35

The Leukaemias
 It is unexplained, abnormal proliferation of WBCs series.
 Proliferation initially within B.M before dissemination to the
peripheral blood, spleen, lymph nodes and other tissues. So there are 3
problems :-
1- Infiltration of B.M. interfere with
haemopoiesis :

 RBCs Plat 
2- Immunological troubles

WBCs (immature) WBCs (abnormal)

 
Infection Auto AB
3- Other tissue infiltration

Liver Spleen CNS

So causes of death infections
Hge
Infiltration of vital organs.
Aetiology
1- Genetic theory familial.
Abnormal chromosome in chr. Myel leuk.
 in Down’s, kleinfilter syndromes
2- Chemicals benzene. In industry
3- Irradiations CML, AML and ALL.
4- Alkylating agents myeloid leukemia
5- Immune deficiency states are associated with an increase in
hematological malignancy.
6- Virus (retrovirus) e.g.
 HTLVI T-cell leukemia
 HTLVII hairy cell leukemia
 36

Classification (According to the cell origin

and the rapidity of the course).

 Acute leuk Lymphoblastic

Myeloblastic (myelogenous)
 Chronic leuk Myelocytic (myeloid)
Lymphocytic.
Acute rapid, clinical course
resulting in death
within months without
effective ttt, this is
due to early B.M
failure
Chronic a more prolonged natural history, this is due to
late B.M failure.
 37

Acute Leukaemia
It may occur any age but :
Lymphoblastic Myeloblastic

Common in children common in young adults

C/P Of acute leukemia
(The manifestations are mainly due to B.M failure).
 Fever : inf. – pyrogens – hypermetabolic state.
 Infection : mouth – throat (sore throat).
 Anaemia : blood loss – enchroachment on RBCs precursors.
 Bleeding : platlets
 Bone pains : + arthritis tender sternum.
 LN +++ (generalized)
 Liver ++, spleen ++.
 Tissue infiltration Skin itching
Bone pathological fracture
CN.S.

m
e
n
i
n
g
i
t
i
s

w
i
t
h
 38

h
e
a
d
a
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e

a
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d

c
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a
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a
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 39

i
s
Retina  vision

Porta hepatis obstructive. J.

Serous
membranes effusion.

Hr. cardiomyopathy
Kidney tubular disorder
with  Na-  K

N.B. Liver, Spleen ++, L.N. common with lymphoblastic leuk,

also lymphoblastic leuk have better prognosis myeloblastic
(V. bas prognosis).

Investigations
1- WBCs 20 – 100.000/c.mm with blasts 90%
2- RBCs normochromic – normocytic Anaemia
3- Platelets Thromobocytopenia.

N.B. Subleukaemic leuk Nr. Or subnormal WBCs

count with predominant blasts.
A leukaemic leuk normal WBCs with no blast B.M.
4- B.M. ex. Confirmatory
D.D. * Fever with sore throat. E.g. infectious mononucleosis.
* Other causes of An.
* Other causes of thromobocytopenia.
* Causes of leukmoid picture.
Poor of acute lymphoblastic leuk
* Age < 2 yrs > 10
* TLC > 100.000
* Plat < 25.000
* L3 – CNS infiltration
 40

TTT
 General supportive measures
 Anaemia blood transfusion
 Bleeding plat transfusion
 Infections Ab, gamma glob, / antifungal /, sutrim for
pneumocystis carnii, acyclovir for H. simplex, gancyclovir for
CMV.
 Hyperuracemia allopurinol
 Treatment of acute lymphoblastic leuk
I – Induction of Remission (ttt for 4-6 wks) VAP

Vincristine adriamycin prednisolone

1.5 mg/m2/wk I.V 25 mg/m2/wk I.V. 60mg/m2/oral/D
or Dexamethasone
Signs of remission
Improvement of C/P B.M blasts below 5% no blast in blood
II- Consolidation therapy (Intensive ttt)
To treatment residual leukemic cells, CNS directed
treatment
By : * Whole brain irradiation
* Intrathecal methotrexate or cytosine arabinoside.
 41

III- Maintenance therapy (2M)

For about 2 yrs

Mercaptopurine oral Methotrexate oral

Treatment of acute myeloid leuk

Remission :
 Cytkosin arabinoside (are – c)

 6 thioguanine (lanvis) or doxorubicin after remission the best is

B.M transplantation the course may be repeated.

