Contents:

1. Introduction.
2. What are low molecular weight heparins and why are they different from standard heparin?
3. Administration, dosage and reversal of LMWH
4. LMWH as prophylactic agents
5. LMWH as therapeutic agents
6. LMWH and neuraxial anaesthesia
7. Key Points

Introduction

FDA PUBLIC HEALTH ADVISORY¹

Anesthesiology Volume 88 • Number 2 • February 1998
Subject: Reports of epidural or spinal hematomas with the concurrent use of low molecular weight heparin and spinal/epidural anesthesia or spinal puncture¹

At this time, the FDA believes practitioners should be aware of the following points if using these products:

What are Low Molecular Weight Heparins and how do they differ from standard heparin?

• Standard Unfractionated Heparin is a mixture of linear polysaccharide molecules of variable chain lengths and molecular weights.

• The mean molecular weight of SH ranges from 12,000 to 15,000 Daltons.
• Heparin acts as an anticoagulant by binding and catalyzing antithrombin III, a plasma serine protease inhibitor.

• The heparin-antithrombin III complex catalises the inhibition of several procoagulant serine proteases, including factors IIa (thrombin), IXa, Xa, XIa, and XIIa.
• Heparin catalytic activity is dependent on:

1. The polysaccharide chain length

2. A specific pentasaccharide sequence within the heparin molecule, which is a high-affinity binding site for antithrombin III.

• Approximately 30% of SH molecules contain the pentasaccharide high-affinity binding sequence and can catalyze antithrombin III.
• To efficiently inhibit factor IIa (thrombin), a heparin molecule must contain both the pentasaccharide high-affinity binding sequence as well as a chain length of at least 13 additional polysaccharides.
• To catalyze antithrombin III inhibition of factor Xa, only the pentasaccharide high-affinity binding sequence is required: LMWH act by this mechanism.
• LMWH is produced by either chemical or enzymatic depolymerization of SH and has a mean molecular weight of 4000–6500 Daltons and a chain length of 13–22 sugars.

• LMWH retains full anti-Xa activity with relatively less anti-IIa (thrombin) activity.
• The concentration of LMWH is referenced to an international standard and usually expressed as anti-Xa U/mL.
• The bioavailability and anticoagulant effect of SH is reduced due to binding of SH:

1. Plasma and platelet proteins
2. Endothelial cells
3. Vascular wall matrix proteins .
4. Acute Phase reactants

• Many of these plasma proteins increase with illness as acute phase reactants (especially factor VIII and von Willebrand factor), which accounts in part for the large interpatient variability in the anticoagulant response to SH.
• The clearance of SH is dose dependent:

Phase 1: a saturable mechanism uptake and degredation by endothelial cells and binding to plasma proteins.

Phase 2: slower nonsaturable renal clearance.

• LMWH has a much lower affinity for plasma and matrix proteins.
• This results in greater than 90% bioavailability after subcutaneous administration and a very predictable and reproducible anticoagulant response when dosed on a weight-adjusted basis.
• The result of this is a longer t1/2, predictable effect, and clearance by first order kinetics, through the renal route.
• Neither laboratory monitoring of the anticoagulant response to LMWH (anti-Xa levels) nor dose adjustment is necessary.

The plasma half-life of LMWH is approximately 2–4 times longer than that of SH and increases in patients with renal failure .

Administration, dosage and reversal of LMWH

• The most common indication for LMWH usage is DVT prophylaxis.
• Europe and North America differ in their dosage regimens in this regard:

• European regimens typically administer the first dose 6 h preoperatively and use a once-daily schedule (enoxaparin 20 - 40 mg once daily).

• North American LMWH prophylaxis regimens (for hip or knee replacement surgery) administer the first dose from 12 to 24 h postoperatively and on a once- or twice-daily dosing schedule enoxaparin 30 mg twice daily.

• The activated partial thromboplastin time is a relatively insensitive measure of LMWH activity.
• The anti-Xa level can be measured and it is a more sensitive measure of LMWH anticoagulant effect.

• The anticoagulant effects of SH are neutralized by an equimolar dose of protamine.
• Protamine is not fully effective against LMWH.
• Only the anti-IIa activity of LMWH is completely reversed, whereas anti-Xa activity is not fully neutralized.
• A dose of 1 mg protamine/100 LMWH anti-Xa units reverses 90% of anti-IIa and 60% of anti-Xa activity.
• Both anti-IIa and anti-Xa activity may return up to 3 h after protamine reversal, possibly due to release of additional LMWH from the subcutaneous depot .

