3.4.4. Hemostasis Flashcards
What are the three stages of hemostasis?
Primary
Secondary
Fibrinolysis
What is the primary stage of hemostasis?
(vasconstriction) activation, adhesion and aggregation (of platelets/ forms white thrombus, predominantly in the arteries - causes ischemia)
What is the secondary stage of hemostasis?
activation of the coagulation cascade - conversion of fibrinogen to fibrin (red thrombus - predominantly in the veins - causes embolism)
What is the fibrinolysis stage of hemostasis?
activation of plasmin to break down fibrin
***In order to prevent occlusion, drugs inhibit what?***
***In order to prevent occlusion, drugs inhibit primary and secondary and activate fibrinolysis***
Endothelium of vessels is inherently anti-thrombogenic, damage exposes the underlying extracellular matrix, which activates _____ and triggers the formation of a thrombus.
Endothelium of vessels is inherently anti-thrombogenic, damage exposes the underlying extracellular matrix, which activates platelets and triggers the formation of a thrombus.
How does the primary stage of hemostasis progress? (What is its mechanism of action)
How is Aspirin an anti-thrombogenic? Does this effect of Aspirin benefit from increased dosages?
- 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]
What are the risks of Aspirin use?
- Risks: GI bleed, allergic reaction (asthma), contraindicated in children (Reye’s Syndrome)
What are the Thienopyridines? What are some examples of these?
ADP Receptor Inhibitors: “Thienopyridines”
Clopidogrel, Ticlopidine, Prasugrel, (-grel)
How do the thienopyridines work?
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]
Are the thienopyridines pro-drugs? What is their speed of onset?
Are ***pro-drugs***, activated hepatically and of slow onset (prasugrel is slightly faster)
Thienopyridines may be used in conjunction with what to increase their anti-platelet activity?
May be used in conjunction with aspirin to provide additional anti-platelet activity
What are the side effects of Thienopyridine use?
Side effects:
neutropenia
thrombocytopenia
TTP/HUS may be seen
Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic-Uremic Syndrome (HUS)
What are some indications for use of thienopyridines?
Use for: acute coronary syndrome, coronary stenting, and decreasing the incidence or recurrence of thrombotic stroke
Are there any reversible ADP inhibitors?
***Ticagrelor is a reversible ADP inhibitor, that is not a pro-drug and better overall in efficacy but is MUCH more expensive***
What is the mechanism of action of Dipyridanole?
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
What are the indicated uses for Dipyridanole?
- 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)
What are the risks associated with taking dipyridanole?
Risks: nausea, headaches, hypersensitivity, hypotension, facial flushing, abdominal pain
What does Cilostizol do?
inhibits platelet aggregation
antithrombotic and vasodilator
PDE3 inhibitor; increases cAMP
What is an indicated use of Cilostizol?
approved for use with claudication due to peripheral arterial disease
What are the risk of taking Cilostizol?
Risks: use of drugs that inhibit metabolism via CYP3A4 or CYP2C19
Once present what must happen to GPIIa/IIIb for a clot to form? What drugs interfere with this process?
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
How do you administer Fibrinogen Receptor Blockers (FRBs)
These drugs will be administered via IV (often with aspirin or warfarin)
What are the indications for FRBs?
Indications: unstable angina, percutaneous transluminal coronary angioplasty
What is a major side effect of FRBs?
Major side effect is bleeding, as well as thrombocytopenia
What is Abciximab?
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!
What does Abciximab prevent?
prevents platelet aggregation and formation of thrombus
What are the uses of abciximab?
Uses: during angioplasty (reduces the risk of ischemia, MI)
What is eptifibatide?
reversible (synthetic) heptapeptide inhibitor of the fibrinogen binding site, inhibits ligand binding
What is a contraindication of eptifibatide?
renally cleared
contraindicated with renal insufficiency
What is a use of Eptifibatide?
use to treat unstable angina
What is Tirofiban?
similar, smaller synthetic molecule inhibitor of GPIIa/IIIb
What are the uses of Tirofiban?
Use: management of unstable angina, angioplasty
What is unfractionated heparin (UFH)?
highly sulfated glycosaminoglycan (negatively charged) Made by mast cells used to prevent venous thrombus
What does UFH do to prevent venous thrombus?
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
When do we use UFH?
Use for embolism, MI/stroke
What should we see in the aPTT with UFH treatment?
Should observe 1.5-2 fold increase in aPTT
How do we give UFH? Why might we use it instead of Low Molecular Weight Heparin (LMWH)?
