REVIEW

Advances in Topical Hemostatic Agent Therapies:A Comprehensive Update

Liang Huang . Geoffrey L. Liu . Alan D. Kaye . Henry Liu

Received: July 9, 2020 / Published online: August 19, 2020� The Author(s) 2020

ABSTRACT

Severe hemorrhage causes significant metabolicand cellular dysfunction secondary to deficienttissue perfusion and oxygen delivery. If bleed-ing continues, hemodynamic destabilization,hypoxemia, multiple organ failure, and deathwill occur. Techniques employed to promotehemostasis include surgical suture ligatures,cautery, chemical agents, self-assemblingnanoparticles, and physical methods, like

mechanical pressure. Improved understandingof the natural clotting cascade has allowednewly designed agents to become more targetedfor clinical and military use. Topically-appliedhemostatic agents have enormous clinicalapplications in achieving hemostasis. Thismanuscript describes currently available anddeveloping topical hemostatic materials,including topical active agents, mechanicalagents, synthetic/hemisynthetic hemostaticagents, and external hemostatic dressings forclinical practice.

Keywords: Adhesive; Fibrin; Gelatin;Hemostatic dressings; Hemostats; Sealant;Thrombin; Topical agent

Key Summary Points

Severe hemorrhage causes significanthemodynamic instability, hypoxemia,multiple organ failure, and death.

Perioperative hemostasis techniquesinclude surgical ligatures, cautery,chemical agents, self-assemblingnanoparticles, and topical methods.

Topically-applied hemostatic agentsinclude active agents, mechanical agents,synthetic agents, and external dressings.

Digital Features To view digital features for this articlego to https://doi.org/10.6084/m9.figshare.12767606.

L. HuangDepartment of Anesthesiology, Perioperative andPain Medicine, New York University LangoneSchool of Medicine, New York, USA

G. L. LiuDepartment of Radiology, Ochsner ClinicFoundation, New Orleans, LA, USA

A. D. KayeDepartment of Anesthesiology and Pharmacology,LSU Health Shreveport, Shreveport, LA, USA

A. D. KayeDepartment of Toxicology, and Neurosciences, LSUHealth Shreveport, Shreveport, LA, USA

H. Liu (&)Department of Anesthesiology and PerioperativeMedicine, Milton S. Hershey Medical Center, PennState University School of Medicine, Hershey, PA,USAe-mail: henryliupa@gmail.com

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https://doi.org/10.1007/s12325-020-01467-y

Topical mechanical agents only work inpatients with intact coagulation system.

Appropriate method is determined by thetype of bleeding, the specific etiology, theindividual coagulation status, and theclinician’s experience and preference.

Future hemostatic agents can beengineered towards both primary andsecondary hemostasis mechanisms for anenhanced hemostatic response.

INTRODUCTION

Various factors, such as surgery and trauma, cancause hemorrhage in human beings. Severehemorrhage can potentially induce significantmorbidity and mortality. Hemorrhage ensues ifthe vascular wall integrity gets disrupted [1].The extent of cellular injury and organ dys-function secondary to hemorrhage is a complexprocess dependent upon the duration andseverity of bleeding and hypoperfusion [2].Some of these patients will require allogeneicblood transfusion, which has its own intrinsicrisks, such as infectious disease transmission,allergic reactions, hemolytic reaction, and lunginjury. There are pharmacological and non-pharmacological strategies to facilitatehemostasis. In this review, we summarize whatis new in topical hemostatic agents. When thereis a bleeding, surgeons and other health careproviders can utilize many techniques to stopbleeding. Intraoperatively, surgeons usuallyemploy direct mechanical pressure or compres-sion, thermoelectric cautery, and surgical liga-tion to stop bleeding. In emergency rooms,trauma sites or battlefields, tourniquet and anti-shock trousers are commonly used options.Some new intravenously-administered phar-macological agents and topically-appliedhemostatic agents have been developed in thelast decades aiming to facilitate hemostasis byproviding either intravascular coagulation cas-cade component(s) or extravascular substrate(s).External hemostatic dressings can be used tostop bleeding in emergency situations, such asin combat injury or junctional (groin or

axillary) hemorrhage. Topical hemostats areoften used as adjunctive measures to improvehemostasis during or after surgery [3]. The aimof this manuscript, therefore, is to help allhealthcare providers understand and appropri-ately use these new hemostatic agents inaccordance with clinical settings, patient coag-ulation status, and surgical scenarios.

METHODS

We searched the PubMed Central with ‘‘topicalhemostatic agent’’ inApril 2020,whenwe startedworking on this manuscript, and found 1859items. Since we are aiming for perioperative andtraumatic hemostasis, we did not include dentalliterature or veterinary literature. We summa-rized other pertinent literature and categorizedthe topical hemostatic agents into four majorcategories: topical active agents, topicalmechanical agents, topical synthetic/hemisyn-thetic agents, and external hemostatic dressings.We selected more pertinent literature to validateeach category based on our classifications. Allauthors participated in the preparation of thismanuscript by searching PubMed and selectingliterature, categorizing the topical hemostaticagents, drafting the preliminary version of themanuscript, and revising the manuscript multi-ple times. This article is based on previouslyconducted studies and does not involve anystudies with human participants or animals per-formed by any of the authors. None of theauthors have any conflicting interest from thecommercial products mentioned in this article.

