Low Molecular Weight Heparin

Multiple randomized clinical trials have established the efficacy of standard heparin (SH) anticoagulation for venous thromboembolism prophylaxis. However, for high-risk populations, such as patients undergoing total hip or knee replacement, SH is relatively ineffective and may be associated with significant bleeding complications 1. Initial animal model studies suggested that low molecular weight fractions of heparin, when administered at equivalent antithrombotic doses, caused less bleeding than SH 2. These early studies raised the exciting possibility of separating the antithrombotic from the bleeding effects of heparin. The efficacy and safety of low molecular weight heparins (LMWH) as postoperative venous thromboembolism prophylaxis subsequently has been demonstrated in more than 60 clinical trials including more than 20,000 patients 3. However, reports of spinal hematoma occurring spontaneously and in association with regional anesthesia 4,5 have generated concern regarding the safety of spinal or epidural anesthesia in patients receiving LMWH. In this review, we focus on the biochemistry and pharmacology of LMWH compared with SH, current LMWH prophylaxis regimens, and the implications of perioperative LMWH prophylaxis for anesthesia, particularly among patients receiving regional anesthesia and analgesia. Guidelines will be provided for minimizing the risk of spinal hematoma in patients undergoing regional anesthesia while receiving perioperative anticoagulant-based prophylaxis. Biochemistry and Pharmacology of SH and LMWH SH is a mixture of linear polysaccharide molecules of variable chain lengths (45-50 sugar units) and molecular weights (5,000-30,000 daltons). 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 inhibits several procoagulant serine proteases, including factors IIa (thrombin), IXa, Xa, XIa, and XIIa (Figure 1).Figure 1: Schematic of the procoagulant system. Circulating procoagulants are shown in ellipses, and activated coagulation factors are shown in rectangles. Heparin catalyzes antithrombin III inhibition of all procoagulant factors enclosed in the rectangles except factor VIIa. Vitamin K-antagonist drugs reduce the plasma activities of factors II (prothrombin), VII, IX, and X. (Reproduced with permission from Horlocker TT, Wedel DJ. Anitcoagulants, antiplatelet therapy, and neuraxis blockade. In: Batra MS, ed. Anesthesiology clinics of North America. Vol 10. Philadelphia: WB Saunders, 1992:3.)Heparin catalytic activity is dependent on both the polysaccharide chain length as well as 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. Heparin chain length partially determines antithrombin III substrate specificity. For example, to efficiently catalyze antithrombin III inhibition of 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 sugars. Conversely, only the pentasaccharide high-affinity binding sequence is required for heparin to catalyze antithrombin III inhibition of factor Xa. Commercial 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. Consequently, 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 by plasma and platelet proteins, endothelial cells, and vascular wall matrix proteins 5. 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. In contrast, LMWH has a much lower affinity for plasma and matrix proteins 6, which results in greater than 90% bioavailability after subcutaneous administration and a very predictable and reproducible anticoagulant response when dosed on a weight-adjusted basis. Consequently, neither laboratory monitoring of the anticoagulant response to LMWH (anti-Xa levels) nor dose adjustment is necessary. Peak anti-Xa activity occurs 3-4 h after a subcutaneous LMWH injection, and 12-h anti-Xa levels are approximately 50% of peak levels. The clearance of SH is dose-dependent and occurs through a saturable mechanism due to binding by plasma proteins and endothelial cells, and a slower nonsaturable renal clearance. Because LMWH is not highly protein- or endothelial cell-bound, the saturable mechanism is minimal, and clearance is primarily renal. Therefore, the plasma half-life of LMWH is approximately 2-4 times longer than that of SH and increases in patients with renal failure 5,7. A comparison of the biochemistry and pharmacology of SH and LMWH is shown in Table 1.Table 1: Biochemical and Pharmacologic Properties of Standard Heparin and Low Molecular Weight HeparinsFive LMWHs and one heparinoid (heparan and dermatan sulfate) are currently marketed or under development (Table 2). Low molecular weight heparin drugs vary both