• Bleeding: patients treated with LMWH have equal bleeding risk to those treated with UFH. ⁴
• Heparin Induced Thrombocytopenia: Heparin-associated thrombocytopenia, with or without thrombosis, is caused by a platelet-activating IgG that is induced by heparin treatment.
• Laboratory tests reveal nearly 100% cross-reactivity between LMWH and standard heparin for the heparin-dependent IgG. Hence, LMWH is not generally recommended for therapy of heparin-associated thrombocytopenia.⁵
• The use of LMWH, however, may decrease the risk of developing heparin-induced thrombocytopenia.⁶
• Osteoporosis: Osteoporosis has been reported following prolonged UFH administration, typically longer than 6 months at high doses (at least 15,000 IU/day). This complication usually presents with pathologic fractures. There is limited clinical data are available on the risk of osteoporosis associated with LMWH, however, data in an animal model suggest that LMWHs may have less of an effect on bone density than does UFH.⁷

LMWH as prophylactic agents

• UFH: reduces the risk of venous thromboembolism by 70%, and fatal pulmonary embolism by 70% ⁸. LMWH are marginally more effective in the prevention of thromboembolism⁹ and cause fewer wound haematomas¹⁰.

• Without prophylaxis, deep-vein thrombosis occurs in 50 to 70 percent of patients undergoing total hip replacement, total knee replacement, or surgery for hip fractures.
• As compared with placebo in randomized clinical trials¹¹, low-molecular-weight heparins significantly reduced the risk of deep-vein thrombosis (range of risk reduction, 31 percent to 79 percent) without increasing bleeding.
• Low-molecular-weight heparins were more effective than low-dose unfractionated heparin¹² and equal or superior¹³ to adjusted-dose unfractionated heparin.
• both low-dose unfractionated heparin¹⁴ and low-molecular-weight heparins¹⁵ result in a 45 percent reduction in the incidence of deep-vein thrombosis in patients undergoing surgery for hip fracture.
• Deep-vein thrombosis develops in about 40 percent of patients with acute spinal cord injuries
• Low-molecular-weight heparins are effective in patients with acute spinal cord injuries.¹⁶
• Low molecular weight heparins are more effective than low dose UFH in preventing DVT and proximal vein thrombosis following major trauma. ¹⁷

LMWH as therapeutic agents

Essence Trial¹⁸ (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events):

Large double-blind, multicenter study - enoxaparin (1 mg/kg, or approximately 100 anti-Xa IU/kg, twice a day) was compared with intravenous UFH (usually 5000 units bolus and then continuous infusion adjusted to keep the APTT at 55 to 85 seconds) given for 2 to 8 days.

All patients also received aspirin.

The investigators found that the combined risk of death, myocardial infarction, or recurrent angina was significantly lower at both 14 days (16.6% versus 19.8%, P = 0.02) and 30 days (19.8% versus 23.3%, P = 0.02) of follow-up for the LMWH treated group.

LMWH has been shown to improve outcomes at six months as compared to placebo in patients presenting with acute ischaemic stroke.¹⁹

• THESEE study group²⁰:
• 612 patients who did not receive thrombolytic therapy of pulmonary embolectomy, randomised to receive either unfractionated heparin (308 patients -50 iu per kilogram iv then APTT kept 2-3 x control) or tinzaparin [innohep] (304 patients - 175 iu/kg sc daily).
• Warfarin was started between days 1 & 3 and heparins stopped when INR > 2.0.
• Aspirin and NSAIDS were prohibited during the study period.
• Warfarin was continued for 3 months.
• Primary end points were death and major bleeding; secondary end-points were scintigraphically detectable pulmonary vascular obstruction.
• Results: no significant difference between iv heparin and tinzaparin in terms of all endpoints: equally efficacious.

Once or twice daily? This issue remains unresolved. There appears to be little difference between once and twice daily dosing regimes, and adequate comparative studies have not been undertaken.

Pregnancy: LMWH do not cross the placenta and appear to be safe in pregnancy.²¹

Equally effective: again few studies, but they probably are equally effective.

Neuraxial Anaesthesia, LMWH and Spinal haematomas

• Spinal bleeding following epidural catheter blocks occours in approx 1: 200,000 cases²⁵.
• 60 - 80% of these are associated with haenostatic disorders or a bloody tap²⁶.
• Removal of an epidural catheter should be considered a significant risk factor of spinal bleeding: 30-60% of clinically important haematomas occur in this circumstance.²⁵
• European guidelines²⁸ suggest: an interval of 12 or more hours between administration of LMWH and puncture, next dose no sooner than 4 hours after puncture, catheters should be removed > 12 hours following last dose.
• No increased risk of spinal haematomas has been observed using low dose UFH in patients undergoing neuraxial block²⁷

• From May 1993 to February 1998 43 cases of spinal haematoma associated with the use of LMWH had been reported to the FDA.²⁴

• 75% of patients were elderly women.
• 26 involved the placement of an epidural catheter.
• The first dose of LMWH was administered when the catheter was indwelling in 17.
• 16 patients received antiplatelet of warfarin therapy in addition to LMWH.
• Few patients developed neurological complications while the catheter was indwelling.
• In most cases 24 or more hours had elapsed between catheter removal and neurological dysfunction.
• The initial sysmptoms in most cases was weakness and numbness, not radicular pain.

