Normocytic 

1. Loss of RBC's (hemmorrhage)
2. Increased RBC destruction (hemolytic anemia
3. decreased RBC production

This anemia has a deficiency in spectrin (alpha or beta) on cytoskeltal proteins on the inside of the RBC lipd cell surface,  RBC membrane is less flexible and breaks easy, Splenomegaly

Jaundice

Hereditary sperocytosis

Extravascular Hemolysis

Normocytic, with defective RBC's

Anemia with spherocytes w/o central zone of pallor, Howell-Jolly bodies, increased retics

Treat: remove spleen

Extravascular Hemolysis

Hereditary sperocytosis

Normocytic

Genetic defect deficiency--enzyme required for glutathione (antioxidant) production.

RBC's damaged from oxidative stress

Damaged cells are destroyed in spleen

Glucose-6-phosphate dehydrogenase deficiency

Normocytic

Extravascular hemolysis

Blood smear shows spherical bodies (poikilocytosis and anisocytosis

Heinz bodies and bite cells

G-6-PD anemia

Normocytic

extravascular hemolosis

Heridary mutation, transforms Hgb A to Hgb S

proportion of hemoglobin is abnormal

Vaso occlusive crisis from low oxygen and pain, occurs in bones, liver, lung, brain and spleen

-short red cell survival:

anemia, jaundice and gallstones

Sickle cell anemia

normocytic

extravascular hemolysis

Failure of suppression of myeloid stem cells

1. Idiopathic: immune mediated suppression (65-80%)

attack by T-cells on bone marrow stem cells

2. Acquired (20-30%), drugs, chemicals, radiation

Aplastic anemia

normocytic

decreased RBC production

pancytopenia: anemia, neutropenia, thrombocytopenia

No spleen enlargment

bone marrow hypocellular

petechia and purpura

Aplastic anemia

normocytic

decreased RBC production

production of interferon and TNF alpha that decreases erythropoietin production, so RBC production and inhibits release of iron from storage pool

Mild anemia

low serum iron reduced TIBC

high serum ferritin

low erythropoietin

Anemia of Chronic Disease

normocytic

decreased RBD production

Point mutation of B-globin genes

Reduced synthesis of B globins to total absence

If fewer B-chanins, then fewer molecules of Hgb, then RBC have low intracellular Hgb (microcytic, hypochromic)

Free alpha-globin chains

apoptosis of defective RBC precursor in marrow

  beta thalassemias

Microcytic

Blood smear: anisocytosis and poikilocytosis,

increased reticulocytes, normoblasts

splenomeg, hepatomeg, osteoporosis

beta thalassemias

Microcytic

Common med descent

reduced synthesis of alpha globins to total absence of alpha globin chains

blood smear:  increased retics, normoblasts

Alpha thalassemia

microcytic

Not enough Fe to make heme

Most common anemia world wide

low dietary intake, impaired absorption, increased requirement from chronic blood loss

Fe deficiency Anemia

microcytic

RBC's are pale, smaller than normal, abnormal size and shape, decreased retics, deficiency of iron interrupts heme synthesis

low ferritin

Fe deficiency Anemia

microcytic

General Vitamin B12 deficiency

macrocytic

B12 needed for brain and blood formation

Autoimmune destruction of gastric parietal cells

Possible antibodies to parietal cell membrane proteins
o Possible antibodies to intrinsic factor
o Possible antibodies to intrinsic factor/Vit B12 complex
o Inflammatory response to immune process
o Results in:
o Parietal cell damage and loss
o Loss of gastric acid and intrinsic factor
o No B12 extraction or absorption

Pernicious anemia: Vitamin B12 deficiency that is autoimmune in origin

Macrocytic

Anemia
o Low serum B12 levels. Positive Schilling test
o Bone marrow biopsy -> Large ovoid megaloblasts

Blood smear -> Few reticulocytes, Howell-Jolly bodies,
o GI cytology -> parietal cell atrophy; glossitis
o Neuro: numbness, tingling, loss of balance and coordination, dementia (Vit B12 also needed for neuronal development)
o Immunology: Anti-intrinsic factor antibodies (~60% positive), Anti-parietal cell antibodies (~90% positive)
 

Pernicious anemia: vitamin B12 deficiency that is autoimmne,

macrocytic

impaired DNA synthesis and megaloblastic transformation

smear: few retics, large ovoid megoblasts

DECREASED FOLIC ACID anemia

macrocytic

Types of White cell Disorders

decreased WBC production, decreased activity

aplastic anemia, drugs

or:

Decreased survival
When infectious processes exhaust supply
Immune destruction
Splenic destruction

Too Few (agranulocytosis, neutropenia, lymphopenia)

White cell disorder

Pathogenesis of pernicious anemia that results in :

