You are on page 1of 83

Anaemia

:definition •
Hb < 14 g/dl in adult ♂ or -
.♀ g/dl in adult 12 <
HCV < 42% in adult ♂ or -
.♀ in adult % 37 <
a limitation of this definition is that alternation of Hb •
→ & HCV may result from changes in plasma volume
plasma volume ( e.g. pregnancy )→ spurious ↑ -
.anaemia
. plasma volume → spuriously high Hb & HCV ↓ -
after major bleeding , anaemia may be not apparent •
.for several days until plasma volume returns to normal

C/P
anaemia may be asymptomatic ;particularly when •
slowly developing when haemodynamic compensation
→ & rise of erythrocyte 2,3 DPG occur. This 2,3 DPG
Shift O2 dissociation curve to Rt.→ O2 to be liberated
.readily to tissues
rapidly developing anaemia→ more symptoms (esp.in •
( old people
Symptoms
fatigue -
headache -
palpitation & dyspnea -
angina -
.intermittent claudication -
Signs
A- general : pallor, tachycardia,high pulse volume
.systolic flow murmur,HF,edema

1
.rarely;papilloedema& retinal He
( B- specific ( of different types of anaemia
. koilonychias ( spoon shaped nail ) → in iron ↓ anemia -
.jaundice → in haemolytic anaemia -
.bone deformities→ thalassaemia major -
.leg ulcers → in sickle cell disease -
:Classification
→ .According to appearance of red cells

Red cell MCV MCH diagnosis


appearance
microcytic-1 Low Low iron↓ •
(hypochromic) microcytic) hypochromic) anaemia
( ( -
thalassaemia
-
sideroblastic
anaemia
an.of •
.chronic dis
normocytic-2 normal normal acute blood-
(normochromic) .loss
haemolytic-
.anaemia
aplastic-
.anaemia
.An.of ch.dis
.macrocytic-3 high -------------- ↓B12/folate-
.liver dis-
alcoholism-
myxaedema-
reticulocytosis-
-
.myelodysplasia

:dimorphic anaemia •
When there are both small & large red cells→ denotes
mixed deficiency ( e.g. Fe & folate ) or following
.treatment with appropriate haematenic

2
:Investigations

blood count & film:→ red cell indeces -1


( MCV = HCV/ red cell count ( n= 80 – 96 fl •
(MCH = Hb / red cell count × 10 ( n=27-33 pg •
( %MCHC = Hb / HCV × 100 ( n= 32-35 g •

→ : automated counters •
numerical index of the distribution of red cell -
(volumes called the red cell distribution width(RDW
this is measured at 2 points on the red cell -
→ distribution curve
RDW-CV→ is the ratio of the width of the -1
distribution curve ( at one standard deviation ) divided
( % by MCV ( n= 12-14
RDW-SD→ is the width of the distribution curve (at-2
( 20% frequency level ) ( n= 37 – 47 fl

: BM : aspiration & biopsy → in order to -2


.determine BM cellularity -
the type of erythropoiesis → e.g. normoblastic " " -
. or megaloblastic
.determine the proportion of various cell lines -
.confirm the diagnosis -
.determine the size of Fe stores -
. look for BM infiltration -

3
Iron deficiency anaemia
( causes: ( ankylostoma is the commonest cause in ARE •
.poor intake : a contributing factor only -1
.absorption : in gastrectomy & celiac dis ↓-2
:NB: factors affecting Fe absorption
.haem-Fe is absorbed better than nonhaem-Fe -
.ferrous-Fe is absorbed better than ferric-Fe -
gastric acidity → helps to keep Fe in the ferrous state -
( & soluble in the upper gut .(↓acidity →↓ absorption
formation of insoluble complexes with phytate or -
.phosphate→↓ Fe absorption
.low Fe stores →↑ Fe absorption -
erythropoeitic activity ( e.g bleeding,haemolysis,high ↑ -
.altitude ) →↑ absorption
( Fe over load ( except hereditary haemochromatosis -
.Fe absorption ↓→

Fe absorption

Fe absorption ↑ Fe absorption↓
haem-Fe - nonhaem-Fe -
ferrous state - ferric state -
gastric acidity - no gastric acidity -
soluble complexes - insoluble coplexes -
low Fe stores - high Fe stores -
erythropoietic activity↑ - Fe over load(except -
.heridetary haemochromatosis

.demands : growth & child bearing ↑-3


blood loss : GIT, parasitic infestation& genitourinary -4
.disorders

4
C/P
the usual clinical manifestations of anaemia in -1
(↓ general + the following ( d.t. Fe
brittle & spoon shaped nails -
.atrophy of the papillae of the tongue -
.angular stomatitis -
.brittle hair -
syndrome of dysphagia & glossitis( Plummer- -
.( Vinson=Peterson-Brownkelly
in severe cases : parotid enlargement, splenomegaly& -
.failure to grow
.… History taking : should include -2
.dietary intake -
.aspirin ingetion -
.rectal bleeding -
( ♀ details of menses ( in -
Rectal exam & proctoscopy : in suspected cases -3
.should be done

Investigations
: blood count & film -1
red cells are microcytic ( MCV < 80fl ) & -
( hypochromic ( MCH < 27 pg
. anisocytosis : variation in size -
.poikilocytosis : variation in shape -
target cells & hyperpigmented polymorphs may -
.appear
↓..…: S. Fe -2
↑ → ( Total Fe binding capacity ( TIBC -
transferring saturation ( S.Fe / TIBC ) → < 19% -
→ ( S. ferretin ( = reflects the amount of stored Fe -3
(♀It's < normal values (n=30-300ug/l ♂ &15-200ug/l

5
BM : →↓ of Fe granules.( not needed for diagnosis -4
( except in complicated cases
.↓ investigations for the cause of Fe -5

Treatment
.treatment of the underlying cause -1
ferrous sulphate 200 mg tid PO -2
is the best preparation , provides 120 mg ferrous Fe/d -
if the Pt.develops S.Es ( e.g. nausea,diarrhea or -
constipation ) → the dose may be ↓ or another preparation
with less Fe content is given ( eg ferrous gluconate 200 mg
.( tid PO ; provides only 70 mg ferrous Fe /d
: parenteral Fe -3
.Fe dextran 50 – 250 mg/d by deep IM inj -
.for Pt totally intolerant to oral therapy -

→ NB: •• enough therapy should be given


& restore Hb -
.replase body's Fe stores -
→ therapy is monitored by ••
.follow-up of reticulocytic count -
( Hb level ( w' expected to ↑ 1g/w -

Sideroblastic anaemia

6
there is failure to form protoporphyrine ( w' normally •
( combines with Fe in the erythroblasts to form haem
so , Fe taken up by erythroblasts is deposited in the •
mitochondria ( around the nucleus ) to form ring
.siderblasts

:Causes
conginetal :X-linked ( transmitted by ♀s ) , it's one -1
.of myelodysplastic syndromes
→ acquired : may be -2
a- 1ry : idiopathic
: b- 2ry
. drugs : INH, phenacetin -
.alcohol -
.lead -
.myeloproliferative dis -
.leukaemia -
( carcinomas & CT diseases ( e.g SLE -

→:Blood film
Dimorphic picture ( with normal & microcytic cells d.t.
( defective Hb synthesis

:Treatment
.withdrawal of the causative agents -
.folic acid -
.pyridoxine ( B6 ) → may improve some cases -

.Anaemia of chronic dis

7
:Causes
chronic inflammatory diseases : rheumatoid arthritis, -1
.SLE, Crohn's dis
.hepatic dis -2
.CRF-3
.malignant disorders -4
:Pathogenesis

→ Inflammatory cytokines
release of Fe from BM to the developing ↓-
.erythroblasts
. inadequate erythropoietin response to the anaemia -
( red cell survival ( haemolysis ↓ -
Investigations
↓→ both S.Fe & TIBC •
.Fe stores → normal •
: Treatment
.Is that of the cause

:D.D of microcytic anaemia


8
Fe ↓ anaemia An. Of ch.dis Thalassaemia Sideroblastic
(Trait (α,β anaemia
MCV • reduced /Low normal Very low for in →↓ -
normal Degree of Inherited type
.Anaemia in →↑ -
.Acquired type
S. Fe • ↓ ↓ normal ↑

S.TIBC • ↑ ↓ normal normal

S.ferritin• ↓ ↑/Normal normal ↑


(stores )

Fe in BM• absent present present present

Fe in• absent /Absent present .Ring forms


-Erythrobl reduced
ast

Macrocytic anaemia

9
:Causes
.megaloblastic anaemia-1
→ normoblastic anaemia : in -2
.liver dis -
.alcohol -
.myxaedema -
.reticulocytosis -
.aplastic anaemia -
.pregnancy -

Megaloblastic anaemia
characterized by presense of erythroblasts ( in BM ) •
with delayed nuclear maturation d.t. defective DNA
( synthesis ( → big cells = megaloblasts
:Causes
↓ Vit.B12 -1
↓ folic acid -2
:other defects in DNA synthesis -3
.congenital : orotic aciduria -
acquired : hydroxyurea, azathioprine, zidovudine -
((=chemotherapy
.myelodysplasia -4

Vit.B12 ↓ anaemia
10
:Causes
.low dietary intake : strict vegetarians -1
,absorption : pernicious anaemia,gastrectomy ↓ -2
( .malabsorption syndromes (terminal ileal dis &
,miscellaneous : diphylobothrium latum,nitrous oxid -3
Congenital ↓ of intrinsic factor or transcobalamin ΙΙ
:Pathogenesis
.Vit.B12 is found in : meat,fish,egg&milk •
it takes up to 5y ( after absorption failure ) to develop •
.↓ Vit.B12
: absorption •

in the small gut; Vit.B12 binds e' the intrinsic factor -


in gastric juice ) → carry it to specific receptors on )
.the mucosa of the ileum
→ Vit.B12 is liberated there to bind e' their receptors -
→.Absorption of Vit.B12
then transported by ( transcobalamin ΙΙ ) to BM -
where it acts as Co-enzyme for transformation of
methyltetrahydrofolate to tetrahydrofolate ( that is
( essential for the formation of DNA
in the absence of Vit.B12 → DNA production is thus -
.impaired

(.Pernicious anaemia: ( P.A


an autoimmune disease characterized by atrophy of the •
gastric mucosa → failure of the intrinsic factor production
.failure of Vit.B12 absorption →
there's an association with other autoimmune diseases e.g. •
.thyroid dis.,Adisson's dis.&vitiligo

