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									Anaemia
Impaired Red Blood Cell (RBC) Production
                    In adequate supply of nutrients essential for erythropoiesis
                           Iron Deficiency
                           Vitamin B12 Deficiency
                           Folic Acid Deficiency
                           Protein
                    Depression of erythropoietic activity
                           Anaemia of Chronic Disorders
                           Anaemia of Renal Failure
                           Aplastic Anaemia
                           Anaemia Due to Replacement of Normal Bone Marrow
              (BM)

                     Leukaemia/Lymphoma
                     Myeloma
                     Carcinoma
                     Myeloproliferative Disorders

                    Inherited Disorders

              Thalassaemia




Iron
                    Trace element found widely in the body
           1. Compounds that serve as storage forms for iron
           2. Compound that serve in metabolic or enzymatic functions
                    In an average 70kg man, the haemoglobin is distributed as
       follows: 65% in Hb; 4% in Mb (Methaemoglobin); 0.08% Cytochrome C;
       0.15% Transferrin; 30% Ferritin (tissue)
                    The average total iron concentration in the body is 2-4g (1g
       iron per kg RBCs)
                       Total daily male requirement approx. 1mg/day (menstruation
        female approx 2mg/day; pregnant female approx. 3-4mg/day)
                       A woman stores approx. half as much iron as a man
                       Only small amounts of iron are used - once in Hb, it remains
        there until RBC degradation
                       A very small amount of iron is left in the epithelial cells, some is
        lost in the urine and some is stuck in the gut
                       Iron is recycled as macrophages take RBCs out of the system -
        principally in the:

                 Liver Spleen Bone Marrow

                        Porphyrins break down in the circulation to give bilirubin

New look for June 2003




Anaemia
The erythrocyte as seen by the routine haematologist is essentially at the final stage
of maturation. The "cell" is anucleate, without mitochondria, lysosomes or
endoplasmic reticulum (ER), and relies on the Embden-Meyerhof and Heptose
Monophosphate pathways to maintain the cell's shape etc.

All cells (except for T cells) are produced in haematopoietic tissue called Bone
Marrow. In a child, this is found in the tibia. In an adult, bone marrow is found in the
anterior/posterior iliac crest, sternum, ribs, vertebrae and skull.

The bone marrow houses the most primitive haematological cells - called Stem cells.
These cells are pluripotential, which means they are able to differentiate into a range
of haematological cell types.

The bone marrow is influenced by Erythropoietin produced mostly in the kidneys, but
also the liver.

Anaemia is functionally described as a decrease in the competence of blood to carry
oxygen to tissues therefore causing tissue hypoxia.
The haematologist looks at haemoglobin, an indirect measure of anaemia:


                                    M = P x S (L)
                                                 Where,
                                     M = No./Mass of erythrocytes
                           P = Production of erythrocytes by the bone marrow
                                 S (L) = Survival (loss) of erythrocytes


Anaemia can be due to a lack of the raw materials necessary for erythrocyte
production (eg. iron, vitamin B12 or folate) or because of the presence of chemicals /
drugs which affect the stem cell.
A decrease in "M" leads to anaemia.
An increase in "P" = increased erythropoiesis. The marrow can increase production
6-8x to compensate for an anaemic condition.
An increase in "L" can be due to an increase in haemolysis eg. haemolytic anaemia,
or because of haemorrhage.

                      Acute Haemorrhage
                             20% (1000mL) loss with no resting clinical anaemic
               signs
                            30-40% (1500-2999mL) loss leads to circulatory
               collapse and shock
                            50% loss - death
                     Chronic Haemorrhage
                            eg. Ulcer
                            The body adapts slowly using mechanisms that allow
               organ function with up to 50% haemoglobin loss. These mechanisms
               include:
                                    Increased Oxygen Flow to Tissues
                                           Increase the cardiac output, cardiac rate
                             and circulation rate by decreasing viscosity and
                             peripheral resistance together with preferential blood
                             delivery.
                                    Increased Oxygen Flow to Tissues
                                           Increase 2,3 DPG producing a shift to the
                             right in the oxygen dissociation curve

The Haematology Profile (HP)
To determine whether the patient is anaemic or not
Factors affecting the components of the HP include...

