The white cell

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.

2

• 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 gt 10x105/l
  in bacterial infection or tissue damage
• exercise
• corticosteroid administration

3

• 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

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• 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)
• Feltys syndrome
• megaloblastic anaemia
• drugs
• pancytopenia from any cause

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• 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

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• eosinophils
• Occur when the number of eosinophils is gt 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

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• 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

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• lymphocytes
• Form nearly the circulating white cells
• Originate in the lymph glands, spleen, Peyers
  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

9

• 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
• Acute lymphoblastic leukaemia
• Acute non-lymphocytic leukaemia (called also
  acute myelogenous (myeloblastic) leukaemia)
• The CHRONIC FORMS of these conditions are
• Chronic granulocytic leukaemia
• Chronic lymphatic leukaemia

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• 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 Downs syndrome (who have chromosomal
  abnormalities)

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• 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

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• Acute leukaemia
• Cellular types
• 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
• Acute non-lymphocytic leukaemia

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classification
M1 Acute myelocytic leukaemia without differentiation predominant myeloblasts, distinct nucleoli few granules Auer rods rare
M2 Acute myelocytic Leukaemia with Differentiation myeloblasts and promyelocytes predominant further maturation abnormal auer rods many
M3 Acute promyelocytic leukaemia promyelocytes predominate hipergranular auer rods rare
M4 Acute myelomonocytic leukaemia myelocytic and monocytic maturation evident may be peripheral auer rods rare
M5 Acute monocytic leukaemia promonocytes predominant with differentiation
M5A Acute monoblastic leukaemia completely with differentiation undifferentiated blast cells
M6 Erytroleukaemia bizzare, multinucleated megaloblasted erythroblasts predominate myeloblasts also present
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• 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)

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• 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.

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• 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)

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• 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 gt 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.

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Gum-hypertrophy ALL
19

• investigation
• 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
• The CSF should be examined will contain blasts
  cells if meningeal leukaemia is present
• Test of renal function
• Serum uric acid
• Serum calcium
• Serum electrolytes (potassium)
• Blood cultures
• Chest X ray (to determine the presence of a
  mediastinal mass)

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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.

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• 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.

22

• 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.

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Blasts-and-Auer-body
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• 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 T-cell 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.

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ALL
ALL Blast
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ALL-L1-Marrow
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Prognosis

• Approximately 7080 of adults with AML under age
  60 years achieve complete remission.
• High-dose postremission chemotherapy leads to
  cure in 3540 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 5060 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 1015) 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.

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Acute LeukemiaEssentials 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).

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• 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
  Philadelphia chromosome
• 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

30

• CML (or CGL) has a distinct chromosome marker,
  the Ph chromosome, resulting from the reciprocal
  translocation t(922), 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.

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• 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 myeloiderythroid ratio is greater than 101
  with few erythroblasts. The bone marrow trephine
  is necessary to assess the degree of fibrosis
  and, occasionally, to distinguish from idiopathic
  myelofibrosis.

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• Phisical signs
• anaemia
• lymphadenopathy (uncommon)
• a large spleen (common) biggest spleen in
  pathology
• haemorrhage and thrombosis bruising, bleeding,
  priapism may occur
• gout

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• 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.

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• 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 preparation shows the Philadelphia
  chromosome
• the leucyte alkaline phosphatase (lap) is very
  low
• levels of serum vit. B12 and B12 binding proteins
  are elevated

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• 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).

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• 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.

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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.

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Prognosis

• In the past, median survival was 34 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.

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Essentials of Diagnosis

• Elevated white blood count. (100,000-500,000)
• 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.

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• 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

44

• 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.

45

• signs
• moderate enlargement of lymph nodes in the neck,
  axilla and groin
• splenic and hepatic enlargement, but not usually
  massive

46

• 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 510 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).

47
investigations

• mild anaemia, normochromic, normocytic
• white cell count gt 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 ?

48

• 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 7598 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

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Essentials of Diagnosis

• Lymphocytosis gt 5000/mcL.
• Coexpression of CD19, CD5 on lymphocytes.

50

• The lymphomas
• These are malignant tumors of the lymphoreticular
  system
• There are two main types histologically
• Hodgkins disease
• non Hodgkins lymphoma

51

• Hodgkins 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

52

• 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

53

• 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.