11
C/P of Vit.B12 ↓ anaemia
the disease is particularly common in fair haired & blue- •
.eyed people
:Symptoms
.that of anaemia in general -1
neurological changes : occur only with very low level of -2
→ S.Vit.B12
( peripheral neuropathy ( P.N -
progressive involvement of the posterior & lateral columns -
: of the spinal cord → the Pt. present with
.symmetrical parathesia of fingers & toes •
.early loss of vibration sense& proprioception •
.progressive weakness & ataxia •
.paraplegia may result •
.mental changes : → irritability, psychosis & dementia may occur •
: Signs
general signs of anaemia , skin occasionally has a lemon-yellow -1
.tint d.t. hyperbilirubinaemia
.low grade fever may occur -2
.glossitis & angular stomatitis -3
. hepatosplenomegaly -4
.purpura & bleeding tendency d.t. thrombocytopenia -5
neurological exam. → signs of peripheral neuropathy ( PN ) & -6
.( less often subacute combined degeneration of the cord ( SCD
: Investigations
CBC & film : anaemia with macrocytosis ( MCV < 96 fl ), -1
hypersegmented polymorphs.& in sever cases → neutropenia &
.thrombocytopenia
( S.Vit.B12 →↓ ( usually < 50 ng /L -2
( S.bilirubin → usually ↑ ( d.t. haemolysis -3
→ S.autoantibodies -4
% to parietal cells → in 90 -
% to intrinsic factor → in 50 -

12
: Schilling test : consists of 2 parts -5
→ Part Ι : 2 forms of Vit.B12 are given
& radioactive : CO-58B12, 1 ug PO -
nonradioactive : Vit.B12 1000 ug IM ( to saturate B12 binding -
→.… ( protein
.urine is collected for 24h -
normally < 10 % of the radioactive dose is excreted, if less, -
.proceed to part ΙΙ
: Part ΙΙ
( repeat part Ι ( after giving intrinsic factor capsules PO -
: the result -
.if excretion is normalized → diagnosis is PA -
if still abnormal → there is terminal ileal disease or bacterial over -
.growth
: GIT investigations -6
.marked gastric atrophy with achlorhydria -
.endoscopy is necessary to exclude gastric carcinoma -
.BM : → hypercellular e' megaloblastic changes -7
: Treatment
Hydroxylcobalamine 1 mg twice weekly for 3Ws, then every 3 Ms
→ for the Pts' life
.reticulocytosis → occurs after 5 – 7 days •
neurological improvement may take 6 – 12 M •
.long-standing lesions → irreversible •

13
↓ Folate
: Causes
poor intake ( major cause ) in : old age, starvation, GIT disease -1
( ( e.g. gastrectomy
.absorption : → small bowel disease ↓ -2
utilization : pregnancy, haemolysis, malignant disease & ↑ -3
.dialysis
.antifolate drugs : anticonvulsants, methotrexate & trimethoprim -4
: Pathogenesis
.folic acid is widely distributed in plants -
folic acid is the parent of a large group of compounds called the -
.folates
in the upper GIT & during absorption, folates are broken down to -
→ monoglutamates → methyltetrahydrofolate ( essential for DNA
( synthesis
unlike Vit.B12, body reservoirs of folates are low, so on ↓ diet, -
( folate ↓ rapidely develops ( over about 4 Ms
: C/P
.folate ↓ may be asymptomatic -
.symptoms ( if present ) → those of anaemia -
.neuropathy → rare -
: Investigations
( CBC & film →↑ MCV ( with / without anaemia -1
.BM examination → megaloblastic erythropoeisis -2
( red cell folate →↓… S.folate is also ↓ ( but is less accurate -3
GIT investigations : to confirm a suspected cause of ↓ intake / -4
.absorption
: Treatment
.folic acid : 5 mg /d PO -1
( prophylactic folate : indicated in pregnancy ( with Fe -2

14
folic acid should not be given alone in megaloblastic anaemia -3
until B12↓ excluded, as folate may → neurological changes in
.B12↓ cases

15
Anaemia d.t. BM failure
( Aplastic anaemia (

.denotes aplasia of BM e' peripheral blood pancytopenia •


: Causes
congenital : Fanconi anaemia ( autosomal recessive, associated -1
( e' skeletal, renal & nervous abnormalities
: acquired -2
a- idiopathic → usually d.t. ↓ of BM stem cells by cytotoxic
.T-cells
.b- chemicals → benzene
→ c- drugs
.antineoplastic : mercaptopurine, methotrexate, doxorubicin -
.anti-inflammatory : phenylbutazone, gold, NSAIDs -
.antidiabetic : chlorpropamide, tolbutamide -
.antithyroid : carbimazole, propylthiouracil -
.antibiotics : chloramphenicol, sulfonamides -
.tranquilizers : chlorpromazine -
.d- insecticides
.e- ionizing radiation
f- infection : viral hepatitis, measles, TB
g- pregnancy & thymoma , both → alternation of immunological
.& hormonal states →↓ BM
( h- paroxysmal nocturnal haemoglobinuria ( PNH
: C/P
acute / insidious onset of symptoms & signs resulting from -1
.anaemia, neutropenia & thrombocytopenia
( mouth infections → particularly fungal ( common -2
.lymphadenopathy, splenomegaly & hepatomegaly → rare -3
: Investigations : diagnosis is made on the basis of
.pancytopenia -1
.virtual absence of reticulocytes -2
.hypocellular or aplastic BM, with large fat spaces -3

16
: bad prognostic features include -4
.peripheral blood neutrophil count < 500/cmm -
.platelet count < 20,000/cmm " " " " -
.reticulocytic count < 10,000/cmm -
.sever hypocellularity of BM -
: D.D : from other causes of pancytopenia
( megaloblastic anaemia ( in sever cases -1
BM infiltiration : lymphoma, acute leukaemia, myeloma, -2
.myelofibrosis, 2ry carcinoma
.myelodysplasia -3
.hypersplenism -4
.SLE -5
.disseminated TB -6
.sepsis -7
.drugs -8
: Treatment
( removal of the cause ( if possible -1
supportive care : with blood transfusion, platelets concentrates -2
.& ttt.of infection
: BM transplantation -3
.ttt.of choice for Pts < 20 y who have HLA identical sibling donor -
( this also can be used in Pts < 45 y )
Pts < 45 y are not suitable for BM transplantation because of -
.high risk of graft-versus-host disease
immunosuppressive therapy : for Pts < 45 y -4
: by combination of
.antithymocyte globulin ( ATG ) 40 mg /kg/d → for 4 days -
.cyclosporine : 6 mg/kg PO twice daily -
.prednisolone : 1 – 2 mg /kg/d initially, followed by a rapid taper -
for Pts with marked neutropenia : → granulocyte-colony -5
stimulating factor ( G-CSF ) & granulocyte-macrophage colony
( stimulating factor ( GM-CSF

17
androgens : ( e.g. oxymetholone ) 2 – 3 mg/kg PO daily → may -6
.be helpful in few cases
.steroids : helpful in ttt.of congenital pure red cell aplasia -7
:NB •
adults with pure red cell aplasia may have thymoma ( w' is -
hyperplasia & hyperfunction of thymus gland → cytotoxic T-cells
→↓ BM → BM aplasia ) → removal of thymoma may →
.remission

18
Haemolytic anaemias

. Def. : short red cell survival •


: Causes
: A- inherited
: red cell membrane defect -1
. hereditary spherocytosis -
.elliptocytosis " "-
: Hb abnormalities -2
.thalassaemia -
.sickle cell disease -
: metabolic defects -3
.↓ G6PD -
.↓ pyruvate kinase -
: B- acquired
: immune -1
.autoimmune -
. alloimmune -
: nonimmune -2
: membrane defects •
paroxysmal nocturnal haemoglobinuria -
.liver diseases -
. renal diseases -
: mechanical •
.damaged vessels -
.valve prosthesis -
: miscellaneous -3
( infections ( malaria -
.drugs -
.chemicals -
.hypersplenism -
.burns -

19
: Pathophysiology
short red cell survival : → anaemia when the compensatory -1
.power of BM is exceeded
expanding the volume of active BM →↑ erythropoisis → release -
of reticulocytes in the peripheral blood ( w' are immature red cells
( larger than mature RBCs
. haemolysis : → may be intravascular / extravascular -2
intravascular haemolysis : destroyed red cells → Hb → removed •
. by haptoglobin → liver
.remaining Hb → oxidized to met-Hb → ferrihaem + globin -
→ : … ferrihaem -
.attached to albumin → methaemalbumin -
.binds to haemopexin → liver -
extravascular haemolysis : red cells are removed by macrophages •
.→ spleen
→ : red cells haemolysis -3
.S.bilirubin ↑ -
urine urobilinogen ( urobilinogen results from bilirubin ↑ -
( breakdown in the intestine
.S.haptoglobin ↓ -
: Lab.evidence of haemolysis -4
→ red cells breakdown ↑ •
( s.bilirubin ( unconjugated ↑ -
.urine urobilinogen ↑ -
.plasma haptoglobin ↓ -
.abnormal cells ( large cells ) in the peripheral blood -
: red cells production ↑ •
.reticulocytosis -
.erythroid hyperplasia of BM -
NB: ↑ plasma Hb, low or absent haptoglobin & presence of ••
.methaemalbumin → suggest intravascular haemolysis
→ severity of haemolysis : is determined by -5
.frequency of transfusion -

20
( measuring red cells survival time, using Chromium-51 ( C-51 -

( Hereditary spherocytosis ( HS

Pathogenesis : red cell memb.is ↓ in structural proteins → red cell


memb.more rigid → rapid destruction in spleen & abnormal ↑
+permeability to Na
: C/P
.jaundice -1
manifestations of anaemia , the course may be interrupted by -2
aplastic ( esp.after infection ) or megaloblastic crises ( d.t. folate ↓
( by hyperactive BM
. splenomegaly -3
( leg ulcers ( esp.in adults -4
. hypertrophy of bone of the skull & of maxillary sinus -5
( growth ↓ ( in sever cases -6
( pigm.gall stones ( d.t. haemolysis -7
: Investigations
.CBC & film : anaemia , film → spherocytes & reticulocytosis -1
.other Lab.evidences of haemolysis -2
osmotic fragility : ↑ if placed in hypotonic solution but direct -3
Coomb's test is –ve ( to differenciate from autoimmune haemolytic
.( anaemia w' also have spherocytosis
: Treatment
splenectomy ( but may be postponed after childhood to ↓ risk of -
( pneumococcal infection
splenectomy is preceded by pneumococcal & H.influenza -
.( immunization & followed by penicillin prophylaxis ( life-long

21
Thalassaemia

characterized by : ↓ in synthesis of the globin chains of Hb with •


accumulation of abnormal chains in the red cells → ineffective
.erythropoeisis & haemolysis
: Pathogenesis
: in β-thalassaemia -1
no β chains are produced ( β˚ ) or β chain production is ↓ ( β + ) •
. ( i.e. unstable ) → d.t. mutations
α-chain production is normal & may combine with γ or ∂ chains •
( → formation of ↑ quantities of HbA2 ( α2, δ ) & HbF ( α2, γ2
both β˚ & β + thalassaemia may be in homozygous / •
.heterozygous states
: in α-thalassaemia -2
no α chain production ( α˚ ) or ↓ α chain production ( α+ ) → d.t. •
→ ( deletions ( = absence
genes deletions → Hb barts ( γ4 ) w' can't carry O2 →-4 -
.incompatible with life
genes deletions → moderate anaemia & splenomegaly-3 -
( ( HbH dis : β4
or 2 genes deletions → α-thalassaemia trait → microcytosis e' / 1 -
.e'out mild anaemia

