PHRX 5040 Cardio Module - Exam #2 (Dr. Baker's Section)

define hemostasis

the stoppage of blood loss from a damaged vessel

define thrombosis

- formation of a blood clot inside of a blood vessel

- which can slow or block normal blood flow

what are the 3 major components of hemostasis?

- platelets

- endothelial cells = lining the blood vessels

- coagulation factors

describe the end result of the activated coagulation system

formation of a complex of cross linked fibrin molecules and platelets to stop hemorrhage AFTER injury

overall, describe the process of thrombus formation

- wall defect/damage occurs

- platelets stick to the damaged areas and release other substances to recruit others to help

- downstream more substances are recruited to be activated

- degranulation eventually occurs and glycoproteins are unregulated to stick platelets together

in general, describe the process of platelet activation and aggregation

in the order listed below, there is a progressive increase in platelets brought to that area:

- flowing

- adhesion

- activation

- aggregation and thrombosis

overall, describe what happens when tissue factor (TF) is released from damaged muscle cells

triggers the coagulation cascade

- TF is released and activates the extrinsic coagulation cascade

- downstream it form a fibrinogen mesh

describe the intrinsic coagulation pathway

contact activation via damaged surface leads to activation of the following in this order:

- 12

- 11

- 9

- 10

- 10a

describe the extrinsic coagulation pathway

- stimulated by TF release when the vessel is damaged

- TF-VIIa stimulates the conversion of 10 to 10a

describe the prothrombinase complex activation

- overall, the formation of 10 to 10a in both the intrinsic and extrinsic pathways leads to the activation of the prothrombinase complex

- at this point, fibrin = Ia makes the fibrin mesh that plugs damaged areas wit platelets

what are the 2 most common types of venous thromboembolism (VTE)?

- deep vein thrombosis = DVT

- pulmonary embolism = PE

describe a DVT

- a thrombus is a clot that forms in a deep vein = most commonly in peripheries (legs)

- stasis of blood occurs = clotting

describe a PE

- an embolus = detached clot

- travels through the venous system to the lungs = blocks the lungs

- causes a pulmonary embolism

what 3 main categories of events increase risk of thrombus? (Virchow's triad)

- hypercoagulable state

- vascular wall injury

- circulatory stasis

what are 8 examples of hyper coagulable states?

- malignancy

- pregnancy or peri partum period

- estrogen therapy

- trauma or surgery of lower extremity

- IBS

- nephrotic syndrome

- sepsis

- thrombophilia

what are 6 examples of vascular wall injury?

- trauma or surgery

- venipuncture

- chemical irritation

- heart valve disease or replacement

- asthesclerosis

- indwelling catheters

what are 5 things that may contribute to circulatory stasis?

- a fib

- left ventricular dysfunction

- immobility or paralysis

- venous insufficiency or varicose veins

- venus obstruction from tumor, obesity or pregnancy

what are 3 drug types that are considered anticlotting drugs?

- anticoagulants

- thrombolytics

- anti platelet drugs

what are 3 drug types that facilitate clotting?

- replacement factors

- vitamin K

- antiplasmin drugs

what 3 drug classes are examples of indirect thrombin inhibitors?

- UFH

- LMWH

- pentasaccharides

how does the structure of UFH contribute to its activity?

- has the longest chain connected to the pentasaccharide sequence

- this chain allows it to bind to and inhibit BOTH factor Xa and thrombin IIa

how does the structure of LMWH contribute to its activity?

- shorter chain attached to pentasaccharide sequence

- has more activity against Xa and less, but some, activity against IIa because of this shorter chain

how doe the structure of pentasaccharides contribute to its activity?

- pentasaccharide sequence with NO chain

- it will bind to and inhibit factor Xa but has NO impact on thrombin IIa due to that lack of chain

describe the MOA of UFH

- heparin is an indirect thrombin inhibitor

- heparin binds to antithrombin III

- ATIII binds to and inhibits key clotting factors = specifically Xa and IIa

- this stops growth and propagation of a formed thrombus = important to note that it does not break down already formed clots, only prevents growth

describe the onset of UFH

- IV = immediate with bolus

- SC = 20-30 mins

describe the elimination of UFH

- both hepatic and renal elimination

- dose dependent

- need to monitor levels because PK is unpredictable

describe the MOA of LMWH

- indirect thrombin inhibitor

- binds to and activates ATIII

- ATII binds to and inactivates Xa and IIa = BUT it binds more to Xa then IIa

- stops growth and propagation of a formed thrombus

what is the main idea behind the use of LMWH for VTE?

