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Pulm > Anticoagulants for Venouse Thromboembolism (VTE) > Flashcards

Anticoagulants for Venouse Thromboembolism (VTE) Flashcards

1
Q

Contrast the prognosis of DVT versus PE

A

DVT/deep vein thrombosis is rarely fatal

PE/pulmonary embolism can result in death within minutes of symptom onset – occurs when an embolus breaks off a thrombus in a vein and occludes blood vessels of the pulmonary artery tree; acute PE can cause arrhythmia and massive right ventricular failure

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2
Q

what are the phases of treatment for venous thromboembolism/VTE and how do they differ?

A
  1. acute phase (first 7 days): use of fast acting parenteral or a direct oral anticoagulant (DOAC)
  2. early maintenance phase (8 days - 3 months)
  3. extended phase (>3 months)

intermediate/extended phases typically accomplished using DOAC or warfarin

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3
Q

which coagulation factors are involved in the intrinsic versus extrinsic versus common pathway of coagulation?

A

intrinsic: XII (12) —> XI (11) —> IX (9) —> VIII (8)

extrinsic: tissue factor (TF) —> VII (7)

common: X (10) —> II (prothrombin) —> I (fibrinogen)

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4
Q

Which assays are used to measure the factors in the intrinsic versus extrinsic coagulation pathways, respectively?

A

activated partial thromboplastin time (aPTT): measures intrinsic + common pathways [XII (12) —> XI (11) —> IX (9) —> VIII (8)]

prothrombin time (PT): measures extrinsic + common pathways [tissue factor (TF) —> VII (7)]

[common: X (10) —> II (prothrombin) —> I (fibrinogen)]

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5
Q

Name the two classes of parenteral anticoagulants, and the three classes of oral anticoagulants, respectively?

A

parenteral:
1. antithrombin potentiators (Heparins)
2. Direct thrombin inhibitors (DTIs)

oral:
1. direct Factor Xa inhibitors
2. Direct Thrombin Inhibitors (DTIs)
3. vitamin K reductase (VKOR) inhibitors

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6
Q

What is the effect of heparin on coagulation?

A

heparin – heterogeneous mixture of sulfated mucopolysaccharides

binds antithrombin (AT) and dramatically accelerates the rate at which AT inhibits activated coagulation factors, particularly thrombin (IIa) and factor Xa

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7
Q

What are the three forms in which heparin is available as a parenteral anticoagulant?

A
  1. unfractionated heparin (UFH, largest): large enough to inhibit both thrombin/IIa and factor xa
  2. low-molecular weight heparins (LMWHs, mid-size): Enoxaparin, Dalteparin, inhibits factor Xa
  3. synthetic pentasaccharide (smallest): Fondaparinux, inhibits factor Xa
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8
Q

which of these forms of heparin is able to inhibit both thrombin/IIa and factor Xa?
a. Enoxaparin
b. Dalteparin
c. UFH
d. Fondaparinux

A

c. unfractionated heparin: large enough to inhibit both thrombin/IIa and factor Xa

a. Enoxaparin and b. Dalteparin are low molecular weight heparins (LMWHs); d. Fondaparinux is a synthetic pentasaccharide —> these can only inhibit factor Xa

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9
Q

Enoxaparin

A

Low molecular weight heparin – parenteral anticoagulant used to treat the VTE

heparin binds antithrombin, accelerating the rate at which it inhibits factor Xa

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10
Q

Fondaparinux

A

synthetic pentasaccharide derivative of heparin – parenteral anticoagulant used to treat VTE

heparin binds antithrombin, accelerating the rate at which it inhibits factor Xa

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11
Q

how do UFHs, LMWHs (Enoxaparin), and Fondaparinux (synthetic pentasaccharide) affect the following assays:
a. prothrombin time (PT)
b. activated partial thromboplastin time (aPTT)
c. thrombin time (TT)
d. anti-factor Xa

A

a. prothrombin time (PT, extrinsic): increased by UFH (largest form of heparin)

b. activated partial thromboplastin time (aPTT, intrinsic): increased by UFH

c. thrombin time (TT): increased by UFH

d. anti-factor Xa: increased by UFH, Enoxaparin, and Fondaparinux

*LMWHs and Fondaparinux are too small, can only bind/inhibit Factor Xa (common pathway) - this is why anti-factor Xa is best assay for their activity

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12
Q

when is use of unfractionated heparin vs LMWHs and Fondaparinux implicated, respectively?

