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Approach to Anaemia (Anemia) by adult patients, symptoms, causes, diagnosis algorithm, kinetic approach and morphological approach

Anaemia


Definition:
HGB <13.5 g/dL or a HCT <41.0 in men
HGB <12.0 g/dL or a HCT <36.0 percent in women.

THE RBC LIFE CYCLE
Erythropoiesis in the adult takes place within the bone marrow under the influence of erythropoietin (EPO).
EPO is a true endocrine hormone produced in the kidney by cells that sense the adequacy of tissue oxygenation relative to the individual's metabolic activity
reticulocyte which comes after normoblast in the RBC’s Production chain, still has a ribosomal network and retains it for about four days, of which three days are spent in the marrow and one day in the peripheral blood.
The mature RBC circulates for 110 to 120 days, after which it is removed from.
Under steady-state conditions reticulocytes will represent approximately 1% OF total circulating blood (50,000 reticulocytes/microL of whole blood each day).
Stable HGB will be achieved when Production of RBC = Destruction = 1% of blood

Normal red cell function:
RBCs carry oxygen from the lungs to tissue capillaries.
each gram of hemoglobin carrying 1.3 mL of oxygen. Thus, approximately 20 mL by 15 g/dL of hemoglobin at full saturation. Approximately 25 % of the total is normally removed by the tissues


Oxygen is then released from hemoglobin according to the characteristics of the oxyhemoglobin dissociation curve:


Source: https://vivadifferences.com/myoglobin-vs-hemoglobin-oxygen-dissociation-curve/
Symptoms related to anemia result from two factors:
1-   decreased oxygen delivery to tissues:
-      Exertional dyspnea, dyspnea at rest
-      fatigue,
-      signs and symptoms of the hyperdynamic state, such as bounding pulses, palpitations, and "roaring in the ears".
-      lethargy and confusion
-      heart complications such as congestive heart failure, angina, arrhythmia, and/or myocardial infarction. 
2-    Hypovolemia by bleeding:
-      postural dizziness
-      syncope,
-      Persistent hypotension,
-      shock, and death.

CAUSES OF ANEMIA  
There are two general approaches one can use to help identify the cause of anemia:
  • A kinetic approach: which mechanism is responsible for anemia
  • A morphologic approach categorizing anemias via alterations in RBC size   and the reticulocyte response.
Kinetic approach:
Anemia could be caused of three independent mechanisms:
1-     Decreased RBC production:
  • Lack of nutrients, such as iron, B12, or folate. This can be due to dietary lack, malabsorption (eg, pernicious anemia, sprue), or blood loss (iron deficiency).
  • Bone marrow disorders (eg, aplastic anemia, pure RBC aplasia, myelodysplasia, tumor infiltration)
  • Bone marrow suppression (eg, drugs, chemotherapy, irradiation).
  • Low levels of EPO (eg, chronic renal failure), thyroid hormone (eg, hypothyroidism), and androgens (eg, hypogonadism).

2-     Increased RBC destruction:
  • Inherited hemolytic anemias (eg, hereditary spherocytosis, sickle cell disease, thalassemia major)
  • Acquired hemolytic anemias (eg, Coombs'-positive autoimmune hemolytic anemia, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, malaria)
3-     Blood loss:
  • Obvious bleeding (eg, trauma, melena, hematemesis, menometrorrhagia)
  • Occult bleeding (eg, slowly bleeding ulcer or carcinoma
  • Induced bleeding (eg, repeated diagnostic testing, hemodialysis losses, excessive blood donation)
loss of the iron contained in the RBCs will ultimately lead to iron deficiency. This usually occurs in males and females after losses of ≥1200 mL and ≥600 mL, respectively.


Morphologic approach:


1-   Macrocytic anemia: MCV > 100 fL
-      A folate or cobalamin deficiency
-      drugs interfering with nucleic acid synthesis, such zidovudine and hydroxyurea).
-      Abnormal RBC maturation (eg, myelodysplastic syndrome, acute leukemia, LGL leukemia).
-      Other common causes include alcohol abuse, liver disease, and hypothyroidism.


2-   Microcytic anemia: MCV < 80 fL).
-      severe iron deficiency, the anemia of chronic disease, copper deficiency
-      Reduced heme synthesis — lead poisoning, congenital or acquired sideroblastic anemia
-      Reduced globin production — thalassemic states, other hemoglobinopathies

The three most common causes of microcytosis in clinical practice are iron deficiency, alpha or beta thalassemia minor, and (less often) the anemia of chronic disease (anemia of chronic inflammation).

