Perioperative Anticoagulation Management

Question 1

___, ___, and ___ are the leading causes of anticoagulation treatment.

Answer 1

AF, DVT, and PE

Question 2

Aspirin (Acetylsalicylic Acid)

This agent is the most commonly prescribed antiplatelet drug for the prevention of cardiovascular disorders. Its mechanism of action is the irreversible inhibition of _______.

Answer 2

The cyclooxygenase (COX) 1 and 2 enzymes.

Question 3

Regarding the MOA of aspirin, the action of COX is necessary for the conversion of ______ to ________.

This is rapidly converted to several bioactive prostanoids, including ________, a potent vasoconstrictor, and an inductor of platelet aggregation.

Answer 3

Arachidonic acid
Prostaglandin (PG) H2

Thromboxane A2

Question 4

Despite the short half-life of aspirin (3 to 6 hours), its irreversible effects will last for the complete lifetime of the platelet (__ to ___ days).

After the interruption of aspirin therapy, recovery of platelet function depends on its turnover (approximately __% per day).

Answer 4

8 to 9 days

10%

Question 5

The effect of NSAIDs on platelet function is considered a short-term effect that normalizes within _____ days; nonetheless, this can vary between drugs in the class.
For short-acting drugs like ibuprofen, diclofenac, and indomethacin, 50% of platelet function is restored ____ hours after the last dose and normalized after _____ hours.

Answer 5

Three days

Six hours; normalize in 24 hours.

Question 6

Thienopyridines (_____ and _____)

Answer 6

Clopidogrel and Prasugrel

Question 7

Thienopyridines (Clopidogrel and Prasugrel)

These are inhibitors of the _______ receptor, also called the ______ receptor, in platelets.

Answer 7

Adenosine diphosphate (ADP) receptor, also called the P2Y12 receptor. This is an irreversible mechanism.

Question 8

Physiologically, the union of ADP with its receptor on platelets increases levels of intracellular calcium and activates the _____ platelet receptor that promotes the stabilization of the platelet clot through fibrinogen bonds.

Answer 8

GpIIB/IIIa

Question 9

Due to the irreversible mechanism of action of thienopyridines, it is recommended to interrupt these drugs ______ days before non-cardiac elective surgery.

Answer 9

5 to 7

Question 10

Non-thienopyridines (Ticagrelor and Cangrelor)

Ticagrelor is a reversible, non-competitive ____ analog that binds to a G-protein in the _____ receptor, preventing its activation and signaling.

Cangrelor is a direct, reversible, and intravenously administered drug that inhibits the _____ receptor.

Answer 10

ATP analog; P2Y12

P2Y12 receptor

Question 11

After a loading dose of ticagrelor, the maximum antiplatelet effect is achieved within 2 hours, plasma half-life is 8 to 12 hours, and steady-state concentration in 2 to 3 days. Due to the reversible effect of ticagrelor on platelets, it is recommended to be suspended ___ days before surgery.

Answer 11

Five days

Question 12

Cangrelor can inhibit 95% to 100% of platelet activity within the first two minutes of administration; the plasma half-life of cangrelor (3 to 6 minutes) allows recovery of 80% to 90% platelet function within ________ of discontinuing the intravenous infusion.

Answer 12

60 to 90 minutes

Question 13

Vitamin K Antagonists (Warfarin, Acenocoumarol, Phenprocoumon)

These are also called coumarins. The most recognized and widely used drug of this group is warfarin, which has been available for more than 50 years. The mechanism of action of warfarin is the inhibition of the ___________ enzyme, responsible for the cyclical conversion of _____ vitamin K to a _____ state.

The latter is necessary as a cofactor for the ________ of glutamic acid at the N-terminus of coagulation factors. Without ______ residues, clotting factors II, VII, IX, and X cannot bind to the ________ necessary for normal activation.

Answer 13

2,3 epoxide reductase

Oxidized; reduced

Carboxylation

Gamma carboxyglutamate

Divalent calcium

Question 15

Why is it that there is a temporary hypercoagulable state after starting warfarin?

Answer 15

The inhibition of carboxylation also affects the production of protein C and S anticoagulants. This creates a transient procoagulant state that can be explained by the shorter half-life of these anticoagulants (8 and 30 hours), compared to factor II and factor X (60 and 72 hours). This phenomenon is more frequent, with higher doses of vitamin K antagonists at the beginning of anticoagulation therapy.

Question 16

What are the common Direct Inhibitors of Factor Xa?

These are also known as?

Answer 16

Rivaroxaban, Apixaban, Edoxaban, Betrixaban

Direct oral anticoagulants (DOACs)

Question 17

How do DOACs work?

Answer 17

Bind to the active site of factor Xa, thus inactivating it. Factor Xa is considered the rate-limiting step for the progression of the coagulation cascade, thrombin activation, and ultimately clot formation.

Question 18

Review the table of DOAC pharmacokinetics.

Answer 18

Question 19

Review the Anticoagulation Reversal table for DOACs.

Question 20

Review the Anticoagulation Reversal table for DOACs.