Β-thalassaemia
: clinically, the disease is divided into •
T-major ( Mediterranean / Cooley's anaemia ) : d.t. -1
.homozygous inheritance → sever anaemia
T-intermedia : d.t. combination of homozygous mild β- & α- -2
( thalassaemia → moderate anaemia ( rarely requiring transfusion
T-minor ( β-thalassaemia trait ) : d.t. heterozygous inheritance -3
( asymptomatic carrier ) , present with microcytic hypochromic
. ( blood picture ( but no / mild anaemia

22
: β-thalassaemia major in childhood, presents with •
.failure to thrive -
sever anaemia ( starts at 3 – 6 Ms; time of normal switch from γ -
( to β chain production
.recurrent infections -
extramedullary haemopoeisis : → hepatosplenomegaly & bone -
. expansion → classical facies
skull X-ray → hair- on- end appearance ( as a result of expansion -
( of BM into cortical bone
: Investigations
: CBC & film -1
.moderate / sever anaemia with ↓ MCV & MCH -
reticulocytic count , peripheral blood → target cells & ↑ -
.poikilocytosis
: Hb electrophoresis -2
,HbF ↑ -
.HbA2 is normal -
.˚HbA is absent in β -
: Treatment
.regular blood transfusion : to keep Hb < 10 gm/dl -1
.febrile reactions prevented by → use of leucocyte-depleted blood -
.Fe-over load prevented by → desferrioxamine & ascorbic acid -
.splenectomy : indicated if transfusion is required < every 7 Ws -2
.folic acid : d.t. over active BM. 4- BM transplantation -3
α-thalassaemia
: clinically, present in 2 forms •
genes deleted : → all Hb produced is physiologically useless 4 -1
( ( Hb barts
genes deleted : → HbH ppt-ed in red cells → haemolysed in 3 -2
.the spleen → splenomegaly . & anaemia is variable
NB: for defenetive diagnosis of α-thalassaemia traits → Globin •
.chain studies → detection of reduced ratio of α to β chains

23
antenatal diagnosis : fetus with β-thalassaemia major is •
identified by DNA analysis of chrionic villous → in 1st trimester or
test the umbilical cord blood → in 2nd trimester. If the fetus is
.affected → abortion

24
: Thalassaemia findings

Type findings in homoz .Findings in heteroz


+Β thalassaemia major - .thalassaemia minor -
( Hb ( A + F + A2 - .↑ HbA2 -
˚B .thalassaemia major - .thalassaemia minor -
( Hb ( F + A2 - .↑ HbA2 -
δβ thalassaemia intermed - .thalassaemia minor -
.- HbF only HbF = 5-15% -
HbA2 : normal -
( δβ ( lepore .T-major / intermedia - .thalassaemia minor -
.HbF & Lepore - . Hb Lepore = 5-15% -
.HbA2 : normal -
γδβ not viable - .neonatal haemolysis -
T-minor in adults e' -
.normal HbF & A2

: The α-thalassaemia

Gene Deletion Hb type C/P


genes 4 --/ -- ˚α ( Barts ( γ 4 hydropdfaetalis
genes 3 α˚ --/-α ( H ( B4 moderate anaem -
.splenomegaly -
genes 2 α˚ --/αα or some HbH - .mild anaemia -
α /-α- .α-T trait -
HbA -
gene 1 α+ - α/ αα normal - .α-T trait -

Sickling disorders

25
formation of ( HbS ) by change happen in globin B chain ( valine •
( for glutamine in the 6th position
.it may be : - homozygous → sickle cell disease •
.heterozygous → sickle cell trait -
Sickle cell anaemia

: Pathogenesis
of red cell Hb is HbS w' in deoxygenated state → the 80% -
.molecules link → chains → sickling & ↑ rigidity of red cells
.sickling →↓ red cell survival & obstruction of microcirculation -
.Ppt-factors : infection, dehydration, cold & hypoxia -
the Pt feels well despite being anaemic ( because HbS releases its -
O2 to tissues more readily than does normal Hb ) except during
. crises or complications
: C/P
: painful crisis -1
. d.t. infarctions in various organs -
hand & foot syndrome : → in children , painful swelling of digits -
.of hands & feet d.t. infarcts of small bones
.ppt- by infection, dehydration & hypoxia -
: aplastic crisis -2
.sudden ↓ in Hb with ↓ reticulocytic count -
.usually follow infection with parovirus -
.haemolytic crisis -3
sequestration crisis : rapid ↓ in Hb d.t. red cells traping in liver -4
.& spleen
… ( Complications : ( too dangerous
( osteomyelitis ( bone -
. papillary necrosis of the kidney -
spleen → recurrent infarctions → autosplenectomy →↑ infection -
( with encapsulated organisms ( e.g. pneumococci
.cardiac enlargement , myocardial necrosis -
.pulmonary infarction & pulm-HTN -

26
.cerebral damage -
.painful priapism -
( blindness ( eyes -
: Investigations
.Lab.findings of haemolytic anaemia -1
sickling : → seen in blood film or induced by Na-metabisulphite -2
..…rapid screening test : sickle solubility test -3
.HbS + Na-dithrionite → turbid -
.normal Hb + Na-dithrionite → clear solution -
→Hb electrophoresis : → cell Hb -4
.HbSS 80% -
( HbS ( no HbA 20% -
.parents of the Pt : → features of sickle cell trait -5
: Treatment
. ppt factors : → avoided or treated quickly -1
regular blood transfusion : →↓ production of HbS →↓ sickling -2
( ( used for sever anaemia & frequent crisis
. haemolytic crisis : → blood transfusion -3
: painful crisis -4
.analgesics, IV fluids & O2 -
hydroxyurea : →↑ erythropoeisis →↑ HbF ( indicated for -
( frequent painful crisis
( aplastic crisis : antibiotics for infection ( if present -5
.vascular occlusion : → exchange transfusion -6
.gene therapy : may be possible in the future -7

Sickle cell trait


.HbS is < 40% -
(no symptoms unless subjected to anoxia ( e.g. during anaesthesia -
.sickle cell trait protects against malaria -
. diagnosis : by +ve sickle test / Hb electrophoresis -

↓ G6PD

27
: Pathogenesis
the red cell derives energy from glucose metabolism via 2 •
: pathways
.Embden-Myerhof glycolytic → 90 % of glucose -1
.hexose monophosphate shunt → 10 % of glucose -2
mature red cell doesn't have a neucleus, mitochondria or any •
( .intracellular apparatus needed for production of proteins ( enz
So, it receives a package of enzs.at its birth & when these
.enzs.used up → the cell dies
G6PD enz. : is the 1st enz.in the hexose monophosphate shunt w' •
helps maintaining glutathione in a reduced state, once reduced
form of glutathione becomes unavailable → oxidation of haem →
.meta-Hb
the gene for G6PD is sex liked, carried on X-chromosome, ↓ •
.♀ affects ♂ & carried by
→ variants of the enz. : 2 variants ••
: G6PD GdA •
.found in 10% of Africans -
.young cells → moderate enz.activity -
.↓ older cells → sever -
in this variant, haemolysis is selflimiting as BM compensates by -
.↑ its output of young cells
: G6PD Gd med •
.found in mediterranian people -
.both young & old cells → very poor enz -
.haemolysis is sever → death -
: Factors that ppt haemolysis
.infections •
.acute illness e.g. DKA •
( fava beans ( not seen e' G6PD GdA •
: drugs •
,analgesics → aspirin, phenacetin -

28
.antimalarial → quinine, chloroquine, primaquine -
antibiotics → sulfonamides, dapson, nitrofurazone, -
.chloramphenicol, ciprofloxacin
.miscellaneous → Vit.K, quinidine, nalidixic acid -
: C/P
.haemolysis : develops within a day or so after exposure -1
chronic haemolysis : ( in G6PD GdA ) persist for sometime after -2
.exposure
: Investigations
: CBC & film -1
.count is normal between the attacks •
→ blood film during the attack •
.bite cells : cells with indentation of membrane -
blister cells : Hb appears to be partially detached from cell -
.membrane
.Heinz bodies : oxidized denaturated Hb -
.Lab.findings of haemolytic anaemia -2
enz. ↓ → reduce dyes ( screening test ). also level of the enz. -3
.may be directly assayed
: Treatment
.offending drugs → must be stopped -
.underlying infections → must be treated -
.blood transfusion -

Immune haemolytic anaemia

29
.autoimmune or alloimmune •
in autoimmune haemolytic anaemia, the body produces •
.antibodies against its own cells
: antibodies attached to red cells at •
.C˚ → warm autoimmune HA 37 -
.lower temperature → cold autoimmune HA -
Warm autoimmune HA
: Causes
.idiopathic -
.autoimmune disease e.g. SLE -
.lymphomas -
.carcinomas -
.chronic lymphatic leukaemia -
.drugs : e.g. methyl dopa -
.C/P : varies from mild haemolysis to life-threatining anaemia
: Investigations
.Lab.findings of HA -
.microspherocytosis d.t. ↓ red cell surface membrane -
direct Coomb's test +ve e' IgG alone -
Coomb's = antiglobulin, IgG found on the surface of the red cells •
.˚→ antibodies are best detected at 37C

( NB: Coomb's test ( = antiglobulin test •

Indirect Direct
Pt serum+ normal RBCs - Pt's cells ( Igs found on -
( surface of the RBCs

Antiglobulin
Agglutination

30
So, the normal cells are So, the Pt's cells are sensitized
.Sensitized in vitro .In vivo, e.g
.autoimmune HA -
.haemolytic transf.reaction -
.HDN -
.drug-induced immune HA -

: Treatment
. blood transfusion : → may be required -
.prednisolone : 40 – 60 mg/d -
. splenectomy : if no response to steroid -
immunosupressive drugs : azathioprine & cyclophosphamide → -
. if no response to steroids & splenectomy
.Cold autoimmune HA
: Causes
.idiopathic -
.infection e.g. IMN, mycoplasma, pneumonia -
.lymphoma -
( paroxysmal cold haemoglobinuria ( PCH -
( chronic cold haemoagglutinin disease ( CHD -
: C/P
.features of HA ppt-ed by cold exposure -
.Raynaud's phenomenon -
in these conditions → haemolysis is d.t. IgM w' can attach to •
.RBCs at low temperature.→ agglutination in the cold peripheries
when the cells return to high temperature in the core of the body •
.→ activation of the complement → intravascular haemolysis
: Investigations
.red cells agglutinate in the cold or at room temperature -
.˚S.antibodies → IgM type & best react at 4C -
.direct Coomb's test → shows only C3 complement on red cells -
: PCH
.rare condition -

