The Clinical Aspect Of Anemia

• THE CLINICAL ASPECT OF ANEMIA
  
• DEFINITION of ANEMIA
  

Normally defined as haemoglobin concent less than :

13.5 g/dl in adult male

11.5 g/dl in adult female

Children : Newborn Hb 15-21 g/dl

        3 month Hb 9.5-12.5 g/dl

        1 year-puberty Hb 11.0-13.5 g/dl

• INTRODUCTION — Although anemia can be defined as a reduced number of circulating red blood cells (ie, a reduced red blood cell volume), such studies are not practical, cost-effective, or generally available.
  
• As a result, anemia has been defined as a reduction in one or more of the major red blood cell (RBC) measurements: hemoglobin concentration, hematocrit, or RBC count
  
• Hb concentration (HGB) measures the concentration of the major oxygen-carrying pigment in whole blood. Values may be expressed as grams of hemoglobin per 100 mL of whole blood (g/dL) or per liter of blood (g/L)
  
• Hematocrit (HCT) is the % of a sample of whole blood occupied by intact RBC
  
• RBC count is the number of red blood cells contained in a specified volume of whole blood, usually expressed as millions of red blood cells per microL of whole blood.
  
• Normal range — One set of "normal ranges" (95 percent confidence limits) for HGB, HCT, and RBC count is shown in the table .
  
• If anemia is defined as values which are more than two standard deviations (SD) below the mean, then, by using these ranges, a HGB <13.5 g/dL or a HCT <41.0 percent represents anemia in men and a value <12.0 g/dL or <36.0 percent, respectively, represents anemia in women.
  
• Normal ranges other than the above have been proposed: Other authors have proposed diffrent lower limits of normal, ranging from 13.0 - 14.2 g/dL for men & 11.6 to 12.3 g/dL for women [1].
  
• WHO criteria for anemia in men and women are <13 and <12 g/dL, respectively [2].
  
• Other lower limits according to sex, age, and race, based on data from NHANES III and Scripps-Kaiser studies, have been proposed [1]. These values are as low as 12.7 g/dL for black men >60 years of age and 11.5 g/dL for black women >20 years of age.
  
• HEMOGLOBIN
  
• The Hb protein and its nonprotein iron-containing porphyrin cofactor, heme, are so central to the evolution of our understanding of blood diseases that the field of hematology takes name from the molecules.
  
• The processes of the globin proteins and heme biosynthetic pathway occurred throughout evolution.
  
• Understanding of the Hb molecule underlies the pathophysiology of many of the red cell diseases.
  
• INTRODUCTION- HEMATOPOIESIS
  
• Hematopoiesis is difined as the process by which pluripotent hematopoietic stem cells both self-renew and differentiate into all of th specialized circulating blood cells, including white blood cells, red blood cells, and platelets.
  
• Some factors such as a humoral factor was originally favored as containing a critical stimulatory factor.
  
• KEY POINTS- HEMATOPOIESIS
  
• There is ordered progression of hematopoietic development during ontogeny: blood elements are first produced by precursor cells in the yolk sac, then in the fetal liver, and finnally in the bone marrow.
  
• A wide variety of informative experimental assays exits for hematopoietic stem and progenitor cells. Each assay has limitations. The only true assay for long-term repopulating stem cells is reconstitution of hematopoiesis in vivo.
  
• Hematopoietic stem cells can be defined by the expression pattern of spesific cells surface proteins, cell cycle quiescence, and telomerase activity.
  
• Hematopoiesis occurs in a specialized bone marrow microenvironment, composed of cellular and cellular elements critical to localization and control of blood cell production.
  
• Hematopoietic … count
  
• The processes of stem cell mobilization and homing are governed by modulation of interactions between primitive hematopoietic cells and their microenvironment.
  
• Populations of nonhematopoietic stem cells in the bone marrow, including mesenchymal stem cells, are capable of generating bone, cartilage, and other tissues, along with more undifferentiated cell populations that potentially contribute to a wide variety of adult tissues.
  
• THE RBC LIFE CYCLE
  
• Overview — Erythropoiesis in the adult takes place within the bone marrow under the influence of the stromal framework, cytokines, and the erythroid specific growth factor, 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 (show figure 2).
  
• EPO enhances the growth and differentiation of the two erythroid progenitors: burst forming units-erythroid (BFU-E) and colony forming units-erythroid (CFU-E) into normoblasts of increasing maturity.
  
• When the normoblast extrudes its nucleus to form a red blood cell, it still has a ribosomal network which, when stained supravitally, identifies it as a reticulocyte, a cell still capable of a limited amount of hemoglobin and protein synthesis
  
• Subtances needed for erythropoiesis
  
• 1. Metal : Fe, Mg, Co
  
• 2. Vitamins : B1, B6, B12, riboflavin, panthothenic acid, Folate, Vit C, Vit E
  
• Amino acids
  
• Hormones: erythropoietin, androgens, thyroxine
  
• Main function Hb :
  
• Carry oxygen® the tissue
  
• Return carbon dioxide (CO₂) from the tissue to the lung.
  
• PATHOPHYSIOLOGY — Most patients with breathing discomfort can be categorized into one of two groups: respiratory system dyspnea or cardiovascular system dyspnea.
  
• Respiratory system dyspnea includes discomfort related to disorders of the central controller, the ventilatory pump, and the gas exchanger.
  
• While cardiovascular system dyspnea includes cardiac diseases (eg, acute ischemia, systolic dysfunction, valvular disorders, pericardial diseases), anemia, and deconditioning.
  
• Anemia — Anemia can severely impair oxygen delivery because the bulk of oxygen carried in the blood is hemoglobin-bound. Nevertheless, the exact mechanism by which anemia produces dyspnea is unknown.
  
