Transcript Slide 1

The white cell
The five types of leucocytes found in peripheral blood are:
• polymorphonuclear leucocytes (neutrophil leucocytes)
• eosinophil leucocytes
• basophil granulocytes
• lymphocytes
• monocytes
Polymorphonuclear leucocytes originate in the bone marrow and
are carried to tissues via the blood, where they are involved in
immune defense and may continue to circulate between the
lymphatic tissue and blood stream.
neutrophilis
The neutrophil granulocyte originates in the bone marrow as
myeloblast → promyelocyte → myelocyte (stored up to 10 days)
Function
– ingest and kill bacteria
– accumulation of degenerate neutrophils gives rise to pus
Neutrophil luecocytosis
 rise in the number of neutrophils to > 10x105/l in bacterial
infection or tissue damage
 exercise
 corticosteroid administration
Neutrophil leucocytosis
 leukaemia
 myeloproliferative disease
 leukaemoid reaction
 leucoerytroblastic anaemia
 the leucocytosis may be accompanied by a pyrexia due to the
production of a leucocyte pyrogen
 a leukaemoid reaction (the overproduction of white cells,
many of them primitive) may occur in - severe infections
- tuberculosis
-malignant infiltration
neutrophilis
Neutropenia and agranulocytosis
 defined as a circulatory neutrophil count below 1,5x109/l
 the absence of heutrophilis is called agranulocytosis
causes of neutropenia
 rasial (neutropenia is common in black rases)
 viral infection
 severe bacterial infection (typhoid)
 Felty’s syndrome
 megaloblastic anaemia
 drugs
 pancytopenia from any cause
Clinical features:
 infections
 glazed mucositis occurs in the mouth and ulceeration is
common
 septicaemia
investigation
 blood film shows neutropenia
 bone marrow – absence of cells from the neutrophil
granulocyte series
eosinophils
– Occur when the number of eosinophils is > 1x109/l
causes of eosinophils increase no
 Parasitic infestation
– ascaris
– strongyloides
 Allergic disorders
– hayfever (allergic rhinitis)
– other hypersensitivity reactions, including drug reactions
 Skin disorders
– urticaria
– eczema
– pemphiguscre
 Pulmonary disorders
– bronchial asthma
– tropical pulmonary eosinophilia
– allergic bronchopulmonary aspergillosis
– polyarteritis nodosa (Churg – Strauss syndrome)
 Malignant disorders
– lymphoma
– carcinoma
– melanoma
– eosinophilic leukemia
 Miscellaneous
– sarcoidosis
– hypoadrenalism
– eosinophilic gastroenteritis
– hypereosinophilic syndrome
lymphocytes
• Form nearly the circulating white cells
• Originate in the lymph glands, spleen, Peyer’s patches, bone
marrow, thymus
2 types:
 thymus dependent or T lymphocytes concerned with
cellular immunity
 “bursa – dependent” or B lymphocytes concerned with
humoral immunity
Lymphocytosis occurs in:
• viral infections: Epstein – Barr, cytomegalvirus
• chronic infections: syphilis, tuberculosis
• acute viral infections: pertussis, brucellosis
The leukaemias
Characterized by the proliferation of a single malignantly
transformed progenitor cell in the haemopoietic system.
