ADD-ONS / MEDICATION / ANTICOAGULANTS

Low Molecular Weight Heparins ( LMWHs )

David Goldemund M.D.
Updated on 02/12/2023, published on 18/11/2021

  • Low Molecular Weight Heparins (LMWHs) are anticoagulant drugs derived from Unfractionated Heparin (UFH) by chemical or enzymatic depolymerization, transforming longer heparin chains into shorter ones. These shorter strands give LMWH a longer duration and more predictable action compared to UFH
  • LMWHs have reduced inhibitory activity against thrombin relative to factor Xa
  • LMWHs are used in the treatment or prophylaxis of venous thromboembolic disease (VTE)
    • VTE = deep vein thrombosis (DVT) ± 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 effects of LMWH are 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, preventing the conversion of fibrinogen to fibrin for clot formation
    • LMWH acts as a cofactor, increasing the inhibitory activity of AT III on clotting proteases by up to 2000-fold
    • heparin inhibits both Xa and thrombin (while LMWH primarily targets 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 the inhibition of the Xa effect (such as inhibition of leukocyte procoagulant activity, antiplatelet effect, promotion of fibrinolysis, restitution of endothelial dysfunction, or ↑ TFPI)
  • their ability to inactivate thrombin already bound by fibrin is limited
  • LMWH does not inhibit platelet function
Mechanism of action of LMWH and UFH
Characteristics of LMWHs
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
Main characteristics of LMWH, fondaparinux and UFH
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

(Gerotziafas, 2007)

Pharmacokinetics

  • LMWHs exhibit pharmacokinetic advantages over unfractionated heparin
  • following subcutaneous injection, the bioavailability of LMWHs is about 90% and LMWHs yield a more predictable anticoagulant response compared to heparin
  • the elimination half-life of LMWHs, ranging from 3 to 6 hours after subcutaneous administration, is dose-independent, and anti-Xa levels peak 3-5 hours after dosing
  • a notable limitation of LMWHs is that their predominant renal clearance extending their biological half-life in patients with renal impairment

Indications

  • prevention of venous thromboembolic disease (VTE) in intermediate- and high-risk populations (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 the interruption of warfarin therapy or when the INR is not within a therapeutic range
  • treatment of STEMI
  • LMWHs do not cross the placenta and do not harm the fetus ⇒ preferred anticoagulants in pregnancy
  • UHF, LMWHs, and fondaparinux are compatible with breastfeeding
  • LMWHs are also the preferred treatment for 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 )

Intermediate dose:

  • enoxaparin 0.5 mg-1 mg/kg administered SC once or twice daily
  • intermediate dosing of nadroparin is not standardized
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

  • there is a higher exposure to LMWH in renal insufficiency ⇒ ↑ risk of bleeding
Fraxiparine
creatinine clearance (CrCl) ≥ 0.83 ml/s
no dose reduction
CrCl 0.5-0.83 ml/s
CrCl < 0.5 ml/s
↓ dose by 25-33 %
Clexane
creatinine clearance (CrCl) ≥ 0.83 ml/s
no dose reduction
CrCl 0.5-0.83 ml/s
no dose reduction
CrCl < 0.5 ml/s
↓ dose by 50%
100 UI/kg 1x daily in the therapeutic indication
2000 IU (0,2ml) 1x daily s.c. in prophylaxis
Although dosage adjustments are not necessary for enoxaparin in patients with moderate (creatinine clearance 30-50 ml/min) and mild (creatinine clearance 50-80 ml/min) renal impairment, careful clinical and laboratory monitoring is advisable

Administration

  • LMWHs are administered via subcutaneous (SC) injection
  • compared to heparin, LMWHs have a longer half-life and more predictable action, and they are typically administered once or twice daily

LMWH bridging

  • bridging anticoagulation involves the administration of a short-acting anticoagulant (usually LMWH) in the following situations:
Bridging in stroke patients

