Low Molecular Weight Heparins and Their Clinical Applications

Home , Ardeparin sodium, Reviparin sodium

CHAPTER TWO

Low molecular weight heparins and their clinical applications

Cui Haoa,*, Mojian Sunb, Hongmei Wangc, Lijuan Zhanga, Wei Wangd aSystems Biology and Medicine Center for Complex Diseases, Affiliated Hospital of Qingdao University, Qingdao, China bDepartment of Medical Records, Affiliated Hospital of Qingdao University, Qingdao, China cRespiratory Department, Affiliated Hospital of Qingdao University, Qingdao, China dKey Laboratory of Marine Drugs, Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience & Glycoengineering, Ocean University of China, Qingdao, China *Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 22 2. Structure of LMWHs 23 3. Clinical uses of LMWHs 25 4. Update on the LMWHs under clinic trials and its potential applications 27 4.1 Anti-tumor 27 4.2 Anti-viral 30 4.3 Anti-inflammation 30 4.4 Anti-diabetes-associated complications 31 4.5 Other applications 32 5. Concluding remarks 32 Acknowledgments 33 References 34

Abstract Heparin is an anticoagulant medication that was discovered in 1917 and used in clinic since 1935. Low molecular weight heparins (LMWHs) represent a refined use of heparin as anticoagulant medications that were developed in 1980s. LMWHs are obtained by cleaving heparin with different chemical or enzymatic methods. Eight chemically distinct and officially approved LMWHs are Bemiparin, Certoparin, Dalteparin, Enoxaparin, Nadroparin, Parnaparin, Reviparin, and Tinzaparin. LMWHs are mainly used for preventing blood clots, for treating deep vein thrombosis and pulmonary embolism, and for treating myocardial infarction. LMWHs have advantages over heparin in that they can be used at home with good predictability, dose-dependent plasma levels, a long half-life, less bleeding for a given antithrombotic even, smaller risk of osteoporosis in long-term use, and smaller risk of heparin-induced thrombocytopenia and thrombosis, a potential side effect of heparin. However, heparin is reversible with protamine sulfate while LMWHs have no antidote. Moreover, LMWHs have less of an effect on inhibiting thrombin activity than heparin. Furthermore, patients with end-stage renal

diseases have to use heparin because LMWHs are dependent on functioning kidney for their clearance but heparin is primarily cleared in the liver. We will review the recent progress made on the clinically approved and under clinical trialed LMWHs and their potential medical applications. In particular, we will provide an update on the chemical characteristics and clinical use of different branded LMWHs. In addition, the potential clinical applications of LMWHs in other therapeutic area will also be discussed.

1. Introduction Low molecular weight heparins (LMWHs) are derived from unfractioned heparin that are isolated from either porcine intestinal mucosa or bovine lungs. The medical grade unfractioned heparin has an average molecular weight of 12–16,000 Da.1,2 LMWHs were developed as anticoagulant/ – antithrombotic drugs since 1980s3 7 and defined as heparin salts having an average molecular weight of less than 8000 Da and for which at least 60% of all chains have a molecular weight less than 8000 Da.8 LMWHs represent a refined use of heparin and have several advantages over heparin in that they have longer half-life in the blood circulation, more predictable effects after a given dose, require less blood tests to check for their effectiveness and side effects, and do not have to be given in the hospital settings that is required for heparin.9 Eight chemically distinct and officially approved LMWHs are Bemiparin, Certoparin, Dalteparin, Enoxaparin, Nadroparin, Parnaparin, Reviparin, and Tinzaparin. LMWHs are originally developed and used for preventing blood clots and for treating myocardial infarction. Many clinical trials are currently conducting to expand the medical applications of LMWHs to other diseases. Each LMWH is a pleiotropic biological agent with its own chemical, biochemical, biophysical, and biological characteristics. Each LMWH also displays unique pharmacodynamic and pharmacokinetic profiles.8 Moreover, each LMWH is independently studied in preclinical assays or in clinical trials during their development.10 Thus, therapeutic interchange is regarded as inap- propriate among different LMWHs on the basis of differences in the biochemical and pharmacologic profiles and clinical effect identified in clinical trials.11 This review presents an overview of recent progress on LMWHs. We will mainly focus on the chemical characteristics, biological activities, and clinical use of different branded LMWHs. Recent developments of LMWHs in other therapeutic area will also be discussed in detail. Low molecular weight heparins 23

