count is raised, though definitive diagnosis needs
3
Sideroblastic anaemias (very rare, heterogeneous group): p
NB:
there is iron accumulation in the last two conditions, and so tests will show in-
is 76– 96 femtolitres (×
(microcytic anaemia) check iron studies (Fe,
creased serum iron and ferritin with a low total iron- binding capacity (
Normal
1 Acute blood loss.
2
3
4
NB:
High
1
2
3
4
(normocytic anaemia) Further tests (eg smear, retics,
Anaemia of chronic disease (or
Bone marrow failure. 7 Pregnancy.
Chronic kidney disease.
if
WCC
or platelets in normocytic anaemia, suspect marrow failure: see p
(macrocytic anaemia) Further tests (eg
B
or folate deficiency.
12
Alcohol excess— or liver disease. 6 Marrow infiltration.
Reticulocytosis (p
Cytotoxics, eg hydroxycarbamide. 8 Ant ifolat e drugs (eg phenyt oin).
320
Haemolytic anaemias These do not fit into the above- mentioned classification as
the anaemia may be normocytic or, if there are many young (hence larger)
and reticulocytes, macrocytic (
RBC
S; or reticulocyte count >
of
bilirubin,
LDH
, urobilinogen, or positive direct antiglobulin test (
tients will often be mildly jaundiced.
Does the patient need a blood transfusion? Probably not if Hb >70g/ L. Chronic
anaemia in particular can be well tolerated (though it is crucial to ascertain the
cause), and in
In acute anaemia (eg haemorrhage with active peptic ulcer), transfusion for those
with Hb <
and whether the patient is symptomatic. A higher transfusion threshold of <
IDA,
iro n su pple men ts wi ll ra ise the H b mo re sa fely and cost - eectively.
70
g/ L may be indicated. Other factors to consider include comorbidities
appropriate in a patient with pre- existing
In severe anaemia with heart failure, transfusion is vital to restore Hb to a safe
80
level, eg
furosemide
etics; do not mix with blood). Check for signs of worsening overload: rising
basal crackles: in this eventuality, stop and treat.
g/ L, but this must be done with great care. Give it slowly with 40mg
IV/ PO
with alternate units (dose depends on previous exposure to diur-
135
g/ L for men and <
120
g/ L for women. Low red cell mass
RBC
S and has many causes.
).
8.18
, although this is not a reliable sign). In severe anaemia (Hb
−
15
10
L) (fig
8.19
).
TIBC,
IDA
), the most common cause: see p
MCV
is ‘too low’ for the Hb level and the red cell
MCV
). 6 Haemolysis (or
, eg with haemolysis).
p
328
). Suspect if there is a reticulocytosis (>2%
100
×
109/ L), mild macrocytosis, haptoglobin,
IHD.
5
Hypothyroidism (or
5
7
ferritin)
326
.
DNA
analysis): see p
B
, folate,
LFT
12
Myelodysplastic syndromes.
326
LDH,
MCV
S).
.
TIBC
creatinine).
MCV
).
338
Hypothyroidism.
DAT
). These pa-
).
).
80
JVP
.
348
RBC
g/ L is
and
RA
,
.
S
8 Haematology
Fig 8.
Reticulocyte Index and
Blood loss
MCV
V
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18
‘Conjunctival pallor’, the classic sign of anaemia, is a confusing term as the
conjunctiva is translucent, transmitting the colour of structures under it. The ‘pallor’
refers to the vasculature on the inner surface of the lid which is lacking Hb. It is this
colour
but it should be:
325
Red cell distribution width (
In health or in unifactorial anaemia, all the red cells in a sample are about the
same size, and the graph of their volume distribution forms a narrow peak. In
mixed anaemias, however, this peak broadens, reflecting an abnormally large
RDW
— this may be the first clue to dual pathology. In coeliac disease, for example,
poor absorption of iron (
sulting in a combination of microcytes and macrocytes in the circulation. The
visual analogue of this is anisocytosis (
measure is an
mean
RDW
the
RDW
MCV
, where
, multiplied by
is normal, the cause is likely to be alcohol, liver disease, or a marrow
problem (chemotherapy or aplastic anaemia).
Low retic index
High retic index
Fig 8.
19
Evaluation of anaemia: consider both a combined morphological (
ticulocyte index/ count) approach. Anaemia can be due to one or more of these mechanisms: red
cell production (low retic count), red cell destruction (high retic count), or red cell loss (high retic
count).
