Q2i: Heparins & Direct Thrombin Inhibitors table

Thrombin

UFH

Inactivates

Long chain bridging when on ATIII

But does not affect Thrombin bound to Fibrin; already enzymatically active & protected from inactivation

LMWH

Indirect effect

By binding ATIII inhibits Xa activity

So reduced formation of Thrombin

Bivalirudin

Direct & Reversible Thrombin Inhibition

Hirudin

Direct and Irreversible Thrombin inhibitor

Xa

UFH

Inactivates

LMWH

Inactivates

Bivalirudin

Hirudin

Xa:IIa activity ratio

UFH

1:1

LMWH

2:1 or 4:1

Bivalirudin

Hirudin

AT III

UFH

Mediates effect

LMWH

Mediates effect

Bivalirudin

Hirudin

Platelets

UFH

Via thrombin inhibition

LMWH

Moderate plat inhibition

Bivalirudin

Through Thrombin blocking = potent antiplat effect

Hirudin

Through thrombin potent antiplat effect

Fibrin

UFH

Prevents cross-linking due to Thrombin inhibition

LMWH

Inhibits formation of Fibrin Stabilising Factor

Bivalirudin

Prevents Fibrin formation

Binds to Thrombin free & in clot

Hirudin

Prevents Fibrin formation

Binds to Thrombin free & in clot

Factor V, VIII, XI, XIII

UFH

Via Thrombin inhibition

LMWH

Bivalirudin

Hirudin

Time to peak effect

UFH

IV ~1min

SC ~45min

LMWH

~4hrs

Bivalirudin

5-10min

Hirudin

10 mins after IV bolus

Time to normal hemostasis on cessation

UFH

4-6h

LMWH

>12hrs

Bivalirudin

25 min

Hirudin

1.5h

Predictability of effect

UFH

unpredicatable

LMWH

Predictable

(remember it is like a refined selection of the heparins)

Bivalirudin

Requires monitoring

Hirudin

Requires monitoring

PK

UFH

LMWH

Bivalirudin

Hirudin

D

UFH

High PPB

Binds many proteins ∴large interpatient variability

LMWH

Much less PPB

Great 100% bioavailability after sc injection

Bivalirudin

Distributed to ECF + ISF

Hirudin

Distributed in ECF

Vd 12-32L

M

UFH

Heparinases of liver, kidney, RES

LMWH

Desulfation +/- depolymerisation in liver

Bivalirudin

Digested by plasma proteases

Hirudin

Metabolism through renal clearance

E

UFH

Metabolites excreted renally

(no dose adj w renal impair)

LMWH

Majority of dose renally cleared as active/inactive metabolites

Needs dose adjustment in renal impairment

Bivalirudin

Renally cleared

20% unchanged

Needs dose adjustment for severe renal impairment

Hirudin

35% dose unchanged

Monitoring

UFH

APTT

ACT (high dose

LMWH

Anti-Xa-levels

Bivalirudin

APTT, PT, ACT

Hirudin

APTT

PT

Reversal

UFH

Protamine

LMWH

Protamine

But variable, up to 60% of dose

May rebound due to cont subcut depot after protamine dose

Bivalirudin

No antidote

But quick offset on cessation of infusion

Try FFP, Prothrombinex, Haem consult

Hirudin

No antidote

Desmopressin somewhat

Haemodialysis

UFH

SC injection twice daily

LMWH

Excellent bioavailability -> predictable dosing od

Daily monitoring for Tx dose

Predictable, no monitoring for prophylactic/Tx dose

Not easily used for outpatients

Outpatients can use much easier

Plat dysfn; reduce count or HITS

Lower incidence of HITS

Risk of bleeding

Less risk of bleeding

Osteoporosis

Less risk of osteoporosis

Fully reversible w Protamine

Up to 60% reversibility w Protamine

Can be used in renal impairment

Accumulates in renal impairment

Rapid onset & clearance

Delayed Clearance – need to wait 12-24h post dose for CNB

Thrombin

Dabigatran

–

Apixiban

–

Rivaroxaban

–

–

Xa

Dabigatan

–

Apixiban

–

Rivaroxaban

–

–

Xa:IIa activity ratio

Dabigatan

–

Apixiban

–

Rivaroxaban

–

–

AT III

Dabigatan

–

Apixiban

–

Rivaroxaban

–

–

Platelets

Dabigatan

–

Apixiban

–

Rivaroxaban

Through Thrombin blocking = potent antiplat effect

Through thrombin potent antiplat effect

Fibrin

Dabigatan

–

Apixiban

Inhibits formation of Fibrin Stabilising Factor

Rivaroxaban

Prevents Fibrin formation

Binds to Thrombin free & in clot

Prevents Fibrin formation

Binds to Thrombin free & in clot

Factor V, VIII, XI, XIII

Dabigatan

–

Apixiban

–

Rivaroxaban

–

–

Time to peak effect

Dabigatan

–

Apixiban

~4hrs

Rivaroxaban

5-10min

10 mins after IV bolus

Time to normal hemostasis on cessation

Dabigatan

–

Apixiban

>12hrs

Rivaroxaban

25 min

1.5h

Predictability of effect

Dabigatan

–

Apixiban

Predictable

(remember it is like a refined selection of the heparins)

Rivaroxaban

Requires monitoring

Requires monitoring

PK

Dabigatan

–

Apixiban

–

Rivaroxaban

–

–

D

Dabigatan

–

Apixiban

Much less PPB

Great 100% bioavailability after sc injection

Rivaroxaban

Distributed to ECF + ISF

Distributed in ECF

Vd 12-32L

M

Dabigatan

–

Apixiban

Desulfation +/- depolymerisation in liver

Rivaroxaban

Digested by plasma proteases

Metabolism through renal clearance

E

Dabigatan

–

Apixiban

Majority of dose renally cleared as active/inactive metabolites

Needs dose adjustment in renal impairment

Rivaroxaban

Renally cleared

20% unchanged

Needs dose adjustment for severe renal impairment

35% dose unchanged

Monitoring

Dabigatan

–

Apixiban

Anti-Xa-levels

Rivaroxaban

APTT, PT, ACT

APTT

PT

Reversal

Dabigatan

–

Apixiban

Protamine

But variable, up to 60% of dose

May rebound due to cont subcut depot after protamine dose

Rivaroxaban

No antidote

But quick offset on cessation of infusion

Try FFP, Prothrombinex, Haem consult

No antidote

Desmopressin somewhat

Haemodialysis