2021-08-17
Introduction
Representing an outstanding group of naturally generated poly- saccharide, heparin was termed due to its original isolation from liver tissue one century ago. To date, heparin has been serving as a main- stream anticoagulant medicine in the clinical practice for eight deca- des since the ?rst human application against thrombotic disorders [1,2]. Biochemically, the fundamental structure of heparin consists of repeating disaccharide units of uronic acids (L-iduronic or D-glucur- onic acid) and N-acetyl-D-glucosamine [3]. Depending on a contained unique pentasaccharide sequence, heparin exerts anticoagulant activity upon binding with antithrombin, in turn to suppress activa- tion of factor Xa and IIa in the coagulation cascade [1, 3].
The discovery and clinical application of heparin have signi?-cantly improved the outcomes in numerous aspects of serious medi- cal conditions. In this light, several heparin-based agents, such as unfractionated heparin (UFH) and low molecular weight heparin (LMWH), are included in World Health Organization’s (WHO) List of Essential Medicines [4]. UFH is the preliminary product usually proc- essed from porcine or bovine intestine tissues in pharmaceutic indus- try, and has various molecular lengths ranging from 2000 up to 40,000 Dalton (Da). On the other hand, with molecular weights below 7000 Da LMWH compounds are derived from UFH through depo- lymerization reactions facilitated by certain chemical and enzymatic reagents [1, 4]. Pharmacologically, LMWH medications have better bio-availability, higher anti-factor Xa/IIa activity ratios, and mini- mized risks of hemorrhage and heparin-induced thrombocytopenia (HIT), compared to those of UFH [4−6].
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As a classic anticoagulant, heparin family drugs are typically uti- lized to prevent or to treat thrombotic pathogenesis-linked medical conditions such as pulmonary embolism, coronary artery disease, and potential clotting events in hemodialysis for renal failure [1, 7]. Additionally, heparin represents a widely used surface coating agent to improve blood compatibility of numerous medical devices includ- ing cardiopulmonary bypass, extracorporeal circulation, vascular stent, among others [8]. Interestingly in recent years, heparin treat- ment is going beyond these traditional indications and entering into a broad spectrum of expanded clinical ?elds, inspired by the insights from advanced polysaccharide science and contemporary disease biology [1, 4, 9]. Herein, this article thus highlights an emerging pro- ?le of novel medical applications for heparin-based medications (Table 1).
The pregnant clinic
It has been recently noted that, in addition to the well-known anticoagulant ef?cacy, heparin can also orchestrate an extra-array of biological effects including anti-in?ammation/anti-complement, vas- cular endothelial protection, trophoblast promotion and apoptotic inhibition [9, 10]. As such, this functional pro?le appears helpful for certain obstetric patients to improve the clinical outcomes through alleviating the hyper-coagulant state, modulating micro-vascular/ placental biology, among other modes [10]. To date while the expanded indications in this perspective are yet to be corroborated by relevant large-scale clinical trials for regulatory approval in terms of the drug labeling update, there has been a professional consensus that heparin agents can be used as an empirical approach to treat or prevent early pregnancy complications such as spontaneous abortion [10, 11]. In this regard, prophylactic management with LMWH of Table 1
Updated application pro?le of heparin products.
|
Mode |
Medical usage |
References |
|
|
Deep vein thromboembolism |
[1, 3] |
|
|
Unstable coronary artery disease |
[1, 3] |
|
Anticoagulant |
Extracorporeal circulation processes |
[4, 7] |
|
|
Thromboprophylaxis in perioperative period |
[1, 4] |
|
|
Medical device intervention |
[4, 8] |
|
|
Coating of bio-materials contacting blood |
[8] |
|
|
Spontaneous abortion |
[10, 11] |
|
|
Chronic obstructive pulmonary disease |
[16, 17] |
|
Comprehensive |
Diabetic nephropathy/nephrotic syndrome |
[20, 21] |
|
|
Sepsis/severe COVID19 |
[26, 30] |
|
|
Pancreatitis |
[31, 32] |
|
|
Burning wound (topic use) |
48] |
standardized dosage until abortion or delivery has been demon- strated to signi?cantly raise the live-birth rates (by 20%~30%) in patients suffering from recurrent miscarriage, and particularly in the cases with antiphospholipid antibody or methylenetetrahydrofolate reductase gene polymorphisms [11, 12]. Moreover, LMWH was also revealed to dramatically improve pregnancy events and live-birth rates upon in vitro fertilization (IVF) in women with recurrent implantation failure and thrombophilic disorders [13]. In these sce- narios, the underlying comprehensive mechanisms included prevent- ing microthromboses, facilitating trophoblast differentiation/ migration, and up-regulating the level of free insulin-like growth fac- tor [14].