CLASSIFICATIONS OF TOPICALHEMOSTATIC AGENTS

The topically-applied hemostats are categorizedas active or adhesive agents, mechanicalhemostats, synthetic/hemisynthetic sealants,and external dressings. Topical active agents area category which contains fibrinogen andthrombin and works by actively triggering thecoagulation cascade and fibrin clot formation[3, 4]. These agents are especially useful inpatients with coagulation disorders. They are

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usually supplied in flowable liquid formulation(fibrin glues) [5] or in combination with colla-gen (fibrin patch). These agents are sometimesalso called adhesive hemostats due to theirhemostatic and adhesive sealing effect [6].Topical mechanical hemostats contain bovinecollagen-oxidized cellulose, porcine gelatin,and plant-derived polysaccharide spheres.These topically-applied products promote pla-telet activation and aggregation, thus form aclotting matrix at the bleeding site. Thesehemostatic agents are known as passive hemo-stats. The action of these hemostats canenhance the functional coagulation system toachieve hemostasis. Topical synthetic/hemisynthetic sealants are usually supplied inlow-viscosity liquids, which form a solid filmthrough a process of polymerization to connecttissue surfaces [7]. These sealants can be cate-gorized as synthetic sealants, such ascyanoacrylate and polyethylene glycol sealants[8], and semisynthetic, such as glutaraldehydealbumin-derived sealants [9]. Newly developedhemostats with nanotechnology have also beenclinically employed, such as self-assemblingpeptide nanofibers and chitosan nanofibers.

TOPICAL ACTIVE HEMOSTATS

Fibrin-Based Active Adhesives

Adhesive hemostats participate at late stages ofthe coagulation cascade to form a fibrin clot.They are usually made of two essential compo-nents: human purified fibrinogen and throm-bin. Factor XIII, fibronectin, and anti-fibrinolytic agents, such as aprotinin or tranex-amic acid, may be added [8]. Some aprotinin-free and tranexamic acid-free adhesives havebeen developed, since aprotinin may be associ-ated with hypersensitivity and tranexamic acidwith potential neurotoxicity [10, 11]. Thesenewer agents are generally believed to havefewer side effects. Several adhesives come inliquid formulations or as medicated sponge-s/patches (Tachosil, Evarrest). Adhesives aremetabolized by fibrinolysis and phagocytosis,such as endogenous fibrin [1]. Liquid fibrinadhesives supply exogenous fibrinogen and/or

thrombin, thus being particularly effective inachieving hemostasis in congenital or acquiredbleeding disorders (e.g., hemophilia, and anti-platelet or anticoagulation therapies) [11].Reports have indicated that fibrin adhesiveadministration leads to significantly less bloodtransfusion requirements in hemophiliacsundergoing total knee and total hip replace-ment, and facilitate hemostasis and less intra-operative blood loss post-cardiopulmonarybypass [10, 11]. The effectiveness of liquid fibrinadhesives in achieving hemostasis in polyte-trafluoroethylene arterial anastomosis bleedinghas been proved [10, 11]. Fibrin adhesive effi-cacy as a hemostat has been demonstrated inmore than 20 multicenter clinical trials,demonstrating benefits in abdominal [10], car-diac [1], pediatric extracorporeal oxygenationcannulation, liver resection, peripheral vascu-lar, skin graft donor harvest site, and total hip orknee arthroplasty [12].

Liquid fibrin adhesives can be used aftersurgical hemostasis to manage residual oozing,especially on broad exposed tissue surfaces andvascular anastomoses. Foam fibrin adhesives arebetter in irregular and deep surfaces. Liquidfibrin adhesives have both fibrinogen andthrombin. High fibrinogen concentration willenhance clot strength, whereas high thrombinconcentration will enhance clotting time. Pla-telet-rich or platelet-poor plasma may be addedwith calcium, and any one of the three free-standing thrombin to manufacture fibrin sea-lant. Platelet-rich fibrin sealant has a lowerfibrinogen concentration with lower mechani-cal strength, but the platelet activity offersclinical value [13]. Combinations of separateadditional absorbable gelatin sponges with liq-uid fibrin sealants allow pressure application forseveral minutes [4].

Any product containing thrombin shouldnever be injected intravascularly because of therisk of thrombosis, hypotension, and death.Gas-driven sprayers at higher pressures ([ 20 to25 psi) or at shorter distances (\10 to 15 cm)are potentially associated with air embolism [5].Adhesives containing tranexamic acid must notbe used if cerebrospinal fluid leakage or duramater tear are present because of neurotoxicity.Tranexamic acid-induced hyperexcitability and

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convulsions via GABA-mediated inhibition hasbeen reported [14]. While HIV and hepatitistransmission appear unlikely, parvovirus B19transmission by fibrin sealant has been reported[15]. Poor wound healing and infection mayoccur with excess use. Hypersensitivity, edema,and coagulopathy are potential adverse effectswhen using aprotinin (Tisseel), bovine (Vitagel),or equine products (Tachosil).

