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Cardio > Anti-thrombotic Dr. Roane > Flashcards

Anti-thrombotic Dr. Roane Flashcards

Dr. Roane EXAM III

1
Q

How do platelets become activated?

A

Willebrand Factor

Plasma/tissue/platelet protein binding to platelets and collagen

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2
Q

What is released upon platelet activation?

A

-ADP -> activates more platelets
-TXA2 (thromboxane) -> activates more platelets
-serotonin (increases muscle tone -> vasoconstriction)

-> Attraction and activation of other platelets

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3
Q

Function of fibrin

A

-coating aggregated platelets
-binding platelets together in a plug

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4
Q

How does the platelet activation cascade get deactivated?

A

-by undamaged adjacent cells
-PGI2 (prostacyclin) and NO (nitric oxide

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5
Q

Intrinsic Pathway

Clotting pathway

A

12 - 11 - 9 - 10 - Prothrombin to Thrombin

Vessel damage -> Collagen exposed
Collagen on 12: 12 to 12a
12a activates 11: 11 to 11a
11a activates 9: 9 to 9a
9a activates 10: 10 to 10a
10a activates: Prothrombin: to Thrombin

Thrombin: positive loop to 5, 8, and 11

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6
Q

Extrinsic pathway

Clotting pathway

A

Vessel damage -> subendothelial exposure to blood -> Tissue factor activates 7: 7 to 7a
7a activates 9: 9 to 9a
9a activates 10: 10 to 10a
10a activates: Prothrombin: to Thrombin

7a also activates 10 directly: 10 to 10a

Thrombin: positive loop to 5, 8, and 11

(8 helps 9, 5 helps 10)

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7
Q

What is the role of Thrombin?

A

-Thrombin can also activate Fibrin:
Fibrinogen to loose Fibrin

-Thrombin activates 13: 13 to 13a
13a activates loose fibrin: loose fibrin to stabilized fibrin (bind platelets together)

-Thrombin acting in a positive loop to further stimulate the clotting cascade

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8
Q

Function of Antithrombin III

A

-turns off the intrinsic pathway (12-11-9-10): acts on 12a, 11a, 9a and 10a

-turns off the common pathway: 10a and Thrombin

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9
Q

Where is Antithrombin III synthesized?

A

-in the liver
-naturally occurring
plasma protein
-Human recombinant ATIII is
available as the drug

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10
Q

What is the indirect thrombin inhibitor?

A

Heparin (naturally polysaccharid), variable lenght of chains

-Unfractionated heparin (UFH): all chain
-Low molecular weight heparin (LMWH) - short chain

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11
Q

Which form of heparin is known to be very short?

A

Fondaparinux (Arixtra)

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12
Q

How does Heparin work?

A

it attaches Antithrombin III to Thrombin

-Antithrombin turns Thrombin off and terminates the clotting pathway

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13
Q

half-life, onset, formulation

A

-injectable
-short-halflife
-quick onset
-very potent (can also be turned off quickly)

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14
Q

What do all heparin forms have in common?

A

all contain a penta(5)saccharide sequence

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15
Q

How are the heparin forms different?

A

-vary in the length of the GAG tail

-UFH: has a long GAG + penta(5)saccharide
long links Antithrombin and thrombin
links antithrombin and factor 10a (also 12a, 11a, 9a)

-LMWH: has a short GAG + penta(5)saccharide
links antithrombin and 10a

-Fondaparinux has no GAG, only the penta(5)saccharide
links antithrombin and 10a

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16
Q

How is the short form of heparin different in therapy?

A

they only link ATIII with 10a, so not as potent, lower risk of causing bleeding

17
Q

Low molecular weight heparin drugs

A

-parin
Enoxaparin, Dalteparin, Tinzaparin

-short form of heparin
-activity at Xa and Thrombin 2a?
-t1/2 of 4h, renal clearance !!!

18
Q

Side effects

A

-Bleeding
-platelet activation and clotting (paradox)
-Thrombocytopenia (low number of platelets bc destroyed by immune cells or used up heparin-induced thrombocytopenia)
-LMWH can cause kidney damage: contraindicated in GFR < 30 ml/min

19
Q

What are the antidotes of heparin?

A

-for UFH: Protamine sulfate

-for Fondaparinux: PCC (prothrombin complex concentrate)

20
Q

Which form of heparin is preferred to spare the kidneys?

