HEMATOLOGIC MANIFESTATIONS

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HEMATOLOGIC MANIFESTATIONS OF SYSTEMIC ILLNESS
Prof. Mervat A Hesham 2010
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hematologic manifestations mechanisms

• 1. Bone marrow dysfunction
• a. Anemia or polycythemia
• b. Thrombocytopenia or
  thrombocytosis
• c. Leukopenia or leukocytosis
• 2. Hemolysis
• 3. Immune cytopenias
• 4. Alterations in hemostasis
• a. Acquired inhibitors to
  coagulation factors
• b. Acquired von Willebrand disease
• c. Acquired platelet dysfunction
• 5. Alterations in leukocyte function.

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ANEMIA OF CHRONIC ILLNESS

• ? Normochromic, normocytic, occasionally
  microcytic
• ? Usually mild, characterized by decreased plasma
  iron.
• ? Impaired flow of iron from reticuloendothelial
  cells to the bone marrow
• ? Decreased sideroblasts in the bone marrow.
• Treatment involves treating the underlying
  illness. Iron is of little value because the iron
  is cleared by the reticuloendothelial system.

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Connective Tissue Diseases
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1 - Rheumatoid Arthritis

• ? Anemia of chronic illness (normocytic,
  normochromic)
• ? High incidence of iron deficiency
• ? Leukocytosis and neutropenia common in
  exacerbations of juvenile rheumatoid
• arthritis (JRA)
• ? Thrombocytosis , there may be transient
  episodes of thrombocytopenia.

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2 - Systemic Lupus Erythematosus

• ? Two types of anemia are common anemia of
  chronic illness (normocytic, normochromic) and
  acquired autoimmune hemolytic anemia (Coombs
  positive).
• ? Neutropenia is common as a result of decreased
  marrow production and immune mediated
  destruction.
• ? Lymphopenia with abnormalities of T-cell
  function.
• ? Immune thrombocytopenia.
• ? A circulating anticoagulant (antiphospholipid
  antibody) may be present and is associated with
  thrombosis.

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3- Polyarteritis Nodosa

• ? Microangiopathic hemolytic anemia,
• possibly associated with renal disease or
• hypertensive crises
• ? Prominent eosinophilia
• 4- Feltys Syndrome
• ? Triad of rheumatoid arthritis, splenomegaly,
  and neutropenia

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5- Kawasaki Syndrome

• ? Mild normochromic, normocytic anemia with
  reticulocytopenia
• ? Leukocytosis with neutrophilia and toxic
  granulation of neutrophils and vacuoles
• ? Decreased T-suppressor cells
• ? High C3 levels
• ? Increased cytokines IL-1, IL-6, IL-8,
  interferon-á, and tumor necrosis factor (TNF)
• ? Marked thrombocytosis (mean platelet count of
  700,000/mm3)
• ? DIC.

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6- HenochSchönlein Purpura

• ? Anemia occasionally occurs as a result of GI
  bleeding or decreased RBC production
• caused by renal failure.
• ? Transient decreased F XIII activity may occur.
• ? Vitamin K deficiency from severe
  vasculitis-induced intestinal malabsorption.

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7- Wegener Granulomatosis

• This autoimmune disorder is rare in children.
  Hematologic features include
• ? Anemia normocytic RBC fragmentation with
  microangiopathic hemolytic anemia
• ? Leukocytosis with neutrophilia
• ? Eosinophilia
• ? Thrombocytosis.

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Infections

• A- Viral and Bacterial Illnesses Associated
• with Marked Hematologic Sequelae

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A - Anemia OF INFECTIONS

• ? Chronic infection is associated with the anemia
  of chronic illness.
• ? Acute infection, particularly viral infection,
  can produce transient bone marrow aplasia or
  selective transient erythrocytopenia.
• ?
• ? Many viral and bacterial illnesses may be
  associated with hemolysis.

