Current role of heparin in thromboprophylaxis of major orthopaedic surgery

Total knee replacement (TKR), total hip replacement (THR), and hip fracture (HFx) surgeries carry a high risk for venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE) [1]; it is estimated that about 5 percent of patients undergoing the above major orthopaedic surgery could have symptomatic VTE without prophylaxis. However, thromboprophylaxis and increasing use of early mobilization have caused the recent decrease in the postoperative VTE rate. The antithrombotic prophylaxis reduces the incidence of deep vein thrombosis (DVT) by 50% to 60% and pulmonary embolism (PE) by about two-thirds [2]. For patients undergoing THR or TKR the recommendation is to use one of the following for a minimum of 10 to 14 days: low-molecular-weight heparins (LMWHs), fondaparinux, apixaban, dabigatran, rivaroxaban, low-dose unfractionated heparin, adjusted-dose vitamin K antagonist (VKA), aspirin, or an intermittent pneumatic compression device[1]. Despite the increasing popularity of direct oral anticoagulants (DOACS), the LMWH are still the main option for in-hospital prophylaxis.


Introduction
Total knee replacement (TKR), total hip replacement (THR), and hip fracture (HFx) surgeries carry a high risk for venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE) [1]; it is estimated that about 5 percent of patients undergoing the above major orthopaedic surgery could have symptomatic VTE without prophylaxis. However, thromboprophylaxis and increasing use of early mobilization have caused the recent decrease in the postoperative VTE rate. The antithrombotic prophylaxis reduces the incidence of deep vein thrombosis (DVT) by 50% to 60% and pulmonary embolism (PE) by about two-thirds [2]. For patients undergoing THR or TKR the recommendation is to use one of the following for a minimum of 10 to 14 days: low-molecular-weight heparins (LMWHs), fondaparinux, apixaban, dabigatran, rivaroxaban, low-dose unfractionated heparin, adjusted-dose vitamin K antagonist (VKA), aspirin, or an intermittent pneumatic compression device [1]. Despite the increasing popularity of direct oral anticoagulants (DOACS), the LMWH are still the main option for in-hospital prophylaxis.

Pharmacodynamics and pharmacokinetics of LMWHs
About 95% of unfractionated heparin (UHF) components exhibit both anti-Xa and IIa actions. On the other hand, the LMWHs contain less than 30% of molecular components showing both anti-Xa and anti-IIa actions. Only high-molecular-weight molecules are able to potentiate the inhibition of anti-IIa, whereas inhibition of factor Xa is not dependent on molecular weight [3]. The relative prevalence of oligosaccharides presenting sole anti-Xa activity is much higher than in UHF. Moreover, the clearance of heparin components is different than with the LMWHs, and over time the anti-Xa/IIa ratio of LMWHs increases [4]. It was suggested in animal studies that a high of anti-Xa to anti-IIa activity may be related to a reduced tendency to cause bleeding [5]; however, it has not yet been confirmed in clinical trial. Importantly, despite different production LMWH technologies influencing the chemical structure of glucosamine chains and their functional groups, their anti-Xa activity and inhibition of haemostatic system activation is very similar [6].
Heparin leads to the release of tissue factor pathway inhibitor (TFPI), which has inhibitory effects on the coagulation cascade [5]. Increases in the concentration of free TFPI are similar after single doses of UHF or LMWH [7], but effects may differ after multiple doses. After five days of administration of UHF, total TFPI activity is partially depleted, but not following injection of LMWH [8].
Heparins interact also with platelets. Platelet factor 4 (PF4), which is released by activated platelets, has a strong potential to inhibit high-molecular-weight fractions of heparin [9]. Importantly, it has a much weaker effect on the low-molecular-weight fractions that inhibit factor Xa activity. Therefore the anti-Xa activity of LMWHs is largely intact in the face of PF4 inhibition [10]. However, the anti-IIa action of LMWH is reduced by PF4, and overall antithrombotic activity is retained [10] In contrast, UHF can be completely inactivated in the presence of PF4 [10]. UHF can both inhibit platelet aggregation [11], and cause platelet activation [12]. However, the effect of LMWHs on platelets is less extreme, as both the activation and the inhibition of platelets is weaker than that of UHF [11].
UHF binds to endothelial cells with much higher affinity than LMWH, that may be partly responsible for the faster degradation and elimination of UHF, and explain the poor bioavailability of UHF after subcutaneous administration compared with LMWH [3]. LMWHs are easily absorbed from subcutaneous tissue and have a lower tendency to bind to endothelial cells. The bioavailability of anti-Xa activity varies from about 87% for dalteparin, about 91% for enoxaparin, up to 98% for nadroparin [13].
Heparins are partially degraded by the liver to inactive fragments and are partially eliminated by the kidneys 3 . In a comparative study between enoxaparin 20mg and 40mg, dalteparin 2500IU, and nadroparin 7500IU injected subcutaneously, the average apparent total body clearance of enoxaparin was 15.6 mL/min. This was considerably lower than that of dalteparin (33 mL/min) and nadroparin (21.4 mL/ min) [13]. Consequently, dalteparin is cleared from the body more rapidly than nadroparin and enoxaparin. Importantly, for enoxaparin 20mg and 40mg, urinary excretion represents 6.4% and 8.7% of the injected dose, which differs from those of nadroparin (3.9%) and dalteparin (3.4%) [13]. Enoxaparin has a longer apparent half-life (mean 4.1 hours) in the anti-Xa assay than dalteparin (mean 2.8 hours) and nadroparin (mean 3.7 hours), which is a reflection of their respective clearance values [13]. LMWHs' anti-Xa clearance decreases with the degree of renal function [4]. Therefore, dosage reduction is recommended in patients with severe renal impairment (creatinine clearance <30 mL/min).

