CHEST 2012-Parenteral Anticoagulants

Question 1

Heparin MOA

Answer 1

Heparin binds to positively charged residues on Antithrombin (AT) and causes conformational change of AT’s arginine reactive center.

Conformational change converts AT so that it quickly binds covalently to the active center serine of Thrombin and other coag factors (aka allows AT to become a fast inhibitor of serine proteases).

AT’s covalent bond to the coag enzymes irreversibly inhibits their procoag activity.

Heparin then dissociates from AT and is reused.

Question 2

Heparin molecule size

Answer 2

Heparin molecules range in molecular weight from 3,000 to 30,000 kDa with a mean of 15,000, which corresponds to approximately 45 saccharide units

Question 3

The fraction of heparin molecules that contain the high-affinity pentasaccharide sequence needed for anticoagulant activity

Answer 3

Only about one-third at therapeutic concentrations

Question 4

Clearance of heparin’s high-weight vs low-weight molecules

Answer 4

High-weight moieties are more rapidly cleared vs low-weight

Question 5

Binding of heparin to AT catalyzes the inactivation of which factors at therapeutic concentrations?

Answer 5

Thrombin, IIa, Xa, IXa, XIa, XIIa, VIIa

Antithrombin targets proteases on the contact activation pathway (intrinsic pathway): activated forms of Factor X (Xa), Factor IX (IXa), Factor XI (XIa), Factor XII (XIIa), Factor II (thrombin) (IIa).Also Factor VII (VIIa) from the tissue factor pathway (extrinsic pathway).

Question 6

If Thrombin is reduced b/c of heparin, what other effects on the coag cascade will result?

Answer 6

Decrease in fibrin formation, thrombin-induced platelet activation, and decreased V, VIII, and XI formation

Question 7

How does heparin cause osteoporosis?

Answer 7

Heparin inhibits osteoblast formation and activates osteoclasts, which promotes bone loss

Question 8

Heparin route of admin

Answer 8

Heparin is not absorbed orally and therefore must be administered parenterally.

The two preferred routes of administration are by continuous IV infusion or subcutaneous injection.

If an immediate anticoagulant effect is required, a higher initial subcutaneous dose of heparin can be administered. Alternatively, an IV bolus of heparin can be given in conjunction with the first subcutaneous dose.

Question 9

Heparin dosing suggestion for SQ vs IV

Answer 9

SQ dose of heparin should be higher than the usual IV dose because subcutaneous administration is associated with reduced bioavailability.

Question 10

Heparin dosing suggestion if immediate anticoag effect is needed

Answer 10

A higher initial SQ dose, or an IV bolus of heparin can be given in conjunction with the first subcutaneous dose.

Question 11

Initial dose of heparin for VTE

Answer 11

Either weight-based (80 units/kg bolus and 18 units/kg/h infusion) or administered as a bolus of 5,000 units followed by an infusion of at least 32,000 units/day.

If heparin is given subcutaneously for treatment of VTE, there are at least two options: (1) an initial IV bolus of ∼5,000 units followed by 250 units/kg twice daily; or (2) an initial subcutaneous dose of 333 units/kg followed by 250 units/kg twice daily thereafter.

Question 12

Heparin dose for ACS (Unstable Angina, NSTEMI, STEMI)

Answer 12

The doses of heparin recommended for treatment
of acute coronary syndromes are lower than those
used to treat VTE.

Heparin bolus of 60 units/kg (max 4,000 units) then infusion of 12 units/kg/h (max 1,000 units/h)

Question 13

Tests to monitor heparin doses

Answer 13

When given in therapeutic doses, the anticoagulant
effect of heparin is usually monitored using the aPTT. (goal is 1.5-2.5 times the normal)

Activated clotting time (ACT) is used to monitor the
higher heparin doses given to patients undergoing
percutaneous coronary interventions or cardiopulmonary bypass surgery.

Question 14

Reversal agent for heparin, and dose

Answer 14

Protamine sulfate

1mg binds to 100 units of heparin

Calculate protamine dose based on amount of heparin given over the last 2-3 hours (b/c heparin’s half-life is 60-90 mins if given IV)

Question 15

Possible side effects of Protamine sulfate

Answer 15

Hypotension or bradycardia–can be minimized by administering the protamine slowly.