2. Structure of LMWHs Each LMWH is made by a unique manufacturing process. The eight LMWHs can be distinguished from each other by their specific molecular – and structural differences (Table 1).12 15 TheLMWHsareusuallysodium salt except Nadroparin (Fraxiparin), which is a calcium salt. The average molecular weight of the LMWHs is usually around 4000–6000 Da (Table 1). Moreover, among them, Bemiparin has best anticoagulation activity with the ratio of anti-Xa/anti-IIa activity more than 9.0 (Table 1). Each LMWH in clinical use is derived from standard commercial grade unfractioned heparin by chemical or enzymatic depolymerization. Each preparation uses a unique, proprietary manufacturing process to produce specific structural features. For example, Oxidative depolymerization with hydrogen peroxide is used in the manufacture of Ardeparin while oxidative depolymerization with Cu2+ and hydrogen peroxide is used in the

Table 1 The eight commercially available LMWHs. Trade Anti-Xa/IIa LMWH Salt name Manufacturer MW(kD) ratio Nadroparin Calcium Fraxiparin Sanofi- 4.3 3.3 Winthrop Enoxaparin Sodium Clexane, AVENTIS 4.5 3.9 Lovenox Dalteparin Sodium Fragmin Pfizer Kissei 6.0 2.5 Certoparin Sodium Sandoparin Novartis 5.4 2.4 Tinzaparin Sodium Innohep, Braun Novo/ 6.5 2.6 Logiparin Leo/Pharmiom Parnaparin Sodium Fluxum Alfa Wassermann 5.0 2.3 Reviparin Sodium Clivarin ABBOT 4.4 4.2 Bemiparin Sodium Beparine Biological Evans 3.6 9.7 Adapted from Gray E, Mulloy B, Barrowcliffe TW. Heparin and low-molecular-weight heparin. Thromb Haemost. 2008;99(5):807–818; Fareed J, Leong W, Hoppensteadt DA, Jeske WP, Walenga J, Bick RL. Development of generic low molecular weight heparins: a perspective. Hematol Oncol Clin North Am. 2005;19(1):53–68, v-vi; Mulloy B, Gee C, Wheeler SF, Wait R, Gray E, Barrowcliffe TW. Molecular weight measurements of low molecular weight heparins by gel permeation chromatography. Thromb Haemost. 1997;77(4):668–674. 24 Cui Hao et al. manufacture of Parnaparin. Deaminative cleavage with isoamyl nitrite is used in the manufacture of Certoparin. Alkaline beta-eliminative cleavage of the benzyl ester of heparin is used in the manufacture of enoxaparin. Deaminative cleavage with nitrous acid is used in the manufacture of Dalteparin, Reviparin, and Nadroparin. Beta-eliminative cleavage by the heparinase enzyme is used in the manufacture of Tinzaparin. The preparation of LMWHs using the different cleavage methods results in subtle structural differences among these pharmaceutical agents (Table 2 and Fig. 1).8 In summary, each LMWH is unique with specific molecular and structural signature.

Table 2 Characteristics and the method of preparation of LMWHs. LMWH Characteristics Method of preparation

Dalteparin Presence of 2,5-anhydro-D-mannose Nitrous acid depolymerization at reducing terminus

Reviparin Presence of 2,5-anhydro-D-mannose Nitrous acid depolymerization at reducing terminus

Nadroparin Presence of 2,5-anhydro-D-mannose Nitrous acid depolymerization at reducing terminus

Certoparin Presence of 2,5-anhydro-D-mannose Deaminative cleavage with at reducing terminus isoamyl nitrite Enoxaparin Presence of 4,5 unsaturated uronic Benzylation followed by acid at non-reducing terminus alkaline depolymerization Bemiparin Presence of 2-O- Depolymerized heparin sulfo-4-enepyranosuronic acid obtained by alkaline structure at non-reducing terminus degradation Tinzaparin Presence of 4,5 unsaturated uronic Enzymatic depolymerization acid at non-reducing terminus with heparinase

Parnaparin Presence of a 2-N,6-O-disulfo-D- Oxidative depolymerization glucosamine structure at reducing with Cu2+ and hydrogen terminus peroxide

Adapted from Gray E, Mulloy B, Barrowcliffe TW. Heparin and low-molecular-weight heparin. Thromb Haemost. 2008;99(5):807–818; Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl): 188S–203S; Ingle RG, Agarwal AS. A world of low molecular weight heparins (LMWHs) enoxaparin as a promising moiety—a review. Carbohydr Polym. 15 2014;106:148–153. Low molecular weight heparins 25

