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Hematosis - 2024 > Week 2 > Flashcards

Week 2 Flashcards

1
Q

what is hemoglobin production dependent on and when is it made

A

-iron supply and delivery
-protoporphyrin synthesis (heme is composed of Protoporphyrin IX and 1 central Ferrous iron)
-globin and heme synthesis
-heme allows for reversible oxygen binding by hemoglobin and Globin surrounds and protects the heme molecule

-65% of hemoglobin is synthesized in the nucleated stages and the rest occurs in Retics
-mature RBCs cannot make hemoglobin because they do not have nuclear parts or organelles like ribosome to allow them to make proteins

1 heme to 4 O2

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2
Q

what is hemoglobin

A

-protein composed of long amino acid chains with different AA sequences which combine to house the heme molecule

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3
Q

how are globin chain synthesized

A

-there are different types of globin chains with different AA sequences
-occur in combinations of two - 2 alpha and 2 others

-globin chain production occurs in RBC precursors via gene transcription and translation into polypeptide chains on ribosomes in RBC cytoplasm where molecule assembly takes place

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4
Q

how is Heme made

A

-ingest iron is absorbed in the GI tract as Ferrous iron (Fe2+)
-iron is then transported to BM as transferrin and reoxidized to Ferric ion (Fe3+)
-RBC precursors have receptors to Transferrin which when bound are taken into the erythroblast by endocytosis and Ferric ions are released into the cytoplasm
-Iron will then go into the mitochondria and be reduced to ferrous state and taken into Protoporphyrin IX to make heme
-Heme then leaves the mitochondria to join the globin chains

Dimers of 1 alpha heme + 1 non alpha heme = tetramer

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5
Q

what are the energetics involved with hemoglobin

A
  • energy is NOT required to exchange O2/CO2 its passive
    -Energy IS REQUIRED for RBC metabolic processes
  • RBCs cant produce enzymes - anucleate
    -ATP production in RBC relies on glucose from plasma and enzyme pathways but once the enzymes run out, the cell will lose membrane function
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6
Q

what are the 4 metabolic pathways important for hemoglobin energetics

A

Embden-Meyerhof Pathway
-anaerobic glycolysis
-ATP production

Hexose Monophosphate Shunt /pentose shunt
-oxidative glycolysis - producing NADPH and GSH protecting RBC from oxidative injury

Methemoglobin Reductase Pathway
-maintains iron in reduced functional state

Leubering - Rapoport Shunt
-maintains 2,3 BPG production as per O2 demands from tissues

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7
Q

What is the function of hemoglobin

A

-protein in mature RBCs
-helps with gas exchange ; carries O2 from lungs to tissues and return CO2 from tissue to lungs
-helps with acid base balance; acts as pH buffer by binding and releasing hydrogen ions
-transports nitric oxide which is a vascular patency regulator
-dont undergo simultaneous oxygenation and de oxygenation
-deoxygenated hgb has little affinity for oxygen
-the more O2 binds the higher the HGB avidity

in the lungs HGB binds to O2- high pH
-needs high O2 affinity meaning Hgb will not give up the O2

Hgb transports and releases O2 to tissues - low pH
-needs low O2 affinity

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8
Q

what is HGB affinity

A
  • relationship seen on oxygen dissociation curve where partial pressure of O2 is on the x axis and Oxygen saturation is on the y axis
    -27mm Hg results in 50% O2 saturation
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9
Q

what condition cause a left vs right shift on the O2 dissociation curve

A

Left shift - occurs as PP less than 27 mm Hg causing increased O2 affinity of Hgb meaning less O2 for tissues
-Lowered body temp
-Decreased 2,3-BPG
-Multiple transfusions
-Increased blood pH (Alkalosis)
-Presence of other Hgb variants with high affinity for oxygen

RIGHT SHIFT- occurs at pp greater than 27mm Hg meaning decreased O2 affinity of Hgb so more O2 is available to the tissues
-Increased body temp
-Increased 2,3-BPG
-Decreased blood pH (Acidosis)
-Presence of other Hgb variants with low affinity for oxygen

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10
Q

how does the Concentration of 2,3 - bisphosphoglycerate (2,3-BPG) affect oxygen affinity:

A

TENSE or deoxygenated Hgb with 1 2,3 BPG molecule
-lower affinity of O2- does not transport it
-tight binding structure with 2,3 BPG in the middle
-O2 released from Hgb to tissues

