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Pathological Basis of Disease I > Robbins Ch. 4 - Hemostasis and the Clotting Cascade > Flashcards

Robbins Ch. 4 - Hemostasis and the Clotting Cascade Flashcards

1
Q

What is hemostasis?

A

Process by which blood clots form at injury sites

Precisely orchestrated cascade involving platelets, clotting factors, and endothelium that occurs at the site of a vascular injury and culminates in the formation of a blood clot

clot stops bleeding and loss of fluids

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2
Q

A 27 yo male prisoner is shanked in the arm with a long screwdriver. What is the first step in hemostasis/formation of clot/plugging hole?

A

Arteriolar vasoconstriction

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3
Q

What 2 things mediates the first step in the clotting process?

A

First step is vasoconstriction

Transient, mediated by reflex neurogenic mechanisms

augmented by localized secretion of things like endothelin, an endothelium-derived vasoconstrictor

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4
Q

After vasoconstriction, what happens next in hemostasis to control bleeding?

A

Formation of platelet plug

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5
Q

How is the platelet plug created?

A

Endothelium is breached/shanked

Endothelium will now show the previously hidden von Willebrand Factor (vWF) and collagen

vWF and collagen adhere and activate platelets

activated platelets go from cute, clumsy blebs to spiky tinker toys to increase surface area.

Platelet granules released.

Additional platelets are recruited, aggregate to form primary hemostatic plug

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6
Q

Congratulations, a primary hemostatic plug has been formed. Snitches will indeed only get stitches today. What is the next step in hemostasis?

A

Secondary hemostasis: deposition of fibrin

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7
Q

What is the process for secondary hemostasis?

A

Tissue factor is also revealed when endothelium is breached

  • procoagulant glycoprotein, expressed in subendothelial vessel wall (in smooth mm cells, fibroblasts)

Tissue factor binds and activates Factor VII

Clotting cascade happens

Thrombin formed

Thrombin cleaves fibrinogen into fibrin

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8
Q

Fibrin has been created in secondary hemostasis. How does this help with hemostasis?

A

Fibrin will form an insoluble meshwork

  • also a potent activator of platelets, creating more platelet aggregation at injury site

Secondary hemostasis will consolidate plug created in primary hemostasis

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9
Q

Primary and secondary hemostasis has occurred, and a robust clot/plug has been formed. What happens now?

A

Clot stabilization and resorption

Polymerized fibrin and platelet aggregates undergo contraction to form a solid, permanent plug that prevents further hemorrhage

t-PA works here

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10
Q

What is t-PA?

A

tissue plasminogen activator

A blood protein that limits clotting to site of injury

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11
Q

What general role do platelets play in hemostasis?

A

Forms initial primary plug

  • seals vascular defects/injury/site of shanking
  • makes surface that binds and concentrates activated coagulation factors
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12
Q

What is the cellular origin and rough morphology of platelets?

A

Platelets are disc-shaped bags of proteins, with no nucleus

Shed from megakaryocytes in bone marrow, released into blood stream

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13
Q

What general components do platelets need in order to function?

A
  1. several glycoprotein receptors
  2. contractile cytoskeleton
  3. 2 types of cytoplasmic granules
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14
Q

Platelets have 2 types of granules - alpha and gamma. What is in alpha granules? (7)

A

Alpha granules

adhesion molecule P-selectin on membranes

also contain coagulation proteins - fibrinogen, Factor V, vWF

wound healing proteins - fibronectin, platelet factor 4, PDGF, TGF-þ

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15
Q

What are the contents of gamma granules in platelets? (5)

A

Gamma/dense granules:

ADP

ATP

Ca++

5HT - serotonin

epinephrine

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16
Q

After a traumatic injury, platelets come into contact with vWF and collagen. What series of reactions happen next to form a platelet plug?

A

Platelet adhesion

Platelets changing shape

Secretion/release of granule contents

Platelet activation

Platelet aggregation

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17
Q

How is platelet adhesion mediated?

A

Interactions with vWF

vWF will act as a ‘bridge’ between platelet surface glycoprotein receptor Ib (GpIb) and exposed collagen

18
Q

Platelets need to change shape in order to form a plug and create hemostasis. What other changes accompany this process?

A

Platelets get spiky in order to increase surface area

With this you get:

  • alterations in glycoprotein IIb/IIIa, increases affinity for fibrinogen
  • translocation of negatively charged phospholipids to platelet surface
19
Q

Platelets need to put negatively charged phospholipids on its surface during adhesion. Why? What phospholipids?