Fig. 1 Structural characteristics of the LMWHs. Adapted from Fareed J, Leong W, Hoppensteadt DA, Jeske WP, Walenga J, Bick RL. Development of generic low molecular weight heparins: a perspective. Hematol Oncol Clin North Am. 2005;19(1):53–68, v–vi; Jeske WP, Walenga JM, Hoppensteadt DA, et al. Differentiating low-molecular-weight heparins based on chemical, biological, and pharmacologic properties: implications for the development of generic versions of low-molecular-weight heparins. Semin Thromb Hemost. 2008;34 (1):74–85; Yan Y, Ji Y, Su N, et al. Non-anticoagulant effects of low molecular weight heparins in inflammatory disorders: a review. Carbohydr Polym. 2017;160:71–81.

3. Clinical uses of LMWHs Thrombosis occurs at sites of injury to the vessel wall by inflammatory processes leading to the activation of platelets, the platelet adherence to the vessel wall and the formation of a fibrin network.16 LMWHs represent a group of antithrombotic and anticoagulant drugs that were initially developed for the prophylaxis of surgical thrombosis in the 1980s.17 Nowadays, these drugs have been used in expanded indication including venous thrombosis, cardiovascular disorders, thrombotic and ischemic strokes, and inflam- – matory diseases.18 27 26 Cui Hao et al.

Table 3 The activities and clinical applications of LMWHs. LMWHs Activity and application Refs. – Dalteparin Dalteparin binds to antithrombin and enhances the inhibition 29 34 of Factor Xa. It is associated with lower incidences of osteoporosis and heparin-induced thrombocytopenia – Reviparin Reviparin inhibits complement-mediated myocardial injury 35 40 as assessed in an ex vivo model of complement activation – Nadroparin Nadroparin is used for prophylaxis of thromboembolic 41 44 disorders and general orthopedic surgery, treatment of DVT, and prevention of clotting during hemodialysis – Certoparin Certoparin has proved to be effective and safe for preventing 45 48 VTE in different surgical and medical settings. It represents a valid option for VTE prevention and DVT treatment – Enoxaparin As an anticoagulant/antithrombotic agent, it also has anti- 49 56 inflammatory properties by inhibiting monocyte adhesion to TNFα or lipopolysaccharide-activated endothelial cells – Bemiparin It is mainly used for prevention of VTE and treatment of DVT 57 64 – Tinzaparin Tinzaparin is used for the prevention of VTE in patients 65 67 undergoing orthopedic surgery and in patients undergoing general surgery who are at high risk of developing postoperative VTE – Parnaparin Parnaparin is safe and effective for the prevention and 68 73 treatment of VTE, acute coronary syndromes and PAOD Ardeparin For prevention of DVT, which may result in pulmonary 74,75 (Withdrawn) embolism following knee surgery Semuloparin The prevention of VTE following some surgery such as hip 76,77 replacement as well as for patients undergoing chemotherapy

Since the early trials in the 1980s there has been a wealth of data published on the use of LMWHs in both prophylaxis and treatment of thrombosis. LMWHs have been replacing heparin for traditional indications since then.28 Each LMWH can be characterized by specific differences in molecular structure, biochemical and pharmacologic profiles, and clinical effect (Table 3).15 However, the diversity of pharmacological and clinical properties,68 as well as the poor-quality, inconsistent evidence for equivalence between agents, make the LMWHs unsuitable candidates for therapeutic interchange programs.78 Low molecular weight heparins 27

Venous thromboembolism (VTE) begins with deep vein thrombosis (DVT), which forms in the deep veins of the leg or pelvis. VTE is respon- sible for a substantial number of deaths per year in Europe.16 Anticoagulants are the mainstay of both VTE treatment and VTE prevention and many pro- fessional organizations have published guidelines on the appropriate use of anticoagulant therapies for VTE and DVT.16 Therapeutic advantages of LMWHs over unfractionated heparin include once- or twice-daily subcutaneous dosing, reduced hospital stays, elimination of therapeutic monitoring for most patients, and possibly less bone density loss.79 Studies have demonstrated that most LMWHs such as Enoxaparin, Nadroparin, and Bemiparin have good therapeutic effect on VTE with high efficacy and safety.16,80 Opportunities for future study include evaluation of LMWH’s efficacy for the prevention of deep vein thrombosis within high-risk groups and for the treatment of thrombosis in the conditions such as pregnancy, – cancer, obesity, and renal insufficiency, and in children.53,81 87

