Coagulation

Question 1

1. Define hemostasis.

Answer 1

The cessation of blood loss from a damaged vessel. Primary hemostasis involves platelet aggregation whereas secondary hemostasis involves the coagulation of the platelets and stabilization with fibrin. Inactive fibrinogen is activated to fibrin via thrombin.

Question 2

2. Define fibrinolysis.

Answer 2

Fibrinolysis is the digestion of fibrin+platelet aggregation via plasmin. Inactive plasminogen is converted to the proteolytic enzyme plasmin.

Question 3

3. What are platelet aggregation inhibitors?

Answer 3

Platelet aggregation inhibitors decrease synthesis or action of chemical signals that promote platelet aggregation. The platelets are being directly acted on. This category includes: COX inhibitors, ADP receptor blockers, phosphodiesterase inhibitors and blockers of platelet IIb/IIIa receptors.

Question 4

4. What is the MOA of Aspirin (acetylsalicylate)?

Answer 4

Aspirin is an irreversible cyclooxygenase inhibitor used to antagonize thromboxane A2 synthesis. Aspirin acetylates COX enzymes and due to the lack of platelet nuclei there is an inability to synthesize more COX in the individual platelet. Therefore, once the platelet COX enzyme is acetylated it will be unable to produce COX again and therefore will be inactive during its 10 day lifetime. Thromboxane A2 normally causes platelet aggregation and degranulation. TXA2 usually activates the Gq receptor signal leading to PLA2 activation and fibrinogen binding to GPIIb/IIIa. [fibrinogen forms bridges between adjacent platelets] By inhibiting TXA2 there is no platelet aggregation therefore a prolonged bleeding time.

Question 5

5. What are the clinical uses of Aspirin (cyclooxygenase inhibitor)?

Answer 5

1. prophylactic tx for transient cerebral ischemia
2. reduce incidence of recurrent MI
3. decrease mortality in post MI pts

Question 6

6. Give examples of ADP receptor blockers.

Answer 6

1. Clopidogrel (Plavix) – preferred over Ticlopidine due to fewer adverse effects
2. Ticlopidine

Question 7

7. What is the MOA and uses of ADP receptor blockers?

Answer 7

Clopidogrel and Ticlopidine are irreversible inhibitors of P2Y12 (located on surface of platelet). They are used to reduce the rate of stroke, MI and death in pts with recent MI, stroke and acute coronary syndrome. This can be given as an alternative to pts who are unable to tolerate Aspirin.

Question 8

8. What are the different drug interactions to watch out for with use of Clopidogrel?

Answer 8

1. Clopidogrel is consumed as a prodrug that needs to be activated by CYP2C19. Pts who are CYP2C19 poor metabolizes have lower plasma levels of active Clopidogrel therefore it does not reach therapeutic level and is not effective. Therefore alternative treatments need to be considered with these patients.
2. Omeprazole (CYP2C19 inhibitor) reduces levels of CYP2C19 in the body therefore making Clopidogrel prodrug not metabolically active. Therefore, concurrent use of Clopidogrel and Omeprazole should be avoided.

Question 9

9. Give an example of Phosphodiesterase inhibitors.

Answer 9

Dipyridamole

Question 10

10. What is the MOA and use of phosphodiesterase inhibitors?

Answer 10

Phosphodiesterase normally breaks down cAMP and cGMP. An increased amt of cGMP allows for vasodilation. When Dipyrodamole is given, it inhibits phosphodiesterase preventing a decrease in cAMP/cGMP levels allowing for coronary vasodilation. Dipyrodamole is used prophylactically to treat angina pectoris. This drug has little beneficial effect when used alone but does have therapeutic effect when used in combination with warfarin or aspirin.

Question 11

11. What is the MOA and uses of blockers of platelet GP IIb/IIIa receptors?

Answer 11

Fibrinogen binds to GP IIb/IIIa on platelets. Activation of the receptor is the final common pathway for platelet aggregation. These blockers are used to reduce thrombotic CV events in pts with non-STEMIs. It is also used as an adjunct to PCI (?) for the prevention of cardiac ischemic complications.

Question 12

12. What are examples of blockers of platelet GP IIb/IIIa receptors?

Answer 12

1. Abciximab – monoclonal Ab against the GP IIb/IIIA receptor
2. Eptifibatide – cyclic peptide reversible antagonist of the GP IIb/IIIa receptor
3. Tirofiban – non-peptide reversible antagonist of the GP IIb/IIIa receptor

Question 13

13. What are the different categories of indirect thrombin and factor Xa inhibitors?

Answer 13

1. unfractionated heparin (UFH)
2. low-MW heparins (LMWH)
3. Fondaparinux

Question 14

14. What are the UFH and LMWH?

Answer 14

Heparin is a mixture of straight chain, sulfated mucopolysaccharides give as an injectable, RAPIDLY ACTING ANTICOAGULANT, used acutely to interfere with formation of thrombi. UFH has a molecular weight range of 5,000-30,000 [wide range!]. LMWH is produced by depolymerized UFH that ranges from 1,000-5,000. LMWH have equal efficacy to UFH, higher bioavailability, longer half-life and less frequent dosing requirements therefore are replacing UFHs in many clinical situations.