clasification
There are TWO MAJOR of acute leukemia:
A. Acute lymphoblastic leukaemia
B. Acute non-lymphocytic leukaemia
myelogenous (myeloblastic) leukaemia)
(called
The CHRONIC FORMS of these conditions are:
Chronic granulocytic leukaemia
Chronic lymphatic leukaemia
also
acute
incidence
– the commonest childhood leukaemia is acute lymphoblastic in
type (80%)
– adults B and in elderly – chronic forms
aetiology
– remains unknown
Genetic factors:
– are important: low frequency of all in black children
– a high incidence of leukaemia in the identical twin
– ↑ risk of developing acute leukaemia in children with Down’s
syndrome (who have chromosomal abnormalities)
Enviromental factors:
 radiation (in survivors of the atomic bomb of Hiroshima)
 chemicals
 drugs and chemotherapeutic agents
 viruses (human leukaemia virus type I) which was first
discovered in Japanese with T cell leukaemia and
hypercalcaemia
Acute leukaemia
Cellular types
1. Acute lymphoblastic leukaemia
– blast cells involved may vary
– histologically: L1, L2 and L3 types
– the phenotypic markers have proved to be of considerable
importance assessing the likelihood importance of
response and the long-term outlook
2. Acute non-lymphocytic leukaemia
classification
M1
M2
M3
M4
M5
M5
A
M6
• predominant myeloblasts, distinct
nucleoli
• few granules Auer rods – rare
• myeloblasts and promyelocytes
predominant
• further maturation abnormal
• auer rods – many
Acute
• promyelocytes predominate
promyelocytic
hipergranular
leukaemia
• auer rods – rare
Acute
• myelocytic and monocytic maturation
myelomonocytic evident may be peripheral
leukaemia
• auer rods – rare
Acute monocytic • promonocytes predominant with
differentiation
leukaemia
Acute monoblastic • completely with differentiation
leukaemia
• undifferentiated blast cells
• bizzare, multinucleated megaloblasted
Erytroleukaemia erythroblasts predominate
• myeloblasts also present
Acute myelocytic
leukaemia without
differentiation
Acute myelocytic
Leukaemia with
Differentiation
Acute leukaemia
clinical features
Hystory short
 symptoms of anaemia and maladive
 acute infections such as mouth ulceration, sore throat,
pneumonia, perianal and skin infections
 painful and enlarging lymphadenopathy
 bruising and bleeding
 bone pain (particularly common in children with all)
 symptoms due to infiltration of tissues with leukaemic blast
cells, marked gum hypertrophy
 headache, nausea, vomiting and blurred vision (raised
intracranial pressure)
• Most patients have been ill only for days or weeks.
• Bleeding (usually due to thrombocytopenia) occurs in the
skin and mucosal surfaces, with gingival bleeding,
epistaxis or menorrhagia.
• Less commonly, widespread bleeding is seen in patients
with disseminated intravascular coagulation (DIC) (in
APL and monocytic leukemia).
• Infection is due to neutropenia, with the risk of infection
rising as the neutrophil count falls below 500/mcL; with
neutrophil counts less than 100/mcL, infection within
days is the rule.
• The most common pathogens are gram-negative
bacteria (Escherichia coli, Klebsiella, Pseudomonas) or
fungi (Candida, Aspergillus).
• Common presentations include cellulitis, pneumonia,
and perirectal infections; death within a few hours may
occur if treatment with appropriate antibiotics is delayed.
Signs
These may be relatively few, but commonly they are:
 pallor
 bruising, petechial haemorrages, bleeding gums and gum
hypertrophy
 lymphadenopathy
 splenomegaly and hepatomegaly
 haemorrhages in the optic fundi with characteristic central
white deposit in the middle of the fundal haemorrhage →
leukaemic retinopathy
 meningeal leukaemia
 boys – hard enlarged testicles (infiltrated with leukaemic
tissue)
• Patients may also seek medical attention
because of gum hypertrophy and bone and joint
pain.
• The most dramatic presentation is
hyperleukocytosis, in which a markedly elevated
circulating blast count (usually > 200,000/mcL)
leads to impaired circulation, presenting as
headache, confusion and dyspnea.
• Such patients require emergent leukapheresis
and chemotherapy.
• There is variable enlargement of the liver,
spleen, and lymph nodes. Bone tenderness may
be present, particularly in the sternum, tibia, and
femur.
Gum-hypertrophy ALL
investigation
1. Peripheral blood film and bone marrow
– normochromic and normocytic anaemia
– the white cell count may be normal or raised; rarely a few
blast cells may be seen in the peripheral blood, or none at
all
– the platelet count is usually reduced
– hypercellular bone marrow with characteristic blasts in
the trail of the fragments on the microscope slide
2. The CSF should be examined – will contain blasts cells if
meningeal leukaemia is present
3. Test of renal function
4. Serum uric acid
5. Serum calcium
6. Serum electrolytes (potassium)
7. Blood cultures
8. Chest X ray (to determine the presence of a mediastinal mass)
Laboratory Findings
• WBC count elevated
• Sometimes combination of pancytopenia with
circulating blasts.
• However, blasts may be absent from the
peripheral smear in as many as 10% of cases
("aleukemic leukemia").
