ADD-ONS / MEDICATION / ANTICOAGULANTS
Low Molecular Weight Heparins ( LMWHs )
Created 18/11/2021, last revision 18/02/2023
- Low Molecular Weight Heparins (LMWHs) are anticoagulant drugs, which are derived from Unfractionated Heparin (UFH) by digestion or depolymerization of longer heparin chains into shorter chains. These short strands make LMWH last longer and act more predictably than UFH
- LMWHs are used in the treatment or prophylaxis of venous thromboembolic disease (VTE)
- VTE = deep vein thrombosis (DVT) and/or pulmonary embolism (PE)
- the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of LMWH are discussed
Mechanism of action
- LMWHs inhibit the final common pathway of the coagulation cascade (conversion of fibrinogen into fibrin)
- anti-Xa and, to a lesser extent, anti-IIa effect of LMWH is mediated by antithrombin III (heparins are indirect thrombin inhibitors) (Gerotziafas, 2007)
- AT III binds to and inhibits factor Xa, and factor IIa ⇒ prothrombin is not activated to thrombin, thereby not converting fibrinogen into fibrin for the formation of a clot
- LMWH acts as a cofactor, increasing up to 2000 x the inhibitory activity of AT III on coagulation proteases
- heparin inhibits both Xa and thrombin (while LMWH targets mainly on Xa inhibition)
- only pentasaccharide chains with at least 18 saccharide units long can inactivate thrombin (IIa)
- the anti-Xa activity of individual LMWHs is not directly correlated with the anticoagulant and antithrombotic effect because each LMWH has several effects mediated by mechanisms other than inhibition of the Xa effect (inhibition of leukocyte procoagulant activity, antiplatelet effect, promotion of fibrinolysis, restitution of endothelial dysfunction, ↑ TFPI)
- the ability to inactivate thrombin already bound by fibrin is limited
- LMWH does not inhibit platelet function
| Pharmacokinetic characteristics | Clinical significance |
| reduced protein binding | good bioavailability predictable dose-response no resistance observed |
| predictable dose-response | dosage according to body weight, no monitoring required |
| higher plasma half-life | dosage 1-2 × daily |
| low molecular weight | good absorption after subcutaneous application |
| limited effect on platelets and endothelial cells | ↓ risk of thrombocytopenia |
| absence of a specific antidote | inability to stop treatment quickly |
| limited ability to inactivate bound thrombin | incomplete dissolution of the thrombus |
| LMWH | Average molecular weight | Ratio anti-Xa/anti-IIa activity |
|---|---|---|
| Bemiparin (IVOR, ZIBOR) |
3600 | 8.0 |
| Nadroparin (FRAXIPARINE, FRAXODI) |
4300 | 3.3 |
| Reviparin | 4400 | 4.2 |
| Enoxaparin (CLEXANE, LOVENOX) |
4500 | 3.9 |
| Parnaparin | 5000 | 2.3 |
| Certoparin (SANDOPARIN, EMBOLEX) |
5400 | 2.4 |
| Dalteparin (FRAGMIN) |
5000 | 2.5 |
| Tinzaparin (INNOHEP) |
6500 | 1.6 |
| FONDAPARINUX |
1725 |
only anti-Xa |
| UFH |
15000 |
1 |
Indications
- prevention of venous thromboembolic disease (VTE) in medium and high-risk groups (surgical, orthopedic, and medical patients)
- treatment of deep vein thromboses (DVT) and pulmonary embolism (PE)
- treatment of cerebral venous sinus thrombosis (CVST)
- bridging therapy during interruption of warfarin therapy or when the INR is not within a therapeutic range
- treatment of STEMI
- LMWHs do not cross the placenta or harm the fetus ⇒ preferred anticoagulants in pregnancy
- UHF, LMWHs, and fondaparinux are compatible with breastfeeding
- LMWHs are also the favored treatment in cancer-related thromboembolic disease
LMWH Dosing
| Medication |
Prophylactic dose
|
Therapeutic dose (full anticoagulation)
|
|
FRAXIPARINE
nadroparin
1ml/9500IU
|
0.3 ml (2850IU) s.c. 1-2 x daily
|
100 IU/kg 2x daily
(70kg= 2 x 0,7 ml)
|
|
CLEXANE
enoxaparin
1ml/10000IU/100mg
|
0.4 ml s.c. 1x daily (high risk)
0.2 ml s.c. 1x daily (low risk)
|
100 UI (1mg) /kg 2x daily
(70kg=2 x 0,7 ml )
|
|
Weight (kg)
|
Therapeutic dose
FRAXIPARINE (1ml/9500IU)
2x daily s.c.
|
Therapeutic dose
CLEXANE 1ml/10000IU/100mg 2x daily s.c.
|
|
<50
|
0,4 ml (3800 IU anti-Xa)
|
0,4 ml (4000 IU anti-Xa)
|
|
50-59
|
0,5 ml (4750 IU anti-Xa)
|
0,5 ml (5000 IU anti-Xa)
|
|
60-69
|
0,6 ml (5700 IU anti-Xa)
|
0,6 ml (6000 IU anti-Xa)
|
|
70-79
|
0,7 ml (6650 IU anti-Xa)
|
0,7 ml (7000 IU anti-Xa)
|
|
80-89
|
0,8 ml (7600 IU anti-Xa)
|
0,8 ml (8000 IU anti-Xa)
|
|
90-99
|
0,9 ml (8550 IU anti-Xa)
|
0,9 ml (9000 IU anti-Xa)
|
|
>100
|
1,0 ml (9500 IU anti-Xa)
|
1,0 ml (10000 IU anti-Xa)
|
Renal function-based dose reduction
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Administration
- LMWHs are administered as a subcutaneous injection (SC)
- compared to heparin, LMWHs have a longer half-life, more predictable effect, and are administered once or twice daily
LMWH bridging
- bridging anticoagulation refers to the administration of a short-acting anticoagulant (usually LMWH) in these situations:
- initiation of anticoagulant therapy
- periprocedural bridging → see separate chapter
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Monitoring of the anticoagulant effect
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Contraindications
- hypersensitivity to the active substance
- history of thrombocytopenia after LMWH administration
- active bleeding or increased risk related to bleeding disorders (except DIC not caused by heparin)
- organic lesions with a propensity to bleed (e.g., peptic ulcer disease, recent eye or nervous system surgery)
- acute infective endocarditis
- severe renal impairment (creatinine clearance < 30ml/min)
Complications of treatment with LMWH
-
bleeding complications → neutralizing effect of LMWH
-
injection site reactions
-
elevated liver enzymes
- allergic reaction
-
- it is much less common with LMWH than with UFH
-
risk of osteoporosis with long-term use (> 6 months); the risk is lower than with heparin (UHF) , 2016)