biochemically and pharmacologically, including molecular weight, anti-IIa and anti-Xa activities, and plasma half-life. Therefore, each drug must be administered based on the drug-specific dose and dosing schedule that have been determined in clinical trials to be safe and effective for the specific prophylaxis indication.Table 2: Commercially Available Low Molecular Weight HeparinsAdministration, Monitoring, and Reversal of LMWH Anticoagulant Effect To avoid bleeding and optimize convenience, most 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 (dalteparin 5000 U once daily or enoxaparin 30 mg twice daily) 1. In contrast, European regimens typically administer the first dose 6 h preoperatively and use a once-daily schedule (enoxaparin 40 mg once daily). Neither regimen requires laboratory monitoring or dose adjustment. Several additional issues regarding the optimal LMWH prophylaxis regimen are unresolved, including fixed versus weight-adjusted dosing and the duration of prophylaxis (inpatient versus extended outpatient prophylaxis) 8,9. Because there are no adequate trials comparing the efficacy and safety of one LMWH with another, it is impossible to recommend one specific LMWH drug over another. When LMWH is administered at prophylaxis doses, the activated partial thromboplastin time is a relatively insensitive measure of LMWH activity. The anti-Xa level, as measured by either clot-based assays, such as the Heptest, or amidolytic assays, is a more sensitive measure of LMWH anticoagulant effect. Peak anti-Xa levels of 0.1-0.2 U / mL provide safe and effective venous thromboembolism prophylaxis after hip or knee replacement surgery 10,11. The anticoagulant effects of SH are neutralized by an equimolar dose of protamine. Because of reduced protamine binding to LMWH fractions, 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. The clinical significance of the residual anti-Xa effect is unknown. 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 12. LMWH for Venous Thromboembolism Prophylaxis A comprehensive review of venous thromboembolism prophylaxis is beyond the scope of this article. We have restricted our review to the current Food and Drug Administration (FDA)-approved indications for LMWH as venous thromboembolism prophylaxis. For a more comprehensive review, the reader is referred to another publication 1. Orthopedic Surgery Patients In the absence of prophylaxis, the prevalence of deep venous thrombosis as detected by venography among patients undergoing major orthopedic surgery ranges from 50% for total hip replacement to 80% for total knee replacement patients 1. LMWH provides safe and effective prophylaxis in patients undergoing total knee or hip replacement. However, the efficacy varies by type of orthopedic procedure. For patients undergoing total hip replacement, LMWH is as effective as adjusted-dose subcutaneous SH and low-intensity oral anticoagulation (international normalized ratio 2.0-3.0) 13,14. However, for patients undergoing total knee replacement, LMWH is significantly more effective than all other anticoagulant-based methods of prophylaxis 15-19. The risk of major bleeding among patients receiving LMWH is similar to that with other anticoagulant-based methods of prophylaxis 20,21. Currently, dalteparin and enoxaparin are FDA-approved and are marketed for prophylaxis after lower extremity joint replacement surgery, and ardeparin will be marketed for the same indication in the near future. LMWH prophylaxis is more effective and is as safe as low-dose SH prophylaxis after major trauma 22. General Surgery Patients Several large studies and meta-analyses report a modest decrease in venous thromboembolism prevalence among general surgery patients receiving LMWH compared with low-dose SH prophylaxis 20,21,23,24. In one study, the incidence of major bleeding was significantly less among LMWH patients compared with SH patients 24. Prophylaxis with LMWH may be appropriate for general surgery patients at especially high risk, such as those patients undergoing abdominal or pelvic surgery for malignancy. However, due to the greater LMWH cost and lower risk for postoperative deep venous thrombosis, LMWH is unlikely to replace SH as standard prophylaxis for other general surgery patients. Currently, dalteparin and enoxaparin are FDA-approved and are marketed for prophylaxis after general surgery. Bleeding and heparin-induced thrombocytopenia and thrombosis (HITT) are the major complications associated with SH or LMWH prophylaxis. HITT, which is characterized by the presence of heparin-dependent, platelet-activating