Low-Dose Unfractionated Heparin
Heparin is a naturally occurring anticoagulant that is produced by basophils and mast cells. Two types of heparins are commonly used as anticoagulants to prevent thrombosis: LDUH and LMWH. The mechanism of action of LDUH includes binding to antithrombin III, and together this heparin/antithrombin complex then binds to factor Xa, causing inactivation. LMWH is synthesized from unfractionated heparin (UFH) by depolymerization and thus has a reduced size and molecular weight (3000-7000 daltons) in comparison to LDUH (3000-30000 daltons). LDUH also binds to and inactivates thrombin (factor II), although this process requires larger heparin molecules (at least 18 saccharide units in length). Therefore, LMWH has a reduced ability to inhibit thrombin due to the smaller molecular structure not being able to simultaneously bind antithrombin and thrombin. However, this reduced binding to plasma proteins contributes to a more predictable dose-dependent response for LMWH. Pharmacokinetically, LMWH has a higher and more efficient bioavailability compared to LDUH, although LMWHs are themselves a heterogeneous class of compounds that differ in weight, anticoagulant activity, and pharmacokinetic properties. Various LMWHs exist including Enoxaparin, Dalteparin, Ardeparin, Nadroparin, Parnaparin, Reviparin, and Tinzaparin. A major complication associated with the use of heparin for thromboprophylaxis is the risk of hemorrhaging, although LMWH is associated with a lower incidence of hemorrhaging as a result of reduced binding to platelets and endothelium (Hirsh & Raschke 2004; Quader et al. 1998). Additionally, spinal epidural hematoma is a rare but devastating complication that has been reported to occur after spinal surgery; this may potentially be associated with pre-operative use of chemical thromboprophylaxis although evidence has shown this to be a rare occurrence. Nevertheless, the benefits of thromboprophylaxis must be weighed against the risk of potential hematoma formation (Al-Dujaili et al. 2012; Awad et al. 2005; Cunningham et al. 2011).
Discussion
Unfractionated heparin has been the standard treatment for VTE post SCI for years. Evidence for its effectiveness, however, is unclear. Using LDUH alone is not recommended as a prophylactic treatment (Dhall et al. 2013) and is associated with high rates of DVTs and PEs in individuals with acute SCI (Kulkarni et al. 1992). Seven studies examined the independent prophylactic effectiveness on the incidence of DVT and PE in acute SCI individuals.
Agarwal and Mathur (2009) conducted a randomized controlled trial (RCT) in which acute SCI individuals who had sustained injury within an average of 8 days were randomly allocated into either the experimental group receiving 5000 IU LDUH every 12 hours for 3 months, or the control group (receiving no intervention). The results showed that 1.8% of participants who received LDUH developed DVT (within 6-10 days after injury), while 3% of participants in the control group developed DVT (within 5-28 days after injury); the two groups were not significantly different in terms of DVT incidence (p>0.05). This low incidence rate in the control group can perhaps be attributed to the study being conducted within an Asian population, where it is believed that Eastern populations have lower incidence rates of DVT compared to Western populations (Rathore et al. 2008).
Green et al. (1988) studied 75 individuals with SCI who were randomized to receive either a fixed dose or an adjusted dose of unfractionated heparin. The fixed-dose heparin was 5000 IU; the adjusted heparin group started off at 5000 IU and was adjusted according to (activated partial thromboplastin time to a maximum of 15000 IU (mean=13200 IU). Thromboembolism was detected in 9/29 on fixed-dose regimen with no bleeding complications while 2/29 on the adjusted-dose regimen developed thromboembolism and 7/29 had bleeding complications.
Typically, prophylactic treatment involves 5000 IU of heparin. Two RCTs and one controlled study examining the efficacy of this dose and a placebo found no difference in the incidence of venous thrombosis in both the treatment and the placebo groups. Interestingly, Merli et al. (1988) found that heparin plus electrical muscle stimulation significantly reduced the incidence of venous thrombosis when compared to heparin alone. Finally, one RCT (Green et al. 1988) has shown that while 5000 IU of heparin was not an effective dose in reducing the incidence of thromboembolism, higher doses were more effective but had a higher risk of bleeding complications. In a recent systematic review and meta-analysis, Chen and Wang (2013) conclude that among individuals with acute SCI, LDUH has no thromboprophylaxis effect compared with placebo or no treatment.
Merli et al. (1988) evaluated 53 individuals with acute SCI who were randomly assigned to one of three groups: placebo saline (n=17), 5000 IU LDUH (n=16), or 5000 IU LDUH plus electrical stimulation of the tibialis anterior and gastrocnemius muscles (n=15) over 28 days. There was no difference between the placebo saline and heparin groups in the incidence of DVT while there was a significant improvement in the heparin and electrical stimulation group. The study was prematurely discontinued because of the benefit of the heparin plus electrical stimulation group and lack of efficacy in the control group.
Frisbie and Sasahara (1981) conducted a non-randomized trial of 32 individuals with SCI receiving either no treatment or 5000 IU of LDUH until day 60 post-SCI. Incidence of DVT was rare in both the control (1/17) and the LDUH group (1/15).
A case series by Winemiller et al. (1999) retrospectively reviewed individuals who were administered LDUH for the initial 42 days to 6 weeks after injury (dosage unspecified). VTE events were first detected at a median of 14.5 days after injury. Multivariate analysis suggested that these individuals had a reduced risk of thromboembolism when treated with LDUH within the first 14 to 42 days after injury, suggesting that LDUH may be most effective within the first 14 days after injury in preventing thromboembolic events.
In a post-test study conducted by Gunduz et al. (1993), all SCI individuals also received 5000 IU LDUH every 12 hours, administered for 12 weeks from the time of admission. All participants were admitted within an average of 27 days after injury. The incidence of DVT was 53.3% but the onset timing was not indicated.
In a case series study, Kulkarni et al. (1992) examined SCI individuals who were admitted<24 hours following injury. Participants received 5000 IU LDUH every 8 hours. The researchers noted that 27% of individuals still developed thromboembolic complications, including 17 DVT, 7 PE, and 2 DVT + PE events.
Conclusions
There is level 2 evidence (from one RCT: Agarwal & Mathur 2009) that low-dose unfractionated heparin is not effective as prophylaxis for venous thromboembolism in acute SCI individuals; However, there is level 4 evidence (from one case series: Winemiller et al. 1999) that low-dose unfractionated heparin is effective as prophylaxis for venous thromboembolism if provided early (within 14 days after injury).
There is level 1b evidence (from one RCT: Green et al. 1988) that adjusted (higher) dose unfractionated heparin is more effective in prophylaxis of venous thromboembolism than 5000 IU low-dose unfractionated heparin but has a higher incidence of bleeding complications.
There is level 2 evidence (from two RCTs and one prospective controlled trial: Agarwal & Mathur 2009; Frisbie & Sasahara 1981; Merli et al. 1988) that 5000 IU of low-dose unfractionated heparin is no more effective than placebo in the prophylaxis of venous thrombosis post-SCI.
