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Heme - Strom > Basic Science of Platelets and Coagulation Factors > Flashcards

Basic Science of Platelets and Coagulation Factors Flashcards

1
Q

Von Willibrand Factor
• Tertiary Structure
• Alterations needed for a functional protein
• Binding sites

A

vWF
Tertiary Structure:
• Very Long Linear Multimer of Homodimers

Alterations
• These MUST be trimmed to the optimal length
• BINDING TO COLLAGEN ALTERS THE TERTIARY STRUCTURE TO EXPOSE MORE PLATELET BINDING SITES

Binding Sites
• Collagen
• Platelet Gp1b
• Factor VIII

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2
Q

What is the relationship between vWF and factor VIII?

A

Von Willibrand Factor Stabilizes it

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3
Q

What proteins are involved in platelet BINDING?

A
  • Gp1b binds vWF

* GPIa/IIa binds collagen

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4
Q

What is secreted by platelets on ACTIVATION?

A

• TXA2
• ADP
• Including Ca2+
**Factor 5, fibrinOGEN

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5
Q

What proteins allow for platelet aggregation?

A

• ACTIVATION of GpIIb/IIIa which binds fibrinOGEN

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6
Q

In general how does a protease act on a pro-enzyme and co-factor to AMPLIFY each step of the cascade?

A

Pro-enzyme and cofactor are EACH acted on by the Protease and combine to form an ACTIVE Protease:Cofactor product

• Many of this Protease:Cofactor product will be made and Each of these will initiate another step by acting on Pro-enzyme2 and cofactor2 (so forth and so on)

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7
Q

how does calcium act to activate factor VII and other proteases?

A
  • Ca2+ binds Negative residues and and puts more charge around hydrophobic residues on the inside of the protein
  • Hydrophobic residues move to the exterior to avoid the charge and hang down allowing them to interact with hydrophobic residues in the membrane

***Ca2+ putting + charge where the negative charge once was also allows for favorable electrostatic interactions with the exterior of the cells

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8
Q

T or F: the conformational change created by Ca2+ binding is important for enzyme ACTIVATION only.

A

False, it IS needed for ACTIVATION but it is also needed to flip out hydrophobic residues so that it can anchor into the membrane

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9
Q

What is the importance of Vit. K in blood coagulation?

• SPECIFICALLY, what factors is this important to?

A
  • Vit. K is needed in gamma-carboxylation of AA residues so that they become bi-dentate and can bind divalent Ca2+
  • NEEDED FOR: Factors II, VII, IX, X
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10
Q

What is the INITIAL job of thrombin (factor II) in the coagulation cascade?
• What does it do later?

A

• activated thrombin (IIa) catalyzes 2 rxns

  1. VIII to VIIIa
  2. IX to IXa

at this point Thrombin is localized to the endothelial cell surface so it does NOT yet cleave fibrinogen to fibrin

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11
Q

What activates the intrisic pathway?

• how is this done?

A

Activated Thrombin (IIa) Kicks of the intrinsic cascade through catalysis of 2 rxns that lead to the formation of TENASE (VIIIa/IXa)

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12
Q

What is the importance of Factor IXa being able to “swim?”

A

it can diffuse from the damaged endothelial surface to the site where there is more substrate (aka Factor 10)

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13
Q

T or F: Activated thrombin (IIa) ACCELERATES and FINALIZES the process of fibrin generation

A

True

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14
Q

What 5 rxns are catalyzed by thrombin?

A 
Factor VIII activation
Factor IX activation
Factor V activation (Propagation phase only)
Fibrinogen ----> Fibrin
Factor XIII activation
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15
Q

What does Antithrombin inactivate?
• Where is it produced?
• Where does it typically exist?

A

Antithrombin inactivates Thrombin (IIa) as well as factor Xa

  • Produced by the Liver
  • Typically exists in Plasma
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16
Q

How does thrombomodulin work?

• Where is typically found?

A

Co-Factor for thrombin FOUND ON NORMAL EPITHELIAL cells that MODULATES thrombin activity to Activate Protein C

17
Q

How does protein C work?
• what pathways does it work on?
• How so?

A

Protein C is activated by Thombin:Thombomodulin and combines with protein S to make APC:S which INACTIVATES Factor VIIIa and Factor Va

18
Q

What protein works to break down Cross-Linked Fibrin and Limit the extent of the clot to damage area only?
• Where is the protein made?
• How is it activated?
• How does the clot stay local?

A
  • Plasmin breaks down the clot, its precursor PLASMINOGEN circulates normally in the blood.
  • Plasminogen is activated to Plasmin by t-PA (tissue plasminogen activator)
  • t-PA is found on NORMAL-UNDAMAGED epithelial cells, thus fibrin is broken down only in that region
19
Q

What does the PT measure?
• How is the assay performed?
• What specifically is being measured?
• Factors involved?

