APLASTIC ANEMIA

Guided By Mr.S.K.Sharma Mr.A.P.Chauchan

Presented by Manpreet Kaur B.Sc.M.L.T. Part III

Anemia
Anemia is not a disease in itself but

merely an objective sign of the presence of underlying disorder. Anemia is characterized by reduction in Haemoglobin conc. Red cell no. or count PCV

Anemia
Impaired production Increased destruction
1. Aplastic anemia 2. Megaloblastic anemia 3. Thalassemia
1. Haemolytic anemia 2. Auto Immune haemolytic anemia 3. Haemoglobinopathie s 4. Anemias of spleenomegaly

Anemia caused by marrow malfunction or impaired production

1.
2. 3.

Failure of stem cell to supply adequate no. of functional CFU(cell forming units) Ineffective erythropoiesis caused by impaired or slowed DNA synthesis DNA synthesis and maturation-division are primarily normal but in which hemoglobin synthesis by individual cell is inadequate.

Normal Bone Marrow

Aplastic anemia
Aplastic anemia is a stem cell disorder

characterized by fatty replacement of hemopoetic tissue. The reduction in functional marrow mass is believed to be caused by Toxic Radiant Imunnological injury to marrow stem cells reducing their capacity for normal cellular renewal.

Cont.
As a result of shortage of marrow stem cells.The marrow cavity is under populated with all three non lymphoid haemopoetic cell lines. Erthroblast Granulocyte Megakaryocyte

History
Concept of aplastic anemia was introduced in 1888 by

Ehrlich Discribed a rapid fatal case of sever anemia and leukocytopenia with fever Ulcerated gums Menorrhgia In a young women; at autopsy there was no active marrow is found

History cont.
In 1904 Chauffard introduced the term aplastic

anemia By 1934 aplastic anemia ,although still not clearly defined ,was described as a distinct clinical entity characterized by pancytopenia.

Aplastic Anemia

Primary or Idiopathic

Secondary

Other causes

PRCA

PRIMARY OR IDIOPATHIC APLASTIC ANEMIA

- Is less common than the secondary type - When a sufficiently intensive search for a causative agent was undertaken many cases of apparent aplasia was found to be secondary

Secondary Aplastic Anemia

By the toxic action of various chemicals and physical agents on the bone marrow. The chemical agents

Agents causing dose dependent marrow injury

Agents causing idiosyncratic Marrow injury

Secondary Aplastic Anemia

AGENTS CAUSING DOSE DEPENDENT DAMAGE TO MARROW 1. Ionizing radiations 2. Agents used in chemotherapy 3. Benzene 4. Arsenic 5. Alcohol

Radiations that removes electrons from atoms or molecules. Included among ionizing radiations are 1. Electromagnetic radiations such as - X rays - Gamma Rays - Alpha particles - Beta particles Effect of radiation are subjected to 3 major determinants Physical nature and quantity of radiant energy Mitotic activity of cell population Duration of radiation exposure

IONIZING RADIATIONS

Agents used in chemoterapy

Cytotoxic chemotherapeutic agents are the most common

and increasingly frequent chemical cause of myelosuppression, severity of witch is dose dependent and predictable. Anti tumor drugs are an electic group of drugs that bind covalently to DNA,RNA,DNA or RNA polymerase or topomerase or that interfere with DNA expression. Busulfan is mostly used and notorious for cousing generalized persisting cellular atypia effecting not only marrow parenchyma but also marrow stroma endothelium and other components of micoenvirment essential to colony growth.

 All body cells are susceptible to damage by ionizing

radiation. Radiation cause injury either through direct hits by particles or waves or through the production of free radicals . Effects of radiation are subject to three major determinants physical nature and quantity of radiant energy. Mitotic activity of cell population. Duration of radiation exposure.

Benzene and its derivatives

Well documented chemical cause of marrow

suppression . Unsubsitituted cyclohexatriene . Volatile lipophilic hydrocarbon Soluble in water Used as a solvent in a large no. of industries rubber, gum ,resins fat and manufactures of drugs dye and explosions.

Three factors determine the occurrence of benzene toxicity

Individual susceptibility Duration of exposure Conc. Of fumes

Benzene levels exceed about 100ppm(parts per min) for many months or years is suggestive to cause aplasia .

Mode of action
Exposure to very high vapor conc.impairs marrow cell replication effecting both committed and pleuripotential stem cells.

Mode of action cont.

Exposure to benzene vapor , the actively cycling,

differentiating progenitor cells (BFU-Es, colony forming unit-erythroid or CFU-Es)is selectively damaged. Production of all differentiated marrow cell is impinged. Incompletely differentiated ,dysplastic cells are prematurely pressed into service.

