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CPR Week 4 > 3.4.4. Hemostasis > Flashcards

3.4.4. Hemostasis Flashcards

1
Q

What are the three stages of hemostasis?

A

Primary

Secondary

Fibrinolysis

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2
Q

What is the primary stage of hemostasis?

A

(vasconstriction) activation, adhesion and aggregation (of platelets/ forms white thrombus, predominantly in the arteries - causes ischemia)

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3
Q

What is the secondary stage of hemostasis?

A

activation of the coagulation cascade - conversion of fibrinogen to fibrin (red thrombus - predominantly in the veins - causes embolism)

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4
Q

What is the fibrinolysis stage of hemostasis?

A

activation of plasmin to break down fibrin

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5
Q

***In order to prevent occlusion, drugs inhibit what?***

A

***In order to prevent occlusion, drugs inhibit primary and secondary and activate fibrinolysis***

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6
Q

Endothelium of vessels is inherently anti-thrombogenic, damage exposes the underlying extracellular matrix, which activates _____ and triggers the formation of a thrombus.

A

Endothelium of vessels is inherently anti-thrombogenic, damage exposes the underlying extracellular matrix, which activates platelets and triggers the formation of a thrombus.

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7
Q

How does the primary stage of hemostasis progress? (What is its mechanism of action)

A
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8
Q

How is Aspirin an anti-thrombogenic? Does this effect of Aspirin benefit from increased dosages?

A
  • COX-1 inhibitor (irreversible)
  • Decreases the production of Thromboxane A2 (potent stimulator of platelet aggregation and adhesion)
  • At high doses, may decrease anti-thrombotic action by decreasing the synthesis of PGI2 [no additional benefit to increased aspirin dosing]
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9
Q

What are the risks of Aspirin use?

A
  • Risks: GI bleed, allergic reaction (asthma), contraindicated in children (Reye’s Syndrome)
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10
Q

What are the Thienopyridines? What are some examples of these?

A

ADP Receptor Inhibitors: “Thienopyridines”

Clopidogrel, Ticlopidine, Prasugrel, (-grel)

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11
Q

How do the thienopyridines work?

A

irreversible inhibitors of ADP receptors [which inhibit fibrinogen binding by preventing glycoprotein IIb/IIIa from binding to fibrinogen by preventing their expression on the platelet cell surface]

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12
Q

Are the thienopyridines pro-drugs? What is their speed of onset?

A

Are ***pro-drugs***, activated hepatically and of slow onset (prasugrel is slightly faster)

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13
Q

Thienopyridines may be used in conjunction with what to increase their anti-platelet activity?

A

May be used in conjunction with aspirin to provide additional anti-platelet activity

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14
Q

What are the side effects of Thienopyridine use?

A

Side effects:

neutropenia

thrombocytopenia

TTP/HUS may be seen

 Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic-Uremic Syndrome (HUS)
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15
Q

What are some indications for use of thienopyridines?

A

Use for: acute coronary syndrome, coronary stenting, and decreasing the incidence or recurrence of thrombotic stroke

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16
Q

Are there any reversible ADP inhibitors?

A

***Ticagrelor is a reversible ADP inhibitor, that is not a pro-drug and better overall in efficacy but is MUCH more expensive***

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17
Q

What is the mechanism of action of Dipyridanole?

A

inhibits the cellular uptake of adenosine (which modulates vasodilation and aggregation activity) and increases cGMP/AMP levels through PDE inhibition [specifically PDE3]

  • ultimately inhibits platelet aggregation and causes vasodilation
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18
Q

What are the indicated uses for Dipyridanole?

A
  • limited use: usually prophylaxis of angina or thrombus with prosthetic heart valves [when combined with warfarin]
    • also indicated for: intermittent claudication, coronary vasodilation, prevention of stroke or other TIAs (when combined w/aspirin)
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19
Q

What are the risks associated with taking dipyridanole?

A

Risks: nausea, headaches, hypersensitivity, hypotension, facial flushing, abdominal pain

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20
Q

What does Cilostizol do?

A

inhibits platelet aggregation

antithrombotic and vasodilator

PDE3 inhibitor; increases cAMP

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21
Q

What is an indicated use of Cilostizol?

A

approved for use with claudication due to peripheral arterial disease

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22
Q

What are the risk of taking Cilostizol?

