L28: RBC Physiology and Homeostasis Flashcards
1
Q
Why is biconcave shape of RBCs important?
A
Important for gas exchange (shorter distance for gases to diffuse in and out) and flexibility (a they go through small vasculature, RBCs have to bend to get through)
2
Q
Do RBCs have a nucleus?
A
No
3
Q
What can RBCs NOT do due to lack of nucleus and other organelles?
A
Cannot synthesize new proteins, lipids, or undergo oxidative phosphorylation
4
Q
What are the 2 types of proteins in RBC membrane?
A
Transmembrane proteins: traverse the membrane
Cytoskeletal proteins: intracellular, on the inner side of the membrane
5
Q
Why is RBC membrane important for RBC turnover?
A
Macrophages in spleen detect changes in membrane and remove old RBCs
6
Q
What are the cytoskeletal proteins of RBCs?
A
Alpha and beta spectrin
Ankyrin
Others
7
Q
What can mutations in genes for ankyrin and spectrin result in?
A
Hereditary spherocytosis
8
Q
Describe RBC cation balance
A
Intracellular: High K+, low Na+ and Ca++
Extracellular: Low K+, High Na+ and Ca++
9
Q
Describe hemoglobin structure
A
Consists of 4 hemes and 4 polypeptide chains
Heme = iron inserted into a protoporphyrin IX ring structure
Heme fits into a pocket in each polypeptide chain
10
Q
In what form does hemoglobin bind O2?
A
Binds O2 in reduced, ferrous state or Fe2+
Unable to bind O2 in oxidized, ferric state or Fe3+
11
Q
Methemoglobin
A
Oxidized, ferric state or Fe3+
Unable to bind O2
12
Q
What occurs in right shift on hemoglobin-oxygen dissociation curve?
A
↓ affinity for oxygen ↑ O2 release to tissues ↑ body temp ↑ pCO2 ↓ pH
13
Q
What does Hb F do to hemoglobin-oxygen dissociation curve?
A
Shifts curve to left
Since it has higher affinity for oxygen; decreases oxygen release to the tissue and thus shifts the curve to the left
14
Q
What occurs to hemoglobin-oxygen dissociation curve during exercise?
A
Muscles have an ↑ metabolic rate, ↑ temp, and produce ↑ CO2 and lactic acid which ↓ the pH; this shifts the curve to the right which unloads more O2 to the muscle tissue
15
Q
What RBC metabolic pathway generates ATP to maintain cell functions?
A
Embden-Myherhoff pathway
16
Q
What RBC metabolic pathway detoxifies oxidants that denature hemoglobin?
A
Hexose monophosphate pathway (HMP)
G6PD (glucose-6-phosphate dehydrogenase) important component
17
Q
What RBC metabolic pathway reduces methemoglobin (oxidized Hb) back to active (reduced) Hb?
A
Methemoglobin reductase pathway
18
Q
What is the manifestation of ↑ methemoglobin?
A
Cyanosis
19
Q
What RBC metabolic pathway generates 2, 3 BPG? What does this cause?
A
Rapoport - Luebering pathway
Shifts Hb-O2 dissociation curve to the right; promotes O2 release from Hb
20
Q
Where in the RBC does Hb synthesis occur?
A
Starts in mitochondria, continues in cytosol, and finishes back in mitochondria
21
Q
What forms a pocket for heme in hemoglobin?
A
Tertiary structure of polypeptide chain
22
Q
What are the hemoglobin polypeptide chains? How many genes are there for each?
A
Alpha - 2 genes per chromosome
Beta - 1 gene per chromosome
Delta - 1 gene per chromosome
Gamma - 2 genes per chromosome
23
Q
What polypeptide chains do each of the hemoglobins consist of?
A
HbF - α2, γ2
HbA - α2, β2
HbA2 - α2, δ2
24
Q
By what age does β chain reach maximal and γ chain reach minimal?
A
6 months of age
25
When does γ to β chain switch occur?
Begins at the end of the 3rd trimester
26
How much of each hemoglobin is present in fetus/6 months?
HbF - >90%
HbA - <10%
HbA2 - 0
27
How much of each hemoglobin is present at birth?