54

• 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).

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• Clinical examination
• lymphadenopathy
• hepatomegaly
• splenomegaly

56

• 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.

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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)

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Finger-warts-Hodgkins-disease
60

• histological classification
• Four histological types of Hodgkins disease
• Lymphocyte predominent
• Nodular sclerosing
• Mixed cellularity
• Lymphocyte depleted

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Hodgkins-disease-lymphoc
Hodgkins-diffused- -Reed-Sternberg
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Hodgkins-Marrow
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Hodgkin DiseaseEssentials of Diagnosis

• Painless lymphadenopathy.
• Constitutional symptoms may or may not be
  present.
• Pathologic diagnosis by lymph node biopsy.

64

• non Hodgkins lymphoma
• Tumor of lymporeticular tissue derived from
  malignant clones of B or T cells
• Presentation at extra nodal sites such as
  Waldayers ring tonsils, adenoids and
  nasopharyngeal glands, the gut or skin is common

65

• clinical features
• lymphadenopathy
• abdominal lymph node involvement is common
• splenomegaly, hepatomegaly
• wasting, fever and sweating
• nodular infiltration of the skin

66

• 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.

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Lymphoma
69

• 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.

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Lymphoma
71
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

72

• 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.

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• 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.

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• histological classification
• Two main system of pathological classification
• Rappaport classification
• nodular or follicular pattern
• diffuse pattern of infiltration
• Kiel classification
• low grade
• high grade

malignancy
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• BLEEDING DISORDERS
• There is abnormal bleeding due to impairment of
  haemostasis
• haemostasis

Injury
Factors XII XI VII activated
Exposed collagen
Serotonina
Platelet adhesion
Coagulation sequence
Platelets release factors
Vasoconstriction
PF3
Fibrinogen
ADP
Platelet prostagladin synthesis
Thrombin
Blood flow to injured area reduced
Fibrin
Tromboxane A2
Platelet aggregation
Thrombus
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bleeding disorders
-disorders of platels -disorders of
vessels -coagulation disorders cloting defects
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• 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

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causes of thrombocytopenia
Impaired production Marrow infiltration luekaemia tumors myelosclerosis myeloma
Impaired production Marrow damage chemotherapy chemicals alcohol drugs aplastic anaemia B 12/folate deficiency
Excessive destruction Immune idiophatic thrombocytopenic purpura autoimmune haemolytic anaemia system lupus erythematosus drugs
Excessive destruction Coagulation disseminated intravascular coagulation thrombotic thrombocytopenic purpura haemolytic uraemic syndrome
Excessive destruction Massive transfusion
Excessive destruction Sequestration hypersplenism hemangioma
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• 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

80

• 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)

81

• 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).

82

• 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.

83

• 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.

84
investigation

• anaemia is uncommon
• thrombocytopenia (lt20 000 / mmc)
• bone marrow ? megakayocytes
• platelets antibodies

85

• 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 Willebrands disease platelet functional
  impairment caused by inherited abnormality of
  FVIII

86

• the purpuras
• non thrombocytopenic purpura
• Causes
• Congenital
• congenital hereditary haemorrhagic telangiectazia
  (Osler Weber rendu disease)
• Ehlers Danlos syndrome
• 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.

87

• 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

88

• 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

89

• 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

90

• 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

91

• clinical features
• haemarthroses, often spontaneous and lead to
  arthritic changes
• severe bleeding follows injury and isolated
  bleeding may occur into muscles, kidney, mouth,
  neck

92
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

93

• 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.

94

• 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

95

• 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

96

• The importance of the clinical context is
  illustrated by two patient scenarios that have in
  common a prolonged INR (6.0 usual therapeutic
  range, 2.03.0) 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.

97
Rendu Osler
98
Heriditary-Telangiectasia
99
Idiopathic Thrombocytopenic Purpura
100
Senile Purpura
101
Haemarthroses-Haemophilia
102
Thrombocytopenia-and-drug
103
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.

104

• DIC is usually triggered by the extrinsic
  coagulation pathway tissue factor and factor
  VIIa.
• The proinflammatory cytokine, interleukin-6 (
  IL-6), 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.