RELAXED or oxygenated Hgb -2,3-BPG is released:
-Hgb binds O2 by pulling chains tight ; the 2,3 BPG is released
-high affinity for O2- can transport it -oxyhaemoglobin
-relaxed structure

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11
Q

what are the Physiological Adaptations in Anemia

A

-decreased Hgb therefore lower O2 delivery to tissues
-increase EPO production and secretion by kidneys
-RBC precursor stimulation in BM
-increase RBC in circulation

-tissue hypoxia triggers 2,3 BPG increase shifting curve to right decrease O2 affinity of Hgb allowing increased O2 delivery to tissues

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12
Q

what role does 2,3 - BPG play in IDA

A

-IDA is low iron
-2,3 BPG needs iron for synthesis
-therefore when 2,3 BPG concentration is reduced Hgb binds O2 and its release into tissues is decreased manifesting as hypoxia

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13
Q

what are dyshemoglobins - two types

A
  • dysfunctional hemoglobin’s that dont transport O2

1-Variant hemoglobin - genetic changes in globin genes - structurally abnormal Hgb
Hgb S in sickle cell
Decrease in globin chains that cause thalassemia

2-Dyshemoglobins - hgb changed by drugs or chemical
Methemoglobin
Sulfhemoglobin
Carboxyhemoglobin

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14
Q

What is Methemoglobin -Dyshemoglobins

A

-contains Ferric Fe 3+
-O2 cant bind to Fe3, however when the fe3 is bound to heme it increases O2 affinity by changing its tetramer shape causing left shift resulting in a decrease of O2 delivery to tissues
-Methemoglobin levels are <1% of Hgb and are measured via CO oximetry

can be acquired - after drug/chemical exposure

can be congenital - globin chain mutation

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15
Q

what are the symptoms of Methmoglobinemia

A

brown blood
Tissue hypoxia
Shortness of breath
Cyanosis (decreased O2 in tissue) - BLUE SKIN
Mental status changes
Headache
Fatigue
Exercise intolerance
Dizziness
Loss of hairlines
Seizures
Coma
Death

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16
Q

What is sulfhemoglobin -Dyshemoglobin

A
  • hemoglobin with a sulfur atom on porphyrin ring
    -cant bind to O2
    -stay for the entirety of RBC life
    -drug induced
    -resolves itself with RBC turnover; transfusion may be needed

symptoms include:
-cyanosis : blue skin or mucous membrane
-green pigment to blood sample
-cell count may not show abnormality

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17
Q

What is Carboxyhemoglobin (COHb) Dyshemoglobin

A

-Carbon monoxide and heme iron complex
-shift O2 dissociation curve to left - CO binds Hgb on same sites as O2 but tighter and releases 10000x slower. There fore less O2 for the whole body
-cause hypoxia quickly - silent killer

symptoms - cherry red skin , unconsciousness

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18
Q

what is Normal RBC Destruction

A

-RBC live for 120 days
-mature RBC have no nucleus, ribosomes or mito therefore they lose ATP over time
-as RBC get older the membrane get rigid and fragile - membrane loses deformability . Selective permeability decreases and the cells become more permeable to water resulting in a spheroid shape
-hemolysis is mostly Extravascular or Macrophage Mediated Hemolysis with destruction primarily in spleen and liver
-there is also Intravascular, Mechanical or Fragmentation Hemolysis which occurs less frequently but in the blood vessels

19
Q

what is Extravascular Hemolysis

A

-RBCs are phagocytosed and lysed by macrophages in spleen
-macrophage phagosome enzymes salvage or metabolize RBC contents
-Globin chains are broken down into individual AA that are used to make new proteins
-Iron is released from HEME and returned to plasma via ferroportin, oxidized to Fe3, it is binds to transferrin in plasma to be stored in tissues or used in cells in BM, RBC or to make new Hgb
-Protoporphyrin degraded into Bilirubin, Bile or Urobillinogen

20
Q

what is Intravascular Hemolysis

A

-when there is internal trauma causing Hgb release directly into plasma
-trauma like
Turbulence in vessels- mechanical or traumatic stress
Damage to blood vessels - small fibrin clots that trap RBCs
-free plasma Hgb attaches to transport proteins that are taken to liver or removed through the kidney

21
Q

how can we prevent oxidation of Hgb iron

A

-Hgb binds Haptoglobin (liver produced plasma protein)
-Haptoglobin-Hemoglobin complex is ingested by macrophages where iron is separated from the protoporphyrin ring and delivered back to the BM

-Oxidized iron- forms Metheme binds Hemopexin
which is then Transported to liver- Heme broken down into components- bilirubin with reuse of iron

Metheme-Albumin system

22
Q

Hemoglobin Portland I

A

hemoglobin at embryonic and fetal life
two zeta chains and two gamma chains.