HbF - 60 - 90%
HbA - 10 - 40%
HbA2 - <2%
28
How much of each hemoglobin is present at 2 years to adulthood?
HbF - <2%
HbA - >95%
HbA2 - <3.5%
29
What are the 2 methods of hemoglobin degradation?
Extravascular hemolysis (macrophage-mediated): senescent RBCs phagocytized by macrophages in spleen (mainly), liver
Intravascular hemolysis (fragementation hemolysis): RBCs lysed in circulation, heme binds w/ haptoglobin, hemopexin, transported to liver
30
What type of hemolysis is more common?
Extravascular (80 - 90%)
31
What is hemoglobin broken down into? Are these recycled?
Iron - recycled
Polypeptides - recycled
Protoporphyrin - cannot be recycled and must be excreted
32
Describe extravascular hemolysis
Old or damaged RBC goes into macrophage (mainly in spleen) →
red cell is lysed and Hb is released →
protoporphyrin is converted to biliverdin →
converted to unconjugated bilirubin →
released into plasma and bound to plasma albumin (insoluble) →
in hepatocyte, is conjugated with glucuronic acid to become conjugated bilirubin → goes into bile duct → is converted to urobilinogen in intestines →
mostly excreted in feces; some small amount goes to kidney and is excreted in urine
33
What occurs in bile duct obstruction?
Bilirubin can't get into intestine to be converted to urobilinogen → pale stool
34
Describe intravascular hemolysis
Old or damaged RBC is destroyed in circulation →
free plasma hemoglobin →
forms hemoglobin-haptoglobin complex → goes to macrophage and iron is recycled →
get unconjugated bilirubin that goes to hepatocyte
35
What occurs in intravascular hemolysis after haptoglobin is depleted?
Hemopexin combines w/ oxidize heme to form metheme-hemopexin complex →
goes into hepatocyte to be processed
36
What occurs in intravascular hemolysis after both haptoglobin and hemopexin are depleted?
Hemoglobin will go out through the kidneys
37
Hemoglobinuria
Hemoglobin excretion in urine (when capacity to reabsorb in kidney is exceeded)
38
Hemosiderinuria
When hemoglobin is reabsorbed in the tubular cells of kidney → tubular cells slough off →
iron gets into urine
39
What does tea or root beer-colored urine indicate?
There is oxidized Hb in the urine
Myoglobin will also give you brown urine; occurs when there is muscle damage such as in crush injury
40
What are lab findings in excessive hemolysis that are common to both intravascular and extravascular hemolysis?
Decrease in HGB, HCT, RBC
Increase in retics
Nucleated RBCs in peripheral blood present if severe hemolysis
Erythroid hyperplasia in bone marrow present
Serum unconjugated (indirect) bilirubin increased
Urine urobilinogen increased
Intracellular lactate dehydrogenase (LD) increased
41
What are lab findings that can help you determine if intravascular or extravascular hemolysis is occurring?
Free plasma hemoglobin is greatly increased in intravascular and is not present in extravascular
Serum haptoglobin is greatly decreased in intravascular and slightly decreased in extavascular hemolysis
Urine hemoglobin is present in intravascular and not present in extravascular
Urine hemosiderin is present in intravascular and not present in extravascular
42
Why is free iron toxic to tissues?
Can form free radicals that can damage cellular components
43
What is iron concentration in the body controlled by? Why?
Controlled by absorption bc there is no good mechanism for iron excretion
44
What is transferrin? What are its forms?
Iron transport protein
Forms: transferrin (has 1 or 2 bound iron atoms) and apotransferrin (has no iron bound)
Normally 1/3 saturated w/ iron
Measured as total
45
Where is transferrin produced?
Produced in liver
46
How much is transferrin normally saturated?
Normally 1/3 saturated w/ iron
47
What is transferrin usually measured as?
Measured as total iron binding capacity (TIBC)
Represents total transferrin concentration
48
When is transferrin decreased?
Decreased in inflammation
49
What is ferritin? Where is it stored? When does it increase?