31
IgG complement fixing antibodies → biphasic reaction , -
→ ( ( haemolysis
.in cold peripheries → react e' red cells -
in central circulation → complement activation → intravascular -
.haemolysis
this biphasic reaction is demonstrated by incubating the Pt's red -
cells & serum at 4C˚ & then warming the mixture to 37C˚ →
.haemolytic reaction
.ttt. : → transfusion of warmed blood -

CHD : haemolytic anaemia d.t. IgM → red cell agglutination after


( .exposure to cold → acrocyanosis ( similar to Raynaud's phenom
: Treatment of cold autoimmune HA
.avoid cold exposure -
.chlorambucil : occasionally helpful -
.high dose IV immunoglobulins & interferon -

: Causes & major features of autoimmune HAs •

32
Warm Cold
temp.at w' Abs attach - ˚37C ˚lower than 37C
Best to red cells
: type of Ab - IgG IgM
: direct Coomb's test - Strongly +ve ve+
:cause of 1ry condition - Idiopathic Idiopathic
.causes of 2ry condit.s - autoimmune dis.,e.g. - ,infections e.g. IMN -
SLE Mycoplasma,pneumon
.chronic lymph.leuk - ( viral inf.( rare &
.Hodgkin's disease - .lymphomas -
.carcinomas - .parox.cold haemogl -
.drugs e.g. M.dopa - ( IgG )

( Haemolytic disease of the newborn ( HDN


: Pathogenesis
it's alloimmune HA d.t. passage of IgG antibodies from maternal -
. circulation → fetus → destroy the fetal red cells
sensitization of RhD –ve mother occurs at a previous delivery by -
.fetal Rh+ve cells entering the maternal circulation
: C/P
.mild → anaemia with /without jaundice -
moderate → sever anaemia, jaundice, hepatosplenomegaly, -
edema & cardiac failure. If Conj.bilirubin < 12mg% → deposited
in the basal ganglia → Kernicterus ( mental ↓, deafness, epilepsy
( & spasticity
sever → intrauterine fetal death ( IUFD ) d.t. hydrops fetalis -
( ( = hepatosplenomegaly, edema & HF
: Investigations
: antenatal serology •
.ABO & RhD groups determination for all mothers -
serum → for atypical Abs w' rising titre → amniocentesis → -
.level of bilirubin in the fetus

33
→ at birth of an affected baby : → sample of the cord blood •
.anaemia with ↑ reticulocytic count -
.ve direct Coomb's test+ -
.S.bilirubin ↑ -
: Treatment
: A- management of the baby
mild cases : phototherapy → convert bilirubin → harmless •
.biliverdin → excreted by the kidney →↓ Kernicterus
: sever cases : exchange transfusion….. indicated if •
.cord Hb < 14g/dl -
.cord bilirubin < 3.5 mg/dl -
.rapidly rising bilirubin level -
the exchanged blood should be : fresh, ABO compatible, lack of ••
.Ag to w' maternal Ad is directed & - ve of CMV
: B- prevention of Rh disease
by immunization of the mother by Anti-D after delivery when all •
: the following are present
.mother is Rh –ve -
.fetus is Rh +ve -
.no maternal Anti-D in the mother's serum -
immunization must be within 48h of delivery by 500IU of IgG •
. anti-D IM

( Paroxysmal nocturnal haemoglobinuria ( PNH

34
: Pathogenesis : there is a stem cell disorder
.the affected clone → abnormal red cells, leucocytes & platelets -
the red cells have a membrane defect → lysis by complement → -
.chronic intravascular haemolysis
.low white cells & platelets count -
the condition may be transforms to : aplastic anaemia or acute -
.leukaemia
: C/P
: haemolysis •
.esp.at night -
( urine → dark in colour ( at night or 1st in the morning -
.may be ppt-ed by infection, Fe therapy or surgery •
recurrent thrombotic episodes ( platelets ) → MI, acute abd.pain / •
.stroke
: Investigations
.Lab.findings of HA -
Ham's test : red cells lyse more readily in acidified serum than -
.normal cells, they also lyse in sucrose solutions
.blood film : → leucopenia & thrombocytopenia -
: Treatment
.blood transfusion → in sever anaemia -
.steroids → effective -
.anticoagulants → in thrombotic episodes -
.BM transplantation -

Drug-induced haemolysis

35
: by one of 3 mechanisms •
immune complex formation : drug-Ab-complex → attaches to -1
(red cells → activate complement → red cells destruction( quinine
membrane adsorption : drug-red cell-complex → formation & -2
( adsorption of Abs → red cell destruction ( penicillin
autoantibodies formation : drug → red cell autoantibody -3
( (M.dopa

Mechanical HA
: physical damage to red cells when pass through •
.prothetic valves / arterial grafts -1
fibrin strands deposited in small vessels e.g. in → DIC, -2
malignant HTN, haemolytic uraemic syndrome, thrombotic
.thrombocytopenic purpura
small bones of feet : during prolonged marching or running → -3
.march haemoglobinuria

Hypersplenism

Def. - peripheral blood cytopenia w' can be cured by •


.splenectomy
. spleen → enlarged -
.BM → hypercellular -
: pathogenesis : hypersplenism resulting from •
.pooling of blood into spleen -1
.rapid destruction of cells in it -2
.in plasma volume ↑ -3
: Treatment
. that of the cause of splenomegaly -
.splenectomy : in sever anaemia or thrombocytopenia -
: Causes of splenomegaly

36
: A- 1ry haematological disease
.HAs •
.lymphoproliferative disorders •
. myeloproliferative disorders •
: B- non-haematological disease
: congestive splenomegaly •
.portal HTN -
.splenic / portal vein thrombosis -
.congestive HF -
: infections •
.bacterial → typhoid, TB, septicaemia -
.viral → hepatitis, IMN -
.parasitic → bilharziasis, malaria, Kala-azar -
.collagen disease : SLE, RA •
.metabolic storage disease : amyloidosis •
.sarcoidosis •

Polycythaemia

37
: this denotes ↑ of •
.%Hb% < 18 gm -
.red cell count < 6,000,000/cmm -
haematocrite ( PCV ) < 55% -
.red cell volume : ♂ < 36ml/kg & ♀ < 32ml/kg -
true polycythaemia is differentiated from relative polycythaemia •
.( haemoconcentration ) by → measuring red cell volume
: Classification
( A- 1ry : polycythaemia vera ( is stem cell disease
( B- 2ry : ( ↑ erythropoietin
: .appropriate ↑ ( i.e. compensatory )…. d.t -1
.high altitude -
.lung disease -
.heavy smoking -
.cardiovascular disease -
.affinity of Hb for O2 → in familial polycythaemia ↑ -
.inappropriate ↑ : ….. d.t -2
.renal disease e.g. hydronephrosis, carcinoma, cysts -
.liver carcinoma -
.adrenal tumours -
.cerebellar haemangioblastoma -
.massive uterine fibroma -
( C- relative ( = haemoconcetration = ↓ plasma volume
.stress ( spurious ) polycythaemia -
.dehydration -
.burns -

( Polycythaemia vera ( PV

38
'Pathogenesis : PV is stem cell disorder in w
there is alternation in the pluripotent generator cell →↑ -
proliferation of erythroid, myeloid, megakaryocytic progenitor
.cells
this is d.t. failure of apoptosis ( programmed cell death ) as a -
result of deregulation of gene ( Bcl – XL ) w' is known to oppose
.that process
.C/P : usually present in Pt < 60 y
symptoms : headache, dizziness, tinnitus, blurring of vision, -
.angina, intermittent claudication, V.thrombosis
: ( signs ( & complications -
.plethoric appearance, retinal venous engorgement -1
splenomegaly : in 2/3 of the Pts d.t. extramedullary -2
haemopoeisis → this is helpful in distinguishing PV from 2ry cases
.hepatomegaly : in 1/2 of cases -3
.HTN : in 1/3 of cases -4
vascular : → Hge ( in GIT, cerebral, genitourinary ) or -5
( Thrombosis ( of arteries & veins
.gout : d.t. ↑ uric acid production -6
.PUD : 5 – 10 % of cases -7
: Investigations
: CBC -1
% Hb < 18 gm -
PCV < 55% -
.WBCs & platelets →↑ in 1/2 of cases -
: blood volume -2
red cell volume ( measured by Chromium-51 ) → 36ml/kg ( ♂ ) -
( ♀ ) or 32ml/kg
.↑ / plasma volume → normal -
.BM : → erythroid hyperplasia & ↑ megakaryocytes-3
.↑ LAP ( leucocyte alkaline phosphatase ) : → usually -4
S.erythropoeitin level : not diagnostic , but may be helpful in -5
→ distinguishing PV from 2ry polycythaemia

39
S.erythropoeitin → •↓→ PV -
.2ry p. but its levels may be normal →↑•
.Treatment : aims at keeping PCV < 45%
: venesection -1
.will relieve many of the symptoms of the disease -
.the resulting Fe ↓→↓ erythropoeisis -
it's used as the sole ttt ( other therapeutic measures are reserved to -
( control thrombocytosis
.chemotherapy : hydroxyurea →↓ platelete count -2
: radioactive phosphorous-32 -3
.used for Pts < 70 y with sever disease -
one dose is effective for up to 18 Ms ( but →↑ rate of -
( transformation to acute leukaemia
: allopurinol -4
.to block uric acid synthesis -
H2-receptor antagonist ( not H1 ) → effective in relieving -
.pruritus
→ Prognosis : may transition to
( myelofibrosis ( in 30% -
( AML ( in 5% -
2ry polycythaemia
.Causes : given before
Complications : similar to those of PV ( but other
( myeloproliferative disorders not developed
.… Differentiation from PV : is helped by
.WBCs & platelet counts → normal -
.spleen → not enlarged -
.↑ → erythropoietin level -
.LAP score → normal -
arterial O2 saturation → low ( in Pts with cardiac & pulmonary -
(.dis
.Treatment : - that of the cause. – venesection : helpful

40
: Differentiation between 1ry & 2ry polycythaemia

1ry polycythaemia 2ry polycythaemia


WBCs & platelet count - ↑ Normal
spleen - Enlarged Not enlarged
erythropoietin - Normal ↑
LAP - ↑ Normal
O2 saturation - ↑ (d.t. lung /heart dis ) ↓

