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HIID > L28: RBC Physiology and Homeostasis > Flashcards

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)

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2
Q

Do RBCs have a nucleus?

A

No

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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

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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

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5
Q

Why is RBC membrane important for RBC turnover?

A

Macrophages in spleen detect changes in membrane and remove old RBCs

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6
Q

What are the cytoskeletal proteins of RBCs?

A

Alpha and beta spectrin

Ankyrin

Others

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7
Q

What can mutations in genes for ankyrin and spectrin result in?

A

Hereditary spherocytosis

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8
Q

Describe RBC cation balance

A

Intracellular: High K+, low Na+ and Ca++

Extracellular: Low K+, High Na+ and Ca++

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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

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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+

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11
Q

Methemoglobin

A

Oxidized, ferric state or Fe3+

Unable to bind O2

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12
Q

What occurs in right shift on hemoglobin-oxygen dissociation curve?

A 
↓ affinity for oxygen
↑ O2 release to tissues
↑ body temp
↑ pCO2
↓ pH
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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

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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

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15
Q

What RBC metabolic pathway generates ATP to maintain cell functions?

A

Embden-Myherhoff pathway

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16
Q

What RBC metabolic pathway detoxifies oxidants that denature hemoglobin?

A

Hexose monophosphate pathway (HMP)

G6PD (glucose-6-phosphate dehydrogenase) important component

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17
Q

What RBC metabolic pathway reduces methemoglobin (oxidized Hb) back to active (reduced) Hb?

A

Methemoglobin reductase pathway

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18
Q

What is the manifestation of ↑ methemoglobin?

A

Cyanosis

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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

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20
Q

Where in the RBC does Hb synthesis occur?

A

Starts in mitochondria, continues in cytosol, and finishes back in mitochondria

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21
Q

What forms a pocket for heme in hemoglobin?

A

Tertiary structure of polypeptide chain

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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

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23
Q

What polypeptide chains do each of the hemoglobins consist of?

A

HbF - α2, γ2

HbA - α2, β2

HbA2 - α2, δ2

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24
Q

By what age does β chain reach maximal and γ chain reach minimal?

A

6 months of age

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25
Q

When does γ to β chain switch occur?

A

Begins at the end of the 3rd trimester

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26
Q

How much of each hemoglobin is present in fetus/6 months?

A

HbF - >90%
HbA - <10%
HbA2 - 0

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27
Q

How much of each hemoglobin is present at birth?

A

HbF - 60 - 90%
HbA - 10 - 40%
HbA2 - <2%

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28
Q

How much of each hemoglobin is present at 2 years to adulthood?

A

HbF - <2%
HbA - >95%
HbA2 - <3.5%

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29
Q

What are the 2 methods of hemoglobin degradation?

A

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

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30
Q

What type of hemolysis is more common?

A

Extravascular (80 - 90%)

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31
Q

What is hemoglobin broken down into? Are these recycled?

A

Iron - recycled
Polypeptides - recycled
Protoporphyrin - cannot be recycled and must be excreted

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32
Q

Describe extravascular hemolysis

A

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

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33
Q

What occurs in bile duct obstruction?

A

Bilirubin can’t get into intestine to be converted to urobilinogen → pale stool

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34
Q

Describe intravascular hemolysis

A

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

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35
Q

What occurs in intravascular hemolysis after haptoglobin is depleted?

A

Hemopexin combines w/ oxidize heme to form metheme-hemopexin complex →
goes into hepatocyte to be processed

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36
Q

What occurs in intravascular hemolysis after both haptoglobin and hemopexin are depleted?

A

Hemoglobin will go out through the kidneys

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37
Q

Hemoglobinuria

A

Hemoglobin excretion in urine (when capacity to reabsorb in kidney is exceeded)

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38
Q

Hemosiderinuria

A

When hemoglobin is reabsorbed in the tubular cells of kidney → tubular cells slough off →
iron gets into urine

39
Q

What does tea or root beer-colored urine indicate?

A

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
Q

What are lab findings in excessive hemolysis that are common to both intravascular and extravascular hemolysis?

A

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
Q

What are lab findings that can help you determine if intravascular or extravascular hemolysis is occurring?

A

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
Q

Why is free iron toxic to tissues?

A

Can form free radicals that can damage cellular components

43
Q

What is iron concentration in the body controlled by? Why?

A

Controlled by absorption bc there is no good mechanism for iron excretion

44
Q

What is transferrin? What are its forms?

A

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
Q

Where is transferrin produced?

A

Produced in liver

46
Q

How much is transferrin normally saturated?

A

Normally 1/3 saturated w/ iron

47
Q

What is transferrin usually measured as?

A

Measured as total iron binding capacity (TIBC)

Represents total transferrin concentration

48
Q

When is transferrin decreased?

A

Decreased in inflammation

49
Q

What is ferritin? Where is it stored? When does it increase?

A

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
Q

What is transferrin receptor? Where is it found?

A

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
Q

What are the 2 sources of iron for absorption in the intestine?

A

Heme iron

Non-heme iron (enters as Fe2+)

52
Q

What is required for transport of iron out of cells?

