Anticoag, antiplate, thrombolytic textbook

Question 1

Stage one of hemostasis; formation of a platelet plug

Answer 1

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

Question 2

How can GP IIb/IIIa receptors become activated

Answer 2

Thromboxane A2
Thrombin
Collagen
Platelet activation factor
ADP

Question 3

Stage two of hemostasis; coagulation

Answer 3

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

Question 4

Extrinsic pathway

Answer 4

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

Question 5

Factors affected by warfarin

Answer 5

II (prothrombin), VII, IX, X,

VII is extrinsic

Question 6

Factors affected by heparin

Answer 6

IXa, Xa, XIa, XIIa and thrombin (IIa)

XIIa, XIa, IXa are unique to intrinsic (doesn’t hit any extrinsic until Xa)

Question 7

Contact activation (intrinsic) pathway

Answer 7

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

Question 8

Which factors require vitamin K for synthesis

Answer 8

VII, IX, X and II(prothrombin)

Question 9

Antithrombin

Answer 9

Inactivates clotting factors that stray from site of vessel injury. XIIa, XIa, IXa (intrinsic) and Xa, IIa (thrombin)
Antithrombin involved with heparin

Question 10

Physiologic removal of clots

Answer 10

Plasmin degrades fibrin meshwork of the clot.
Produced through activation of plasminogen
Fibrinolytic drugs act by promoting conversion of plasminogen into plasmin

Question 11

Arterial thrombosis

Answer 11

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

Question 12

Venous thrombosis

Answer 12

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

Question 13

Overview of three main drugs

Answer 13

Anticoagulants (heparin, warfarin, dabigatran) disrupt coagulation cascade and therefore suppress fibrin
Antiplatelet drugs (aspirin, clopidogrel) inhibit platelet aggregation
Thrombolytic drugs promote lysis of fibrin

Question 14

Antiplatelet drugs most effective against

Answer 14

Preventing arterial thrombosis

Question 15

Anticoagulants are most effected against

Answer 15

Venous thrombosis

Question 16

Warfarin vs other anticoagulants

Answer 16

Warfarin inhibits synthesis of clotting factors including X and thrombin
All others inhibit activity of clotting factors, either Xa, thrombin or both

Question 17

Heparin and its derivatives

Answer 17

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

Question 18

Heparin distribution

Answer 18

Has many negatively charged groups making it highly polar, and hence cannot readily cross membranes

Question 19

Heparin MOA

Answer 19

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

Question 20

Heparin pharmacokinetics

Answer 20

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

Question 21

Uses of heparin

Answer 21

Pregnancy, pulmonary embolism, DVT, open heart surg and renal dialysis and low dose for postop prevention of thrombosis. DIC and MI

Question 22

Adverse effects of heparin

Answer 22

Bleeding (10%)

Shock, bruises, petechiae, hematomas, discoloured poo, headache or faintness (cerebral) lumbar pain (adrenal hemorrhage)

Question 23

Heparin induced thrombocytopenia (HIT)

Answer 23

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

Question 24

Heparin interaction

Answer 24

Platelet aggregation is the major remaining defence against hemorrhage. Aspirin and other drugs that depress platelet function will weaken this defence.

Question 25

Heparin OD

Answer 25

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

Question 26

Lab monitoring for heparin

Answer 26

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

Question 27

Heparin routes

Answer 27

IV or subq. IM causes hematoma

Question 28

LMW heparins

Answer 28

As effective as unfractionated. Don't require aPTT monitoring, can be used at home. First line therapy for DVT Enoxaparin (lovenox) and dalteparin (fragmin)

Question 29

LMW heparins MOA

Answer 29

Preferentially inactivate Xa, and are much less active on thrombin. They are too short to provide a binding site for thrombin