• The bone marrow is usually hypercellular
and dominated by blasts.
• More than 20% blasts are required to make a
diagnosis of acute leukemia.
• Hyperuricemia may be seen.
• If DIC is present, the fibrinogen level will be
reduced, the prothrombin time prolonged, and
fibrin degradation products or fibrin D-dimers
present.
• Patients with ALL (especially T cell) may have a
mediastinal mass visible on chest radiograph.
• Meningeal leukemia will have blasts present in
the spinal fluid, seen in approximately 5% of
cases at diagnosis; it is more common in
monocytic types of AML.
• The Auer rod, an eosinophilic needle-like
inclusion in the cytoplasm, is pathognomonic of
AML (see micrograph) and, if seen, secures the
diagnosis.
• Leukemia cells retain properties of the lineages
from which they are derived.
• Thus, histochemistry will demonstrate
peroxidase in myeloid cells and butyrate
esterase in monocytic cells, whereas ALL cells
will not contain either of these enzymes.
Blasts-and-Auer-body
• The phenotype of leukemia cells is usually demonstrated
by flow cytometry.
• AML cells usually express myeloid antigens such as CD
13 or CD 33.
• ALL cells of B lineage will express CD19, common to all
B cells, and most cases will express CD10, formerly
known as the "common ALL antigen."
• ALL cells of T lineage will usually not express mature Tcell markers, such as CD 3, 4, or 8, but will express
some combination of CD 2, 5, and 7 and do not express
surface immunoglobulin.
• Almost all ALL cells express terminal deoxynucleotidyl
transferase (TdT).
• The uncommon Burkitt type of ALL has a "lymphoma"
phenotype, expressing CD19. CD20 and surface
immunoglobulin but not TdT.
ALL
ALL Blast
ALL-L1-Marrow
Prognosis
• Approximately 70–80% of adults with AML under age 60 years
achieve complete remission.
• High-dose postremission chemotherapy leads to cure in 35–40% of
these patients, and high-dose cytarabine has been shown to be
superior to therapy with lower doses.
• Allogeneic bone marrow transplantation (for younger adults with
HLA-matched siblings) is curative in 50–60% of cases. Autologous
bone marrow transplantation may be superior to nonablative
chemotherapy.
• Older adults with AML achieve complete remission in up to 50% of
instances. The cure rates for older patients with AML have been
very low (approximately 10–15%) even if they achieve remission
and are able to receive postremission chemotherapy. The use of
reduced-intensity allogeneic transplantation is being explored in
order to improve on these outcomes.
Acute Leukemia
Essentials of Diagnosis
• Short duration of symptoms, including
fatigue, fever and bleeding.
• Increase numeber WBC (sometimes
normal or low).
• More than 20% blasts in the bone
marrow.
• Blasts in peripheral blood in 90% of
patients.
• Classify as acute myeloid leukemia (AML)
or acute lymphoblastic leukemia (ALL).
Chronic granulocytic leukaemia
– occurs in middle-aged and elderly people
– it occurs in the myeloproliferative syndromes, which include:
polycythaemia vera, myelofibrosis, essential trombocytosis
– it is characterised by the presence of
chromosome
Philadelphia
Clinical features
 often of insidious onset (may only be discovered on a routine
blood count)
 anaemia
 bruising and bleeding manifestations
 pain or discomfort due to a very large spleen →
gastrointestinal disturbance
 sweating, fever and loss of weight as the result of a high
metabolic rate
• CML (or CGL) has a distinct chromosome
marker, the Ph chromosome, resulting from the
reciprocal translocation t(9;22), found in 95 per
cent of cases.
• Cases with similar haematological features, but
which are cytogenetically Ph-negative, often
have the same molecular rearrangement that
results from the juxtaposition of the BCR and
ABL genes to form a hybrid BCR/ABL gene.
• Understanding of the molecular biology of CML
leads to significant advances in treatment.
• The diagnosis of Ph-positive CML can be established by the
morphological appearance of peripheral blood and bone marrow
films, and confirmed by cytogenetic and/or molecular analysis.
• The leucocyte differential count in CML shows the full spectrum of
granulocytic cells but with a predominance of myelocytes (about 30
per cent) and mature neutrophils (about 50 per cent), as well as
almost invariably basophilia (approximately 5 per cent) and frequent
eosinophilia; the percentage of monocytes is low, usually less than 3
per cent.