A

-UFH (long chain form) bc of the short half-life

21
Q

MOA of Warfarin

A

-factors 7, 9,10 (extrinsic), and 2 (Prothrombin) need the reduced form of Vitamin K and carboxylation to be activated

-Warfarin blocks the enzyme VKORC1: reduction of Vitamin K

-Warfarin is a competitive inhibitor of Vitamin K, with enough Vitamin K intake, the potency of warfarin is lowered

22
Q

Warfarin pharmacokinetic profile

A

100% oral bioavailability
99% protein bound to albumin (watch out for other protein binders -> displace warfarin from albumin and increases warfarin’s potency -> bleeding)
-long half-life, long onset
-racemic mixture: L-isomer is 4x potent

23
Q

What is the antidote of warfarin?

A

-PCC (prothrombin complex concentrate)
-also the antidote of Fondaparinux

24
Q

What are the available clotting tests?

A

-PT: prothrombin time (12sec): evaluates the extrinsic and common pathway (so it contains the tissue factor)

-INR: international normalized ratio: more accurate and useful for patients taking Vitamin K antagonists (like warfarin) -> bc Vitamin K needed to build Prothrombin

-aPTT: activated partial thrombin time (30-45 sec): evaluates the intrinsic and common pathway
more sensitive to patients on heparin
-> bc heparin binds to the factors in the intrinsic pathway and thrombin

25
Q

Name the oral Factor Xa inhibitors

A

-Rivaroxaban (Xarelto)
-Apixaban (Eliquis)
-Edoxaban (Savaysa)

-don’t need monitoring (like heparin or warfarin)
-Most seen in DVT prevention

26
Q

What is the antidote for Factor Xa inhibitors?

A

-Andexanet alfa (recombinant gene product)
-injected

-decoy binding site for Rivaroxaban, Apixaban, Edoxaban -> the drugs will bind andexanet alfa instead of Factor Xa

27
Q

Direct thrombin inhibitor (factor 2a)

A

-block the thrombin catalytic site and the substrate
binding site on thrombin
-> blocks the conversion of Fibrinogen to loose fibrin and to stabilized fibrin

-Hirudin
-Bivalirudin
-quick onset, short-acting, safer than heparin

28
Q

What are the large molecule thrombin inhibitors?

A

-Hirudin
-Bivalirudin
-quick onset, short-acting, safer than heparin

29
Q

What are the small molecule thrombin inhibitors?

A

-Argatroban, IV (contraindicated in hepatic dysfunction)

-Dabigatran, PO: slow onset long half-life - renal elimination

30
Q

What is the reversal agent Dabigatran?

A

Idarucizumab

31
Q

Thrombolytics

A

-TA: tissue plasminogen activator
-convert Plasminogen to Plasmin (Clotbuster, cuts clots)

-Streptokinase
-Urokinase
-Altepase (t-PA)
-Reteplase
-Tenecteplase

32
Q

Where are thrombolytics used?

A

-to remove clots
-MI
-ischemic stroke

33
Q

Platelet activation

A

-exposure of collagen -> GPV1 protein on moving platelets bind to collagen

Activation of:
-COX-1 -> TxA2 (thromboxane): recruits other platelets
-GPIIb/IIa: activates fibrinogen receptor for platelet clotting
-ADP: stimulates GPIIb/IIa and TxA2 in other recruited platelets
-Serotonin: vasoconstriction

34
Q

What is the receptor on platelets that respond to soluble thrombin (IIa)?

A

PAR-1/PAR-4
-thrombin binds to PAR-1/PAR-4 for platelet recruiting and activation via TxA2

-blocked by the drug: Vorapaxar

35
Q

Which molecules inhibit platelet aggregation?

A

-PGI2 (prostacyclin)
-NO (nitric oxide)
-from adjacent endothelial cells

36
Q

Antiplatelet drugs

A

-Aspirin (blocks irreversibly COX-1 -> no platelet recruiting)

-Vorapaxar (Zontivity) (blocks thrombin from binding to thrombin receptor PAR-1/PAR-4 -> no platelet recruiting via TxA2)

-Clopidogrel (prodrug CYP2C19)
-Prasugrel (prodrug)
-Cangrelor (short-acting)
-Ticagrelor (reversible, AE: dyspnea)
-> blocking ADP receptor irreversibly

-Abciximab
-Eptifibatide
-Tirofiban
-> Blocking GPIIa/IIb for platelet fusion

37
Q

Why are high doses of aspirin harmful?

A

-because it not only blocks COX-1 but also inhibits PGI2 (prostacyclin) which stops the platelet cascade

38
Q

Which drug is used to stop bleeding?
MOA

A

-Amino caproic acid (Amicar)
-used esp after surgery

-binds to Plasminogen, inhibits conversion to active Plasmin (inhibits the “clot cutter”)

39
Q

Treatment of the inherited bleeding disorder Hemophilia

A

Hemophilia A (missing factor 8)
Hemophilia B (missing factor 9)

-administration of the missing factor

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