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Pharmacotherapy II > Anticoagulation Hockerman Exam 4 > Flashcards

Anticoagulation Hockerman Exam 4 Flashcards

1
Q

What is hemostasis?

A

Arrest of bleeding from a damaged blood vessel

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2
Q

What is the precursor cell to platelets?

A

Megakaryocytes

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3
Q

What is the name of the process where megakaryocytes form platelets?

A

Endomitosis followed by breaking apart into platelets.

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4
Q

What cellular organelle is not in a platelet?

A

Nucleus. However, platelets do have secretory granules and other organelles.

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5
Q

What factor adheres to exposed collagen in damaged endothelia?

A

VonWillebrand factor

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6
Q

Von Willebrand factor binding to extracellular matrix initiates 3 aspects of platelet plug formation:

A

Adhesion and shape change, secretion reaction, and aggregation.

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7
Q

What are the two things that platelets bind to that mediate adhesion?

A

Binding to collagen and von Willebrand factor bridged to collagen. Shape change facilitates.

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8
Q

What endothelial function is lost when it is damaged that contributes to thrombogenesis?

A

Loss of PGI2 (prostacyclin) release, which normally inhibits thrombogenesis.

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9
Q

In the secretion step of platelet aggregation, what three molecules are released from platelet granules?

A

ADP, Thromboxane A1 (TXA2), serotonin

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10
Q

What is the function of the molecules released during platelet degranulation?

A

ADP, TXA2, and 5-HT activate and recruit other platelets. TXA2 and 5-HT are also potent vasoconstrictors.

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11
Q

In the aggregation step of platelet activation, ADP, 5-HT, and TXA2 induce conformation of _____ receptors, which allows for _____.

A

Change conformation of GPIIb/IIIa receptors so that platelets can bind and cross-link by fibrinogen, forming hemostatic plug. Platelet contraction enhances.

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12
Q

How does aspirin impact clotting?

A

Irreversible inhibition of COX-1 inhibits TXA2 synthesis in platelets, which interferes with aggregation especially in arteries.

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13
Q

Why does aspirin impact TXA2 production in platelets more than prostacyclin productin in endothelia?

A

Platelets lack a nucleus so they cannot synthesize more COX-1 after irreversible inhibition. However, endothelia can make more COX-1.

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14
Q

What bleeding measure does aspirin impact? How long does the effect of aspirin last?

A

Prolongs bleeding time without increasing PT time. Hemostasis returns to normal in 36 hours.

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15
Q

What ADP receptors are both required for platelet activation? Which on is a pharmacologic target?

A

P2Y1 (coupled to Gq) and P2Y12 (Gi, inhibits cAMP) both required. P2Y12 is better target.

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16
Q

What ADP receptor inhibitors are prodrugs and irreversible inhibitors?

A

Ticlopidine (Ticlid), clopidogrel (Plavix), and prasugrel (Effient)

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17
Q

What ADP receptor inhibitor may induce thrombotic thrombocytopenic purpura (TTP)? How?

A

Ticlopidine (Ticlid); induces antibodies against the protease that normally cleaves circulating vWF, leading to excessive platelet aggregation that can be fatal.

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18
Q

What ADP receptor inhibitor must be given IV due to its fast onset and short half life?

A

Cangrelor (Kangreal), an ATP analog

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19
Q

What ADP receptor inhibitor has a fast onset of action because it does not require bioactivation but still has a long duration of action?

A

Ticagrelor (Brilinta)

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20
Q

What is the primary use for ADP receptor inhibitors?

A

Acute coronary syndrome including recent MI, stroke, established PVD, and coronary stent procedures (PCI)

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21
Q

What ADP receptor inhibitor has variable response in patients due to metabolism by CYP2C19?

A

Clopidogrel (Plavix)

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22
Q

What fibrinogen mimic can be administered IV to prevent thromboembolism in unstable angina and angioplastic coronary procedures?

A

Eptifibatide (Ingrilin)

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23
Q

What is the target of eptifibatide (Ingrilin)

A

Glycoprotein (GP) IIb/IIIa receptor (inhibits fibrinogen binding to decrease platelet aggregation)

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24
Q

What monoclonal antibody binds to the GP IIb/IIIa receptor and is given with tPA for early treatment of acute MI or to prevent thromboembolism in coronary angioplasty?

A

Abciximab (ReoPro) – caution d/t long duration of action which increases bleeding risk.