Abnormalities of proliferating cells in body, megaloblastic anemia, neurologic disease

cell-mediated, type IV autohypersensitivity

cytotoxic T cell: damages parietal cell in stomach

Antoantibodies

Anti-H-K AT pase

All above damages stomach

Chronic gastritis:  loss of parietal cells, decreased intrinsic factor, and HCl, lymphocytes and plasma cells infiltrate gut.:

risk of cancer, loss of intrinsic factor, failure of B12 absorption:

 Etiology: increased WBC's
a. Increased activity
b. Release from bone marrow
c. Demargination from vessel walls
d. Reactive Inflammatory States

Lymphocytosis:  B cells become activated

                       Secrete antibodies including ones for mono

                      Body is activated to make antibodies against EBV

Elevated WBC (15-150,000/mm3) (more red marrow) from malignant cells
o Neutropenia (because of stem cell suppression)  infections, fever, tachycardia (increased susceptability to infection)
o Anemia (because of stem cell suppression) Also secondary to TNF alpha and inferon from producing cells which decrease erythropoietin production
o Thrombocytopenia  (because of stem cell suppression) bleeding
o Bone pain from pressure in marrow
o Splenomegaly, hepatomegaly, lymphadenopathy
o Constitutional symptoms (B symptoms) – fatigue, fever, nightsweats and weight loss(remember action of IL-1 and TNF alpha)

Lymphomas

Reed-Sternberg giant cells

painless enlarged nodes

Originates from a B cell clone that is a malignant neoplasm of terminally differentiated plasma cell.

Occurs most commonly in adults between 50 and 60 years old, males and in the black population

Farmers, petrochemical workers, cosmetologists, radiation, Herpes virus

Myeloma plasma cells have adhesion molucules in cell surface.

Fibroblasts and macrophages in marrow produce IL-6 that proliferates the neoplastic plasma cells

lymph nodes and extranodal sites

Excessive numbers of IgG or A that don't work

Also called Serum M protein (mutated)

BENCE JONES proteins

Bone pain from punched out bone
 Hypercalcemia and pathologic fractures
 Increased infection
 Pancytopenia
 Peripheral blood smear contains myeloma cells
 Renal insufficiency secondary to damage from Bence-Jones proteins

Pre-B, T cell neoplasm

bone marrow failure

overproduction of undiff B lymphoblasts in marrow. and spill out

Acute lymphoblastic leukemia

80% B-cell origin: express ALL antigen (B cell restricted antigen)

accumulation of immature leukemics blasts due to block in differentiation

Neoplasm of mature B cells
o Unable to differentiate into plasma cells
o Progressive accumulation
b. Epidemiology:
o Most common leukemia of 50-60 y/o adults in the Western world
o Males>females

-can't make anitbodies and can't mature

SMUDGE CELLS

Develops slowly and is asymptomatic for a long time before discovery
o Blood smear
o Clonal elevation in WBC (up to 200,000)
o Smudge cells small, round lymphocytes, fragile and easily disrupted - (PPT 20)
o Hypogammaglobulinemia and increased susceptibility to bacterial infections
o Anemia, Thrombocytopenia
o Lymphadenopathy/splenomegaly in 50% to 60% of cases

Marrow failure caused by replacement of normal cells by leukemic blasts

Neoplasm of myeloid stem cells
o Abnormal proliferation of myeloid precursor cells
o Arrested cellular differentiation

Etiology -
o Toxins, exposure to radiation and chemotherapy
o Chromosomal abnormalities
o Myelodysplastic syndrome

Neoplasm involving immature granulocytes but more differentiated/mature cells

Adults age 25 to 60 years, with peak incidence in the thirties and forties
c. Etiology
o Radiation, chemical exposure, others that cause the acquired genetic alteration
o 95% of cases due to a 9,22 translocation of (bcr-abl) chromosome – Philadelphia chromosome

Hallmark of CML is the Philadelphia chromosome.
o Blood Smear – Marked leukocytosis > abnormal granulocytes\

o Bone Marrow
o Marked increase in neoplastic granulocytic precursors 
 Splenomegaly
 Increased hematopoiesis -/Extramedullary hematopoiesis
 Three stages: Chronic/stable, accelerated, acute/blast crisis

Platelet count of <100,000

normal PT, PTT

How do platelet membranes help in coagulation?

Three ways

Phospholipis ensure clotting begins and stays put

Expression of receptors (P selectin) in coag cascade

Metabolizes phospholipid AA to Thromboxane A2 (aggregation)

Activated by exposure to collagen, PAF, thrombin and vWF and others:

Adhesion and shape change

Secretion of granules

Aggregation and stabilization (thromboxane A2, ADP, fibrinogen.