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• ? Parvovirus B19 infection in people with an
  underlying hemolytic disorder (such as sickle
  cell disease, hereditary spherocytosis) can
  produce
• - a rapid fall in hemoglobin
• - an erythroblastopenic crisis
• marked by anemia and
• reticulocytopenia.
• - There may be an associated
• neutropenia.

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B- White Cell Alterations

• ? Viral infections can produce leukopenia and
  neutropenia.
• ?Neutrophilia with an increased band count and
  left shift frequently results from bacterial
  infection.
• ? Neonates, particularly premature infants, may
  not develop an increase in white cell count in
  response to infection.
• ? Eosinophilia may develop in response to
  parasitic infections.

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C- Clotting Abnormalities

• Severe infections can produce DIC.
• D - Thrombocytopenia
• Infection can produce thrombocytopenia through
  decreased marrow production,
• immune destruction, or DIC.

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1- Parvovirus

• transient erythroblastopenic crisis, particularly
  in individuals with an underlying hemolytic
  disorder.
• thrombocytopenia, neutropenia, and a
  hemophagocytic syndrome.
• In immunocompromised individuals, parvovirus B19
  infection can produce prolonged aplasia.

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2- EpsteinBarr Virus

• ? Atypical lymphocytosis
• ? Acquired immune hemolytic anemia
• ? Agranulocytosis
• ? Aplastic anemia
• ? Lymphadenopathy and splenomegaly
• ? Immune thrombocytopenia.
• ? immunologic and oncologic associations
• - acquired hypogammaglobulinemia, and
  lymphoma
• - Clonal T-cell proliferations
• - Hemophagocytic syndrome
• - Endemic form of Burkitts lymphoma
  in Africa.

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3- Human Immunodeficiency Virus

• Thrombocytopenia occurs in about 40 of patients
  with AIDS Initially .
• Thrombotic thrombocytopenic purpura (TTP) in
  advanced AIDS.
• Anemia occurs in approximately 7080 of patients
  and neutropenia in 50.
• Coagulation Abnormalities
• ? Dysregulation of immunoglobulin
  production may affect the coagulation cascade.
• ? Lupus-like anticoagulant
  (antiphospholipid antibodies) or anticardiolipin
  antibodies occur in 82 of patients. Thrombosis
  may occur secondary to protein S deficiency. Not
  due to Lupus-like anticoagulant .

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Cancers in Children with HIV Infection

• Non-Hodgkin lymphoma
• Burkitt lymphoma (B-cell, small noncleaved)
• Immunoblastic lymphoma (B-cell, large cell)
• Central nervous system lymphomas
• Mucosa-associated lymphoid tissue (MALT) type
• Leiomyosarcoma and leiomyoma
• Kaposis sarcoma
• Leukemias

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The pathogenesis of the hematologic disorders in
HIV

• ? Infections Myelosuppression is frequently
  caused by involvement of the bone marrow by
  infecting organisms (e.g., mycobacteria,
  cytomegalovirus CMV,parvovirus, fungi, and,
  rarely, Pneumocystis carinii).
• ? Neoplasms Non-Hodgkin lymphoma (NHL) in AIDS
  patients is associated with
• infiltration of the bone marrow in up to 30
  of cases.

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• Medications Widely used antiviral agents in AIDS
  patients are myelotoxic
• - zidovudine (AZT) causes anemia
• - Ganciclovir and trimethoprim/
• sulfamethoxazole cause neutropenia.
• ? Nutrition Poor intake is common accompanied
  by poor absorption.
• Vitamin B12 levels may be decreased due to
• - vitamin B12 malabsorption
• - abnormalities in vitamin B12binding
• proteins.

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4- Torch Infections

• neonatal anemia, jaundice.
• thrombocytopenia, and HSM.
• 5- Bordetella Pertussis
• marked lymphocytosis (gt25,000/mm3) in early
  stages of infection.
• 6 - Tuberculosis
• leukemoid reaction mimicking CML, monocytosis,
  and rarely pancytopenia.