Stress polycythaemia
( Gaisbock's syndrome (

commonly occur in middle aged men, who are : hypertensive, -


.( obese & smoker ( HOS
red cell volume is normal but there is relative polycythaemia d.t. -
.↓ plasma volume
this condition is often presents as a cardiovascular problem e.g. -
.myocardial or cerebral ischaemia
smoking : → produces up to 10% carboxyHb →↓ O2 carrying -
capacity of the blood → consequent polycythaemia →↑ PCV →
.ischaemia
.treatment : - stop smoking •
.venesection → until PCV is normalized -

( Myelofibrosis ( myelosclerosis

41
there is proliferation of the stem cells & fibrosis of BM with •
( extramedullary haemopoeisis ( in liver & spleen
pathophysiology : abnormal proliferation → release of growth
factors ( platelet derived growth factor = PDGF ) →↑ fibroblasts in
.BM → fibrosis
: C/P
: Symptoms
.weakness & Wt loss -
massive splenomegaly : → fullness of upper abdomen, abdominal -
.pain may occur d.t. perisplenitis 2ry to splenic infarction
.bony pains & gout -
.bleeding → occur in thrombocytopaenic Pts -
: Signs
( fever ( infection -
. anaemia -
massive splenomegaly …. ( other causes of massive -
splenomegaly that must be differentiated include : bilharziasis,
( CML, malaria, Kala-azar & Gaucher's disease
: Investigations
: CBC & film -1
there is anaemia with leucoerythroblastic features ( = appearance -
( of erythroblasts & primitive WBCs in peripheral blood
. characteristic red cells seen → tear drop red cells -
WBCs & platelet counts → initially high but later on → -
.leucopenia & thrombocytopenia
the differential WBCs count → may be very similar to that of -
.CML
: BM aspiration -2
( not usually successful ( d.t. fibrosis -
trephine biopsy is necessary to show → ↑ fibrosis & ↑ № of -
.megakaryocytes
the Philadelphia chromosome ( Ph' ) : → is absent ( unlike most -3
( case of CML

42
.↑ / leucocyte alkaline phosphatase ( LAP ) score : normal -4
: Treatment
.supportive : blood transfusion & folic acid -1
alkylating agents ( e.g. hydroxyurea ) : → in cases with gross -2
. myeloproliferation
.allopurinol : is needed to prevent gross hyperuricaemia -3
.splenic irradiation : → to ↓ its size -4
: splenectomy : is indicated if -5
.spleen becomes very large & painful -
.transfusion requirements are high -
.sever thrombocytopenia occur -
: Prognosis
.median survival → is 3 y -
.transformation to AML → may occur -

** NB **
myeloproliferative disease : e.g. in •
.PV -
.chronic granulocytic leukaemia -
leukaemoid reaction : e.g. in •
.sever infection -
.TB -
.malignant BM infiltration -
leucoerythroblastic anaemia : e.g. in •
.sever Hge -
.haemolysis -
.BM infiltration -
.myeloid leukaemia -

The white cells

43
: types of leucocytes are found in the peripheral blood 5 •
.neutrophil ( polymorphnuclear ) granulocytes -1
.esinophil granulocytes -2
.basophil granulocytes -3
.lymphocytes -4
.monocytes -5

( Neutrophil leucocytosis ( neutrophilia , = < 10,000/cmm


: Causes
.pregnancy & exercise -
.bacterial infections -
.corticosteroid therapy -
.myeloproliferative disease -
.leukaemoid reaction -
. leucoerythroblastic anaemia -

( Neutropenia ( < 1500/cmm


: Causes
( racial ( common in black races -
( viral infection ( commonest -
( sever bacterial infection ( e.g. typhoid -
Felty's syndrome ( rheumatoid arthritis, splenomegaly, -
( neutropenia
( megaloblastic anaemia ( ↓ formation of cells -
.drugs → causing BM aplasia -
.pancytopenia : from any cause -
.autoimmune neutropenia -
. NB: agranulocytosis = absence of neutrophils

: C/P of neutropenia
( recurrent infections ( esp.in mouth & throat -
.septicemia : may occur -

44
.mouth : → characteristic glazed mucositis with ulceration -
Investigations : BM examination is essential to differentiat
: between
granulocyte formation ( there is ↓ in immature precursors ) or ↓ -
removal of neutrophil from the circulation ( no ↓ immature ↑ -
( precursors
: Treatment
( stop the causative drug ( that →↓ BM -
.infections : use antibiotic therapy -
myeloid growth factors : G-CSF or GM-CSF → usefull in -
.shortening the duration of neutropenia associated e' chemotherapy
.in autoimmune neutropenia : → use steroids & high doses IV Igs -

( Esinophelia ( < 400/cmm


: Causes
. parasitic disorders -
allergic disorders : allergic rhinitis, drug reactions & other -
.hypersensitivity reactions
.skin disorders : urticaria, eczema -
.pulmonary disorders : BA, bronchopulmonary aspergillosis -
malignant disorders : lymphoma, esinophilic leukaemia, -
.carcinoma & melanoma
.miscellaneous : sarcoidosis & hypoadrenalism -
( Basophilia ( < 100/cmm
: Causes
.myeloproliferative disorders -
.myxaedema -
.ulcerative colitis -
.small pox & chicken pox -

45
( Lymphocytosis ( < 5000/cmm
: Causes
→ infections -
.acute : IMN, rubella, pertusis, infective hepatitis, CMV infection •
.chronic : TB, toxoplasmosis, brucellosis •
.thyrotoxicosis -
.↓ adrenal -
.chronic lymphatic leukaemia( CLL ) & some lymphomas -

( Monocytosis ( < 800/cmm


: Causes
chronic bacterial infections : TB, typhoid, brucellosis, -
.bact.endocarditis
.protozoal disease -
.Hodgkin's disease -
.( myelodysplasia ( particularly myelomonocytic leukaemias -

The leukaemias

.malignant neoplasms of the stem cells •

46
characterized by diffuse replacement of BM by neoplastic cells •
.→ leukaemic cells into the blood → infiltrates various tissues
: Classification
: A- acute
( acute lymphoblastic leukaemia ( ALL -1
( acute myeloid leukaemia ( AML -2
: B- chronic
( chronic lymphocytic leukaemia ( CLL -1
( chronic myeloid leukaemia ( CML -2

: A/E of leukaemia : unknown , but several factors interact


: Ι- genetic factors
.incidence of leukaemia in chromosomal abnormalities e.g ↑ •
.Down's syndrome
→ .Ph' chromosome : is found in 95% of Pts with CML •
In Ph', the long arm of chromosome 22 is shortened by reciprocal -
.translocation to the long arm of chromosome 9
the oncogene ( C-ABL ) normaly present on chromosome 9 is -
thus translocated to come near the break point cluster region
(BCR) → hybrid transcription unit → transcripted as chimeric
mRNA → translated into a fusion protein e' tyrosine kinase &
.enhanced phosphorylation activities
a new gene is created on Ph' chromosome → encode a fusion •
.protein likely to be important in pathogenesis of CML
: ΙΙ- environmental factors
.chemicals : e.g. benzene -
.drugs : e.g. cytotoxic drugs -
.radiation exposure -
.viruses : human leukaemia virus discovered in T-cell leukaemia -

Acute leukaemia

: Classification

47
A- acute lymphoblastic leukaemia ( ALL ) → subdivide according
: to different markers on the surface of lymphocytes into
( common ( nonB, nonT ) ALL = ( C-ALL -
.null cell ALL -
.B cell ALL -
.T cell ALL -
B- acute myeloid leukaemia ( AML ) → differentiated according to
morphology & cell cytochemistry of blast cells ( more useful than
: cell surface phenotypes ) → clinical forms
.M0 → undifferentiated blast cells predominate -
.M1 → myeloblast predominate -
.M2 → myeloblast & promyelocyte predominate -
.M3 → promyelocyte predominate -
.M4 → myelocyte & monocyte evident -
. M5 → poorly differentiated monoblasts -
.M6 → multinucleated megablastic erythroblasts -
M7 → megakaryoblastic leukaemia : presents as myelofibrosis -
( ( with few megakaryoblasts in BM
: C/P
→ A- BM failure
.anaemia : pallor, dyspnea, tachycardia •
leucopenia : fever, malaise, infections ( mouth, throat, skin, •
( respiratory, perianal
thrombocytopenia : purpura, spontannous bruising, bleeding •
.gums & may be internal Hge
→ ( B- organ infiltration ( esp.in ALL
( bone pain & tenderness ( particularly in ALL in children •
( painful lymphadenopathy ( in ALL •
( moderate hepatosplenomegaly ( in ALL •
.gum hypertrophy & infiltration •
skin infiltration & rectal ulceration ( particularly in •
( myelomonocytic & monoblastic
: meningeal manifestations •

48
.headache, nausea, vomiting -
blurring of vision, diplopia, papillaedema & retinal Hge ( with -
( characteristic central white deposit
.( testicular swelling ( in ALL •
: Investigations
: CBC & film -1
.anaemia → normocytic normochromic -
.WBCs count → ↑ or ↓ or normal -
( blast cells → variable number ( but occasionally none at all -
in AML → blasts may contain ( auer rods ) w' are rod like -
.cytoplasmic inclusions
( platelet count →↓ ( esp.in AML -
( BM examination : → hypercellular ( e' characteristic blasts -2
: blood tests -3
.++renal function tests. - S.uric acid. - S.Ca -
( S.electrolytes. – blood cultures ( necessary -
.chest X-ray : → may show mediastinal mass -4

: Differentiation of ALL & AML


Differ.item Lymphoblasts Myeloblasts

49
: morphology - : cell size - .small - .large -
: cytoplasm - .scanty - .abundant -
:cyt.granules - .rare - .often -
: auer rods - .absent - .may be found -
: nucleoli - . 2- 1 - .2 < -

: cytochemistry - :PAS - ve+ ve-


peroxidaes/sudan- ve - ve+
black
: immunology - -terminal deoxynucleo - ve+ Usually –ve
(Tidyl transferase ( Tdt
immunological markers - T cell marker : CD2 - .Myeloid cell markerse.g
( CD ) B cell marker : CD 19 - .CD 13 or CD33

genetics - :IgG light chain gene - ve ( in C-ALL& null+ ve-


( ALL
: T cell receptor gene - ( ve ( in T ALL+ ve-

We can differentiate by using : morphological criteria, •


.cytochemical, immunological & genetic studies

: Treatment
: A- supportive care
.ttt.of anaemia → red cell transfusion -1
ttt.& prophylaxis of Hge → clotting factors, fresh frozen plasma -2
.,platelet concentrate / fresh blood
.ttt.& prevention of infection -3
.correction of dehydration -4
.ttt.of hyperuricaemia by IV fluids & allopurinol -5
: prevention of acute tumour lysis syndrome -6
chemotherapy → tumour cell death → release of its products → -
hyperkalaemia, hyperuricaemia, hyperphosphataemia,
.hypercalcaemia
.this is corrected by : - adequate hydration & allopurinol -
( haemodialysis ( to correct the metabolic disturbances -
: leucopharesis -7