Haemoglobin (Hb)
Values are higher for a standing patient or if a tourniquet has been applied for too
long resulting in haemoconcentration
Decreases after 65yrs, in 2nd and 3rd trimesters of pregnancy and in females

Red Cell Count (RCC)
Varies according to altitude (usually increasing proportionally), age (usually
decreasing with increasing age) or smoking (usually increasing)

Haematocrit (Hct)
An absolute increase in plasma volume or an absolute decrease in red blood cells
(RBC) may give a low Hct
An absolute decrease in plasma volume with a normal RBC volume may give an
elevated Hct
Acute haemorrhage (decreased RBC and plasma volume) may appear normal

Mean Cell Volume (MCV)
Reliable
Relating volume to diameter - spherocytes may have anormal volume but appear
with a much smaller diameter

Mean Cell Haemoglobin (MCH)
Does not take into account the size of the cell
Best used with MCV

Mean Cell Haemoglobin Concentration (MCHC)
Concentration of haemoglobin relative to its size
Hb / Hct = Hb / (MCV+RCC) Therefore if increased MCV, MCHC decreases and if
decreased MCV, MCHC increases
RBC clumps produce increased MCHC, MCH and MCV with a decreased RCC, and a
normal Hb, ie a smaller cell will show a smaller central pallor (hyperchromic-the only
cell described as this is the microspherocyte) whilst a larger cell will show a larger
central pallor (hypochromic), with a constant Hb
Microspheocytes have decreased MCV and therefore an increased MCHC (constant
Hb)

Red Cell Distribution Width (RDW)
Equivalent to anisocytosis in a blood film

White Cell Count (WCC)

A leukaemia can crowd out RBC production leading to anaemia

 Validation and Description
Check the results with the request film and the blood film
X10 Power
Scan for evidence of errors in the blood film production
Estimate WCC (1field/4 or 5 fields/20)
X40 Power
Differential
If normal, may stop here
If immature cells are present:

                                    Anisocytosis - compare to RDW - Normocytic?
                                     (7um), Macrocytic? (>9um), Microcytic? (6um)
                                    Poikilocytosis - slight, moderate, marked
                                    Haemoglobinisation - colour of RBCs in relation
                                     to central pallor (1/3 of area = normal)
                                    Immature Forms - NRBC's (nucleated red blood
                                     cells); polychromasia -reticulocytes
                                    Inclusion Bodies
                                          Basophilic Stippling - aggregated
                                             ribosomes visualised as bluish-black
                                             granular inclusions throughout cellular
                                             volume. Can be proportional to chain
                                             precipitation in thalassaemia
                                          Sideroblastic anaemia
                                          Lead poisoning
                                          Thalassaemia
                                          Abnormal haemoglobin synthesis
                                          Enzyme deficiencies
                                          Heinz Bodies
                                              Precipitated or denatured Hb
                                              Visible fresh as refractile bodies
                                              Visible in methyl violet/brilliant cresyl
                                          blue/new methylene blue/crystal violet
                                          (supravital stains)
                                          Invisible with Romanowsky stain
                                        Howell Jolly Bodies - dark purple/violet,
                                          spherical, nuclear remnants in RBC
                                          (usually 2 or less, resulting from mitotic
                                          problems)
                                        Pappenheimer bodies - small, irregular,
                                          iron containing granules seen with
                                          Romanowsky staining, confirmed with
                                          Prussian blue staining
                                        Malarial parasites




Megaloblastic Anaemia
Diagnosis
                    Many cases are seen that have a decreased serum B12 with a
      normal haematological profile and possibly normal clinical findings
                    Test for methylmalonic acid in the serum as an indicator of
      vitB12 deficiency
                    Test for homocysteine to check folate levels