Arsenic
Inorganic state As2O3 arsenic has been used in

manufacture of glass, paint, enamals,tanning agents and other products. Arsenic inhibits the DNA synthesis and impair the utilization and absorption of folic acid. Hematological effect of chronic poisoning by arsenic is Pancytopenia Which may progress to fatal aplasia Marrow shows dyerthropoitic aberrations Megaloblastic changes Nuclearanomalies And form cell death

Alcohol
The most prevalent popular and pixilation dose dependent

heamato suppressive is alcohol. The anemia of alcoholism and the anemia of chronic alcoholic liver disease are self-limited unless accompanied by bleeding or foliate deficiency. Habitual alcohol ingestion leads to a decline in marrow cellularity and to characteristic morphological aberration. Alcohol cause moderate macrocytic anemia, mild neutropenia and severe thrombocytopenia . A multitude of other defects occur with time including bleeding gastritis Cirrhosis pneumonia scurvy

Drug causing idiosyncratic injury to marrow cells

At least 400 chemicals and drugs have been suspected of causing aplastic anemia unpredictably or occasionally Chloromphenicol Phenylbutazon Congeners Gold therapy

Chloremphenicol
During the period 1950-1965 chloremphenicol was being used widely however leading to 40% of all drug induced aplastic anemia due to its direct toxic effect on bone marrow leads to bone marrow suppression Awareness of the risk of severe aplastic anemia in patients treated with chloremphenicol, despite the rarity of its occurrence effected the prescribing habits of physician particularly those internist whose coign of vantage was hematological.

individuals exposed to large dose of chloremphenicol for a week or longer develop reversibly Mild erythroid suppression Reticulocytopenia Mild anemia Increased serum iron level Slowed iron clearance

Gold Therapy
Jacques Forestier,A French doctor pioneered gold therapy. Gold therapy is used as a potential treatment for Rheumatoid arthritis Autoimmune diseases Causes severe cytopenias in about 5% of patients and aplastic anemia in about 1% Occurrence of aplastic anemia is unrelated to the dose or plasma conc. of gold and may be associated with both the aurothiomalate and aurothioglucose from the drugs

Other drugs causing aplastic anemia

Acetazolamide Chloramphenicol Colachine Diclofanac Diphenylhydantion sodium Epinephrin Furoemide Gold salts Mepazin Methazolamide

Methicillin penicillamine Phenantoin Primidone Salicylamide Streptomycin Sulfadimethoxine Sulphonamide Trimethadione Trimethoprim

Clinical Features

Weight loss Bruising Petechiae Bleeding menifestations Weakness Fatigue Lassitude Exertion Hemmorhage in skin Sore throat or other infections

Investigations
HISTORY

Age,Sex,Occupation Exposure to toxic chemical agents or radiations Bone pain,Fever,Weight loss PHYSICAL EXAMINATION -Lymph node enlargement -Spleenomegaly -Bone tenderness -Hepatomegaly -Gum hypertrophy

Laboratory Features
Pancytopenia is an invariable finding in aplastic

anemia RBC Count . Decreased WBC Count . Decreased Platelet Count . Decreased PBF Red cells are normochromic and macrocytic Slight change in shape and size . n RBCs are present suggest marrow dysfunction. Reticulocytes are large and immature

Granulocytopenia,Monocytopenia are usually present WBC Count less than 1500 cells / ul Thrombocytopenia is also present leading to impaired --bleeding time -capillary fragility -clot retraction test 1. Increased conc. Of erythropoietin 2. Increased serum iron conc. with an almost complete saturation of iron binding capacity This increase may be the first sign of erythroid suppression and is of considerable screening value in patients received potentially toxic drug such as chloremphenicol

Ferro kinetic studies reveals a prolonged clearance time of injected iron and a subnormal incorporation of iron into circulating RBC. This indicate overall reduced in erythroid iron consuming activity and constitute one of the diagnostic criteria. Plasma iron turnover rate, as calculated from the conc. of serum iron ,plasma volume and iron clearance time and expressed in milligrams of iron/dl of blood /24hr. Normal range :--0.6 -0.8mg/dl of blood/24hr .

PBF in Aplastic Anemia

Bone marrow aspiration

Bone marrow aspirate is usually a dry tap or sometimes marrow fragments are obtained which demonstrate. Marked hypo cellularity with replacement of marrow cells by fat in >75%of the marrow. Paucity of erythroid,myloid, and megakaryocytic precursors. Focal areas of haemopoiesis are present in initial stage.