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25
Q

What GP IIb/IIIa receptor inhibitor is administered IV in dilute solution with heparin to treat acute coronary syndrome?

A

Tirofiban (Aggrastat)

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26
Q

How do PDE3 inhibitors like dipyridamole and cilostazol prevent clotting?

A

PDE inhibition increases cAMP (opposes P2Y12 action).

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27
Q

What condition is cilostazole used for? Dipyridamole?

A

Cilostazol – intermittent claudication

Dipyridamole – prosthetic heart valves, cerebrovascular ischemia

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28
Q

How do the new protease activated receptor inhibitors work?

A

Proteolytic cleavage of PAR-1 receptors on platelet surface, preventing thrombin-induced activation.

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29
Q

What ion is critical in clotting? Why?

A

Calcium – vital to bind to y carboxylated glutamate residues and localize factors to plasma membranes.

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30
Q

What is the ultimate protein in the clotting cascade that polymerizes to form a clot?

A

Fibrinogen (polymerized when activated to fibrin)

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31
Q

What clotting factors are glycoprotein co-factors for protease activation?

A

Factor VIII, V, and III (aka tissue factor)

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32
Q

What clotting factor cross links fibrin to form more solid clot?

A

Factor XIII

33
Q

What are the clot-inhibiting factors?

A

Protein C (protease anticoagulant), protein S (inhibits thrombin), antithrombin III, and tissue plasminogen activator

34
Q

What clotting factors are serine proteases?

A

Factors XII, XI, IX, X, VII, and II (thrombin)

35
Q

Which hemophilia is more common and caused by a deficiency in factor VIII?

A

Hemophilia A – factor VIII deficiency

Hemophilia B is less common, tied to factor IX

36
Q

What is the most common genetic clotting disorder, caused by a resistance to activated protein C? What are these patients at higher risk of?

A

Factor V Leiden – higher risk of thrombosis

37
Q

What are the only two clotting factors to be made outside the liver?

A

von Willebrand factor – from endothelium, subendothelium, and megakaryocytes
Factor VIII – endothelium as well as liver
Liver disease has unpredictable effect on coagulation

38
Q

What clotting pathway requires tissue factor from tissue outside damaged vessels?

A

Extrinsic pathway

39
Q

What clotting pathway is triggered by collagen exposure or exposure to negative charges (glass)?

A

Intrinsic pathway

40
Q

Once exposed to blood, tissue factor binds to factor ___ in the blood to activate it, which then activates factor X.

A

TF activates factor VII, which then cleaves factor X.

41
Q

What happens in the common clotting pathway?

A

Activated factor X activates prothrombin to thrombin (IIa), which then cleaves fibrinogen to fibrin. Thrombin also activates factor XIII to XIIIa, which crosslinks fibrin into a fibrin clot.

42
Q

Once a low level of thrombin is activated by the extrinsic pathway, what other factors does it act on to amplify the clotting cascade?

A

Activates factor VIII and V.

43
Q

How is a prothrombin time measured?

A

The time it takes for recalcified blood and thromboplastin to clot–basis for INR. Factor VII sensitive (extrinsic or common pathways)

44
Q

How is aPTT measured?

A

The time it takes for recalcified blood and phospholipid to clot. Measure of heparin therapy (factor IX–intrinsic or common pathway sensitive).

45
Q

How is PT standardized?

A

By giving as INR – ratio of patient PT to control PT to an international sensitivity index factor C.

46
Q

Which isomer of warfarin is more potent?

A

S isomer

47
Q

What role does vitamin K have in clotting?

A

It is essential in post-translational modification (y-carboxylation) of clotting factors including VII, IX, X, and II in addition to proteins C and S. It is oxidized in the process.

48
Q

How does warfarin act?

A

It inhibits the enzyme that reduces vitamin K to recycle it, leading to less post-translational modification of many clotting and some anticlotting factors.

49
Q

Why does warfarin have a delayed onset of action?

A

The pool of circulating clotting factors must be depleted before an effect can be seen–takes 3-5 days after initiation. This also means that the effect does not go away quickly after discontinuing warfarin.

50
Q

What enzyme metabolizes S-warfarin and is responsible for the high interpatient variability?

A

CYP 2C9

51
Q

True or false: warfarin is safe in pregnant and breast feeding women.