• To the extent that the local pH of metabolically active cells decreases due to the inability to sustain aerobic metabolism, there may be stimulation of "ergoreceptors" which are believed to be located in the muscles and which respond to such changes in the microenvironment of the cell
  
• Anemia also leads to increased cardiac output, which may necessitate elevated left ventricular volume and pulmonary vascular pressures. However, the quality of dyspnea is usually quite different in these two clinical situations.
  
• IV. Marrow examination
  A. Aspirate
  1. E/G ratioa
  2. Cell morphology
  3. Iron stain
  B. Biopsy
  1. Cellularity
  2. Morphology
  

E. Cell morphology

1. Cell size

2. Hemoglobin content

3. Anisocytosis

4. Poikilocytosis

5. Polychromasia

II. Reticulocyte count

III. Iron supply studies

A. Serum iron

B. Total iron-binding capacity

C. Serum ferritin, marrow iron stain

• CAUSES OF ANEMIA — There are two general approaches one can use to help identify the cause of anemia:
  
• A kinetic approach, addressing the mechanism(s) responsible for the fall in hemoglobin concentration
  
• A morphologic approach categorizing anemias via alterations in RBC size (ie, mean corpuscular volume) and the reticulocyte response
  
• Kinetic approach — Anemia can be caused by one or more of three independent mechanisms:
  
• Decreased RBC production,
  
• Increased RBC destruction,
  
• Blood loss
  
• Decreased RBC production —The more common causes for reduced (effective) RBC production include:
  
• 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 trophic hormones which stimulate RBC production, such as EPO (eg, chronic renal failure), thyroid hormone (eg, hypothyroidism), and androgens (eg, hypogonadism).
  
• The anemia of chronic disease/inflammation, associated with infectious, inflammatory, or malignant disorders, is characterized by reduced availability of iron due to decreased absorption from the gastrointestinal tract and decreased release from macrophages, a relative reduction in erythropoietin levels.
  
• Increased RBC destruction — A RBC life span below 100 days is the operational definition of hemolysis
  
• Hemolytic anemia will ensue when the bone marrow is unable to keep up with the need to replace more than about 5 percent of the RBC mass per day, corresponding to a RBC survival of about 20 days.
  
• Examples include 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)
  
• Morphologic approach — The causes of anemia can also be classified according to measurement of RBC size, as seen on the blood smear and as reported by automatic cell counter . The normal RBC has a volume of 80 to 96 femtoliters (fL, 10)
  
• The anemia is first classified via the mean corpuscular volume (MCV), which is part of the CBC (show algorithm 1): Microcytic anemias are associated with an MCV below 80 fL. The most commonly seen causes are iron deficiency thalassemia, and the anemia of chronic disease (see "Microcytic anemia" above and see "Evaluation for iron deficiency" above).
  
• Macrocytic anemias are characterized by an MCV above 100 fL The most common causes include alcoholism, liver disease, folic acid and vitamin B12 deficiency, and myelodysplasia. (See "Macrocytosis", section on Evaluation).
  
• The MCV is between 80 and 100 fL in patients with normocytic anemia or would raise suspicion of an acute or chronic hemolytic state (eg, spherocytes, sickle forms, ovalocytes).
  
• Therapy
  

Mild to moderate ® Tx underlying Disease

( Hb levels greader than 9 -10 g/dl)

Severe :

Transfusion support

Erythropoetin Therapy

• OTHER HYPOPROLIFERATIVE ANEMIAS IN SYSTEMIC DISEASE
  

By Ibnu Purwanto

• Approach Anemia
  
• Introduction
  
• Anemia is common in patient :
  
• Acute & chronic inflammatory disease, Renal inssufficiency
  
• Hypothyroidism
  
• There is an apparent failure erythropoetin stimulation of the marrow
  
• Needed skill in evaluating patient with a hyproliferative
  
• The of erythropoetin production
  
• Anemia of chronic inflamatory states
  (The Anemia of chronic Disease)
  
• When the inflamatory states is present®for a long period® manifestasion of iron Deffisien
  
• The smear because mild microcytic (MCV: 75-85%)
  
• Hypochromic
  
• Hb falls to levels below 10 gr%
  
• Reticulosit ¯
  
• Low serum iron
  
• Ion TIBC
  
• Ferritin normal/ elevated
  
• Active Rheumatoid Artritis
  
• Hb level range 8 -12 g/dL
  
• Hematocrit range 25 -35%
  
• The severity of the anemia »IL1 level
  
• AIDS
  
• The Anemia of renal disease
  
• Characterized :
  
• Normocytic normocromic morphology
  
• MCV normal
  
• Reticolusit ¯
  
• The severity anemia » with severity of the renal failure
  
• Acute loss of renal functions as acute tubuler necrosis ® as associated with severe anemia (Hb level below 7 gr/dL)
  
• The serum iron , TIBC, Ferritin® level normal.
  
• Hypomethabolic states
  
• Protein Deprivation
  
• Endocrine deficiency Status
  
• Protein Deprivation
  
• The hypoproliferative anemi of protein deprivation is mild ® 1 to 3 g/dl reduction in Hb level.
  
• Poor protein nutritions as a possible cause of hypoproliferative anemi in elderly.
  
• Endocrine deficiency Status
  
• Diagnosis of Hypoproliferative Anemia
  

STAGES OF IRON DEFICIENCY

These can be divided into three stages.

1. Negative iron balance
   
2. Blood loss,
   
3. Pregnancy
   
4. Rapid growth spurts in the adolescent
   
5. Inadequate dietary iron intake.
   

Lecture by:

dr.Ibnu Purwanto,SpPD-KHOM

Sub division of Haematology & Medical Oncology

Department of Internal Medicine

Medical Faculty of Gadjah Mada University /

Sardjito Hospital

Jogjakarta