• Blasts represent 1 or 2 per cent of the circulating cells unless the
disease is in accelerated phase or in transformation;
myelodysplastic changes are minimal.
• The bone marrow aspirate is hypercellular with granulocytic
hyperplasia and numerous megakaryocytes, and is less useful than
the peripheral blood for a differential diagnosis between CGL and
the other chronic myeloid leukaemias.
• The myeloid:erythroid ratio is greater than 10:1 with few
erythroblasts. The bone marrow trephine is necessary to assess the
degree of fibrosis and, occasionally, to distinguish from idiopathic
myelofibrosis.
Phisical signs
 anaemia
 lymphadenopathy (uncommon)
 a large spleen (common) biggest spleen in pathology
 haemorrhage and thrombosis; bruising, bleeding, priapism
may occur
 gout
• Patients usually present with fatigue, night
sweats, and low-grade fever related to the
hypermetabolic state caused by overproduction
of white blood cells.
• At other times, the patient complains of
abdominal fullness related to splenomegaly.
• In some cases, especially with the increased
used of laboratory tests, an elevated white blood
count is discovered incidentally.
• Rarely, the patient will present with a clinical
syndrome related to leukostasis with blurred
vision, respiratory distress or priapism.
Investigations
 normal Hb (initially), than a normocytic, normochromic
anaemia
 white cell count is greater than 100 000 /mmc (100 000 – 500
000 /mmc)
 blood film: abundance of neutrophils, mielocytes and even a
few blast cell are present
 platelets count: N or ↑
 bone marrow: hypercellular marrow with the granulocyte
precursors markedly increased
 a chromosome
chromosome
preparation
shows
the
Philadelphia
 the leucyte alkaline phosphatase (lap) is very low
 levels of serum vit. B12 and B12 binding proteins are elevated
• Acceleration of the disease is often associated with
fever in the absence of infection, bone pain and
splenomegaly.
• The myeloid series is left-shifted, with mature forms
dominating and with cells usually present in proportion to
their degree of maturation.
• Blasts are usually less than 5%. Basophilia and
eosinophilia of granulocytes may be present. At
presentation, the patient is usually not anemic.
• Red blood cell morphology is normal, and nucleated red
blood cells are rarely seen.
• The platelet count may be normal or elevated
(sometimes to strikingly high levels).
• The hallmark of the disease is that the bcr/abl gene is
detected in the peripheral blood. This is best done by the
polymerase chain reaction (PCR) test, which has now
supplanted cytogenetics.
• A bone marrow examination is not necessary for
diagnosis, although it is useful for prognosis and for
detecting additional chromosomal abnormalities in
addition to the Philadelphia chromosome.
• With progression to the accelerated and blast phases,
progressive anemia and thrombocytopenia occur, and
the percentage of blasts in the blood and bone marrow
increases.
• Blast phase CML is diagnosed when blasts comprise
more than 30% of bone marrow cells.
Differential Diagnosis
• Early CML must be differentiated from the
reactive leukocytosis associated with infection.
In such cases, the white blood count is usually
less than 50,000/mcL, splenomegaly is absent
and the bcr/abl gene is not present.
• CML must be distinguished from other
myeloproliferative disease. The hematocrit
should not be elevated, the red blood cell
morphology is normal, and nucleated red blood
cells are rare or absent. Definitive diagnosis is
made by finding the bcr/abl gene.
Prognosis
• In the past, median survival was 3–4 years.
• In the era of imatinib therapy (since 2001), and with the
development of molecular targeted agents, more than
80% of patients remain alive and without disease
progression at 6 years.
• It is clear that the prognosis of CML has been
dramatically altered by new therapies.
• While allogeneic stem cell transplantation is the only
proven curative option, some patients may be cured by
well-tolerated oral agents.
Essentials of Diagnosis
• Elevated white blood count. (100,000500,000)
• Markedly left-shifted myeloid series but
with a low percentage of promyelocytes
and blasts; all the precursors of myeloid
series are present.
• Presence of Philadelphia chromosome or
bcr/abl gene.