Recent trends in ttt of leuk

 Monocional Abs to the leukemia blasts.
 BCG
 Interleuk in 2
 Activated natural killer cells
 B.M. transplantation

N.B. * Pt who develop meningeal leuk. Is treated with

Cranial irradiation.
Intrathecal methotrexate. Or cytosin arabinoside
* Retenoic acid can correct coagulation defects especially in M3

Classification of acute leuk

(lymphoblastic)

L1 L2 L3
Cells are small cells large mitotic index early
And homgenous and heterogenous CNS infiltration

Acute myeloid
M1 undifferentiated M2 differentiated
M3 promoyelocytic M4 myelomonocytic
M5 monocytic M6 erythrocytic leuk
M7 megakaryocytic leuk
 42

Cytochemical classification of acute leuk

ALL AML
Peroxidose – ve + ve
Sudanblack – ve + ve

Chronic myeloid leukemia

= chr. Granuloeytic leuk.

Abnormal proliferation of immature granulocytes in the blood, B.M. liver

& other tissues.
C/P middle age – gradual onset
Sympt. * drag. Pain in if hypochand. (spleen)
* stitching pain splenic infarction * bony aches
* fever, sore throat. * bleeding tendency
Signs - huge spleen - fever
- L.N. ++ - liver may ++.

N.B. Blast crisis

i.e. cases with chr. M leuk develop a transformation into a pattern
indistinguishable from acute myeloblastic leuk. It is a fatal
condition.

Investingation
1- Bl. Picture WBCs (100.000 – 500.000/c.mm)
myelocytes 15-20%  myeloblast with blastic
crises. Basphilia and eosinophilia usually
present , platelet may normal, low or raised.
2- Sternal puncture, liver biopsy myelocytes.
3-  Uric, acid vit B12, due to granulocyte production of
transcobalamin I.

4- Chromosomal study Philadelphia chromoscome. It is

translocation of long arm of Chr. No. 22
 43

to long arm of chr. No. 9. it is present in

granulocytes precursor.
Treatment
1- G. measures Bl. Transfusion
Ab for infetion
2- Specific ttt (The goal of ttt in chronic phase is to myelopoiesis)
 Busulphan or hydroxy urea orally, stopped when
TLC<20.000.
 Radio therapy for the spleen.
 Alpha interferon IM or S.C it can maintain control of this
disease + hydroxy urea.
 Leucopharesis.
 Splenectomy  sympt.
 Blastic crises.

If insidious onset if acute onset

Hydroxy ures prednisone
 Bone narrow transplantation can be done.

 Dose of businlphan 6-8 mg/D ocal, usually lower WBCs count and
 the size of spleen within 4-6 wks.
 Hydroxy urea 1000-1500mg/d improvement within 2-6wks.
 44

Chronic lymphocytic leuk.

It is a leukemia CCC By mostly, the cells of origin is B lymphocyte

Infiltration of lymphoid organs e.g. liver,
spleen, L.N. and also B.M.
 Ab formation infection.
Abnormal immune reaction auto Ab
C/P 1- Old age (usually the disease occur at age >50 yrs).
2- Some cases are asympt.
3- G.L.N. ++ moderate in size.
4- Liver & spleen ++.
5- Aut. Imm. H. anemia
6- Bleeding tendency.

Staging of chr. I.L. A * Lymphocytosis.