Question 21

What is Dabigatran?

Answer 21

Direct Inhibitors of Thrombin

Dabigatran is the only medication in this group. Its mechanism of action is the direct inhibition of thrombin, preventing the conversion of fibrinogen to fibrin and thus clot formation. Dabigatran has a quick onset of action (0.5 to 2 hours) and is metabolized by non-specific plasma esterases. The plasma half-life is around 12 hour

Question 22

What is fondaparinux?

Answer 22

Fondaparinux

This drug is a pentasaccharide that acts as an indirect factor Xa inhibitor. The exact mechanism of action is the reversible binding of the drug to the antithrombin factor, potentiating its activity to inactivate Factor Xa. The plasma half-life of fondaparinux is approximately 15 to 17 hours. Its anticoagulant activity persists even 2 to 4 days after the last dose of the drug in a person with normal renal function.

Question 23

How do the heparins work?

Answer 23

Heparins

The binding of the heparin molecule to the antithrombin receptor enhances its potency to inactivate factors II and Xa.

Question 24

In patients with a recent episode of VTE (less than 1 month ago), the risk of recurrence in the subsequent month can be as high as 40%. An elective surgical procedure should be deferred up to _______ after an episode of VTE, if possible.

For patients with a recent acute ischemic stroke undergoing non-cardiac elective surgical procedures, the risk of having a major cardiovascular event after surgery is high, especially within the first 3 months. The American College of Surgeons recommends deferring the surgery up to ________ in this scenario when the risk of cardiac events has plateaued after a stroke.

Answer 24

Three months

Nine months

Question 25

If aspirin and thienopyridine need to be suspended during the perioperative period, the elective surgical procedure should be delayed ________ for patients with bare-metal stents and _______ for drug-eluting stents. In case the elective surgery cannot be postponed, the dual anti-aggregation therapy should be continued throughout the perioperative period.

Answer 25

Six-weeks

Six-months

Question 26

T orF: Evidence on bridging therapy follows a trend against its use.

Answer 26

True

Bridging anticoagulation consists of the substitution of a long-acting anticoagulant (usually with warfarin) for a shorter-acting anticoagulant (usually LMWH) to limit the time of subtherapeutic anticoagulation levels and minimize thromboembolic risk. Despite the growing evidence about the limited to nonexistent benefits of bridging therapy, it is still being used on a case-by-case basis.

Question 27

Here is a typical bridging plan:

How to bridge

Our bridging recommendations follow the AT9 guidelines, which agree with the American Society of Regional Anesthesia (ASRA) 2018 guidelines and are similar to the American College of Surgeons 2018 guidelines.

During the preoperative period:

Discontinue warfarin five days before surgery.
Three days before surgery, start subcutaneous LMWH or unfractionated heparin (UFH), depending on the renal function of the patient at therapeutic doses.
Two days before surgery assess INR, if greater than 1.5 vitamin K can be administered at a dose of 1 to 2 mg.
Discontinue LMWH 24 hours before surgery or 4 to 6 hours before surgery if UFH.
During the postoperative period:

If the patient is tolerating oral intake, and there are no unexpected surgical issues that would increase bleeding risk, restart warfarin 12 to 24 hours after surgery.

Question 28

What are a few typical ways to manage anticoagulation wiith elective surgery?

Answer 28

In patients at high risk of cardiac events, aspirin should be continued throughout the perioperative period, with clopidogrel and prasugrel discontinued 5 days prior to surgery and resumed 24 hours postoperatively.

For patients at low risk of cardiac events, dual antiplatelet therapy can be discontinued 7 to 10 days before surgery and restarted 24 hours postoperatively.

Question 29

Reversal of warfarin: For non-significant bleeding with alterations of the INR, conservative strategies such as interruption of the drug and oral vitamin K are suitable options. In the emergent scenario, the reversal of warfarin anticoagulation is based on prothrombin complex concentrate (PCC) and fresh frozen plasma (FFP) administration as follows:

INR 2-4: (1)
INR ≥4-6: (2)
INR >6: (3)
Vitamin K: (4) administered slowly
FFP: (5)
Trauma patients: 1 gm of tranexamic acid can be used at arrival and repeat dose of 1 gm in 8 hours
PCC is commercially available as prothrombin complex concentrate both contain heparin and are thus contraindicated in patients with a past medical history of (6).

Answer 29

(1) PCC: 25 IU/kg IV
(2) PCC: 35 IU/kg IV
(3) PCC: 50 IU/kg IV
(4) 10 mg
(5) 10 - 20 ml/kg
(6) Heparin induced thrombocytopenia

Question 30

The required time for anticoagulant reversal and INR correction with vitamin K is? (1)
and PCC? (2)

(3) should be administered if there is ongoing bleeding or PCC is not available. The timing of anticoagulation reversal depends on the timing to complete infusion. Complete reversal usually takes up to 32 hours.

PCC must be administered with (4)

Answer 30

(1) Six to 24-hours
(2) 15-minutes after a 10-minute or one-hour infusion
(3) FFP
(4) Vit K