Bone marrow trephine biopsy

It is required in case of dry tap and also to assess the

exact cellularity. Features are Infiltration of fat by lymphocytes and plasma cells. Increase in mast cells. Increase bone marrow iron.

Aplastic Marrow

Fanconis Syndrome
Aplasia emerges during childhood or adolescence. In 1927 in switzerland Fanconi described a family in which 3

brothers developed aplastic anemia Genital hypoplasia Genetic diversity The basic defect in fanconis syndrome is an increased senstivity of cells to chromosomal damage of DNA linking agents. Cytogenetic analysis reveals an increase in chromatid abnormality, these chromatid abnormalities are non specific occur in normal cell culture but at much low frequency than in Fanconis anemia gap, breaks , reduplication,exchange,translocation and constrictions are present in increased number.

Clinical Features
Common Findings are - Low birth weight - Short stature - Microcephaly - Skeletal abnormalities - Pigmentation of skin - Patches of hyper pigmentation - Patches of depigmentation Rare and uncommon findings are - Mental retardation - Growth hormone deficiency

Lab Findings
PBF similar as aplastic anemia
Hb F is elevated Osmotic Fragility increased

Chromosomal instability

Pure Red cell Aplasia

Erythroid aplasia occuring as an isolated defect in particularized by the word Pure". Anemia unassociated with other cytopenias and erythroid aplasia in an otherwise normally cellular marrow may be Acquired Congenital Anemia due to selective aplasia of red cell precursors in marrow

Marrow PRCA

Pure Red Cell Aplasia

Acquired

Congenital

Primary

Secondary

Diamond Black Fan Syndrome

Congenital PRCA ( Diamond Black fan Syndrome)

Children are born with anemia and reticulocytopenia due to congenital stem cell defect. They may be detected within a few weeks of birth. Patient shows - Macrocytosis - Raised Hb F - Reticulocytopenia - Bone marrow shows an absence of erythrocyte precursors. Some infants show maturation arrest.

Acquired PRCA
Primary cause due to 1.Autoimmune 2.Idiopathic Disorders Rare Idiopathic condition Slowly progressive anemia Coombs test may be weakly positive Demonstrate a humeral inhibitor to erythropoiesis Bone marrow is cellular without red cell precursor

Secondary acquired PRCA

Anemia due to selective aplasia of red cell precursors in marrow One half of cases are in association of tumor of thymus, and very occasionally there is an associated carcinoma Chromosomal abnormalities have been described in some and in others an antibody to erythroblast nuclei have been demonstrated The marrow shows selective hyperplasia of red cell precursors with a normal number of WBCs and megakaryocytes In PBF N/N anemia with normal white cell and platelet count Occasionally there is an associated thrombocytopenia and more rarely pancytopenia.

Aplastic anemia associated with viral infections

Many viruses of unlike structure are myelosuppersive

cause depression of haematopoesis. Persistiting chromosomal aberration. Viruses cause aplastic anemia are Hepatitis B Epstein barr virus

CONGENITAL DYSERYTHROPOITIC ANEMIA

Comprise a group of rare familial disorder in which

anemia and ineffective erythropoesis are associated with binuclearity or multynuclearity or multinuclearity of erythropoitic marrow cells. Characterized by anemia, pronounced erythroid hyperplasia without reticulocytosis and complete sparing of other hematopoietic cell lines. Classified in to three types

CDA Type 1
Megaloblastic changes
Macrocytosis Internuclear

Chromatin bridges
Binuclearity not prominent Proerythroblasts Basophilic erythroblasts

CDA Type 2
Binuclearity Multinuclearity Karyorrhexis Pleuripolar mitosis Late erythroblasts

CDA Type3
Multinuclearity with up to 12 nuclei macrocytosis

Treatment
Prevention
since many cases of aplastic anemia are due to the toxic action of chemical or physical agents the qeustion of prevention is utmost importance.

Drugs
Large no. of potential marrow depressant drugs now used in therapeutics the occasional occurrence of marrow depression is inevitable.

 Nevertheless,both the incidence and severity of this

toxic complication can be significantly reduced if the following simple precautions are observed Careful selection of therapeutic agents Watch for early toxic manifestation Regular blood examination

Treatment will be considered under the following headings

Search for and removal of any possible toxic agent. Symptomatic and supportive therapy

Prevention and treatment of infection Prevention and treatment of haemorrhage Blood transfusion

Measure designed to increase cell counts

Administration of endrogens Spleenctomy Bone marrow transplant