* <3 groups of L.N.
C B * No An. thrombocytopenia
An. plat > 3 L.N only

Investigations
* WBCs 50-250.000
> 75 (small lymphocytes)
* Hb 
* Plat.
* Coomb’s + ve H. An. (warm Ab).
* Str. Puncture Lymphocytes.
* L.N. biopsy lymphocytes.
Treatment (stage A not ttt, stage B no ttt if sympt. Stages C ttt)
Aim of ttt is to  sympt.
 Pt. Old, disease s. prog., cytotoxic drugs are harmful.
 Usually, no remission. So give supportive treatment + follow up.
The disease may remain stable for several years.
 45

Indication of ttt
1- Severe cytopenia.
2- Autoimm. H. An
3- Disfiguring L.N. or sympotomatic or ganomegally.
Chemotherapy C horni C

(oral) chlorambucil Or cyclophosphamid (oral)

(0.1-0.3 mg/kg)/d (2-3 mg/kg)/d for 5 days every 3wks
 The treatment given till improvement of the above indication but
maintenance therapy has no definite value.

Steroids taken with

Autoimm. H. An pancytopenia

Hairy cell leukemia

 It is a lymphoid neoplasm, the term hairy is descriptive of
cytomplasmic projections of the leukemic cells (hairs). It is caused by
HTLV II.
 There is proliferation of abnormal B. cells.

C/P * Spleen ++ - L.N ++ (rare)

 Infections – vasculitis – erythema nodosum

ttt * Splenectomy in the past was the corner stone of therapy, now it
is indicated in severe cytompenia.
* Ab for infection.
* Interferon.
* steroids for vasculitis.
 46

Hematopoletic growth factors

 Cux CSP – granulocyte – macrohage clonny. Stimulating
colour proliferation and production of eosinophils,
monocytes.
 G. CSP grandtocyte colony stimulating factors
granulocyes.
 IL 3,5 monocytes, eosiniphils
 thrombopoietin platelets

The myelo proliferative

disorders

Group of disease ch. Ch. By proliferation of all B.M. elements with

certain clonal predominance.

Proliferation of fibroblasts proliferation of stem cells

Increase of B.M. fibrosis expansion of all BM elments

Myelofibrosis RBCs, WBCs, platelets with

dominant one element
They include :
 Polycythemia verra dominant RBCs
 Myelo fibrosis dominant fibroblasts
 Essential thromobocythemia dominant plastelets
 Chr. Myeloid leukemia dominant WBCs
 47

Polycythemia rubravera
Polycythemia rubravera
It is a neoplasm of B.M. stem cells affects mainly erythroi, ine (mainly,
but also there are increase on WBCs and platelets.

Causes of polycythemia
1- Polycyth. Rubra vera (myeloprolifecative disorder).
1. Secondary  hypoxia e.g. G.O.A.D.
 Cushing (cortison)
 Polycystic kid disease (erythropoietin)
 Hypernephroma, hepatoma (erythropoientin)
2. Relative (Gaisbock’s polycth)  affect obese hypertensive men.
That is decrease of plasma volume.
C/P 1- Features of the cause in secondary polycythemia.
2- polycythemia Rubra vera.
 Plethora hyperviscosity * hyperuircemia. Engorged
 Spleen ++ plat.Dysfunction * itching due to retinal v.
* C. H. F. Thrombosis  histamine Production
* thrombosis * Hge by basophilia
* cerebral blood flow

N.B.
In 2ry polycythemia there are plethora, hyperviseosity but no spleen and
erythropoietin.

Criteria for dagnosis polycyth. Vera :-

A1 : red cell mass B1 : platelet > 400.000
> 36 ml/kg (male) > 32 (female) B2 : TLC > 12.000
A2 : Normal O2 (arterial) B3 : leucocytic Alk. P.
A3 : splenomegally B4 : serum B12

Diagnosis = A1 + A2 + A3
Or A1 + A2 + only two from B
 48

Investingations
1- Bl. Picture  in all series mainly
RBCs
2- B.M.  in B.m. expansion
3- See above criteria + erythropoietin.
Treatment
1- Radioactive p (I.V) or chlorambucil but they may  acute
leukemia.
2- Venesection to keep the PCV < 45%.
3- Hydroxy urea is better than chlorambucil and radioactive P.
4- ttt of complication.