50
blood is collected from a vein → centrifuged → remove the -
leukaemic cells → both red cells & plasma returned to the Pt by
.another vein
done if blast cell count in peripheral blood is very high ( to -
( prevent infiltration of the brai & the lungs
: B- specific therapy
: a- for ALL : 5 phases of therapy
induction of remission : by a combination of → vincristine, -1
( prednisolone, daunorubicin & L-asparaginase ( DPL-V
.consolidation : using drugs not given in induction -2
.craniospinal prophylaxis : → to prevent relapse -3
.repeated inj.of intrathecal methotrexate -
.cranial irradiation -
: maintenance : by cyclic combination of -4
.methotrexate, 6-mercaptopurine, vincristine & prednisone -
.with ttt-free intervals → to allow BM recovery -
.duration of the therapy : 2 – 3 y -
: late intensification therapy -5
.after 6Ms of start of maitenence -
.BM transplantation -
: b- for AML : 3 phases of therapy
induction of remission : by very intensive chemotherapy → -1
( ( sufficient to induce hypoplastic BM
consolidation : by giving several further courses of induction -2
. therapy
: postremission therapy : by one of 3 options -3
.a- repeated intensive chemotherapy
.b- high dose chemotherapy + BM transplantation
.c- " " " " + autologous BM transplantation

: C- types of acute leukaemia that require special management


: promyelocytic leukaemia -1

51
breakdown of promyelocytes → DIC , this needs ttt.e' platelets, -
fresh frozen plasma transfusion & heparin before specific
. chemotherapy is started
: hairy cell leukaemia -2
: characterized by •
.pancytpenia -
blast cells ( with cytoplasmic projections → hairy cells ) in blood -
.& BM
. giant splenomegaly -
responds dramatically to ( CdA ) = chlorodeoxyadenosine → •
.complete remission in 80% of cases
: Prognosis
: ALL -1
.children → ttt.success upto 80% cure rate -
.Pts ( 20 – 70 y old ) → 30% cure rate -
wores prognosis : in males, blacks, ↑ leucocytic count, CNS -
.involvement, T & B cell types
.BM transplantation : curative in 40% of Pts -
: AML -2
Pts < 60 y → complete remission in 80% of cases , but relapse -
.occur within 1 – 3 y
worse prognosis in : → older age, presence of nuclear Tdt & -
. associated chromosomal abnormalities
.BM transplantation → curative in 60% of cases -

( Chronic myeloid leukaemia ( CML

52
.seen most frequently between ages of 50 – 60 y •
Ph' chromosome : present in all dividing granulocytic, erythroid •
.( & megakaryocytic cells in BM ( & also in B-lymphocytes
in 70% of cases → there is terminal metamorphosis to an acute •
.form of leukaemia
: C/P
.manifestations of anaemia : → pallor, dyspnea, tachycardia -1
of hypermetabolism ( d.t. ↑ total body " " " -2
granulocyte mass ) → fever, Wt loss, lassitude, anorexia & night
.sweats
slpenomegaly ( frequently massive ) but lymphadenopathy is -3
.not common
………,bruising, epistaxis, menorrhagia -4
.less common features include : visual disturbances & gout -5
: Investigations
: CBC & film -1
Hb → initially normal, then anaemia ( normocytic -
.normochromic) develop
.WBCs : → < 100,000 /cm -
myeloid cells : → complete spectrum is seen but, neutrophils & -
.myelocytes exceed blast cells & promyelocytes
.platelet count : → variable -
.↑ BM : hypercellular & granulocyte precursors markedly -2
( cytogenic analysis of blood or BM : → Ph' ( in < 90% of cases -3
.leucocyte alkaline phosphatase score ( LAP ) → very low -4
: Treatment
hydroxyurea: 2 – 4 g/d PO at the beginning, followed by → -1
( 0.5 – 2 g/d maintainance ( to keep WBCs 5000 – 10,000 /cmm
.α-interferon : 5 – 10 million U/d -2
.is now the ttt of choice -
.it can ↓ the Ph' & allow normal cells to appear -
.BM transplantation : within 1y of diagnosis -3

53
myelofibrotic transformation : is treated by blood transfusion & -4
.splenectomy
.blast crisis : treated as acute leukaemia -5
: Prognosis
.median survival is → 3 y •
death : usually occurs from terminal acute transformation, Hge / •
.infection
: acute transformation : takes the form of •
.increasing myelofibrosis -
transition to acute leukaemia ( blast crisis ) → where blast cells -
predominate in the blood, these blast cells are : myeloblasts ( in
( 80% of cases ) or pre-B-lymphoblasts ( in remaining 20%
.BM transplantation : within 1 y of diagnosis → 75% success rate •

Chronic lymphocytic leukaemia

. occur mainly in the elderly •


( it's a disorder of B-cells ( T-cells in few cases •
accumulation of mature lymphocytes in the tissues & → •
.peripheral blood
: with advanced disease, there is •
.BM failure -
( lymphadenopathy ( generalized, discrete -
.softe tissue lymphoid masses -
immunological failure : results from reduced humoral & cellular •
.immune processes
: C/P
enlargement of LNs ( in the neck, axilla & groin ), → usually -1
.discrete, moderate size & not tender
.manifestations of anaemia : pallor, dyspnoea, tachycardia -2
splenic & hepatic enlargement : not massive, pruritus occurs in -3
.many Pts but skin infiltration occurs rarely

54
tonsillar enlargement : may occur, but salivary & lacrimal -4
.glands involvement → rare
about 20% of cases diagnosed only when routine blood test is -5
.done
: Investigations
: CBC & film -1
.mild anaemia, but may be sever d.t. autoimmune haemolysis -
WBCs count : usually < 15,000/ cmm. ( of w' 40% are -
( lymphocytes
.thrombocytopenia : in advanced cases -
BM examination : → lymphocytic replacement of normal BM -2
.→ BM failure
S.immunoglobulins : ↓ ( esp.in advanced cases ) because → -3
B-cell malignancy suppress normal Igs production →
.immunological failure
( Staging ( classification
: A- Rai staging
( stage 0 : → lymphocytosis ( < 15,000/cmm -
.stage Ι : → lymphocytosis + enlarged LNs -
stage ΙΙ : → lymphocytosis + enlarged LNs + splenomegaly or -
. hepatomegaly
.% stage ΙΙΙ : → 0 + Ι / ΙΙ & Hb < 11gm -
stage ΙV : → 0 + Ι + ΙΙ / ΙΙΙ & platelets < 100,000 -
NB: Hb & platelets ↓ in stages ΙΙΙ & ΙV → not made by
.autoimmune haemolytic anaemia / autoimmune thrombocytopenia
: B- Binet staging
stage A : no anaemia ( Hb < 10 g/dl ), no thrombocytopenia…. -
.( platelets < 100,000 /cmm ), involved lymphoid areas : < 3
stage B : no anaemia, no thrombocytopenia, involved lymphoid -
.areas : 3 or more
stage C : anaemia & / thrombocytopenia present, involved -
.lymphoid areas : any number

55
: Binet staging •

A B C
anaemia - No No Yes
thrombocytopenia - No No Yes
lymphoid areas - 3< 3 =/< № Any

Treatment : there is no need to treat stage 0, but other stages need


.ttt
.A- supportive : as with acute leukaemia
Pt.with hypogammaglobulinaemia → take potent IV γ-globulin -
.B- specific therapy : indicated only for symptomatic disease
chlorambucil : 0.6 – 1 mg PO every 3 Ws → is the ttt of choice -1
.for initial ttt
corticosteroids : indicated for autoimmune haemolytic anaemia / -2
( thrombocytopenia ( but often these require splenectomy
fludarabine : used for refractory cases ( but → prolonged -3
( immunosuppression

: Prognosis
: median survival •
( 8y → in stage 0 ( Rai ) / A ( Binet -
( 2y → in stage ΙΙΙ or ΙV ( Rai ) / C ( Binet -
.↓ death is d.t. infection ( 2ry to BM failure or immune •
.prognosis is much worse in BM failure •
transformation to aggressive large cell lymphoma : → rare but •
.( may occur ( Richter's syndrome

56
Myelodysplastic syndrome
( MDS (
a group of acquired BM disorders that are d.t. defect in stem cells •
they are characterized by increasing BM failure with •
abnormalities in all 3 myeloid cell lines ( i.e. red cells,
.granulocytes/ monocytes & platelets ) → pancytopenia
: A/E
. idiopathic ( 1ry ) → usually •
2ry : → after cytotoxic chemotherapy ( esp.with procarpazine & •
( melphalan
: Classification
.refractory anaemia -1
.refractory anaemia with ringed sideroblasts -2
( % refractory anaemia with excess blasts ( blasts 5 – 20 -3
refractory anaemia with excess blasts in transformation ( blasts -4
( % 20- 30
.chronic myelomonocytic leukaemia -5
: C/P
MDS occur in elderly Pts who present with symptoms of •
. anaemia, infection or bleeding d.t. pancytopenia
.bone pains & splenomegaly may occur •
: Investigations
CBC : serial counts → evidence of increasing BM failure ; with -1
.anaemia, neutropenia, thrombocytopenia & monocytosis
→ in chronic myelomonocytic leukaemia •
.monocytes < 1000 / cmm -
.WBCs count < 100,000 / cmm -
→ : BM -2
.reveals ↑ cellularity despite the pancytopenia -
.dyserythropoiesis → is present -
granulocyte precursors & megacaryocytes → abnormal -
.morphology
.ringed sideroblasts → present in all types -

57
in conditions of excess blasts → there is excess blasts in BM → -
the prognosis is worse than in types with normal number of blast
( % cells ( i.e. < 5
: Prognosis
refractory anaemia with ringed sideroblasts & normal white & -1
.platelets counts → stable for years
refractory anaemia with excess blasts → progress rapidly & -2
transforms to acute myeloblastic leukaemia. ( this may be called
preleukaemia but this name is better to be avoided because death
usually arises from ↑ cytopenia rather than transformation to acute
(.leukaemia
: Treatment
→ : Pts with < 5% blasts in BM -1
. red cell & platelet transfusion -
.antibiotic for infection -
haemopoeitic growth factors ( e.g. erythropoietin & granulocyte -
( CSF
→ : Pts with < 5% blasts in BM -2
supportive measures : for elderly Pts with other medical -
.problems
.single agent chemotherapy : for Pts with ↑ WBCs count -
. intensive chemotherapy : ( as AML ) → in Pts < 60 y -
.BM transplantation -