RCDW
or
RDW
)
MCV
) and folate (
RDW
= the standard deviation of
100
. Reference interval: 11.5– .6
MCV
p
320
) on a blood film. The laboratory
Iron deficiency
Anaemia of inflammation
Sideroblastic anaemia
Thalassaemias
Renal failure
Anaemia of inflammation
Hypothyroidism
B
/folate deficiency
12
MDS
Alcohol/liver disease
Haemolytic anaemia
) may occur simultaneously, re-
MCV
divided by the
%. If the
MCV
is high and
Low MCV
Normal MC
High MCV
MCV
) and kinetic (re-
8 Haematology
Iron- deficiency anaemia (
IDA
ACD
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326
This is common— according to the
are anaemic, the majority of these are
Causes •Blood loss (assume to be the cause until proven otherwise, eg menor-
GI
rhagia or
• Poor diet or poverty may cause
• Malabsorption (eg coeliac disease) is a cause of refractory
• In the tropics, hookworm (GI blood loss) is the most common cause.
Signs Chronic
gular cheilosis (
Tests Blood film: microcytic, hypochromic anaemia with anisocytosis and poikilo-
cytosis (
iron with
bleeding (upper p
IDA (
signs now rare): koilonychia (fig
fig
8.21
figs
8.22, 8.23
TIBC,
but these are less reliable, see table
phase protein, with inflammation, eg infection, malignancy, and therefore may be
‘falsely normal’ in iron- deficient patients with comorbidities. Transferrin saturation
TSAT
) is the ratio of serum iron to
(
coeliac serology in all (
females for gastroscopy and colonoscopy. Consider stool microscopy for ova if
relevant travel history. Faecal occult blood is not recommended as sensitivity is
IDA
with no obvious source of bleeding mandates careful GI workup.
poor.
Treatment Treat the cause. Oral iron, eg ferrous sulfate
abdominal discomfort, diarrhoea or constipation, black stools. Hb should rise by
1
g/ L/ week, with a modest reticulocytosis (young
3
months after Hb normalizes to replenish stores. Oral iron should be eective for
most patients but consider
IBD
), if rapid correction/ resolution of symptoms required, or where oral iron is likely
to be ineective (eg functional iron deficiency in
tory states).
Check compliance if
GI
disturbance? Modifying the dose of elemental iron with a dierent preparation
or alternate- day dosing may help. Alternatively, there may be continued blood loss,
malabsorption, anaemia of chronic disease, or misdiagnosis.
Anaemia of chronic disease (
The commonest anaemia in hospital patients (and the 2nd commonest, after
worldwide). It arises from three problems (in which the polypeptide, hepcidin,
plays a key role):
RBC
survival. 3 Production of and response to erythropoietin.
of
Causes Many, eg chronic infection, vasculitis, rheumatoid, malignancy,
1
Poor use of iron in erythropoiesis. 2 Cytokine- induced shortening
Tests Ferritin normal or in mild normocytic or microcytic anaemia (see table
ESR/ CRP.
Often
Tre at men t Treating the underlying disease may help, as may an erythropoietin-
stimulating agent (
thromboembolism). It may improve quality of life in non- haematological malignancies (or low- risk
(seek expert advice).
Check blood film,
ESA— SE
MDS)
Sideroblastic anaemia
Refers to a heterogeneous group of rare anaemias characterized by ineective
erythropoiesis, leading to iron absorption, iron loading in marrow ± haemosiderosis
(endocrine, liver, and heart damage due to iron deposition).
Causes Congenital (rare, X- linked) or acquired, eg idiopathic as one of the
myelodysplastic/ myeloproliferative diseases, can also follow chemotherapy, antidrugs, irradiation, alcohol or lead excess.
Te st s Look for ferritin, a hypochromic blood film, and disease- defining sideroblasts
in the marrow (
Tre at me nt Remove the cause. Pyridoxine ± repeated transfusions for severe anaemia.
figs
8.24, 8.25
)
WHO
, one- third of all women of reproductive age
2
IDA
.
252
; lower p
621
IDA
)).
in babies or children (but rarely in adults).
IDA
.
8.20
and p75), atrophic glossitis, an-
), and, rarely, post- cricoid webs (Plummer– Vinson syndrome).
).
MCV
,
MCH
, and
MCHC.
Confirmed by ferritin (also serum
8.1
).
NB:
ferritin is an acute
TIBC. TSAT
p
262
): if negative then refer all males and post- menopausal
IV
iron if likely to be poorly tolerated (eg older patients,
IDA
fails to respond to therapy. Is the reason for the problem
B
<20% indicates iron deficiency. Check
200
mg/ 8h PO. SE: nausea,
RBC
, p
320
). Continue for at least
CKD
, malabsorption or inflamma-
)
, folate,
TSH
12
, and tests for haemolysis (p
CKD
.