Immediate onset (IV use only)
LMWHeparin is better, but UFH has antidote for overdose (protamine sulfate - but too much PS causes increased bleeding)
When administering anti-coagulants, what two lab values do we need to keep track of?
monitor aPTT vs INR
What is fondaparinux?
Synthetic version of LMWH
What are two bonuses of using LMWH or fondaparinux?
Don’t need to monitor aPTT because does not inhibit thrombin, only factor Xa
better/more predictable pharmacokinetics
What do we use LMWH or fondaparinux for?
Used for DVTs
What are the risks and contraindications of LMWH and fondaparinux?
Risks: bleeding, heparin induced thrombocytopenia “HIT” (autoimmune reaction that destroys platelets (Ig-mediated)
Contraindicated prior to major surgeries
What is a class of alternatives to heparin?
hirudin derived compounds (-irudin)
What are the hirudin derived compounds?
direct and irreversible thrombin inhibitors found in leech saliva
What is lepirudin and how does it work?
lepirudin: recombinant version of hirudin, works independently of antithrombin to inactivate fibrin-bound thrombin. Rapid onset, renal clearance
What is bivalirudin, does it work fast, how is it cleared?
bivalirudin: bivalent thrombin inhibitor, rapid onset, short half-life, renal clearance
What is argatroban?
argatroban: small synthetic molecule, short half-life, needs continuous IV
What are the risk associated with argatroban use?
risks: cleared by CYP450 system, dose reduction required with liver disease, elevated INR - difficult to transition to warfarin
What are the indications for use of the hirudin compounds?
Indications for use: HIT-induced thrombosis, coronary angioplasty - USED IN PLACE OF HEPARIN FOR ANTICOAGULATION
Whe monitoring the aPTT with hirudin compounds, what increases are we looking for?
MUST monitor aPTT, aim for 1.5-3 fold increase
What is warfarin?
THE oral coagulant, dicumarol based analogue
Originally was rat poison, may have also been used in IEDs/bombs
Is warfarin a safe drug to use?
No, LOTS of issues (and drug interactions)
What is the MoA of Warfarin?
(Mech of Action)
- 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
Warfarin is used for:
Use for: DVT, PE, a. fib, heart valve replacement, less effective for prevention of new thrombus
What kind of therapeutic index are we looking at with Warfarin?
Very narrow therapeutic index
What are we worried about with Warfarin?
May cause excessive bleeding, “catastrophic hemorrhage”
low renal clearance
How can we fix Warfarin caused issues?
“Antidote” is vitamin K and fresh frozen plasma
What is a contraindication for Warfarin?
Contraindicated in pregnancy, crosses the placenta and is teratogenic
Compare Warfarin and Heparin
What is the bonus of using Warfarin alternatives?
No longer requires the blood monitoring
What is dabigatran?
orally active direct thrombin inhibitor
prodrug
How is dabigatran cleared? What are some uses for it?
Use: a. fib, prevent DVT, in hip/knee replacements
no CYP450 metabolism; renal clearance
What is Rivaroxaban? How is it metabolized and where is it cleared?
orally active, direct inhibitor of factor Xa
CYP3A4 metabolism; mainly renal clearance
What is Apixaban?
orally active, direct inhibitor of factor Xa
What do we use Apixaban for? How is it metabolized and where is it cleared?
prevent DVT
CYP3A4 metabolism; less renal clearance
What is the clinical use of Warfarin alternatives?
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
What is the toxicity associated with riva- and apixaban?
toxicity (both riva- & apixaban): bleeding (no specific reversal agent available)
In an acute event, how do we administer thrombolytic drugs?
Thrombolytic Drugs: exclusively IV use in an acute event
What are some uses for thrombolytic drugs?
acute myocardial infarction
acute ischemic stroke
acute PE
acute DVT
What are some contraindications of thrombolytic drugs?
bleeding, HTN, and surgery
What are some thrombolytic drugs?
Alteplase (tPA), reteplase (rPA), tenecteplase (TNK-tPA)
What is the MoA of these thrombolytics? Their clinical use? What about their toxicities?
What are the Tissue Plasminogen activators?
“plase”s
natural endothelium derived
only cleaves fibrin-bound plasminogen
increased bleeding risk
What is Streptokinase? How does it work?
bacterially derived
complexes with plasminogen proactivator to catalyze conversion of plasminogen to plasmin
active on circulating and fibrin-bound plasminogen
What is urokinase? What does it do?
found in the kidney
directly converts plasminogen to plasmin
active on bound circulating and fibrin-bound plasminogen
What are we interested in Factor VII use as a pro-coagulant?
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
