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What is Anemia defined as?

A reduction in one or more of the major red blood cell (RBC) measurements: hemoglobin concentration, hematocrit, or RBC count


What are the signs & symptoms of Anemia?

-Tiredness/fatigue/exercise intolerance
-Shortness of breath
-Worsening of angina


What signs & symptoms of Anemia are more like with persons of Severe Anemia?

1) Elderly
2) Sudden drop in HgB concentration
3) Other co-existing pathologies (e.g cardiorespiratory disease)


What signs & symptoms of Mild Anemia are more likely?

1) Younger patients
2) Gradual drop in HgB concentration
3) Absence of other diseases


What are Acquired Anemias due to?

1) Specific deficiencies (e.g iron, vitamin B12, folate)
2) Blood loss (e.g., acute or chronic)
3) Chronic disease (e.g., chronic infections such as tuberculosis, osteomyelitis; chronic inflammatory disease such as rheumatoid arthritis, lupus; malignancy; and renal failure)
4) Hemolysis (e.g., AIHA- required autoimmune hemolytic anemia)


What are Iron Deficient Anemias?

***Most COMMON anemia worldwide!
-Without iron there is a defective synthesis of hemoglobin, resulting in RBCs that are both:
*MICROCYTIC* (MCV decreased) & *HYPOCHROMIC* (MHC & MCHC are decreased)


What can be seen on a blood smear with Iron deficient Anemias? Why?

-Occasional "pencil cells" may be seen because of unbalanced surface membrane to cytoplasmic volume due to reduced hemoglobin


What does a reduced rate of hemoglobin synthesis result in?

-More CELL DIVISION & subsequently smaller cells.
-Lower levels of hemoglobin in the RBCs make them appear "pale".


What are sources of Fe in the stomach?

1) Meals
2) Transfusion (RBC--Hemoglobin)
3) Iron pill


Is Iron digested/absorbed in the stomach ?



Iron is absorbed where?

Across the small intestine


What is Transferrin?

When Iron binds to proteins to make it soluble.
(Controls the level of free iron in biological fluids)


Where can the iron be stored? What is iron called when its stored in the liver ?

1) Mainly in the LIVER
2) Some in the spleen

***Iron stored in LIVER is called FERRITIN (Hemosiderin)


What does the bone marrow do with the iron when it receives it from the liver?

It utilizes it to make Hemoglobin


What are the causes of Iron deficiency ?

1) Blood loss
2) Decreased Iron Absorption
3) Dietary
4) Increased Iron Requirements
5) Other


What is the MAJOR cause of iron deficiency? Explain

***Blood loss !
-Can be Overt: obvious and easy to recognize
Examples: severe traumatic hemorrhage, hematemesis(vomiting blood), melena (stool), hemoptysis( coughing in sputum), severe menorrhagia (menstruation) and gross hematuria (blood in urine)

-Can be Occult: Difficult to discern


Why would a patient have decreased Iron?

A problem w/ the GI tract (e.g., bleeding ulcer, inflammation bowl disease, etc) or an issue w/ a drug impairing iron absorption.


Why would a patient have Dietary Iron deficiency?

Most likely vegans and elderly patients


Why would a patient have Increased Iron requirements?

Classic examples are pregnancy & growth spurts in children


What does DECREASED vitamin B 12 levels produce?

-RBCs that are MACROCYTIC (MCV elevated)



What do all actively dividing RBCs in the bone marrow require?

DNA synthesis in order to undergo mitosis.

-This involves both vitamin B12 & Folate


Is RNA synthesis affected? Explain

No; Not being used so protein accumulates and red cells get LARGER.
(Protein synthesis continues )


What are the causes of Vitamin B12 deficiency ?

1) Lack of Intrinsic Factor (IF)
2) Dietary
3) Total or Partial Gastrectomy & other stomach procedures


What does LACK of INTRINSIC FACTOR (IF) lead to?

DECREASED Vitamin B12 absorption; Vitamin B12 deficiency due to decreased IF produces "PERNICIOUS ANEMIA"


Why would a person LACK INTRINSIC FACTOR (IF) ?

