Unit 2. Thrombosis

Question 1

Unfractionated heparin

Answer 1

Class: Anticoag, Indirect thrombin inhibitor
MOA: binds antithrombin, potentiating its formation of anti-thrombin-coag factor complex (Xa, IIa)
Use: prev/tx of venous thromboembolism; maintain patency for dialysis, lines; pregnant patients
Tox: HIT (Tcpenia, thrombosis); osteoporosis (long term use), bleeding
Other: parenteral (SC, IV), short t1/2 (1hr = rapid on/off); monitor via PTT (2-2.5x normal)
-reversal via protamine sulfate

Question 2

Dalteparin

Answer 2

Class: Anticoag, Indirect thrombin inhibitor
MOA: LMWH that inhibits thrombin (IIa) less effectively than Xa
Use: prev/tx of venous thromboembolism; maintain patency for dialysis, lines; pregnant patients
Tox: bleeding (HIT, osteoporosis uncommon)
Other: shorter chain hep; longer t1/2 (QD, BID dosing); monitor with heparin assay (anti-Xa assay); reverse w protamine; more predictable than hep

Question 3

Enoxaprin

Answer 3

Class: Anticoag, Indirect thrombin inhibitor
MOA: LMWH that inhibits thrombin (IIa) less effectively than Xa
Use: prev/tx of venous thromboembolism; maintain patency for dialysis, lines; pregnant patients
Tox: bleeding (HIT, osteoporosis uncommon)
Other: shorter chain hep; longer t1/2 (QD, BID dosing); monitor with heparin assay (anti-Xa assay); reverse w protamine; more predictable than hep

Question 4

Tinzaparin

Answer 4

Class: Anticoag, Indirect thrombin inhibitor
MOA: LMWH that inhibits thrombin (IIa) less effectively than Xa
Use: prev/tx of venous thromboembolism; maintain patency for dialysis, lines; pregnant patients
Tox: bleeding (HIT, osteoporosis uncommon)
Other: shorter chain hep; longer t1/2 (QD, BID dosing); monitor with heparin assay (anti-Xa assay); reverse w protamine; more predictable than hep

Question 5

Fondaparinux

Answer 5

Class: Anticoag, Indirect thrombin inhibitor
MOA: synthetic pentasaccharide that binds active site of antithrombin, inhibiting Xa (ineffective against thrombin)
Use: HIT patients
Tox: bleeding
Other: long t1/2 (15 hrs); NO antidote

Question 6

Warfarin

Answer 6

Class: Anticoag, Vit K antagonist
MOA: blocks vit K-dependent gamma carboxylation of factors 2, 7, 9, 10, C, S (via inhibition of vit K epoxide reductase)
Use: long term oral anti-coagulation
Tox: thrombosis @ onset (Prot C depletion) leading to skin necrosis; bleeding
Other: monitor freq w INR/PT; metab enhanced by increased p450s (e.g. w barbituates); albumen-bound in plasma (drug interactions!); competes w diet/gut flora vit K; not used in pregnancy (terat)
-reversal by stopping drug (1-2d), vit k (10 hrs), FFP or factors 2, 7 (immediate)

Question 7

Lepirudin

Answer 7

Class: anticoagulant, Direct thrombin inhibitor
MOA: irreversibly inactivates both unbound and fibrinogen-bound thrombin (unlike hep)
Uses: HIT
Tox: bleeding
Other: parenteral; monitor w PTT; NO antidote; derivative of leech hirudin; renal clearance

Question 8

Bivalirudin

Answer 8

Class: anticoagulant, Direct thrombin inhibitor
MOA: irreversibly inactivates both unbound and fibrinogen-bound thrombin (unlike hep)
Uses: PCI (due to short t1/2)
Tox: bleeding
Other: parenteral; monitor w PTT; NO antidote; synthetic polypeptide; renal clearance

Question 9

Argatroban

Answer 9

Class: anticoagulant, Direct thrombin inhibitor
MOA: irreversibly inactivates both unbound and fibrinogen-bound thrombin (unlike hep)
Uses: HIT
Tox: bleeding
Other: parenteral; monitor w PTT; NO antidote; synthetic analog of arginine; hepatic clearance

Question 10

Dabigatran

Answer 10

Class: anticoagulant, Direct thrombin inhibitor
MOA: competitive inhibitor of thrombin (unbound and bound)
Use: ORAL anticoag, superior to warf in trials
Tox: bleeding
Other: standard dosing (qd, bid), no need to monitor, but NO antidote