58
Malignant lymphomas
: main types 2 •
( Hodgkin's disease ( HD -1
( non-Hodgkin's lymphomas ( NHL -2

( Hodgkin's disease ( HD
characterized by : enlargement of LNs with hyperplasia & •
infiltration with histiocytes & lymphocytes & presence of
.( characteristic ( Reed-sternberg cells
after a period → the disease is disseminated to involve non- •
.lymphatic tissues
.C/P : age distribution → early peak : 20 y & later peak : 50 y
enlargement of superficial LNs : → painless, not tender, -1
asymmetrical, firm, discrete & rubbery ( the cervical LNs are
( involved in 60 – 70 % of Pts
.splenomegaly & hepatomegaly -2
mediastinal involvement : → is a feature of nodular sclerosis -3
.type
late in the disease : → involvement of skin, bones, lungs & CNS -4
constitutional manifestations : prominent with widespread -5
: disease
fever → continuous / cyclic ,( Pel-Ebstein's fever w' consists of -
(.few days of high fever followed by few days of apyrexia is rare
.pruritus -
.Wt loss, profuse sweating & cachexia -
( alcohol-induced pain ( at the site of enlarged nodes -
: Investigations
: CBC & film -1
( normocytic normochromic anaemia ( late in the disease -
.with BM infiltration → leucoerythroblastic anaemia -
↑ : ESR -

59
chest X-ray & CT : → mediastinal lymphadenopathy / -2
.pulmonary infiltration
.liver function tests : → abnormal in hepatic involvement -3
→ : LN biopsy -4
Reed-sternberg cells : w' are large binucleated cells ( with •
vesicular nuclei & prominent nucleoli ), they are associated with
.a mixture of lymphocytes & histeocytes
…( Histological classification : ( 4 types •
lymphocytes predominant : there is heavy lymphocytes -1
.infiltration → the best prognosis
nodular sclerosis : there is much fibrous tissue, may be -2
.associated with any type
.mixed cellularity : both lymphocytes & histeocytes are present -3
lymphocyte depleted : there is few lymphocytes → poor -4
.prognosis

( Staging : ( Ann Arbor system


.determines both the prognosis & the appropriate ttt -
it requires : → a thorough history & physical examination, X-ray -
chest, liver function tests, abdominal imaging ( U/S, CT or MRI )
.& BM biopsy
lymphangiography, laparotomy & splenectomy → now done less -
. frequently
……… - A
Stage Ι : → involvement of a single LN region or a single
( extralymphatic organ site ( ΙE
Stage ΙΙ : → involvement of 2 or more LN region on the same side
of the diaphragm or localized involvement of an extralymphatic or
site & 1 or more LN regions on the same side of the diaphragm →
( ( ΙΙE
Stage ΙΙΙ : involvement of LNs in both sides of the diaphragm, it
may be accompanied e' spleen ( ΙΙΙS ) or extralymphatic ( ΙΙΙE ) or
( both ( ΙΙΙSE

60
Stage ΙV : diffuse / disseminated involvement of 1 or more
( extralymphatic ( with /without associated LN involvement
B- ……. In all stages, A or B → indicates absence ( A ) or
→ presence ( B ) of 1 or more of the following
.˚unexplained fever < 38 C -
.night sweats -
.loss of < 10% of body Wt.within 6 Ms -
C- …… bulky disease : → denoted by X
NB : bulky = LN mass < 10cm in diameter, mediastinal mass <
.1/3 intrathoracic diameter at T 10 level

: Ann Arbor system of staging of Hodgkin's disease


Stage LN region Diaphragm Extra-L- site
Ι Single .………… ( Single ( ΙE
ΙΙ more / 2 same side
more / 1 Same side Localized
ΙΙΙ LNs Both sides / -extra -
/ spleen -
.both -
ΙV / Diffuse
Dissiminated

: Treatment
: radiotherapy -1
irradiate all nodes areas ( above & below the diaphragm ) -
.according to the site of the disease
.the relapse rate following supradiaphragmatic disease is ↑; 40% -
when there is a large mediastinal mass → give chemotherapy + -
.radiotherapy
: chemotherapy -2
the standard ttt is 6 – 8 month cycles of mustin, vincrestine, -
.procarbazine, prednisolone … combination therapy

61
other drugs : such as adriamycin, bleomycin, vinblastine & -
decarbasine → added to the standard course as alternative courses
( ( alternating regimen ) or combination drugs ( hybrid regimen
→ : NB: the choice of ttt depends on the stage •
.radiotherapy : → ΙA, ΙB, ΙΙA -
.chemotherapy : → ΙΙB, ΙΙΙA, ΙΙΙB, ΙVA, ΙVB -
.…… -3
.Pts recur after initial radiotherapy → give chemotherapy -
Pts relapse after initial chemotherapy → are treated with -
.myeloablative therapy & BM transplantation

: Prognosis
long term survival depends on : stage & histological grade of the •
.disease
: the 5 y survival rates are as follow •
.stage Ι & ΙΙ→ 85% -
.stage ΙΙΙA → 70% -
.stage ΙΙΙB & ΙV → 60% -

62
Non-Hodgkin's lymphomas
( NHL (

these are tumours of lymphoreticular tissue derived from •


.malignant clones of B / T cells
: C/P
.the mean age at presentation is 50 y -
LN enlargement : is the dominant feature , the involved sites -1
. may be non-contageous
.LN is painless -
.mediastinal LN → less common, except in T-cell type -
.abdominal LN → common -
.splenomegaly & hepatomegaly → occur early -2
oropharyngeal lymphatic structures ( = Waldeyer's ring ) → -3
.involved → sore throat / obstructed breathing
.diffuse BM infiltration : → anaemia, infection & purpura -4
→ : extranodal sites involvement -5
.BM -
→ GIT , then -
.skin, brain, testes & thyroid gland -
.pruritus → is uncommon -
constitutional manifestations : such as fever, night sweats & Wt -6
.loss → less frequent than in HD
: Investigations
→ : CBC & film -1
.anaemia -
advanced cases → leucoerythroblastic picture d.t. BM infiltration -
.lymphoma cells → may seen in the peripheral blood -
.liver function tests : → abnormal in hepatic involvement -2
.imaging : → chest X-ray, chest CT, CT abdomen → LNs -3
.BM biopsy : → infiltration by lymphoid tissue -4

63
S.immunoglobulins : since the majority of cases are B-cell -5
tumours → there may be an associated monoclonal paraprotein →
.IgM or IgG
biopsy : of LN or involved extranodal tissue → is the most -6
.important investigation
( Histological classification : ( still controversial
: A- low grade
.small lymphocytic -1
.small lymphocytic & plasmacytoid -2
.follicular small-cleaved cell -3
.follicular mixed cell -4
.follicular large cell -5
.diffuse small-cleaved cell -6
.diffuse mixed cell -7
.diffuse large cell -8
( B- high grade : …..( the most aggressive
.diffuse large cell -1
.immunoblastic -2
( small non-cleaved ( Burkitt's & non-Burkitt's -3
.lymphoblastic -4
.true histiocytic -5
Staging : → the same as HD ( i.e. Ann Arbor system ) but less
.clearly related to prognosis than the histological grading

: Treatment
radiotherapy : → restricted to cases of localized low grade -1
.lymphoma if symptomatic
: chemotherapy -2
used for Pts with disseminated low grade lymphoma & all high •
.grade lymphomas
→ : in disseminated low grade •
single agent therapy is sufficient to induce response e.g. → -
.chlorambucil 5 – 10 mg /d PO

64
.stopped once a good response is achieved -
( re-used if relapse occurs ( relapse is frequent -
→ : in high grade lymphoma •
.may be curable, & treated by high dose combimation regimens -
.ttt is usually continued for about 3Ms after complete remission -
in Pts with lymphoblastic / small non-cleaved cell lymphoma → •
cranial irradiation & intrathecal methotrexate is necessary to avoid
.CNS relapse
BM transplantation : considered for high grade lymphomas Pts -3
.who relapse after combination therapy
:.choice of ttt ••
: low grade lymphoma -1
( stage Ι & ΙΙ → radiotherapy ( if symptomatic -
( stage ΙΙΙ & ΙV → single agent chemotherapy ( if symptomatic -
: high grade lymphoma -2
.combination chemotherapy -
.if relapse → BM transplantation -
: Prognosis
low grade lymphoma → relapse & continuing risk of death are -
.the rule
high grade lymphoma → 2/3 of Pts who obtain a complete -
.remission are probably cured
.by 10 y, the over all survival of low & high grade → the same -

65
: D.D. of lymphadenopathy

: A- localized
→ infections -1
.pyogenic : pharyngitis, dental abscess -
.viral : cat scratch fever, lymphogranuloma venereum -
.TB -
.fungal : actinomycosis -
.lymphomas → HD & NHL -2
: B- generalized
→ infections -1
.viral : infectious mononucleosis, measles, rubella & HIV -
.bacterial : brucellosis, syphilis, TB, salmonella -
.fungal : histoplasmosis -
.protozoal : toxoplasmosis -
→ inflammatory, noninfective -2
.sarcoidosis -
.rheumatoid arthritis -
.SLE -
( leukaemia : esp.( CLL & ALL -3
.lymphomas : HD & NHL -4
.carcinoma → 2rys -5
.drug reaction : hydantoin -6
.hyperthyroidism -7
.Kawasaki's syndrome -8

66
Paraproteinaemias
a group of disorders characterized by monoclonal proliferation of •
( B-cells accompanied by secretion of monoclonal Ig ( paraprotein
→ A/E : they include
.multiple myeloma -1
.Waldenstorm's macroglobulinaemia -2
MGUS ( monoclonal gammopathy of undetermined significance -3
.plasma cell leukaemia -4
paraproteins are demonistrated by a single band ( dark staining ) •
on serum electrophoresis → referred to as M or ( monoclonal band

Multiple myeloma
Pathogenesis : there is malignant proliferation of plasma cells in
: the BM → leads to
skeletal destruction : 2ry to release of osteoclast activating -1
factor ( OAF ) → osteoporosis, bone lytic lesions, fractures &
.hypercalcaemia
replacement of BM : → anaemia, leucopenia & -2
.thrombocytopenia
.recurrent infections d.t. ↓ of normal Ig production -3
production of abnormal protein ( paraprotein ) → hyperviscosity -4
., renal damage, bleeding tendency & amyloid deposition
.C/P :→ occurs predominantly in the elderly
.bone pains ( backache ) & pathological fractures -1
.manifestations of anaemia -2
repeated infections : d.t. ↓ antibody ( Ig ) production & later on -3
.neutropenia
bleeding tendency : d.t. interference with the platelet function, -4
.coagulation factors , later on → thrombocytopenia

