Universitatea Titu

Maiorescu
CU
RS
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Pro U MA DI
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ni v LO NA I
dr GI NT
Ion E ER
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oiu
- Other
Connective
Tissue Diseases
Antiphospholipid
Syndrome
• Triad: Any TEST plus:
– Thrombotic events
– Spontaneous PTT/LAC
abortion(s)
– Thrombocytopenia
• Others: Migraine,
Raynauds, Libman- RPR Cardiolipin
Sacks endocarditis, MR,
Transverse myelitis,
neuropathy 3 Tests
• Ab found in >30% SLE,
other CTD
• Correlates with IgG Ab
Reiter's Syndrome
• Arthritis that produces pain, swelling, redness and
heat in the joints. It can affect the spine and
commonly involves the joints of the spine and
sacroiliac joints. It can also affect many other
parts of the body such as arms and legs. Main
characteristic features are inflammation of
the joints, urinary tract, eyes, and
ulceration of skin and mouth.

• The symptoms are fever, weight loss, skin rash,

inflammation, sores, and pain.
Reiter's Syndrome
• Reiter's often begins
following inflammation
of the intestinal or
urinary tract. It sets off
a disease process
involving the joints,
eyes, urinary tract, and
skin. Many people have
periodic attacks that
last from three to six
months. Some people
have repeated attacks,
which are usually
followed by symptom-
free periods.
Psoriatic Arthritis
• Causes pain and swelling in
some joints and scaly skin
patches on some areas of the
body.
• The symptoms are:
– About 95% of those with
psoriatic arthritis have
swelling in joints outside
the spine, and more than
80% of people with
psoriatic arthritis have
nail lesions. The course of
psoriatic arthritis varies,
with most doing
reasonably well.
– Silver or grey scaly spots
on the scalp, elbows,
knees and/or lower end of
the spine.
– Pitting of
fingernails/toenails
– Pain and swelling in one or
Degenerative Joint
Disease
• In early disease,
pain occurs only
after joint use and
is relieved by rest

• As the disease
progresses, pain
occurs with
minimal motion or
even at rest

• Nocturnal pain is
Treatment and Prognosis
of Degenerative Joint
Disease
• Meds
• Early PT/exercises
• Heat/cold therapy
• Joint protection
• Surgery

• Osteoarthritis is a slowly progressive

disease
• The eventual outcome is complete
destruction of the joint, and
ultimately surgical intervention is
required
 ARTRITA JUVENILA
IDIOPATICA
Juvenile
Idiopathic
Arthritis (JIA)
and Other
Rheumatic
Diseases in
Children

-
Etiology
• Immune mediated disease
– Abnormal immunoregulation
– Abnormal cytokine production in
the inflammatory pathway (TNF,
IL-6, IL-2R, IL-1alpha)
• Complex genetic
predispositions
– HLA associations
• Environmental triggers
– Infections
– Trauma
– Stress
Diagnostic Tests

• There is no lab test that

diagnoses JIA
– CBC
– Rheumatoid factor
– Antinuclear Antibody (ANA) – with
titer
– ESR or CRP
Classification Criteria for JIA
• Age at onset <16 years
• Duration of Arthritis: 6 weeks
• Arthritis in one or more joints
defined as swelling or effusion, or
presence of two or more of the
following signs: (in 1 or more joints)
– Limitation of ROM
– Tenderness or pain on motion
– Increased heat
• Exclusion of other diseases
Chronic arthritis
in childhood: JIA
• It’s not a single disease, but a group
of related, genetically
heterogeneous, phenotypically
diverse immunoinflammatory
disorders affecting joints and
other structures, possibly
activated by contact with an external
antigen or antigens.
 Polyarticular JIA - RF
negative
• Five or more
joints in the first
6 months of
disease
• Asymmetric joint
involvement
• Large joints of
knees, wrists,
elbows and
ankles often
affected
• Morning stiffness,
Polyarticular - RF positive
• Arthritis affecting 5 or more joints in
the first 6 months of disease.
• Similar to adult RA
• Females with onset in adolescence
• Rheumatoid nodules
• Early onset of erosive synovitis
• Symmetric joint involvement
• Small joints of hands or feet are
affected
• TMJ: micronathia
• Cervical spine may be affected
 Rheumatoid Nodules
• Occur in 5-10% of
children with JIA
• Most frequently on elbow
• Pressure points, digital
flexor tendon sheaths,
Achilles tendons, bridge
of nose in child who
wears glasses
• Firm or hard, usually
mobile, nontender.
• Solitary or multiple, may
change in size, may last
months to years.
 JIA: Psoriatic Arthritis
• Arthritis and psoriasis or
• Arthritis with 2 of the
following:
– Dactylitis - sausage like
swelling of toe or finger
– Nail pitting
– Psoriasis in a first degree
relative (parents,
siblings)
• Slightly more females
• Symmetrical involving
large and small joints
Medications
• NSAIDs
• DMARDs:
Methotrexate,
Plaquenil,
Sulfasalazine
• Biologic response
modifiers
• Glucocorticosteroid
s
• Miscellaneous
Methotrexate
• Standard dose: 10-15 mg/m2 or 0.3-
0.6 mg/kg/week, subQ
• Improvement seen in 6-8 weeks, but
may take up to 6 months.
• Labs every 6 weeks: CBC, CMP
• No alcohol
• Used for treatment of uveitis (4-6
months to determine efficacy)
Glucocorticosteroids
• IV Solumedrol and daily oral
Prednisone

• systemic flares ~ pericarditis or persistent

Sx
• temporary measure until DMARD is
effective

• Joint injections - usually under

sedation
– Triamcinolone hexacetonide (Aristaspan)
Universitatea Titu
Maiorescu
CU
RS
HE ME
Pro MAT DI
CI
fu OL
ni v OG NA I
dr IE NT
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i nt
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ersitatea “Titu Maiorescu”

S MEDICINA INTERNA
atologie I
Va fi greu???
Topics
Hematopoiesis
Complete blood count (CBC)
Anemia
Polycythemia
Leukopenia
Leukemia
Lymphoma
Myeloma
Coagulation
Transfusion
How much blood is in the
human body?
• About 5 liters
 Composition of blood
• . Blood is composed of:
– Plasma
– RBC
– WBC
– Platelets
Plasma
• Plasma consists of:
– 90% water.
10 % solutes:
– albumin,
– electrolytes and proteins.
– clotting factors ,
– imuno-globulins
– circulating antibodies and
– fibrinogen
ABO blood groups:

A, B, AB, and O
Blood Typing
ABO blood groups: A, B, AB, and O

35
If a blood transfusion is given to
a person who has antibodies to
that type of blood, then the
transfused blood will be attacked
and destroyed (transfusion
reaction)
36
Rh factor

• The “Rh factor” is another

major antigen on the RBC,
called D – is autosomal
recessive
–DD and
Dd: Rh+
Dd: Rh-
37
Hematopoiesis
 HEMATOPOIEZA

All cells arise from same blood stem cell

(pluripotent hematopoietic stem cells)

Definiţie
= formare al elementelor figurate ale sângelui:
• proliferarea
• diferenţierea
• trecerea în circulaţie
• cuprinde:
• 1-Eritropoieza = formarea eritrocitelor
• 2- Leucopoieza = formarea leucocitelor
• 3- Trombocitopoieza = formarea trombocitelor
Summary of blood
forming organs
Bone Marrow
Bone marrow is the spongy substance
found in the center of the bones.
• It manufactures bone
marrow stem cells,
• which in turn produce blood cells.
• Red blood cells – carry oxygen to tissue
Contain hemoglobin,
• Platelets – help blood to clot
• White blood cells – fight infection
ZA
2.lymphoid stem cells
ERITROPOIEZA
ERITROPOIEZA
Maturarea eritrocitelor:
 reducerea dimensiunii
 creşterea volumului citoplasmatic + mai puţin bazofilă,
 reducerea dimensiunii nucleului  expulzia lui.

Durata de evoluţie CSP - reticulocit = 5 - 7 zile.

Producţia eritrocite/zi = Distrugere eritrocite/zi
= 50 ml sânge.
ERITROPOIEZA
Substanţe necesare eritropoiezei

 A-Proteine
 B. Minerale: fier, cupru, cobalt,
zinc
 C. Vitamine: B12, acid folic,
B6, C
 What does hemoglobin
do
• Hemoglobin picks
up the oxygen
molecules and
drops off CO2
Leukocyte types
• Artificial division into

1-Granulocytes
- neutrophils,
- eosinophils,
-basophils

• 2-Agranulocytes:
lymphocytes,
monocytes
48
 Leukocytes granulocytes

neutrophil eosinophil

basophil

small lymphocyte monocyte

49
 Agranulocytes: Lymphocytes*

• 20-45%
• lymphoid
connective
tissue, e.g.
lymph nodes,
tonsils, spleen
• Two main
types attack
antigens in
different ways
• T cells
* • B cells

50
T cells attack foreign cells
directly
Killer cells (“cytotoxic”), or
CD8+ is a main type

51
B cells
• Differentiate into plasma cells
• Plasma cells secrete antibodies

52
 Agranulocyte
s Monocytes*

• 4-8% of WBCs
• In connective
tissue they
transform into
macrophages
(phagocytic
cells with
pseudopods)
*
53
 Platelets*

*
54
Disorders of Blood
cells
• .

55
Disorders of Erythrocytes
Introduction
• The main function of red blood cell
• Transfer of O2 from lungs to tissue
• Transfer of CO2 from tissue to
lungs

• To accomplish this function red cells has

haemoglobin (Hb)

• Each red cell has 640 million

molecules of Hb
Structure and function
of Haemoglobin
.
Introduction
• Haemoglobin (Hb), protein
constituting 1/3 of the red blood
cells

• Synthesis begins in proerythroblast

• 65% at erythroblast stage
• 35% at reticulocyte stage
Two parts
• Haem
• Globin
Synthesis of
Haemoglobin (Hb)
• Haem & globin produced at two
different sites in the cells

• Haem in
mitochondria
• Globin in
polyribosomes
Synthesis of
Haemoglobin
Structure of Haem
Synthesis of globin
Synthesis of globin
• Various types of globin combines with
haem to from different haemoglobin

• Eight functional globin chains,

arranged in two clusters the
• - cluster (, ,  and  globin genes)
on the short arm of chromosome 11
• - cluster ( and  globin genes) on
the short arm of chromosome 16
Globin gene clusters
Synthesis of globin
Globin synthesis, starts at 3rd
week of gestation
• Embryonic
Haemoglobin Gower I (  2 2)
Haemoglobin Portland (  2 2)
Haemoglobin Gower II ( 2)
• Fetal : HbF ( 2 2), HbA ( 2 2)
• Adult : HbA, HbA2 (  2 2), HbF.
Alpha & beta chains
Functions of
Haemoglobin
• Oxygen delivery to the tissues
• Reaction of Hb & oxygen

• Oxygenation not oxidation

• One Hb can bind to four O2 molecules
• Less than .01 sec required for
oxygenation
• chain move closer when oxygenated
• When oxygenated 2,3-DPG is pushed out
• chains are pulled apart when O2 is
unloaded, permitting entry of 2,3-DPG
resulting in lower affinity of O2
Oxy &
deoxyhaemoglobin
Summary
• Normal structure including the
proportion of globin chains are
necessary for the normal function of
haemoglobin

• Reduced haemoglobin in the red blood

cells due to any abnormality of any of
its constituents result into a clinical
situation called anaemia

• Metabolic & other abnormalities result

into abnormal oxygen supply to the
tissue
Disorders of Erythrocytes
• 1-Anemia: not enough cells
• 2-Defect in hemoglobin
• 3-Polycythemia: too many
cells

71
Disorders of Heme
synthesis
Disorders of Heme
synthesis
HEME-CONTAINING PROTEINS

 Hemoglobin

 Myoglobin

 Cytochromes

 Catalase

 Some peroxidases
STRUCTURE OF HEME

Ferrous iron (Fe2+)

Protoporphyrin IX:
contains 4 pyrrole
rings linked
together by
methenyl bridges
 The two major cell types that are active in heme
synthesis are hepatocytes and bone marrow
erythroblasts
 85% of total synthesis occurs in erythroid cells

Heme Synthesis
Disorders of Heme metabolism

Heme biosynthesis
Porphyrias

Heme degradation
Jaundice
BLOOD
CELLS Stercobilin
excreted in feces Urobilin
excreted in urine
Hemoglobin
Globin Urobilinogen
Heme formed by bacteria KIDNEY
O2 reabsorbed
INTESTINE into blood
Heme oxygenase
CO via bile duct to intestines
Biliverdin IX
NADP Bilirubin diglucuronide
H
Biliverdin (water-soluble)
reductase

NADP 2 UDP-glucuronic acid

Bilirubin+ Bilirubin
(water-insoluble) (water-insoluble) LIVE
via blood to R
the liver

Figure 2. Catabolism of hemoglobin

Classification of the
Porphyrias
• Multiple ways to categorize porphyrias:
– Hepatic vs. Erythropoietic: Organ in which
accumulation of porphyrins and their
precursors appears
– Cutaneous vs. Non- cutaneous
– Acute and non-acute forms

• Acute:
– Aminolevulinate dehydratase deficiency
porphyria (ALA-D)
– Acute intermittent porphyria (AIP)
– Hereditary coproporphyria (HCP)
– Variegate porphyria (VP)

• Chronic:
– Porphyria cutanea tarda (PCT)
– Erythropoietic protoporphyria (EPP)
– Congenital erythropoietic porphyria (CEP)
– Hepatoerythropoietic porphyria (HEP)
Enzymatic
Deficiencies

• All of the heme

pathway intermediates
are potentially toxic.

• Their overproduction
causes the
characteristic
neurovisceral and/or
photosensitizing
symptoms.
PORPHYRIA CUTANEA TARDA
 Most common porphyria

 Hepatic, autosomal dominant

 Disease is caused by a deficiency in uroporphyrinogen

decarboxylase, which is involved in the conversion of
uroporphyrinogen III to coproporphyrinogen III

 Uroporphyrinogen accumulates in urine

 Patients are photosensitive (cutaneous photosensitivity)
Accumulation of porphyrinogens results in their
conversion to porphyrins by light
Porphyrins react with molecular oxygen to form
oxygen radicals
Oxygen radicals can cause severe damage to the
skin
 PORPHYRIA
CUTANEA TARDA
 Acute intermittent
porphyria

Van Gogh

King George III

Mary Queen of Scots
Acute intermittent porphyria

• The prevalence of AIP in the United States is thought

to be 5–10 per 100 000.
– It is more common in northern European countries,
such as Sweden (60–100 per 100 000), Britain and
Ireland.

• Acute intermittent porphyria PBGD gene mutation is

inherited in an autosomal dominant fashion.

• Affects women more than men, with a ratio of 2:1.

• Most patients become symptomatic at age 18-40
years.
– Attacks occurring before puberty or after age 40
years are unusual unless a major provocation
• Most patients are completely free of symptoms
between attacks.
• Course of the neurological manifestations is highly
variable.
– Acute attacks of porphyria may resolve quite
 Symptoms
• Attacks involve neuro-visceral symptoms but no skin
manifestations:
– The sequence of events in attacks usually is (1) abdominal
pain, (2) psychiatric symptoms, such as hysteria, and (3)
peripheral neuropathies, mainly motor neuropathies.

• Gastroenterological Symptoms most common:

– Constipation (48–84%), colicky abdominal pain (occurring in
85–95% cases), vomiting (43–88%), diarrhea (5–12%)
• Patients may have CNS signs consisting of seizures (10–
20%), mental status changes, cortical blindness , and coma.

• Patients often experience peripheral neuropathies (42–

60%) that are predominantly motor and can mimic Guillain-Barré
syndrome.