A

Risks: use of drugs that inhibit metabolism via CYP3A4 or CYP2C19

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23
Q

Once present what must happen to GPIIa/IIIb for a clot to form? What drugs interfere with this process?

A

GPIIa/IIIb must be activated by agonists (such as TxA2, collagen, chronic tissue damage) in order to bind fibrinogen and lead to aggregation of activated platelets

Fibrinogen Receptor Blockers interfere with this

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24
Q

How do you administer Fibrinogen Receptor Blockers (FRBs)

A

These drugs will be administered via IV (often with aspirin or warfarin)

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25
Q

What are the indications for FRBs?

A

Indications: unstable angina, percutaneous transluminal coronary angioplasty

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26
Q

What is a major side effect of FRBs?

A

Major side effect is bleeding, as well as thrombocytopenia

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27
Q

What is Abciximab?

A

a Fab (fragment antigen binding) fragment of humanized monoclonal antibody (partially derived from mouse IgG) which binds GPIIb/IIIa and blocks ligand binding

An FRB!

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28
Q

What does Abciximab prevent?

A

prevents platelet aggregation and formation of thrombus

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29
Q

What are the uses of abciximab?

A

Uses: during angioplasty (reduces the risk of ischemia, MI)

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30
Q

What is eptifibatide?

A

reversible (synthetic) heptapeptide inhibitor of the fibrinogen binding site, inhibits ligand binding

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31
Q

What is a contraindication of eptifibatide?

A

renally cleared

contraindicated with renal insufficiency

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32
Q

What is a use of Eptifibatide?

A

use to treat unstable angina

33
Q

What is Tirofiban?

A

similar, smaller synthetic molecule inhibitor of GPIIa/IIIb

34
Q

What are the uses of Tirofiban?

A

Use: management of unstable angina, angioplasty

35
Q

What is unfractionated heparin (UFH)?

A

highly sulfated glycosaminoglycan (negatively charged) Made by mast cells used to prevent venous thrombus

36
Q

What does UFH do to prevent venous thrombus?

A

enhances the activity of endogenous antithrombin protein to inhibit thrombin and factor Xa

***binds antithrombin and acts as a catalytic surface and increase activity by 1,000 fold***

Thrombin can then detach and inhibit other thrombin/Xa molecules

37
Q

When do we use UFH?

A

Use for embolism, MI/stroke

38
Q

What should we see in the aPTT with UFH treatment?

A

Should observe 1.5-2 fold increase in aPTT

39
Q

How do we give UFH? Why might we use it instead of Low Molecular Weight Heparin (LMWH)?

A

Immediate onset (IV use only)

LMWHeparin is better, but UFH has antidote for overdose (protamine sulfate - but too much PS causes increased bleeding)

40
Q

When administering anti-coagulants, what two lab values do we need to keep track of?

A

monitor aPTT vs INR

41
Q

What is fondaparinux?

A

Synthetic version of LMWH

42
Q

What are two bonuses of using LMWH or fondaparinux?

A

Don’t need to monitor aPTT because does not inhibit thrombin, only factor Xa

better/more predictable pharmacokinetics

43
Q

What do we use LMWH or fondaparinux for?

A

Used for DVTs

44
Q

What are the risks and contraindications of LMWH and fondaparinux?

A

Risks: bleeding, heparin induced thrombocytopenia “HIT” (autoimmune reaction that destroys platelets (Ig-mediated)

Contraindicated prior to major surgeries

45
Q

What is a class of alternatives to heparin?

A

hirudin derived compounds (-irudin)

46
Q

What are the hirudin derived compounds?

A

direct and irreversible thrombin inhibitors found in leech saliva

47
Q

What is lepirudin and how does it work?

A

lepirudin: recombinant version of hirudin, works independently of antithrombin to inactivate fibrin-bound thrombin. Rapid onset, renal clearance

48
Q

What is bivalirudin, does it work fast, how is it cleared?

A

bivalirudin: bivalent thrombin inhibitor, rapid onset, short half-life, renal clearance

49
Q

What is argatroban?

A

argatroban: small synthetic molecule, short half-life, needs continuous IV

50
Q

What are the risk associated with argatroban use?

A

risks: cleared by CYP450 system, dose reduction required with liver disease, elevated INR - difficult to transition to warfarin

51
Q

What are the indications for use of the hirudin compounds?

