Exam 4 heme lecture

Anemia sources of error

Hypervolemia= overhydration leads to HCT and HGB falsely decreased

Hypovolemia= Dehydration leads to HCT and HGB falsely elevated

Acute blood loss= Plasma and RBCs are lost equally so may appear normal
- plasma is replaced first causing HGB and HCT to be decreased while recovering

Bohr Effect

Aerobic glycolysis causes lactic acid buildup making HGB O2 affinity decrease due to acidosis
- causes increased O2 in tissues

Factors shifting O2-HGB Disassociation curve to the right

Bohr effect, decreased pH, increased temp, increased CO2, increased 2,3 BPG

Normal RBC kinetics equation

M= P * S

M= amount of mass of RBCs (mL)
P= number of RBCs produced (mL/day)
S= Length of RBC survival (days)

Moderate anemia

HGB is 7-10 g/dL

Severe anemia

HGB is <7 g/dL HGB

Functional anemia

by mechanism, either less/ destruction of RBCs or impaired production

Ineffective erythropoiesis

Defective RBC precursors (maturation, survival, or proliferative defect) - B12/folate deficiency, thalassemia, etc

Morphological anemia

Based on indices and reticulocyte count

Insufficient Erythropoesis

decreased number of RBC precursors causing decreased production
- iron deficiency, EPO deficiency, autoimmune, or BM suppression (leukemia)

Normal adult relative reticulocyte

0.5 - 2.5%

Normal absolute reticulocyte count

20-115 * 10^3 / uL

Corrected Reticulocyte count

(patient HCT/ Normal HCT) * % reticulocytes

normal= 45% male or 42% females

Reticulocyte production index (RPI)

corrected reticulocyte count %/ expected maturation time

>3 = hemolysis
>2= effective erythropoiesis
<2= ineffective erythropoiesis

Functional anemia classifications

Proliferative defects= BM damage, tissue infiltration, HSC issues

Maturation defects= nuclear or cytoplasmic defects

Survival defects= hemolysis or hemorrhage

Normocytic, normochromic

if increased reticulocytes then the body is recovering from something: acute hemorrhage, hemolytic anemia, etc

if decreased or normal reticulocyte count then body is not responding properly and greater problem: Renal insufficency or failure, BM cancer, combined anemias, etc

Microcytic

If decreased ferritin then iron deficency

if increased or normal ferritin then thalassemia, sideroblastic anemia, or anemia of chronic disease

Thalassemia

inherited blood disorder with decreased HGB

Macrocytic

If increased reticulocytes then recovery in progress: recovering from hemorrhage or hemolysis

If decreased or normal reticulocytes and megaloblastic (hyper-segmented neutrophils) then B12/ folate deficiency

If decreased or normal reticulocytes and not megaloblastic then more than just temporary DNA synthesis impairment and could be liver disease or myelodysplastic anemia

Defects in globin

quality= Thalassemia

Structure= hemoglobinopathy

Primary iron containing cells

enterocytes (intestinal absorption cells)

Ferric iron

Fe3+

- from plants

Ferrous iron

Fe2+

- from red meat

Iron absorption pathway

1. Fe3+ turned to Fe2+ by Dcyt B
2. Fe2+ enters enterocyte through DMT1
3. Some Fe2+ stored in ferritin
4. Fe2+ leaves cell and enters blood through ferroportin
5. Hephaestin turns Fe 2+ back into Fe3+ to board transferrin

Transferrin (TIBC) testing

Amount of transferrin in blood
- if Fe is low in storage and serum then TIBC will go up as the body tries to compensate

Ferritin testing

proportional to the amount of storage Fe
- if ferritin decreases then thats the 1st indicator of Iron deficiency anemia

Serum transferrin receptor (sTFR) testing

inversely proportional to the amount of Fe in the body
- increases when body lacks Fe

Zinc Protoporphyrin

-Zn substituted for iron within Hgb when inadequate iron available; rise during iron deficiency

Hepcidin

regulatory hormone made by liver to down regulate Fe absorption

% saturation of transferrin

serum iron/TIBC x 100

-% of bus thats full

Unsaturated Iron Binding Capacity (UIBC)

TIBC - Serum iron

- number of empty seats

iron deficiency anemia iron panel

Low Iron, ferritin, and % transferrin saturation

High TIBC and UIBC

Iron depleted so stores and % of bound transferrin also decreased; UIBC and TIBC increased since binding affinity increased as compensation and # of empty seats increased without passengers

Hemochromatosis (excess iron)

High Iron, ferritin, and % transferrin saturation

Low TIBC and UIBC

Overload of Fe causes stores and saturation to be high, body down regulates TIBC to calm down and UIBC is low since not a lot of empty seats

Anemia of Chronic illness iron panel

Low iron, TIBC, and % transferrin saturation

Normal/Low UIBC

Normal/High ferritin

Fe is hidden from threat so TIBC is also down regulated to hide it, % saturation decreased since little Fe in circulation; TIBC and UIBC low since don't want people riding the bus and not many people are out to anywho

Sideroblastic anemia iron panel

High ferritin and % Transferrin saturation

Normal/ High Iron

Normal/Low TIBC and UIBC

Fe is not properly utilized so the stores and % are increased due to inability to use, TIBBC and UIBC either low or normal since body already has a lot of iron