A

Often will phosphatidylserine on platelet surface

Negative phospholipids will bind Ca++ and serve as nucleation sites for assembly of coagulation factor complexes

20
Q

Platelet activation often includes what 2 events?

A

Release of granules

Change in shape

21
Q

What triggers platelet activation?

A

Thrombin cleaving PAR (protease-activated receptor, a GPCR)

Release of ADP

22
Q

What is recruitment?

A

Platelet activation and release of ADP, which induces more platelets to activate and join the plug.

23
Q

After platelet activation has happened, what occurs?

A

Platelet aggregation

Conformational change in GIIb/IIIa allows for fibrinogen to bind

  • fibrinogen will form bridges between adjacent platelets, which leads to aggregation
24
Q

Platelet aggregation also occurs with thrombin activation. What does thrombin activation contribute to?

A

Converts fibrinogen into insoluble fibrin

  • cements platelets in place and creates definitive secondary hemostasic plug
25
Q

In addition to fibrin and platelets, what else should you expect to see in a hemostatic plug?

A

Trapped RBCs and leukocytes

  • leukocytes get stuck on p-selectin on activated platelets
26
Q

Each step of the clotting cascade involves what 3 general actors?

A

Enzyme - activated coagulation factor

Substrate - inactive proenzyme form of a coagulation factor

Cofactor - reaction accelerator

27
Q

What coagulation factors need calcium as a cofactor? What other cofactor do these need?

A

Factors II, VII, IX and X

Also will need Vitamin K

Antagonized by coumadin

28
Q

What are the steps of the intrinsic pathway?

A

Negative charged surface

XII → XIIa

XIIa, XI → XIa

XIa, IX → IXa + VIIIa

IXa + VIIIa → X

X → Xa + Va

prothrombin → thrombin

fibrinogen → fibrin

29
Q

What is the quick and dirty run down of the steps of the intrinsic pathway?

A

XII

XI

IX

VIII

X and V

thrombin and fibrin

30
Q

What are the steps of the extrinsic pathway?

A

TF and VII → TF + VIIa

X → Xa + Va

Prothrombin to thrombin

fibrinogen to fibrin

31
Q

You have learned about the intrinsic and extrinsic pathway for clotting in vitro, what is the cascade for clotting in vivo?

A

VII + TF → VIIaTF, works on

IX → IXaVIIIa, works on

X → XaVa, works on

prothrombin → thrombin

fibrinogen → fibrin

32
Q

What are the inhibitory elements of the clotting cascade in vivo?

A

Thrombin will inhibit severel places upstream:

XaVa

IxaVIIIa

conversion of Xi to XIa

XIa will inhibit activation of IX

33
Q

What are the platelet inhibitory effects of endothelium?

A

Serves as a barrier between platelets and vWF

Releases:

Prostacyclin - PGI2

NO

Adenosine disphospatase - breaks down ADP

Binds and alters activity of thrombin (potent platelet activator)

34
Q

What are the anticoagulant effects of endothelium?

A

Normal epithelium shields coagulation factors from tissue factors

Expresses factors that actively oppose coagulation:

thrombomodulin

endothelial protein C receptor

heparin-like molecules

tissue-factor pathway inhibitor

35
Q

What does thrombomodulin and endothelial protein C receptor do?

A

Bind thrombin and protein C in a complex on the endothelial surface

  • thrombin will lose ability to activate coagulation factors and platelets
  • thrombin will activate protein C
36
Q

What is protein C? How does it do, and how is it activated?

A

It’s a vitamin-K dependent protease that requires a cofactor - protein S

Protein C/Protein S is a potent inhibitor of Factors Va and VIIIa

37
Q

What do heparin-like molecules present on the surface of endothelium do?

A

Bind and activates thrombin III

38
Q

What does heparin III do?

A

Heparin III inhibits thrombin and factors IXa, Xa, XIa, and XIIa

  • most of the intrinsic pathway
39
Q

How does tissue factor pathway inhibitor work?

A

Requires protein S as a cofactor

Binds and inhibits tissue factor and factor VIIa complexes

40
Q

Endothelium also has some fibrinolytic effects. How are these mediated?

A

Normal epithelials make t-PA, a key component of the fibrinolytic pathway

Pathological Basis of Disease I (11 decks)

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