Question 30

Pharmacokinetics of LMW heparins

Answer 30

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

Question 31

Adverse effects of LMW heparin

Answer 31

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

Question 32

Warfarin, a vitamin K antagonist

Answer 32

Prevents thrombosis like heparin, but has delayed onset so not used in emergency

Question 33

Warfarin MOA

Answer 33

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%

Question 34

Pharmacokinetis of warfarin

Answer 34

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

Question 35

Warfarin uses

Answer 35

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

Question 36

Monitoring TX with warfarin

Answer 36

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

Question 37

INR timing

Answer 37

Daily for 5 days 2X a week for 1-2 weeks Once a week for 1-2 months 1-2X a month after

Question 38

INR AND aPTT numbers

Answer 38

2-3 for INR sometimes 2.5-3.5 | 60-80 seconds for aPTT (partial thromboplastin time)

Question 39

Warfarin hemorrhage

Answer 39

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

Question 40

Warfarin interactions

Answer 40

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

Question 41

Vitamin K1, for warfarin OD

Answer 41

2.5mg PO or 0.5 to 1mg IV. | IV can cause anaphylatic like reactions, give it slow and dilute it.

Question 42

Dabigatran (pradax) vs warfarin

Answer 42

``` 5 advantages to pradax Rapid onset No need to monitor INR Fewer interactions Lower risk of major bleed Predictable dose responses ```

Question 43

MOA dabigatran

Answer 43

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.

Question 44

Rivaroxaban (xarelto)

Answer 44

Selective inhibition of factor Xa, inhibits production of thrombin Rapid onset, fixed dose, lower bleed risk, less interactions, no INR monitoring

Question 45

Pharmacokinetics of rivaroxaban (xarelto)

Answer 45

``` 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) ```

Question 46

Apixaban

Answer 46

Selectively inhibits Xa and prothrombinase activity.

Question 47

Three major classes of antiplatelet drugs

Answer 47

Aspirin, P2Y12ADP receptor antagonists, GP IIb/IIIa receptor antagonists (strongest effects)

Question 48

Aspirin MOA

Answer 48

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)

Question 49

Aspirin risks

Answer 49

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

Question 50

P2Y12ADP receptor antagonists

Answer 50

Block P2Y12ADP receptors on platelet surface, preventing ADP-stimulated aggregation. Clopidogrel, prasugrel, ticlopidine cause irreversible blockade and ticagrelor causes reversible blockade.

Question 51

Clopidogrel (plavix)

Answer 51

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

Question 52

Thrombotic thrombocytopenic purpura (TTP) in clopidogrel

Answer 52

Rare, potentially fatal Thrombocytopenia, hemolytic anemia, neuro symptoms, renal dysfunction and fever. Urgent tx including plasmapheresis

Question 53

Clopidogrel PPIs

Answer 53

Often given to prevent GI bleeding but they may inhibit CYP2C19 making clopidogrel (plavix) less active

Question 54

Ticagrelor (brilinta)

Answer 54

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

Question 55

Glycoprotein IIb/IIIa receptor antagonists

Answer 55

Abciximab, tirofiban, eptifibatide. All 3 given IV with ASA and low dose hpearin, tx is $1000 or more per course SUPER ASPIRIN

Question 56

GP IIb/IIIa receptor antagonists MOA

Answer 56

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

Question 57

Thrombolytic (fibrinolytic) drugs

Answer 57

To remove thrombi which have formed. | Alteplase, reteplase, tenecteplase (VHR).

Question 58

Alteplase (tPA)

Answer 58

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)

Question 59

Therapeutic uses tPA

Answer 59

MI, stroke, massive PE

Question 60

Pharmacokinetics tPA

Answer 60

Large molecule must be given parenterally, 5 minute half life from hepatic inactivation. 50% cleared in 5 minutes, 80% in ten

Question 61

Fixing tPA

Answer 61

Blood products usually. If not aminocaproic acid prevents activation of plasminogen and directly inhibits plasmin

Question 62

Tenecteplase (TNKase)

Answer 62

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)