Application of these liquid fibrin adhesiveswithout a component of an antifibrinolytic,bovine collagen, and thrombin, or an equinecollagen patch, may minimize the above-men-tioned risks (Evicel). The efficacy of fibrin sea-lant as a hemostat has been shown by multipleclinical investigations, which demonstratedsignificant benefits in various surgical proce-dures [11, 16, 17]. However, a significantimpediment to the use of fibrin adhesives hasbeen the challenges of preparing the liq-uid products. Significant efforts have alreadybeen made to simplify liquid formulationpreparations. After warming, the liquid must beused within 4 h by either dripping or sprayingwith and without compressed air propulsion inopen as well as laparoscopic and thoracoscopicprocedures. If the package is unopened, thepouch may be stored at room temperature foruse within 24–48 h. Another brand of liquidfibrin adhesive, such as Evicel by Ethicon/Johnson & Johnson, Somerville, NJ, USA, can bethawed and used in 24 h at room temperature.It can even be stored in a refrigerator for up to1 month.

Fibrin adhesives in liquid formulation arealso effective to improve the watertight closureof the dural suture line for the prevention ofcerebrospinal fluid leak [14]. However, cautionsare warranted in using fibrin adhesive contain-ing tranexamic acid in a neurosurgical settingbecause tranexamic acid may cause hyperex-citability and convulsions by blockade of GABA-mediated inhibition [14]. However, evidenceregarding the efficacy of liquid fibrin adhesivesin preventing pancreatic, biliary, and intestinaland air leakages is still controversial [4, 18]. Inthoracic settings, the effect of liquid fibrinadhesive to prevent or treat air leaks is notsignificant.

Fibrin Patch

Fibrin patch adhesives are usually provided as apatch (TachoSil, PGA-felt, Fibrin Pad). Fibrinpatches are effective in ongoing severe hemor-rhage as well as preventing oozing or spurting,since they prevent the ‘‘streaming effect’’ ofblood, and thus are good for controlling resid-ual bleeding on vascular anastomosis. They areroutinely used by some surgeons in preventingpancreatic, biliary, and urinary leakages,although it is not recommended because of theweak evidence [4, 18, 19].

The advantage of a fibrin patch comparedwith liquid formulations is the mechanicalsupport provided by collagen or oxidized cel-lulose/polyglactin 910 matrix. This allows bet-ter adherence to bleeding tissues/materials,preventing the ‘‘streaming effect’’ observed withfluid adhesives. The sponge formulation addi-tionally allows pressure application at activebleeding sites, which can potentially be moreadvantageous in certain clinical scenarios. Adisadvantage is the high cost of the fibrin patch.The fibrin patch has also been demonstratedefficacious in some clinical trials in cardiacsurgical procedures, nephrectomy, and liverresection [10–12].

Some fibrin patches come in a pouch (Ta-choSil) stored at room temperature and usedimmediately in the sterile field. TachoSil is anequine collagen patch coated with coagulationfactors, human fibrinogen, and human throm-bin. Fibrin Pad and PGA-felt are absorbablehemostats made with polyglactin (PG 910),oxidized regenerated cellulose (ORC), throm-bin, and fibrinogen [20]. Reports supported itsuse in bleeding during abdominal, retroperi-toneal, and pelvic surgical procedures[11, 12, 20]. TachoSil in preventing air leaksafter thoracic surgery and bile leaks after pan-creatic procedure are controversial [6, 21].

Thrombin-Based Hemostats

These topical active agents include throm-bin derived from different sources: humanpooled plasma, bovine thrombin, and recom-binant thrombin. Thrombin facilitates the

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conversion of fibrinogen to fibrin, leading to afaster thrombus formation [22]. Both recombi-nant human thrombin and bovine thrombincan be stored at room temperature in powderform; thus, they need to be reconstituted withsaline solution before use, with a shelf life of8–24 h after reconstitution [4]. Human pooledplasma preparation is provided as a frozen liq-uid which can be kept at room temperature forup to 24 h after thawing. The efficacy ofthrombin product can be enhanced by a por-cine gelatin sponge which enables direct pres-sure application [22]. A meta-analysis indicatedthat thrombin-based hemostatic agent appliedbefore wound closure decreased postoperativeblood loss and transfusion rate without elevatedrisk of infection, deep vein thrombosis, or othercomplications [4]. Fu et al. revealed that athrombin-based hemostatic agent is effective inprimary total knee arthroplasty [23]. However,the utility of thrombin-based hemostatic agentsto reduce transfusions remains controversial[23].

Thrombin collected from pooled humanplasma risks transmission of viral disease (e.g.,HIV, hepatitis, parvovirus B19) or prion disease(e.g., Creutzfeldt–Jakob). There has not beenreported for HIV or hepatitis transmission bysealants derived from pooled human plasma forover 20 years. Recombinant human thrombinsolves this safety issue. However, the recombi-nant product may be theoretically associatedwith allergic responses to the cell lines (ham-ster) and proteases (reptile) used in its manu-facturing process. Rarer complications caninclude thrombosis of cardiopulmonary bypassor cell saver circuits resulting from thrombin’scompetitive inhibition of the heparin used toanticoagulate the system.

Topical Combined Flowable Gelatinand Thrombin-Based Hemostats

Bovine or porcine gelatin matrix may be com-bined with human pooled plasma thrombin.Their efficacy can be enhanced with combina-tion of a porcine gelatin sponge, which facili-tates direct pressure application. Topical gelatinand thrombin-based hemostats include Surgiflo

(Johnson & Johnson) and Floseal (BaxterHealthcare). Both Surgiflo and Floseal areabsorbable gelatin-based products that formhemostatic matrices. They are indicated asadjuncts to hemostasis when control of bleed-ing by suture, ligature, or cautery is inadequateor impractical.