WARFARIN

  • there is a short-term procoagulant effect of warfarin at the beginning of treatment, and this period is associated with a higher risk of ischemic stroke  [Diener, 2014]
    • this effect is attributed to warfarin’s influence not only on coagulation factors but also on proteins C and S
    • both proteins have a shorter biological half-life than clotting factors, and when warfarin treatment is initiated, their deficiency occurs before clotting factor levels decrease
    • this results in a short-term increase in plasma thrombogenic activity
  • this brief hypercoagulable state can be bridged by the administration of LMWH/heparin
    • the efficacy of bridging has been demonstrated in treatment of DVT
    • no trial data is available in stroke prevention
  • patients without acute stroke – bridging is recommended for patients with a high risk of thromboembolism (e.g., history of stroke, bioprosthetic valve, intracardiac thrombus, or mitral stenosis) with a low risk of bleeding (according to American College of Chest Physicians guidelines from 2012)
  • acute stroke patients – bridging is generally not recommended; full-dose LMWH is associated with an increased risk of bleeding that outweighs its prophylactic effect  [Hallevi, 2008]
  • an alternative approach involves administering of  a prophylactic dose of LMWH + slow titration of warfarin to prevent the initial hypercoagulable state

DOACs – LMWH bridging is not recommended!

  • no increased risk of recurrent stroke was observed with DOACs
  • the RAF-NOACs trial found the risk of bleeding 7.3% (with LMWH bridging) vs. 1.9% (without LMWH bridging), and the combined outcome was 12% vs. 4.4% (with LMWH vs. without LMWH)
  • data analysis from both the RAF and RAF-NOACs trials also showed no benefit from bridging therapy  [Altavilla, 2019]
  • according to the IAC trial, bridging is associated with a higher risk of sICH (HR 2.74)  [Yaghi, 2020]
Bridging in patients with VTE
warfarin
  • LMWH twice daily for ≥ 5 days; meanwhile, start warfarin
  • discontinue LMWH when INR> 2 on two consecutive days
dabigatran (PRADAXA)
edoxaban (LIXIANA)		 LMWH bridging for 5 days
apixaban (ELIQUIS)
rivaroxaban (XARELTO) 		no bridging; start DOAC immediately

Monitoring of the anticoagulant effect

  • check platelets count on days 3-5  to assess the risk of heparin-induced thrombocytopenia (HIT)
  • LMWH treatment typically does not require laboratory monitoring of efficacy in routine practice [Bounameaux, 2004]
  • the anticoagulant effect can be assessed by measuring anti-Xa activity, especially in the following cases:  [Aguilera, 2016]

    • very low- and very high-weight individuals (standard dose effects are unpredictable)
      • BMI > 40 / weight > 150 kg, control at 48 and 96 hours
      • women < 45kg and men < 57kg
    • patients with renal insufficiency (as LMWH is excreted by the kidneys)
      • CrCl < 30 mL/min (0.5 mL/s)
    • pregnancy (weight gain with the risk of underdosing)
    • patients at high risk of complications (thromboembolism/bleeding)

Principles of proper blood collection

  • correct results from anti-Xa testing depend on proper sample collection
  • collect blood 3-4 hours after subcutaneous LMWH administration (at the time of plasma peak levels) after achieving steady-state (≥ 48h of LMWH application)
    • collecting blood earlier or later results in lower values, potentially leading to overdosage
  • ensure rapid, gentle injection with the careful aspiration of blood; prefilled citrate tubes should be filled to the mark
  • avoid collecting blood from IV lines flushed with heparin if possible. If the blood must be drawn from an indwelling catheter, consider possible heparin contamination and sample dilution
    • the line should be flushed with 5 mL of saline, and the first 5 mL of blood or six times the line volume should be drawn off and discarded before filling the coagulation tube
    • for samples collected from a normal saline lock, twice the dead space volume of the catheter and extension set should be discarded
  • for larger larger blood samples, collect the biochemistry and CBC tubes first, followed by coagulation tubes
  • mix the blood gently and transport it to the lab as quickly as possible; samples should be processed within 1 hour of collection

Reference range:

  • anti-Xa – prophylactic dose: 0.2 – 0.5 kIU/L [Wei, 2015]
  • anti-Xa – therapeutic dose: 0.5 – 1.2 kIU/L (if taken twice a day)  1-2 kIU/L (if taken once a day)

Contraindications

  • hypersensitivity to the drug
  • history of thrombocytopenia following LMWH administration
  • active bleeding or increased risk associated  with bleeding disorders (except DIC not caused by heparin)
  • organic lesions with a tendency 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 LMWH treatment

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Low Molecular Weight Heparins (LMWHs)
link: https://www.stroke-manual.com/low-molecular-weight-heparins-lmwh/