Chronic lymphatic leukaemia
 disease of late middle-aged and elderly people
 disorder of B cells, with accumulation of mature lymphocytes
in the tissues and peripheral blood
 few cases the lymphocytes are T cells and skin involvement
can occur (mycosis fungoides, the Sézary syndrome,
peripheral T cell lymphoma)
clinical features
• the onset is insidous
• lethargy
• fever and sweating
• loss of weight
• CLL is a disease of older patients, with
90% of cases occurring after age 50 years
and a median age at presentation of 65
years.
• Many patients will be incidentally
discovered to have lymphocytosis.
• Others present with fatigue or
lymphadenopathy.
• On examination, 80% of patients will have
lymphadenopathy and 50% will have
enlargement of the liver or spleen.
signs
moderate enlargement of lymph nodes in the
neck, axilla and groin
splenic and hepatic enlargement, but not
usually massive
• CLL usually pursues an indolent course, but some
subtypes behave more aggressively; a variant,
prolymphocytic leukemia, is more aggressive.
• The morphology of the latter is different, characterized
by larger and more immature cells.
• In 5–10% of cases, CLL may be complicated by
autoimmune hemolytic anemia or autoimmune
thrombocytopenia.
• In approximately 5% of cases, while the systemic
disease remains stable, an isolated lymph node
transforms into an aggressive large cell lymphoma
(Richter syndrome).
investigations
mild anaemia, normochromic, normocytic
white cell count > 15x109 &l, which more than
40% lymphocytes
platelet count is usually normal as the disease
progresses, anaemia may become severe due to
Coombs positive haemolysis and the number
of lymphocytes ↑
• The hallmark of CLL is isolated lymphocytosis.
• The white blood count is usually greater than
20,000/mcL and may be markedly elevated to several
hundred thousand.
• Usually 75–98% of the circulating cells are lymphocytes.
• Lymphocytes appear small and mature, with condensed
nuclear chromatin and are morphologically
indistinguishable from normal small lymphocytes, but
smaller numbers of larger and activated lymphocytes
may be seen.
• The hematocrit and platelet count are usually normal at
presentation.
• The bone marrow is variably infiltrated with small
lymphocytes
Essentials of Diagnosis
• Lymphocytosis > 5000/mcL.
• Coexpression of CD19, CD5 on
lymphocytes.
The lymphomas
These are malignant tumors of the lymphoreticular system
There are two main types histologically
– Hodgkin’s disease
– non Hodgkin’s lymphoma
Hodgkin’s disease
Characterised by aggressive enlargement of the lymph nodes,
with hyperplasia, infiltration with histiocytes and lymphocytes
and the presence of characterisitc cells described by Sternberg
and Reed.
epidemiology
 rare in children (boys twice affected than girls)
 early peak of incidence in twenties, later peak in middle – age
Clinical features
 enlargement of the cervical lymph nodes, which are painless
and rubbery
 weakness, fatigue and anorexia
 feaver and sweating
 pruritus
 loss of weight
 alcohol – induced pain at the site of the enlarged node
 clinical symptoms are seen in more advanced stages of the
disease (intermitent fever with drenching sweats)
 pel – Ebstein fever – consists of a few days of high pyrexia
followed by apyrexia for a few days
 symptoms due to the involvement of bone, lung, skin
• Most patients present because of a
painless mass, commonly in the neck.
• Others may seek medical attention
because of constitutional symptoms such
as fever, weight loss, or drenching night
sweats, or because of generalized
pruritus.
• An unusual symptom of Hodgkin disease
is pain in an involved lymph node following
alcohol ingestion.
• Hodgkin disease is divided into several
subtypes: lymphocyte predominance,
nodular sclerosis, mixed cellularity and
lymphocyte depletion.
• Hodgkin disease should be distinguished
pathologically from other malignant
lymphomas and may occasionally be
confused with reactive lymph nodes seen
in infectious mononucleosis, cat-scratch
disease or drug reactions (eg, phenytoin).
Clinical examination
 lymphadenopathy
hepatomegaly
 splenomegaly
• Patients undergo a staging evaluation to determine the
extent of disease.
• The staging nomenclature (Ann Arbor) is as follows:
stage I, one lymph node region involved; stage II,
involvement of two lymph node areas on one side of the
diaphragm; stage III, lymph node regions involved on
both sides of the diaphragm; and stage IV, disseminated
disease with bone marrow or liver involvement.