23
Q

What are the sources of iron and their forms

A

-Ingested and absorbed in GI tract as FE2 or ferrous iron

Stored in liver as:
Ferritin: Iron-Apoferritin complex
Apoferritin (cage like protein)- fe3 or Ferric iron

Hemosiderin:
Form of intracellular storage found in liver, spleen, and BM - a breakdown product of ferritin

Transported via:
Transferrin: plasma iron transport protein that moves iron between absorption and storage site in hematopoietic tissue to become normoblasts

24
Q

what is iron used for

A
  • critical for energy production and oxygen transport
    -no excretion mechanism
    -excess can be harmful
    -distributed into 3 compartments :Functional, Storage, and Transport
25
Q

What is the functional compartment for iron

A
  • contains all functioning iron
    68% is found in hemoglobin in Ferrous fe2 state bound to heme
    10% of Ferrous fe2 is bound to Myoglobin (O2 carrying molecule in muscles)
    3% in enzymes like peroxidase, catalase, cytochromes, and riboflavin
26
Q

what is the storage compartment of iron

A

-iron repository in body
-main repositories are BM macrophages and hepatocytes
-serum ferritin assays are used in lab to assess iron stores

27
Q

what is the transport compartment

A
  • when iron is moved from one site to another by plasma

Transferrin moves iron from duodenum to transferrin receptors on normoblasts in BM
Plasma transferrin and transferrin saturation tests are used to diagnose iron deficiency

28
Q

what is the iron cycle like

A

-iron absorbed form GI tract
-transported via transferrin to BM
-in BM it is inserted into protoporphyrin IX in erythroid precursors to make Heme
-Iron in RBCs in ferrous form bound to Hgb
-Iron from RBCs is broken down in macrophages and reused

29
Q

what is needed for iron hemostasis

A

-usually iron is recycled and used for cellular processes
-iron hemostasis is regulated by absorption into the body because there is no excretion method

Ferritin and Transferrin
-Storage and transport is controlled by
1-Dietary intake
2-Iron Loss (bleeding, hemolysis)- can cause anemia

Hepcidin
-maintains iron level fluctuations
-systemic iron regulatory hormone
-produced by the liver, binds and blocks protein carrier Ferroportin from leaving iron regulating cells - enterocytes, macrophages and hepatocytes
-regulates intestinal iron absorption, plasma iron concentration, tissue iron distribution

30
Q

what is anemia

A

-“without blood”
-when blood cannot supply tissues with oxygen
-manifestation of insufficient hemoglobin or non functional hemoglobin
-seen by Low RBCs, Low Hgb, Low Hematocrit

Seen by fatigue, shortness of breath (dyspnea), pallor (paleness)

diagnosed by: pt history, lab findings, symptoms

31
Q

what can cause anemia

A

1-Ineffective Erythropoiesis
2-Insufficient Erythopoiesis
(impaired RBC production , defective DNA or Hgb synthesis)

3-Acute (traumatic) /Chronic (GI polyp) Blood loss

4-RBC destruction via Hemolytic Anemia
RBC lifespan shortened

32
Q

What is ineffective Erythropoiesis, how is it caused and what does it lead to

A

-low Hgb even though there is an increase in RBC precursors in BM
-production of defective Erythroid precursor cells
-effective production rate is lower that total production rate

caused by:
-Impaired DNA synthesis leading to b12 or folate def
-deficient globin chain synthesis
-deficient protoporphyrin synthesis

leads to:
Megaloblastic Anemia
Thalassemia
Sideroblastic Anemia

33
Q

What is insufficient Erythropoiesis, how is it caused and what does it lead to

A

-when there is a decrease in erythroid precursors in BM causing low RBC production causing low RBCs in circulation

caused by:
-Iron deficiency: due to inadequate intake, malabsorption, or excessive loss
-deficiency of erythropoietin: due to renal disease
-loss of erythroid precursors- due to autoimmune reactions (aplastic anemia), infection (parvo), suppression of erythroid precursors

leads to:
IDA
Aplastic anemia
Anemia of chronic infection

34
Q

what does the lab look at to diagnose anemia

A

cbc, smear, retic, bone marrow examination, urinalysis, Fer, Hap, LD

35
Q

what is looked at in a bone marrow examination for anemia

A

-BM aspiration and biopsy aid in establishing a cause for anemia; either unexplained with/out cytopenia
-determines if abnormal BM infiltration by evaluating hematopoiesis
- an underlying cause can be determined
-Hypocellularity - Aplastic anemia
-Ineffective erythropoiesis – Megaloblastic anemia
-Lack of Iron from iron stains – IDA
-Inhibition of normal Erythropoiesis – Tumor cells present