Question 15

15. What specific drugs fall under the LMWH category?

Answer 15

1. Enoxaparin
2. Dalteparin
3. Tinzaparin

Question 16

16. What is the MOA of heparin?

Answer 16

Heparin with antithrombin III inhibits clotting factor proteases (thrombin, IXa, Xa). Without heparin, antithrombin III inhibits them very slowly therefor the binding of heparin (which acts as a cofactor) to antithrombin III accelerates the inhibition. Different MW of heparin have different anticoagulant activities.
UFH → efficiently inactivates both thrombin and factor Xa b/c due to its large structure can wrap around ATIII and inhibit/bind IIa
LMWH → efficiently inhibits Xa but has less effect on thrombin b/c the structure is unable to wrap around and inhibit IIa after binding ATIII

Question 17

17. How are Heparin levels monitored?

Answer 17

Heparin is monitored with activated partial thromboplastin time assay (aPTT). aPTT is a test of integrity of the intrinsic and common pathways of coagulation. LMWH dosing provides a much more predictable plasma levels therefore monitoring is not required. Potency of LMWH can be assessed with anti-factor Xa assay.

Question 18

18. What are the clinical uses of Heparin?

Answer 18

1. DVT
2. Pulmonary embolism
3. MI
4. DOC during pregnancy
   * *give heparin during pregnancy as Warfarin is Class X and therefore contraindicated as it can cross the placenta

Question 19

19. What are the adverse effects of Heparin?

Answer 19

1. Bleeding
2. Hypersensitivity reactions
3. Heparin-induced thrombocytopenia (HIT) – antibodies recognize complexes that consist of heparin and platelet protein (platelet factor 4). The binding of these complexes to antibodies leads to platelet aggregation and release of platelet contents (degranulation) including more PF4 that leads to more immune complexes. This all can result in thrombocytopenia and thrombosis that can be life-threatening, therefore the heparin needs to be discontinued and administration of a DTI or fondaparinux needs to be given.

Question 20

20. How do you reverse the action of heparin?

Answer 20

Excessive anticoagulant action of heparin is treated by discontinuance of drugs. Because heparin is negatively charged, if bleeding occurs, PROTAMINE SULFATE is given.

Question 21

21. What is Fondaparinux?

Answer 21

Fondaparinux is a synthetic pentasacharide that consists of 5 carbohydrates that bind to antithrombin III and specifically inhibit Xa. This treatment is approved for prevention and treatment of DVTs.

Question 22

22. What are direct thrombin inhibitors (DTIs)?

Answer 22

DTIs exert anticoagulant effect by directly binding to the active site of thrombin. DTIs can be administered parenterally or orally.

Question 23

23. What are the different parenteral DTIs?

Answer 23

1. Lepirudin
2. Bivalirudin
3. Argatroban

Question 24

24. What is Lepirudin?

Answer 24

Lepirudin is a parenteral DTI that acts as a recombinant form of hirudin that is a specific thrombin inhibitor from the leech. Its actions are independent from antithrombin III and therefore can inactivate fibrin-bound thrombin in thrombi. Lepiruden can be monitored by the aPTT and used in pts with HIT. There is no antidote that exists.

Question 25

25. What is Bivalirudin and Argatroban?

Answer 25

Bivalirudin → synthetic derivative of hirudin, monitored by aPTT, used in pts undergoing PCI Argatroban → small molecule thrombin inhibitor, monitored by aPTT, used in pts with or at risk for HIT undergoing PCI *These are parenteral DTIs

Question 26

26. What is Dabigatran Etexilate?

Answer 26

This is an oral DTI that is given as a prodrug and is converted to dabigatran. It produces a predictable anticoagulant response therefore routine monitoring is unnecessary. Dabigatran Etexilate is used to prevent thromboembolic strokes in pts with non-valvular a-fib as well as the prevention and treatment of DVTs and PEs.

Question 27

27. What are examples of direct factor Xa inhibitors? What are their uses?

Answer 27

1. Apixaban 2. Rivaroxaban * Direct factor Xa inhibitors are oral administered drugs that do not require monitoring. They are used for prevention and treatment of DVT and PE.