ASA blocks thromboxane A2 formation, thus blocks clot)

Shows extrinsic clotting system:

time plasma takes to clot with thromboplastin and Calcium present

test: Shows intrinsic clotting system:

common clotting paths

Secretes endothelin:  vasoconstriction

Synthesize tissue thromboplastic (F 3): activates extrinsic clotting cascade

Produces von Willebrand Factor: for platelet binding to collagen and other surfaces.

What are these properties of?

Antiplatelet: 
    Endothelial prostacyclin (PGI2):inhibis plat aggregatn
    Secretes NO  (vasodilate)
Anticoagulant
    Heparin like molecules
    Thrombomodulin – binds thrombin
Fibrinolytic
    Synthesize t-PA – promoting fibrinolytic activity    to       clear fibrin deposits from endothelial surfaces
C. Others
Leukocytes -> contribute to inflammatory responses

Thrombolytic System/fibrinolytic system

Inhibitors to Coagulation

PLASMIN breaks down fibrin

Plasmin stimulated by Factor XIIa and t-PA

  Antithrombin III
i. Binds to Heparin-like molecules on endothelial cells
ii. Inhibits activity of thrombin, IXa, Xa, XIa, XIIa
b. Protein C
i. Works with Protein S to inactivate Factor Va and VIIIa
c. Protein S
i. Works with Protein C to inactivate Factor Va and VIIIa
d. Endothelial released substances (see above)

Abnormal Thrombosis

Platelet Errors in Numbers

Clotting Factor Deficiency

Endothelial injury

Alterations in normal flow

Hypercoagulability

platelet error in number: excess clotting

Occur in recovery from iron deficiency anemia, secondary to inflammatory response and myeloproliferative disorders.
 Essential thrombocythemia (unknown etiology)

Risk for bleeding, due to:

decreased prod of platelets

increased platelet destruction

infection/radiation/chemo

inherited (vWF)

Heparin binds to platelet factor 4 (circulating protein)

IgG antibodies bind the heparin/PF4 complex and activates the platelet to aggregate or clot

Prolonged clotting time

Low platelet count
   o In drug induced thrombocytopenia, thrombocytopenia usually occurs 5 to 7 days after exposure to the drug
o Ecchymoses – bruising (from escape of blood into the subcutaneous tissues
o Petechiae – tiny red spots on the skin ( from burst capillaries)
o Epitaxis
o Prolonged bleeding time when platelet counts fall below 90,000 PT, PTT is normal
o Spontaneous bleeding occurs then levels fall below 20,000.
o In heparin induced thrombocytopenia - paradoxical clotting

below 90,000

Spontaneous bleeding below 20,000

Acquired is liver disease and decreased Vit K

Hereditary is hemophilias and von Willebrand

X-linked recessive disorder Type A and B

Type A is Factor VIII deficiency

Type B is Factor IX def

von Willebrand Disease (Autosomal dominant

Subendothelial vWF acts as a bridge between platelets and subendothelial collagen
 Circulating vWF carries and stabilizes Factor VIII
 In von Willebrand disease, vWF is reduced or defective

a. Cells range from well differentiated to undifferentiated (anaplasia)
 Pleomorphic - Cells and nuclei display variation in size and shape from their neighbors
 Lose normal polarity
b. Higher rate of replication
c. Do not respond to normal controls
d. Evasion of immune system
e. Loss of cell-to-cell adhesion. Exhibit anchorage independence which allows them to metastasize
f. Hyper- or hypo-functional , or odd functions
g. Invasive
 Infiltrate and destroy surrounding tissue by securing and enhancing proteolytic enzymes
 Poorly demarcated from surrounding tissue
 A well defined cleavage plane is lacking
h. Metastatic (Figure 6-26 p.201, K PPT 29) (tumor implants discontinuous with the primary tumor) (30% of cancer presents with metastasis)
i. Induce vascular in growth
 Neovascular growth

Mutations of encoding growth factors

Mutations of encoding growth factor receptors

Mutations that mimic funcion of normal cytoplasmic signal proteins

Mutations of encoding nuclear transcription factors

Mutations dysregulating cyclins and cyclin dependidnt kinases

Over expresion of growth factor

melanoma, stomach CA

Mutant receptors that deliver continuous mitogenic signals to the cell is continually activated

overexpression of normal growth factors

allows for continuous cell transformation (favors growth and proliferation of malignant cells

p53 is most common mutated gene

When coupled with activation of oncogene: cells don't have time to repair DNA damage, promotes growth of undiff cells, tumor growth to hypoxia

Most commonly mutated gene

Functions: stimulates DNA repair pathways (temporary cell cycle arrest), triggers apoptosis, permanent cell cycle arrest.

allows cell proliferation

EXAMPLE: Bcl-2 is a large family of pro-apop and anti-apop proteins located in the mitrochondial membrane.

When inhibited, allows cell proliferation