Myelofibrosis
 Expansion of all B.M. elements with predominant marrow fibrosis
(late).
 Extramedullary
hematopoiesis liver & spleen ++.

C/P
Anaemia DD of huge spleen
Huge spleen – liver ++
Portal H. due to portal blood flow

Investigation
1- Hb  - tear drop cells (RBCs) ?!
2- Leucocytosis with shift to the left.
3- B.M.  dry tap.
4- B.M biopsy (trephine from iliaccrest).
Treatment
* Supportive folic A., iron, androgens (danazole)
Bl. Transfusion + B.M.
* Splenectomy * B.M. transplant
 49

* Hydroxy urea to  WBCs count, steroids with automimmune.

H.An.
 50

Essential thrombocytosis
  plat. Count > 1 million/ml with
hge

thrombosis
 Asymptomatic patients observed but with symptoms we can use
hydroxy urea.
N.B. Benign reactive thromobcytosis
causes

Plat. <1 million splenectomy bleeding hemolytic An.

Stress and exercise chronic inflammatory disease

e.g. rheumatoid arthritis
 51

Haemostasis
Definition
ㄱ It means stoppage of bleeding and prevention of blood loss
when a blood vessel is injured.
ㄱ It occurs by the following:
* vasoconstriction * platelet plug
* blood clot * repair of damaged bl. V.
So it’s requirements Coagulation
factors
Platelets.
Vascular
endothelium and blood vessel wall
stoppage of bleeding = thrombus formation
similar to a building

base stones cement substance

blood vessel platelets fibrin (coag.)

A) Platelets tests

I- Plat. Count. Normally 140.000 – 400.000cmm.

Thromobcytopenia clinical purpura spontaneous bleeding

< 100.000 < 40.000 < 20.000
N.B. The role of drug of plat, is very important so sudden
drop
Count  hge (regardless the exact count)

II- Bleeding time

IVY’s method : or (template method)
Asphygmomanometer cuff is placed around the pt’s arm & inflated
to 40 mm. The forearm is punctured by special lancet. A filter
paper is used to blot off gently at intervals.
Duke method : Bleeding time IVY = 2-7m.
Duke = 1-4 m.
 52

If bleeding t. is prolonged; Thrombocytopenia

Thromboasthenia
III- Hess capillary fragility test (it detects vascular purpura, may be
positive in other types of purpura)
Put syphygmomanometer cuff on the arm & inflate between systolic and
diastolic then draw an area below the cubital fossa 5cm diameter
Normally : 0-5 petichae are seen in this area, after 5 minutes.
N.B. In vasculitis and H. schonlein P, hereditary hagic telangiectasia,
bleeding time may be normal.

B) Platelets function

Adhesion Aggregation

Role of platelets in
haemostasis
Vascular injury

Exposure of collage Tissue

thrombo-
Vasoconstriction plastin
By: Release of (vwf) from endothelium
Nervous reflex
Myogenic contraction Plat. Adhesions
Release of

Plat. Release P1 F3

+ Coag.
P.G. + ADP
TA2 + serotonine+
+ aggregation

Plat. Plug
 53

fibrin
Other Function of platelets:
Release of growth factor that causes multiplication and growth of
fibroblastic as well as the vascular endutieled and smooth muscle
cells (which repair the damaged vascular walls).

Process of coagulation
1. Extrinsic pathway : (It is more rapid) i.e. occur in 15 seconds
It is triggered by trauma

Release tissue thromboplastin

Activation of factor VII

To common pathway to activate factor 10 in presence of Ca

2. Intrimsic pathway : (it requires few minutes)
It is triggered by contact of blood with foreign tissue e.g. anything
other than endothelium. eg. Collagen.
Ca
12 a12
Throbus
11 a11

9 Ca a9 + a8
Atheroma

activate factor 10 in presence of Ca

Common pathway:
Intr. P. Or extr. P.