antibodies, typically occurs 7-10 days after initiation of heparin prophylaxis and may be associated with both venous and arterial thrombosis. In a clinical trial randomizing total hip replacement patients to either LMWH or SH prophylaxis, the incidence of HITT and heparin-dependent antibodies was significantly greater among patients receiving prophylaxis with SH (2.7%) compared with those receiving LMWH (0%) 25. However, HITT associated with LMWH therapy has been reported 26. Furthermore, antibody cross-reactivity between SH and LMWHs occurs in 40%-90% of patient sera with known heparin antibodies 27. Therefore, LMWH should be avoided in patients with established HITT. Heparinoids such as danaparoid, which contain no heparin, have minimal cross-reactivity and have been used successfully in patients with HITT 28. Spinal and Epidural Anesthesia in the Patient Receiving Standard or Low Molecular Weight Heparin Neurologic dysfunction due to bleeding after neuraxial blockade is rare, with an estimated incidence of less than 0.5 per 100,000 spinal anesthetics and less than 0.7 per 100,000 epidural anesthetics 29. A review of clinical studies involving patients undergoing regional anesthesia while receiving anticoagulants, as well as case reports of spinal hematoma after neuraxial block, is helpful in evaluating potential risk factors for spinal bleeding. Vandermuelen et al. 4 reported 61 cases of spinal hematoma associated with spinal or epidural anesthesia. In 42 (68%) of the patients, there was evidence of a hemostatic abnormality. Twenty-five patients had received intravenous (IV) heparin (18 patients), subcutaneous heparin (3 patients), or LMWH (4 patients), whereas an additional 5 patients presumably received heparin during a vascular surgical procedure. Timing of needle placement relative to heparinization was not reported. A spinal anesthetic was performed in 15 patients, whereas the remaining 46 patients received an epidural anesthetic, including 32 patients with an indwelling catheter. In 15 of these 32 patients, the spinal hematoma occurred immediately after removal of the epidural catheter. These results are noteworthy, as they suggest that both catheter removal and the patient's coagulation status at the time of removal are critical factors in the development of spinal bleeding. A more recent investigation of 8501 spinal and 9232 epidural anesthetics performed from 1991 to 1994 reported three spinal hematomas, which all occurred in anticoagulated patients receiving postoperative epidural analgesia 30. Two patients received an anticoagulant before catheter placement (one patient was chronically anticoagulated with dicoumarol and one patient received LMWH); the third patient received dextran intraoperatively and IV heparin postoperatively. IV and Subcutaneous Heparin Several large studies have demonstrated that spinal or epidural anesthesia followed by systemic heparinization is relatively safe 31,32. Rao and El-Etr 31 reported no spinal hematomas in over 4000 patients undergoing lower extremity vascular surgery under continuous spinal or epidural anesthesia. However, patients with preexisting coagulation disorders were excluded, heparinization occurred at least 60 min after catheter placement, the level of anticoagulation was carefully monitored, and the indwelling catheters were removed at a time when heparin activity was low. Surgery in patients with frank blood noted in the needle was canceled and was performed the following day under general anesthesia. Subsequent investigations 4 of patients undergoing complete heparinization during cardiopulmonary bypass after subarachnoid or epidural needle / catheter placement typically followed the techniques described by Rao and El-Etr, including exclusion of patients with preexisting coagulapathies, a minimum of 1 h between needle placement and heparinization, close monitoring of clotting times, and postponement of surgery should a bloody tap occur. These methods were also substantiated in a subsequent report in the neurologic literature. Ruff and Dougherty 33 noted spinal hematomas in 7 of 342 (2%) patients who underwent lumbar puncture and subsequent heparinization for evaluation of cerebral ischemia. The presence of blood during needle or catheter placement, concomitant aspirin therapy, and heparinization within 1 h were identified as risk factors for spinal hematoma 33. The safety of subcutaneous administration of SH also is well documented. A review by Schwander and Bachman 34 reported no spinal hematomas in more than 5000 patients undergoing spinal or epidural