• Patients may develop fever(9–37%), hypertension (36–

54%) and tachycardia (28–80%).
Mechanism
• The exact mechanism underlying these
complaints is not yet well understood,
various hypotheses have been put forward:

– Excess amounts of PBG or ALA may cause

neurotoxicity (Meyer et al, 1998)

– Increased ALA concentrations in the brain may

inhibit gamma-aminobutyric acid release
(Mueller & Snyder, 1977; Brennan & Cantrill,
1979)

– Heme deficiency may result in degenerative

changes in the central nervous system (Whetsell
et al, 1984)

– Decreased heme synthesis in the liver results in

decreased activity of hepatic tryptophan
pyrrolase (TP), a heme-dependent enzyme,
possibly resulting in increased levels of
serotonin
Precipitants
• Drugs: most common precipitate of acute attacks :
– Barbiturates and sulphonamides being most
common

• Reduced energy intake: even brief periods of

starvation during dieting, postoperative periods, or
concurrent illness.

• Tobacco smoke: polycyclic aromatic hydrocarbons,

are known inducers of hepatic cytochrome P450
enzymes and heme synthesis.
– An association between cigarette smoking and
repeated attacks of porphyria was found in a
survey of 144 patients with AIP in Britain (Lip et
al, 1991).

• Infections, surgery and stress.

 Diagnosi
s • Demonstration of porphyrin
precursors, such as ALA and/or PBG, is
essential for the diagnosis of acute
porphyrias.

• Porphyrin analysis is necessary for

PBG in urine is
oxidized to porphobilin
upon standing, which
gives a dark-brown
color to urine, and often • Molecular diagnostic testing:
referred to as ‘port-
wine reddish urine’.
the diagnosis of porphyrias with
cutaneous photosensitivity.
– PBG usually is not included in a urine
porphyrin screen and must be ordered
specially
– Detection of PBGD mutations in AIP
provides 95% sensitivity and around
100% specificity
– Possible to screen asymptomatic gene
carriers.
– Less Useful in acute attacks
Erythropoietic
Protoporphyria
It is the most common childhood porphyria. Pathogenesis
 It is usually evident by 2 years of age. deficient activity of
ferrochelatase enzyme
Lab. finding:
Plasma porphyrin level and fluorescence spectrum
Increased free protoporphyrin in RBCs, stool
CBC, LFTs
Liver/gallbladder imaging
 Congenital Erythropoietic porphyria
( Gunther's disease ):
It is a very rare autosomal recessive disorder.

Patients usually present during infancy and rarely present in adult life with
milder forms.
Pathogenesis
It is caused by elevation of both water-soluble and lipid-soluble porphyrin levels
due to deficiency of uroporphyrinogen III synthase enzyme.
Clinical features 1. Very severe photosensitivity with phototoxic burning and
blistering leading to mutilation of light exposed parts.
2. Erythrodontia.
3. Scleromalacia perforans.
4. Hypersplenism.
5. Hemolytic anemia.
6. Thrombocytopenia

Lab. finding Uroporphyrin and Coproporphyrin in urine

Corproporphyrin in stool
Hepatoerythropoietic
Porphyria
Inheritance/Pathogenesis:
AD
Uroporphyrinogen (UROGEN) decarboxylase deficient
Incidence:
Very rare -Presents at age 1
Prognosis:
Normal life span
Clinical picture:
Skin
Similar to CEP—Severe photosensitivity with burning, edema,
vesicles/bullae, erosions, infection
Late changes—Mutilating scars with deformation of nose, ears, fingers;
scarring alopecia, pigmentary changes, sclerodermoid changes
Hypertrichosis
Teeth
Red/brown color
Eyes
Photophobia, ectropion, conjunctivitis
Heme
Hemolytic anemia
GI
Splenomegaly
GU
Dark urine at birth

Plasma porphyrin level and

fluorescence spectrum
Lab. finding: protoporphyrin in RBCs
urinary uroporphyrin
fecal coproporphyrin
CBC
Treatment for Acute
Porphyria
• Panhematin 1

o 3-4 mg once a day 1

o Used to correct heme deficiency in liver and
stop production of porphyrin precursors 1
o Also acts as a mild anti-coagulant 1
• High carbohydrate diet 1
• Last Resort: Liver transplant 3
Treatment for Cutaneous
Porphyria
• Avoid sunlight 8
• Iron chelation 8
• Blood Removal 8
• Avoid drinking alcohol 8
Other Treatments
• Heme transfusion 1
• Medication that induce cytochrome
p450 have a chance of causing
porphyria attacks 1
Red Cell
Disorders
.
Anemia
Definition:

Anemia is operationally defined as a reduction in

one or more of the major RBC measurements:

hemoglobin concentration, hematocrit, or RBC

count

Keep in mind these are all concentration

measures
 Anemia

?
Production? Survival/Destruction?

ERITROPOITINA
Anemia

• DEFINITION -Decrease erytrocytes in

blood

1-Decreased production of
erythrocytes
2-Increased destruction of
erythrocytes
3 -Blood loss-
19/04/2011 101
 Anemia
• Clinical Manifestations:

1. Pallor.
2. Fatigue, weakness.
3. Dyspnea.
4. Palpitations, tachycardia.
5. Headache, dizziness, and
restlessness.
6. Slowing of thought.
7. Paresthesia.

19/04/2011 102
Anemia
Caused by

Decreased Erythrocyte Production

Anemia
Caused by

Decreased Erythrocyte Production

1-Iron Deficiency Anemia

2-Megaloblastic Anemias
3-Aplastic Anemia

19/04/2011 104
Anemia
Caused by

Decreased Erythrocyte Production

Iron Deficiency
Anemia

19/04/2011 105
 Iron-Deficiency
Anemia
Etiology
1. Inadequate dietary intake
• Found in 30% of the
world’s population
2. Malabsorption
• Absorbed in duodenum
• GI surgery
3. Blood loss
• 2 mls blood contain 1mg
iron
• GI, GU losses
4. Hemolysis 106
Iron-Deficiency Anemia
• Clinical Manifestations
– Most common: pallor
– Second most common: inflammation
of the tongue (glossistis)
– Cheilitis=inflammation/fissures of lips
– Sensitivity to cold
– Weakness and fatigue
• Diagnostic Studies
– CBC
– Iron studies Diagnostics:
– Iron levels: Total iron-binding capacity
(TIBC), Serum Ferritin.
19/04/2011
– Endoscopy/Colonscopy 107
Treatment of Iron-Deficiency
Anemia

Replacing iron
– Diet
– Drug Therapy
• Iron replacement
– Oral iron
» Feosol, DexFerrum, etc
» Absorbed best in acidic environemtn
» GI effects
– Parenteral iron
» IM or IV
» Less desirable than P
Iron therapy for 2-3 months after the
hemoglobin levels return to normal
19/04/2011 108
Anemia
Caused by

Decreased Erythrocyte Production

(COBLAMIN)12
VITAMIN B Deficiency

19/04/2011 109
Macrocytic
Anemia (COBLAMIN)12 VITAMIN B
*Vit B12 is synthesized by certain micro-
organism.

*Sources: meat, fish, eggs, and milk but not

plants

*It is not destroyed by cooking .

*Daily requirement is 1-2 mg / day.

*Storage : the average adult stores 2-3 mg in the

liver, it may take two years or more before B12
deficiency, develops as the daily losses are small
(1-2mg).
Macrocytic
Anemia Absorption: Vit. B12 is liberated in the
stomach, bound by intrinsic factor (IF)
and absorbed through the terminal ileum,
transported by transcobalamin I and to
lesser extend by transcobalamin II and
III.

It is essential for:
1-haematopoiesis
2-GIT mucosa integration
3-Formation of myelin of nervous system.
Macrocytic CAUSES OF VIT. B12 DEFICIENCY
Anemia
I- True deficiency: (Decreased intake)
-Poor socioeconomic status.
-Vegetarians, alcoholic

II-condition deficiency
A-Decreased absorption .
1-Decreased intrinsic factors commonest cause.
*Pernicious anaemia.
*Total or partial gastrectomy
*Atrophic gastritis.
*Gastric cancer.
*Non- Addisonian pernicious anaemia
a- In association with hypogammaglobulinemia,
gastric atrophy, achlorhydria and absent intrinsic
factor but no antibodies
b-In infancy: Selective failure of IF, normal mucosa.
C- Juvenil PA failure of IF secretion with gastric
atrophy rarely with antibodies
Macrocytic
Anemia 2-Malabsorption syndrome.

3-Ileal diseases:
* Terminal ileum resection
* TB enteritis.
* Chron’s disease.
* Blind loop syndrome with bacterial over-
growth.
* Infestation by fish tape worm
Diphyllobothrium latum.
 B-Decreased utilization:
Macrocytic *Rare congenital enzyme deficiency.
Anemia *Lack of transcoblamin II.

III-Relative deficiency : (increased demand)

*Infancy, pregnancy, lactation
*Haemolylsis and active haematopoiesis
*Malignancy.
*Thyrotoxicosis

IV- Increased loss: Hemodialysis

V- Decrease of stores. Far advanced chronic liver

diseases
Macrocytic
Anemia

PERNICIOUS ANAEMIA
(ADDISONIAN ANAEMIA)
DEFINITION

Pernicious anaemia (PA) is a condition in which

there is atrophy of the gastric mucosa with
consequent failure of intrinsic factor production
and vitamin B12 malabsorption.
Macrocytic AETIOLOGY
Anemia 1-Most probably autoimmune disease with genetic tendency .

2-There is an association with other autoimmune disease

(Thyroid disease, vitiligo and Addison’s disease).

3-Atrophic gastritis (decrease HCL + IF) associated with

production of parietal cell antibodies

4-Intrinsic factor antibodies which are specific for the diagnosis

and are of two types, blocking antibodies which inhibit the
binding of IF to B12 and precipitating antibodies which inhibit
the binding of B12-IF complex to its receptor sites in the ileum.

5-It is common in the elderly over 60 years in fair haired and

blue eyed people and in females than males.

6-The relatives may have clinical features of autoimmune

disease
Macrocytic
Anemia
PATHOPHYSIOLOGY

Both vit Bi2 and folic acid are essential for DNA
synthesis and maturation.

In cases of megaloblastic anaemia there is a deficient

DNA synthesis, so the rate of cell division of many
cells in the body is rate. The most affected cells are
those with rapid rate of division and growth. i.e.
haematoportic cells (RBC, WBC, platelet ) and,
gastric mucosa + inability to form myelin sheath
Macrocytic
Anemia
RBCs (Megaloblastosis = cellular gigantism)

1-Megaloblasts (cell gigantism ): these are large cells

(megalo) with relatively small nucleus (blasts).
The cytoplasm is markedly in crease because RNA
synthesis is normal while the nucleus is slowly
growing because deficient DNA synthesis.

2-In BM, the normblast are replaced by these

megaloblasts. Some of these abnormal cells are
destroyed in BM. (intramedullary haemolysis)
Macrocytic
Anemia 3-Some of these erythroid megaloblasts lose their
nuclei and joined peripheral blood as macrocytes,
irregular shape with remnant of the nucleus .
these cells are hatched and destroyed by the
spleen. During its circulation.

4-So anaemia is multifactorial

- Defective erythropoiesis
- Intramedullary haemolysis.
- Destruction by the spleen .

5-Increased Serum bilirubin

-Increased medullary haemolysis.
-Increased splenic destruction of RBCs.
Macrocytic WBCs: (leucopenia)
Anemia Myeloid megaloblasts are present in BM and give hypersegmented
PNL to the peripheral blood.
Leucopenia due to deficient DNA synthesis

Thrombocytopenia
Due to deficient DNA synthesis .

NB : Since the three blood elements are effected in

megaloblastic anaemia, it is better to call it
megaloblastic pancytopenia.
GIT
Is affected in the same manner, with secondary
atrophy epithelial cells of the tongue, stomach and
even intestine.
Nervous system
Only with B12 deficiency., failure of synthesis of
myelin synthesis
Macrocytic CLINICAL FEATURES
Anemia
The onset is insidious.

1- Haemtological manifestations

-General manifestation of anaemia .

-Thrombocytepenia  Bleeding tendencies

-Leucpenia  risk of infection

-Hepatosplenomegaly.

-Colour of the skin is lemon yellow owing to

combination of pallor and jaundice.
Macrocytic
2- GIT manifestations
Anemia
-Atrophic glossitis, (red – glozed tongue)

-Angular stomatitis .

-Gastric atrophy dyspepsia, anorexia nausea,

vomiting .

-Intestinal atrophy diarrhoea and malabsorption

Cancer stomach on top of atrophic gastritis

Macrocytic 3- Neuropsychatice manifestations (only with vit B12
Anemia deficiency).

A-Neurological manifestations (3Ps):

Peripheral neuropathy (LMNL)

Pyramidal tract affection (UMNL) spastic paraplegia.

Posterior column affection  loss of deep sensation and

sensory ataxia .

NB: Combination of the two lessons is called sub acute

combined degeneration of the spinal cord (SCD)

b- Dementia

c- Optic atrophy

d- psychosis rare
Macrocytic
Anemia
4- Association with other autoimmune features: (in
pernicious anaemia)

1- Thyrotoxcoais

2- Hashimoto’s disease.

3-Vitiligo

4-Rheumatoid disease

5-Primary billiard cirrhosis

Macrocytic INVESTIGATIONS:
Anemia I- CBC

a- RBCs:
Marocytic normochromic anaemia .
Poikilocytosis and anisocytosis
Howell-Jolly bodies may be present

b-WBCs:
Moderate Leucopenia.
Shift to the right
Giant hyperpigmented neutrophil.

C -Platelets
Moderate thrombocytopenia.
Giant platelets

d-Reticulocyte
are decreased but increased by treatment with vit B12 or
folic acid
Macrocytic
Anemia II- Bone marrow:

Show megaloblastic erythropoiesis. The most

characteristic is dissociation between nuclear &
cytoplasmic development in erythroblasts with the
nucleus maintaining a primitive appearance despite
maturation and haemoglobinization of the
cytoplasm.

Erythroid hyperplasia, maturation defect in

erythropoiesis, giant metamyelocytes, atypical
megakaryocytes with hypersegmented nuclei.
Macrocytic
Anemia
III- Estimation of serum B12 level
is low using radioisotope dilution or immunological
assays.
IV. Biochemistry
Serum iron is high, more than 175 mcg/100 ml.
Increased serum indirect bilirubin reflect mild
haemolysis and ineffective erythropoiesis.
Increased serum lactic dehydrogenase (LDH)
reflecting ineffective megaloblastic
erythropoiesis.
V. Immunology
Parietal cells antibodies and gastrin receptor
antibodies, present in 70% of patients. (not
specific)
Intrinsic factor antibodies type I blocking (more
specific) and type II precipitating antibodies.
 VI- other investigations
Macrocytic ***Gastric biopsy: proximal 2/3 of stomach atrophic.
Anemia ***Augmented histamine test: achlorhydria.
***Schilling test.
*Aim
1- Diagnosis of pernicious anaemia.
2- To detect its cause whether malabsorption or IF deficiency.

*Methodology
Large dose of unlabelled B12 (1000ug) is given IV to saturate
body sores.
Radiolabelled B12 (lug) is given orally, the amount of radio
labellol B12 on the urine.
Urine of the next 24 hours is measured
Results

If radiolabelled B12 excretion is low there may be

1- Malabsorption
2- Pernicious anaemia.
Repeated the test after giving IF orally if it increase in the urine,
this means that the cause is IF deficiency.
Macrocytic
Anemia TREATMENT

Treatment of the cause : if possible .

Replacement therapy .

Initial treatment is often as the 1000 mg B12

IM/day for 2 weeks then in a dosage of
1000 mg twice/week till correction of
anaemia. Maintenance therapy 1000 mg
IM every 3 months.
Neurological damage can be precipitated by
treating incorrectly with folic acid.
Transfusion therapy by packed RBCs in the flowing
conditions
sever anaemia (Hb < 7 gm/dl )
Heart failure .
Marked symptoms .
Macrocytic FOLATE DEFICIENCY

Anemia Basic nutritional features and metabolism of folate***

Dietary folate source :

***Important sources are liver, kidney and fresh green vegetables,

nuts, yeast, cooking probably destroys, at least half the folate in
food,

***Minimum daily requirements 100-200 ug.

Absorption is chiefly in the jejunum.
Total body store is about 10 mg mainly in the liver
Store is sufficient for 4 months.