4. Update on the LMWHs under clinic trials and its potential applications Heparins are glycosaminoglycans that are largely used as anticoagulant and antithrombotic drugs. While the mechanisms of their anticoagulant actions in blood have been extensively studied, their effects on other diseases are still under investigation.88 Recently, LMWHs have been used in expanded indications such as cancer, viral infections, inflammatory diseases and diabetic complications.89 The top five diseases that clinical trials were conducted on LMWHs are DVT (42%), cancer (22%), peritoneal disease (10%), abortion and pregnancy (9%), renal insufficiency (8%) (Table 4, Fig. 2). Moreover, the top five LMWHs used for clinical trials are Dalteparin, Enoxaparin, Tinzaparin, Nadroparin and Bemiparin (Table 5).

4.1 Anti-tumor All cancers are associated with hypercoagulable state.90 The relationship between cancer and thrombosis is intertwined with the hemostatic system and mechanisms of cancer growth and metastasis inextricably linked.91 The possibility that anti-thrombotics may confer a survival benefit on cancer patients has been considered for over 60 years, over which time a growing body of evidence has suggested that drugs such as LMWHs might inhibit cancer growth and metastasis through a myriad of mechanisms.91 Ettelaie and coworkers found that LMWH down-regulates tissue factor expression Table 4 The numbers of publications on the specific disease while the clinical trials were conducted on LMWHs. Ranking Diseases # of publications 1 DVT/PM 241 2 Cancer 126 3 Coronary 58 4 Abortion and pregnancy 54 5 Renal insufficiency 44 6 Healthy 8 7 Fibrillation 8 8 Inflammation 8 9 Stroke 7 10 Obesity 7 11 Diabetes 5 12 Peritoneal disease 3 13 Vitreoretinopathy 3 14 Thrombocytopenia 2 15 Skin burn 2 16 Arthritis 2 17 Gastrointestinal 1 Total 580

1% 1% 0% DVT/PM 1% 0% Obesity Cancer Renal Insufficiency 10% Diabetes Peritoneal Diseases Gastrointestinal Healthy Thrombocytopenia Fibrillation Abortion and pregnancy 9% Coronary Stroke 42% Inflammation Vitreoretinopathy 1% Skin Bum 0% 1% Arthritis 0% 1% 1%

22% 1% Fig. 2 The clinical trials of LMWHs on different types of disease. Low molecular weight heparins 29

Table 5 The number of clinical trials conducted on LMWHs. Ranking LMWHs # of trials 1 Dalteparin 302 2 Enoxaparin 204 3 Tinzaparin 32 4 Nadroparin 27 5 Bemiparin 15 6 Semuloprin 9 7 Certoparin 7 8 Parnaparin 3 9 Reviparin 1 Total 580 in vitro through a mechanism that involves interference with the function of growth factors that in turn is mediated through the down-regulation of the transcriptional activity of NF-κB.92 This mechanism may also explain some of the beneficial influences attributed to LMWH therapy in the treatment of cancer patients.92 Moreover, LMWH reduces the risk of venous thromboembolism (VTE) and may have antineoplastic effects by interfering with angiogenesis, tumor – growth and metastasis.93 96 Lung cancer is the most common cancer in the world, but the patient survivals have not been improved much during the past. It has been suggested that LMWH might be able to improve the survival of lung cancer patients by preventing VTE-related mortality or by exhibiting anti-metastatic effects.97 A multicenter phase II randomized trial has been done to evaluate the antineoplastic potential of Dalteparin in ovarian cancer. The results showed that Dalteparin is safe and well tolerated in women receiving chemotherapy for newly-diagnosed epithelial ovarian cancer, but the lack of control group precluded any inference on the antineoplastic effect of Dalteparin.93 In summary, LMWHs have anti-tumor effect in vitro and in animal models of malignancy through interfering of tumor growth and metastasis. Although LMWH can prevent VTE, the risk-effect ratio (in case of an increased bleeding event) when LMWH is used in patients with cancer should be considered. Thus, further study is still needed to confirm the published findings.94,96,98 30 Cui Hao et al.