A

UFH: IV infusion during acute phase of VTE treatment, requires close monitoring (interpatient variability)

LMWHs (Enoxaparin) and Fondaparinux: subcutaneous (SC) injection during acute phase of VTE, improved pharmacokinetics (longer t1/2, better renal clearance) - does not require routine monitoring/dose adjusting

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13
Q

what are two major adverse reactions associated with heparin use?

A
  1. bleeding (UFH, LMWHs, Fondaparinux) - often associated with underlying cause
  2. Heparin-induced thrombocytopenia (HIT) - mostly associated with UFH, must monitor platelet count, necrotizing skin lesion can occur at injection sites
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14
Q

how can protamine and ciraparantag be used in the management of adverse reactions related to heparin use?

A

major adverse effect of heparin use is bleeding

protamine: binds/neutralizes heparin, used in life-threatening hemorrhage (rapidly reverses anticoagulant effects of UFH)

Ciraparantag: new drug, may safely reverse anticoagulant effects of UFH/LMWHs/fondaparinux

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15
Q

what kind of drugs are Bivalirudin, Argatroban, and Desirudin, what is the mechanism of action?

A

Bivalirudin, Argatroban: direct thrombin inhibitors (DTI) – parenteral anticoagulants, unlike heparins, do not require antithrombin as a cofactor

Bivalirudin and Argatroban are both reversible inhibitors

Bivalirudin: binds active site + fibrin-binding site
Argatroban: binds only active site

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16
Q

how do direct thrombin inhibitors (DTIs) such as Bivalirudin and Argatroban impact the following coagulation assays:
a. prothrombin time (PT)
b. activated partial thromboplastin time (aPTT)
c. thrombin time (TT)
d. anti-factor Xa

A

a. prothrombin time (PT): increased

b. activated partial thromboplastin time (aPTT): increased

c. thrombin time (TT): increased

d. anti-factor Xa: no change

[recall factor X is activated before thrombin in common pathway: X (10) —> II (prothrombin) —> I (fibrinogen)]

17
Q

When is use of Bivalirudin or Argatroban implicated?

A

Bivalirudin, Argatroban: direct thrombin inhibitors (DTI) - parenteral anticoagulants

DOC for the treatment of VTE in patients with a diagnosis/history of the HIT (heparin-induced thrombocytopenia)

administered via IV

18
Q

what adverse affects are associated with Bivalirudin and Argatroban?

A

Bivalirudin, Argatroban: parenteral direct thrombin inhibitors (DTI)

bleeding is most common adverse effect

Bivalirudin - renal excretion, use with caution in patients with renal insufficiency

19
Q

what kind of drugs are Apixaban, Rivaroxaban, Edoxaban, and Betrixaban, and what is their mechanism of action?

A

ApiXAban, RivaroXAban: direct factor Xa inhibitors – direct oral anticoagulants (DOAC) used to treat VTE

recall Factor Xa is in common coagulation pathway: X (10) —> II (prothrombin) —> I (fibrinogen)

reduce thrombin generation – suppression of platelet aggregation, fibrin formation

20
Q

Bivalirudin

A

direct thrombin inhibitor (DTI) - parenteral anticoagulant, used in treatment of VTE

reversible inhibitor, binds active site + fibrin-binding site

21
Q

Argatroban

A

direct thrombin inhibitor (DTI) - parenteral anticoagulant, used in treatment of VTE

reversible inhibitor, binds active site

22
Q

Apixaban

A

direct factor Xa inhibitor: oral anticoagulant used to treat VTE

23
Q

Rivaroxaban

A

direct factor Xa inhibitor: oral anticoagulant used to treat VTE

24
Q

how will Apixaban and Rivaroxaban affect the following coagulation assays:
a. prothrombin time (PT)
b. activated partial thromboplastin time (aPTT)
c. thrombin time (TT)
d. anti-factor Xa