Function
It is essential for nucleic acid synthesis maturation. It is deficiency
lead to
Nuclear maturation defect., of blood cells and megaloblastic
erythropoiesis.
GIT: mucosal cells.
Macrocytic
Anemia

CAUSES OF FOLATE DEFICIENCY:

I- True deficiency (decreased intake)

Poor intake particularly in infancy, old age, poor
social conditions, starvation alcohol excess.
Poor intake due to anorexia as in GIT disease e.g.
Partial gastrectomy, coeliac disease, Crohn’s disease,
cancer.
Macrocytic II- Relative deficiency (increased demand)
Anemia
Physiological: pregnancy, lactation,
prematurity
Pathological:
Haematological disease with excess red cells

production e.g haemolysis.

Malignant disease with increased cell
turnover
Inflammatory disease e.g. rheumatoid
arthritis,
Crohn’s disease.
Metabolic disease e.g. homocystinuria (rare
congenital defect in the conversion of
homocysteine to cystathion folate).
Macrocytic III - Conditioned deficiency normal intake and
Anemia requirement but their may be :

a) Decreased absorption
* Malabsorption: in small bowel disease.
* Drugs : pill or anticonvulsant.

b) Decreased utilization

* Antifolate drugs. anticonvulsants,

methotrexate, pyrimethamine and trimethoprim

IV- Increased loss

* Haemodialysis or peritoneal dialysis closely

bound to plasma protein, so easily removed.
Anemia CLINICAL FEATURES

* May occur at any age, degrees of folate

deficiency are very common and mild deficiency
states are frequently unrecognised.

* The clinical picture is multivarious because of

the variety of possible underlying causes.

* The onset may be insidious or rapid as when

negative folate balance is precipitated by e.g
infection

* Anaemia and sometimes slight jaundice.

* Glossitis.

* No defined neurological changes.

 INVESTIGATIONS
Macrocytic
Anemia * Essentially as in vit B12 deficiency .

* Howell Jolly bodies and target cells in the

blood film would suggest splenic atrophy
(coeliac disease)

* Bone marrow show megaloblastic changes.

* Reduced folate levels: (N= 2.5-25mg/ml)

serum levels are labile and red cell levels are
better reflection of tissue folate by radioisotope
dilution or immunological methods

N.B Microbiological methods were used in the

past but has the disadvantage that antibiotic
therapy could lead to falsely low results.
 Treatment
Macrocytic
Anemia
1) Folic acid therapy is contraindicated if
there is any suspicion of B12 deficiency
(Neurololgical changes may be
precipitated or worsen).

2) Folic acid: 5mg daily is more than

adequate.

3) Prophylactic folic acid is also given in

chronic hematological disorders where
there is rapid cell turnover 5mg each
week.

4) Prophylactic folic acid (400ug daily) is

recommended in pregnancy.
Macrocytic
Anemia
MACROCYTOSIS WITHOUT
MEGALOBLASTIC CHANGES

A raised MCV with macrocytosis on the

peripheral blood film can occur with a
normablastic BM. In all these conditions, the
level of Vit B12 and folate are normal.

The exact mechanisms are uncertain, but

it seems there is increased lipid deposition in the
red cell membrane.
 CAUSES
Macrocytic
Anemia 1) Physiological : pregnancy and newborn.

2) Pathological

* Alcohol excess
* Liver disease
* Reticulocytosis
* Hypothyroidism
* Some haematological disorders (e.g aplastic
anaemia, sideroblastic anaemia
* Drugs (e.g cytotoxics as azathioprine)
* Agglutinated red cell measured on red counters.
* Cold agglutinis due to autoagglutination of red
cells, MCV decreases to normal with warming
of the sample to 37OC.

An increased number of reticulocytes lead to a

 Decreased Erythrocyte Production
Megaloblastic Anemias

• SUMARY

This picture shows large, dense,

oversized, red blood cells (RBCs) that
are seen in megaloblastic anemia.

19/04/2011 139
 Decreased Erythrocyte Production
Megaloblastic Anemias

• Characterized by
large RBCs which
are fragile and
easily destroyed
• Common forms of
megaloblastic
anemia
1. Cobalamin This picture shows large, dense,
oversized, red blood cells (RBCs) that

deficiency (Vitamin are seen in megaloblastic anemia.

B12)
19/04/2011 140
Cobalamin (Vitamin B12)
Deficiency pernicious anemia

• Cobalamin Deficiency--formerly known as

pernicious anemia
• Vitamin B12 (cobalamin) is an important
water-soluble vitamin.
• Intrinsic factor (IF) is required for
cobalamin absorption
• Causes of cobalamin deficiency
– Gastric mucosa not secreting IF
– GI surgery loss of IF-secreting gastric mucosal
cells
– Long-term use of H2-histamine receptor blockers
cause atrophy or loss of gastric mucosa.
– Nutritional deficiency
– Hereditary defects of cobalamine utilization
19/04/2011 141
Cobalamin (Vitamin B12)
Deficiency
• Clinical manifestations
– General symptoms of anemia
– Sore tongue
– Anorexia
– Weakness
– Parathesias of the feet and hands
– Altered thought processes
• Confusion  dementia

19/04/2011 142
Cobalamin Deficiency
Diagnostic

• RBCs appear large

• Abnormal shapes
• Structure contributes to erythrocyte
destruction
• Schilling Test: a medical
investigation used for patients with
vitamin B12 deficiency. The purpose
of the test is to determine if the
patient has pernicious anemia.
19/04/2011 143
Cobalamin Deficiency
• TREATMENT
– Parenteral administration of
cobalamin
– ↑ Dietary cobalamin does not
correct the anemia
• Still important to emphasize
adequate dietary intake
– Intranasal form of
cyanocobalamin (Nascobal) is
available
– High dose oral cobalamin and SL
19/04/2011 cobalamin can use be used
144
Decreased Erythrocyte Production
Folic Acid Deficiency

Folic Acid Deficiency also causes

megablastic anemia (RBCs that
are large and fewer in number)
• Folic Acid required for RBC
formation and maturation
Causes
– Poor dietary intake
– Malabsorption syndromes
– Drugs that inhibit absorption
– Alcohol abuse
19/04/2011 – Hemodialysis 145
Folic Acid Deficiency
• Clinical manifestations are similar to those of
cobalamin deficiency
• Insidious onset: progress slowly
• Absence of neurologic problems

• Treated by folate replacement therapy

• Encourage patient to eat foods with large amounts

of folic acid
• Leafy green vegetables
• Liver
• Mushrooms
• Oatmeal
• Peanut butter
• Red beans
19/04/2011 146
Universitatea Titu
Maiorescu
CU
RS
RE ME
Pro U MA DI
fu TO CI
ni v LO NA I
dr GI NT
Ion E ER
C.Ț NA
i nt
oiu
Decreased production of
erythrocyte
• Aplastic anemia
Aplastic Anemia

• Characterized by Pancytopenia

19/04/2011 148
Decreased production of erythrocyte
Aplastic Anemia

• Characterized by Pancytopenia
– ↓ of all blood cell types
• RBCs
• White blood cells (WBCs)
• Platelets
– Hypocellular bone marrow
• Etiology
– Congenital
• Chromosomal alterations
– Acquired
• Results from exposure to ionizing radiation,
19/04/2011 chemical agents, viral and bacterial
149 infections
Aplastic Anemia
• Etiology

– Low incidence
• Affecting 4 of every 1 million
persons
– Manageable with erythropoietin
or blood transfusion
– Can be a critical condition
• Hemorrhage
19/04/2011 • Sepsis 150
Aplastic Anemia
• Clinical
Manifestations
– Gradual development
– Symptoms caused by suppression of
any or all bone marrow elements
– General manifestations of anemia
• Fatigue
• Dyspnea
• Pale skin
• Frequent or prolonged infections
• Unexplained or easy bruising
• Nosebleed and bleeding gums
• Prolonged bleeding from cuts
• Dizziness
19/04/2011
• headache 151
Aplastic Anemia
• Diagnosis
– Blood tests
• CBC
– Bone marrow biopsy

19/04/2011 152
 Aplastic Anemia
Treatment
– Identifying cause
– Blood transfusions
– Antibiotics
– Immunosuppressants (neoral, sandimmune)
• Corticosteroids (Medrol, solu-medrol)
– Bone marrow stimulants
• Filgrastim (Neupogen)
• Epoetin alfa (Epogen, Procrit)
– Bone marrow transplantation
– Prognosis is poor if untreated
/ • 75% fatal
4
/
2 153
0
 Blood loss
anemia

. 154
 Acute Blood Loss

• Result of sudden hemorrhage

– Trauma, surgery, vascular
disruption
• Collaborative Care
1.Replacing blood volume
2- Identifying source of
hemorrhage
3-Stopping blood loss

. 155
 Chronic Blood Loss

• Sources/Symptoms
– Similar to iron deficiency anemia
– GI bleeding, hemorrhoids,
menstrual blood loss
• Diagnostic Studies
– Identifying source
– Stopping bleeding
• Collaborative Care
– Supplemental iron
.
administration 156
 Anemia caused
by

Increased Erythrocyte Destruction

. 157
 Anemia caused
by

Increased Erythrocyte Destruction

HAEMOLYTIC ANAEMIAS

. 158
Macrocytic
Anemia

HAEMOLYTIC ANAEMIAS
Definition :

The haemolytic anaemias are a group of

diseases in which red cell life span is shortened.
Macrocytic
PATHOPYSIOLOGY:
Anemia
* Haemolysis of RBC can occur either .

1) Intravascular ie within the circulation .

2) Extra vascular ie : by phagocytes in RES in the

liver, bone, spleen.

* Bone marrow compensatory reactions:

Erythriod hyperplasia in BM, can increase

erythropoiesis several times, so that anaemia may
not develop till RBCs life span is less than 20 days

Reticuylocytosis is hallmark.

Slight macroytosis in the peripheral

blood
Macrocytic CAUSES:
Anemia
A - CORPUSCULAR CAUSES:

1) Congenital Abnormalities:

Membrane defects:
* Hereditary spherocytosis
* Hereditary elliptocytosis
• Hereditary stomatocytosis

Haemoglobinopathies:
* Sickle cell anaemia
* Thalassaemia

Enzymopathies
1) Abnormal aerobic glycolysis e.g. G6PD deficiency
2) Abnormal anerobic glycolysis e.g pyruvate kinase
deficiency
3) Non glycolytic enzymopathies
Haemolytic 2) Acquired Abnormalities
Anemia 1- Paroxysmal nocturnal haemoglobinuria
2- Vitamin E deficiency

B- EXTRACORPUSCULAR CAUSES:

1- Immune mechanisms
a ) Alloimmune antibodies (iso-immune):
* Incompatible blood transfusion
* Haemolytic disease of the newborn
* After allogenic BM or organ transplantation

b) Autoimmune haemolytic anaemias

1-Warm reactive antibodies (react at 37 oC and does not
bring
agglutination type of AB= IgG ).

* Idiopathic
* Secondary to CLL, Lymphoma, SLE and rheumatoid
disease
* Secondary to drugs e.g methyldopa.
Haemolytic 2- Cold reactive antibodies (react at 32oC
Anemia and usually agglutinates and haemolyse red
cells, type of AB = IgM).

* Cold haemoagglutinin disease

- Idiopathic
- Secondary (mycopolasma pneunemia
infection, infectious mononucleosis,
lymphomas.

* Paroxysmal cold haemoglobinuria

- Idiopathic
- Secondary (some viral infections
congenital & tertiary syphilis).

c) Immunochemical mechanisms: drug

induced haemolytic anaemias
Haemolytic
Anemia 2- Mechanical injury

* Cardiac haemolytic anaemia (valve prosthesis).

* Microangiopathic haemolytic anaemias.
• March haemoglobinuria.

3- Chemicals and Drugs

* Snake venom
* Lead
* Naphthaline
* Phenacetin
* Sulpha drugs
* Hypophosphataemia
Haemolytic
* Clostridium welchii septicemia (Secondary to
Anemia
septic abortion)
* Malarial infestation (Black water fever)

5- Metabolic causes

* A betalipoproteinemia : A canthocytosis
* Liver porphyria :
* Spurr cell anaemia
* Zieve’s syndrome
* Wilson disease
* Severe hypophosphataemia

6- Secondary to systemic disease :

* Renal and liver failure
* Burn
 General features of haemolytic anaemia
Haemolytic 1)Haemalytic jaundice .
Anemia * Mild degree.
* Skin is lemon yellow
* Sclera tinge of jaundice .
* Dark stool.
* Normal urine which darken on exposure to
air
2)Heapatosplenomegaly:
* Common in chronic haemolysis except in
cases of sickle cell anaemia where there self-
splenectomy
3) Biliary obstruction and /or gall bladder
stones.
* Pigment stones: extra hepatic obstruction .
* Viscid bile: intrahepatic obstruction.
NB. In this situation jaundice becomes, mixed
( haemolytic + obstructive) and abdominal pain
my be present.
 * Fever, rigors: pyrogen release from RBCs .
Haemolytic * Generalized bone pain
Anemia * Acute abdominal pain, backache, may be vomiting.
* Aggravation of anaemia (pallor), deepening as
jaundice, and dark colouration of urine
* Investigations:
- Dark urine: haemoglobinuria.
- Increased serum biliurbin
- Reticulocytosis
- BM erythroid hyperplasia.
* Cause may be infection
B- A plastic crisis
* Inability of BM to replaced the destructed
RBCs
- Severe anaemia without jaundice.
- Reticulocytopenia .
- BM erythroid hypoplasia.
* Cause: viral infection especially parvovirus
B19 and
Haemolytic C- Sequestration crisis
Anemia Trapping and pooling of RBCs in the spleen
(mainly and liver).

D- Megaloblastic crisis
* Anaemia severe without jaundice .
* Decreased reticulocytic count
* Macrocytic anaemia.
* BM : megabloblastic
Cause: folic acid deficiency.

E- Vaso-occlusive crisis (Thrombotic

phenomenon)
* Painful.
* Only in cases of sickle cell anaemia.
Haemolytic
Anemia

Features or the cause

e.g thalassaemia, sickle cell anaemia.