1)Due to an autoimmune attack on IF

2) Loss of The PARIETAL CELLS in the STOMACH (This produces chronic atrophic gastritis)
- This is responsible in part for secretion of IF a protein essential for B12 absorption in the ileum.


In regards to DIETARY behavior which persons are more sysceptible to Vitamin B12 deficiency?

Strict vegans


What is Vitamin B 12 deficiency common with person that undergo Total/Partial Gastrectomy & Other Stomach procedures?

On the rise w/ more people turning to surgical procedures to lose weight


What is the other key player in DNA synthesis ?

Folate (more soluble!)


What does a deficiency in folate produce?

The same clinical picture as a deficiency in vitamin B 12 (increased MCV)


Does Folate required IF like Vitamin B12 Deficient Anemia?

NO does not require IF to be absorbed


What are potential causes of Folate Deficient Anemia?

1) Poor nutrition (Seen in poverty, elderly, and alcoholics)
2) Increased requirements (Pregnancy)
3) Malabsorption (inflammatory diseases of the intestine)
4) Drugs (interfering w/ absorption) [e.g., some anti-epileptics, oral contraceptives]


What is Anemia due to acute blood loss? What are the general feature of this?

When large volumes of blood are lost from the body in a short space of time.

Features of volume depletion:
1) Increased HR
2) Low blood pressure


Why is the anemia due to acute blood loss described as NORMOCYTIC?

-The hemoglobin concentration will be normal for several hours following the bleed; b/c red cells & plasma are lost together.
-Anemia only develops once the blood volume has been restored thru the movement of fluid from the extravascular space to the intravascular space.

**** The MVC remains normal so its Normocytic


What is Anemia due to Chronic Blood loss due to? Examples?

-Often associated w/ iron deficient anemia in the developed world.

Examples: Unrecognized loss from a bleeding gastric ulcer or heavy menstrual flow


What are characteristic of Anemia of Chronic Disease?

-Not clear w/ many chronic diseases that produce anemia as to why they do.
-Anemia they produce is NORMOCYTIC
**Most understood is Renal failure


Why does chronic renal failure cause anemia?

Due to the Erythropoietin made in the Kidney being LOW


What some characteristics of Acquired Autoimmune Hemolytic Anemia (AIHA)?

-Red cells are destroyed faster than normal (reduced life span)
-Bone marrow can't keep up w. the rate of destruction
-RBCs may live for only 20 days (instead of 120)
-RBC breakdown is increased as a response to the anemia and so will the production as a response to the anemia.

****IF the bone marrow can increase erythropoiesis sufficiently, the patient may not even become anemic


How can Hemolytic anemias be obtained?

1) Acquired
2) Inherited


What is Acquired Autoimmune Hemolytic Anemia (AIHA)?

An autoimmune response directed against the RBCs own antigens


What are Inherited Anemias ?

-Hereditary anemias are ALL HEMOLYTIC in nature
-May be classified by the pathological process causing decreased RBC lifespan.


What can the Inherited Anemias be grouped as ?

1) Red cell membrane (e.g, hereditary Spherocytosis, hereditary elliptocytosis)
2) Red cell enzymes (e.g., G6PD deficiency)
3) Hemoglobin molecules (e.g sickle cell disease, thalassemias)


What is Hereditary Spherocytosis caused by?

A variety of molecular defects in the genes that code for spectrin (alpha & beta), ankyrin, band 3 protein, protein 4.2 & other erythrocyte membrane proteins


What is the most helpful red cell index for Hereditary Spherocytosis?

The mean cell hemoglobin concentration (MCHC)
-IT is routinely elevated, reflecting membrane loss & red cell dehydration.
-An elevated red cell distribution width (RDW) also favors the diagnosis of HS.


What is Elliptocytosis?

A red cell membrane hereditary disorder caused by a variety of molecular defects in the same genes affected by hereditary Spherocytosis.

***The end result is the same--> The defects destabilize the cytoskeletal scaffolding of cells & the cells go poof!


What is the Osmotic Fragility Test?