67
manifestations of hypercalcaemia : → polyuria, polydepsia, -5
anorexia, vomiting, abdominal pain, constipation & mental
.disturbances
→ renal failure : d.t. precipitation of -6
.Ig light chain -
.amyloid deposition -
.hypercalcaemia -
.hyperuricaemia -
.myeloma infiltration -
amyloid disease → macroglossia, carpal tunnel syndrome, -7
.diarrhea
hyperviscosity syndrome : → lethargy, confusion, loss of vision -8
.& coma
some paraproteins are also cryoglobulin ( = act on low -9
.temperature i.e. at tissue periphery ) → Raynaud's phenomenon
: Investigations
: CBC & film -1
normocytic normochromic anaemia with rouleaux formation ( d.t. -
( hyperviscosity
.neutropenia & thrombocytopenia → in advanced cases -
.↑ ESR : always -
.abnormal plasma cells → rarly appear in blood film -
: BM -2
.plasma cells : №↑ & abnormal shape -
( plasmacytosis ( < 10% -
.plasma cells are often abnormal with centrally placed nucleus -
plasma protein electrophoresis : → narrow monoclonal band ( in -3
.75% of cases ) : 1/2 cases → IgG & 1/4 cases → IgA
urine : → Bence-Jones' proteiuria w' consists of free light chains -4
.↑ S.B2-microglobulin → usually -5
S.Ca++ : →↑ in 1/3 of Pts but, S.alkaline phosphatase → normal -6
( ( except following pathological fractures
.lab.manifestations of RF : encountered in 20% of cases -7

68
→ skeletal survey : may show -8
osteolytic areas ( without evidence of surrounding osteoblastic -
( reaction
.sclerosis -
.generalized osteoporosis -
.pathological fractures → very common -
Diagnosis : is established by the presense of at least 2 of the
: following criteria
BM plasmacytosis ( < 20% but lower level is acceptable if -1
( monoclonal
lytic lesions on X-ray ( sever osteoporosis is acceptable if BM -2
( plasmacytosis < 30%
.paraproteins in blood / urine -3

: Treatment
→ A- supportive : …..for
.pain → local radiotherapy -
hypercalcaemia → rehydration, loop diuretics, steroids & -
.bisphosphonates
.infections → antibiotics -
.anaemia & thrombocytopenia → blood & platelet transfusion -
.hyperviscosity → plasmapharasis -
.lytic bone lesions → orthopedic surgery -
: B- specific
.…… combination of -1
melphalan 7mg /m² daily is given for 4 days every 3Ws …. -
(providing that the renal function is normal ) + prednisone
.60 mg/m² /d. over the ttt days
.courses can be gradually extended until → ↓ WBCs count -
in resistance to melphalan → combination regimen containing -2
doxorubicin, nitrosouria, vika alkaloid & very high dose steroid are
. tried

69
α-interferon : → used to prolong remission induced by other -3
.drugs
in Pts < 40 y → intensive use of high dose of melphalan & BM -4
.transplantation used

: Prognosis
presense of sever anaemia & RF at presentation → poor -
.prognostic factors
.if they present → 2 y survival is 10% -
.if they absent → this rises to 75% -

70
Amyloidosis
tissue infiltration with amorphous hyaline substance that stain •
.pink with H & E and red with congo red stain
with congo red stain + polarized light → it shows green •
.florescence
characteristically, the amyloid protein consists of β-pleated sheets •
.that are responsible for its insolubility & resistance to proteolysis
classification : amyloidosis is classified according to the nature
: of protein deposited into 4 groups
: A- amyloidosis associated with Ig-producing tumours
the amyloid deposits ( AL ) consists of Ig light chains/ fragments •
.of them
substitution of a particular amino acid into their regions → •
.deposition of ( AL ) in tissues
: this condition may be •
.1ry : → no cause is found -
2ry : → associated with myeloma / Waldenstorm's -
.macroglobulinaemia
C/P : d.t. involvement of the heart, tongue, peripheral nerves & •
→ the kidney
.HF -
.macroglossia -
.peripheral neuropathy -
.carpal tunnel syndrome -
.nephrotic syndrome -
: B- reactive systemic amyloidosis
the amyloid deposit ( AA ) consists of an acute phase protein → •
( ( amyloid A protein
( it occurs 2ry to ( i.e. A/E of reactive systemic •
.chronic infection : TB & bronchiectasis -
.chronic inflammation : RA -
.malignancy : e.g. Hodgkin's disease -

71
( familial mediterranian fever ( FMF -
C/P : it's d.t. involvement of the liver, spleen & the kidney → •
.- hepatosplenomegaly
.nephrotic syndrome & RF -
.renal vein thrombosis -
NB: renal amyloid is more prominent in reactive amyloidosis, but •
cardiac & gut involvement predominate in Ig-producing tumours,
.however the overlape is wide
: C- familial amyloidosis
.a group of autosomal dominant diseases •
.start usually in middle age •
in the most common form, amyloid deposits consists of a mutant •
variant of transthyretin ( transport protein for thyroxin ) →
destabilization of the protein → PPt in peripheral & autonomic
→ nerves, heart & the kidney
: C/P •
( neuropathy ( peripheral sensory & autonomic -
.cardiomyopathy & conduction defects -
( renal affection ( less common than AL amyloidosis -
: D- localized ( organ-limited ( amyloidosis
d.t. deposition of other types of amyloid protein in specific •
.organs
: include •
: cerebral amyloidosis -1
intracerebral / cerebrovascular amyloid deposits are seen in -
Alzheimer's disease, hereditary spongiform encephalopathy &
.Down's syndrome
in these conditions : → apoprotein E interacts with B-A4 protein -
( ( in the senile plaques & neurofibrillary angles found in the brain
the gene of apoprotein E is found on chromosome 19 & may be -
.an important factor in the pathogenesis of Alzheimer's disease
haemodialysis : → released amyloidosis d.t. deposition of B2- -2
.microglobulin

72
.senile amyloidosis : → d.t. cerebral deposition of A4 protein -3
: Investigations
histological examination of the infiltrated tissues → diagnosis -1
NB: when tissues aren't readily available → rectal / gum biopsy •
.or abdominal fat aspiration → the characteristic amyloid deposits
electrophoresis & immunoelectrophoresis of serum & urine → -2
.detecting paraproteins
scintigraphy : → using I-123-labeled serum amyloid protein -3
component → useful in assessment of various types of amyloidosis

: Treatment
( ttt.of the underlying A/E ( if present -1
1ry amyloidosis : → regimens incorporating prednisone & -2
( alkylating agents ( e.g. hydroxy urea
transthyretin associated amyloidosis : → is treated by liver -3
( transplantation ( as the liver is the source of this abnormal protein
renal transplantation : → effective in some Pts with renal -4
.disease

73
Bleeding disorders

: diagnosis of bleeding disorders ••


: A- history & examination
? is bleeding a local / generalized problem •
: type of bleeding •
.purpura & mucosal bleeding → platelet disorder -
skin bruising, MS haematoma, haemarthrosis → co-agulation -
.disorder
.F.H : → of bleeding tendency •
.drug history : → in details •
: B- screening tests
CBC & film :→ to detect thrombocytopenia, abnormal platelet -
morphology . the cause of bleeding may be revealed e.g. DIC or
.acute leukaemia
bleeding time : prolonged in vascular wall & platelet defects and -
.in Von-Willebrand's disease
prothrombin time ( PT ) : prolonged in defects of extrinsic & -
.common coagulation pathways
activated partial thromboplastin time ( APTT ) : prolonged in -
.defects of intrinsic & common coagulation pathways
thrombin time ( TT ) : prolonged in fibrinogen ↓, -
( dysfibrinogenaemia & coagulation inhibitors ( e.g. heparin

PT : →↑ in abnormalities in factors VΙΙ, X, V or ΙΙ , liver •


. disease or if the Pt is on warfarin
.( aPTT : →↑ in ↓ of VΙΙΙ, ΙX, X, XΙ, XΙΙ, Ι, ΙΙ & V ( but not VΙΙ •
.BT : →↑ vascular wall defects, platelet defects & Von-Will.dis •
TT : →↑ in ↓ fibrinogen, dysfibrinogenaemia or coagulation •
.inhibitors

74
: C- further tests
if an abnormality is detected in the coagulation cascade, the test -
is repeated using 50/50 mixture of Pt's plasma & normal plasma.
→ if full correction does't occur, this means the presence of a
.coagulation inhibitor
specific factors can be measured functionally by the use of -
mixtures of Pt's serum & serum known to be deficient in a single
specific factor. → thus, if a prolonged aPTT is obtained w' is
corrected by normal plasma but not corrected by plasma with
.factor ΙX deficiency → SO, the Pt is deficient in factor ΙX
. some factors can be measured immunologicaly -
→ platelet aggregation studies : to detect -
.Von-Wellibrand's factor activity •
.congenital platelet abnormalities •
→ other tests : include -
( estimation of fibrinogen & fibrin degradation products ( FDPs •
.assays of coagulation factors •
.tests of fibrinolytic pathway •

75
The purpuras
Def. : a group of disorders associated with superficial capillary •
bleeding mainly in skin & mucous membranes d.t.
thrombocytopenia, platelet functional disorders or ↑ capillary
( permeability ( vascular purpura
purpuric rash : consists of small spots ( purple red ) that does •
.not blanch on pressure, …… when confluent → ecchymosis

Thrombocytopenic purpura
: Causes
. №↓ & platelet function : →↓ survival ↓ -1
.BM infiltration : leukaemia, tumours, myelofibrosis, myeloma -
BM damage : chemotherapy, chemicals, alcohol, drugs, aplastic -
.anaemia
.↓ B12 / folate -
: platelet destruction ↑ -2
.autoimmune : SLE -
coagulation : DIC, thrombotic thrombocytopenic purpura, -
.( haemolytic uraemic syndrome ( HUS
. massive transfusion -
: abnormal platelet sequestration -3
. hypersplenism -
.haemangiomas -

76
Autoimmune thrombocytopenic purpura

the platelets are sensitized with an autoantibody ( IgG ) → •


( removal by liver & spleen ( RES
: C/P
: acute form -1
.seen in children -
.following a viral infection / vaccination -
. remits spontaneously -
: chronic form -2
. seen in adults -
presents with → purpuric rash, superficial bruising, epistaxis & -
.menorrhagia
.splenomegaly is rare -

: Investigations
.platelet count : < 20,000 / cmm -1
.BM examination : →↑№ of megakaryocytes -2
. % platelets antibodies : detected in 70 -3
: Treatment
steroids : prednisone 60 mg/d with cautious ↓ of dose after -1
.remission is achieved
splenectomy : for non-responder to steroids or requires high -2
doses to maintain platelet count < 50,000 / cmm ( most adults will
( need splenectomy
high dose Ig : → block FC receptors of macrophages → -3
removal of sensitized platelets. This must be reserved for
.emergency conditions only → as it's expensive
immunosuppressive drugs : e.g. azathioprine ( for refractory -4
( cases
: platelet transfusion -5
. in life-threatining bleeding -

77
however, because of the presence of antibodies; transfused -
.platelets do not survive longer than Pt's own platelets
danazol : ( = non-virilizing androgen ) → 600 mg /d. → useful -6
.in some cases failing to respond to steroids & splenectomy

78
79
80
81
82
83