A

• How long it takes the Plasma to form Fibrin

How its performed:
• “Prothrombin” - a mixture of Ca2+, Phospholipids, and Tissue Factor (TF) are mixed with Pts. blood and time to clot is measured

Pathways measured:
• Extrinsic and Common Pathways

20
Q

What drugs is the PT test particularly sensitive to? why?
• Factors measured?
• Why include calcium?

A

Sensitive to:
Warfarin —> because warfarin is a gamma carboxylation antagonist that works by acting on Vit. K

Factors measured (all the Vit. K factors except IX):
• Factor VII (MAINLY) - b/c it has fastest turnover rate of all Vit. K dep. factors
• Factor II
• Factor V
• Factor X

21
Q

What does the PTT assay measure?

• Pathway, Factors?

A

Measures time it takes the EXTRINSIC pathway to create a clot
• Factor IIa
• Factor VIIIa
• Factor IXa

**These are the primary factors that are measured

22
Q

What reagent is added to perform the PTT assay?

A

Activated Partial Thromboplastin:
• Ground Glass
• Phospholipids
• Ca2+

23
Q

T or F: Factors XII and VII play huge roles in the coagulation cascade in vivo and thats why we measure them using PTT and PT respectively.

A

False, in vivo these proteins just kick of the cascades

24
Q

What happens when there are defects in the actual structure of the vWF homo dimers?
• what disorder occurs as a result?
• Inherited?

A

Von Willibrand’s Disease
• Bleeding Disorder
• Autosomal Dominant

25
Q

What drugs upregulates circulating vWF AND Factor VIII?

A

DDAVP

26
Q

What disorders occur as a result of failure to cleave vWF?

• what type of disorders are these?

A

Thrombophilia disorders

TTP (thrombotic thrombocytopenia purpura)
HUS (hemolytic uremic syndrome)

27
Q

What causes the subtypes of Von Willibrand’s disease?

A

Defects in:
• Gp1b - Bernard-Soulier Syndrome (RARE)
• Factor VIII

28
Q

What causes Bernard-Soullier?
• compare frequency of cases compared to von Willibrand’s disease.
• Inherited?

A

Defects in Gp1b

  • Much more rare than von Willibrand’s Disease
  • Yes, inherited (mode not stated)
29
Q

What drug blocks the receptor for ADP?

• Irreversible or Reversible?

A

Clopidogrel

• IRREVERSIBLE

30
Q

What disease results from inability to activate GpIIb/IIIa?

• Drugs are used to induce a similar state?

A

Glanzmann’s Thrombasthenia (rare bleeding disorder)

Used at Drug Target for:
• abciximab
• eptifibatide
• tirofiban

31
Q

What disease result from defects in factors VIII and IX?

A 
Hemophilia A (VIII)
Hemophilia B (IX)
32
Q

What drugs act as direct factor Xa inhibitors?

A
  • Apixaban

* Rivaroxaban

33
Q

What drugs act as direct thrombin (II) inhibitors?

A
  • Dabigatran

* Hirudin

34
Q

Which test would you want to use to see if the coumadin you gave is working? why?
• How does this drug work?

A

PT
• It measures the EXTRINSIC pathway that is kicked off by Factor VII
• Factor VII is vit. K dependent (as are II, IX, X), BUT it is the fastest protein to be turned over so it is the 1st factor to show affect

Coumadin = Warfarin
• Both inhibit Vit. K dependent gamma carboxylation

35
Q

How does heparin work?

A

Heparin (high or low MW) activates Antithrombin just like Heparin-Like Molecules do in nature

**antithrombin will just go on to block IIa (thrombin) from converting fibrinogen to fibrin

36
Q

What are some defects involving Protein C that you should be aware of?
• state whether each of these conditions are inherited or not?

A

ALL are inherited PROTHROMBOTIC conditions
• Protein C deficiency
• Protein S deficiency
• Factor V leiden (APC resistant)

37
Q

What test would you use to test for Hemophilia A?

• would this work for hemophilia B?

A

PTT because it measures the extrinsic pathway

  • The intrinsic pathways involves factors XII, XI, IX, and VIII
  • Factors 8 and 9 are involved in hemophilia A and B so PTT is a useful test here
38
Q

In addition to being used to test for Hemophilia A and B. What drug is the PTT useful for measuring the effectiveness of?

A

PTT good at measuring Heparin effectivness because Heparin activates thrombomodulin which inactivates thrombin (IIa)

**Note: PTT is good for measure COMMON and INTRINSIC pathways

Heme - Strom (13 decks)

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