332
: ‘flu- like symptoms, hypertension, mild platelets and
where there is symptomatic anaemia due to chemotherapy
IV
iron can safely overcome the functional iron deficiency.
; table
8.1
).
).
IDA,
8.1
).
TB
8 Haematology
Table 8.
https://t.me/med1917
1
Interpreting plasma iron studies
Iron deficiency
Anaemia of chronic disease
3
Iron
TIBC
Chronic haemolysis
Haemochromatosis (or )
Pregnancy
Sideroblastic anaemia
Fig 8.
20
Koilonychia: spoon- shaped nails.
Fig 8.
22
Microcytic hypochromic cells.
Courtesy of Prof. Krzysztof Lewandowski.
Fig 8.
21
Angular cheilosis (also known as stomatitis): ulceration at the side of the mouth.
Also a feature of vitamin
deficiency, and glucagonoma (
Fig 8.
23
Poikilocytosis and anisocytosis.
Courtesy of Prof. Christine Lawrence.
B
and
12
Courtesy of Dr Joseph Thompson:
AskAnOrthodontist.com.
Ferritin
B
2
p
217
(riboflavin)
).
327
Fig 8.
24
Ring sideroblasts in the marrow, with
a perinuclear ring of iron granules, found in
sideroblastic anaemia.
3
There is also an acute variant of ACD known as ‘acute event- related anaemia’ which may occur after major
surgery, trauma, or in the setting of severe sepsis (a condition known as ‘anaemia of critical illness’). It shares
many features of ACD including low serum iron, high ferritin, and blunted response to EPO. Several mechanisms may be involved including inflammation inducing a functional iron deficiency, shorted red cell survival
and chronic blood loss from ongoing procedures, repeated phlebotomy etc. Dx of exclusion.
Courtesy of Prof. Christine Lawrence.
Fig 8.
25
Two ringed sideroblasts showing
how the distribution of perinuclear mitochondrial ferritin can vary. The problem in congenital sideroblastic anaemia is disordered
mitochondrial haem synthesis.
Courtesy of Prof. Tangün and Dr Köroğlu.
8 Haematology
Macrocytic anaemia
BNF
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328
Macrocytosis (increased
accompanied by anaemia (eg in alcohol excess). Due to abnormal
the bone marrow, altered
cytes are immature
RBC
Causes of macrocytosis (
The three most common are alcohol,
• Megaloblastic (fig
delayed compared with the cytoplasm (note only seen on bone marrow biopsy,
not in the peripheral smear). This occurs with
both are required for
the most rapidly dividing cells in the body and hence sensitive to abnormal
synthesis.) Certain medications may also cause this including cytotoxic drugs,
hydroxycarbamide, antiretroviral or anti- epileptic drugs.
• Non- megaloblastic Alcohol excess, reticulocytosis (eg in haemolysis, bone
marrow, or following
• Other haematological disease Myelodysplasia (fig
Tests Ask about alcohol, diet, and medications. Severe macrocytosis
usually associated with megaloblastic anaemias.
similar blood film and bone marrow biopsy appearances.
borderline/ normal and high suspicion for deficiency, test methylmalonic acid (
and homocysteine levels (intermediates in
elevated, this indicates
this suggests folate deficiency.
Blood film Hypersegmented neutrophils (fig
Target cells if liver disease; see
Other tests Reticulocyte count,
(or red cell folate— a more reliable indicator of folate status, as serum folate only
reflects recent intake; not routinely used as costly). Test copper if recent gastric
bypass or history of excessive zinc intake.
Bone marrow biopsy is indicated if the cause is not revealed by the above tests, in
the setting of other cytopenias, or the presence of immature white cells on peripheral smear. It is likely to show one of the following four states:
1
Megaloblastic marrow.
2
Normoblastic marrow (eg in liver disease, alcohol abuse, hypothyroidism).
3
Abnormal erythropoiesis (eg sideroblastic anaemia, p
4
Increased erythropoiesis (eg haemolysis).
Folate Found in green vegetables, nuts, yeast, and liver; it is synthesized by gut
bacteria. Body stores can last for
neural tube defects. It is absorbed by duodenum/ proximal jejunum.
Causes of deficiency
• Poor/ restricted diet, eg poverty, alcoholics, elderly.
• Increased demand, eg pregnancy or cell turnover (seen in haemolysis, malig-
nancy, inflammatory disease, and dialysis).
• Malabsorption, eg coeliac disease, tropical sprue.