Iron storage protein in cells
Most ferritin is stored in RBC precursors, BM macrophages, hepatocytes
Serum ferritin is estimate of storage iron
Increased in inflammation (acute phase reactant)
50
What is transferrin receptor? Where is it found?
TfR
Determines amount of iron entering cell
On all cell surfaces
Increased receptors on cells that use and store a large amount of iron, eg. RBC progenitors, hepatocytes
51
What are the 2 sources of iron for absorption in the intestine?
Heme iron
Non-heme iron (enters as Fe2+)
52
What is required for transport of iron out of cells?
Ferroportin (a one-way transporter)
53
How does hepcidin inhibit iron transport out of cell?
Binds to ferroportin and prevents it from transporting iron out of the cell
54
If the body has enough iron and ferritin stays in the cell rather than being released to the blood, what happens to it?
Ferritin is lost in feces in shedding of enterocyte
55
How is iron homeostasis regulated when plasma iron is low?
Liver recognizes low plasma iron and decreases production of hepcidin → ferroportin is able to transport iron out of cells, resulting in more absorption of iron by enterocytes AND more release of iron from storage in the macrophages and hepatocytes
Overall, there is increased iron absorption in intestines and increased iron release from storage. End result is an increase in plasma iron
56
How is iron homeostasis regulated when plasma iron is high?
When plasma iron increases, the liver upregulates production of hepcidin → hepcidin binds to ferroportin on the membrane of enterocytes and prevents iron absorption AND also binds to ferroportin on the bone marrow macrophages and hepatocytes and prevents release of stored iron
Overall, there is decreased iron absorption in intestine and decreased iron release from storage.
End result is a decrease in plasma iron
57
What occurs with hepcidin in inflammation?
Liver synthesis of hepcidin is upregulated, thus decreasing iron absorption from the intestines and iron release from storage
This is a protective mechanism to keep iron from invading microorganisms
58
Hemostasis
Interaction of multiple systems to keep blood flowing and stop bleeding
Consists of primary hemostasis, secondary hemostasis, and fibrinolysis
59
Descrine primary hemostasis, secondary hemostasis, and fibrinolysis
Primary hemostasis: formation of primary thrombus (platelet plug); involves blood vessels, platelets, and von Willebrand factor; rapid, but short-term response; localizes thrombus to site of injury
Secondary hemostasis: coagulation proteins form a fibrin clot on the surface of activated platelets; stabilizes the primary thrombus; delayed, but longer-term response
Fibrinolysis: plasmin (enzyme) digests fibrin in the clot when it is no longer needed
60
Describe how hemostasis is balanced
Is a balance b/w pro-thrombotic and anti-thrombotic mechanisms
```
Pro-thrombotic factors:
Increase →
thrombosis
Decrease →
bleeding
```
```
Anti-thrombotic factors:
Increase →
bleeding
Decrease →
thrombosis
```
61
What steps are included in platelet activation?
Adhesion
Secretion
Aggregation
62
What do platelet granules contain?
ADP, ATP, Ca2+, some clotting factors
63
Describe platelet adhesion
After vessel injury, von Willebrand factor (VWF) binds to collagen in the exposed subendothelium and "unrolls"
Platelets bind to VWF by their GP Ib-IX-V receptors
VWF forms a bridge b/w platelet GP Ib and collagen in subendothelium to initially "tether" platelets to the subendothelium
Platelets bind directly to collagen via their GP VI receptors which generates signals in the platelet for activation
64
What is VWF? Where is it synthesized? Where is it present?
von Willebran Factor is a large multimeric protein
Synthesized by endothelial cells and megakaryocytes
Present in: plasma, α-granules of platelets, and Weibel-Palade bodies of endothelial cells
65
Bernard Soulier syndrome
Deficient in GP Ib-IX-V receptors
66
What secretes VWF in endothelial cells?
Weibel-Palade bodies
67
How is VWF secreted? How is it processed?
Secreted as ultra-large multimers
ADAMTS-13 reduces size of multimers
68
What leads to thrombotic thrombocytopenic purpura (TTP)?
Inhibition of ADAMTS-13 (normal function is to reduce size of VWF multimers)
69
What does VWF monomer bind?