The efficacy of these combined agents isamong the best of any category of hemostats.Floseal was used locally to reduce blood loss ingynecological, cardiac, knee, and general sur-gery [4]. Surgiflo use may have some cost sav-ings for flowable products without difference inclinical outcomes when compared with Floseal[24]. A systematic review demonstrated thatgelatin–thrombin matrix sealant was associatedwith a significantly higher rate and shorter timeof successful hemostasis in different surgicalfields compared with other alternatives [25].Several multicenter prospective randomizedtrials documented efficacy across multiple spe-cialties, with some superiority of products con-taining bovine thrombin over a porcine gelatinsponge [22]. Other recent single-centerprospective randomized studies for adenoidec-tomy, acute anterior epistaxis, adenotonsillec-tomy, total thyroidectomy, and cardiacprocedures have revealed the significant bene-fits of using bovine gelatin matrix and throm-bin in achieving more rapid hemostasis [26].

Cost savings may be achieved by combiningthe porcine gelatin matrix with any of thefreestanding thrombin products. To obtain thebest hemostatic effect, it is important to repro-ducibly create this material by adding theappropriate volume of the liquid thrombin(usually 3–5 mL) to the porcine gelatin matrixso that the final material is neither too dilutednor too thick. Related to swelling and followingpotential induction of a compression of othernearby anatomic structures, the minimalamount of gelatin agent should be used toachieve hemostasis. Risks for this gelatin andthrombin combined product are matrix swel-ling and potential subsequent infection. Otherrisks are similar with those of both themechanical and active hemostat agents dis-cussed above.

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TOPICAL MECHANICALHEMOSTATS

The topical mechanical products contain oxi-dized regenrated cellulose (ORC)-based, gela-tins, collagen-based agents, andpolysaccharides. Mechanical hemostats are onlyappropriate for patients with a functioningcoagulation system to improve control ofresidual oozing [27]. Mechanical hemostatsabsorb fluid several times of their own weight.They also promote platelet activation andaggregation, produce a matrix at the site ofbleeding, and activate the extrinsic clottingpathway. These agents can be used as first-lineagents because of their immediate availabilityand cost-effectiveness [27]. In the absence ofplasma constituents, especially factors VIII andXII, they usually fail to induce adequatehemostasis [27].

The mechanical materials are easy to use andstorable at room temperature. The porcinegelatin and bovine collagen classes are manu-factured in sponges, sheets, and powders. TheORC-based material is provided in single ormultiple woven sheets, or fibrillar with cottonpuff-like consistency. The polysaccharidespheres are usually supplied in two differentproduct volumes in blunt tip or bellows appli-cators. All mechanical agents perform bestwhen placed with manual pressure.

Oxidized Cellulose

Cellulose is a homopolysaccharide produced bypolymerization of glucopyranose through b-glucosidic bonds. Oxidized cellulose can beeither regenerated (ORC, organized fibers areformed before oxidation) or non-regenerated(ONRC, with unorganized fibers prior to oxida-tion). Oxidized cellulose is known for its ease ofuse, favorable biocompatibility, and bactericidalproperties. Direct pressure applied at the hem-orrhage site is required to optimize efficacy, andoxidized cellulose may be used as an adjunct togauze packing [28].

ONRC-based topical hemostats are seem-ingly more effective, but unhandy comparedwith ORC-based topical hemostats. Hemostasis

at 90-s post-application was 97.5% for ONRCand 70% for ORC. Oxidized cellulose-basedtopical hemostats are unable to control biliary,urinary, pancreatic, and air leakage. As anadjunct to packing to control bleeding fromparenchymal injuries, these topical hemostatscarry the risk of ischemia due to compression orlocal inflammatory reaction. They should notbe left in place in proximity to nerves, ureters,or intestinal and vascular structures. The addi-tional benefit of ORC (Surgicel, Surgicel Fibril-lar, Nu-Knit) may be its bactericidal effect bycreating an acidic environment [29]. If possible,mechanical agents should be removed to reducethe risk of infection. Although oxidized cellu-lose can be absorbed in 2–5 weeks, excessmaterial may cause granulation formationwithout bio-degradation, complicating radio-logical and clinical diagnosis of abscess, resid-ual/recurrent tumors, and granuloma. Pooradhesion to tissue in wet environments maypotentially complicate deployment. When oxi-dized cellulose is used in proximity to nervestructure in areas of bony confinement (e.g.,foramina, spinal cord, optic chiasm), it maylead to nerve damage [30]. Surgicel Fibrillarapplied to epidural venous plexus led to swel-ling and significant mass effect causing rapidneurological deterioration. Moreover, whenORC has been applied as a wrap during vascularor urologic procedures, a stenotic effect wasreported [30]. Thus, it is important to be cau-tious when applying it tightly as a wrappingmaterial.

