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