• Alcohol.
• Drugs: anti- epileptics (phenytoin, valproate), methotrexate, trimethoprim.
Treatment Assess for an underlying cause, eg poor diet, malabsorption. Treat
5
with folic acid
mg/ day PO for 4 months, never without
known to have a normal
subacute combined degeneration of the cord (
doses of folate (
12
wks; this helps prevent spina bifida, as well as anaemia.
NB
: in unwell patients (eg
treat before serum
400
mcg/ day) are given from ≥1 month preconception until at least
B
doses of hydroxocobalamin, eg
RBC
size;
MCV
>96fL) is common, and may not always be
RBC
membrane composition, or reticulocytosis (reticulo-
s larger than mature
MCV
>96fL)
8.26
) A megaloblast is a cell in which nuclear maturation is
DNA
synthesis. (Haematopoietic precursor cells are among
EPO
treatment).
RBC
).
B
/ folate deficiency, and reticulocytosis.
12
B
(p
12
8.27
B
and folate deficiency result in
12
B
and folate metabolism). If both are
B
deficiency. If homocysteine is elevated and
12
fig
LFT
4
B
level, as in low
12
CCF
) with megaloblastic anaemia, it may be necessary to
and folate results are known. Do tests then treat with large
12
1
mg/ 48h IM— see
12
8.28
and fig
) in
8.44
TFT
, p
, serum
8.7
, p
321
(include GT),
months. Maternal folate deficiency causes fetal
B
states it may precipitate, or worsen,
12
p
330
). In pregnancy, prophylactic
, with folic acid 5mg/ 24h PO.
RBC
production in
330
) and folate deficiency:
).
MCV
>
If the
B
or folate level is
12
MMA
B
and folate deficiency.
12
339
.
B
, and serum folate
12
326
).
B
unless the patient is
12
110
MMA
normal,
DNA
fL is
)
8 Haematology
Fig 8.
Cobalamin II
DNA (thymine) Synthesis for the TCA cycle
Cbl III
https://t.me/med1917
26
Megaloblastic anaemia: peripheral
blood film showing many macrocytes and one
hypersegmented neutrophil (normally there
≤
5
should be
segments).
From the New England Journal of Medicine,
Bain, B, ‘Diagnosis from the blood smear’,
498
. Copyright ©
2005
Society. Reprinted with permission from
Massachusetts Medical
Massachusetts Medical Society.
353(5
),
in tissues
adenosylCbl
methionine
homocysteine Methylmalonic acid
Fig 8.
methylCbl
12
B
28
Physiology of
THF
5
-Methyl THF
B
.
12
Marvellous Marmite®
In
1928
, a British haematologist called Lucy Wills travelled to India to investigate macrocytic anaemia in pregnancy, prevalent in female textile workers in
Bombay. Since the anaemia was most frequent in poorer populations with diets
deficient in protein, fruit, and vegetables, Wills extrapolated that a nutritional deficiency may be the root cause. She studied the eects of changes in diet on the
macrocytic anaemia of albino rats produced by a deficient diet and Bartonella
infection. The anaemia was prevented by yeast added to a B vitamin- deplete diet.
Yeast or yeast extract (Marmite®) was then found to correct the macrocytic anaemia in the pregnant Bombay patients. It was the folic acid contained in the
extract, a discovery initially dubbed the ‘Wills factor’, that corrected the anaemia
and thus changed the face of preventive prenatal care for women. Wills also
undertook a placebo trial of routine iron supplementation in pregnant women
in London during the World War
restrictions.
II
, unhampered by bombing interruptions and
Folinic acid
Folinic acid, also known as leucovorin, is a naturally occurring form of reduced
folate. It is typically used as a folic acid antagonist in the case of methotrexate
overdose or to potentiate cytotoxicity of fluorouracil (
mens for colon cancer. It is rapidly converted to the metabolically active form
of folate required in cells (tetrahydrofolate) without the need for dihydrofolate
reductase, which is inhibited by methotrexate.
Fig 8.
27
Oval macrocytes seen here in
myelodysplastic syndromes. Note aniso- and
poikilocytosis with small fragmented cells
(schistocytes).
cause oval macrocytes, but macrocytes caused
by alcohol and liver disease are usually round.
NB: B
and folate deficiencies also
12
Courtesy of Prof. Tangün and Dr Körogˇ lu.
Succinyl CoA
B
12
FU
) in chemotherapy regi-
329
8 Haematology
B
https://t.me/med1917
330
deficiency and pernicious anaemia
12
Vitamin
B
deficiency is common, occurring in up to 15% of older people.
