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Endocrine Exam 2 > 31 - Homeostasis > Flashcards

31 - Homeostasis Flashcards

1
Q

Give an overview of blood clotting

A
  • Immediately following injury, LOCAL factors (i.e. endothelin) trigger localized
    vasoconstriction
  • This vasoconstriction reduces blood flow to injured area
  • Vascular damage (mechanical damage from a cut) exposes components of the extracellular matrix **
  • The exposure of the extracellular matrix allows for platelets to adhere to the injured area and activate
  • Once activated, a hemostatic plug forms
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2
Q

Give an overview of the coagulation cascade

A
  • Exposure of tissue factor at the site of damage sets in motion the coagulation cascade
  • Ultimately this results in the activation of thrombin ***
  • Thrombin cleaves soluble fibrinogen to yield insoluble fibrin
  • A fibrin network forms, which recruits additional platelets and stabilizes the clot
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3
Q

Give an overview of the counterregulatory mechanisms of clot formation

A
  • Counterregulatory mechanisms activate
  • This limits the spread of the clot
  • Eventually, the clot reabsorbs and the tissues repair
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4
Q

Describe the characteristics of platelets

A
  • Platelets are anuclear (no nucleus) cell fragments which are derived from megakaryocytes ***
  • Each megakaryocyte gives rise to many platelets
  • Platelets circulate at 200,000-400,000 per microliter of blood
  • Platelets contain mRNA, ribosomes and can even synthesize a limited quantity of protein
  • The significance of this protein production is unclear
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5
Q

What is the lifespan of a platelet?

A

Each individual platelet persists for 9-10 days

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6
Q

What type of cells produce von Willebrand factor (vWF)?

A

Endothelial cells produce von Willebrand factor (vWF)

When endothelial damage occurs, vWF is secreted into the subendothelial extracellular matrix***

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7
Q

How does the vWF secreted into the subendothelial extracellular matrix contact blood?

A

Vascular damage

There is physical damage to the capillary endothelium, meaning everything in the extracellular matrix is now exposed to blood

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8
Q

What interactions occur between vWF and blood?

A
  • vWF is exposed to platelets
  • Platelets have a surface glycoprotein called glycoprotein Ib (GpIb)
  • vWF is able to bind to platelets via GpIb
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9
Q

What does the interaction between vWF and platelets accomplish?

A
  • Once vWF is able to bind to platelets, it can tether the platelets to collagen of the ECM
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10
Q

What else is needed for platelet adhesion to occur?

A
  • vWF needs to also bind to a coagulation factor called factor VIII (factor 8)
  • Factor 8 is required for an effective coagulation response (the cascade)
  • When vWF binds to factor 8 (needed for the cascade), it is able to keep factor 8 at the site of injury so it doesn’t get swept away in the blood
  • vWF also increased the half life of factor 8 when they are bound together
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11
Q

What other receptor is found on the surface of platelets that is utilized in platelet adhesion?

A

Integrin alpha2 beta1

  • This platelet membrane receptor binds to collagen
  • It helps platelets adhere to the extracellular membrane
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12
Q

What are the specific interactions that are required for platelets to withstand high shear forces?

A
  • Specific interactions between the vWF and the GpIb on the surface of the platelets
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13
Q

What does the adhesion of platelets to the ECM (via vWF) trigger?

A

A Ca++ signal

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14
Q

What is the purpose of the Ca++ signal?

A

This Ca++ signal causes platelets to undergo a dramatic shape change

  • The platelets become “spiny”
  • They no longer look like pita bread
  • The platelets extend long processes which help them “hold on”
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15
Q

What do activated platelets secrete?

A

Two types of secretory granules

  • Dense granules
  • Alpha granules
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16
Q

Describe the contents of dense granules of activated platelets

A
  • ADP
  • ATP
  • Ca++
  • Histamine
  • Serotonin*
  • Epinephrine*
  • = function as vasoconstricters
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17
Q

Describe the contents of alpha granules of activated platelets

A
  • Fibrinogen
  • Fibronectin
  • vWF
  • Coagulation factor V
  • PDGF
  • Other signaling molecules
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18
Q

What is the other substance that activated platelets release?