A

Indications for use: HIT-induced thrombosis, coronary angioplasty - USED IN PLACE OF HEPARIN FOR ANTICOAGULATION

52
Q

Whe monitoring the aPTT with hirudin compounds, what increases are we looking for?

A

MUST monitor aPTT, aim for 1.5-3 fold increase

53
Q

What is warfarin?

A

THE oral coagulant, dicumarol based analogue

Originally was rat poison, may have also been used in IEDs/bombs

54
Q

Is warfarin a safe drug to use?

A

No, LOTS of issues (and drug interactions)

55
Q

What is the MoA of Warfarin?

(Mech of Action)

A
  • Blocks the formation of inactive forms of clotting factors
  • no effect on those previously synthesized
  • slow onset of action
  • inhibits the Vitamin K epoxide reductase and decreases available K+ (essential cofactor for factor generation)
  • prevents gamma-carboxyglutamate post-translational modification of “Gla domains” and activation of clotting factors
56
Q

Warfarin is used for:

A

Use for: DVT, PE, a. fib, heart valve replacement, less effective for prevention of new thrombus

57
Q

What kind of therapeutic index are we looking at with Warfarin?

A

Very narrow therapeutic index

58
Q

What are we worried about with Warfarin?

A

May cause excessive bleeding, “catastrophic hemorrhage”

low renal clearance

59
Q

How can we fix Warfarin caused issues?

A

“Antidote” is vitamin K and fresh frozen plasma

60
Q

What is a contraindication for Warfarin?

A

Contraindicated in pregnancy, crosses the placenta and is teratogenic

61
Q

Compare Warfarin and Heparin

A
62
Q

What is the bonus of using Warfarin alternatives?

A

No longer requires the blood monitoring

63
Q

What is dabigatran?

A

orally active direct thrombin inhibitor

prodrug

64
Q

How is dabigatran cleared? What are some uses for it?

A

Use: a. fib, prevent DVT, in hip/knee replacements

no CYP450 metabolism; renal clearance

65
Q

What is Rivaroxaban? How is it metabolized and where is it cleared?

A

orally active, direct inhibitor of factor Xa

CYP3A4 metabolism; mainly renal clearance

66
Q

What is Apixaban?

A

orally active, direct inhibitor of factor Xa

67
Q

What do we use Apixaban for? How is it metabolized and where is it cleared?

A

prevent DVT

CYP3A4 metabolism; less renal clearance

68
Q

What is the clinical use of Warfarin alternatives?

A

clinical use (both riva- & apixaban): Treatment and prophylaxis of DVT and PE (rivaroxaban), stroke prophylaxis in patients with atrial fibrillation. Oral agents do not usually require coagulation monitoring

69
Q

What is the toxicity associated with riva- and apixaban?

A

toxicity (both riva- & apixaban): bleeding (no specific reversal agent available)

70
Q

In an acute event, how do we administer thrombolytic drugs?

A

Thrombolytic Drugs: exclusively IV use in an acute event

71
Q

What are some uses for thrombolytic drugs?

A

acute myocardial infarction

acute ischemic stroke

acute PE

acute DVT

72
Q

What are some contraindications of thrombolytic drugs?

A

bleeding, HTN, and surgery

73
Q

What are some thrombolytic drugs?

A

Alteplase (tPA), reteplase (rPA), tenecteplase (TNK-tPA)

74
Q

What is the MoA of these thrombolytics? Their clinical use? What about their toxicities?

A
75
Q

What are the Tissue Plasminogen activators?

A

“plase”s

natural endothelium derived

only cleaves fibrin-bound plasminogen

increased bleeding risk

76
Q

What is Streptokinase? How does it work?

A

bacterially derived

complexes with plasminogen proactivator to catalyze conversion of plasminogen to plasmin

active on circulating and fibrin-bound plasminogen

77
Q

What is urokinase? What does it do?

A

found in the kidney

directly converts plasminogen to plasmin

active on bound circulating and fibrin-bound plasminogen

78
Q

What are we interested in Factor VII use as a pro-coagulant?

A

In trauma, giving factor VII as a pro-coagulant has been promising in pre-clinical studies

should only work at the site of injury

Reduce # of blood transfusions

No proof of increased survival (YET!!!!)

Currently only used in hemophilliacs that don’t respond to factor 8

CPR Week 4 (19 decks)

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