Gelatin-Based Mechanical Hemostats

Gelatin-based agents are mechanical hemostatsprepared from porcine or bovine skin-derivedgelatin, acting at the end stage of the coagula-tion cascade by facilitating fibrin formation [4].They provide a mechanical matrix for clot toadhere and are reabsorbable within 4–6 weeks.Caution should be used because gelatin swellingcould result in compression and necrosis ofsurrounding structures, especially within bonyspaces [4]. Gelfoam paste is associated with lessinhibition of bone healing and less infectionthan bone wax. Gelfoam swells more than

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collagen or cellulose products, increasing com-pressive complications. Penetrating traumathrough solid organs (e.g., hepatic gunshotwounds) can be treated with a hemostatic plugcomposed of gelatin foam wrapped in oxidizedcellulose inserted into the traumatic cavity.Recent novel hemostatic agents induce in situgel formation via microbial transglutaminase tocross-link gelatin, which showed similar hemo-static effect with stronger adhesion and elastic-ity in rat liver models compared to Surgiflo [31].

Bovine Collagen Based MechanicalHemostats

Bovine collagen-based products provide aphysical matrix that stimulates clot formationby promoting platelet aggregation and clottingfactor release. Microfibrillar collagen is derivedfrom bovine corium and supplied in powder,nonwoven sheet, sponge, and pad forms (e.g.,Avitene Ultrafoam, EndoAvitene, AviteneUltraWrap, Helitene, Helistat). Collagen pro-vides a large surface area to allow platelets toactivate, aggregate, and adhere to wide-areaparenchymal hemorrhage. Thus, it is less effec-tive in patients with severe thrombocytopeniabut successfully achieves hemostasis even in thesetting of heparinization. Its use was reported tohave improved blood loss and postoperativedrainage volume compared with gelatin-basedproducts during spinal fusion surgery [32].

It usually does not swell significantly andgets absorbed in less than 8 weeks. Cautionshould be used during blood-saving device usebecause bovine collagen-based agents can nor-mally pass through their filters; thus, bloodcollected from operative sites where collagenwas used should not be given back to thepatient [3, 32].

Polysaccharide-Based MechanicalHemostats

Microporous polysaccharide hemospheresenhance endogenous clotting processes byabsorbing water and concentrating platelets andclotting proteins [7]. Their application leads toreduction in hemostasis time, postoperative

chest drain output, and transfusion require-ments during cardiothoracic surgery [7]. Theyare completely re-absorbable, thus limitinginfection or granuloma formation [7]. Limitedneurotoxicity compared to ORC improves safetyand efficacy in the brain hemorrhage model.Polysaccharide spheres also demonstrate supe-riority over ORC in animal models of partialnephrectomy. They may be equally effective asflowable hemostats in endoscopic sinus surgery.There is embolic risk if accidentally injectedinto blood vessels. No more than 50 g of thisproduct should be used in diabetic patients dueto the product’s glucose load [7].

TOPICAL SYNTHETIC HEMOSTATICAGENTS

Cyanoacrylates

Cyanoacrylates form polymers from liquidmonomers in the presence of water to glueadjacent surfaces together. Octyl-2-cyanoacry-late (such as Dermabond) was initially devel-oped to repair combat wounds, and theembolization of portosystemic venous shunts,pseudoaneurysm anastomoses, arteriovenousfistulas, vascular reconstructions, and cardiacsurgery [33–35]. Butyl-2-cyanoacrylate wasdeveloped in Asia for the embolization of gastricand esophageal varices by direct injection intothe bleeding vessels. Cyanoacrylates need nofollow-up visit for suture removal and provide awaterproof barrier. Octyl-2-cyanoacrylate doesnot show any difference in the incidence ofinfection, dehiscence, or cosmetic appearancewhen repairing lacerations as compared tostandard sutures, staples, or adhesive strips[34, 35]. It is safe to use cyanoacrylates forwounds, lacerations, and minimal incisions(e.g., laparoscopy).

Antibiotic ointment or petroleum jellyshould not be concomitantly applied for 7 daysto avoid polymer breakdown. It cannot be usedon avulsed tissues, joints, hands, feet, ormucosal surfaces. Use around vascular anasto-moses is not recommended due to lack of largeclinical trials. There is embolic risk if acciden-tally injected into blood vessels. There is

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toxicity evident from cyanoacrylates degrada-tion products, namely formaldehyde andcyanoacetate.

Polyethylene Glycol Hydrogel

Polyethylene glycol polymer (such as CoSeal)can be sprayed on tissue to form a hydrogelmatrix with contacting tissue. CoSeal wasreported to be noninferior to Gelfoam/throm-bin during aortic aneurysm grafting, infra-in-guinal revascularization, and dialysis shuntcreation. This cross-linked network functions asa sealant as well as a barrier to adhesion for-mation. The reaction is not exothermic and isnot prone to inflammation or infection. It hasbeen shown to decrease pericardial adhesionfrom multiple sternotomies in children withcongenital heart defects [36].

CoSeal continues to swell the first day afterapplication, and should be avoided when com-pressing surrounding structures is an antici-pated potential harm. CoSeal has been reportedto adhere poorly to renal parenchyma [36].

Glutaraldehyde Cross-Linked Albumin

Glutaraldehyde covalently cross-links lysineresidues of albumin to form a tough scaffold.BioGlue is a 10% glutaraldehyde and 45%bovine serum albumin loaded into a single-nozzle dispenser that mixes components atapplication. BioGlue can adhere to syntheticgraft materials. Thus, it has increased roles incardiac graft and vascular anastomotic surgery[37, 38]. BioGlue and bovine pericardium with apolytetrafluoroethylene patch have been usedto repair atrioventricular disruption and spleniclacerations [38, 39]. Glutaraldehyde is a toxicfixative, and its cross-linking proteins kills cellsin the application field and should be used withcaution. It is often avoided in young patients forfear of compromising tissue growth. BioGluecan react with tissue to contribute to stenosis[37].