• In addition, patients are designated stage A if they lack
constitutional symptoms and stage B if 10% weight loss
over 6 months, fever or night sweats are present.
• If symptoms indicate careful evaluation for higher
numerical stage, clinical stage IB (for example) is highly
likely to emerge as stage II or stage IIIB.
investigation
normochromic, normocytic anaemia
 raised ESR
 white cells levels ↑, with eosinophilia
 hypercalcaemia
 slightly abnormal liver function
 x-ray:
 mediastinal lymphadenopathy
 pulmonary infiltration
 CT scanning of the chest and abdomen
 biopsy of a suitable node (a whole node should be
removed)
Finger-warts-Hodgkins-disease
histological classification
Four histological types of Hodgkin’s disease:
1. Lymphocyte – predominent
2. Nodular sclerosing
3. Mixed cellularity
4. Lymphocyte – depleted
Hodgkins-disease-lymphoc
Hodgkins-diffused-Reed-Sternberg
Hodgkins-Marrow
Hodgkin Disease
Essentials of Diagnosis
• Painless lymphadenopathy.
• Constitutional symptoms may or may not
be present.
• Pathologic diagnosis by lymph node
biopsy.
non – Hodgkin’s lympHoma
Tumor of lymporeticular tissue derived from malignant clones
of B or T cells
Presentation at extra nodal sites such as Waldayer’s ring tonsils,
adenoids and nasopharyngeal glands, the gut or skin is common
clinical features
 lymphadenopathy
 abdominal lymph node involvement is
common
 splenomegaly, hepatomegaly
 wasting, fever and sweating
 nodular infiltration of the skin
• Patients with indolent lymphomas usually
present with painless lymphadenopathy, which
may be isolated or widespread.
• Involved lymph nodes may be present in the
retroperitoneum, mesentery and pelvis.
• The indolent lymphomas are usually
disseminated at the time of diagnosis and bone
marrow involvement is frequent.
• Patients with intermediate and high-grade
lymphomas may have constitutional symptoms
such as fever, drenching night sweats or weight
loss.
Lymphoma
• On examination, lymphadenopathy may
be isolated, or extranodal sites of disease
(skin, gastrointestinal tract) may be found.
• Patients with Burkitt lymphoma are noted
to have abdominal pain or abdominal
fullness because of the predilection of the
disease for the abdomen.
Lymphoma
investigation
normochromic, normocytic anaemia or a
leucoerythroblastic picture
liver tests abnormal
 bone marrow biopsy may show infiltration
by lymphoid tissue
biopsy of a lymph node from an accesible
site
• The peripheral blood is usually normal, but a
number of lymphomas may present in a
leukemic phase.
• Bone marrow involvement is manifested as
paratrabecular lymphoid aggregates.
• In some high-grade lymphomas, the meninges
are involved and malignant cells are found with
cerebrospinal fluid cytology.
• The chest radiograph may show a mediastinal
mass in lymphoblastic lymphoma.
• The serum LDH has been shown to be a useful
prognostic marker and is now incorporated in
risk stratification of treatment.
• The diagnosis of lymphoma is made by
tissue biopsy.
• Needle aspiration may yield suspicious
results, but a lymph node biopsy (or
biopsy of involved extranodal tissue) is
required for diagnosis and staging.
• Molecular profiling based on the
examination of gene expression may lead
to a new classification of the lymphomas.
histological classification
Two main system of pathological classification:
A. Rappaport classification:
 nodular or follicular pattern
 diffuse pattern of infiltration
B. Kiel classification:
 low grade
malignancy
 high grade
}
BLEEDING
DISORDERS
There is abnormal bleeding due to impairment of haemostasis
haemostasis
Injury
Exposed collagen
Serotonina
Vasoconstriction
Platelet adhesion
Platelets release factors
ADP
Blood flow to
injured area reduced
Platelet prostagladin
synthesis
Tromboxane A2
Platelet aggregation
Factors
XII + XI + VII
activated
PF3
Coagulation
sequence
Fibrinogen
Thrombin
Fibrin
Thrombus
bleeding disorders
-disorders of platels
-disorders of vessels
-coagulation disorders
cloting defects
the purpuras
Group of disorders associated with superficial capillary
bleeding, mainly in skin and mucous membranes, due to
thrombocytopenia, platelet functional disorders or increased
capillary permeability.