10 active 10

prothrombin thrombin

fibrinogen fibrin
 54

then to plat
Plug

N.B. Both systems are involved in clotting following tissue injury, where
the extrinsic system occurs first followed by the intrinsic system.

Factors of coagulation: (all present in the plasma except

F III)
I : Fibrinogen II :
Prothrombin
III : Thromoboplastin (in tissue only.) IV : Ca
V : Proaccelerin VII : Proconvertin
VIII : Anti-hemophilic globulin IX : Christmas F.
X : Stuart prower factor. XI : Hegman F
XII : Plasma thromboplastin
XIII : Fibrin stabilizing factor.

Tests for the intrinsic coagulation

1. Whole blood clotting time
It is about 5-10m. this test is insensitive as activation of hagman F
takes several minutes.
2. Partial thromboplastin time
It is very sensitive
MCQ/ It is normally 35-45 seconds. It is prolonged in  of factors :-
I, II, V, VIII, IX, XI OR XII

N.B. * Tests for intrinsic pathway measures factors XII, XI, X, IX,
VIII.
* Heparin therapy affect clott. T. & P.T.T.
* Ptn under heparin therapy we can adjust dose
according to P.T.T. it must be double of normal.
* Therombin time (TT): 10-20 seconds prolonged in
 Hypofibrinogenaemia
 55

  FDPs
 heparin therapy
 56

Test for extrinsic coagulation

Prothrombin time (P.T.) normally 10-14 sec.

It is prolonged in  liver D.
  of factors I, II, V, VII and X.
 oral anticoag.

N.B. * Pt under oral anticoagulant  we can adjust the dose  P.T.

must be doubled.
* Prolonged P.T.  extrinsic pathway defect.
* Prolonged P.T.  intrinsic pathway defect.
* Prolonged P.T & P.T.T.  common therapy defect or combined
defects.

Fibrinolytic system
plasminogen
Plasminogen activator plasmin

Fibrin FDP
 57

Purpura
Definition Multiple spontaneous capillary hge in the skin & m.m.
due to defects in plat. Or in the cap. Wall.

Causes

A. Platelet abnomarlity
1. Thrombocytopenia

1-ry 2-ry
(ITP)
 plat. Survival  pla. Production
* hypersplenism * B 12
* Aut. Ab e.g. SLE * B.M.
* Uraemia * Uraemia

N.B. * Alchohol, thazides, estrogens, cyclophosphamide

- of megakaryocytic series production

* Penicillin & cebalosporine. Sulfa & methyl dopa &
earthamazepine destroy plat.
* Heparin may lead to thecombocytopenia due to drug Ab
binding to platelets or by direct agglutuation of platelets by
heparin.

2. Thromboathenia

Hereditary acquired

Drugs Uremia
3. Thrombocytosis leading to

Purpura with coagulation

Platelete dysfunction
 58

B. Vascular purpura

Senile inherited allergic p infections

= Purpura simple = henoch. Sch.P. (meningitis with
septicemia)

C/P of purpura :

I- Bleeding Skin : multiple petichae. UL, LL,

neck,
Upper chest. Pinhead not raised
M.M. : epistaxis
Internal organ : e.g. cerebral hge
II- Features of the cause
 59

Idiopathic thrombocytopenic
purpura
Autoimmune diseases auto Ab attack
platelets
C/P 2 types :

Acute
* child male = female
* acute onset
* spleen usually not++
* plat.  < 20.000
* 10%  chronic
chronic
* young females
* Gradual (lasts for months)
* spleen just palpable.
* plat < 100.00

N.B. Evan’s – antoimmune H. An + T.T.P.

Abs attack RBCs
Plat.

