25th July 2014

BULLETIN

Heparin vs Enoxaparin vs Fondaparinux

In Post Delivery

Background:

For many years, unfractionated heparin (UFH) was the mainstay of anti-coagulation therapy for treat-

ment and prevention of thrombosis. Newer agents with more predictable pharmacokinetics profiles

such as the low molecular weight heparins ( LMWHs ) and fondaparinux, have proven to be just as effec-

tive for the same indications as heparin. Currently has two LMWHs formulary, Dalteparin and Enoxapa-

rin. Although these agents share similarities, differences in their mechanism of action, pharmacokinetic

profiles, contraindications.

—Mechanism of Action—

Heparin:

Binds to and potentiates the actions of anti-thrombin (AT) to inactivate

factor Xa and prevent the conversion of prothrombin to thrombin, as well

as prevent the conversion of fibrinogen to fibrin. Binds to and potentiates

the actions of anti-thrombin (AT) to inactivate factor Xa and prevent the

conversion of prothrombin to thrombin, as well as prevent the conversion

of fibrinogen to fibrin.

LMWHs ( Dalteparin and Enoxaparin )

LMWHs bind and accelerate the activity of

AT, but with a preferential, and longer lasting

effect on factor Xa. When compared to hepa-

rin, LMWHs are less able to inhibit the pro-

duction of thrombin and bind to plasma pro-

teins and endothelial cell less due to their

decreased sized. This accounts for an 85-99%

bioavailability when administered subcuta-

neous, more predictable anti-coagulant re-

sponse, less inter-patient variability, and

longer duration of action than heparin.

Fondaparinux

Fondaparinux binds and enhances the anti-

Xa activity of AT by 300 fold. AT specificity

does not allow binding to other plasma pro-

teins. It has no direct effect on thrombin,

has excellent bioavailability after subcuta-

neous administration and a long half-life.

Comparison of Pharmacokinetic Parameters, and Indications

for

Heparin, Enoxaparin, & Fondaparinux

Heparin Enoxaparin Fondaparinux

Images

Mechanism Enhances AT effects on Factor Xa and thrombin. Binds non-specifically to plasma protein and cause unpredict-able dose response.

Enhances AT effects more selectively on Factor Xa than on thrombin. Less binding to plas-ma protein, so more predictable dose re-sponse, less inter-patient variability.

Enhances anti-Xa ac-tivity of AT

Specificity for AT so no binding to other plas-ma

proteins, good predict-ability

Half-Life 1-2 hours 4.5 – 7 hours

17 - 21 hours

Clearance Hepatic and Reticulo-endothelial system

No renal adjustments

Renal Adjust for CrCl < 30 mL/min

Renal Contraindicated in CrCl < 30 mL/min

Pregnancy OK OK CI – Insufficient data

Case reports available

Breast Feeding OK ( does not pass into breast milk )

OK (Low bioavailabil-ity when ingested orally )

Unknown if excreted in breast milk

Ability to cause HIT

YES YES No in vitro cross reac-tivity to anti-PF4/heparin antibodies

Case reports

Use in HIT treatment

NO NO Yes

Why Heparin is Needed for Pregnant Women?

Pregnancy requires special consideration with respect to the preven-

tion and treatment of blood clots. Pregnancy does not cause blood

clots, but increases the chance that a blood clot will develop by four-

to five-fold.

Pregnancy’s tendency to form clots is an evolutionary response to

protect women against the bleeding challenges of miscarriage and

childbirth.

In general:

Women who have had a blood clot in the past and are on anticoagulation

will need to continue their anticoagulation during pregnancy.

Most women who have had a blood clot in the past, but are not currently

on anticoagulation, will need to be restarted on anticoagulation during

pregnancy.

Women who develop a blood clot during pregnancy will need to be start-

ed on anticoagulation.

Warfarin, the most commonly prescribed anticoagulant, or the new oral anticoagulants

(dabigatran, rivaroxaban and apixaban), are convenient to take because they do not have to

be injected, but they are not considered safe for unborn babies.