Purpuric rash – consists of small purplish red spots which do not
fade on pressure.
Confluent  ecchymoses
thrombocytopenic purpura
Caused by either - reduced platelet production in the marrow
- or excessive peripheral destruction of platelets
- bleeding when platelets are less than 50 000 / mmc
causes of thrombocytopenia
Marrow infiltration
Impaired
production
Marrow damage
Immune
Excessive
destruction
Coagulation
Massive transfusion
Sequestration
– luekaemia
– tumors
– myelosclerosis
– myeloma
– chemotherapy
– chemicals
– alcohol
– drugs
– aplastic anaemia
– B 12/folate deficiency
– idiophatic thrombocytopenic purpura
– autoimmune haemolytic anaemia
– system lupus erythematosus drugs
–disseminated intravascular coagulation
– thrombotic thrombocytopenic purpura
– haemolytic uraemic syndrome
– hypersplenism
– hemangioma
the purpuras
idiopathic thrombocytopenic purpura
 autoimmune disorder (commoner in women)
 autoantibody (lg G) to platelets is found in 70%
 sensitized platelets are removed by the reticuloendothelial
system
 antibodies cross the placenta  neonatal thrombocytopenia
clinical features
acute form – children following a viral infection
 adults – insidiously with a purpuric rash and superficial
bruising
 epistaxis, digestive bleeding
 menorrhagia
 rarely – splenomegaly
 phisical examination is normal (expect evidence of bleeding)
• The anemia may be very mild to very severe, and the
thrombocytopenia often parallels it.
• The neurologic and renal symptoms are usually seen only when the
platelet count is markedly diminished (20 to 30 103/L).
• Fever is not reliably present. TTP may be
acute in onset, but its course spans days
to weeks in most patients and occasionally
continues for months.
• Proteinuria and a moderate elevation of
blood urea nitrogen may be found on initial
presentation; the latter continues to rise
while urine output falls if the patient
develops renal failure.
• Neurologic symptoms develop in 90% of
patients whose disease terminates in
death.
• Initially, changes in mental status such as
confusion, delirium, or altered states of
consciousness may occur.
• Focal findings include seizures,
hemiparesis, aphasia, and visual field
defects.
• These neurologic symptoms may fluctuate
and terminate in coma.
investigation
anaemia is uncommon
 thrombocytopenia (<20 000 / mmc)
 bone marrow: ↑ megakayocytes
platelets antibodies
the purpuras
platelet functional disorders
 usually associated with excessive bruising and bleeding, and in
some acquired forms with thrombosis
 platelet count is normal or ↑
 bleeding time is prolonged
 congenital forms are rare
 acquired forms of platelet dysfunction are seen in:
 myeloproliferative disorders with morphologically
abnormal platelets
 uraemia and liver disease
 paraproteinemias which alter platelet aggregation and
adherence
 drugs (aspirin) – inhibits prostaglandin synthetase and
thereby interferes with platelet aggregation
 Von Willebrand’s disease – platelet functional impairment
caused by inherited abnormality of FVIII
the purpuras
non – thrombocytopenic purpura
Causes
A. Congenital
♦ congenital hereditary haemorrhagic telangiectazia (Osler –
Weber – rendu disease)
♦ Ehlers – Danlos syndrome
B. Acquired
♦ severe infections (septicaemia, measles, typhoid)
♦ allergic
 Henoch – Schönlein purpura
 connective tissue disorders
♦ drugs (steroids)
♦ others
 senile purpura
 easy brusing syndrome
 paraproteinaemias
There is increased capillary permeability resulting in purpura.