Question 11

Rivaroxaban

Answer 11

Class: anticoag, direct Xa inhibitor
MOA: sm molecule that reversibly binds active site of Xa
Note: oral, QD, no need to monitor, but NO antidote

Question 12

Apixaban

Answer 12

Class: anticoag, direct Xa inhibitor
MOA: sm molecule that reversibly binds active site of Xa
Note: oral, QD, no need to monitor, but NO antidote

Question 13

Betrixaban

Answer 13

Class: anticoag, direct Xa inhibitor
MOA: sm molecule that reversibly binds active site of Xa
Note: oral, QD, no need to monitor, but NO antidote

Question 14

Streptokinase

Answer 14

Class: anticoag, fibrinolytic
MOA: bact protein that lyses already formed clots by activating circulating plasminogen (not clot specific)
Uses: acute MI, stroke, central DVT, multiple PEs
Tox: bleeding
Note: immunogenic, so can use once

Question 15

Urokinase

Answer 15

Class: anticoag, fibrinolytic
MOA: lyses already formed clots by activating circulating plasminogen (not clot specific)
Uses: acute MI, stroke, central DVT, multiple PEs
Tox: bleeding

Question 16

Tissue Plasminogen activator

Answer 16

Class: anticoag, fibrinolytic
MOA: lyses already formed clots by activating fibrin-bound plasminogen (more clot-specific)
Uses: acute MI, stroke, central DVT, multiple PEs
Tox: less systemic activation, so less bleeding
Note: genetically engineered variants = reteplase, tenecteplase

Question 17

Dipyridamole

Answer 17

Class: Anticoag, Antiplatelet
MOA: phosphodiesterase (PDE) inhibitor–> incr in platelet cAMP –> decreased aggregation
Uses: secondary stroke prevention; weak agent
Note: parenteral

Question 18

Clopidogrel

Answer 18

Class: anticoag, antiplatelet aka Plavix
MOA: ADP receptor inhibitor (irreversible)–>decr aggregation
Use: prevent/treat MIA, TIA, PAD; in PCI
Tox: rarely TTP
Note: slow onset (activated by p450s); 10d long effect (irreversible); reversal via platelet transf

• PRASUGREL: same mech, but uses diff p450 (use for plavix-resistance); more potent
• CANGRELOR: use for immediate effect (t1/2 3-5 mins); use for PCI

Question 19

Abciximab

Answer 19

Class: Anticoag, antiplatelet
MOA: mAB against GpIIb/IIIa–>inhibits aggregation by blocking fibrinogen bridging
Use: ACS spectrum
Note: parenteral, can be immunogenic

Question 20

Eptifibatide

Answer 20

Class: Anticoag, antiplatelet
MOA: fibrinogen analog which competes w fibrinogen and vWF for binding to GpIIa/IIIb
Use: ACS spectrum
Note: parenteral

Question 21

Tirofiban

Answer 21

Class: Anticoag, antiplatelet
MOA: fibrinogen analog which competes w fibrinogen and vWF for binding to GpIIa/IIIb
Use: ACS spectrum
Note: parenteral

Question 22

Why give baby aspirin for cardioprotection?

Answer 22

ASA inhibits platelet cox formation of TxA2, but also inhibits endothelial cell formation of PgI2 (prostracyclin); at low doses, the main effect is on platelets (the effect on endoth cells is short lived due to ability to regenerate COX enzymes)

Question 23

Name the indirect thrombin inhibitors

Answer 23

Unfractionated heparin
LMWHs: Dalteparin, enoxaprin, tinzaparin
Fondaparinux

Question 24

Name the direct thrombin inhibitors; which can be given orally?

Answer 24

Lepirudin, bivalirudin, argatroban, dabigatran

-dabigatran = PO

Question 25

Which factors are vit K dependent? Which has the shorted half life?

Answer 25

2, 7, 9, 10 C, S

C (–>thrombosis, warfarin skin necrosis)

Question 26

Name the fibrinolytics

Answer 26

Streptokinase, urokinase, t-PA (and derivatived reteplase, tenecteplase)

Question 27

Four ways to inhibit platelets

Answer 27

1. inhibit COX formation of TxA2 (ASA)
2. inhibit PDE (dipyridamole)
3. block ADP receptors (clopidogrel)
4. block GpIIb/IIIa receptors w mAB (abciximab) or fibrinogen analog (eptifibatide)

Question 28

Six classes in anticoagulation

Answer 28

1. Indirect thrombin inhibitors
2. Vit K antagonists
3. Direct thrombin inhibitors
4. Direct Xa inhibitors
5. Fibrinolytics
6. Antiplatelets