Chronic respiratory in?ammation
Heparin medicine can confer certain anti-in?ammatory effects through several mechanisms of actions such as regulating cytokine/ chemokine expression, suppressing immune cell in?ltration and par- ticularly minimizing obstructive mucous secretion [3, 15]. These in?ammatory-modulating roles of heparin in synergy with its anti- coagulant activity thus come up with an exceptional set of therapeu- tic potentials for managing chronic obstructive pulmonary disease (COPD). In this light, adding LMWH to the existing treatment was revealed to improve blood coagulation parameters of patients with COPD, including elongated prothrombin time (PT)/activated partial thromboplastin time (APTT) and reduced blood viscosity/D-dimer/ ?brinogen levels, compared to those of the subjects on conventional therapy only. Meanwhile, these combined medications were able to result in higher forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC), oxygen saturation of blood (SaO2), and lower partial pressure of carbon dioxide (PaCO2) [16, 17]. On the other hand, it has been noted that inhaled heparin or its derivatives confer the thera- peutic ef?cacy of relieving respiratory hyper-reactivity disorders such as asthma, through diminishing histamine and leukotriene- induced bronchial constriction [9, 15]. Moreover, LMWH was discov- ered to be capable of down-regulating the release of interlukine (IL)-4, IL-5, IL-13 and tumor necrosis factor (TNF)-a from the peripheral blood mononuclear cells (PBMCs) of asthmatic patients [18]. Thus, it is conceivable that pulmonary medicine can evolve with including heparin agents to circumvent hyper-coagulation and in?ammation.
Renal disease
Physiologically, the glomerular capillary ?ltration membrane con- trols the macro-molecule ?ltration based upon molecular weight, charge, and shape; in consistent, the ionic charge of the glomerular basement membrane (GBM) is characterized by containing highly sulfated glycosaminoglycan heparan (SGH) [19]. Diminished SGH in GBM due to up-regulated heparanase in certain renal pathology is prone to increase permeability to negatively charged macromolecules such as albumin, consequently resulting in protein- uria [9, 19].
Interestingly it has been proposed that LMWH may serve as an in vivo heparanase inhibitor to restore CSH dominance in GBM, thus alleviating the leaking of plasma protein into urine. In this regard without affecting hemodynamic physiology, enoxaparin and an oral LMWH (sulodexide) were revealed to signi?cantly minimize the severity of proteinuria in the patients with diabetic nephropathy, but not in glomerulonephritis [19, 20].
Likewise, LMWH was noted capable of facilitating clinical remission of patients with steroid-sen- sitive nephrotic syndrome through signi?cant reducing proteinuria, urinary glycosaminoglycans and nephrotic periods [21, 22].
Regard- ing the therapeutic mechanisms in this case, besides the above hep- aranase inhibitory mode, another possibility is suppressing the hyper-active elastase which can degrade subendothelial matrix thus causing glomerular damage and proteinuria [21]. Of note, whereas with an improved pro?le of adverse reaction LMWH has been more popularly utilized in managing relevant medical conditions recently, UFH is still preferred in patients with renal failure due to its shorter half life time and better reversibility by protamine for minimizing potential drug-accumulated toxicities [3, 23].