-Used to detect spherocytosis and elliptocytosis (red cell membrane disorders).
-The degree of red cell lysis caused by incubating red cells in NaCL solutions of carious strengthens is measured


What are the curves generated for in the Osmotic Fragility Test?

Generated for normal and test samples and the mean corpuscular fragility (MCF) is calculated
-This is the NaCI concentration at which 50% lysis occurs


What happens In the Osmotic Fragility Test, normal red cells remain intact until the NaCL concentration reaches 50% ?

Lysis increases as the solution becomes more hypotonic


What happens if Spherocytes & Elliptocytes, have a lower surface to volume ratio?

They lyse more readily


What is the red cell enzyme disorder G6PD Deficiency?

***Most common enzymatic disorder or RBCs in humans
-Glucose 6-Phosphate dehydrogenase (G6PD) deficiency, an X-linked disorder (so males affected)

(Affects 400 million people) worldwide


What is the ONLY source of NADPH in red cells and fully functioning pathway that is essential to keep the red cells intact?

in the Pentose phosphate pathway


What does NADPH do for RBCs?

Maintains glutathione in its reduced form


What are the particular characteristics seen in G6PD Deficiency?

In addition to the hemolytic anemia
1) Heniz bodies
2) Bite cells


What are Heinz Bodies?

Seen with particular stains where hemoglobin has been rendered unstable due to oxidant damage; the Heinz body is basically a clusteer or denatured hemoglobin


What are Bite Cells?

thought to result from the processing of cells through the SPLEEN and removal of Heinz bodies.
(Spleen takes a bite :)


What is sickle cell disease?

A hemoglobin disorder that results from a point mutation in the Beta Globin gene, resulting in a change of amino acid number 6


What is Hemoglobin S (HbS) ?

The resultant hemoglobin produced by the faulty gene 6 (Glu-->Val) in sickle cell is HbS


What are some characteristic of Sickle Cell?

RBCs containing the sickle cell hemoglobin elongate under conditions of reduced oxygenation, and form characteristic sickle cell shaped cells.


What does the sickle cell shape cause?


-Since the RBCs do not flow well thru small vessels and more adherent than normal RBCs to vascular occlusion and lead to the crises.


Where is sickle cell mostly seen?

Widespread throughout Africa, Middle East, and parts of India and the Mediterranean


What is Thalassemias?

This groups of disorders arises as a result of diminished or absent production of one or more of the Globin chains.


What is the net result of Thalassemias?

Unbalanced Globin chain production. Globin chains in excess precipitate w/ Red cells, leading to chronic hemolysis


Where do Thalassemias occur?

In parts of Africa, the Mediterranean, Middle East, India and Asia


What is Thalassemia's classified as?

After the gene affected

-Example: alpha thalassemia, the alpha globin gene is altered in such a way that either alpha globin synthesis is reduced or abolished from RBCs.


What is the consequence of impaired production of Globin chains lead to?



What are Leukemias?

Is caused because the White Blood Cells are in enormous numbers in the peripheral blood of patients w/ leukemia at the time of diagnosis.


In Leukemias, cancer occurs with__________?

the white blood cell PRECURSORS.


Leukeimas are divided into what?



What is Acute Leukemia?

-Tends to present more dramatically
-Must be treated EARLY or DEATH will occur within a short period of time


What is Chronic Leukemia?

-More indolent (slow growing)
-May not require therapy for years
-Discovered by chance


What does Chronic and Acute Lekiemas have in common?

1) There is a progressive accumulation of abnormal WBCs in the bone marrow and other organs, which will spill out into the peripheral blood.
2) Progressive bone marrow failure w/ a reduction in other normal cell types
*****Patients tend to also have a REDUCED # of RBCs & Megakaryocytes


What are some characteristics of Acute Myeloid Leukemia (Acute Myelogenous Leukemia) AML ?

Cancer of the myeloid line of stem cells, characterized by the rapid growth of abnormal WBCs that accumulate in the bone marrow & interfere w/ the production of normal blood cells.