Platelet GP Ibα, collagen (mediates platelet adhesion to subendothelium)
Platelet GB IIb/IIIa (mediates platelet aggregation)
Factor VIII (protects it from proteolysis
70
Describe platelet activation
Platelets undergo a shape change
GP IIb-IIIa receptor becomes activated on surface
Other receptors also become activated
71
What causes Glanzmann thrombasthenia
Deficiency in GP IIb-IIIa receptor
72
Describe platelet secretion
Activated platelets synthesize and release Thromboxane A2 (TxA2) and release contents of granules (eg. ADP, many others)
73
What pathway is thromboxane A2 generated through?
The eicosanoid pathway
74
How does aspirin inhibit platelet activity?
Asprin acetylates and irreversible inactivates cyclooxygenase; platelets cannot make more; this inhibits activation of the platelet for the remainder of its life span
75
Describe platelet aggregation
Fibrinogen and VWF forms bridges b/w the GP IIb-IIIa of adjacent platelets to form primary platelet plug
76
How are the platelet and conjugation systems interrelated?
Platelets provide the phospholipid surface for fibrin formation; granules contain coagulation factors
Coagulation proteins generate thrombin which binds to its receptor on platelets causing platelet aggregation; thrombin is a potent activator of platelets; fibrin formed on the surface of the platelet stabilizes the platelet plug
77
What are the plasma coagulation factors?
```
I - fibrinogen
II - prothrombin
V
VII (6 hour half-life)
VIII - antihemophilic factor
IX - Christmas factor
X
XI
XII
PK
HK
XIII
```
78
Which plasma coagulation factors are vitamin K dependent?
II, VII, IX, X
79
Deficiencies in which plasma coagulation factors result in no bleeding symptoms?
XII
PK
HK
80
Which plasma coagulation factor is not tested in coagulation screening tests?
XIII
81
Where are coagulation factors synthesized?
Liver
82
How does factor VIII circulate?
As a complex with VWF
When VWF decreases, factor VIII decreases
83
Which coagulation factors are acute phase reactants?
Fibrinogen, VIII, VWF increase in inflammatory response
84
Which coagulation factors have X-linked mode of inheritance?
Factors VIII and IX
85
Why does liver disease sometimes lead to bleeding disorder?
Liver disease results in multiple factor deficiencies and causes coagulopathy
86
What coagulation factors are extrinsic? Intrinsic? Common?
Extrinsic: TF, VII
Intrinsic: XII, PK, HK, XI, IX, VIII
Common: X, V, II, I
87
What coagulation factors are co-factors?
VIII and V
88
What does thrombin do?
Is a very powerful enzyme that converts fibrinogen to fibrin polymer
Activates factor XIII to XIIIa
Causes cross-linked fibrin
89
What are the major inhibitors of coagulation?
Antithrombin (AT): serine protease inhibitor (SERPIN); Inhibits IIa (thrombin), IXa, Xa, XIa
Activate protein C (APC), protein S (cofactor): inactivates Va and VIIIa
90
How does heparin work?
Binds to antithrombin (AT), causing more rapid inhibition of thrombin
91
What is fibrinolysis? Describe how it occurs?
Fibrinolysis = degradation of fibrin
Activators (tissue plasminogen activator or TPA and urokinase plasminogen activator or UPA) convert plasminogen to plasmin
Plasmin will break down the fibrin clot to the D-dimer and the fibrin degradation products (FDPs)
92
Thrombolytic therapy
TPA is used to digest fibrin clots in acute ischemic strokes, early MI, PE
93
What does D-dimer form from? What does D-dimer in the plasma indicate?
Forms from cross-linked fibrin
If there is D-dimer in the plasma, it is bc cross-linked fibrin has formed in the circulation; this is an abnormal situation
94
What are the coagulation screening tests? What do they test for?
PT (prothrombin time): tests for extrinsic and common pathway
APTT (activated partial thromboplastin time): tests for intrinsic and common pathway
TCT (thrombin clotting time) or fibrinogen assay: tests for conversion of fibrinogen to fibrin