Sepsis
With the high mortality, sepsis remains a critical medical condi- tion that needs intensive care. Although antibiotic agents serve as an ef?cacious means for controlling the etiological microorganisms, an of?cial strategy of managing the induced patho-physiology during sepsis, septic shock in particular, is yet to be established [24, 25]. Anyhow in regard to the core pathogenesis, it has been recognized that the interactions between in?ammatory factors and endothelial injury activate the coagulating cascade to form micro-thrombosis, consequently resulting in organ damages [24]. As such to cope with this comprehensive challenge, heparin is emerging as an attractive medicine owing to the functional pro?le of pleiotropic effects about clotting inhibition, endothelial protection and immune modulation [3, 9]. In corollary through a multi-center retrospective clinical inves- tigation, heparin was utilized to be an effective adjuvant therapy for sepsis and signi?cantly diminished the mortality in a subset of patients with disseminated intravascular coagulation (DIC) dynami- cally over 3 months following the treatment [25]. Consistently in par- allel, controlled clinical trials of anticoagulant versus placebo demonstrated that prophylactic treatment with UFH or LMWH (up to 15,000 units/day, intravenously) signi?cantly reduced 28-day mor- tality (from 38% to 30%) in the patients with sepsis or severe sepsis [26]. Moreover, while conferring a better survival bene?t and improving coagulant parameters for the patients with sepsis, heparin was also noted to restore the protective proteoglycans on endothelial surface, and to down-regulate the levels of serum in?ammatory cyto-kines such as IL-6 as well as TNF-a [24,27,28] Additionally, sepsis was observed to be the most frequent complication in patients with coronavirus disease 2019 (COVID-19), of which aberrant coagulating function such as elevated D-dimer was noted as one of the risk factors for poor prognosis [29]. Impressively, treatment with LMWH appeared to improve the clinical outcomes of COVID-19 patients, upon down-regulation of D-dimer level and improvement of the immune pro?le [30].
Pancreatitis
As a complicated in?ammatory condition, acute pancreatitis (AP) presents various degrees of clinical severity, and severe AP is associ- ated high mortality due to systemic pathology without speci?c treat- ments. While AP pathogenesis is yet to be well delineated, the comprehensive interactions has been noted between in?ammatory factors, pro-coagulant pathways and vascular endothelial injury [31,32]. To cope with these multidimensional challenges, the functional pro?le of heparin can in this case confer an exceptional set of thera- peutic ef?cacy covering anti-in?ammation, anti-coagulation and endothelial protection [4, 9, 31]. In particular, heparin also contrib- utes to suppressing activity of digestive enzymes (trypsin and chy- motrypsin), an additional key mediator in early AP pathogenesis [31]. Clinically in corollary, LMWH has been demonstrated to signi?cantly improve the prognosis of severe AP without increasing bleeding events, including reducing hospital stay, mortality and systemic com- plications [32, 33]. Of note, LMWH strikingly diminished pancreatic necrosis development to 3.1% from 22.6% of the patients, which rep-resents a phenotype of organ damages resulting from TNF-a. Besides,heparin in synergy with insulin is particularly ef?cacious on manag- ing hypertriglyceridemia-induced AP, since heparin binds with lipo- protein lipase (LPL) and releases LPL from tissues into the blood to catabolize circulating triglycerides [34, 35].
Cancer
Neoplastic disorders are known to be epidemiologically associ- ated with a higher co-morbidity of venous thromboembolism (VTE). The incidence of VTE is elevated by up to 6 fold in patients with can- cer compared to those without tumor, and vice versa oncologic patients represent approximately 20% VTE cases newly diagnosed [36]. In terms of pathogenesis, cancer-linked hyper-coagulating state appears directly resulting from up-regulated tissue factor expression which thus leads to constitutive activation of the extrinsic coagulant pathway. Meanwhile, development of cancer-associated VTE can also be indirectly facilitated by several systemic factors including platelet/ endothelial activation and pro-in?ammatory cytokines [36−38]. Interestingly, while serving as an well-established anti-coagulant medication for preventing and managing cancer-associated VTE, hep- arin has been proposed to potentially go beyond this aspect and to exert certain anti-neoplasm effects through inhibiting angiogenesis, metastasis and P-glycoprotein-mediated drug resistance [3, 4]. Nev- ertheless, the results of clinical studies with heparin regarding thera- peutic ef?cacy against malignancies have so far been controversial. Although LMWH was revealed to signi?cantly improve overall sur- vival (OS) of 1 and 2 years in neoplastic patients with chemotherapy [39], a prophylactic investigation showed that adding dalteparin to the standard therapy did not confer a survival bene?t to lung cancer patients [3]. Anyhow, there is a medical consensus of using anti-coag- ulant medications to minimize the morbidity of cancer-associated VTE [4, 39].
Thrombotic disorders during cancer progressing result from not only neoplastic pathogenesis-associated coagulating pathways, but also the oncologic medications including chemotherapy, hormonal treatment, and targeted drugs implicating both small chemical com- pounds and monoclonal antibodies [37, 40, 41]. Recently with the clinical advantages of non-painful administration and improved ther- apeutic window novel oral anticoagulants (NOACs) such as apixaban and dabigatran are emerging as an attractive wave of pharmaceutical options for managing hyper-coagulant pathology [41, 42].