A

Apixaban and Rivaroxaban: direct factor Xa inhibitors (oral anticoagulants, treat VTE)

a. prothrombin time (PT): increased
b. activated partial thromboplastin time (aPTT): increased
c. thrombin time (TT): no change
d. anti-factor Xa: increased

25
Q

When is use of Apixaban and Rivaroxaban indicated?

A

Apixaban and Rivaroxaban: direct factor Xa inhibitors (oral anticoagulants, treat VTE)

approved for all treatment phases of VTE - wider therapeutic index than warfarin

26
Q

what important adverse reactions and drug–drug interactions are associated with Apixaban and Rivaroxaban?

A

Apixaban and Rivaroxaban: direct factor Xa inhibitors (oral anticoagulants, treat VTE)

adverse reactions: bleeding (less risk than warfarin), can be reversed with recombinant factor Xa (Andexxa)

Apixaban metabolized by CYP3A4

27
Q

what kind of drug is Dabigatran and what is its mechanism of action?

A

Dabigatran: oral anticoagulant – direct thrombin inhibitor (DTI) used to treat VTE

competitively/reversibly blocks active site of thrombin (factor IIa) —> blocks thrombin-mediated conversion of fibrinogen to fibrin and platelet activation

*converted to active drug by plasma esterases

28
Q

when is use of Dabigatran indicated?

A

Dabigatran: oral anticoagulant – direct thrombin inhibitor (DTI)

approved for all phases of VTE treatment (acute, early maintenance, extended)

only started after 5+ days of treatment with UFH or LMWH or fondaparinux (heparin/derivatives)

29
Q

how can idarucizumab (Praxbind) be used to reverse the adverse effects of Dabigatran?

A

Dabigatran: oral anticoagulant – direct thrombin inhibitor (DTI) used to treat VTE

bleeding is major side effect - can be reversed with idarucizumab (Praxbind), mAb of dabigatran

30
Q

what is the mechanism of action of warfarin?

A

Warfarin: oral anticoagulant, Vitamin K reductase (VKOR) inhibitor

recall clotting factors II (2), VII (7), IX (9), and X (10) are synthesized in liver as prozymogens and require Vit. K for conversion to zymogens

*therefore, warfarin has no effect on zymogens already in circulation

31
Q

which clotting factors are reduced by warfarin?

A

Warfarin: oral anticoagulant, Vitamin K reductase (VKOR) inhibitor

recall clotting factors II (2), VII (7), IX (9), and X (10) are synthesized in liver as prozymogens and require Vit. K for conversion to zymogens

*therefore, warfarin has no effect on zymogens already in circulation

32
Q

Which clotting factors are synthesized in the liver and require vitamin K to become zymogens?

A

clotting factors II (2), VII (7), IX (9), and X (10)

[Warfarin: oral anticoagulant, Vitamin K reductase (VKOR) inhibitor ]

33
Q

when is warfarin use implicated?

A

Warfarin: oral anticoagulant, Vitamin K reductase (VKOR) inhibitor

approved for prevention/treatment of VTE - narrow therapeutic index, requires monitoring

34
Q

what are the important adverse effects (2) and drug-drug interactions of warfarin?

A

Warfarin: oral anticoagulant, Vitamin K reductase (VKOR) inhibitor

adverse:
1. bleeding - can be reversed with human prothrombin complex (Kcentra) or fresh frozen plasma to replace Vit. K dep. clotting factors (2, 7, 9, 10)
2. skin necrosis: 3-10 days post treatment, typically on extremities

drug-drug: drugs/food that affect CYP3A4, CYP2C9, CYP1A2, or fluctuating intake of dietary Vit. K (green leafy vegetables, beef liver)

Pulm (30 decks)

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