Investig
 Plat C. 
 B.M. hyperplasia of megakaryocytes.
 Ig G against plat.
ttt
acute :
Good response to cortisone 1-2 mg/kg/d. for few wks  remission
Chronic :
Prednisone for 2-3 ms. (1 mg/kg)
Value of cortisone :
1- improve cap. Fragility
2- Ab
3-  phagocytic activity of spleen.
 If no response splenectomy.
 Some cases resist after splenectomy give
cytotoxic D.
 Other lines :
 60

Plasmaphoresis danazol blocking Ab

Ig G + BM
 61

Platelet consumption $
1- DIC.
2- Thrombotic thrombocytopenic purpura.
3- Hemolytic uremic $
T.T.P. middle aged female.
thrombocytopenia.
Microangiopathic H. An
Neuro & renal abnormalities.
Hemolytic uremic $
Child – postpartum
Microangiopathic H. An.
Plat 
Hyaline thrombi in the kidnneys.
N.B. * Dilutional thrombocytopenia can follow massive
transfusion.
* Huge spleen can sequester up to 90% of platelets.

Qualitative plat. Disorders

1- Inherited
Adhesion defect * Aggregation defect
(Von Willebrand’s D) e.g. Glanzmann’s disease
female & male * Adhesion defect e.g.
Bernard
Aut. Dominant soulier $
B1. Time normal; plat count
normal plat. Aggregation
Abnormal adhesion
V.W.F. which synthesized by endothelium
ttt Factor 8
Fr. Frozen plasma
DDAVP (synthetic ADHr.) release VWF
2. Acquired disorder of plat
Plat. Arachidonic
Cyclo-oxygenase Causes:
T A2  Aspinine & NSAID
suppress the cyclo
my genase
aggregation  Uremia
 62

Henoch – schonlein purpura

It is a self – limited type of vasculitis which occurs in children and young

adults.
Aet. Allergy.
Post – strept. ?!
After intake of drugs.

C/P * Child =- abd – Pain.

* arthritis.
* purpuric eruption (mainly buttock)
 kid G.N. with hematuria, small percent may develop
acute renal failure.

ttt Self limited, or we can use steroids to provide symptomatic relief

of the joint and abdominal pains but do not alter the course.

Hemophilia
It is transmitted as X-linked recessive
C/P
ㄱ Severe cases diagnosed after birth, by cephalhematoma or
bleeding at circumcision.
ㄴ Excessive prolonged he after trauma.
ㄷ Ecchymosis, haematoma.
ㄹ CIT bleeding CNS bleeding.
ㅁ Haemarthrosis fibrosis & deformity
ㅂ Femoral neuropathy due to pressure from retroperationeal
hematoma.
ㅅ Calcified masses of blood (pseudotumour syndrome).
Investig * Clott. T.  - P.T.T.  * normal plat. Count
* normal P.T *  factor VIII
Complications
ㄱ He – arthropathy
ㄱ Hepatitis – AIDS  factor 8
ㄱ Arthropathy
Genetically : made F8
 63

Severity of Haemonbillics
 Severe factors  sport Haemorthosis.
 Moderate factor  post frumalit.
 Mild factor 8 (10-50%)  more injury  bleeding
ttt
 Avoid trauma – and antiplatelet.
 Fr. Fr. Plasma.
 Factor 8 – fresh blood
 Antifibrinolytic e.g. tranxamic acid.
 DDAVP (desmopressin)  level of factor
8.

Q. Evaluation of case with bleeding tendency

Coag. Defect Plat. Defect Vascular defect
* Inherited * Acquired * Acquired
* Male * Female * Female
* +ve F.H. * F.H. –ve * -ve F.H.
* Haematoma * Mucosal (epistaxis) * Petichae with raised
* Haemoarthrosis * petichae without edge
raised edge
* Poor effect of * Good effect of * Good effect of
compression compression compression
* Bleeding is post- * Spontaneous * Traumatic
traumatic bleeding

N.B.
 Purpura Gum bleeding
petichae
or small
ecchymosis
 Coagulation defect large ecchymosis
ha
ematoma
lar
ge marthrosis
 64

 Factor IX  (hemophilia B) – Christmas D. X linbed R C/P

similar to bemophilia A but factor IX  .
  Hegman factor, there is prolonged P.T.T but with no bleeding
tendency.