Serum iron
transferrin
ferritin

Iron deficiency
-
+
-

Chronic disease
-
-
n/+


3-   Normocytic anemia: MCV > 80 and <100 fL):
-      Acute blood loss
-      Iron deficiency anemia (early)
-      Anemia of inflammation/anemia of chronic disease (also microcytic) (eg, infection, inflammation, malignancy)
-      Bone marrow suppression (may also be macrocytic)
-      Bone marrow invasion
-      Acquired pure red blood cell aplasia, Aplastic anemia
-      Chronic renal insufficiency
-      Hypothyroidism (also macrocytic)
-      Hypopituitarism


EVALUATION OF THE PATIENT
Anemia is never normal, and its cause(s) should always be sought.

The initial approach to anemia should try to answer the questions:
1-     Is there bleeding: gastrointestinal, urogenital, skin
2-     Are there nutrition’s deficiencies: B12, folate, Iron? and why?
3-     Is there blood destruction? Hemolysis
4-     Is there bone marrow suppression? Medications? Tumor?

History:
-      Symptoms of the anemia
-      Is it new or lifelong?
-      Other conditions that result to anemia such as renal failure, malignancies
-      History of bleeding (tarry stool, hematemesis)
-      Medications: NSAIDS
-      Exposure to toxins
-      Transfusion history
-      Nutrition status

Physical examination:
-      tachycardia, dyspnea, hypotension 
-      Pallor
-      Jaundice
-      petechiae, ecchymoses, purpura
-      rectal test: malignancies, blood, tarry stool

 Laboratory tests:
-      HBG, HCT
-      CBC, MCV, MCH, MCHC
-      Reticulocytes
-      WBC with differential
-      Blood smear
-      Bilirubin, LDH, Haptoglobin
-      platelets

Reticulocytes:
-      Anemia with a high reticulocyte count: increased erythropoietic response to continued hemolysis or blood loss (exception: concurrent disorder that impairs RBC production (eg, infection, prior chemotherapy)
-      Anemia with a low reticulocyte count: deficient production of RBCs (ie, a reduced marrow response to the anemia).
-      A low reticulocyte accompanied by pancytopenia: aplastic anemia
-      reticulocyte percentage of zero with normal white blood cell and platelet counts suggests a diagnosis of pure red cell aplasia.

White blood cell count and differential:
A low total white blood cell (WBC) count (leukopenia) in a patient with anemia:  consider:
-      bone marrow suppression or replacement,
-      hypersplenism,
-      deficiencies of cobalamin or folate.
high total WBC count (leukocytosis) may reflect:
-      the presence of infection, inflammation
-      hematologic malignancy.

Blood smear:
Some findings and its meaning:
Finding
Meaning
DDx:
 ("helmet cells", schistocytes)
(1)
microangiopathic hemolysis 
microspherocytes
(2)
autoimmune hemolytic anemia
critical ill patients
Sepsis
teardrop RBCs
(2)
Myelofibrosis
Bone marrow infiltration
Megaloblastic anemia
Hemolytic anemia
Thalassemia major

leukoerythroblastic pattern
(2)
bone marrow replacement
bite cells
(2)
oxidative hemolysis 
RBC parasites: malaria or babesiosis
(2)
Source:(1) American society of hematology. (2) https://doctorlib.info/hematology/atlas/1.html

Pancytopenia:
The combination of anemia, thrombocytopenia, and neutropenia is termed pancytopenia: may be seen in:
-      aplastic anemia,
-      folate or cobalamin deficiency,
-      hematologic malignancy (eg, acute myeloid leukemia).
-      Bone marrow suppression (chemotherapy)


Evaluation for hemolysis:
The usual ancillary findings of hemolysis are:
-      increase in LDH
-      increase in indirect bilirubin concentrations
-      reduction in the serum haptoglobin concentration.
-      Intravascular hemolysis: Serum or plasma hemoglobin and urinary hemosiderin should be measured if intravascular hemolysis is a consideration, as with paroxysmal nocturnal hemoglobinuria. 

Examination of the bone marrow:
Indications:
-      pancytopenia
-      presence of abnormal cells in the circulation, such as blast forms.
-      Such patients may have aplastic anemia, myelodysplasia, marrow replacement with malignancy, or a myeloproliferative disease.

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