COMPLICATIONS
* Haemolytic crisis:.
* A plastic crisis:
* Folate deficiency caused by increased BM
requirement
* Gall stones
*In sickle cell anaemia: signs and symptoms
of thrombotic
phenomena.
Of ,ce greu! Si inca nu s-a
erminat !
Anemia of chronic disease
and Erythropoietin

• .
Anemia of Chronic Disease
(ACD)
Classical definition
• Anemia occurring in –
chronic infectious, inflammatory
or neoplastic disorders
• not due to –
marrow replacement by tumor,
bleeding, or hemolysis
• characterized by –
hypoferremia in the presence of
adequate iron stores
Means RT Jun, Krantz SB. Blood 1992; 80(7): 1639-1647
 *
Anemia of Chronic Disease
 Inflammation, neoplasia
 Blunted erythropoietin response
 Impaired iron utilization
 Bone marrow stores adequate
 Low serum iron

Ludwig (1998)
Anemia of chronic disease
• Excessive production of
cytokines
• Ineffective erythropoiesis
• Interfere with:
– Effect of EPO on bone marrow
– Release of stored iron in
Reticuloendothelial system
Anemia of Chronic
Disease
 Major steps of erythropoiesis and
erythropoietin dependence
Hematopoietic stem cell

†BFU-E

‡CFU-E Erythropoietin
dependence

Erythroblasts

Reticulocytes
† BFU-
BFU-E = burst-
burst-forming unit–
unit–erythroid; ‡ CFU-
CFU-E = colony-
colony-forming unit–
unit–erythroid
Bron, Seville 2000
 ERYTHROPOIETIN
carbohydrate

protein

protein + carbohydrate = glycoprotein

 *
Erythropoietin
• Glycoprotein of 34 kDa

• Produced in kidney and liver; trace amounts in brain

• Stimulates survival and differentiation of erythroid progenitors

Lacombe (1998, 1999); Krantz (1991); Bernaudin (2000)

 Amino Acid Sequence *
of Erythropoietin
1 10 20
30
S S
S 160
S
40

150 60
140
50
130 70
80

90 N-linked (3)
120 glycosylation
100 O-linked (1)
110 glycosylation

Amino acid
Erslev (1991); Mulcahy (2001)
 Epo prevents apoptosis of
erythroid progenitors

+Epo

CFU-E

-Epo Macrophage
Physiology of Erythropoietin

Recombinant
Erythropoietin
Biological effects of EPO
Erythropoiesis
• Controls RBC production
• Promotes survival, proliferation,
and differentiation of erythroid
progenitors
• Exerts effects on late erythroid
progenitors
Mulcahy, Seville 2000
 Regulation of Erythropoietin

Hypoxia Inflammatory (HIF-1)

cytokines

+ -
Erythropoietin

HIF-1 = hypoxia-induced factor-1 Ludwig (1998); Lacombe (1999)

 The physiological role of
erythropoietin in the healthy adult

Decreased oxygen delivery to the kidneys

Peritubular interstitial cells detect

low oxygen levels in the blood

Pro-erythroblasts in red
bone marrow mature more
Peritubular interstitial cells quickly into reticulocytes
secrete erythropoietin (EPO) into
EPO the blood

More reticulocytes
enter circulating blood
Increased oxygen delivery to tissues
Larger number of red blood cells (RBC)
Return to homeostasis when response brings in circulation
oxygen delivery to kidneys back to normal
Anemia of Renal Failure

In advanced disease

Toxicity from therapy

Therapy: Erythropoietin
Pathogenesis of anemia in cancer

(Bone marrow involvement)

Renal failure Iron distribution

(multiple myeloma) defect

Haemolysis Shortened erythrocyte

(NHL)
ANAEMIA survival time

Depression of
erythropoiesis or
Pure red cell aplasia
(T cell NHL) EPO production
(cytokine-mediated)
Cytotoxic chemotherapy

Anaemia of Chronic Disease

Anemia in Cancer Patients
Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
Impact of Anemia in *
Patients With Cancer

• Fatigue
• Shortness of breath
• Lack of energy to perform daily functions;  QOL
• Complicates coexisting disease
• Associated with poor prognosis and increased mortality
• May compromise efficacy and tolerability of treatment
Factors involved in the cause and
development of anaemia in cancer patients
Tumour cells

Activated
immune system
RBCs Erythrophagocytosis
TNF Macrophages
Dyserythropoiesis

Shortened
IFN-, IFN- IFN-
survival
IL-1 IL-1 IL-1
TNF TNF TNF
 1-antitrypsin

Reduced Impaired Suppressed

Anaemia EPO iron BFU-e
production utilisation CFU-e

TNF = tumour necrosis factor; IFN = interferon; IL-1 = interleukin-1;

BFU-e = erythroid burst-forming unit; CFU-e = erythroid colony-forming unit
Nowrousian MR. Med Oncol 1998;15(Suppl. 1):S19–28
Anemia in Cancer Patients
Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
BONE MARROW ASPIRATE
Bone marrow involvement

Follicular lymphoma

Neuroblastoma
Anemia Due to Marrow
Infiltration

Except in hematological malignancies,

usually
associated with advanced disease.

 Breast and prostate Ca are an exception –

marrow
involvement often with only mild anemia or
normal
Hb.
BONE MARROW BIOPSY
Anemia in Cancer Patients
Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
Pure Red Cell Aplasia

In lymphoma, NSCLC, breast and gastric cancer.

Humoral and cellular events  suppression of

erythropoiesis.

Therapy of underlying cancer  response in 30-

50%

For others, may need immunosuppressive /

cytotoxic
therapy.
Anemia in Cancer Patients
Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
Anemia in Cancer Patients
Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
Anemia in Cancer Patients
Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
Anemia in Cancer Patients
Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
Autoimmune Hemolytic Anemia
Anemia in Cancer Patients
Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
Treatment Options for
Cancer-Related Anemia

Transfusion
• Used in cases of acute
anemia
• Many associated risks

ERYTHROPOIETIN
Harrison (2000)
Types of Transfusion Reactions

Immediate
• Hemolytic
• Febrile Delayed

• • Delayed hemolytic
Non-cardiogenic
pulmonary edema • Post-transfusion purpura
• Other allergic • Infections
• Graft vs host disease
• Chronic immunosuppression
Guideline Recommendations for Anaemia
Management in Patients with Cancer
ASCO/ASH
• Initiate epoetin in patients with Hb ≤10
g/dl (or
Hb >10 to <12 g/dl depending on clinical
circumstances)
• SC 30 000 IU (150 IU/kg) once weekly;
double dose in absence of response (Hb
increase
<1–2 g/dl) after 4 weeks
• Raise Hb to 12 g/dl and maintain;
insufficient evidence to support
‘normalisation’ of Hb >12 g/dl
Rizzo et al. J Clin Oncol 2002; 20: 4083–107
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Hematologie II
Intrinsic hemolytic
anemia
Hemoglobinopathies
Abnormal hemoglobin
.
• Hemoglobinopathies

• Over 800 different mutations of globin chains of

human hemoglobin have been discovered
• Qualitative
• (Beta subunits are replaced by
beta S,C,SC).
 Sickle cell anemia replaced by beta S
 Hb C disease
 Hb SC disease

Qauntitative
 Thalassemias (α and
 Intrinsic hemolytic
anemia
Hemoglobinopathies
Abnormal hemoglobin

Sickle (secera) Cell Disease .

 
 Sickle (secera) Cell
Disease
• The resultant cellular
defect leads to

• The main
manifestations of the
disease, which
include:
– 1-premature death
of the cells
(hemolytic anemia)
– 2-vascular occlusion
of vessels and
subsequent tissue
infarction
 SICKLE CELL DISEASE
•This results when
both copies of the
hemoglobin beta
gene have an S Hemoglob
in
mutation.

•All of this person’s Alph Beta Beta

Alpha a S S
beta subunits are
replaced by beta
S.
Symptoms
Organs that can be affected by
sickle

• Brain : could cause a stroke

• spleen and kidney : renal and

splenic dysfunction

• Muscle ,bone and joint

• Lungs : acute chest syndrome

Complications of Sickle Cell
Disease
• pain episodes
• kidney damage
• strokes and loss of body
• increased water in urine
infections
• leg ulcers
• blood blockage in
• bone damage the spleen or liver
(osteo-necrosis) (sequestration)
• yellow eyes or • eye damage
jaundice
• anemia
• early gallstones
• • delayed growth
lung blockage
Treatment of Sickle Cell
Disease
• General guidelines
– Taking the vitamin folic acid (folate) daily
to help make new red cells
– Daily penicillin until age six to prevent
serious infection
– Drinking plenty of water daily (8-10
glasses for adults)
– Avoiding too hot or too cold temperatures
– Avoiding over exertion and stress
– Getting plenty of rest
– Getting regular check-ups from
knowledgeable health care providers
Hemoglobin C disease
Hemoglobin C
Hemoglobin C (Hb C) is a beta
globin chain mutation, it is caused
by the amino acid substitution of
lysine instead of glutamine at the
Beta-6 position, making the Hb C
a less soluble protein than Hb A
which is the most abundant
hemoglobin protein in adults
(around 90% of total hemoglobin
in adults.)
Hemoglobin C disease
Some characteristics of homozygous
hemoglobin C disease (Hb CC) include:
• Cell dehydration
• Target cells
• Mild hemolysis with no significant
anemia (mild anemia)
While heterozygous Hemoglobin C
patients are phenotypically normal and
the above symptoms doesn’t apply
Hemoglobin SC disease
Hemoglobin SC disease
This disease is caused by having double
heterozygotes for Beta S and Beta C in patients.

In Hb SC disease, Hb C increases K-Cl

cotransport activity, this causes the high
intraerythrocytic concentration of Hb S to
make polymers, giving the red cell it’s sickled
shape
In Hb SC disease, the cell contains 50% of Hb
S and 50% of Hb C, no normal hemoglobin is
present (Hb A)
Some Hb SC symptoms
Some of the Hb SC disease symptoms
include:
• Retinopathy
• Ischemic necrosis of bone
• Mild painful crisis
• Possible asplenia (about 45% of
patients older than 25) leading to
sepsis (lowering B.P, dysfunction in
kidneys, liver, lungs and CNS)
Methemoglobin
Methemoglobin (M)
• Normal hemoglobin contains ferrous
non FERIC ions on the center of
the heme groups

• Methemoglobin is formed when

ferrous oxidized to ferric
• Our blood contains normally
about 1% Hb Methemoglobin
Causes
• Drugs ( nitrates)

• Endogenous products (reactive o

intermediates)

• Inherited defects (mutations)

• Deficiency of NADH- Hb M reductase

Effects and Symptoms

• Functional Anemia
 Chocolate cyanosis
 Chocolate-cholored blood

• Tissue hypoxia → anxiety,

headache , dyspnoea , weakness ,
lightheadache .

• Rare cases → coma , death.

 emoglobinopathies

Qauntitativ
halassemias (α and
.
Thalassemia

• Syndromes arising form

Decreased rate or absence
of globin chain synthesis.
How to name thalassemia?

• Named after globin chain that is abnormally

synthesized !!!!

• Reduced or absent -globin chain : -thalassemia

• Reduced or absent -globin chain : -thalassemia
• Reduced or absent -globin chain : -thalassemia
• Reduced or absent -globin chain : -thalassemia
• Reduced or absent -globin chains
: -thalassemia
Thalassemia
Hb-A Molecule. Hb-A is the
major adult hemoglobin.
ommon types of thalassemia

• -thalassemia
Reduced or absent -globin chain

• -thalassemia

• Reduced or absent -globin chain :

 ALPHA
THALASSEMIAS
α Thalassemia
• Absence of α chains will
result in increase/ excess of  globin
chains during fetal life and excess β
globin chains later in postnatal life.
• Severity of disease depends on
number of genes affected.

• / (Normal)
 Classification & Terminology
Alpha Thalassemia
• Normal /
• Silent carrier - /
• Minor -/-
--/
• Hb H disease --/-
• Barts hydrops fetalis --/--

• (-) : Indicates a gene deletion:

 Hydrops Fetalis

The blood film of neonate with hemoglobin Bart’s hydrops

fetalis showing anisocytosis, poikilocytosis and numerous
nucleated red blood cells (NRBC).
β THALASSEMIAS
 β Thalassemia
-Absence or reduced of β chains
- gene mutations in the  gene in
chromosome
will result in increase/ excess of  globin chains during fetal life
and excess β globin chains later in postnatal life.
Severity of disease depends on number of genes affected.
Classical Clinical Syndromes of  Thalassemia; 
thalassemia can be presented as:

o Silent carrier state – mildest form of thal.

o  thalassemia minor - heterozygous disorder
resulting in mild hypochromic, microcytic hemolytic
anemia.
o thalassemia intermedia - Severity lies between the
minor and major.
o  thalassemia major - homozygous disorder
resulting in severe life long transfusion-dependent
hemolytic anemia.
β thalassemia minor
β Thalassemia Major
• Characterized by very severe
microcytic, hypochromic anemia. 
• Detected early in childhood:
• Hb level lies between 2 and 8 g/dL.
• Severe anemia causes marked bone
changes due to expansion of marrow
space for increased erythropoiesis
(Epo is increased).
• See characteristic changes in skull,
long bones, and hand bones. 
β Thalassemia Major

Target cells, NRBC, microcytosis,

poikilocytosis
β Thalassemia Major
Expansion of BM
β thalassemia major
Male 18 years
 Clicical avaluation
Hepatosplenomegaly
 Beta thalassemia major
• 2 defected Beta genes no beta
chains synthesis alpha chains
precipitate premature death of
RBCs.

•Complications
•Enlargement…
Dark skin due to iron overload
 TREATMENT OF THALASSEMIA

1. CONVENTIONAL TREATMENT
- BLOOD TRANSFUSION
- IRON CHELATION
2. HEMOGLOBIN F STIMULATION
3. TREATMENT OF COMPLICATION
- INFECTIONS
- HEART FAILURE ETC.
4. CURE
- BONE MARROW AND STEM CELLS
TRANSPLANTATION
- ? GENE THERAPY
 Anemia
by membrane
defects
RBC Membrane
Introduction
• Defects due to
• abnormalities in membrane
proteins
• or lipids
• Defects alter membrane’s
stability, shape, deformability
and permeability

• Hemolysis occurs
extravascularly
Conditions Associated with
Membrane Defects

◦ Membrane proteins disorders

◦ -Hereditary spherocytosis
◦ -Hereditary elliptocytocytosis
◦ -Hereditary pyropoikilocytosis
◦ Overhydrated and dehydrated hereditary
stomatocytosis

◦ Membrane lipid disorders

◦ -Paroxysymal noctural hemoglobinuria

.

Hereditary
spherocytosis
Haemolytic
Anemia

HEREDITARY SPHEROCYTOSIS

Pathogenesis:

A hereditary autosomal dominant

disorder in which the corpuscular membrane is
abnormally less deformable and more
permeable to sodium. This is due to an
abnormality of the protein as pectrin in the
corpuscular membrane which causes water
imbibition and rupture or red blood cells.
Haemolytic
Anemia
CLINICAL PICTURE:

1) Symptoms usually appear during the first decade

of
life, but may be delayed .

2) Common features of haemolytic anaemia .

3) Slight or moderate enlargement of the spleen .

4) Pigment biliary stones in long standing cases .

5) Chronic leg ulcers.

Haemolytic
Anemia 1- CBC

* Spherocytosis, red cells are spherical instead of

being ]
biconcave.
* Reticulocytosis .
* Anaemia of moderate degree.

2- Osmotic fragility

is characteristically increased, haemolysis usually

begins at podium chloride concentration of 0.6 % or
even higher

3- Direct coomb’s test is negative, excluding an

autoimmune cause of spherocytosis and haemolysis.
Haemolytic
Anemia

TREATMENT :

The principal form of treatment is

splenectomy although this should not be
performed unless clinically indicated because of
anaemia.
Splenectomy lengthens the life span of
redcells, correct anaemia, prevents
haemochromatosis, but does not affect the
character of red cells.
 .

Hereditary spherocytosis (HS)

Defect in ankyrin & spectrin


Results in the formation of fragile spherocytic red cells.

Spherocyte becomes less flexible and more permeable to Na+

Clinical Findings
• Varies in severity
• Compensated hemolytic
disease
• No anemia
• Intermittent jaundice
• Splenomegaly
• Cholelithiasis: pigment bile
stones from increased
bilirubin breakdown
Lab Features
–Mild anemia

RBC morphology
– Spherocyte
– Varying degrees of
polychromasia,
anisocytosis and
poikilocytosis
Lab Features
• Bone Marrow
– Normoblastic erythroid hyperplasia
– Increased iron storage

• Chemistry
– Increased
• Bilirubin
• Fecal urobilinogen
• LD
– Decreased
• Haptoglobin

• Immunohematology
– DAT negative
Diagnostic tests for
Hereditary spherocytosis

• Osmotic fragility - ↑
– Cells are incubated in decreasing
concentrations of NaCl. Spherocytes
lyse sooner than normal red cells.
• Autohemolysis test
– Red cells are incubated at 377 C for 48
hours. Degree of hemolysis is
increased when spherocytes are
present.
• Red cell membrane studies
– Membrane proteins are analyzed
using gel electrophoresis.
Treatment of Hereditary
spherocytosis HS

• Splenectomy
–Corrects for the
anemia, but the
membrane defect
remains
.

• Hereditary
elliptocytosis
.

Hereditary
elliptocytosis

– A defect of one of the skeletal

proteins
– Results in the formation of
fragile elliptocytic red cells that
are sensitive to mechanical
stress.
– More permeable to Na+
– Tends to affect blacks, especially
in Africa
Elliptocytosis
Lab Features
• CBC
– Mild anemia
– Hgb level increased
–
• RBC morphology
– Elliptocytes or ovalocytes
Treatment of
Helliptocytosis

–Treatment is usually
not necessary, but if
patients have
hemolysis,
splenectomy is
beneficial.
.

