Anticoag, antiplate, thrombolytic textbook Flashcards
Stage one of hemostasis; formation of a platelet plug
Platelets are activated by interaction with collagen. The GP IIb/IIIa receptors must then undergo activation (a change in shape to allow fibrinogen binding) for aggregation
This plug is unstable and requires coagulation
How can GP IIb/IIIa receptors become activated
Thromboxane A2 Thrombin Collagen Platelet activation factor ADP
Stage two of hemostasis; coagulation
Production of fibrin (a thread like protein to reinforce the platelet plug) activated through intrinsic (contact activation) or extrinsic (tissue factor) pathways
Both converge at Xa
Extrinsic pathway
Vascular wall trauma triggers release of tissue factor AKA thromboplastin (a complex of several compounds) and then:
Activates VII which activates X
X catalyzes conversion of II to IIa (prothrombin to thrombin)
Thrombin does three things:
Catalyzes conversion of fibrinogen into fibrin
Catalyzes V into Va (increases Xa)
Catalyzes VIII into VIIIa which increases activity of IXa
Factors affected by warfarin
II (prothrombin), VII, IX, X,
VII is extrinsic
Factors affected by heparin
IXa, Xa, XIa, XIIa and thrombin (IIa)
XIIa, XIa, IXa are unique to intrinsic (doesn’t hit any extrinsic until Xa)
Contact activation (intrinsic) pathway
Activated when blood makes contact with collagen that has been exposed as a result of trauma
Collagen activates XII to XIIa
XIIa activates XI to XIa
XIa activates IX which activates X
Xa catalyzes conversion of II to IIa (prothrombin to thrombin)
Thrombin does three things:
Catalyzes conversion of fibrinogen into fibrin
Catalyzes V into Va (increases Xa)
Catalyzes VIII into VIIIa which increases activity of IXa
Which factors require vitamin K for synthesis
VII, IX, X and II(prothrombin)
Antithrombin
Inactivates clotting factors that stray from site of vessel injury. XIIa, XIa, IXa (intrinsic) and Xa, IIa (thrombin)
Antithrombin involved with heparin
Physiologic removal of clots
Plasmin degrades fibrin meshwork of the clot.
Produced through activation of plasminogen
Fibrinolytic drugs act by promoting conversion of plasminogen into plasmin
Arterial thrombosis
Adhesion of platelets from damage to wall or rupture of plaque causes platelets to release ADP and TXA2 which attract additional platelets to the evolving thrombus. The rest of the clotting cascade is then activated
Venous thrombosis
Stagnation of blood initiates coagulation cascade resulting in fibrin which enmeshes RBCs and platelets to form a thrombus
Typical venous thombus has a long tail which can produce an embolus, which can travel through the venous system and then become lodged.
Arterial is local venous can be distant from origin
Overview of three main drugs
Anticoagulants (heparin, warfarin, dabigatran) disrupt coagulation cascade and therefore suppress fibrin
Antiplatelet drugs (aspirin, clopidogrel) inhibit platelet aggregation
Thrombolytic drugs promote lysis of fibrin
Antiplatelet drugs most effective against
Preventing arterial thrombosis
Anticoagulants are most effected against
Venous thrombosis
Warfarin vs other anticoagulants
Warfarin inhibits synthesis of clotting factors including X and thrombin
All others inhibit activity of clotting factors, either Xa, thrombin or both
Heparin and its derivatives
Enhance antithrombin, which inactivates thrombin and Xa, therefore fibrin production is reduced and clotting is suppressed.
Heparin reduces activity of thrombin and Xa equally
LMW heparins reduce activity of Xa more than thrombin
Fondaparinux is selective to Xa and doesn’t touch thrombin
Heparin distribution
Has many negatively charged groups making it highly polar, and hence cannot readily cross membranes
Heparin MOA
Helps antithrombin inactivate clotting factors IIa and Xa
Binding of heparin to antithrombin enhances its ability to inactivate thrombin and Xa
Heparin itself does not bind with Xa
Great for prophylaxis of venous thrombosis
Effects seen within a minute IV
Heparin pharmacokinetics
Polarity and large size means it can’t be taken orally and it can’t cross into placenta or breast milk
Hepatic and renal metabolism, normal half life is 1.5 hours and extended with hepatic/renal failure
Highly variable plasma levels as it binds nonselectively
Uses of heparin
Pregnancy, pulmonary embolism, DVT, open heart surg and renal dialysis and low dose for postop prevention of thrombosis. DIC and MI
Adverse effects of heparin
Bleeding (10%)
Shock, bruises, petechiae, hematomas, discoloured poo, headache or faintness (cerebral) lumbar pain (adrenal hemorrhage)
Heparin induced thrombocytopenia (HIT)
Potentially fatal. Development of antibodies against heparin-platelet complexes activate plateletes and damage vascular endothelium, promoting thrombosis and loss of platelets. DVT, PE, stroke and MI risk.
