aplastic anemia

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HYPOPROLIFERATIVE ANEMIAS

• DR.W.C.LWABBY (RESIDENT IM)

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INTRODUCTION

• HYPOPROLIFERATIVE ANEMIAS
• a group of anemias caused by inadequate production
   
• of erythrocytes. 
• Represent absolute or relative bone marrow
  failure.
• In response to acute anemia (i.e. blood loss)
• - the healthy marrow is capable of
  producing erythrocytes 6-8 times the normal rate.
• mediated through erythropoietin

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CLASSIFICATION OF HYPOPROLIFERATIVE ANEMIAS

• The hypoproliferative anemias can be divided into
  four categories
• Chronic inflammation
• Renal disease
• Endocrine and nutritional deficiencies
  (hypometabolic states)
• Marrow damage

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THE ANEMIA OF INFLAMMATION

• Is one of the most common forms of anemia seen
  clinically.
• It encompasses
• Inflammation
• Infection
• Tissue injury
• Other conditions (such as cancer) associated
• with the release of proinflammatory cytokines.

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THE ANEMIA OF INFLAMMATION

• It is the most important anemia in the
  differential diagnosis of iron deficiency
• many of the features of the anemia are brought
  about by
• - inadequate iron delivery to the marrow,
  despite the presence of normal or increased iron
  stores.
• This is reflected by
• a low serum iron
• Increased red cell protoporphyrin

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THE ANEMIA OF INFLAMMATION..

• A hypoproliferative marrow
• Transferrin saturation in the range of 1520
• A normal or increased serum ferritin.

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THE ANEMIA OF INFLAMMATION..

• The serum ferritin values are often the most
  distinguishing features between
• true iron-deficiency anemia and
• the iron-restricted erythropoiesis associated
  with inflammation.
• Serum ferritin values increase three fold over
  basal levels in the face of inflammation.
• These changes are due to the effects of
• Inflammatory cytokines
• Hepcidin (the key iron regulatory hormone, acting
  at several levels of erythropoiesis)

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Pathogenesis

• Interleukin 1 (IL-1)
• Directly decreases EPO production in response to
  anemia.
• Releases interferon ? (IFN-?) suppresses the
  response of the erythroid marrow to EPO
• Tumor necrosis factor (TNF)
• Release of IFN-? by marrow stromal cells
  suppresses the response to EPO.

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Pathogenesis..

• Hepcidin(made by the liver)
• Is increased in inflammation
• Acts to suppress iron absorption and iron release
  from storage sites.

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Pathogenesis..

• With chronic inflammation
• The primary disease will determine the severity
  and characteristics of the anemia.
• For example
• Many patients with cancer have anemia
  that is typically normocytic and
  normochromic.
• Patients with long-standing
• active rheumatoid arthritis or chronic
  infections such as tuberculosis will have a
  microcytic, hypochromic anemia.

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Pathogenesis..

• In both cases, the bone marrow is
  hypoproliferative.
• The differences in red cell indices reflect
  differences in the availability of iron for
  hemoglobin synthesis.
• Some conditions associated with chronic
  inflammation are also associated with chronic
  blood loss.

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ANEMIA OF CHRONIC KIDNEY DISEASE (CKD)

• Progressive CKD is usually associated with a
  moderate to severe hypoproliferative anemia
• The level of the anemia correlates with the stage
  of CKD.
• Red cells are typically normocytic and
  normochromic
• Reticulocytes are decreased.

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Pathogenesis

• The anemia is primarily due to
• Failure of EPO production by the diseased kidney
  
• Reduction in red cell survival
• - Hemolytic-uremic syndrome

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• Patients with the anemia of CKD usually present
  with
• Normal serum iron
• Normal TIBC, and ferritin levels.
• Those maintained on chronic hemodialysis
• may develop iron deficiency from blood loss
  through the dialysis procedure.
• Iron must be replenished in these patients to
  ensure an
• adequate response to EPO therapy

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ANEMIA IN HYPOMETABOLIC STATES

• This affects patients
• Who starve(particularly for protein)
• With a variety of endocrine disorders (that
  produce lower metabolic rates)
• Patients may develop a mild to moderate
  hypoproliferative anemia.

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Pathogenesis

• The release of EPO from the kidney is sensitive
  to the need for O2 , not just O2 levels.
• Thus, EPO production is triggered at lower levels
  of blood O2 content.
• In disease states ( such as hypothyroidism
  and starvation) where low metabolic activity, and
  thus O2 demand, is decreased.

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Endocrine deficiency states

• Androgen and Estrogen affect erythropoiesis.
• This gives the difference in the levels of
  hemoglobin between men and women.
• Testosterone and anabolic steroids augment
  erythropoiesis.
• Castration and estrogen administration to males
  decrease erythropoiesis.
• Patients who are hypothyroid or have deficits in
  pituitary hormones also may develop a mild
  anemia.

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Bone marrow Damage

•  Aplastic anemia
• Is a rare disease in which the bone marrow stops
  producing enough blood cells
• Aplastic anemia can be
• Moderate
• Severe
•  Bone marrow cellularity of less than 25 and
  at least two of the following
• Absolute neutrophil count (ANC) lt500/µL
• Absolute reticulocyte count (ARC) lt20,000/µL
• Platelet count lt20,000/µL

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• Very severe.
• Absolute neutrophil count (ANC) lt200/µL.
• People with severe or very severe aplastic anemia
  are at risk for life-threatening infections or
  bleeding.

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Epidemiology

• Aplastic anemia can strike at any age regardless
  of race or gender.
• However, it is diagnosed more often in
• Children
• Young adults
• Older adults.
• It appears more often in Asian-Americans.