Red cell
enzymopathies
1. Glucose-6-Phosphate
Dehydrogenase ( G6PD )
Deficiency

– Pivotal enzyme in HMP Shunt &

produces NADPH to protect RBC
against oxidative stress
– Most common enzymopathy
-10% world’s population
– Protection against Malaria
– X-linked
• Clinical Features:
– Acute drug induced hemolysis:
• Aspirin, primaquine, quinine,
chloroquine, dapsone….
– Chronic compensated hemolysis
– Infection/acute illness
– Neonatal jaundice
– Favism
• Treatment:
– Stop the precipitating drug or
treat the infection

– Acute transfusions if required

2. Pyruvate Kinase Deficiency
– AR
– Deficient ATP production, Chronic
hemolytic anemia
– Inv;
• P. Smear: Prickle cells
• Decreased enzyme activity
– Treatment:
• Transfusion may be required
Polycythemia
.
Polycythemia Vera
Polycythemia Vera
(lots of red cells - for real)

• An uncommon disorder -
distinguish from other causes of
erythrocytosis
• Diagnosis depends on knowledge of
erythropoeisis
• Complications most commonly
from thrombosis and vascular
incidents
• Long natural history with treatment
Pathophysiology of
Polycythemia
Secondary Polycythemia
• Appropriate EPO (tissue/kidney
hypoxia)
– pulmonary disease
– high altitude
– congenital heart disease
– abnormal hemoglobin
• high affinity
• carboxyhemoglobin
Secondary Polycythemia
• Inappropriate EPO (ectopic
production)
– Tumors (hepatoma, renal
carcinoma, leiomyoma, hamartoma)
– Renal disorders (transplantation,
cysts)
– hemangiomas
– Androgen abuse
– EPO abuse
– Familial polycythemia
Polycythemia Vera
• Clinical features

– Attributed to increased blood

viscosity and poor oxygen
delivery to organs (brain)
– Poor O2 delivery leads to
ischemia and thrombosis
– Expanded blood volume and
viscosity leads to increased
cardiac work load
P. Vera - Symptoms &
Signs
• Symptoms • Signs
– Splenomegaly
– Headache
70%
– Weakness
– Skin plethora
– Pruritis
67%
(aquagenic)
– Hepatomegaly
– Dizziness
40%
– Diaphoresis – Conjunctival
– Visual plethora 59%
disturbance – Systolic
– Weight loss Hypertension
72%
P. Vera - Diagnosis
(PVSG criteria)
• Criteria • Significance
– RBC mass – True vs. spurious
elevated – R/O most 2
– SaO2 > 92% causes
– Splenomegaly – Evidence for MPD
(or)
• thrombocytosis
• Leukocytosis
• high LAP • False Positive
• high B12 0.5%
– smokers, drinkers
P. vera - Bone Marrow
Biopsy
Treatment Options -
Summary
P . V e ra
P h le b o t o m iz e t o H C T < 4 5

Age > 70 Age 50 - 70 Age < 50

H y d ro x y u re a H y d ro x y u re a P h le b o t o m y
32P? P h le b o t o m y H y d ro x y u re a
Hemochromatosi
s .
Hemochromatosis

• Iron overload
disease

• Over absorption and

storage of iron
causing damage
especially to liver,
heart and pancreas

19/04/2011 296
• Clinical:
• Disease penetrance very variable
from early symptoms and severe
disease to no symptoms –
genetic diagnosis very common –
but the disease syndrome much
less so
Of ,ce greu! Bine ca s-a terminat
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Disorders of Leucocyte

Prof univ dr Ion C.Tintoiu

Of ,of,of,of......!!!!
LEUKEMIA OVERVIEW
LEUKEMIA
Definition

Leukemia is a disease resulting from

the neoplastic proliferation of
-hemopoeitic
or
-lymphoid cells
ZA
2.lymphoid stem cells
LEUKEMIA

 It results from the mutation in a

single stem cell
 The progeny of which form a clone of
leukemic cells
LEUKEMIA
Acute leukemia
Chronic leukemia

• Acute Myeloid Leukemia

• Acute Lymphoid Leukemia

• Chronic Myeloid Leukemia

• Chronic Lymphoid Leukemia
Acute leukemia
• Acute leukemia is characterized by an
abnormal proliferation of immature white
blood cells, called blasts or progenitor cells
Two main forms of acute leukemia

– Acute lymphoblastic leukemia

• A cancer at the earliest stages of lymphocyte
maturation
• Occurs more often in the young
– Acute nonlymphoblastic leukemia
• Usually a malignancy of the myeloblast
• More common in adults
 Classification of
leukemias

Acute Chronic

Myeloid Acute Myeloid Chronic Myeloid Leukemia

Leukemia (AML) (CML)
origin

Lymphoid Acute Lymphoblastic Chronic Lymphocytic Leukemia

Leukemia (ALL) (CLL)
origin
 ALL germinal center
naïve

B-lymphocytes
Plasma
Lymphoid cells
progenitor
T-lymphocytes
AML
Hematopoietic Myeloid Neutrophils
progenitor
stem cell Eosinophils

Basophils

Monocytes

Platelets

Red cells
 CLL germinal center
naïve

B-lymphocytes
Plasma
Lymphoid cells
progenitor
T-lymphocytes
CML
Hematopoietic Myeloid Neutrophils
progenitor
stem cell Eosinophils

Basophils

Monocytes

Platelets

Red cells
 How to distinguish AML vs CML
from looking at peripheral blood

Myeloid cell CML AML

normal
blasts q q
promyelocytes q
myelocytes q
metamyelocytes q
bands q
neutrophils q # q
Leukemia
 Normal ALL
granulocytes

AML CML
ACUTE LEUKEMIA
ACUTE LEUKEMIA
ALL AML
ACUTE LEUKEMIA

CLINICAL FEATURES
ONSET
Abrupt, acute
Insidious, slowly progressive
Bone marrow malfunction
Anemia, infection & bleeding
Acute Leukemia
• accumulation of blasts in the
marrow
Causes of acute
leukemias
• idiopathic (most)
• underlying hematologic disorders
• chemicals, drugs
• ionizing radiation
• viruses (HTLV I)
• hereditary/genetic conditions
Clincal manifestations
• symptoms due to:
– marrow failure
– tissue infiltration
– leukostasis
– constitutional symptoms
– other (DIC)
• usually short duration of
symptoms
Marrow failure
• neutropenia:
infections, sepsis
• anemia: fatigue,
pallor
• thrombocytopenia:
bleeding
Infiltration of
tissues/organs
• enlargement of liver, spleen,
lymph nodes
• gum hypertrophy
• bone pain
• other organs: CNS, skin, testis,
any organ
Gum hypertrophy
Chloromas

C
NEJM 1998
Leukostasis
• accumulation of blasts in
microcirculation with impaired
perfusion
• lungs: hypoxemia, pulmonary
infiltrates
• CNS: stroke
• only seen with WBC >> 50 x
109/L
Laboratory features
• WBC usually elevated, but can
be normal or low
• blasts in peripheral blood
• normocytic anemia
• thrombocytopenia
• neutropenia
• DIC
Bone marrow in acute
leukemia
• necessary for diagnosis
• useful for determining type
• useful for prognosis
• Acute leukemias are defined by
the presence of > 20% blasts in
bone marrow (% of nucleated
marrow cells)
Treatment of acute
leukemias
Choice of Rx is influenced by:
• type (AML vs ALL)
• age
• curative vs palliative intent
Principles of treatment
• combination chemotherapy
– first goal is complete remission
– further Rx to prevent relapse
• supportive medical care
– transfusions, antibiotics, nutrition
• psychosocial support
– patient and family
Chemotherapy for acute
leukemias
• Phases of ALL treatment
– induction
– intensification
– CNS prophylaxispost-remission therapy
– maintenance
• Phases of AML treatment
– induction
– consolidation (post-remission
therapy)
Hematopoietic stem cell
transplantation
• permits “rescue” from otherwise
excessively toxic treatment
• additional advantage of graft-vs-
leukemia effect in allogeneic
transplants
• trade-off for allogeneic
transplantation: greater anti-
leukemic effect but more toxic
Acute myeloblastic
leukemias,
 Pathophysiology

• In all AMLs,
• the accumulation of proliferating neoplastic
myeloid precursor cells in the marrow
suppresses remaining normal hematopoietic
progenitor cells by physical replacement as well as
by other unknown mechanisms.
• The failure of normal hematopoiesis results in
anemia, neutropenia, and thrombocytopenia,
which cause most of the major clinical
complications of AML.
Chromosomal
Abnormalities
• Particular chromosomal
abnormalities correlate with
the clinical setting in which
the tumor occurs.
• AML arising de novo in
patients with no risk factors
are often associated with
balanced chromosomal
translocations, particularly
 FAB French-American-British (FAB) Classification
Approximate % of of AML
subtype Name adult patients Prognosis
M0 Undifferentiated acute 5% Worse
myeloblastic leukemia

M1 Acute myeloblastic 15% Average

leukemia with minimal
maturation

M2 Acute myeloblastic 25% Better

leukemia with maturation

M3 Acute promyelocytic 10% Best

leukemia

M4 Acute myelomonocytic 20% Average

leukemia

M4 eos Acute myelomonocytic 5% Better

leukemia with
eosinophilia

M5 Monocytic leukemia 10% Average

M6 Acute erythroid leukemia 5% Worse
M7 Acute megakaryoblastic 5% Worse
Morphology

• The diagnosis of AML is based on

finding that myeloid blasts make
up more than 20% of the cells in
the marrow
Diffuse replacement of normal haematopoiesis in bone
marrow by leukemic cells
AML
AML
Morphology

• Monoblasts often have folded or

lobulated nuclei, lack Auer rods,
and are peroxidase negative and
nonspecific esterase positive.
• In some AMLs, blasts exhibit
megakaryocytic differentiation,
which is often accompanied by
marrow fibrosis caused by the
release of fibrogenic cytokines.
• Rarely, the blasts of AML show
evidence of erythroid differentiation
Auer rods in AML (pathogmonomic for myeloid lineage origin),
A case of AML-M3
Auer rods in an M1/M2 AML
Clinical Features
• Most patients present within weeks
or a few months of the onset of
symptoms related to anemia,
neutropenia, and
thromobocytopenia, most notably
fatigue, fever, and spontaneous
mucosal and cutaneous bleeding.
•
 Clinical Features
• Often, the bleeding diathesis
caused by thrombocytopenia is the
most striking clinical feature.
Cutaneous petechiae and ecchymoses,
serosal hemorrhages into the
linings of the body cavities and
viscera, and mucosal hemorrhages
into the gingivae and urinary tract are
common. Procoagulants and fibrinolytic
factors released by leukemic cells,
especially in acute promyelocytic
leukemia (M3), exacerbate the
Cutaneous petechiae and ecchymoses
Clinical Features

• Infections are frequent,

particularly in the oral cavity, skin,
lungs, kidneys, urinary bladder, and
colon, and are often caused by
opportunists such as fungi,
Pseudomonas, and commensals.
 Clinical Features

• Signs and symptoms related to

infiltration of tissues are usually less
striking in AML.
• Mild lymphadenopathy and
organomegaly can occur. In tumors
with monocytic differentiation (M4 and
M5), infiltration of the skin
(leukemia cutis) and the gingiva can be
observed, likely reflecting the normal
 Clinical Features

• Central nervous system spread is less

common than in ALL but still seen.
• Quite uncommonly, patients present with
localized masses composed of myeloblasts in
the absence of marrow or peripheral blood
involvement. These tumors, known variously
as myeloblastomas, granulocytic sarcomas,
or chloromas, inevitably progress to systemic
AML over a period of up to several years.
Prognosis
• AML is a difficult disease to treat.
• Approximately 60% of the patients
achieve complete remission with
chemotherapy, but only 15% to 30%
remain free from disease for 5 years.
• AMLs associated with t(8;21) or
inv(16) have a relatively good
prognosis with conventional
chemotherapy.
Prognosis
• In contrast, the prognosis is dismal
for patients with AML with prior
myelodysplastic syndrome or
following genotoxic therapy, possibly
because of damage to normal
hematopoietic stem cells. These
"high-risk" forms of AML, as well as
relapsed AML of all types, are
increasingly being treated with
allogeneic bone marrow
Acute lymphoblastic leukemia (ALL)
Acute lymphoblastic
leukemia
• is a malignant (clonal)
disease of the bone
marrow in which early
lymphoid precursors
proliferate and replace
the normal hematopoietic
cells of the marrow.
Pathophysiology
• The malignant cells of ALL are
lymphoid precursor cells (ie,
lymphoblasts) that are arrested in an
early stage of development. This
arrest is caused by an abnormal
expression of genes, often as a result
of chromosomal translocations. The
lymphoblasts replace the normal
marrow elements, resulting in a
marked decrease in the production of
normal blood cells. The lymphoblasts
also proliferate in organs other than
the marrow, particularly the liver,
Acute lymphatic leukaemia Cont.

Signs and symptoms

Anaemia, bleeding,
Clinical
lymphadenopathy, Clinical
infection
manifestation manifestation

Fever Generalized
Pallor lymphadenopathy
Bleeding Infection of respiratory
Anorexia tract
Fatigue Anaemia and bleeding
Weakness of mucus membrane
Bone, joint and Ecchymoses
abdominal pain Weight loss
Increase intracranial Hepatomegaly
ACUTE LYMPHOBLASTIC LEUKEMIA

CLINICAL FEATURES
 Bone pain & tenderness
 Lymphadenopathy
 Splenomegaly
 Hepatomegally
 CNS manifestations
 Testicular involvement
 Skin
 LEUKEMIA

LABORATORY EVALUATION

• Anemia
• Leukocytosis/leukopenia/normal TLC
• Thrombocytopenia
• Bone marrow examination
Aspirate & biopsy
 ALL-L1

Small and homogenous blasts. These may closely resemble

lymphocytes but are distinguished by their finer chromatin
structure and the occasional presence of nucleoli
 ALL-L2
Lymphoblasts of varying size (small and large)
Large blast cells with marked cytoplasmic budding
(blebing).
The differential diagnosis will be: AML-M7 and ALL.