Haematological Profile
                    Hb/RCC/Hct - Dec (due to Dec. DNA production)
                    MCV/MCH - Inc. (As precursors are megaloblastic)
                    MCHC - Normal
                    RDW - Inc. (Anisocytosis due to microcytes, normocytes and
      oval macrocytes)
                    Plt./WCC - Dec
                    Pancytopaenia with a normochromic, macrocytic anaemia
                    Intramedullary haemolysis due to ineffective erythropoiesis
      (reason for hypercellular BM)
                    Poikilocytosis - ++ (tear drops and schistocytes)
                    Anisocytosis - +++ (oval macrocytes)
                    Hypersegmented neutrophils ("Shift-to-the-Right" - seen in
      91% of megaloblastic anaemias where >5% of Neutrophils/Eosinophils have
      5/3 lobes - diagnostic with oval macrocytes)
             A "Shift-to-the-Left" indicates an Inc. in band form WBCs
             "Hypersegmented" refers to >5% nuclei with 6 (or more) lobes

                     Hypercellular bone marrow (M:E at 1:1 or reversed)
                     Erythron
                           Large cells with fine chromatin (Megaloblasts)
                           Nuclear(N)/Cytoplasmic(C) dissociation with N lagging C
              - normal cytoplasmic maturation
                           Multiple Howell-Jolly bodies (diagnostic if observed)
                     Leucon
                           Giant myelocytes and metamyelocytes
                     Thrombon
                           Often not obvious
                     The peripheral blood (PB) and bone marrow (BM) findings do
      not distinguish between a vitamin B12/cobalamin deficiency and a folic acid
      (folate) deficiency

Treatment
                   Shotgun therapy may be used where the causative agent is
      unclear
                            Folate, then vitB12 - attempts to make the patient well
                    Intramuscular hydroxy-cobalamin daily for a week (regime will
      depend on the cause of the anaemia)
                    Monitor the reticulocyte count (should return to normal in 2-3
      weeks) and the Hb concentration (20-30g/L rise every week until normal)
                    If no response occurs, the diagnosis is incorrect
                    If a response occurs and then reaches a plateau, an iron
      deficiency is complicating RBC production

Causes of Vitamin B12 Deficiency
                   Reflected by:
                           Impaired DNA synthesis
                           Defective fatty acid degradation (excessive
             demyelination)
                   Administration of folate will correct the anaemia but will not
      reverse any neurological disease - approximately 5% show no other
      symptoms but neurological disorder
                   Symptoms include:
                           Anaemia
                           Diarrhoea/constipation
                           Glossitis (shiny tongue)
                           Sterility/Infertility
                           Numb, tingling fingers (paresthesia), wobbly gait and
             potential paralysis
                           "Megaloblastic madness" due to mental problems
                   Nutritional
                           Rare
                   Malabsorption
                           Gatsric Disease
                     Gastrectomy - usually preceeded by iron
        deficiency
                      Pernicious Anaemia (PA):
                              Juvenile or adult
                              Can be fatal
                              More common in females
                              Autoimmune disease whereby Ab to
               parietal cells leads to gastric atrophy (loss of epithelial
               cells and intrinsic factor (IF)) or an Ab that blocks the
               function of IF
                              Most frequent in Northern Europe, running
               in families

    
           
           