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7- Bartonellosis

• Bartonella bacilliformis
• fatal syndrome of severe hemolytic anemia with
  fever (Oroya fever).
• Bartonella, B. henselae
• - cat scratch fever. associated with a
  regional (following a scratch by a cat)
  lymphadenitis.
• - Thrombocytopenia may occur .

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8- Leptospirosis (Weil Disease)

• This disease is caused by Leptospira
  icterohaemorrhagiae.
• A coagulopathy occurs and can be corrected with
  vitamin K administration.
• Thrombocytopenia commonly occurs but DIC is rare.

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Infections

• B- Parasitic Illnesses Associated with Marked
• Hematologic Sequelae

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1- Malaria

• Acute infections cause anemia which is
  multifactorial
• ? Intracellular parasite metabolism alters
  negative charges on the RBC membrane,which causes
  altered permeability with increased osmotic
  fragility.
• ? Autoimmune hemolytic anemia may occur. An IgG
  antibody is formed against the parasite and
  resulting immune complex attaches nonspecifically
  to RBC, complement is activated, and cell
  destruction occurs. Positive Coombs test is
  found in 50 of patients.
• ? Thrombocytopenia without DIC is common.

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2- Hookworm(Ancylostoma )

• Heavily infested children may present with -
  profound iron-deficiency anemia.
• - hypoproteinemia.
• - marked eosinophilia.
• 3- Leishmaniasis
• splenomegaly and pancytopenia
• The bone marrow usually is hypercellular with
  hemophagocytosis.
• Some children may show coagulopathy.

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4- Tapeworm(Diphyllobothrium latum)

• worm infestation in the intestine results in
  vitamin B12 deficiency.
• 5- Trypanosomiasis
• Adiagnosis of trypanosomiasis can be made by
  finding trypanosomes in a blood and bone marrow
  smear.

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NUTRITIONAL DISORDERS
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1- Protein-Calorie Malnutrition (kwashiorkor)

• mild normochromic, normocytic anemia secondary to
  
• - reduced RBC production despite normal
• or increased erythropoietin levels.
• - reduced red cell survival.
• impaired leukocyte function.

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2- Scurvy

• mild anemia is common.
• bleeding tendency due to loss of vascular
  integrity,
• 3- Anorexia Nervosa
• hypoplastic bone marrow,
• Mild anemia (macrocytic), neutropenia, and
  thrombocytopenia.
• Predisposition of infection associated with
  neutropenia

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BONE MARROW INFILTRATION
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I. Nonneoplastic

• A. Storage diseases
• 1. Gaucher disease
• 2. NiemannPick disease
• 3. Cystine storage disease
• B. Marble bone disease (osteopetrosis)
• C. Langerhans cell histiocytosis

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II. Neoplastic

• A. Primary
• 1. Leukemia
• B. Secondary
• 1. Neuroblastoma
• 2. Non-Hodgkin lymphoma
• 3. Hodgkin lymphoma
• 4. Wilms tumor (rarely)
• 5. Retinoblastoma 6. Rhabdomyosarcoma

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A- Nonneoplastic1- Gaucher Disease

• Patients with Type 1 Gaucher disease present
  with
• ? Hepatosplenomegaly (rarely, portal
  hypertension)
• ? Pancytopenia secondary to hypersplenism and
  rarely from infiltration of the bone marrow with
  Gaucher cells
• ? Bone pain, osteoporosis, pathologic fractures
• ? Growth delay
• ? Typical foamy cells in the bone marrow
• ? Erlenmeyer flask deformity of the distal femora
  on radiographs
• ? Decreased glucocerebrosidase activity of white
  cells
• ? Characteristic mutations of the
  glucocerebrosidase gene on chromosome 1 on DNA
  analysis.