What is the most common acute leukemia?

Acute Myeloid Leukemia (AML) is the most common acute leukemia affecting adults, and its incidence increases w/ age


What are some symptoms of Acute Myeloid Leukemia (AML) ?

-Tiredness, shortness of breath and anemia--> due to reduced RBCs
-Increased susceptibility to infections--> due to reduced WBCs
-Bruising & bleeding -->due to reduction in platelets
-Bone pain-->accumulation of leukemic cells in ling bones
-Respiratory & neurological symptoms-->due to large number of WBCs in the blood causing hyper-viscosity & "sludging" of blood


What are some characteristics of Acute Lymphoblastic Leukemia?(ALL)

Cancer of the lymphoid line of stem cells, characterized by the rapid growth of abnormal WBCs that accumulate in the bone marrow & interfere with the production of normal blood cells.


What is the most common acute Leukemias in childhood?

Acute Lymphoblastic Leukenmia (ALL) most common with a peak incidence at 2-5 years of age

***symptoms similar to AML


What is Chronic Myeloid Leukemia (Chronic Myelogenous Leukemia) CML?

-Cancer of the myeloid line of stem cells
-Presence of the "Philadelphia chromosome"--> The exact chromosomal defect is translocation, in which parts of 2 chromosomes, 9 & 22 swap places.


With what persons does CML (Chronic Myeloid Leukemia) most commonly occur ?

More common in adults between 40-60 years of age


What does the mutation lead to in CML?

To transcription of proteins w/ high tyrosine kinase activity


What are the 3 main phase of CML?

1) Chronic phase
2) Accelerated Phase
3) Blast Crisis


What is the Chronic Phase in CML?

-85% of patients w/ CML are in chronic phase at the time of diagnosis
-During this phase, patients are usually asymptomatic or have mild symptoms of fatigue, left side pain, joint & hip pain, or abdominal fullness.
-Duration is variable (average = 5 years) & depends on how early diagnosis is and therapies.


What is the Accelerated Phase in CML?

Severity of symptoms increase; labs reflect greater shifts in numbers; therapies used in chronic phase become less effective


What is the Blast Crisis phase in CML?

Resembles an acute leukemia, w/ rapid progression & short survival


What is Chronic Lymphoblastic(Lymphocytic) Leukemia? (CLL)

-Cancer of the lymphoid line of stem cells
-Most COMMON ADULT Leukemia in Western societies w/ a peak incidence in patents between 60-80 & male:female ratio of 2:1


What are some characteristics of Chronic Lymphoblastic(Lymphocytic) Leukemia? (CLL) ?

Slow-growing disorder characterized by progressive accumulation of cancerous cells in the bone marrow, spleen, liver, and lymph nodes


What is the difference between Leukemias & Lymphomas?

-A cancer that occurs in white blood cell precursors & hence, in the bone marrow.
-The excessively produced WBCs then disseminate int he peripheral blood
-Lymphomas are SOLID tumor masses and can originate within many different lymphoid tissues, mainly the lymph nodes (MOST COMMON), spleen, liver, GI tract, thymus or bone marrow


Who published the first description of lymphomas ?

Thomas Hodgkin published it in 1832, specifically of the form names after him Hodgkin's lymphoma (disease)

-Note: since his time many lymphomas have been characterized


What is Hodgkin's Lymphomas?

Cause unknown; annual incidence 2-3 per 100,000

***Reed-Sternberg cells("POPCORN CELLS") are characteristically seen when lymph nodes are biopsied; these are B lymphocytes that have lost the ability to produce antibodies


What are the symptoms of Hodgkin's d lymphomas?

1) Itchy skin
2) night sweats
3) unexplained weight loss
4) Enlarged lymph nodes
5) Splenomegaly
6) Hepatomegaly


What is Non-Hodgkin's Lymphomas (NHL)

Are a group of lymphomas that include everything but Hodgkin's lymphoma.

-Cause unknown ; about 66,000 new cases diagnosed per year
-Similar symptoms to Hodgkin's Lymphomas