Whereas emerging oral anticoagulants are increasingly utilized to prevent and to treat thrombotic disorders including cancer-associated VTE in numerous clinical settings, elevated bleeding events of NOACs (1.904-fold higher hazard ratio) have been noted versus those of LMWH particularly in patients with digestive tract tumors [42]. It thus appears that heparin agents should still be chosen over NOACs for anticoagulant intervention in cases of gastrointestinal neoplasm [42, 43]. Besides, NOACs are known to be the substrates of cyto- chrome P450 C3A4 and P- glycoprotein (P- gp) which signi?cantly contribute to the processing trajectory of pharmacokinetics [43, 44]. Of note, numerous oncologic medications including cytotoxic and targeted compounds have been revealed to either induce or inhibit C3A4 and P-gp [43, 45], raising a challenging issue of drug-drug inter- actions (DDI) to consequently affect ef?cacy and safety of NOACs in the clinic. It is thus plausible that heparin agents represent better options than NOACs for anticoagulant intervention in cancer patients with anti-neoplastic medications, in regard of the minimized DDI. As such, the relevant professional organizations including the American Society of Clinical Oncology and the European Society of Medical Oncology have recommended parenteral anticoagulants to be the ?rst-line medications for the treatment and prevention of VTE in patients with active cancer, whereas NOACs can be considered for early maintenance and long-term therapy in patients with VTE and stable neoplasms being not on anticancer drugs [46].
Perspective
Since being discovered as a naturally-derived polysaccharide compound, heparin has gone through a long journey of life-saving for eight decades, principally serving the anticoagulant purpose in most medical ?elds [1, 3]. Beyond anti-coagulation in recent years, medica- tions of heparin family are noted to confer a broad variety of thera- peutic effects systemically on abortion, sepsis, certain types of in?ammation in several organs, among others [4, 15]. Meanwhile, heparin agents can also substantially contribute to local lesion treat- ment of the patients, including intra-cameral infusion to minimize the in?ammatory response upon cataract surgery [47], and tissue irri- gation of super?cial skin burns to improve the wound healing param- eters [48].
Additionally in interest of medical device practice, a heparin-coated extracorporeal circulating system was noted to down-regulate the in?ammatory signs and bio-markers following cardiopulmonary bypass surgery [49]. In relevance, the heparin- coated ventricular implanting materials were revealed to diminish the risk of HIT comparing to those with systemic heparin application [50]. Impressively, an ex vivo blood cleaning device containing hepa- rin- attached polyethylene beads has just been approved to remove the pathogen and in?ammatory cytokines from the blood circulation of patients with COVID-19 [51].
While contemporary clinical studies have revealed a greater pic- ture regarding the therapeutic potentials of existing heparin medica- tions beyond anti-coagulation, the fundamental innovation of structure-activity relationship is raising a wave of various heparin- like compounds with diminished anticoagulant function to exert novel biologic effects. Of note, these non-anticoagulant heparin ana- logues can confer an optimized therapeutic window, particularly in the medical situations for which anti-coagulation is not needed [4, 9]. Interestingly in this regard, certain naturally derived heparin ana- logues were identi?ed to be capable of inhibiting crucial pathogene- sis pathways of major neuro-degenerative disorders such as Alzheimer’s and Parkinson’s diseases [4, 52].
Furthermore, several non-anticoagulant heparin derivatives resulting from the structural modi?cations have come up with the encouraging performance in clinical studies [9, 53]; for instance, the 2-O, 3-O desulfated heparin CX-01 has been demonstrated to enhance the complete remission and hematological recovery of acute myeloid leukemia with chemo- therapy upon suppressing CXC chemokine CXCL12-mediated cell sequestration within marrow in a pilot clinical investigation [54]; in parallel, the N-acylated glyco-split heparin SST0001(Roneparstat) was identi?ed as a potent inhibitor for heparanase and receptor tyro- sine kinases, thus to confer notable bene?ts of stable disease to advanced multiple myeloma in a phase I clinical trial [53, 55]. Hence, deciphering the iceberg of heparin biology and chemistry has just advanced beneath the surface of water, where novel therapeutic potentials are yet to be translated from the cutting-edge scienti?c discoveries.
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