Farther cytochemical and immunophenotyping studies

showed to be case of B-lineage ALL.
Mature B-ALL with prominent cytoplasmic vacuoles
Etiology
• Epstein-Barr virus
• Higher socioeconimic subgroups
• Trisomy 21 (Down’s syndrome)
• High-energy radiation
• Industrial exposure
• Exposure to agricultural
chemicals
• Smoking
• Preexisting myeloproliferative
disorder
Clinical Features
• Bone pain
• Hepatosplenomegaly, lymphadenopathy.
• Rashes
• Left upper quadrant fullness and early
satiety due to splenomegaly.
• Symptoms related to a large mediastinal
mass, such as shortness of breath.
• Symptoms of leukostasis (eg, respiratory
distress, altered mental status)
• Anemic syndrome
• Increase risk of infection
• Fever
• Disseminated intravascular coagulation
(hemorrhagic or thrombotic complications)
 Lab Studies
• A CBC count: anemia,thrombocytopenia, a
high, normal, or low WBC count,
neutropenia, blasts
 Lab Studies
• Bone marrow aspiration and biopsy
Treatment strategy in
ALL
Medical Care
• A-Induction therapy:
4-drug regimen of vincristine, prednisone,
anthracycline, and cyclophosphamide or L-
asparaginase or a
5-drug regimen of vincristine, prednisone,
anthracycline, cyclophosphamide, and L-
asparaginase given over the course of 4-6
weeks.
• B-Consolidation therapy:
a standard 4- to 5-drug induction usually
include consolidation therapy with Ara-C in
combination with an anthracycline or
epipodophyllotoxin.
• C-Maintenance
• CNS prophylaxis
Supportive Care
• Replacement of blood products: packed
red blood cells, platelets, fresh frozen
plasma
• Antibiotics: a third-generation
cephalosporin (or equivalent) with an
aminoglycoside. Patients with persistent
fever after 3-5 days of antibacterial
antibiotics have amphotericin added to
their regimen.
• The use of prophylactic antibiotics in
neutropenic patients who are not febrile is
controversial. A commonly used regimen
includes ciprofloxacin (500 mg orally twice
daily, fluconazole (Diflucan) (200 mg orally
daily), and acyclovir (200 mg orally 5
times/d).
Post-remission therapy in
standard-risk ALL
1. Chemotherapy
a/. Maintenance therapy: 6-
mercaptopurine,
methotrexate - for 2-3 years.
b/. Intensification treatment
periodically
repeated: daunorubicin/adriablastin,
prednisone, vincristine,
cyclophosphamide.
2. CNS prophylaxis
Post-remission therapy in
high-risk ALL
1. Intensification treatment:
amsacrine, mitoxantrone,
idarubicine, high dose cytosine
arabinoside, high dose
methotrexate, high dose
cyclophosphamide.
2. Hematopoietic stem cell
transplantation
- high-dose therapy
- reduced intencity conditioning
LEUKEMIA
Chronic Myeloid Leukemia (CML)
Chronic Myeloid Leukemia

Clinical Presentation

▪ Asymptomatic (~ 30%)

▪ Fatigue, weight loss, fever

▪ Abdominal fullness, pain and/or early

satiety due to splenomegaly (~ 50-90%)

▪ Easy bruising and purpura

▪ Leukostasis
▪ Pulmonary symptoms
▪ Neurologic symptoms
 CML – Peripheral Blood and BM
Findings

Peripheral smear can only give a presumptive

diagnosis of CML [you need to confirm the t(9;22)]:
1) leukocytosis with a ‘left shift’
2) normocytic anemia
3) thrombocytosis in 50% of pts
4) absolute eosinophilia with a normal % of Eos.
5) absolute and relative increase in basophils
6) LAP score is low (not frequently employed)

Source Undetermined
 How to distinguish AML vs CML
from looking at peripheral blood

Myeloid cell CML AML

normal
blasts q q
promyelocytes q
myelocytes q
metamyelocytes q
bands q
neutrophils q # q
 Therapeutic Options in
Chronic Myeloid Leukemia
 Imatinib (Gleevec, Novartis)
a small molecule tyrosine kinase
inhibitor

X
Source Undetermined
Leukemia Leukemia
Treatment Options for Resistant
Disease

1) Dose Escalation of imatinib

2) Second Generation TKIs

3) Bone Marrow Transplant

4) Clinical Trial Participation

Bone Marrow Transplant
• Donor is placed under anesthesia.
• Marrow is aspirated out of the iliac
crest.
• Marrow is filtered and treated to
remove bits of bone and other
unwanted cells and debris,
transferred to a blood bag, and is
infused into the patient’s blood just
like at transfusion.
Chronic lymphocytic leukemia
Chronic lymphocytic
leukemia (1)
• Is characterised by the accumulation
of nonproliferating mature-
appearing lymphocytes in the
blood, marrow, lymph nodes, and
spleen

• In most cases, the cells are

monoclonal B lymphocytes that are
CD5+
Etiology (1)

• The cause of CLL is unknown

• There is increased incidence in

farmers, rubber manufacturing
workers, asbestos workers, and
tire repair workers

• Genetic factors have been

postulated to play a role in high
incidence of CLL in some families
 Clinical findings (2)
• Most symptomatic patients have enlarged
lymph nodes (more commonly cervical
and supraclavicular) and splenomegaly
• The lymph nodes are usually discrete, freely
movable, and nontender
• Hepatomegaly may occure
• Less common manifestation are infiltration
of tonsils, mesenteric or retroperitoneal
lymphadenopathy, and skin infiltration
• Patients rarely present with features of
anemia, and bruising or bleeding
 Laboratory findings (1)
• The blood lymphocyte count above 5,0 G/L
• In most patients the leukemic cells have
the morphologic appearance of normal
small lymphocytes
• In the blood smears are commonly seen
ruptured lymphocytes (“basket” or
“smudge” cells)
• Careful examination of the blood smear
can usually differentiate CLL, and the
diagnosis can be confirmed by
immunophenotyping
 The diagnostic criteria for
CLL
1) A peripheral blood lymphocyte
count of greater than 5 G/L, with
less than 55% of the cells being
atypical
2) The cell should have the presence
of Bcell-specific differentiation
antigens (CD19, CD20, and CD24)
and be CD5(+)
3) A bone marrow aspirates
showing greater than 30%
 Differential diagnosis
• Infectious causes
– bacterial (tuberculosis)
– viral (mononucleosis)
• Malignant causes
– B-cell
– T-cell
• leukemic phase of non-Hodgkin
lymphomas
• Hairy-cell leukemia
• Waldenstrom macroglobulinemia
• large granular lymphocytic leukemia
Staging (1)
Rai Classification for CLL
– 0 - lymphocytosis (>5 G/L)
– I - lymphocytosis + lymphadenopathy
– II - lymphocytosis + splenomegaly +/-
lymphadenopathy
– III - lymphocytosis + anemia (Hb <11g%)
+/-lymphadenopathy or splenomegaly
– IV - lymphocytosis + thrombocytophenia
(Plt <100G/L) +/- anemia +/-
lymphadenopathy +/- splenomegaly
 Treatment
• Treatment is reserved for patients with low-
or intermediate risk disease who are
symptomatic or have progressive disease
(increasing organomegaly or lymphocyte
doubling time of less than 12 months) and
patients with high -risk disease
– Alkylating agents (chlorambucil,
cyclophosphamide)
– Nucleoside analogs (cladribine, fludarabine)
– Biological response modifiers
– Monoclonal antibodies
– Bone marrow transplantation
– And systemic complications requiring
therapy
• antibiotics
• immunoglobulin
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versitatea Titu Maiorescu

RS MEDICINA INTERNA

H Hematologie V IIIL Lymphoma

Prof univ dr Ion C.Tintoiu
Approach to the Patient
• Hodgkin’s Disease
– approach dictated mainly by where the
disease is located rather (results of
staging) than the exact histologic
subtype
• NHL
– approach is dictated mainly by the
histologic subtype rather than the
results of staging
Lymphoma

Hodgkin’s Disease

.
Lymphoma

• Lymphomas are a
malignant proliferation of
lymphocytes – either B or T
• 3% of all cancers in the US result from
lymphomas
• The lymphomas are classified by the
appearance of malignant lymphocytes
on biopsy of tumor
• 3 categories
– Low-grade
– Intermediate-grade
– High-grade
Functional Presentation of
Lymphoma
• People present with
swollen, growing
lymph glands (nodal
disease) or tumors
in other organs
(extramodal
disease)
• Person can be
asymptomatic
• Common B
symptoms include
fever, drenching
night sweats, loss of
10% of body weight,
Lymphoma
Lymphadenopathy
– .
 Lymphadenopathy
• Enlarged nodes
– tender = infectious
– non-tender =
malignant
• Lymphadenitis
– lymph node is
infected
• Reactive hyperplasia
– acute
• dental infections, sore
throat, genital
infections
– chronic
• TB
Staging of Lymphoma
• Stage I – involvement of a single lymph node
region or single extranodal organ or site

• Stage II – involvement limited to one side of

the diaphragm with 2 or more lymph node
regions

• Stage III – involvement of lymph node regions

on both sides of the diaphragm

• Stage IV – diffuse or disseminated involvement

of one or more extralymphatic organs
Ann Arbor Staging System
Staging of Lymphoma

Stage I Stage II Stage III Stage IV

A: absence of B symptoms
B: fever, night sweats, weight loss
Lymphomas

• Neoplasms of lymphocytes or
lymphoblasts that grow as nodular masses
usually in lymph nodes
• Usually painless,
non-tender enlarged
lymph node in neck
• Weight loss
• Night sweats
• Fever
• Fatigue
• Infection
• Good survival but at
risk for other
malignancies
Skin Lymphoma and Shoulder
Lymphoma
Hodgkin lymphoma

Thomas Hodgkin
(1798-1866)
Classical Hodgkin Lymphoma
Hodgkin lymphoma
• cell of origin: germinal centre B-
cell
• Reed-Sternberg cells (or RS
variants) in the affected tissues
• most cells in affected lymph node are
polyclonal reactive lymphoid cells,
not neoplastic cells
Reed-Sternberg Cell
Hodgkin lymphoma
Histologic subtypes

• Classical Hodgkin lymphoma

– 1-nodular sclerosis (most
common subtype)
– 2-mixed cellularity
– 3-lymphocyte-rich
– 4-lymphocyte depleted
Classic Hodgkin Lymphoma
Nodular Sclerosing
Hodgkin Lymphoma
Hodgkin Lymphoma

• Treatment
– approach depends upon stage,
prognostic factors, and co-
morbidities
– Stage I-II
• consider XRT, chemotherapy, or
combined therapy
– Bulky stage I-II
• combined modality therapy
– Stage III-IV
• ABVD x 6-8 cycles gold standard
Hodgkin’s Disease
• Role for Stem Cell
Transplantation
– clinical trials show benefit for patients
who receive high dose chemotherapy
followed by SCT for patients who have
relapsed after initial therapy or for
patients are primary refractory
Hodgkin’s Disease
• Results of Treatment
• stage 5 year overall survival
–I 90%
– II 90%
– III 80%
– IV 65%
Hodgkin’s: future directions
• Limited stage and good prognosis
advanced stage
– cure rate high
– current goal is to minimize late complications
– trials looking at CMT with less chemotherapy
and less radiation
• Advanced stage
– cure rate around 50-70%
– trial comparing ABVD to Stanford V
• Clinical Trials
• .
Non-Hodgkin Lymphoma

NHL
Lymphoma
• Non-Hodgkin’s Lymphoma
(NHL)
– Heterogeneous group of cancers
affecting lymphocytes
• Usually classified by histologic
grade (low to high)
– Follicular lymphoma
– Small lymphocytic lymphoma
– Diffuse large B-cell lymphoma
– Burkitt’s lymphoma
– Many others
Lymphoma Biology
• Indolent vs. Aggressive NHL
– key principle in understanding biology,
and approach to the patient
– Indolent = incurable
– Aggressive = curable
– WHY?
• Chromosomal Abnormalities in NHL
– frequent chromosomal translocations into
Ig gene loci
• t(8;14), t(2;8), t(8;22) Burkitt’s
• t(14;18) follicular NHL
NHL: Classification
• Terminology (refers to natural
history)
– low grade = indolent
– intermediate grade = aggressive
– high grade = aggressive

• Principle
– indolent: slow growing, incurable
– aggressive: rapidly growing,
curable
NHL: Approach to the
Patient
• Indolent NHL: treatment options
– watchful waiting
– radiation to involved fields
– single agent chemotherapy
• chlorambucil + prednisone, fludarabine
– combination chemotherapy
• CVP, CF, FND, CHOP
– chemotherapy + interferon
– chemotherapy + monoclonal antibodies
– monoclonal antibodies
– radiolabeled monoclonal antibodies
– stem cell transplantation
Summary

• NHL incidence increasing, Hodgkin’s

decreasing
• Hodgkin’s cure rate quite high
– approach is dictated mainly by disease stage
• NHL cure rate mediocre
– approach is dictated mainly by histologic
subtype
– indolent vs. aggressive
• indolent: watchful waiting perfectly acceptable
for asymptomatic patients
• aggressive: require aggressive treatment ASAP
to achieve cure
Multiple Myeloma
Multiple Myeloma
• Malignant cells appear as
nodular masses in bone marrow
• “punched out” lesions in skull &
spine
• Hypogammaglobinemia
• Susceptible to infections
• Elderly most commonly affected
Multiple Myeloma
• Malignant neoplasm of bone
marrow
Tumor destroys bone
Results in:
– Pain
– Fractures
– Hypercalcemia
– Skeletal deformities
– Kidney problems
Copyright © 2007, 2006, 2001, 1994 by Mosby, Inc., an affiliate of Elsevier Inc.
Multiple Myeloma
• Diagnosed by:
– X-ray
– Blood studies
– Biopsy

• Treatment
– Chemotherapy
– Radiation
– Bone marrow transplant
Copyright © 2007, 2006, 2001, 1994 by Mosby, Inc., an affiliate of Elsevier Inc.
Myeloma
Osteolytic lesions
.
Of ,gata!
Of ,ce greu! Incepe alt curs ?
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BLEEDING DISORDERS?
BLEEDING DISORDERS
The normal haemostasis prevents:

● spontaneous haemorrhage and undue blood loss

from injured vessels
● intravascular thrombus
formation.

bleeding
thrombosis
 HEMOSTASIS

1. VASCULAR PHASE
2. PLATELET PHASE
3. COAGULATION PHASE
4. FIBRINOLYTIC PHASE
Hemostasis Lab Tests
• CBC-Plt
• BT,(CT)
BV Injury
• PT
Tissue • PTT
Neural Factor

Blood Vessel Platelet Coagulation

Constriction Aggregation Cascade
Primary hemostatic plug

Reduced Platelet
Activation Fibrin
Blood flow formation

Plt Study
Morphology
Stable Hemostatic Plug
Function
Antibody
NORMAL CLOTTING
Response to vessle injury
1. Vasoconstriction to reduce blood flow
2. Platelet plug formation (von willebrand factor
binds damaged vessle and platelets)
3. Activation of clotting cascade with generation
of fibrin clot formation
4. Fibrinlysis (clot breakdown)
 Screening tests of blood coagulation
• Disorders of vessels:
– Rumpel-Leede test
• Disorders of platelets:
– Platelet count and morphology
– Bleeding time (Ivy)
• Coagulopathies:
– Coagulation time
– Aktivated partial thromboplastin
time (APTT)
– Prothrombin (INR-
International Normalized
Ratio)
– Thrombin time (TT)
VASCULAR PHASE

WHEN A BLOOD VESSEL IS

DAMAGED, VASOCONSTRICTION
RESULTS.
PLATELET PHASE
PLATELETS ADHERE TO THE
DAMAGED SURFACE AND
FORM A TEMPORARY PLUG.
COAGULATION PHASE
THROUGH TWO SEPARATE
PATHWAYS THE CONVERSION OF
FIBRINOGEN TO FIBRIN IS
COMPLETE.
 THE CLOTTING MECHANISM

INTRINSI EXTRINS
CCollagen Tissue
ICThromboplastin
XII
XI VII
IX
VIII

V FIBRINOGE
N (I)

PROTHROMBIN THROMBIN
(II) (III) FIBRIN
FIBRINOLYTIC PHASE
ANTICLOTTING MECHANISMS ARE
ACTIVATED TO ALLOW CLOT
DISINTEGRATION AND REPAIR OF
THE DAMAGED VESSEL.
HEMOSTASIS

DEPENDENT UPON:
 Vessel Wall Integrity
 Adequate Numbers of Platelets
 Proper Functioning Platelets
 Adequate Levels of Clotting Factors
 Proper Function of Fibrinolytic
Pathway
LABORATORY EVALUATION
• PLATELET COUNT
• BLEEDING TIME (BT)
• PROTHROMBIN TIME (PT)
• PARTIAL THROMBOPLASTIN TIME
(PTT)
• THROMBIN TIME (TT)
PLATELET COUNT
 NORMAL 100,000 - 400,000
CELLS/MM3

< 100,000 Thrombocytopenia

50,000 - 100,000 Mild Thrombocytopenia

< 50,000 Sev Thrombocytopenia

BLEEDING TIME

 PROVIDES ASSESSMENT OF
PLATELET COUNT AND FUNCTION

NORMAL VALUE
2-8 MINUTES
 PROTHROMBIN TIME
 Measures Effectiveness of the Extrinsic Pathway
 Mnemonic - PET

NORMAL VALUE
10-15 SECS
PARTIAL THROMBOPLASTIN TIME

 Measures Effectiveness of the Intrinsic

Pathway
 Mnemonic - PITT

NORMAL VALUE
25-40 SECS
 THROMBIN TIME
 Time for Thrombin To Convert
Fibrinogen Fibrin
 A Measure of Fibrinolytic Pathway

NORMAL VALUE
9-13 SECS
So What Causes Bleeding Disorders?