A

Ferroportin (a one-way transporter)

53
Q

How does hepcidin inhibit iron transport out of cell?

A

Binds to ferroportin and prevents it from transporting iron out of the cell

54
Q

If the body has enough iron and ferritin stays in the cell rather than being released to the blood, what happens to it?

A

Ferritin is lost in feces in shedding of enterocyte

55
Q

How is iron homeostasis regulated when plasma iron is low?

A

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
Q

How is iron homeostasis regulated when plasma iron is high?

A

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
Q

What occurs with hepcidin in inflammation?

A

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
Q

Hemostasis

A

Interaction of multiple systems to keep blood flowing and stop bleeding

Consists of primary hemostasis, secondary hemostasis, and fibrinolysis

59
Q

Descrine primary hemostasis, secondary hemostasis, and fibrinolysis

A

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
Q

Describe how hemostasis is balanced

A

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
Q

What steps are included in platelet activation?

A

Adhesion
Secretion
Aggregation

62
Q

What do platelet granules contain?

A

ADP, ATP, Ca2+, some clotting factors

63
Q

Describe platelet adhesion

A

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
Q

What is VWF? Where is it synthesized? Where is it present?

A

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
Q

Bernard Soulier syndrome

A

Deficient in GP Ib-IX-V receptors

66
Q

What secretes VWF in endothelial cells?

A

Weibel-Palade bodies

67
Q

How is VWF secreted? How is it processed?

A

Secreted as ultra-large multimers

ADAMTS-13 reduces size of multimers

68
Q

What leads to thrombotic thrombocytopenic purpura (TTP)?

A

Inhibition of ADAMTS-13 (normal function is to reduce size of VWF multimers)

69
Q

What does VWF monomer bind?

A

Platelet GP Ibα, collagen (mediates platelet adhesion to subendothelium)

Platelet GB IIb/IIIa (mediates platelet aggregation)

Factor VIII (protects it from proteolysis

70
Q

Describe platelet activation

A

Platelets undergo a shape change

GP IIb-IIIa receptor becomes activated on surface

Other receptors also become activated

71
Q

What causes Glanzmann thrombasthenia

A

Deficiency in GP IIb-IIIa receptor

72
Q

Describe platelet secretion

A

Activated platelets synthesize and release Thromboxane A2 (TxA2) and release contents of granules (eg. ADP, many others)

73
Q

What pathway is thromboxane A2 generated through?

A

The eicosanoid pathway

74
Q

How does aspirin inhibit platelet activity?

A

Asprin acetylates and irreversible inactivates cyclooxygenase; platelets cannot make more; this inhibits activation of the platelet for the remainder of its life span

75
Q

Describe platelet aggregation

A

Fibrinogen and VWF forms bridges b/w the GP IIb-IIIa of adjacent platelets to form primary platelet plug

76
Q

How are the platelet and conjugation systems interrelated?

A

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
Q

What are the plasma coagulation factors?

A 
I - fibrinogen
II - prothrombin
V
VII (6 hour half-life)
VIII - antihemophilic factor
IX - Christmas factor
X
XI
XII
PK
HK
XIII
78
Q

Which plasma coagulation factors are vitamin K dependent?

A

II, VII, IX, X

79
Q

Deficiencies in which plasma coagulation factors result in no bleeding symptoms?

A

XII
PK
HK

80
Q

Which plasma coagulation factor is not tested in coagulation screening tests?

A

XIII

81
Q

Where are coagulation factors synthesized?

A

Liver

82
Q

How does factor VIII circulate?

A

As a complex with VWF

When VWF decreases, factor VIII decreases

83
Q

Which coagulation factors are acute phase reactants?

A

Fibrinogen, VIII, VWF increase in inflammatory response

84
Q

Which coagulation factors have X-linked mode of inheritance?

A

Factors VIII and IX

85
Q

Why does liver disease sometimes lead to bleeding disorder?

A

Liver disease results in multiple factor deficiencies and causes coagulopathy

86
Q

What coagulation factors are extrinsic? Intrinsic? Common?

A

Extrinsic: TF, VII

Intrinsic: XII, PK, HK, XI, IX, VIII

Common: X, V, II, I

87
Q

What coagulation factors are co-factors?

A

VIII and V

88
Q

What does thrombin do?

A

Is a very powerful enzyme that converts fibrinogen to fibrin polymer

Activates factor XIII to XIIIa

Causes cross-linked fibrin

89
Q

What are the major inhibitors of coagulation?

A

Antithrombin (AT): serine protease inhibitor (SERPIN); Inhibits IIa (thrombin), IXa, Xa, XIa

Activate protein C (APC), protein S (cofactor): inactivates Va and VIIIa

90
Q

How does heparin work?

A

Binds to antithrombin (AT), causing more rapid inhibition of thrombin

91
Q

What is fibrinolysis? Describe how it occurs?

A

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
Q

Thrombolytic therapy

A

TPA is used to digest fibrin clots in acute ischemic strokes, early MI, PE

93
Q

What does D-dimer form from? What does D-dimer in the plasma indicate?

A

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
Q

What are the coagulation screening tests? What do they test for?

A

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

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