A

FALSE – risk of fetal hemorrhage and spontaneous abortions in addition to fetal warfarin syndrome (abnormal bone formation)

52
Q

What does heparin bind to? What effect does this have?

A

Heparin binds to antihrombin III (ATIII), which enhances the ability of ATIII to inhibit clotting factors such as factor X, VII, IX, and II (thrombin). Heparin can dissociate from complex and act on another ATIII after a factor is inhibited.

53
Q

True or false: Heparin persists in plasma for hours and has a somewhat prolonged duration of action.

A

False – heparin is cleared in 30-180 minutes and its effect disapears within hours of discontinuation.

54
Q

What patients are at high risk of iatrogenic hemorrhage with heparin use?

A

Patients >50yo, ulcer, severe HTN, concurrent antiplatelet drugs.

55
Q

What is the antidote to heparin?

A

Protamine sulfate – binds tightly to heparin and neutralizes anticoagulant action.

56
Q

How can heparin cause HIT?

A

Antibodies develop to PF4-heparin complex, activating platelets and causing widespread aggregation.

57
Q

What patients are at risk for developing osteoporosis on heparin therapy?

A

Those on heparin for 3-6 months.

58
Q

How does adding EDTA or citrate to blood prevent clotting?

A

These agents chelate calcium, preventing many of the activation steps in the clotting cascade.

59
Q

How is UFH produced? What chemical groups are vital to function?

A

Unfractionated heparin is produced by mast cells and basophils from porcine small intestine or bovine lung. Sulfate groups required for binding to (+) antithrombin.

60
Q

What are advantages to low molecular weight heparins (LMWH)?

A

Equal efficacy with increased SQ bioavailability, less frequent dosing, less protein binding, lower HIT and osteoporosis, and no monitoring of clotting needed.

61
Q

What factor do LMWHs inhibit preferentially?

A

Factor Xa (PT and aPTT ineffective to measure activity)

62
Q

What differentiates fondaparinux from the LMWHs?

A

It is synthetic and contains just the 5 saccharides necessary for function. Inhibits factor Xa selectively like LMWHs though. Longer half life than LMWHs. Lower risk HIT.

63
Q

What orally active factor Xa inhibitor cannot be used in patients with CrCl >95mL/min due to high renal clearance?

A

Edoxaban

64
Q

What parenteral agents directly inhibit free thrombin and fibrin-bound thrombin rather than acting through ATIII?

A

Lepirudin, Bivalrudin, Argatroban

65
Q

What direct thrombin inhibitor shows irreversible inhibition?

A

Lepirudin and desirudin

66
Q

What direct thrombin inhibitor has a short duration of action due to cleavage by thrombin (highly reversible)?

A

Bivalrudin (Angiomax) – doesn’t induce Ab formation due to size.

67
Q

What direct thrombin inhibitor can inhibit free and clot-associated thrombin?

A

Argatroban

68
Q

What is the only orally available direct thrombin inhibitor?

A

Dabigatran (Pradaxa)

69
Q

What are the only oral anticoagulants that have reversal agents?

A

Warfarin (Vit K) and Dabigatran (Praxbind)

70
Q

What endogenous protease activates plasminogen to plasmin?

A

Tissue plasminogen activator (t-PA)

71
Q

What is the function of plasmin?

A

Plasmin digests fibrin and fibrinogen

72
Q

What things inhibit t-PA?

A

PAI-1, PAI-2, and aminocaproic acid

73
Q

What drug forms a complex with plasminogen and makes it activate itself rather than directly cleaving plasminogen?

A

Streptokinase

74
Q

What t-PA product has the fastest onset but less fibrin specificity (activates plasmin in plasma)?

A

Reteplase

75
Q

What t-PA has greatest fibrin specificity?

A

Tenecteplase

76
Q

Why is fibrin specificity desirable in t-PA products?

A

It localizes plasmin activation to the clot.

77
Q

What is special about streptokinase dosing?

A

Must be given with a loading dose to saturate preexisting antibodies.

78
Q

What drugs act as lysine analogs and block plasmin binding to fibrin?

A

Aminocaproic acid and tranexamic acid – prevent clot breakdown and reverse bleeding caused by thrombolytics.

79
Q

Why should the anti-fibrinolytics be used with caution?

A

Because the thrombi formed when they are present excluded plasminogen, so they are not easily broken down.

Pharmacotherapy II (15 decks)

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