 VESSEL DEFECTS ?
 PLATELET DISORDERS
 FACTOR DEFICIENCIES
 OTHER DISORDERS
?
VESSEL DEFECTS

 VITAMIN C DEFICIENCY

 BACTERIAL & VIRAL INFECTIONS

 ACQUIRED &
 HEREDITARY CONDITIONS
Vascular defect - cont.
 Infectious and
hypersensitivity vasculitides
- Rickettsial and meningococcal
infections
- Henoch-Schonlein purpura
(immune)
PLATELET DISORDERS

 THROMBOCYTOPENIA

 THROMBOCYTOPATHY
THROMBOCYTOPENIA

INADEQUATE NUMBER
OF PLATELETS
THROMBOCYTOPATHY
ADEQUATE NUMBER BUT
ABNORMAL FUNCTION
THROMBOCYTOPENIA
 DRUG INDUCED
 BONE MARROW FAILURE
 HYPERSPLENISM
 OTHER CAUSES
 Platelet Coagulation

Petechiae, Purpura Hematoma, Joint bl.

Purpura
Petechiae
Petechiae
(typical of platelet disorders)

Do not blanch with

pressure
(cf. angiomas)
Not palpable
(cf. vasculitis)
Henoch-Schonlein purpura
•
Ecchymosis
Hemarthrosis
Ecchymoses
(typical of
coagulation factor
disorders)
Hemato
ma
Senile Purpura
Petechiae, purpuras:
small capillary haemorrhages ranging from the size of a pinhead to much larger
Haematomas:
may be spontaneous (in a serious hemorrhagic disease) or may occur
after trauma (in a mild hemorrhagic disease).
Haematomas
 Intramuscular injection may be very dangerous to
the patient with a bleeding disorder

Venipuncture (if skilfully

performed) is without danger
becouse the elasticity of the venous
walls.
THROMBOCYTOPATHY
 UREMIA
 INHERITED DISORDERS
 MYELOPROLIFERATIVE DISORDERS
 DRUG INDUCED
. FACTOR DEFICIENCIES
(CONGENITAL)
FACTOR DEFICIENCIES
(CONGENITAL)

 HEMOPHILIA A

 HEMOPHILIA B

 von WILLEBRAND’S DISEASE

FACTOR DEFICIENCIES
 HEMOPHILIA A (Classic Hemophilia)
• 80-85% of all Hemophiliacs
• Deficiency of Factor VIII
• Lab Results - Prolonged PTT

HEMOPHILIA B (Christmas
Disease)
10-15% of all Hemophiliacs
Deficiency of Factor IX
Lab Test - Prolonged PTT
Hemophilia
Clinical manifestations (hemophilia A & B
are indistinguishable)
Hemarthrosis (most common)
Fixed joints
Soft tissue hematomas (e.g., muscle)
Muscle atrophy
Shortened tendons
Other sites of bleeding
Urinary tract
CNS, neck (may be life-threatening)
Prolonged bleeding after surgery or dental
extractions
Petechiae in patient
with Rocky Mountain
Spotted Fever
Hemarthrosis (acute)
 OTHER DISORDERS
(ACQUIRED)
 ORAL ANTICOAGULANTS
 COUMARIN
 HEPARIN
 LIVER DISEASE
 MALABSORPTION
 BROAD-SPECTRUM ANTIBIOTICS
Treatment of hemophilia A

• Intermediate purity plasma products

– Virucidally treated
– May contain von Willebrand factor

• High purity (monoclonal) plasma products

– Virucidally treated
– No functional von Willebrand factor

• Recombinant factor VIII

– Virus free/No apparent risk
– No functional von Willebrand factor
Dosing guidelines for hemophilia A
• Mild bleeding
– Target: 30% dosing q8-12h; 1-2 days (15U/kg)
– Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria

• Major bleeding
– Target: 80-100% q8-12h; 7-14 days (50U/kg)
– CNS trauma, hemorrhage, lumbar puncture
– Surgery
– Retroperitoneal hemorrhage
– GI bleeding

• Adjunctive therapy
– -aminocaproic acid (Amicar) or DDAVP (for mild disease only)
Complications of therapy
• Formation of inhibitors (antibodies)
– 10-15% of severe hemophilia A patients
– 1-2% of severe hemophilia B patients

• Viral infections
– Hepatitis B Human parvovirus
– Hepatitis C Hepatitis A
– HIV Other
Treatment of hemophilia B
• Agent
– High purity factor IX
– Recombinant human factor IX

• Dose
– Initial dose: 100U/kg
– Subsequent: 50U/kg every 24 hours
 Hemophilia A and B
Hemophilia A Hemophilia B

Coagulation factor deficiency Factor VIII Factor IX

Inheritance X-linked X-linked

recessive recessive

Incidence 1/10,000 males 1/50,000 males

Severity Related to factor level

<1% - Severe - spontaneous bleeding
1-5% - Moderate - bleeding with mild injury
5-25% - Mild - bleeding with surgery or trauma

Complications Soft tissue bleeding

Treatment
• Products used to treat hemophilia
are:
– Fresh frozen plasma and
cryoprecipitate which are from
single blood donors and require
special freezing.
– Second generation of factor VIII are
made with animal or human proteins.
HEMATOLOGY -END

• .

• .
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Clinical Features of Bleeding
Disorders
Clinical Features of Bleeding Disorders
Platelet Coagulation
disorders
factor disorders
Site of bleeding Skin Deep in soft
tissues
Mucous membranes (joints,
muscles)
(epistaxis, gum,
vaginal, GI tract)
Petechiae Yes No
Ecchymoses (“bruises”) Small, superficial Large, deep
Hemarthrosis / muscle bleeding Extremely rare Common
Bleeding after cuts & scratches Yes No
Bleeding after surgery or trauma Immediate, Delayed (1-2
days),
Coagulation factor disorders
• Inherited bleeding
disorders
– Hemophilia A and B • Acquired bleeding
– vonWillebrands disorders
disease – Liver disease
– Other factor – Vitamin K
deficiencies deficiency/warfarin
overdose
– DIC
von Willebrand Disease: Clinical
Features

• von Willebrand factor

– Synthesis in endothelium and megakaryocytes
– Forms large multimer
– Carrier of factor VIII
– Anchors platelets to subendothelium
– Bridge between platelets
• Inheritance - autosomal dominant
• Incidence - 1/10,000
• Clinical features - mucocutaneous bleeding
 Laboratory evaluation of
von Willebrand disease
• Classification
– Type 1 Partial quantitative deficiency
– Type 2 Qualitative deficiency
– Type 3 Total quantitative deficiency

• Diagnostic tests:

vonWillebrand type
Assay 1 2 3

vWF antigen  Normal 

vWF activity   
Multimer analysis Normal Normal Absent
Treatment of von Willebrand Disease

• Cryoprecipitate
– Source of fibrinogen, factor VIII and VWF
– Only plasma fraction that consistently contains VWF multimers

• DDAVP (deamino-8-arginine vasopressin)

–  plasma VWF levels by stimulating secretion from endothelium
– Duration of response is variable
– Not generally used in type 2 disease
– Dosage 0.3 µg/kg q 12 hr IV

• Factor VIII concentrate (Intermediate purity)

– Virally inactivated product
Vitamin K deficiency
• Source of vitamin K Green vegetables
Synthesized by intestinal flora

• Required for synthesis Factors II, VII, IX ,X

Protein C and S

• Causes of deficiency Malnutrition

Biliary obstruction
Malabsorption Antibiotic therapy
• Treatment Vitamin K
Fresh frozen plasma
Common clinical conditions associated with
Disseminated Intravascular Coagulation
Activation of both coagulation and fibrinolysis
Triggered by
• Sepsis • Obstetrical
complications
• Trauma – Amniotic fluid embolism
– Head injury – Abruptio placentae
– Fat embolism
• Vascular disorders
• Malignancy • Reaction to toxin (e.g.
snake venom, drugs)

• Immunologic disorders
– Severe allergic reaction
– Transplant rejection
Disseminated Intravascular Coagulation (DIC)
Mechanism

Systemic activation
of coagulation

Intravascular Depletion of platelets

deposition of fibrin and coagulation factors

Thrombosis of small Bleeding

and midsize vessels
with organ failure
Pathogenesis of DIC

Release of
thromboplastic
material into Consumption of
circulation coagulation factors;
presence of FDPs
Coagulation Fibrinolysis
 aPTT
 PT
Fibrinogen  TT
Thrombin Plasmin
 Fibrinogen

Presence of plasmin
Fibrin  FDP
Monomers Fibrin(ogen)
Degradation Intravascular clot
Products  Platelets
Fibrin Schistocytes
Clot
Plasmin
(intravascular)
Disseminated Intravascular Coagulation
Treatment approaches

• Treatment of underlying disorder

• Anticoagulation with heparin

• Platelet transfusion
• Fresh frozen plasma

• Coagulation inhibitor concentrate (ATIII)

Classification of platelet disorders
• Quantitative
disorders
• Qualitative disorders
– Abnormal distribution
– Inherited disorders
– Dilution effect
(rare)
– Decreased
– Acquired disorders
production
• Medications
– Increased • Chronic renal failure
destruction • Cardiopulmonary
bypass
Thrombocytopenia

Immune-mediated
Idioapthic
Drug-induced
Collagen vascular disease
Lymphoproliferative disease
Sarcoidosis
Non-immune mediated
DIC
Microangiopathic hemolytic anemia
Liver Disease and Hemostasis

1. Decreased synthesis of II, VII, IX, X, XI, and fibrinogen

2. Dietary Vitamin K deficiency (Inadequate intake or
malabsortion)
3. Dysfibrinogenemia
4. Enhanced fibrinolysis (Decreased alpha-2-antiplasmin)
5. DIC
6. Thrombocytoepnia due to hypersplenism
Management of Hemostatic
Defects in Liver Disease
Treatment for prolonged PT/PTT
 Vitamin K 10 mg SQ x 3 days - usually ineffective

 Fresh-frozen plasma infusion

 25-30% of plasma volume (1200-1500 ml)
 immediate but temporary effect

Treatment for low fibrinogen

 Cryoprecipitate (1 unit/10kg body weight)

Treatment for DIC (Elevated D-dimer, low factor VIII, thrombocytopenia

 Replacement therapy
Vitamin K deficiency due to warfarin overdose
Managing high INR values

Clinical situation Guidelines

INR therapeutic-5 Lower or omit next dose;

Resume therapy when INR is therapeutic

INR 5-9; no bleeding Lower or omit next dose;

Resume therapy when INR is therapeutic
Omit dose and give vitamin K (1-2.5 mg po)
Rapid reversal: vitamin K 2-4 mg po (repeat)

INR >9; no bleeding Omit dose; vitamin K 3-5 mg po; repeat as necessary
Resume therapy at lower dose when INR therapeutic

Chest 2001:119;22-38s (supplement)

 Vitamin K deficiency due to warfarin overdose
Managing high INR values in bleeding patients

Clinical situation Guidelines

INR > 20; serious bleeding Omit warfarin

Vitamin K 10 mg slow IV infusion
FFP or PCC (depending on urgency)
Repeat vitamin K injections every 12 hrs as needed

Any life-threatening bleeding Omit warfarin

Vitamin K 10 mg slow IV infusion
PCC ( or recombinant human factor VIIa)
Repeat vitamin K injections every 12 hrs as needed

Chest 2001:119;22-38s (supplement)

Approach to Post-operative bleeding

1. Is the bleeding local or due to a hemostatic failure?

1. Local: Single site of bleeding usually rapid with minimal coagulation test
abnormalities
2. Hemostatic failure: Multiple site or unusual pattern with abnormal
coagulation tests
2. Evaluate for causes of peri-operative hemostatic failure
1. Preexisting abnormality
2. Special cases (e.g. Cardiopulmonmary bypass)
3. Diagnosis of hemostatic failure
1. Review pre-operative testing
2. Obtain updated testing
 Laboratory Evaluation of Bleeding
Overview

CBC and smearPlatelet count Thrombocytopenia

RBC and platelet morphology TTP, DIC, etc.

CoagulationProthrombin time Extrinsic/common pathways

Partial thromboplastin time Intrinsic/common pathways
Coagulation factor assays Specific factor deficiencies
50:50 mix Inhibitors (e.g., antibodies)
Fibrinogen assay Decreased fibrinogen
Thrombin time Qualitative/quantitative
fibrinogen defects
FDPs or D-dimer Fibrinolysis (DIC)

Platelet function von Willebrand factor vWD

Bleeding time In vivo test (non-specific)
Platelet function analyzer (PFA) Qualitative platelet disorders
and vWD
Platelet function tests Qualitative platelet disorders
 Laboratory Evaluation of the
Coagulation Pathways
Partial thromboplastin time Prothrombin time
(PTT) (PT)
Surface activating agent Thromboplastin
(Ellagic acid, kaolin) Tissue factor
Phospholipid Phospholipid
Calcium Calcium

Intrinsic pathway Extrinsic pathway

Thrombin time Common pathway

Thrombin

Fibrin clot
Coagulation factor deficiencies
Summary
Sex-linked recessive
 Factors VIII and IX deficiencies cause bleeding
Prolonged PTT; PT normal

Autosomal recessive (rare)

 Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleeding
Prolonged PT and/or PTT

 Factor XIII deficiency is associated with bleeding and

impaired wound healing
PT/ PTT normal; clot solubility abnormal

 Factor XII, prekallikrein, HMWK deficiencies

do not cause bleeding
Thrombin Time

• Bypasses factors II-XII

• Measures rate of fibrinogen conversion to fibrin

• Procedure:
– Add thrombin with patient plasma
– Measure time to clot

• Variables:
– Source and quantity of thrombin
Causes of prolonged Thrombin Time

• Heparin
• Hypofibrinogenemia
• Dysfibrinogenemia
• Elevated FDPs or paraprotein
• Thrombin inhibitors (Hirudin)
• Thrombin antibodies
Classification of thrombocytopenia
• Associated with • Associated with
thrombosis bleeding
– Thrombotic – Immune-mediated
thrombocytopenic thrombocytopenia
purpura (ITP)
– Heparin-associated – Most others
thrombocytopenia
– Trousseau’s
syndrome
– DIC
Bleeding time and bleeding
• 5-10% of patients have a prolonged bleeding
time
• Most of the prolonged bleeding times are due to
aspirin or drug ingestion
• Prolonged bleeding time does not predict excess
surgical blood loss
• Not recommended for routine testing in
preoperative patients
• Drugs and blood products
used for bleeding
Treatment Approaches to
the Bleeding Patient
• Red blood cells
• Platelet transfusions
• Fresh frozen plasma
• Cryoprecipitate
• Amicar
• DDAVP
• Recombinant Human factor VIIa
RBC transfusion therapy
Indications
• Improve oxygen carrying capacity of blood

– Bleeding

– Chronic anemia that is symptomatic

– Peri-operative management
 Red blood cell transfusions
Special preparation

CMV-negative CMV-negative patients Prevent CMV

transmission

Irradiated RBCs Immune deficient recipient Prevent GVHD

or direct donor

Leukopoor Previous non-hemolytic Prevents reaction

transfusion reaction
CMV negative patients Prevents transmission

Washed RBC PNH patients Prevents hemolysis

IgA deficient recipient Prevents anaphylaxis
 Red blood cell transfusions
Adverse reactions
Immunologic reactions

Hemolysis RBC incompatibility

Anaphylaxis Usually unknown; rarely against IgA
Febrile reaction Antibody to neutrophils
Urticaria Antibody to donor plasma proteins
Non-cardiogenic Donor antibody to leukocytes
pulmonary edema
Red blood cell transfusions
Adverse reactions

Non-immunologic reactions

Congestive heart failure Volume overload

Fever and shock Bacterial contamination

Hypocalcemia Massive transfusion

 Transfusion-transmitted disease

Infectious agent Risk

HIV ~1/500,000
Hepatitis C 1/600,000
Hepatitis B 1/500,000
Hepatitis A <1/1,000,000
HTLV I/II 1/640,000
CMV 50% donors are sero-positive
Bacteria 1/250 in platelet transfusions
Creutzfeld-Jakob disease Unknown
Others Unknown
Platelet transfusions
• Source
– Platelet concentrate (Random donor)
– Pheresis platelets (Single donor)

• Target level
– Bone marrow suppressed patient (>10-20,000/µl)
– Bleeding/surgical patient (>50,000/µl)
Platelet transfusions - complications
• Transfusion reactions
– Higher incidence than in RBC transfusions
– Related to length of storage/leukocytes/RBC mismatch
– Bacterial contamination