               The vitB12 Journey.
               IF-Intrinsic Factor; Cbl-vitB12/ or Cobalamin; TC II-
               transcobalamin II)
                             Testing
                                                  Lack of gastric HCl is an indirect
                                  measure of lack of IF as it is due to atrophy of
                                  gastric cells
                                                  Look for IF Ab's (Blocking-prevents
                                  B12 binding to IF; Binding-prevents B12-IF
                                  complex binding to the ileum). 70% of PA
                                  sufferers have these Ab's
                                                  If negative (30%) do a Schilling
                                  Test.
                                                         Patient's vitB12 binding
                                          proteins are saturated by giving a large
                                          dose of unlabelled B12 intravenously
                                                         Absorption (via the ileum)
                                          of cobalamin is measured following
                                          ingestion of radioactively labelled B12.
                                                         In a normal system, more
                                          than 10% of the radioactive cobalamin will
                                          be excreted in the urine over 24hours.
                                                         If less than 10% is
                                          excreted, the patient is given cobalamin +
                                          IF. If the patient is suffering from PA,
                                          greater than 10% of the labelled
                                          cobalamin will appear in the urine within
                                          24hours, otherwise the patient can be said
                                          to have an absorption problem.
                                                         Low results may occur in
                                          patient's with kidney problems
                         Terminal ileal disease
                                 Ileal resections
                                 Ulcerative colitis (may be autoimmune)
                                 Tropical sprue (generalised malabsorption
                  syndrome - seen in New Guinea)
                         Competitive parasites
                                 Diphylobothrium latum
                         Pancreatic failure (enzymes from the pancreas are
           required to allow binding of IF to vitB12)
                         Drug induced
                         Bacterial overgrowth (competition for vitB12)
                 Increased Requirement for B12
                         Pregnancy
                         Infancy
                         Cancer
                         Haemolytic anaemia
                         Leukaemia
                         Exfoliative dermatitis
                         Multiple myeloma
                 Disorders of Transport and Storage

Folic Acid Deficiency
                 Folate is obtained from leafy vegetables
                 Deficiency results in anaemia in approx. 20 weeks
                  Require 50-100ug/day
                  Serum folate assay can be variable and should be carried out
    with a RBC folate assay (which indicates folate levels at the time of
    production of the RBCs)
                  Polyglutamate folate is the most common form of folate in food.
    The broken down, monoglutamate is transported across the intestinal
    mucosa, mostly at the jejunum and is primarily stored in the liver (capacity of
    5-10mg)


    Condition                    Serum B12 Assay RBC Folate Assay
    Pernicious Anaemia                   Low              Decreased
    Alcoholism                         Normal                Low
    Acute Folate Deficiency            Normal               Normal



                   Folate is taken into cells as N5-methyl-tetrahydrofolate(THF).
    This must be demethylated (which is mediated by cobalamin) before
    conjugation can occur. If N5-THF is not conjugated, it will leak out of the cell
    again.
                   If cobalamin is in short supply, demethylation is impaired
                   Normally, dUMP is entirely converted to dTMP. With decreased
    levels of folate, this conversion is limited and a build-up of dUMP occurs
    instead. As a consequence, dUTP concentration rises and begins to replace
    dTTP in DNA synthesis.
                   Error correction attempts to replace the U's but fails due to the
    lack of T's and DNA synthesis is interrupted
                   Note: Goat's milk is lower in folate than cow's milk

    Causes

                   Nutritional
                           An incomplete diet is the most common cause
                           Alcoholics
                           Elderly - overcooking destroys folate
                   Malabsorption
                           Tropical (general bowel disruption) and non-tropical
             (densitive to gluten - coeliac disease) sprue
                           Alcohol - interferes with absorption
                           Drug related - convulsive drugs, folate antagonists (eg.
             methotrexate-used for treatment of some neoplastic diseases), oral
             contraceptives
                           Anatomic and functional intestinal abnormalities
                   Increased Folate Requirement
                           Pregnancy
                           Infancy
                           Haemolytic anaemia
                           Acute leukaemia
                           Exfoliative dermatitis
                           Multiple myeloma
                           Metastatic cancer
                        Haemodialysis
                 Defective Utilization of Folate
                 Enzyme Deficiency




Non Megaloblastic Macrocytic Anaemia
                 Macrocytic anaemias are characterised by large (in volume or
     size) RBCs
                        greater than 100fL
                        greater than 9m
                Classified depending on precursors into:
                        Megaloblastic Anaemia and
                        Non-Megaloblastic Anaemia
                Non-megaloblastic anaemia is a macrocytosis without an
     accompanying megablastosis




     Physiological Causes
     Newborn:

                        Usually not an actual anaemia
                        A newborn's blood always contains a large number of
            macrocytes
Pregnancy:

                    May be unrelated to a vitB12 or folate deficiency

Pathological Causes
Reticulocytosis:

                     Polychromasia seen on a blood film due to increased
               erythropoietin following haemorrhage or haemolysis

Liver Disease:

                    Round macrocytes and target cells
                    May get a normochromic microcytic anaemia

Alcohol:

                            Inc. RBC production may cover the causes of this
               anaemia such as hamolysis, impaired BM response (due to a direct
               toxic/suppressing effect), folate deficiency and blood loss
                            Significant Dec. in the length of RBC survival
                            May cause sideroblastic anaemia




Stem Cell Disorders:

                            Dyserythropoiesis (abnormality in morphology and
               function of RBCs)
                            Leukaemia
                            Myelodysplastic syndromes




Miscellaneous:

                           Hypoxia
                           Post splenectomy
                           Thyroid disorders

                     Note: - pseudomacrocytosis is associated with increased WCC,
       cold agglutinins, hyperglycaemia and increased protein levels
Hypoproliferative Anaemias
                      A pathological depression of all cellular elements of peripheral
         blood

Causes

Bone Marrow (BM) Production Decrease

                      Classical cause of pancytopaenia

                 eg. Aplastic Anaemia

Infiltration or Replacement of normal cells

                 eg. Acute leukaemia
                 Malignancy - lymphomas (may metastasize to the bone marrow
                 Myelofibrosis - fibrosis of the BM
                 Hairy cell leukaemia

Hypersplenism

                      Large, overactive spleen that allows stagnation of pooled of
         blood

Immune Destruction

                      Systemic Lupus Erythematosus (SLE) - a classical autoimmune
         disease

Ineffective Erythropoiesis

                      Megaloblastic anaemia (defective DNA synthesis)
                      Dyserythropoiesis - myelodysplastic syndrome (qualitative
         abnormalities of one or more cell lines in the peripheral blood)
Haematological Reference Ranges
                                    +           12                                                12
Red Cell Count (RCC): Male: 5.5 /- 1.0 x 10 /L                                     (4.5-6.5 x 10 /L)
                                   +         12                                                 12
                      Female: 4.8 /- 1.0 x 10 /L                                   (3.8-5.8 x 10 /L)
                                                                                                  12
                         Infant                                                    (4.0-6.0 x 10 /L)
                                                                      +
                         (Full term, iron sufficient, cord blood): 5.0 /- 1.0 x
                            12
                         10 /L
                                     +
Haemoglobin (Hb):        Male: 155 /- 25 g/L                                       (130-180g/L)
                                        +
                         Female: 140 /- 25g/L                                      (115-165g/L)
                         Infant:
                                 0-2 months: -
                                 2-4 months: 100g/L (lower in premature babies
                                 1.0kg-80g/L; 1.5kg-2.0-90g/L)
                                 4-6 months: 105g/L
                                 6 months-2 years: 110g/L
                                 2-5 years: 110g/L
                                 5-9 years: 115g/L
                                 9-12 years: 120 g/L
                                    +
Packed Cell Volume       Male: 0.47 /- 0.07 L/L                                (0.40-0.54 L/L)
(Hct):
                                        +
                         Female: 0.42 /- 0.05L/L                                   (0.37-0.47 L/L)
                                    +
Mean Cell Volume         Adult: 86 /- 10 fL                                        (76-96 fL)
(MCV):
                         Infant:
                                 0-2 months: Macrocytes
                                 2-4 months: 80 fL
                                 4-6 months: 72 fL
                                 6 months-2 years: 70 fL
                                 2-5 years: 73 fL
                                 5-9 years: 75 fL
                                 9-12 years: 76 fL
                                    +
Mean Cell Hamoglobin     Adult: 29.5 /- 2.5fL                                      (27-32 pg)
(MCH):
                                                +
Mean Cell Haemoglobin    Adult/Children: 325 /- 25 g/L                             (300-350 g/L)
Concentration (MCHC):
Red Cell Distribution    11.5-14.5%
Width (RDW):
                                    +               9                                       9
Leucocyte/White Cell     Adult: 7.5 /- 3.5 x 10 /L                                 (4-11x10 /L)
Count:
Differential Leucocyte   Adult:
Count ("Diff"):
                                                           Neutrophils: 2.0-
                                            9
                                   7.5x10 /L (40-75%)
                                                           Lymphocytes: 1.5-
                                            9
                                   4.0x10 /L (20-45%)
                                                           Monocytes: 0.2-
                                            9
                                   0.8x10 /L (2-10%)
                                                           Eosinophils:0.04-
                                            9
                                   0.4x10 /L (1-6%)
                                                           Basophils: less than
                                              9
                                   0.01-0.1x10 /L (less than 1%)
                        Infant:

                                Lymphocytes
                                                                 9
                                0-6 months: less than 15.0x10 /L
                                                                 9
                                0.5-1 years: less than 11.0x10 /L
                                                            9
                                1-4 years: less than 9.0x10 /L
                                                              9
                                4-10 years: less than 6.5x10 /L
                                                                9
                                10-14 years: less than 6.0x10 /L
                                Neutrophils:
                                             9
                                Up to 20x10 /L on the first day only
                                Lower lmits of normal:
                                                                          9
                                less than 3 months: greater than 2.5.0x10 /L
                                                                       9
                                3 months-3 years: greater than 2.0x10 /L
                                                                 9
                                3-5 years: greater than 1.5x10 /L
                                Eosinophils:
                                                                    9
                                less than 5 years: less than 0.7x10 /L
                                                                       9
                                greater than 5 years: less than 0.5x10 /L
                                            9
Platelet Count (Plt):   Adult: 150-400 x 10 /L
                                           9
Reticulocyte Count:     Adult: 25-85 x 10 /L                                        (0.2-2.0%)
Erythrocyte             Male: 2-10 mm/hr
Sedimentation Rate
(ESR):
                        Female: 2-15 mm/hr
Bone Marrow Cellularity: 25-75% Cells
Fibrinogen:             1-4g/L
Bleeding Time (BT):     Modified Ivy Technique: 1.5-4.5 min
                        Standardized Template Method: 2.5-9.5 min
Activated Partial       Automated aPTT Reagent: 25-43 sec
Thromboplastin Time
(aPTT):
                                   +
Plasma Volume:          Adult: 50 /- 10mL/kg bodyweight
                                   +
Red Cell Mass/Volume: Male: 30 /- 5mL/kg bodyweight
                                       +
                        Female: 25 /- 5mL/kg bodyweight
Acute Leukaemia         AML:
Distribution:
                                                          20% of young children
                                  (2-10) with leukaemia
                                                           40% of adults
                                  (especially >50yr) with leukaemia

                        ALL:

                                                          80% of young children
                                  with leukaemia
                                                          10-20% of adults with
                                  leukaemia

Chronic Leukaemia       CML:
Distribution:
                                                          Rare in young children
                                  with leukaemia
                                                       20-25% of adults with
                                  leukaemia

                          CLL:

                                                       Virtually unheard of in
                                  young children
                                                       25-30% of adults with
                                  leukaemia

Shift To The Left:        N(seg) : N(nonseg) = 1 : 0.1-0.3
                          Immature cells include:
                                  Blasts, promyelocytes, myelocytes,
                                  metamyelocytes, pronormoblasts, basophilic
                                  normoblasts,
                                  polychromatic normoblasts and
                                  orthochromatic normoblasts
Shift To The              Neutrophils:
Right/Hypersegmented:
                                                        More than 5% have 5
                                  lobes / More than 5% have 6 or more lobes

                          Eosinophils:

                                                        More than 5% have 3
                                  lobes / More than 5% have 4 or more lobes


 New look for June 2003

								
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