This document discusses heparin and enoxaparin, two anticoagulant drugs. It begins by outlining the coagulation cascade and where these agents act to inhibit it. Specifically, it notes that heparin inhibits thrombin and factor Xa by enhancing antithrombin, while enoxaparin primarily inhibits factor Xa. The document then covers the indications, dosing, monitoring, and adverse effects of both unfractionated heparin and enoxaparin. Key differences are that enoxaparin has higher bioavailability, longer duration of action, and is dosed subcutaneously rather than via intravenous infusion like unfractionated heparin.

1. HEPARIN AND ENOXAPARIN
Dr. Arun George
PG Registrar
PICU

2. OUTLINE
Physiology
 Coagulation cascade
Classification
Individual drugs
 Heparin
 Enoxaparin

3. COAGULATION CASCADE

5. WHERE DOES THESE
AGENTS ACT ?
Anticoagulants

6. CURR EMERG HOSP MED REP (2013) 1:83–97
ANTICOAGULANTS: A REVIEW OF THE PHARMACOLOGY, DOSING, AND COMPLICATIONS

8. INDICATIONS FOR
ANTICOAGULATION
Venous Thromboembolism (VTE)
Arterial Thromboembolism (ATE)
Conventional anticoagulants in pediatric
 unfractionated heparin (UFH)
 low molecular weight heparins (LMWHs, enoxaparin)
 vitamin K antagonists (warfarin)

9. UFH

10. UFH – INTRODUCTION
Heparin was discovered by a medical student
Heparin – High concentration in liver
Obtained from ox lung / pig intestine mucosa
Molecular weight ranging from 3000 to 30,000 kD

11. UFH
It accelerates the Anti thrombin 3 activity
Inhibits factors - 2, 10, 9,11,12 & 13
UFH + AT’s = inhibition of coagulation serine proteases increases
approximately 1000-fold
UFH increases the intravascular release of tissue factor pathway inhibitor (TFPI)
High dose – anti platelet action

12. INTERACTION OF HEPARIN-ATIII-CLOTTING
FACTORS
Heparin needs to interact with both
ATIII and Thrombin (IIa)
To enhance its effect on Factor Xa,
heparin needs only to interact with
ATIII
LMWH can only increase the action of
ATIII on Factor Xa and not on
thrombin (IIa).
Heparin
ATIII IIa
Heparin
ATIII Xa
LMWH
ATIII Xa

13. Inhibition of thrombin and Factor Xa by the Heparin/AT III
complex through a unique pentasaccharide unit. Binding to
thrombin requires a minimum of 13 saccharide units. Low
molecular weight heparin acts to inhibit Factor Xa and requires
A T I I I T h r ombi n
5 13 or more saccharide units
Heparin
Lysine
Sites
A T I I I F a c t or X a
5
Low Molecular Weight Heparin
Lysine
Sites
<13

14. ANTICOAGULANT THERAPY
Heparin
Actions of Heparin
Inactive by itself as an anticoagulant
Requires the presence of a plasma cofactor-
ANTITHROMBIN III (AT III)
Heparin potentiates the action of AT III
Heparin-AT III-complex neutralizes the actions
of: Factors II, IX, X, XI, XII and XIII
Binds to lysine sites on AT III, leads to
conformational change at the arginine reactive
center

15. Not absorbed
orally / only P
formulations
Monitor aPTT -
1.5 to 2.5 times
the control
UNFRACTIONATED HEPARIN*
Indication Thrombus of indeterminate age
Dose
75 U/kg/bolus, 20-28* U/kg/hr by
continuous infusion IV
Adjustment
↑ dose by 5-10% q6hr until adequate
level or PTT is achieved
Monitors/goal
PTT times control; thrombin time
infinity; heparin level 0.3-0.7 U/mL
Mechanism
Accelerates AT-III–dependent
inactivation of thrombin, FXa
Risk of bleeding Low

16. Heparin Dosing
Initial dosing is based on age, with infants having the highest
requirements.
It is important to continue to monitor the PTT closely.
In some situations, such as patients with a lupus anticoagulant, those
with elevated
factor VIII, or neonates, the PTT may not accurately reflect the degree
of
anticoagulation, and heparin can be monitored using a heparin anti-
Xa level of
0.35-0.7 units/mL.

17. ADVERSE EFFECTS
1. Bleeding
The true frequency of bleeding in pediatric patients receiving heparin
has not been well established and is reported as 1–24%. If the
anticoagulant effect of heparin must be reversed immediately,
protamine sulfate may be administered to neutralize the heparin.
2. Hypersensitive reactions
3. Osteoporosis
4. Reversible alopecia

18. 5. Heparin-induced thrombocytopenia (HIT)
HIT is a prothrombotic, immune-mediated complication in which
antibodies develop to a complex of heparin and platelet factor 4.
These antibodies result in platelet activation, stimulation of
coagulation, thrombocytopenia, and in some cases, life-threatening
thrombosis.
If HIT is strongly suspected, heparin must be discontinued
immediately.
An alternative parenteral anticoagulant, such as argatroban or
bivalirudin, may be used in this situation.

19. MONITORING
Narrow therapeutic window
Recommendations for UFH therapy from the American College of
Chest Physicians (ACCP) suggest target aPPT
APTT of 1.5 to 2.5 times normal values produced desirable UFH safety
and efficacy outcomes

20. SUMMARY OF ASSAYS USED TO
MONITOR UFH THERAPY

21. LMWH – ENOXAPARIN
LMWH - Prepared by altering UFH
The interaction of the smaller chains with AT III results primarily in
the
inhibition of factor Xa, with less of an effect on thrombin.
The several LMWHs available have variable inhibitory effects on
thrombin. For this reason, the PTT is not a reliable measure of the
anticoagulant effect of LMWH, and the anti–factor Xa activity is used
instead.

22. ADVANTAGES OF LMWH
No need for aPTT monitoring
Higher bioavailability
Longer duration of action
Lower side effects
BD/ OD doses

23. NOTE
longer half-life and reduced reversibility compared to UFH
used in patients with less acute risk of haemorrhage

24. ANTI XA – MONITORING
Therapeutic range - between 0.5 and 1.0 unit/mL
An anti-Xa range of 0.3 to 0.5 units/mL - prevention of
thromboembolic disease

25. LMW HEPARIN (ENOXAPARIN)
Indication Thrombus of indeterminate age
Dose 1.0-1.5* mg/kg q12hr SC
Adjustment ↑ or ↓ by 10-20%
Course 5 days-6 mo
Monitors/goal
LMW heparin level 4 hr after 4th dose
= 0.5-1.0 U/mL
Mechanism
Accelerates AT-III–dependent
inactivation of FXa and thrombin
Risk of bleeding Low

26. Enoxaparin Dosing
In general, peak levels are achieved 3-6 hr after injection. A
therapeutic
anti–factor Xa level, drawn 4 hr after the 2nd or 3rd dose, should be
0.5-1.0
IU/mL; the dose can be titrated to achieve this range.
The elimination half-life of enoxaparin is 4-6 hr.
Enoxaparin is cleared by the kidney and should be used with caution
in patients with renal insufficiency. It should be avoided in patients
with renal failure.

27. DIFFERENCE

28. References:
1. Nelson textbook of Paediatrics 21st edition
2. Harriet Lane
3. Anticoagulant therapy in Paediatrics – Journal of Basic and Clinical
Pharmacy 2015