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Causes

• Acquired Aplastic Anemia
• Is usually considered an autoimmune disease.
• Can begin at any time in life.
• About 75 out of 100 cases of acquired aplastic
  anemia are idiopathic.

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• In the remaining cases, the cause can often be
  linked to
• Toxins, such as pesticides, arsenic and benzene
• Radiation and chemotherapy used to treat cancer
• Treatments for other autoimmune diseases, such as
  rheumatoid arthritis and lupus
• Pregnancy - sometimes, this type of aplastic
  anemia improves on its own after the woman gives
  birth
• Infectious diseases, such as hepatitis,
  Epstein-Barr virus, cytomegalovirus
  (si-to-MEG-ah-lo-VI-rus), parvovirus B19 and HIV.
• Sometimes, cancer from another part of the body
  can spread to the bone marrow  and cause aplastic
  anemia.

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• Hereditary Aplastic Anemia
• Is passed down through the genes from parent to
  child.
• It is usually diagnosed in childhood
• Is much less common than acquired aplastic anemia.

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Hereditary Aplastic Anemia..

• Some inherited conditions can damage stem cells
  and lead to aplastic anemia, including
• Fanconi anemia
• Shwachman-Diamond syndrome
• Dyskeratosis (DIS-ker-ah-TO-sis) congenita
• Diamond-Blackfan anemia

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Clinical Features

• Aplastic anemia features vary from person to
  person.
• Specific features depend on
• Which of blood cell types are affected
• How low blood counts have fallen.

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Clinical Features.

• Low Red Blood Cell Counts
• Feel a little tired or very tired
• Feel less alert or have trouble concentrating
• Have a loss of appetite
• Are pale
• Have trouble breathing
• Have rapid heartbeat
• Have difficulty exercising or climbing stairs

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Clinical Features.

• Low White Blood Cell Counts
• Have repeated fevers and infections
• Get lung infections that cause coughing and
  difficulty breathing
• Get mouth sores

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Clinical Features.

• Low Platelet Counts
• Bruise or bleed more easily, even from minor
  scrapes and bumps
• Get heavier than normal menstrual periods
• Get nose bleeds
• Get tiny, flat red spots under the skin
  (petechiae)
• Have bleeding gums, especially after brushing
  teeth.

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Diagnosis

• Medical History
• Physical Examination
• Investigations

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Investigations

• Complete Blood count
• Shows a low number of
• Red blood cells
• White blood cells
• Platelets
• Normocytic normochromic anaemia
• Reticulocyte Count
• Low reticulocyte levels.

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Bone Marrow Tests

• They may include
•  Bone marrow aspirate (liquid bone marrow)
•  Bone marrow biopsy.
• A bone marrow test is done for two main reasons
• To confirm a diagnosis of aplastic anemia
• To understand how well or poorly bone marrow is
  making blood cells

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Bone Marrow Tests.

• The bone marrow test shows
• The quantity (cellularity) bone marrow occupied
  by different cells
• Exactly what types and amounts of cells bone
  marrow is making
• Increased, decreased, or normal levels of iron in
  the bone marrow
• Chromosomal (DNA) abnormalities

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Treatment

• Should focus on increasing the number of healthy
  cells in the blood (blood count).
• Mild or moderate aplastic anemia may not need
  treatment.
• Severe aplastic anemia need medical treatment
  right away to prevent complications.
• Very severe aplastic anemia need emergency
  medical care in a hospital.
• Removing a known cause of aplastic anemia, such
  as exposure to a toxin, may cure the condition.

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Treatment

• Antibiotics
• Antibiotics will help, but they must be started
  quickly for patients with low neutrophil counts
  and fevers.
• Growth Factors
• Man-made growth factors may be given to some
  people with bone marrow failure diseases to help
  increase
•  Red blood cell 
• White blood cell  
• Platelet counts
• E.g -GM-CSF (granulocyte macrophage
  colony-stimulating factor) like sargramostim
• -G-CSF (granulocyte
  colony-stimulating factor) like filgrastim
• -Erythropoietin

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Treatment

• Immunosuppressive Therapy
• This prevents autoimmune activities.
• Thus, allow bone marrow stem cells to grow.

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Treatment.

• Bone Marrow Transplant
• Is also called a stem cell transplant (SCT)
• Replaces unhealthy blood-forming stem cells with
  healthy ones
• Offers some patients the possibility of a cure.

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• Note
• Many patients with hypoproliferative anemias
  experience recovery
• when the underlying disease is appropriately
  treated.
• For those in whom such reversals are not
  possible such as
• End-stage kidney disease, cancer symptomatic
  anemia requires treatment.
• The two major forms of treatment are transfusions
  and EPO.

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TRANSFUSIONS

• Patients without serious underlying
  cardiovascular or pulmonary disease
• Can tolerate hemoglobin levels above 8 g/dl
• Do not require intervention until the hemoglobin
  falls below that level.

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ERYTHROPOIETIN (EPO)

• Is particularly useful in anemias
• in which endogenous EPO levels are
  inappropriately low such as CKD or the anemia
  of chronic inflammation.
• Iron status must be evaluated and iron repleted
  to obtain optimal effects from EPO.
• In patients with CKD, the usual dose of EPO is
  50150U/kg three times a week intravenously.

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ERYTHROPOIETIN (EPO) .

• Hb levels of 1012 g/dL are usually reached
  within 46 weeks if iron levels are adequate.
• 90 of these patients respond.
• Once a target hemoglobin level is achieved, the
  EPO dose can be decreased.
• A decrease in hemoglobin level occurring in the
  face of EPO therapy usually
• signifies the development of an infection or
  iron depletion.

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• THANK YOU