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2- NiemannPick Disease

• The progressive deposition of sphingomyelin in
  the
• 1- central nervous system leads to type A,
  
• 2-in nonneuronal tissues leads to type B.
• 3- Type C is a neuropathic form that
  results from
• the defective cholesterol transport.
• NiemannPick disease has classic signs,
  including
• ? Hepatosplenomegaly
• ? Cherry red spot in macula
• ? Psychomotor deterioration
• ? Reticular pulmonary infiltrates
• ? Foamy cells in the bone marrow
• Diagnosis involves examining leukocytes or
  cultured fibroblasts to determine
  sphingomyelinase activity

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3- Cystinosis

• ? Thermal instability, polydipsia, polyuria
• ? Failure to thrive
• ? Recurrent episodes of vomiting and dehydration
• ? Dwarfism and rickets often prominent
• ? Early renal involvement with tubular
  dysfunction manifesting as a secondary Fanconi
  syndrome, leading to chronic renal failure.
• Diagnosis
• ? Cystine crystals in the bone marrow
• ? Elevated cystine levels in leukocytes or
  fibroblasts.

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4- Infantile Malignant Osteopetrosis (Marble Bone
Disease)

• A- Severe Form (Autosomal Recessive)
• ? Progressive pancytopenia
• ? Compensatory extramedullary hematopoiesis with
  resultant leukoerythroblastic anemia (circulating
  normoblasts, tear-drop-shaped poikilocytosis, and
  early myelocytes), hepatosplenomegaly, and
  lymphadenopathy
• ? Bone marrow hypoplasia
• ? Hemolysis due to splenic sequestration of red
  cells and general overactivity of the
  reticuloendothelial system.
• B- Mild Form (Autosomal Dominant)
• Pathologic fractures occur in sclerotic bone.
  Nerve entrapment syndromes may also be present.

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B- Neoplastic Disease

• ? Hemorrhage.
• ? Nutritional deficiency states.
• ? Dyserythropoietic anemias (including erythroid
  hypoplasia, sideroblastic anemia, and anemia
  similar to that seen in chronic inflammation).
• ? Defect in erythropoietin production.
• ? Hemodilution.
• ? Hemolysis.
• ? Pancytopenia secondary to marrow invasion or to
  cytotoxic therapy.
• ? Acquired von Willebrand disease as in Wilms
  tumor.

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• ? Hypercoagulable states as in non-Hodgkin
  lymphoma.
• ? Coagulopathy as in acute promyelocytic
  leukemia.
• ? Leukoerythroblastic anemia.
• ? marrow Infiltration
• N.B
• Marrow infiltration is suspected when
  leukoerythroblastic anemia develops. This term
  signifies the presence of myelocytes and
  normoblasts with anemia, thrombocytopenia, and
  neutropenia. The explanation of this blood
  picture is that extramedullary erythropoiesis
  occurs when the marrow is infiltrated, permitting
  the escape of early myeloid and erythroid cells
  into the circulation.
• Normal blood findings, however, do not exclude
  marrow infiltration.

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Foam Cells in Bone Marrow

• 1. NeimannPick disease (types A, B, C, D)
• 2. Gaucher disease (types 1, 2, 3)
• 3. Gm1 gangliosidosis (type 1)
• 4. Gm2 gangliosidosis (Sandhoff variant)
• 5. Lactosyl ceramidosis
• 6. Sialidosis I
• 7. Sialidosis II, late infantile type
• 8. Mucolipidosis II
• 9. Mucolipidosis III
• 10. Mucolipidosis IV

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• 11. Fucosidosis
• 12. Mannosidosis
• 13. Neuronal ceroid-lipofuscinosis
• 14. Farber disease
• 15. Wolman disease
• 16. Cholesteryl ester storage disease
• 17. Cerebrotendinous xanthomatosis
• 18. Chronic hyperlipidemia
• 19. Chronic corticosteroid therapy
• 20. Hematologic malignancies (e.g., Hodgkin
  disease, leukemia, myeloma)
• 21. Hematologic disease (e.g., aplastic anemia,
• ITP).

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