4.2 Anti-viral LMWH is a negatively charged glycosaminoglycan with similar structure to that of cell surface heparan sulfate (HS). Thus, LMWH, an analog of HS, may inhibit positively charged virus infection through cooperative electro- static association.99 Guo et al. reported that LMWH can alleviate proteinuria in rats through inhibiting RSV from binding with HS, which plays an important role in the onset of RSV infection.99 To evaluate the effect of indigenous and imported LMWHs in the treatment of chronic hepatitis and cirrhosis, Huang and coworkers performed a prospective randomized controlled clinical study of the treatment of patients with chronic hepatitis B using indigenous and imported LMWHs.100 They found that LMWH in combination with conventional treatment for patients with cirrhosis significantly improves the outcome, which suggested that indigenous LMWH calcium might be a safe and effective alternative drug. Moreover, the indigenous LMWH costs less and the pain is less intense during injection compared to the imported one.100 Furthermore, heparin and other types of sulfated polysaccharides have been shown to have anti-HIV activities in vitro.101 However, many of these compounds are not suited for use in vivo because they present an increased risk of bleeding or cannot be administered daily.102 Howell et al. tested the anti-HIV effects of LMWH (Enoxaparin) using a model system of HIV infection, and found that LMWH could inhibit HIV-1 production both in vitro and in vivo. They then performed a pilot clinical trial in 13 patients with advanced AIDS of 6 months, and found that after treatment there was no appreciable change in serum p24 levels, and no evidence of drug toxicity and bleeding episodes, which suggested that it is feasible to treat patients with AIDS with LMWH on a long-term basis.102 In summary, Heparin especially LMWH can interact with the positive charge regions of cell surface glycoproteins, leading to the shielding effect on these regions, thus prevent the binding of viruses to the cell surface.103 Therefore, LMWH has the potential to be developed into novel anti-viral agents in the future.

4.3 Anti-inflammation Venous thrombosis results in a vein wall inflammatory response initiated by thrombus. Although anticoagulation with standard heparin and LMWH is known to limit further thrombosis, their anti-inflammatory properties are Low molecular weight heparins 31 poorly defined.104 Hochart et al. designed an experiment to assess the effect of LMWH and heparin on production of inflammatory markers and nuclear translocation of NF-κB in human monocytes.105 They found that treatment with pharmacological doses of LMWH and heparin significantly attenuates the LPS-induced production of TNF-alpha, IL-8, IL-6 and IL-1beta as well as NF-κB translocation, which suggested that LMWH and heparin were potential therapeutic inhibitors of inflammation.105 Moreover, Luan et al. found that LMWH is able to reduce pulmonary inflammation in rats with endotoxin-induced acute lung injury.106 They showed that treatment with LMWH significantly decreases the expression of TNF-α, IL-1β, HMGB1 and ICAM-1 in the lung of ALI rats.106 Simi- larly, treatment with LMWH dramatically diminishes LPS-induced neutro- phil sequestration and markedly reduces the enhanced lung permeability, which suggested that LMWH could not only attenuate inflammation but also prevent lethality in endotoxemic rats.106 In summary, heparin and LMWH may offer therapeutic benefit for inflammatory diseases. The inhibition of p38 MAPK and NF-κB activation represents one of the mechanisms by which LMWH exerts its anti- inflammatory effect.88,107

4.4 Anti-diabetes-associated complications Previous study demonstrates a beneficial therapeutic effect based on heparan sulfate proteoglycans and/or other heparin-like substances in insulin- dependent diabetes mellitus.108 Artico et al. described the early morphological alterations in the rat kidney and heart in experimentally induced diabetes to evaluate the possible therapeutic role of LMWH (Parnaparin), and found that Parnaparin treatment is effective for ameliorating the morphological pattern observed early in some diabetic tissues of rats and, above all, in the kidney.108,109 Their findings suggest a possible therapeutic role for Parnaparin in anti-complications of diabetes. Furthermore, to investigate the protective effect of LMWH on early nephropathy in diabetic rats and to explore its possible mechanism, Guo et al. treated diabetic rats with LMWH (Fraxiparine, Nadroparin calcium 205 AXaIU/kg), and found that the LMWH possesses a renal protective effect on early diabetic nephropathy and its possible mechanism may be associated with the beneficial effect of LMWH on regulating abnormal diabetic renal hemodynamics.110 Moreover, Gan et al. treated STZ-induced diabetic rats and diabetic rats with LMWH for 2 weeks, and found that LMWH 32 Cui Hao et al. possesses good renal protective effect on diabetic nephropathy and the inhibition of VEGF expression may be one of the mechanisms of its renal protective effects.111 Diabetic foot ulcer is a major complication of diabetes mellitus, and probably the major component of the diabetic foot. It occurs in 15% of all patients with diabetes and precedes 84% of all diabetes-related lower- leg amputations.112 Rullan and his colleague designed a clinical study to assess the efficacy and safety of Bemiparin in the treatment of chronic diabetic foot ulcers.113 Their results showed that ulcer improvement rates are 70.3% (26 of 37 patients) in the Bemiparin group and 45.5% (15 of 33 patients) in the placebo group (the absolute difference: 24.8; 95%CI: 2.3–47.3; P¼0.035), which suggested that Bemiparin were more effective than placebo in the management of diabetic foot ulcers with few side- effects.113 In summary, LMWHs such as Bemiparin and Parnaparin could also be used for treatment of some diabetic complications although more clinical study are needed in the future.