12
synthesize thymidine, and hence
Untreated, it can lead to megaloblastic anaemia (
Body stores of
cations.
Causes of deficiency • Dietary (eg vegans:
products, but not in plants).
IF
) in the stomach binds
(
Malabsorption can therefore arise in the stomach due to lack of
aemia, post gastrectomy) or the terminal ileum (ileal resection, Crohn’s disease,
bacterial overgrowth, tropical sprue, tapeworms).
onists, metformin).
• Congenital metabolic errors.
Features General Symptoms of anaemia (p
skin due to combination of pallor (anaemia) and mild jaundice (due to haemolysis),
glossitis (beefy- red sore tongue;
Neuropsychiatric Irritability, depression, psychosis, dementia.
DNA
, so in deficiency
B
are sucient for 4yrs.
12
B
• Malabsorption: during digestion, intrinsic factor
B
, enabling it to be absorbed in the terminal ileum.
12
RBC
p
328
is found in meat, fish, and dairy
12
production is slow.
) and irreversible
IF
• Medications (eg
324
), other cytopenias, ‘lemon tinge’ to
fig
8.29
), angular cheilosis (p
326
).
Neurological Paraesthesiae, peripheral neuropathy. Also subacute combined degeneration of the spinal cord
with both upper and lower motor neuron signs due to
play the classical triad of:
sent ankle jerks (
There is a combination of posterior (dorsal) column loss, causing the sensory and
LMN
signs, and corticospinal tract loss, causing the motor and
LMN
, a combination of peripheral sensory neuropathy
B
. The patient may dis-
• extensor plantars (
UMN
12
) • absent knee jerks (
). The onset is insidious (subacute) and signs are symmetrical.
UMN
The spinothalamic tracts are preserved so pain and temperature sensation may
remain intact even in severe cases. Joint- position and vibration sense are often
aected first leading to ataxia, followed by stiness and weakness if untreated.
The neurological signs of
B
deficiency can occur without anaemia.
12
Pernicious anaemia (PA) This is an autoimmune condition caused by autoanti-
IF
bodies against
bound and consequently cannot be absorbed by the terminal ileum.
Incidence 1:
Associations Other autoimmune diseases (p
leading to atrophic gastritis. Dietary
≈
1000
; :
.6:1; usually >40yrs; higher incidence if blood group A.
1
550
B
therefore remains un-
12
): thyroid disease (~25%), vitiligo,
Addison’s disease, hypoparathyroidism. Carcinoma of stomach is ~
common in pernicious anaemia, so have a low threshold for upper
Te st s • Hb. •
may be as production impaired.
• Megaloblasts in the marrow. • Specific tests for PA: 1 Parietal cell antibodies:
found in
but lower sensitivity.
Tre at me nt Treat the cause if possible and treat urgently if symptomatic, neuro-
psychiatric symptoms or pregnant. If pernicious or other macrocytic anaemia, give
hydroxocobalamin
If neurological involvement, give
ther improvement, then
50
mcg daily for 4 weeks then recheck) if mild deficiency due to diet etc.
(
Practical hints • Beware of diagnosing PA if <40yrs old: look for GI malabsorption.
• Watch for hypokalaemia due to uptake into new haematopoietic cells.
• Transfusion is best avoided, but PA with high- output
after doing tests for
• As haematopoiesis accelerates on treatment, additional iron may be needed.
• Hb rises ~10g/ L per week;
Prognosis Supplementation usually improves peripheral neuropathy within the
3– 6
first
MCV
. •
WCC
and platelets if severe. • Serum
• Hypersegmented neutrophils (p
90
% with PA, but also in 3– 10% without. 2 IF antibodies: specific for PA,
1
mg IM 3 times a week for 2 weeks, then 1 mg every 2– 3 months.
FBC
1
mg IM once daily on alternate days until no fur-
1
mg every 2 months. Can treat orally with cyanocobalamin
, folate,
B
, and marrow sampling.
12
WCC
and platelet count should normalize in 1wk.
B
12
.
CCF
may require transfusion,
months, but has little eect on cord signs. Patients do best if treated as
soon as possible after the onset of symptoms: don’t delay!
B
helps
12
CNS
compli-
(pernicious an-
PPI
, H2 antag-
LMN
) • ab-
signs (p
442
3
- fold more
GI
endoscopy.
4
• Reticulocytes
328
).
).
4
Serum
B
levels are normal in many patients with subclinical
12
methylmalonic acid ( if
B
12
B
deficiency. Measuring homocysteine or
low) may be helpful, but these are non- standard tests (pp
12
328, 329
).
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