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  first 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   signifi-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].

E-mail address: daohong@hotmail.com https://doi.org/10.1016/j.retram.2021.103300

2452-3186/© 2021 Elsevier Masson SAS. All rights reserved.

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  fields,  inspired by the  insights from advanced polysaccharide science and  contemporary disease biology  [1, 4, 9]. Herein,  this  article thus highlights an emerging pro- file   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 efficacy,  heparin can also orchestrate an extra-array  of biological effects  including anti-inflammation/anti-complement, vas- cular  endothelial protection, trophoblast promotion and  apoptotic inhibition [9, 10]. As such,  this  functional profile 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 profile of heparin products.

standardized  dosage until   abortion or  delivery has  been demon- strated to  significantly  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 inflammation

Heparin medicine can confer certain anti-inflammatory  effects through several mechanisms of actions such  as regulating cytokine/ chemokine expression, suppressing immune cell infiltration and  par- ticularly minimizing obstructive mucous secretion [3, 15]. These inflammatory-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/ fibrinogen 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  efficacy 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 inflammation.

Renal disease

Physiologically, the  glomerular capillary filtration membrane con- trols  the  macro-molecule filtration 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 significantly 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 significant 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 profile 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 efficacious means for controlling the  etiological microorganisms, an official  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 inflammatory 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 profile 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   significantly  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) significantly reduced 28-day mor- tality  (from  38% to 30%) in the  patients with sepsis or severe sepsis [26].  Moreover, while conferring a  better survival benefit 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 inflammatory 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 profile [30].

Pancreatitis

As a complicated inflammatory condition, acute pancreatitis (AP) presents various degrees of clinical  severity, and  severe AP is associ- ated  high  mortality due  to systemic pathology without specific treat- ments.  While   AP  pathogenesis  is  yet   to  be  well   delineated, the comprehensive interactions has  been noted between inflammatory factors,  pro-coagulant pathways and  vascular endothelial injury [31,32]. To cope  with these multidimensional challenges, the  functional profile of heparin can in this  case  confer an exceptional set  of thera- peutic efficacy covering anti-inflammation, 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 significantly 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 efficacious 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-inflammatory 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 efficacy against malignancies have  so far  been controversial. Although LMWH was  revealed to  significantly 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 benefit 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 significantly 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  efficacy 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 first-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 fields [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 inflammation 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 inflammatory response upon cataract surgery [47], and tissue irri- gation of superficial 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  inflammatory 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  inflammatory 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 identified 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 modifications 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 identified as a potent inhibitor for heparanase and receptor tyro- sine   kinases, thus  to  confer notable benefits  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 scientific discoveries.