4.5 Other applications Besides their well-known anticoagulant effects, LMWHs have also been reported to exhibit numerous other therapeutic properties. Both preclinical and clinical studies have shown that commercially available LMWHs have promising anti-inflammatory, anti-metastatic, and anti-fibrotic activities.89 There is evidence suggesting that LMWH might prevent preeclampsia through anticoagulation-independent mechanisms.114 However, structural heterogeneity of LMWHs makes the structure-activity relationship analysis challenging.

5. Concluding remarks LMWHs belong to the class of anticoagulant medications that have an advantage over heparin in that they have good predictability, dose- dependent plasma levels, a long half-life, less bleeding for a given antithrombotic event, smaller risk of osteoporosis in long-term use, and smaller risk of heparin-induced thrombocytopenia and thrombosis, a potential side effect of heparin.9 However, LMWHs cannot substitute heparin for certain medical purposes for the reasons below. Heparins are reversible with protamine sulfate but LMWHs have no antidote. Moreover, LMWHs have less of an effect on inhibiting thrombin activity than heparin. Furthermore, patients with end-stage renal diseases have to use heparin because LMWHs Low molecular weight heparins 33 are dependent on functioning kidney for their clearance while heparin is primarily cleared in the liver. Even with the limitations, LMWHs have been clinically trialed in an accelerating rate and used in expanded indications such as cancer, viral infection, inflammatory diseases and diabetic complications.28,101,108 Unfractioned heparins used for making LMWHs are isolated in tons quantities of bovine lungs or porcine intestines. Some porcine intestinal heparin is prepared from the mucosa of porcine intestines while others use the whole intestines. Different subspecies of pigs and cows do not make the identical heparins based on their structural analysis, and the mast cell content in the lungs and intestines can also vary based on the diet and envi- ronment in which the animals are raised.115 These variables in unfractioned heparin make each batch of LMWH different as well. Therefore, to what degree the LMWHs should be considered as the same or different drugs is still a pending issue. The diversity of pharmacological and clinical properties, as well as the poor-quality, inconsistent evidence for equivalence between LMWHs or different batches of the same LMWH, makes the LMWHs unsuitable candidates for therapeutic interchange programs.78 LMWHs have increasingly replaced unfractionated heparin in treating acute coronary syndrome in 2003, and it has been proposed that new anticoagulants with enhanced activity against factor Xa might have even greater potential in acute coronary syndrome.116 LMWHs had sales of $6.5 billion in antithrombotic drug market and formed the second-largest drug of this class. Enoxaparin (Lovenox; Sanofi), the leading LMWH, claimed 40.5% share in 2014,52 but it is expected to account for 18.3% in 2018. Therefore, making LMWHs more comprehensible and interchangeable drugs might make the drugs more affordable and useful for patients. In conclusion, LMWH is an addition to the short list of therapies for prophylaxis and treatment of thrombosis and has the potential to be developed into novel agents for treating other thrombosis-related diseases.91 Moreover, opportunities for future study include evaluation of LMWH’s efficacy for the prevention of deep vein thrombosis within high-risk groups and for the treatment of thrombosis in high risk patients suffering cancer, obesity, renal insufficiency, and due to pregnancy.3,79

Acknowledgments This research was supported by Natural Science Foundation of China (Grant No. 81672585); Key Technology Fund of Shandong Province (Grant 2016ZDJS07A07); the “Double First-Class” fund of Shandong Province; and Taishan Scholar Fellowship to L.Z. 34 Cui Hao et al.

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