- almost always given SC and its smaller side again makes its PK more predictable

- by selectively targeting Xa, LMWH effectively prevents new clot formation while maintaining anticoagulant efficacy with a lower bleed risk

describe the elimination of LMWH

- both enoxaparin and dalteparin are renally eliminated

- they require dose adjustments with renal damage

which drug is a pentasaccharide indirect thrombin inhibitor?

fondaparinux

describe the MOA of fondaparinux

- binds ATIII

- selectively inhibits factor Xa

- this means that there is minimal activity against IIa and no direct binding to thrombin

since fondaparinux has a selective mechanism for Xa, what does this imply?

- predictable anticoagulant effect

- once daily SC dosing

- no routine monitoring required = predictable, stable PK

- lower risk of HIT compared UFH/LMWH = does not really affect platelets

what clinical pearl is associated with fondaparinux

- offers a predictable targeted approach with lower risk of HIT

- not used 1st line, only really used if pt has platelet probs like HIT

what are the 2 IV direct thrombin inhibitors?

- agratroban

- bivalirudin

describe the MOA of direct thrombin inhibitors

- bind directly to thrombin = NO cofactor required for activity

- inhibit clot bound thrombin AND free circulating thrombin

which oral anticoagulants inhibit the initiation step of coagulation cascade?

warfarin

which oral anticoagulants inhibit the amplification step of coagulation cascade?

DOACs = inhibit factor Xa

which oral anticoagulants inhibit the propagation step of coagulation cascade?

dabigatran = inhibits IIa

describe the MOA of warfarin

- inhibits vitamin K epoxide reductase

- this prevents activation of vitamin K dependent clotting factors

- only affects FREE clotting factors = prevents formation of new thrombi but no effect on formed thrombi or circulating clotting factors

describe the warfarin SNOT factors

SNOT = 7, 9, 10, 2 in order of which they are inhibited by warfarin

- 7 = 4-6 hrs

9 = 21-30 hrs

- 10 = 27-48 hrs

- 2 = 42-72 hrs

also impacts protein C and S

describe the duration of warfarins effects

- duration = 2-5 days

- caused by the half life of clotting factors inhibited

describe the CYP metabolism of warfarin

warfarin is a racemic mixture = S warfarin more potent

- 2C9 = primary metabolism = S warfarin

- 3A4 = secondary metabolism = R warfarin

overall, describe the MOA of DOACs

they bind to clotting factors directly to inhibit them

what 3 drugs are direct factor Xa inhibitors?

- rivaroxaban

- apixaban

- endoxaban

which drug is a direct thrombin inhibitor?

- dabigatran

- binds to and inhibits IIa

compare the bioavailability of DOACs

- compared to factor Xas, dabigatran has a much lower bioavailibility

- requires special dosage form for better absorption

what is the dosing frequency of the following:

- dabigatran

- rivaroxaban

- apixaban

- dabigatran = once or twice daily

- rivaroxaban = once or twice daily

- apixaban = TWICE daily

which DOAC had the most renal elimination? what does this mean

- dabigatran

- not ideal for renal dysfunction, will require dose adjustments

which DOAC had the least renal elimination? what does this mean

- apixaban

- best option for pts with poor kidney function

what key DDIs are seen with factor Xa inhibitors

potent inducers and inhibitors of P-gp and CYP3A4

which medication is the ONLY oral direct thrombin inhibitor?

dabigatran

describe the metabolism of dabigatran

- P-gp substrate

- NO CYP interactions

describe the bioavailibility of dabigatran, what does this mean?

LOW bioavailibility = needs acidic enviorment for full absorption

- capsule creates an acidic enviorment in the gut

- tablets can NOT be crushed, chewed, broken or opened

- caution with long term PPI use = reduces absorption

describe the clearance of dabigatran

- renally eliminated

- avoid in severe hepatic and renal impairment

what is a unique ADE seen with dabigatran? why does this occur?

dyspepsia

- occurs because of the packaging delivery system

- should take with a full glass of water

what 3 drugs are considered thrombolytics?

- alteplase

- reteplase

- tenecteplase

what is the route of admin for all thrombolytic drugs?

IV

describe the half lives of all thrombolytic drugs, which is shortest acting?

- all short acting

- shortest acting = alteplase so it requires IV bolus and infusion

how is alteplase administered?

IV bolus + infusion

how is reteplase administered?

double IV bolus

how is tenecteplase administered?

single IV bolus