Clinical efficiency and safety
The retrospective, observational, cross-sectional, cohort analysis of 113,936 patients after a major orthopaedic surgery revealed a similar rate of venous thromboembolism in the group receiving thromboprophylaxis with dalteparin (2.1%) and with enoxaparin (2.3%) as prevalence of major bleeding (1.1% vs. 1.5%, respectively) [14].
Anderson et al. compared aspirin to LMWH in a randomized multi-center study that recruited 778 patients. After 28 days, there was no difference in efficacy (1.3 vs. 0.3%, p=0.22) or bleeding complication (5.8 vs. 3.6%; p=0.45) between the cohorts [15]. The meta-analysis of three randomized clinical trials that compared apixaban to LMWH following TKA (n=7,337) noted that DVT rates were lower in the apixaban group (p=0.007) but there was no difference in the risk for PE (p=0.06) [16]. Moreover, the study found less major bleeding within the apixaban cohort (p=0.034). A further meta-analysis (n=24,385 patients) demonstrated that two different oral factor Xa inhibitors (FXaI) (apixaban and rivaroxaban) were superior to LMWH in preventing DVT after THA and TKA (OR 0.44, 95%CI: 0.31-0.63; p<0.00001) [17].
Meta-analysis of thromboprophylaxis intervention after major orthopaedic surgeries of 127 randomized clinical trials and 15 nonrandomized clinical trials [18] showed for THR that LMWH has lower risk than UHF of various VTE outcomes and major bleeding. In addition, it was indicated that LMWHs and aspirin have similar risks of total PE, symptomatic DVT, and major bleeding. Moreover, in the THR group LMWH causes less major bleeding than direct thrombin inhibitors (DTI), but DTI has lower DVT risks. Apparently, thromboprophylaxis with LMWH was associated with a lesser rate of major bleeding than with vitamin K antagonists (VKA). By and large, LMWH and FXaI comparisons are inconsistent across VTE outcomes, but it seems that LMWH cause less major bleeding. Interestingly, longer duration LMWH had lower risk of various VTE outcome risks, while higher dose LMWH lowered total DVT risk with increase of major bleeding.
In the TKR group [18], LMWH thromboprophylaxis showed lower DVT risks than VKA, but VKA had less major bleeding. On the other hand, FXaI appeared to have lower risk than LMWH of various VTE outcomes, while LMWH caused less major bleeding but more studydefined serious adverse events. In the group undergoing TKR higher dose DTI has lower DVT risk, but leaded to a higher rate of major bleeding. Similarly, higher dose FXaI also decreased the risk of various VTE outcomes. In contrast, LMWH had a lower rate of total DVT than FXaI for HFx surgery.

Conclusion
LMWHs were considered the gold standard for the prevention of VTE in major orthopaedic surgery for many years, although they have not shown themselves to be superior to any of the other chemoprophylactic agents. LMWHs remain widely used in tromboprophylaxis after major orthopaedic surgeries, despite growing usage of direct thrombin inhibitors and factor Xa inhibitor, which may have superior efficacy, but their safety profile still must be studied further.