A

Free arachidonic acid

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19
Q

What is the function of free arachidonic acid in the process of clotting?

A

The arachidonic acid is converted to prostaglandin G2 by COX

Ultimately, this gives rise to thromboxane A2

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20
Q

What is the function of thromboxate A2?

A

Vasoconstriction

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21
Q

What else causes vasoconstriction?

A
  • Serotonin
  • Epinephrine

Thromboxane A2, serotonin, epinephrine function as vasoconstrictors, which reduce blood loss at the site of injury

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22
Q

What is a very important substance that is released from platelets in the dense granules that plays a major role in platelet aggregation?

A

ADP

Remember that clot formation requires the aggregation of platelets

If ADP is needed for platelet aggregation, that means that it is required for clot formation

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23
Q

Describe the roles of ADP in the platelet aggregation process

A

Stimulation of platelets

  • ADP and thromboxane 2 form important signals for platelet aggregation
  • They have a feed-forward activation effect
  • This effect simulates the activation of even more platelets

Allows fibrinogen binding

  • ADP also triggers a conformational change in the GpIIb-GpIIIa receptor on the platelet membrane
  • This conformational change allows for fibrinogen to bind to the receptor
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24
Q

What is the overall result of platelet aggregation?

A

Aggregated platelets form an initial “plug” at the site of vascular injury

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25
Q

Describe von Willebrand disease

A
  • It is the most common inherited bleeding disorder
  • There are three types (1, 2 and 3)
  • MOST - 80% of the cases are type 1
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26
Q

What are the symptoms of patients with type 1 von Willebrand disease?

A

Type 1 patients will display…

  • Lowered vWF protein
  • Reduced vWF function
  • Reduced factor 8

Usually diagnosed in childhood…

  • Frequent nose bleeds
  • Excessive bleeding following dental treatment
  • Excessive bruising
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27
Q

How do you medically manage von Willebrand disease?

A

Desmopressin

  • Induces the release of vWF and factor 8
  • These are released from storage sites within the endothelium
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28
Q

What is Bernard-Soulier syndrome?

A
  • Severe, inherited platelet disorder of GIANT platelets ***
  • Giant platelets are present and often times thrombocytopenia will be present as well

Remember, thrombocytopenia is a deficiency of platelets in the blood

29
Q

What happens clinically in patients with Bernard-Soulier syndrome?

A
  • Platelets fail to aggregate in response to stimuli

- This is due to a defect in the interaction between vWF and GpIb

30
Q

Describe the treatment of Bernard-Soulier syndrome

A
  • Therapy aims to REDUCE BLEEDING ***

- Platelet transfusion is needed when bleeding or when bleeding is inevitable (like before surgery)

31
Q

What is Glanzmann thrombasthenia?

A
  • An inherited bleeding disorder

- Due to either a quantitiative or qualitative defect in GpIIb and/or GpIIIa

32
Q

What occurs in patients with Glanzmann thrombasthenia?

A
  • Platelets fail to aggregate in response to various stimuli
  • This means do NOT respond to ADP, collagen or epinephrine
  • There will be prolonged bleeding times
33
Q

How do you treat Glanzmann thrombasthenia?