Synthetic Topical HemostaticNanomolecules

A model of self-assembling fibers comprised ofnanofabricated chitosan fibers shows hemo-static action possibly due to the cation proper-ties of chitosan and nonspecific cell membranebinding to improve platelet aggregation overtraditional chitosan sponge. Mesh structureshave achieved hemostasis in a rabbit livermodel [39, 40]. Another topical hemostaticemployed narrow-sized, rapid-swelling cationichydrogel particlea based on N-(3-aminopropyl)methacrylamide with significant blood lossreduction in a rat liver and tail amputationmodel [40, 41].

EXTERNAL HEMOSTATICDRESSINGS

External hemostatic dressings were invented tostop severe hemorrhage in the battlefield due tolack of surgical care in an urgent scenario. Sev-ere hemorrhage causes a high mortality rate inpotentially survivable casualties in today’s bat-tlefields. Hemostatic dressings are used forexternal hemorrhage at junctional sites (e.g.,axilla, groin) when tourniquets have failed toachieve hemostasis. They are grouped as factorconcentrators (zeolite) [41], procoagulants(kaolin), and mucoadhesive (chitin) [41, 42].These products come as granules, powders, orbandages, and the dressings are commonly usedto increase local concentrations of platelets,clotting factors, and erythrocytes at the wound.Military and civilian groups recommend exter-nal hemostatic agents for prehospital control ofsevere hemorrhage uncontrollable with atourniquet. Significant improvements inhemostatic dressings for prehospital care havebeen introduced, and many tactical and con-ventional care guidelines have been upgraded.

Fibrinogen-Based Hemostatic Dressing

These are attractive alternatives to currentagents because of their ability to form clots inthe absence of host coagulation proteins or in

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the presence of factors such as hypothermiathat contribute to a coagulopathic state [43]. Anexample of fibrinogen-based dressing is SalmonThrombin-Fibrinogen, which can be used foropen wounds, and the clot formation effect isnot hindered by hypothermia.

Zeolites-Based hemostatic dressing

Zeolites are microporous crystalline alumi-nosilicate minerals found in nature. Theirstructure is based on tetrahedral units of[SiO4]

4-and [AlO4]5- which are coordinated

through shared oxygen atoms. Zeolites havecage-like cavities which accommodate bothwater molecules and positively charged ionssuch as Ca2? and Na?. The cations canexchange with other cations in physiologicalsolutions [44]. Zeolites contain a 3D structurewhich helps the movement of water moleculesin and out while remaining rigid. Zeolite ismarketed as QuikClot granular powder (Quik-Clot; Z-Medica, Wallingford, CT, USA) andAdvanced Clotting Sponge (ACS; Z-Medica).Case studies reported QuikClot utilization toachieve hemostasis in trauma victim andpatient with uncontrollable pelvic bleeding[45].

QuikClot increases the temperature at boththe wound surface and the surrounding tissuecausing potential thermal injury and necrosis.Difficulty in removing QuikClot once at the siteof bleeding is an additional concern. QuikClotwas removed from the military inventory in2008, but a newer generation of zeolite hemo-stats, such as ACS and ACS Plus (ACS?), wereapproved by FDA for external use. ACS? pro-duced minimum exothermic reaction and waseasy to use and remove. The product is inef-fective against arterial bleeding, and wasreplaced by second-generation dressings (e.g.,clay materials) [46].

Clay-Based Hemostatic Agents

Clay minerals consist of tetrahedral silicate andoctahedral aluminate sheets. Based on the ratioof tetrahedral to octahedral sheets, these clayscan be classified into two groups, 1:1 and 2:1

[47]. Clay 1:1 is comprised of one silica tetra-hedral layer to one aluminum octahedral layer(e.g., kaolin). Clay 2:1 consists of one octahe-dral sheet between two tetrahedral sheets (e.g.,smectite). Clays possess thermal stability, smallparticle size, large surface area, significant sur-face charge, and ion exchange capability. Zeo-lites are similar to clay minerals (both arealuminosilicates), but they are structurally dif-ferent. Clay minerals have a layered crystallinestructure that can shrink and swell when wateris eliminated and absorbed between the layers[47].

Kaolin GroupKaolin is a 1:1 clay made of the mineral kaoli-nite. Its absorption property and surface chargeare low. It is associated with low surface areaand substitution of other elements (e.g., ferriciron and titanium for aluminum and silicon)[48]. Kaolin in contact with plasma can lead tointrinsic coagulation cascade activation. Thepolar aluminosilicate framework of kaolin pro-vides a surface for contact activation of theintrinsic pathway. Kaolin’s net negative surfacecharge is also involved in triggering the intrin-sic pathway by auto-catalytic activation ofcoagulation factors XII and XI, prekallikrein,and cofactor HWK–kininogen. Kaolin has beenmarketed under various names includingQuikClot Combat Gauze, QuikClot CombatGauze XL, QuikClot Combat Gauze Trauma Padand QuikClot Interventional. The materialsreportedly expedite hemostasis without thecomplications related to previously mentionedQuikClot products. Kaolin-impregnated gauzecontinues to be used as the primary hemostaticdressing by the US military force [43]. QuikClotCombat Gauze may be justified as the optimalagent due to the volume of clinical data onprehospital care of severe hemorrhage [48].