Consider if platelet count falls or thrombosis forms despite adequate anticoagulation
Discontinue and switch
Heparin interaction
Platelet aggregation is the major remaining defence against hemorrhage. Aspirin and other drugs that depress platelet function will weaken this defence.
Heparin OD
Protamine sulfate. Small molecule with positively charged groups which bond ionically with heparin forming a heparin-protamine complex devoid of anticoagulant activity.
Occurs immediately and lasts 2 hours
1mg to 100 units of heparin
Lab monitoring for heparin
Activated partial thromboplastin time (aPTT)
Normal value is 40 seconds. Should increase 1.5-2 folx so 60-80 seconds on heparin.
Should be measured every 4-6 hours
Heparin routes
IV or subq. IM causes hematoma
LMW heparins
As effective as unfractionated.
Don’t require aPTT monitoring, can be used at home.
First line therapy for DVT
Enoxaparin (lovenox) and dalteparin (fragmin)
LMW heparins MOA
Preferentially inactivate Xa, and are much less active on thrombin.
They are too short to provide a binding site for thrombin
Pharmacokinetics of LMW heparins
Higher bioavailability and longer half-lives than heparin.
Up to 6x longer half life.
More specific binding means more predictable plasma levels and slower clearance
Adverse effects of LMW heparin
Bleeding, but less risky than heparin.
Can also cause immune-mediated thrombocytopenia
OD can be treated with protamine sulfate as well
Cost is $63 a day compared to $8 for heparin but don’t require aPTT monitoring
1mg of protamine per mg of enoxaparin
Warfarin, a vitamin K antagonist
Prevents thrombosis like heparin, but has delayed onset so not used in emergency
Warfarin MOA
Decreases 4 clotting factors, VII, IX, X and prothrombin (vit k dependent clotting factors)
Warfarin inhibits Vit K epoxide reductase complex I (VKORC1) which converts K to the active form
Reduces Vit K clotting factors by 30-50%
Pharmacokinetis of warfarin
99% binds to albumin
Unbound can cross membranes readily (placenta and milk)
Inactivated by CYP2C9
Acts quickly to inhibit synthesis of clotting factors, anticoag effects are delayed since those in circulation are not affected.
8-12 hours after first dose, peak effects take days.
After DC, effects last 2-5 days
Half life 1.5-2 days
Warfarin uses
Prevention of PE, thromboembolism with heart valves, prevention of thrombosis with a-fib
Three other options for a-fib now
Dabigatran (pradaxa, pradax) epixaban (eliquis) and rivaroxaban (xarelto) which are easier to use
Monitoring TX with warfarin
Prothrombin time (PT) which is sensitive to Vit K alterations in coagulation
Average PT is 12 seconds.
INR (international normalized ratio) is determined by multiplying PT ratio by a correction factor specific to particular thromboplastin prep used
INR of 2-3 appropriate for most pts (sometimes 2.5-3.5)
May take a week to reach desired INR after adjusting dosage
INR timing
Daily for 5 days
2X a week for 1-2 weeks
Once a week for 1-2 months
1-2X a month after
INR AND aPTT numbers
2-3 for INR sometimes 2.5-3.5
60-80 seconds for aPTT (partial thromboplastin time)
Warfarin hemorrhage
Same signs as heparin
Apixaban, rivaroxaban, and dabigatran pose significantly lower bleeding risks
Soft toothbrush and electric razor for lowering bleeding risk
Class X for preggos
Warfarin interactions
Lots, must avoid all drugs not prescribed.
Remember warfarin is 99% bound to albumin and something that unbinds could cause elevated plasma levels
Acetaminophen was used, but 2g a day increases high INR risk 10fold by preventing degradation of warfarin
Vitamin K1, for warfarin OD
2.5mg PO or 0.5 to 1mg IV.
IV can cause anaphylatic like reactions, give it slow and dilute it.