A

Therapy aims to REDUCE bleeding risk ***

- Platelet transfusion may be needed to address bleeding episodes

34
Q

Give a brief summary of the coagulation cascade

A
  • The initial platelet plug is relatively unstable and is therefore insufficient
  • Activation of the coagulation cascade is required
  • The coagulation cascade is a series of events which are ultimately leading to the activation of the protease thrombin ***
  • There are two pathways of the coagulation cascade: intrinsic and extrinsic

Know thrombin***

35
Q

Give a brief overview of the intrinsic pathway

A
  • This occurs spontaneously in vitro (outside of the body)
  • Blood clots spontaneously upon exposure to a negatively charged surface (i.e. glass)
  • This ability of blood to clot spontaneously on glass is the basis of the clotting test called “partial thromboplastin time test”

*** PARTIAL test

36
Q

Give a brief overview of the extrinsic pathway

A
  • The clotting in the extrinsic pathway is triggered by exogenous material being exposed to blood (i.e. tissue factor from tissue injury)
  • The ability of blood to clot spontaneously when exposed to tissue factor is the bases of the clotting test called “prothrombin time test”

*** PROTHROMBIN test

37
Q

When do the intrinsic and extrinsic pathway converge?

A

Upon the activation of factor X (FACTOR 10)

  • Factor X functions in the activation of thrombin
  • Thrombin is a KEY regulator of coagulation

So pretty much, regardless of how the coagulation cascade begins (either intrinsic or extrinsic), factor 10 is activated and thrombin is activated ***

38
Q

How are coagulation factors named?

A
  • Roman numerals

- They are labeled in order of discovery, not the order of action in the cascade

39
Q

How are many factors of the coagulation cascade produced and secreted?

A

As inactive zymogens

  • This means they need to be activated by proteolysis
  • The active form of the factor is designated by an “a”
  • Activated factor X is factor Xa
40
Q

What is y-carboxyglutamate?

A

An amino acid that is found the following factors

  • Prothrombin
  • Factor VII
  • Factor IX
  • Factor X

These compounds contain a y-carboxyglutamate residue, which is a modified amino acid

It functions to chelate (bind) Ca++

41
Q

What is the function of the bound Ca++ of prothrombin and factor VII, IX and X?

A
  • Coordinate the negatively charged membrane lipids
  • ACTIVATE when attached to the cell membrane
  • This restricts clot formation to the site of injury

This means that y-carboxyglutamate allows clots be limited and localized

42
Q

What enzyme is needed to convert glutamate to y-carboxyglutamate? What else is needed?

A

Carboxylase
- Carboxylase converts glutamate to y-carboxyglutamate

Vitamin K is also needed
- Carboxylase converting glutamate to γ-carboxyglutamate requires vitamin K

43
Q

Why is vitamin K commonly administered to neonates?

A

Because neonates have…

  • Low fat stores
  • Low levels of vitamin K in breast milk
  • No vitamin K in the intestinal tract (because bacteria are a vitamin K source and and the intestinal tract of neonates is sterile)
  • Liver is immature
  • Poor placental transport of vitamin K
44
Q

When do you give vitamin K?

A

When a patient is NOT clotting their blood enough

They are babies without a good ability to clot or they are patients on warfarin that have had too much warfarin and they are bleeding

Remember, vitamin K is needed so that y-carboxyglutamate is preset and y-carboxyglutamate allows clotting factors to accumulate

Vitamin K is known as the clotting vitamin, because without it blood would not clot.

45
Q

What type of drugs are warfarin and its derivatives?

A

Warfarin and derivatives function as anticoagulants

- Originally developed as a rodent killer (rodenticide)

46
Q

How does warfarin function?

A
  • Warfarin prevents the regeneration of vitamin K

- Ultimately this blocks the production of y-carboxyglutamate residues

47
Q

What is the KEY point of the coagulation cascade?

A
  • Both the intrinsic and extrinsic coagulation cascade end in the activation of factor X to factor Xa
48
Q

What does factor Xa activate?

A

Thrombin

49
Q

Describe the function of thrombin

A

Thrombin

  • Cleaves fibrinogen to the form of fibrin
  • This enhances clotting via a positive feedback
  • This induces platelet aggregation
  • Also, it activates endothelial cells
  • This is important for wound healing
50
Q

What is hemophilia?