Heparin LMWH are safe in pregnancy because they do not cross the placenta and, therefore,

do not enter the blood stream of unborn babies. In fact, in women who have thrombophilia,

heparin or LMWH may actually improve the outcome of pregnancy in women who have had a

previous pregnancy that was complicated by severe high blood pressure of pregnancy

(severe preeclampsia).

Heparin and LMWH have been used in pregnancy by thousands of women with no birth defects

or bleeding problems in their unborn babies. Whether women are treated with heparin, or

LMWH, they will ultimately need to receive once or twice-daily injections until at least 6 weeks

after delivery of the baby.

For most of the patients after delivery, one shot daily of heparin injection is more con-venient for them as they are preferred to lay down and rest. But twice shots of daily heparin injection will increase the efficiency of the heparin in anticoagulant properties. Twice shots of heparin do reduce the thrombus size in Vein Thromoembolism (VTE) pa-tients.

Why heparin is taken twice a day?

During heparin management, patients delivery should beware of any bleeding occur.

Occurrence of bleeding may indicates excessive in taking heparin, which will cause blood become thinner and promotes bleeding. Patients are advised to go to hospital to treat the bleeding.

During heparin treatment, patients will have fatigue feel and muscles numbness. Patients are also has tremors. These are causes by low potassium level in the blood. Heparin will lower the potassi-um level in the blood, which will lead to hypokalemia. Hence, patients after delivery who receiving heparin treatment should have accompany by a person to aids in their daily activities.

Patients should be monitored to ensure allergic response occurs on the patients after delivery. If

allergic response does occur, replacement of heparin should be considered with other anticoagu-

lants, such as Warfarin.

Reasons of patients after delivery to miss heparin injection may included:

Patients start to work and missed a dose of injection.

Patients are resting or sleep and forget to have following heparin injection.

Patients feel not convenient to go to nearby health facilities for follow-up heparin injection.

Patients are not compliance due to irritating feel of injection, hence reject injection.

PS: If patients are missed a dose of injection in twice shot of daily heparin treatment,

take the injection immediately. If the time is near the time to take second dose, skip the

dose and take the second dose of heparin injection.

Interactions

Taking of certain medicines will increase the risk of bleeding, which are:

Non-steroidal anti-inflammatory (NASIDs), eg:

Ibuprofen, Aspirin, Diclofenac

Anticoagulant, eg: Warfarin, Low Molecular

Weight Heparin

While certain drugs may decrease the efficiency of the heparin, which are:

Nicotine (smoking)

Benzodiazepine, eg: clonazepam, diazepam

Digitalis, eg: digitoxin, digoxin

Complications

1. Hemorrhage

Excessive in taking heparin injection will leads to hemor-rhagic event. Bleeding will occurs in patients after deliv-ery who taking heparin injection. Symptoms will appear in hemorrhagic effect are nose bleeding, appearance of hematoma and prolonged bleeding from wounds.

If such hemorrhagic event occurs, patients should stop

heparin injection immediately and visit doctors for anto-

coagulating treatment.

2. Hypersensitivity

It is rare, but hypersensitivity response will appear on certain patients after delivery who allergic to the hepa-rin. Symptoms will appear such as rashes, headache, rhi-nitis and nausea. In severe condition, shock will be oc-curred.

Stop the heparin injection and visit doctor for alternative

treatment.

Man

age

me

nts

Missed Dose of Heparin Injection

Article: 1. Formulary Flash, Volume 09, Issue 1, Heparine vs LMWH vs Fondaparinux, What is the difference?,

February 12, 2009. 2. Once versus twice daily heparin for initial treatment of venous thromboembolism, written by Peng

Wong, 07/2013

Website: 1. http://www.rcog.org.uk/womens-health/clinical-guidance/venous-thrombosis-pregnancy-and-after-

birth 2. http://www.drugs.com/cons/heparin-intravenous-subcutaneous.html Heparin (Intravenous route, Subcutaneous route) 3. http://www.netdoctor.co.uk/heart-and-blood/medicines/heparin-injection.html Heparin Injection, 7/2/2007

References