If previously received protamine sulfate-containing insulin, undergone vasectomy, or have known sensitivity to fish–increased risk to have preformed antibodies against protamine sulfate and to suffer from allergic reactions, including anaphylaxis. Pretreat with corticosteroids and antihistamines.

Question 16

Why LMWH inhibit Xa more than Thrombin

Answer 16

Most molecules are too short to allow bridge to form between LMWH-AT complex and Thrombin. LMWH inactive Xa more b/c the LMWH-AT complex does not need this bridge to perform its inactivation reaction.

Question 17

Half-life of LMWH

Answer 17

3-6 hours after SQ injection, but can be prolonged in renal failure

Question 18

Time of peak anti-Xa level after SQ dose of LMWH

Answer 18

3-5 hours

Question 19

Goal anti-Xa level for LMWH for VTE treatment

Answer 19

0.6-1 unit/mL, measured 4 hours after dosing. May be higher than 1 unit/mL for once daily dosing regimens

Question 20

Dosing adjustment considerations for LMWH in obese patients

Answer 20

Increase dose (use actual body weight)

Enox–adjust up to 144kg
Tinzaparin–up to 165kg
Dalteparin–up to 190kg

Question 21

Reversal agent for LMWH, and dose

Answer 21

Protamine sulfate

Give only if LMWH dose was within last 8 hours
1mg per 100 anti-Xa units of LMWH
(note 1mg Enox=100 anti-Xa units)
Max single PS dose of 50mg
Ok to give second dose of 0.5mg/100 anti-Xa units if still bleeding

Question 22

Fondaparinux MOA

Answer 22

Binds to AT and produces a conformational change at the reactive site of AT that enhances its reactivity with factor Xa.

AT then forms a covalent complex with factor Xa. Fondaparinux is released from AT and is available to activate additional AT molecules.

Because it is too short to bridge AT to thrombin, fondaparinux does not increase the rate of thrombin inhibition by AT.

Question 23

Fondaparinux half-life

Answer 23

17-21 hours

Question 24

Reason for fondaparinux contraindicated in CrCl < 30 mL/min

Answer 24

Drug is almost completely dependent on renal clearance

Question 25

Fondaparinux dose for VTE prophylaxis and ACS

Answer 25

2.5mg once daily SQ

Question 26

Fondaparinux dose for VTE treatment

Answer 26

Weight-based dose

<50kg = 5mg SQ daily
50-100kg = 7.5mg SQ daily
>100kg = 10mg SQ daily

Question 27

Fondaparinux dosing requirement if moderate renal impairment (CrCl 30-50mL/min)

Answer 27

Decrease dose by 50% or switch to low-dose heparin

Question 28

Does protamine sulfate work for bleeding with fondaparinux?

Answer 28

No

Protamine sulfate does not bind to this drug

Question 29

Reversal agent for bleeding with fondaparinux

Answer 29

Recombinant factor VIIa

Question 30

MOA of direct thrombin inhibitors

Answer 30

Bind to thrombin and block its enzymatic activity and effects on fibrin formation, platelet aggregation, and the coag cascade

Question 31

Bivalirudin use

Answer 31

Alternative to heparin when undergoing PCI or in patients with HIT

Question 32

Bivalirudin dose

Answer 32

0.75mg mg/kg bolus, then 1.75mg/kg/hr infusion

Question 33

Half-life of Bivalirudin

Answer 33

25 min after IV injection

Question 34

Argatroban half-life

Answer 34

45 minutes

Question 35

Argatroban metabolism

Answer 35

Liver via CYP 3A4/5 enzymes, so caution in liver inpairment

Not renally excreted, so useful in patients with HIT and severe renal function

Question 36

Argatroban dose

Answer 36

2mcg/kg/min infusion

Adjust to maintain aPTT in 1.5-2.5 range

Question 37

Reversing bleeding with DTI’s

Answer 37

No specific antidote, but recombinant factor VIIa may theoretically be useful to generate thrombin.

Hemodialysis can remove bivalirudin or argatroban