Smectite GroupSmectite clays are 2:1 phyllosilicates consistingof one octahedral sheet between two tetrahedralsheets. Smectite product displays a large surfacearea, a large cation exchange capacity, and ahigh viscosity. Smectite can also absorb largeamounts of water. In comparison to kaolin,

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smectite demonstrates higher plasticity,absorption, swelling, and viscosity. Smectitealso has a negative surface charge that activatesthe intrinsic coagulation pathway. AlthoughWoundStat was reported as an effective hemo-static offering improved survival, it can causesignificant inflammatory response, neurovas-cular changes, and necrosis. WoundStatremoval also requires extensive and meticulousdebridement. WoundStat utilization was haltedin 2009 by the U.S. Army while the FDA rec-ommended removal from the United Statesmarket [49].

Polysaccharide and Polyelectrolyte

Some third-generation chitosan-based dressingshave recently been introduced. Both chitin andits deacetylated form, chitosan, have hemo-static properties. For chitin dressings, theseproperties are believed to result from vasocon-striction and mobilization of erythrocytes,clotting factors, and platelets to the site of theinjury. These induce hemostasis through directinteraction with erythrocytes, and are thereforeideal dressings to stop bleeding in coagulo-pathic patients because their hemostasis mech-anism is not dependent on host coagulationpathways. Chitin dressings, such as the rapiddeployment hemostat, are effective in treatingminor wounds and have shown efficacy inswine models of splenic lacerations, being fasterthan with fibrin glue [50]. Although the firstgeneration of rapid deployment hemostats wasineffective in controlling severe bleeding, newermodified formulations are effective in control-ling both venous and arterial bleedings, even inpatients with coagulopathy. These dressings arebelieved to be the most expensive among thehemostatic agents currently available on themarket [51]

Chitosan dressing (as HemCon) containschitosan from shellfish, so it is contra-indicatedin patients with shellfish allergy. However,testing showed no adverse reaction duringbandage challenges in shellfish-allergic patients[50]. As a popular biopolymer for the develop-ment of drug delivery systems, chitosan is aunique positively charged polysaccharide. It

possesses excellent biocompatibility, highbiodegradability, little toxicity, and low pro-duction cost. Its acidic pH allows it to disruptthe membranes of Gram-negative bacteria,resulting in its natural highly microbicidalproperties [50].

Delivery systems are fabricated from naturalbiopolymer-based polyelectrolyte complexes(PEC), formed by electrostatic interactionsbetween two oppositely charged biopolymers.These PECs using carboxymethyl starch andchitosan oligosaccharide were evaluated inrabbit hepatic hemorrhage models. The com-plexes could significantly activate and acceler-ate the coagulation cascade and showed someantimicrobial activity against S. aureus. More-over, the PEC displayed good tissue compati-bility in a rabbit liver model [52]. Variouschitosan-based PEC drug delivery systems havebeen developed for different specific applica-tions, such as nanoparticles, microparticles,beads, tablets, gels, films, and membranes.Chitosan dressings appear to function throughmechanically sealing wounds and adhering tosurrounding tissue. HemCon is currently usedby the US forces and achieved successfulhemostasis in military and civilian settings [53].HemCon needs hands-on training. The efficacyof HemCon depends on the bandage, adheringwell. This may prove difficult in emergenciesand requires training and experience.

Applications of hemostatic agents canpotentially significantly reduce morbidity andmortality from hemorrhage. A variety of topicalagents and external dressings are available forclinical and military use. All currently availabletopical hemostatic agents are summarized inTable 1. The effects of topical hemostatic agentson coagulation cascade was depicted in Fig. 1.The type of bleeding, the specific mechanism ofetiology, the patient’s individual coagulationstatus, and the clinician’s preference and expe-rience may determine which agent or a combi-nation of techniques to be used. Currentmethods of resolving perioperative bleeding orafter trauma include topical hemostats andtransfusion of blood products or recombinantclotting factors to restore hemostatic function,in addition to surgical hemostasis.

Adv Ther (2020) 37:4132–4148 4141

Table

1Topicalhemostaticagents:classification,

mechanism

s,products,and

clinicalfeatures

Category

Class

Mechanism

(s)of

action

Brand

names

Clin

ical

feature

Topicalactive

agent

Fibrin-based

active

adhesives

andfibrinpatch

Containsfibrinogenand/or

thrombin,

fibrin

Trigger

thecoagulationcascadeandfibrinclot

form

ationactively

Rem

oval:metabolized

byfibrinolysisandphagocytosis

Tiesseel,Evicel,Tachosil

Congenitalor

acquired

bleeding

disorders;

coagulationdisorders

Not

good

forpreventing

pancreatic,b

iliary,

urinary,andintestinal

leakages

Throm

bin-basedtopical

hemostats

Throm

binJM

I,

Evithrom

Com

binedflowablegelatin

andthrombinor

collagen-

basedtopicalhemostats

Surgiflo,Floseal,Vitagel,

Tachosil

Topical

mechanical

hemostats

Oxidizedcellulose

Contain

bovine

collagen,

oxidized

cellulose,o

rgelatin,

plant-derivedpolysaccharide

spheres

Provideaclotting

matrix

Prom

oteplatelet

activation

andaggregation

Rem

oval:absorbableby

human

body

Surgicel,N

u-Knit,

SurgicelFibrillar

Onlyindicatedforpatients

withafunctioning

coagulationsystem

Lesseffectivein

patient

withthrombocytopenia;