• Platelet transfusion refractoriness

– Alloimmune destruction of platelets (HLA antigens)
– Non-immune refractoriness
• Microangiopathic hemolytic anemia
• Coagulopathy
• Splenic sequestration
• Fever and infection
• Medications (Amphotericin, vancomycin, ATG, Interferons)
 Fresh frozen plasma
• Content - plasma (decreased factor V and VIII)
• Indications
– Multiple coagulation deficiencies (liver disease, trauma)
– DIC
– Warfarin reversal
– Coagulation deficiency (factor XI or VII)
• Dose (225 ml/unit)
– 10-15 ml/kg
• Note
– Viral screened product
– ABO compatible
Cryoprecipitate
• Prepared from FFP
• Content
– Factor VIII, von Willebrand factor, fibrinogen
• Indications
– Fibrinogen deficiency
– Uremia
– von Willebrand disease
• Dose (1 unit = 1 bag)
– 1-2 units/10 kg body weight
 Hemostatic drugs
Aminocaproic acid (Amicar)
• Mechanism
– Prevent activation plaminogen -> plasmin
• Dose
– 50mg/kg po or IV q 4 hr
• Uses
– Primary menorrhagia
– Oral bleeding
– Bleeding in patients with thrombocytopenia
– Blood loss during cardiac surgery
• Side effects
– GI toxicity
– Thrombi formation
Hemostatic drugs
Desmopressin (DDAVP)
• Mechanism
– Increased release of VWF from endothelium
• Dose
– 0.3µg/kg IV q12 hrs
– 150mg intranasal q12hrs
• Uses
– Most patients with von Willebrand disease
– Mild hemophilia A
• Side effects
– Facial flushing and headache
– Water retention and hyponatremia
Recombinant human factor VIIa (rhVIIa;
Novoseven)
• Mechanism
– Direct activation of common pathway

• Use
– Factor VIII inhibitors
– Bleeding with other clotting disorders
– Warfarin overdose with bleeding
– CNS bleeding with or without warfarin

– Dose
– 90 µg/kg IV q 2 hr
– “Adjust as clinically indicated”

• Cost (70 kg person) - $1 per µg

– ~$5,000/dose or $60,000/day
Approach to bleeding disorders
Summary

• Identify and correct any specific defect of

hemostasis
– Laboratory testing is almost always needed to establish the cause
of bleeding
– Screening tests (PT,PTT, platelet count) will often allow placement
into one of the broad categories
– Specialized testing is usually necessary to establish a specific
diagnosis
• Use non-transfusional drugs whenever possible
• RBC transfusions for surgical procedures or large
blood loss
Bleeding Disorders
Hemophilia
Bleeding Disorders
• Three types Hemophilia: males only
– Type A most common – factor VIII
deficiency
– Type B - lack of factor IX (Christmas
Disease)
– Type C – lack of factor XI

Von Willebrand Disease – 1% of

population – men or women – prolonged
bleeding time
Hemophilia
• Hemophilia is a sex-linked
hereditary bleeding disorder
• Transmitted on the X chromosome
• Female is the carrier
• Women do not suffer from the
disease itself
 Functional Presentation of
Hemophilia
• People with
hemophilia can
bleed anywhere, but
bleeding into joints
(hemarthrosis), soft
tissue (such as
muscle), urine
(hematuria), and the
brain are common
• Chronic bleeding into
joints or an acute
bleed into the brain or
spinal canal can lead
to chronic disabilities,
Treatment
• Products used to treat hemophilia
are:
– Fresh frozen plasma and
cryoprecipitate which are from
single blood donors and require
special freezing.
– Second generation of factor VIII are
made with animal or human proteins.
 Idiopathic
thrombocytopenic
purpura
ITP
• Idiopathic thrombocytopenic purpura

– Idiopathic = cause is unknown

– Thrombocytopenic = blood does not
have enough platelets
– Purpura = excessive bleeding / bruising
Symptoms
• Random purpura
• Epistaxis, hematuria, hematemesis,
and menorrhagia
• Petechiae and hemorrhagic bullae in
mouth
Cutaneous petechiae and ecchymoses
Diagnostic Tests
• Low platelet count
• Peripheral blood smear
• Antiplatelet antibodies

Normal platelet count: 150,000 to

400,000
Management
• IV gamma globulin to block antibody
production, reduce autoimmune
problem
• Corticosteroids to reduce
inflammatory process
• IV anti-D to stimulate platelet
production
Heparin-Induced Thrombocytopenia
(HIT)
– HIT
• Associated with administration of heparin
• Develops when the body develops an antibody, or allergy
to heparin
• Heparin (paradoxically) causes thrombosis
• Immune mediated response that casues intense platelet
activation and relaese of procoaggulation particles.
– Clinical features
• Thrombocytopenia
• Possible thrombosis after heparin therapy
– Can be triggered by any type, route or amount of heparin

19/04/2011 544
Of ,ce greu!
Blood coagulation disorders

Dr. Klara Vezendi

Szeged University
Transfusiology Department
The normal haemostasis prevents:

● spontaneous haemorrhage and undue blood loss

from injured vessels
● intravascular thrombus
formation.

bleeding
thrombosis
There are three components of blood coagulation
system:
HAEMOSTASIS

1. 3.
Capillaries Plasma
2. coagulation
Platelets factors

1. 2: Primary haemostasis (it is enough to stop bleeding from

small injuries)
3: Secundary haemostasis (it is necessary to stop bleeding
definitely)
Primary haemostasis I:
● Capillaries and larger blood vessels react to injury by an
immediate local temporary vasoconstriction (a reflex nervous
mechanism) to reduce the amount of blood lost.
Primary haemostasis II:
● Platelets:
- adhere to the site of injury
- aggregation
- release substances from their cytoplasms to initiate blood
coagulation  haemostatic plug is formed.
Secundary haemostasis:
Blood coagulation factors are necessary to stop bleeding
definitely.
• I: fibrinogen
• II: prothrombin
• III: tissue thromboplastin (tissue factor, TF)
• IV: Ca++
• V: proaccelerin
• VI: -
• VII: proconvertin
• VIII: antihemophilic factor (AHF)
• IX: Christmas factor (plasma thromboplastin component)
• X: Stuart factor
• XI: plasma thromboplastin antecedent (PTA)
• XII: Hageman factor (contact factor)
• XIII: fibrin stabilizing factor (Laki-Lorand factor)
Disorders of the haemostatic mechanism are
devided into three main groups:

• Disorders of the vessels „ purpuric

• Disorders of the platelets diseases”

• Disorders of the coagulation mechanism

(„coagulopathies”)
The investigation of a patient with a
suspected disorder of haemostasis
– case history (personal details, family
history)
– inspection (type of bleeding)
– physical examination
– other known diseases
– drugs and medications
– laboratory tests
Certain signs and symptoms are virtually diagnostic of
disordered haemostasis.
The main symptom of all diseases is the bleeding:

● in the „purpuric disorders” cutaneous and mucosal

bleeding usually is prominent
● in different types of „coagulopathies” hemarthroses,
haematomas are the characteristic bleeding manifestations.
The onset of bleeding following trauma frequently is delayed
(recur in a matter of hours)
(the temporary hemostatic adequacy of the platelet plug
may explain this phenomenon).
Petechiae, purpuras:
small capillary haemorrhages ranging from the size of a pinhead to much larger
Petechiae, purpuras
Haematomas:
may be spontaneous (in a serious hemorrhagic disease) or may occur
after trauma (in a mild hemorrhagic disease).
Haematomas
 Intramuscular injection may be very dangerous to
the patient with a bleeding disorder

Venipuncture (if skilfully

performed) is without danger
becouse the elasticity of the venous
walls.
 Screening tests of blood coagulation
• Disorders of vessels:
– Rumpel-Leede test
• Disorders of platelets:
– Platelet count and morphology
– Bleeding time (Ivy)
• Coagulopathies:
– Coagulation time
– Aktivated partial thromboplastin
time (APTT)
– Prothrombin (INR)
– Thrombin time (TT)
 Laboratory diagnosis of the coagulopathies

Contact activation Tissue thromboplastin (TF)

INTRIN XII EXTRINSI

SIC VII C
XI
IX
Blood VIII
coagulation
Prothrom-
time
bin
X

APTI V
COMM
ON II
I
 Diagnosis of bleeding disorders by the screening tests
Platelet Bleeding APTI Prothrom- Presumptive
count time bin diagnosis
Decreased Prolonged Norm. Norm. Thrombocytopenia

Norm. Prolonged Prolonged Norm. von Willebrand’s disease

Norm./ Prolonged Norm. Norm. Thrombocytopathia

increased
Norm. Norm. Prolonged Norm. „intrinsic” pathway
abnormality
(FVIII. IX. XI. XII)
Norm. Norm. Norm. Prolonged „extrinsic”pathway
abnormality (FVII)
Norm. Norm. Prolonged Prolonged „common” pathway
abnorm. (FI. II. V. X.)
Norm. Norm. Norm. Norm. - /FXIII deficiency/ milde
bleeding disorder
 Coagulopathies

• Aquired:
generally several coagulation
abnormalities are present. • Hereditary:
Clinical picture is complicated deficiency or abnormality of
by signs and symptoms of the a single coagulation factor.
underlying disease.
– Hemofilia A (FVIII)
– Hemofilia B (FIX)
 Deficiencies of the
– Von Willebrand’s disease
vitamin K dependent coagulation
factors (FII, VII, IX, X) – Rare coagulopathies
 Hepatic disorders (FI. II. V. VII. X. XI. XIII)
 Accelerated destruction of blood
coagulation (DIC)
 Inhibitors of coagulation
 Others (massive transfusion,
extracorporal circulation)
 Haemophilia
A bleeding disorder in which clotting factor VIII
(eight) /Haemophilia A/ or IX (nine) /Haemophilia B/
in a person's blood plasma is missing or is at a low
level.

Prevalence:
haemophilia A: 105/million men
haemophilia B: 28/million men
• In haemophilia, VIII
or IX clotting factor is
missing, or the level of
that factor is low.

• This makes it
difficult for the blood
to form a clot, so
bleeding continues
longer than usual.
The hemophilia gene is carried on the X chromosome
 in males who lack a normal allele, the defect is manifested by
clinical haemophilia. Women may be carriers.
Haemophilia is a lifelong disease

• A person born with

haemophilia will
have it for life.
• The level of factor
VIII or IX in his
blood usually stays
the same throughout
his life.
 Clinical manifestations

The most dramatic manifestation of haemophilia is

extensive bleeding into the soft tissue and muscles after
only negligible trauma, or even no known trauma.

The frequency and severity of bleeding generally is

related to the blood level of FVIII or FIX.
Haemophilia can be mild, moderate, or severe, depending on the level of clotting factor.
Three category of severity:

• Severe: FVIII/FIX < 1 %

– Repeated and severe hemarthroses and spontaneous
bleeding, crippling common.
• Moderate: FVIII/FIX: 1-5 %
– Spontaneous bleeding and hemarthroses infrequent.
Serious bleeding from trivial injuries.
• Milde: FVIII/FIX: 5-40 %
– Spontaneous bleeding manifestations may be absent,
although serious bleeding may follow surgical
procedures or traumatic injury.
 Joint bleeding
As blood fills the capsule, the joint
swells and becomes painful and hard to
move.

The most common joint bleeds happen

in ankles, knees, and elbows.
Bleeds into other joints can also happen.
The long-term effects of joint
bleeds:
Repeated bleeding into a joint causes the
synovium to swell and bleed very easily.
Some blood remains in the joint after each
bleed. The synovium stops producing the
slippery, oily fluid that helps the joint move.
This damages the smooth cartilage that
covers the ends of the bones. The joint
becomes stiff, painful to move, and unstable.
It becomes more unstable as muscles around
the joint weaken.

With time, most of the cartilage breaks down

and some bone wears away. Sometimes the
joint cannot move at all.

The whole process is called:

hemophilic arthritis.
Haemophilic arthropathy (radiographs)
Other types of bleeding:
subcutaneous, intramuscular hematomas, gastrointestinal
bleeding, hematuria, cerebral hemorrhage
 Volkmann’s contracture

Large haematoma of the

cerebellum
(computer tomography)
Pseudotumor
Life-threatening bleeding:
- bleeding within the head is a
major cause of death in
haemophilia
- Bleeding into the throat may
cause swelling, as well as
difficulty swallowing and
breathing
- Gastrointestinal bleeding (often
due to peptic ulceration)

Serious, but usually not

life-threatening bleeding:
- bleeds into the eyes, spine and
psoas muscle
 Therapy
The only mode of treatment is replacement therapy: to
inject the missing clotting factor into a vein.
Clotting factor cannot be given by mouth.
 Factor substitution
• On demand:
– in the event of bleeding
episodes
• Profilaxis: to
prevent bleedings and their
consequences
– primary
– secundary
• Home treatment:
– the patient or his relatives are
taught to give iv. injection of
the factor concentrate
immediately when there are
symptoms of bleeding.
 Calculation of the dose of factor replacement

Haemophilia A:
(desired level FVIII % - patient FVIII level %) x bodyweightkg/2

Haemophilia B:
(desired level FIX % - patient FIX level %) x bodyweightkg
Recommended doses of FVIII/FIX for
various types of haemorrhage
Factor replacement
at the consulting
room
Home therapy:
is infusion with clotting factor
replacement away from the hospital.
A person with haemophilia can infuse at
home, school, work, or elsewhere.
 Supplies needed for treatment with factor concentrate:

sharps container
disposable wipes A written record
alcohol wipe of all treatments
bandage
cotton balls
must be kept.
tape
tourniquet
butterfly needle
syringe
transfer needle/
filter needle
factor concentrate
latex gloves
diluent (sterile water) supplied
with the concentrate
Medical treatment is only one part of good health.

People with hemophilia should:

- Exercise and stay fit.

- Wear protection that is appropriate for the sport or activity.
- Get regular check-ups that include joint and muscle
examination.
- Get all vaccinations recommended, including hepatitis A
and hepatitis B protection.
- Maintain a healthy body weight. People who do not exercise
are more likely to put on extra weight. A person with
hemophilia needs to control his weight so that he does not
put extra stress on his joints, especially if he has arthritis.
 Dental health is very important in haemophilia:

- Healthy teeth and gums reduce the need for haemophilia

treatment.

- Regular dental care reduces the need for injections and

surgery.

- Dental care should include brushing, flossing, and check-ups

by a dentist.

- Cooperation between hematologists (hemostaseologists) and

dentists is necessary.
versitatea Titu Maiorescu

RS MEDICINA INTERNA

Hematologie V
Lymphomas
Prof univ dr Ion C.Tintoiu
Normal Hemostasis

SecondaryHemost
Primary Hemostasis asis
• VascularSub • Activation of
endthel
Fibrinogen to
• von Willebrand Fibrin
factor(vWF) (Intrinsic&Extrinsi
• Platelets c Clotting
Cascades)
• Dissolution of
Fibrin Clots
Coagulation cascade
Intrinsic system (surface contact) Extrinsic system (tissue damage

XII XIIa Tissue factor

XI XIa

IX IXa VIIa VII

VIII VIIIa

X Xa
Vitamin K dependant factors
V Va

II IIa (Thrombin)

Fibrinogen Fibrin
 Petechiae
(typical of platelet disorders)

Do not blanch with

pressure
(cf. angiomas)
Not palpable
(cf. vasculitis)
Ecchymoses
(typical of
coagulation
factor
disorders)
Hemarthrosis (acute)
Large pseudocyst involving the left
proximal femur
Pathogenesis of DIC

Release of
thromboplastic
material into Consumption of
circulation coagulation factors;
Coagulation Fibrinolysis
 aPTT
 PT
Fibrinogen  TT
Thrombin Plasmin
 Fibrinogen

Presence of plasmin
Fibrin  FDP
Monomers Fibrin(ogen)
Degradation Intravascular clot
Products  Platelets
Fibrin Schistocytes
Clot
Plasmin
(intravascular)
•THE END
Of ,gata!