anesthesia while receiving varying doses of low-dose SH. Only three cases of spinal bleeding after subcutaneous SH have been reported in the literature, two of which involved a continuous epidural technique 4. LMWH The administration of LMWH in patients undergoing spinal or epidural anesthesia was examined by Bergqvist et al. 35,36 in two reviews published in and These studies the European with LMWH no LMWH had been for general use in the at that Bergqvist et al. identified involving patients who had received the of LMWH and spinal or epidural anesthesia. of the studies were on the of anesthetic of the regional anesthetic technique are not with neurologic complications to spinal or epidural blockade are not The noted that estimated an additional several patients had received LMWH while undergoing regional anesthetic techniques with only one reported case of spinal hematoma on these Bergqvist et al. that neurologic complications after spinal or epidural anesthesia in patients receiving LMWH are rare, and that the However, an In a of the in we identified studies in which LMWH had been administered to surgical or patients. In of these spinal or epidural anesthesia had been used in with perioperative LMWH (Table These studies spinal or epidural A spinal was performed in a continuous spinal in and an epidural anesthetic in The placement of an indwelling epidural catheter was in it is impossible to the of continuous epidural The anesthetic technique was as or or in LMWH was preoperatively in 90% of cases and was typically administered once A of LMWH and doses are In more than of the the LMWH a were no spinal hematomas among the patients in these Because these studies were to and it is unlikely that neurologic complications to the anesthetic technique However, to those of the reports by Bergqvist et al. with of Low Molecular Weight Heparin (LMWH) and Spinal or Epidural trauma associated with the presence of an indwelling catheter was by et al. in the of and patients were patients received enoxaparin vascular patients of to aspirin received IV heparin 100 U / and 24 patients had no anticoagulant or antiplatelet administered and as of were immediately after catheter placement, 1 h after heparinization patients), or 3 h after catheter placement and patients), in the patients and before catheter removal 24 h A total of patients, 5 each in the and vascular patients and 7 patients had more than 100 and in at least one of the was no in among patient patient of spinal The that the indications for the placement of an catheter should be carefully the risk of spinal and that the perioperative administration of SH and LMWH not increase the risk of associated with continuous spinal anesthesia. have been published case reports of spinal hematoma in patients undergoing spinal or epidural anesthesia while receiving LMWH (Table The first were published in the patient to which LMWH was administered at that of patient and anesthetic factors associated with these cases subsequently to for the of regional anesthesia in patients receiving LMWH. that needle and catheter placement should be for at least h after the dose of LMWH. catheter removal should at least h after the with subsequent dosing of LMWH for at least h after catheter were by et al. 4 in These have been effective in the of spinal hematoma in patients receiving the of regional anesthesia and LMWH. However, it is that European have anesthetic of these patients, for by a spinal than a continuous epidural of Spinal with Low Molecular Weight Heparin (LMWH) and Spinal or Epidural was for general use by the in that there have been cases of spinal hematoma in the associated with LMWH reported to the (Table and Table Only one of these has been published as a case report (Table the of spinal hematoma in patients receiving enoxaparin while undergoing spinal or epidural anesthesia is to of the enoxaparin doses administered and the prevalence of regional anesthesia in orthopedic patients the between 1 in and 1 in regional is that the of spinal hematoma reported to European is significantly greater than provided by published and in that in the However, this is as by the of recent in the European of Spinal with and Spinal or Epidural Anesthesia to and anesthetic factors may for the in of spinal hematoma between the and the most factor is the in dosing of which is 30 mg twice daily in the and 40 mg once daily in The twice-daily dose regimen may provide a greater of anticoagulation and not in the same of heparin activity required for the safe placement and removal of spinal and epidural / The in dosing between the