Ferritin

short term Fe storage in liver

- gransules of sideroblast

Hemosiderin

long-term Fe storage in lover

How Fe goes into the cell:

1. transferrin brings Fe to the TfR1
2. membrane breaks off and transferrin goes inside cell through newly formed endosome
3. Acidic vessicle fuses with endosome causing the Fe to release because of acidity
4. iron enters cytoplasm through DMT1 or is stored in ferritin
5. Complex goes to cell surface and proteins are recycled and used again

DMT1

transports Fe from endosome to cytoplasm

DCyt- B

reduces Fe 3+ to Fe 2+

Ferroportin/ Ceruplasmin

In gut: Ferropoportins exports cellular Fe from enterocytes, macrophages, and hepatocytes

Outside gut: Ceruloplasmin exports cellular Fe from macrophages
- requires copper

HFE

regulates hepcidin expression

Hemojuvelin

Regulates hepcidin production

HIF- 2

Regulates EPO, DMT, DCytB, transferrin, and TfR1

Iron depletion stages

1. "Iron depletion stage"- decreased Ferritin
2. "Iron dependent erythropoiesis stage" - decreased ferritin and Serum Fe, increased TIBC
3. "Iron deficiency anemia" - decreased ferritin, Hgb, and Serum Fe, increased TIBC

Functional classifications of anemia

1.) Proliferation defects
2.) Maturation defects
3.) Survival defects

Anemia of chronic disease

Microcytic anemia with ↓ serum iron, ↓ total iron-binding capacity (TIBC), and normal or ↑ ferritin, ↓ EPO, ↑ M:E ratio

Sideroblastic anemia

Defect in 1st enzyme of heme synthesis: ALA synthesis, causing iron ring to form, can be inherited but typically acquired through lead poisoning, alcoholism, and leukemia

Sideroblastic anemia morphology

Microcytic/ hypochromic, ↑ total iron, ↑ ferritin, ↑ %transferrin saturation, normal UIBC and TIBC

lead poisoning sideroblastic anemia

lead accumulation in mitochondria causes issues with delta ALA dehydrogenase, causing heme synthesis impairment

Alcoholic sideroblastic anemia

Inhibits: pyridoxal phosphate, urophyrinogen decarboxylase, and ferrocheletase

Enhances: Delta ALAS

- can be macrocytic (from B12/folate deficency) or microcytic (from Fe deficency)

Sideroblastic anemia treatment

pyridoxine (B6, cofactor for ALA synthase) and Folic acid

What is hemochromatosis? how is it treated?

Iron overload (about 10x normal) that can cause tissue damage.
- low TIBC and UIBC
Treated with phlebotomy and chelation (causes Fe to go down through urine)

What are common symptoms of hemochromatosis?

Fatigue, joint pain, impotence, cardiac disease.

What genetic mutations are associated with hemochromatosis?

Transferritin receptor 2 deficiency and ferroportin deficiency
- mutations in hemojuvelin, hepcidin, and DMT1

What is a potential cause of acquired hemochromatosis?

ineffective erythropoiesis anemia, chronic transfusions, liver disease

Aplastic anemia

Pancytopenia, hypocellular BM - mature cells look and function normally just low numbers, normo or macrocytic, relative lymphocytosis and neutropenia

-acquired or inherited
- acquired can be idiopathic

Fanconi Anemia

Inherited form of aplastic anemia, autosomal recessive trait causes chromosomal defect
- impaired tissue development, retardation, weird thumbs, short stature

Other forms of inherited AA

Dyskeratosis Congenita and Congenital Amegakaryocytic thrombocytopenia

Myelophthisic anemia

Marrow infiltration by fibrotic, neoplastic, or granulomatous cells (can be cancer)
- takes up BM space, causing pancytopenia, increase immature cells in blood, and bizarre platelets

Congenital Dyserythropoietic Anemia (CDA)

abnormal and ineffective erythropoiesis characterized by bi-nucleated RBC precursors
bone marrow is normocellular or hypercellular, but peripheral blood is pancytopenic with basophilic stippling, poilk, and anisocytosis

Diamon Blackfan Anemia

Rare inheritted RBC aplasia due to defect in erythroid progenitor
-in very young children, causes long thumbs
- ↑ EPO levels, BM normocellular with erythroid hypoplasia
-Macrocytic, normochromic, reticulocytopenia
-Treated with RBC transfussions and steroids

Pure Red Cell Aplasia

Targets erythropoesis; normocytic, normochromic anemia
-corrected retic= <1%

-inheritted or acquired through Igs to EPO or T-cell mediated inhibitted erythropoesis

Transient Erythroblastopenia of Childhood (TEC)

transient severe anemia in young children triggered by viral infection
- Ig or T cell mediated repression of RBC precursors
-Not related to anemia

Anemia of Chronic Kidney disease (ACKD)

Decreased erythropoetin, decreased RBC lifespan, Iron and folate deficiency
-Macro or microcytic, schistocytes

Endocrine Abnormalities Causing Hypoproliferative disorders

Decreased erythropoesis and decreased EPO
- normocytic, normochromic
-Erythroid hypoproliferation due to unstable hormone levels