ADD-ONS / MEDICATION / ANTICOAGULANTS

Low Molecular Weight Heparins ( LMWHs )

 Created 25.11.2019, last update  10.11.2021

  • Low Molecular Weight Heparins (LMWHs) 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 as anticoagulants in the prophylaxis of venous thromboembolic disease (VTE) or the treatment of deep vein thrombosis (DVT) and/or pulmonary embolism (PE)

Mechanism of action

  • LMWHs inhibits 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
Mechanism of action of LMWH and UFH
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
(FRAXIPARIN, 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

  • prophylaxis 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
nadroparine
1ml/9500IU
0.3 ml (2850IU) s.c. 1-2 x daily
100 IU/kg 2x daily
(70kg= 2 x 0,7 ml)
CLEXANE
enoxaparine
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)

Dose reduction according to renal function

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Administration

  • LMWHs are administered via subcutaneous injection (SC)
  • compared to heparin, LMWHs have a longer half-life, so dosing is more predictable and can be less frequent

LMWH bridging

  • bridging anticoagulation refers to giving a short-acting anticoagulant (usually LMWH) in these situations:
    • initiation of anticoagulant treatment
    • 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

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