and results from of the clinical investigations at the time of drug review and Timing of the first dose of LMWH also LMWH therapy is preoperatively intraoperatively by the in In the that the first dose be administered h after surgery or when is is initiation of should the safety of regional anesthesia in patients receiving LMWH in the the regional anesthetic technique may the risk of spinal the patients with spinal hematomas associated with LMWH in the had indwelling epidural catheters for at least 24 of of the 24 spinal hematomas reported in Table and Table 5 several risk However, only a partial evaluation is only patients with spinal hematomas are and is reported on the anesthetic, and surgical factors of the several patients who received the of LMWH and spinal or epidural anesthesia the cases of spinal hematoma in which the regional anesthetic technique was involved epidural of which involved catheter In 7 of patients with indwelling epidural catheters within a of catheter which that catheter removal is a Conversely, the of spinal hematomas occurring in patients with epidural anesthesia and analgesia may the patient receiving LMWH and regional anesthetic surgical patients. Several other risk factors are In the patient received additional doses of LMWH or IV heparin and dextran were administered in an additional Bleeding complications in patients receiving antiplatelet therapy in with LMWH is not The of LMWH activity by antiplatelet has been reported in In in response to these the the to in the use of enoxaparin in patients with indwelling or epidural catheters or in patients with platelet Guidelines for the of Anesthesia in Patients Receiving Heparin The to neuraxial blockade on a patient receiving perioperative SH or LMWH must be on an the risk of spinal hematoma with the of regional anesthesia for a specific The following based on the of SH and as well as case reports and clinical studies involving patients undergoing spinal or epidural anesthesia while receiving these will the with this IV Heparin Spinal and epidural anesthesia may be performed in the patient undergoing subsequent heparinization provided heparinization occurs a minimum of 60 min after needle placement, the heparin effect is and within levels clotting time or activated partial thromboplastin time times and indwelling catheters are removed at a time when heparin activity is low or completely also recommend of surgery should bleeding during needle or catheter placement SH for the of regional anesthesia in patients receiving subcutaneous SH of needle placement or catheter removal within h of and monitoring of anticoagulant effect in patients with or to patients receiving LMWH is However, the in must be LMWH LMWH. Patients receiving LMWHs can be to have LMWHs are antithrombotic with a to half-life. Approximately 50% of peak anti-Xa activity is 12 h after administration of such as antiplatelet SH, or dextran an additional risk of complications including spinal A spinal anesthetic may be the neuraxial technique in patients receiving placement should at least h after the LMWH Subsequent dosing should be for at least h after needle The presence of blood during needle placement may an additional in initiation of postoperative LMWH. Patients with postoperative initiation of LMWH may and continuous catheter a continuous technique is the epidural catheter should be indwelling and removed the following with the first dose of LMWH administered h after catheter The to LMWH in the presence of an indwelling catheter must be with and of the patient's neurologic status is or anesthetic is in these patients to continuous monitoring of neurologic For LMWH prophylaxis the of catheter removal is of removal should be for at least h after a dose of LMWH. A of the patient's coagulation status be the dose of LMWH is not and the catheter is removed the following h after the subsequent dosing should not for h after catheter Patients be in the perioperative for early of such as of or and and was in our of patients. spinal hematoma is must be may to ischemia. The of is is unlikely surgery is more than h 4. In regional anesthesia in association with perioperative heparin prophylaxis or systemic heparin anticoagulation is safe and effective with appropriate patient and anesthetic A of SH and LMWH biochemistry and pharmacology will optimal regional anesthesia while minimizing the risk of as well as venous of patients with spinal hematoma associated with LMWH (Table and Table is comprehensive through However, in the first of there have been additional cases reported to the and one published