Question 28

28. What are coumarin anticoagulants?

Answer 28

Warfarin – these are oral anticoagulants b/c unlike heparin they may be administered orally. Warfarin inhibits vitamin K epoxide reductase (which converts vitamin K to an active form) resulting in the production of inactive clotting factors due to lack of gamma-carboxyglutamyl side chains. These coagulation factors involve have half-lives ranging from 6-60hrs and several hours are required prior to seeing an effect. Unlike heparin, it takes time for warfarin to work. Inactivation of factors occurs in the ascending order of.. Factor VII (inactive after 2 days) then Factor IX, X, II (almost 50% active after 4 days). The duration of action of a single dose of warfarin is 2-5 days.

Question 29

29. How can warfarin effect be overcome?

Answer 29

The anticoagulant effects of warfarin can be overcome by the administration of vitamin K – this reversal takes about 24 hours.

Question 30

30. Discuss the need to monitor warfarin levels.

Answer 30

Warfarin has a very narrow therapeutic index (ex. TD/ED) and also participates in drug-drug interactions. Therefore, the effects of warfarin therapy must be monitored regularly (every 2-4 weeks). Monitoring is performed with the prothrombin time (PT) [extrinsic and common pathway] and results are expressed as INR (international normalized ratio).

Question 31

31. What are the therapeutic uses of Warfarin?

Answer 31

Warfarin is used to prevent and treat DVT and PE post initial course of heparin. The prevention and treatment of thromboembolic complications are associated with atrial fibrillation (AF?).

Question 32

32. What are the adverse effects of Warfarin?

Answer 32

1. hemorrhage 2. cutaneous necrosis [increased clotting] due to reduced activity of protein C 3. Because there is inactivation of protein C (anticoagulant) before inactivation of the other factors there may be an initial pro-coagulant effect prior to the anti-coagulant effect. 4. Warfarin crosses the placenta and can cause a hemorrhagic disorder in the fetus and serious birth defects [Warfarin is category X and should NEVER be administered during pregnancy]

Question 33

33. What are thrombolytics?

Answer 33

Thrombolytics = fibrinolytics These drugs lyse blood clots and restore the patency of obstructed vessels before distal tissue necrosis can occur. Thrombolytic agents act by converting plasminogen to plasmin.

Question 34

34. What are the different thrombolytics?

Answer 34

1. streptokinase 2. urokinase 3. alteplase 4. reteplase 5. tenecteplase

Question 35

35. What is Streptokinase?

Answer 35

Protein produced by B-hemolytic strep that acts as a thrombolytic agent. It is rarely used.

Question 36

36. What is Urokinase?

Answer 36

A human enzyme synthesized by the kidney and found in the urine. It is approved for lysis of pulmonary emboli and falls in the category of a thrombolytic agent.

Question 37

37. What are Ateplase, Reteplase, and Tenecteplase?

Answer 37

Tissue plasminogen activator (t-Pa) is a serine protease produced by human endothelial cells. T-Pa activates plasminogen bound to fibrin in the thrombus. T-Pa is “fibrin selective” unlike Streptokinase and urokinase which are non-fibrin-selective.

Question 38

38. What is the difference b/t Ateplase, Reteplase, and Tenecteplase?

Answer 38

1. Ateplase → recombinant t-Pa, indicated for acute MI and acute ischemic stroke management 2. Reteplase → modified recombinant t-Pa, indicated for acute MI management 3. Tenecteplase → mutant form of t-Pa, indicated for acute MI management

Question 39

39. What are the different drugs used to treat bleeding?

Answer 39

1. plasminogen activation inhibitors 2. protamine sulfate 3. vitamin K 4. plasma fractions

Question 40

40. What are plasminogen activation inhibitors?

Answer 40

Plasminogen activation inhibitors – AMINOCAPROIC ACID – inhibits plasminogen activation. It is used as adjunctive therapy in hemophilia and bleeding from fibrinolytic therapy. Blocks plasminogen to plasmin step allowing for maintenance of clot.

Question 41

41. What is the MOA of protamine sulfate?

Answer 41

Protamine sulfate is a chemical antagonist of heparin (negatively charged) that is high in arginine (positively charged). The cationic protein interacts with anionic heparin to form complex preventing anticoagulant activity.

Question 42

42. What are the clinical uses of vitamin K?

Answer 42

1. all babies should receive vitamin K intra-muscularly at birth 2. reverse drug-induced hypoprothrombinemia -- vit K is available oral and parenteral, takes 6hrs to work and effect is complete by 24 hrs

Question 43

43. What is the use of plasma fractions?

Answer 43

Deficiencies in plasma coagulation factors [factor VIII, factor IX] can cause bleeding therefore giving the plasma factors can decrease the bleeding and allow for correct clotting.