A
  • An x-linked recessive bleeding disorder

- There are two types - hemophilia A and B

51
Q

Describe hemophilia A

A
  • 1 in 5000 male births

- Caused by a factor VIII (factor 8) deficiency

52
Q

Describe hemophilia B

A
  • 1 in 30,000 male births

- Caused by a factor IX deficiency (factor 9)

53
Q

What is the therapy for hemophilia?

A

Traditional therapy required blood transfusion, but now recombinant factor VIII or IX is administered

The patient can now just take the factor they are deficient of (either factor 8 (A) or 9 (B))

54
Q

How does the body assure that the entire body does not coagulate (clot) and there is localization of coagulation activity to the site of injury?

A
  • Platelet activation only occurs at the site of injury
  • Adhesion of factors only occurs when factors are exposed to a negatively charged membrane of lipids at the site of injury
55
Q

What are the endogenous anticoagulant activities?

A
  • Thrombin
  • Protein C and S
  • Serpins
  • Tissue factor pathway inhibitor (TFPI)
56
Q

Thrombin functions to both DRIVE and INHIBIT coagulation? How does it inhibit clotting?

A
  • Thrombomodulin present in endothelial cell membranes
  • This alters substrate specificity of thrombin
  • Thrombin/thrombomodulin activates protein C (serine protease)
  • Active protein C which then binds protein S
  • The protein C/S complex then degrades factor Va and factor VIIIa
  • This BLOCKS clotting ***
57
Q

What is factor V Leiden?

A
  • A relatively common mutation in factor V
  • Substitution mutation: This mutation replaces arginine at amino acid position 506 with glutamine
  • The resulting factor V is resistant to cleavage by protein C
58
Q

What is the clinical outcome of factor V Leiden?

A

HYPERCOAGULATION ***

  • Increases clotting
  • Increases the risk of thrombosis

Heterozygotes
- Have 5x increased risk of thrombosis

Homozygotes
- Have 50x increased risk of thrombosis

59
Q

What are Serpins?

A
  • A family of SERine Protease INhibitors (SERPINs)

- They inhibit the activated form of coagulation factors

60
Q

What is the best example of a serpin?

A

Best example is antithrombin III (ATIII)

  • ATIII inhibits thrombin
  • Also binds to heparin

The ATIII-heparin complex also inhibits a lot of factors: IXa, Xa, XIa, and XIIIa

61
Q

What are tissue factor pathway inhibitors (TFPI)?

A
  • Proteins produced by endothelial cells
  • Function as inhibitors of factor VIIa
  • This blocks the EXTRINSIC PATHWAY ***
  • It also inhibits factor Xa
62
Q

What is fibrinolysis?

A

It prevents blood clots that occur naturally from growing and causing problems

  • Clot size is limited by fibrinolysis
  • Fibrin is degraded by serine protease PLASMIN
63
Q

Describe plasminogen

A
  • Plasmin circulates in the blood as inactive plasminogen
  • It has a high affinity for fibrin
  • This means that plasminogen binds to and is incorporated into growing clots
64
Q

How is plasminogen activated?

A
  • Plasminogen converted to active plasmin by plasminogen activators
  • Tissue plasminogen activator (t-PA) secreted by endothelial cells
  • t-PA release is stimulated by activated protein C
65
Q

What does t-PA have a high affinity for?

A

t-PA has high affinity for fibrin and can therefore bind to clots

66
Q

What does t-PA do once it reaches the clot

A
  • Activates plasminogen to plasmin

- Degrades the clot

67
Q

What inhibits t-PA?

A

t-PA that is released into circulation is inhibited by two different factors

  • α2-antiplasmin
  • α2-macroglobulin
68
Q

Describe streptokinase

A
  • Produced by β-hemolytic streptococci
  • Exogenous activator of plasminogen
  • Used to treat pulmonary embolism and deep vein thrombosis
  • May be given prophylactically following heart attack

Endocrine Exam 2 (18 decks)

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