the purpuras
hereditary haemorrhagic telangiectasia
 rare disorder with autosomal dominant inheritance
 dilatation of capillaries and small arterioles produces characteristic
small red spots on the:
 skin
 nose
 mouth
 G.I. tract
 chronic G.I. bleeding is the major problem and the site of bleeding
may be hard to localize
PURPURA DUE TO INFECTIONS
– due to damage to the vascular epithelium
easy bruising syndrome
 occurs in young women
 the purpura may be extensive
 cause – unknown
 investigations  normal
 recovery  spontaneous
senile purpura and purpura due
to steroids
– due to atrophy of the vascular supportive tissue
henoch – schönlein purpura
 occurs in children (usually)
 type III hypersensitivity reaction which is often preceded by
an acute infection
 widespread purpura
 abdominal pain
 haematuria and nephritis
 recovery  spontaneous
coagulation disorders
hereditary coagulation disorders
Isolated deficienties of all factors have been described, but
90% are due to factor VIII deficiency
Haemophilia A
 VIIIc depleted (VIIIc – small protein molecule with coagulant
activity)
 other component of F VIII are normal
 inherited as an X – linked trait
 the locus for this gene has been assigned to the long arm of the
X chromosome so, only males are affected
incidence 1/5000 to 1/10 000 of the population
clinical features
 haemarthroses, often spontaneous and lead to arthritic changes
 severe bleeding follows injury and isolated bleeding may occur
into muscles, kidney, mouth, neck
investigation
females carriers are identified by the family
history
 DNA analysis  detection of carrier
 bleeding time – normal
 PT  normal
Cloting time increase
 PTTK  ↑
 F VIIIc  low
Christmas diesease (haemophilia B)
 deficiency of F IX
 the inheritance and clinical presentation are identical to those
for haemophilia A
 incidence 10% of that of H.A.
coagulation disorders
acquired coagulation disorders
Vitamina K deficiency
 necessary for the F II, VII, IX and X and without it factors are
unable to bind calcium and exert their coagulant function
 deficiency of vitamin K may be due to
 inadequate stores (haemorrhagic disease of the newborn or
protein – energy malnutrition)
 malabsorption of vit. K (cholestatic jaundice)
 oral anticoagulant drugs, which are vit. K antagonists
 PT and PTTK are prolonged
 bruising, haematuria and G.I. or cerebral bleeding
• A 'coagulopathy' is a disorder associated
with an abnormal coagulation assay result,
such as a prolonged prothrombin time
(PT) (often expressed as the
international normalized ratio, or INR),
activated partial thromboplastin time (
aPTT), or thrombin clotting time (TCT).
• Coagulopathies can be associated with
either bleeding or thrombosis, and have
many causes
• The importance of the clinical context is illustrated by two
patient scenarios that have in common a prolonged INR
(6.0; usual therapeutic range, 2.0–3.0) during oral
anticoagulant therapy:
- patient A has a life-threatening intracranial haemorrhage
complicating warfarin therapy given for a prosthetic heart
valve;
- in contrast, patient B, who was treated for deep-vein
thrombosis ( DVT) complicating heparin-induced
thrombocytopenia (HIT), has the limb-threatening
complication of warfarin-induced venous limb gangrene,
caused by microvascular thrombosis.
Rendu Osler
Heriditary-Telangiectasia
Idiopathic Thrombocytopenic Purpura
Senile Purpura
Haemarthroses-Haemophilia
Thrombocytopenia-and-drug
Disseminated intravascular
coagulation or DIC
•
•
•
•
is a group of clinicopathological syndromes characterized by widespread
activation of coagulation; there results intravascular generation of thrombin,
formation of fibrin, and reactive fibrinolysis.
Clinical consequences range from coagulation factor and platelet depletion,
resulting in generalized haemorrhage, to widespread microvascular
thrombosis, predisposing to multisystem organ dysfunction or limb necrosis.
'Acute' DIC, caused by septicaemia, trauma, and obstetrical complications,
is most frequent; 'chronic' DIC, typically caused by malignancy, is often
associated with a dramatic hypercoagulable state.
Although DIC is usually a systemic process, sometimes a localized
abnormality (such as a vascular malformation or aortic aneurysm) leads to
the regional activation of coagulation and resulting in the depletion of
haemostatic factors.
• DIC is usually triggered by the extrinsic
coagulation pathway: tissue factor and factor
VIIa.
• The proinflammatory cytokine, interleukin-6 ( IL6), is a principal mediator of DIC in septicaemia
and other systemic inflammatory responses, and
impairs natural anticoagulant and fibrinolytic
pathways.
• A sustained increase in PAI-1 impairs plasmin
formation despite intravascular fibrin generation.