Gelatin-based

mechanical

hemostats

Gelfilm,

surgifo

am,Gelfoam

Bovinecollagen-based

mechanicalhemostats

Avitene,A

vitene,

Ultrafoam,

UltraW

rap,

Instat,

Helitene,Helistat

Polysaccharide-based

mechanicalhemostats

Arista,Hem

ostase,

Vitasure

Topicalsynthetic/

hemisynthetic

hemostatic

agents

Cyanoacrylates

Form

asolid

film

polymerizationto

conn

ecttissue

surfaces

Dermabond

Dermabondforopen

wound

bond

ing

Butyl-2-cyanoacrylate

for

intravenousem

bolization;

Polyethylene

glycol

hydrogel

Sprayedon

tissue

toform

ahydrogelmatrix

CoSeal

Vascularanastomosis

bleeding

Glutaraldehydecross-lin

ked

albumin

Chemicalreaction

betweenaldehydesandam

ines,

provided

bythee-am

inogroups

oflysine

residues

in

albumin

andextracellularmatrixin

thetissues

BioGlue

Tissuelaceration

or

vascular

graftbleeding

Synthetictopicalh

emostatic

nanomolecules

Self-assemblingpeptideor

chitosan

nanofibers

facilitatingcoagulation

CaM

XS

Especially

suitablefor

bleeding

inbone

defect

4142 Adv Ther (2020) 37:4132–4148

Table

1continued

Category

Class

Mechanism

(s)of

action

Brand

names

Clin

ical

feature

External

hemostatic

dressings

Fibrinogen-based

hemostaticdressings

Externalmechanicalpressure

Increase

localconcentrations

ofplatelets,clotting

factors,anderythrocytes

atthewound

Salmon

thrombin-

fibrinogen(STF)

Clotform

ationnot

hind

ered

byhypothermia

Zeolites

Actsas

amolecular

sieveandrapidlyadsorbswater

Zeolitereaction

withbloodisexotherm

ic

QuikC

lot,Advanced

ClottingSponge

Traum

a-inducedsevere

bleeding,rem

oved

from

marketin

2008

Clay-based

hemostatic

agents

Kaolin

group

Kaolin

activatesfactor

XII

Absorbwater

QuikC

lotCom

bat

Gauze,T

raum

aPad,

Traum

aticopen

wound

Smectite

group

Wound

Stat

Celox

Gauze

(CEG)

Wound

Stat

utilization

was

haltedin

2009

Polysaccharide

and

Polyelectrolyte

3rdgeneration

chitosan-based

dressingsmechanically

sealingwound

s

Hem

Con

Traum

ableeding

Adv Ther (2020) 37:4132–4148 4143

SUMMARY

Topically-applied hemostatic agents are usuallyapplied as a supplemental strategy for surgicalhemostasis and/or pharmacological hemostaticmedications. Their utilization is often limited totreating accessible locations in the body. Topi-cal active agents contain fibrinogen and/orthrombin and fibrin, which actively trigger thecoagulation cascade and fibrin clot formation;thus, they are good for congenital or acquiredbleeding disorders and coagulation abnormali-ties. Topical mechanical hemostats containoxidized cellulose, or collagen, gelatin, or plant-derived polysaccharide spheres, which provide aclotting matrix, and potentially promote plate-let activation and aggregation. However, topicalmechanical hemostats may not be suitable forpancreatic, biliary, urinary, and intestinal leak-ages. Topical synthetic/hemisynthetic hemo-static agents usually form, either forming apolymerized solid film or a matrix to blockbleeding. External hemostatic dressings work by

external mechanical pressure and/or increasedlocal concentrations of local platelet, clottingfactor, or absorbing water. These agents areindicated for severe traumatic hemorrhage, orlocations not easy for surgical hemostasis. Bio-logically-derived products can be effective buthave many limitations, such as short shelf life,risk of disease transmission, involved manufac-turing processes, and protentional compressionof surrounding tissues. Tranexamic acid-con-taining hemostatic agents may have neurotox-icity, so should be avoided for application closeto nerve tissue. Glutaraldehyde is a toxic fixa-tive which may cross-link proteins and kill thecells in the neighboring tissue, and thus shouldbe used with caution. Hemostatic externaldressings, such as minerals and polysaccharidestogether with mechanical compression, areeffective in controlling severe bleeding. In thefuture, hemostatic agents can be engineeredtowards involving both primary and secondaryhemostasis mechanisms for enhanced hemo-static responses.

Fig. 1 Effects of topical hemostatic agents on coagulation cascade

4144 Adv Ther (2020) 37:4132–4148

ACKNOWLEDGEMENTS

Funding. No funding or sponsorship wasreceived for the publication of this article.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Liang Huang, Geoffrey Liu,Alan Kaye and Henry Liu have no conflict ofpersonal, financial, commercial and academicinterests.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Data Availability. The datasets generatedduring and/or analyzed during the currentstudy are available from the correspondingauthor on reasonable request.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

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