36
Q

what type of chemistry testing is done to test if you have anemia

A

Iron studies:
-Ferritin- indicates intracellular metabolically active iron
-TIBC- measures the amount of transferrin that is available to bind to. Indirect measure of transferrin
-Total Iron-serum bound to transferrin
% Saturation for Microcytic anemia- how much iron is already bound to transferrin

Serum Vitamin B12, Folate levels for Macrocytic anemia

Liver and Thyroid function studies for Macrocytic anemia

Hgb Electrophoresis (Chem or Heme) -Differentiates Sickle Cell Anemia & Thalassemia

37
Q

what will Microcytic / Hypochromic Anemia show on a cbc; what types of anemia could that be

A

Low MCV
Low MCH
Low MCHC
Inc/N RDW

Iron Deficiency Anemia
Anemia of Chronic Inflammation
Sideroblastic Anemia
Thalassemia

38
Q

what will Normocytic / Normochromic Anemia show on a cbc; what types of anemia would that be

A

Normal MCV
Normal MCHC

-Anemia of Chronic Inflammation
-Hemolytic anemia’s (increased Destruction of RBCs)
-Anemia of Acute Hemorrhage
-Aplastic anemia (decrease RBC precursors from the BM)
-Burns
-sickle cell
-infection - Malaria, Sepsis
-MAHA- HUG, DIC, TTP
-Membrane disorders- defective spectrin spher or ellip
-Enzyme disorders - PK deficiency or G6PD def

39
Q

what will Macrocytic / Normochromic Anemia show on a cbc; what types of anemia would that be

A

CBC may show:
High MCV
Normal MCHC

Examples include:
Vitamin B12 deficiency
Folic acid deficiency
Liver disease

40
Q

what is IDA and what can it be caused by

A

-when the body doesnt have enough iron to produce Hemoglobin
Caused by:
-Inadequate intake: internal stores have been depleted so you need external sources

-Increased need- growth, pregnancy, EPO treatment

-Impaired absorption-unable to absorb iron from intestines into the blood causing deficiency over time. Result of malabsorption (celiac), Iron regulatory protein mutations, or diseases that decrease stomach acidity

-Chronic blood loss
Hemorrhaging and losing small amount of blood over time. This continous loss depletes internal stores. Caused by repeated blood donations, chronic GI bleeding, periods, fibroid tumors, UTI, Kidney stone

41
Q

what will IDA look like on a cbc and a smear

A

CBC:
RBC, Hgb, Hct, MCV, MCH, MCHC = Decreased
RDW = Increased

Morphology:
Moderate/Marked Hypo
Some/Many Microcytes
Poikilocytosis:
Pencils
Ovals
Tears
Targets (sometimes)

42
Q

what are the three stages of IDA

A

Stage 1 of IDA: Depletion of iron stores
Hgb- normal
Fer- normal
TIBC - normal
Serum Ferritin - decreased

Stage 2 of IDA: Depletion of transport iron
Hgb- normal
Fer- decreased
TIBC -increase
Serum Ferritin - decreased

Stage 3 of IDA: Iron Deficiency Anemia
Hgb- decreased
Fer- decreased
TIBC - increased
Serum Ferritin - decreased
% transferrin saturation: decreased

43
Q

what bone marrow changes will you see in IDA

A

-RBC precursors with poorly filled hemoglobin
-as the nucleus condense they still remain basophilic
-cell membranes as RBC matures look blue and shaggy

In normal BM
-Perls prussian blue will stain Positive for iron stores

in IDA
Perls Prussian blue will stain Negative for iron stores

44
Q

how do you treat IDA

A

-treat the underlying cause first
-start with diet and oral ferrous sulfate
-if there is an issue with GI absorption then administer IV of Iron dextrans
-response will be seen as Hgb increases in 2-3 weeks but PBS will show micro pop for a few months
-will see dual pop with increased poly normo/normo and hypo/micro

Hematosis - 2024 (11 decks)

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