The European Experience

• Only 11 cases of spinal haematoma associated with LMWH and neurozaxial block have been reported in Europe.
• It is speculated that the reason for the lower incidence in Europe is

1. The difference in dosage regimens between the two continents.²²

Dosage in USA: enoxparin 30 mg bd.

Dosage in Europe: enoxparin 20 - 40 mg once daily.

2. The presence of guidelines in many European countries on haemostatic requirements for neuroaxial block.

Recommendations²³

1. Smallest effective dose of LMWH should be used perioperatively: the FDA in the USA has now approved Enoxparin 40 mg once daily for THR.

2. Single daily dosing allows for a true trough in anticoagulant activity, during which time needle placement and removal of epidural catheters can occur.

3. LMWH therapy should be delayed as long as possible ® 12 or, preferably, 24 hours post operatively.

4. The use of concomitant antiplatelet agents and warfarin will increase the risk of spinal haematoma.

5. There is an increased risk of spinal haematoma in patients with indwelling epidural catheters: it may be of advantage to withold LMWH until epidural anesthesia has stopped.

6. Alternatively, catheter removal should be performed when anticoagulant activity is low. It appears safest to remove the catheter at the time that the next dose of LMWH is due, and skipping that dose.

7. All patients undergoing neuroaxial anaesthesia should have repeated neurological evaluations: and if continuous infusions are used, dilute solutions would be preferable to facilitate these examinations.

Additional Recommendations²⁸:

8. Measuring anti-Xa levels is not recommended.

9. Presence of blood during needle or catheter placement does not necessitate postponement of surgery. However initiation of LMWH therapy should be delayed for 24 hours post surgery.

10. Patients who are on LMWH pre-op are assumed to have altered coagulation. Single shot spinal anaesthesia would appear to be the method of least risk. Anaesthesia should be delayed for 12 hours following last dose, if on a standard dose regimen, and >24 hours if on high dose LMWH.

Key Points

• Low Molecular Weight Heparins (LMWH) are at least as effective as unfractionated heparin (UFH) in the prevention of deep venous thrombosis and subsequent embolism.
• LMWH act by selectively inhibiting factor Xa
• LMWH have more predictable activity than UFH, longer duration of action, do not require the measurement of APTT, and can be self administered subcutaneously.
• LMWH cannot be effectively reversed by protamine and duration of action is prolonged in renal failure.
• LMWH in higher doses have been shown to be equally effective with intravenous UFH in unstable angina, pulmonary embolism and ischaemic stroke.
• LMWH are associated with an increasing incidence of spinal haematoma in patients undergoing neuraxial anaesthesia, particularly epidurals.
• The risk can be minimised by reducing the dosage, increasing the interval, avoiding spinal puncture for 12 hours post administration, and vice versa, and removing epidural canulas when anticoagulant activity is minimal.

References

1. Anesthesiology Volume 88 • Number 2 • February 1998

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6. Warkentin TE, Levine MN, Hirsh J, et al: Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 332:1330-1335, 1995

7. Muir JM, Hirsh J, Weitz JI, et al: A histomorphometric comparison of the effects of heparin and low-molecular-weight heparin on cancellous bone in rats. Blood 89:3236-3242, 1997

8. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration ofsubcutaneous heparin: overview of results of randomized trials in general,orthopedic, and urologic surgery. N Engl J Med 1988;318:1162-73.

16. Green D. Prophylaxis of thromboembolism in spinal cord-injured patients. Chest 1994;102:Suppl A:649S-651S.

18. Cohen M, Demers C, Gurfinkel EP, et al: A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 337:447-452, 1997

20. G. Simmonneau et al. A comparison of Low-Molecular-Weight-Heparin with unfractionated heparin for acute pulmonary embolosm. NEJM 1997; 337; 663-669.

22. Tryba M et al. Central neuraxial block and low molecular weight heparin: lessons to be learnt from two different dosing regimes in two different continents. Acta Anaesthesiol Scan 1997; 41: 100 - 4

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24. Corespondence NEJM 1998; 338: 1774 -5

25. Wulf H: Epidural anesthesia and spinal haematomas. Canadian Journal of Anaesthesia 1996; 43: 1260-1271

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27.Tryba M, Reg Anesth 1989: 12: 127-131

28. Tryba M Regional Anaesthesia & Pain Medicine 23(6) Suppl 2: 178-182, 1998

29. Horlocker & Wedel. Neuraxial Block and Low-Molecular-Weight-Heparin Regional Anaesthesia & Pain Medicine 23(6) Suppl 2: 164-177 1998