Dabigatran (pradax) vs warfarin
5 advantages to pradax Rapid onset No need to monitor INR Fewer interactions Lower risk of major bleed Predictable dose responses
MOA dabigatran
Reversible inhibitor of thrombin
Binds and inhibits thrombin that is free as well as thrombin bound to clots (heparin only inhibits free thrombin)
It prevents conversion of fibrinogen to fibrin and prevents activation of XIII thereby preventing conversion of soluble fibrin to insoluble fibrin
No specific antidote to reverse bleeding. Recombinant VIIa or IX may be tried.
Dialysis can remove 60% in 2-3 hours.
Rivaroxaban (xarelto)
Selective inhibition of factor Xa, inhibits production of thrombin
Rapid onset, fixed dose, lower bleed risk, less interactions, no INR monitoring
Pharmacokinetics of rivaroxaban (xarelto)
80-90% bioavailability Peaks 2-4 hours Undergoes partial metabolism by CYP3A4 Half life 5-9 hours No antidoite, but can prevent further absorption with activated charcoal. Unsafe in pregnancy (class C)
Apixaban
Selectively inhibits Xa and prothrombinase activity.
Three major classes of antiplatelet drugs
Aspirin, P2Y12ADP receptor antagonists, GP IIb/IIIa receptor antagonists (strongest effects)
Aspirin MOA
Irreversible inhibition of cyclooxygenase which is required to synthesize TXA2.
TXA2 can promote platelet activation, it also promotes vasoconstriction. Both o which promote hemostasis
Lasts 7-10 days.
Prostacyclin inhibition happens over 325mg and CAUSES platelet aggregation and vasoconstriction (81mg appears as effective as higher dose)
Aspirin risks
GI bleeding in 2-4 per 1000 pts and hemorrhagic stroke 0-2 in 1000 pts in middle aged people taking it for 5 years
P2Y12ADP receptor antagonists
Block P2Y12ADP receptors on platelet surface, preventing ADP-stimulated aggregation.
Clopidogrel, prasugrel, ticlopidine cause irreversible blockade and ticagrelor causes reversible blockade.
Clopidogrel (plavix)
Oral antiplatelet similar to aspirin
Irreversible P2Y12ADP block. Effects begin 2 hours after first dose.
Inhibits platelets 40-60%
Prodrug that activates from CYP2C19
Same adverse effects aspirin
Less GI bleeding and stroke risk than aspirin
Thrombotic thrombocytopenic purpura (TTP) in clopidogrel
Rare, potentially fatal
Thrombocytopenia, hemolytic anemia, neuro symptoms, renal dysfunction and fever.
Urgent tx including plasmapheresis
Clopidogrel PPIs
Often given to prevent GI bleeding but they may inhibit CYP2C19 making clopidogrel (plavix) less active
Ticagrelor (brilinta)
P2Y12ADP receptor antagonist. It is reversible.
Better results than clopidogrel (both were given with ASA) but higher risk of hemorrhage
Not a prodrug like plavix, metabolized by CYP3A4
Dyspnea in 13.8% of pts
Can give ventricular pauses
Glycoprotein IIb/IIIa receptor antagonists
Abciximab, tirofiban, eptifibatide.
All 3 given IV with ASA and low dose hpearin, tx is $1000 or more per course
SUPER ASPIRIN
GP IIb/IIIa receptor antagonists MOA
Reversible blockade of GP IIb/IIIa receptors thereby inhibiting the final step in aggregation. Prevent aggregation by all factors, TXA2, ADP, thrombin, platelet activation factor
Thrombolytic (fibrinolytic) drugs
To remove thrombi which have formed.
Alteplase, reteplase, tenecteplase (VHR).
Alteplase (tPA)
Tissue plasminogen activator. Identical to natural human tPA.
Binds with plasminogen to form active complex. The complex then catalyzes conversion of other plasminogen molecules into plasmin, an enzyme that digests the fibrin meshwork of clots.
It also degrades fibrinogen and other clotting factors (which don’t lyse the thrombi but do increase bleeding risk)
Therapeutic uses tPA
MI, stroke, massive PE
Pharmacokinetics tPA
Large molecule must be given parenterally, 5 minute half life from hepatic inactivation. 50% cleared in 5 minutes, 80% in ten
Fixing tPA
Blood products usually. If not aminocaproic acid prevents activation of plasminogen and directly inhibits plasmin
Tenecteplase (TNKase)
Varient of human tPA for MI.
80X more resistant than tPA to circulating inhibitors. 20-24 minute half life.
Converts plasminogen to plasmin to digest fibrin
Single bolus instead of infusion.
Same risks mostly as tPA but lower major hemorrhage (other than intracranial)
