Mechanism of action of topical hemostatic and adhesive tissue agents

A wide variety of topical hemostatic agents, sealants, and tissue adhesives is currently available. Knowledge of the mechanism of action of each of them is essential for choosing the ideal agent for each type of hemorrhage. Hemostatic agents are divided into two groups according to mechanism of action: a) active, which activates platelets b) passive or mechanical, which promotes blood absorption, increase in volume, and creates pressure on the site of the bleeding. Active agents can be used in coagulopathies and use human plasma components like thrombin and fibrin. As such, they can transmit viral diseases and are more expensive. Mechanical agents, because they stop the bleeding due to volume increase cannot be used in confined areas. This article considers the characteristics of various hemostatic agents.


INTRODUCTION
Proper control of bleeding during surgery is paramount to good per and postoperative evolution.Despite the significant advances in surgical techniques, excessive bleeding remains a problem and is the most serious complication associated with surgical procedures. 1 Excessive bleeding is related to patients characteristics, iatrogenic phenomena, and specific procedures. 1 Patient-related variables are abnormalities in blood coagulation, use of anticoagulants, and other diseases, such as diabetes mellitus, systemic arterial hypertension and renal failure.Eventual iatrogenic phenom-

Mecanismo de ação dos agentes hemostáticos locais e adesivos tissulares
Marcus Vinicius Henriques de Carvalho 1 , Evaldo Marchi 2 1 Cardiac Surgeon.Master and Doctor of Surgery.Adjunct Professor of surgical technique, Faculdade de Medicina de Jundiaí.Jundiaí, SP -Brazil. 2 Thoracic Surgeon.Physician and Full Professor of Surgery.Associate Professor of thoracic surgery, Faculdade de Medicina de Jundiai.Jundiaí, SP -Brazil.Mechanism of action of topical hemostatic and adhesive tissue agents reactions called "coagulation cascade".The coagulation factors that play a major role in this cascade are X and V and thrombin.Factor V has a crucial role since it makes the extrinsic and intrinsic pathways of coagulation converge and has prime importance in the formation of thrombin, which is the final protein of the coagulation cascade, responsible for creating fibrin.

MECHANISM OF ACTION OF LOCAL HEMOSTATIC AGENTS
Local hemostatic agents act in two ways, namely: a. active hemostatics: promote platelet activation and activation in the final step of coagulation; 2,5 b. passive or mechanical hemostatics: 2,5 act in order to increase volume (they swell) by absorbing blood, which creates pressure on the site of bleeding.They also act through contact with platelets, which creates the foundation that promotes platelet aggregation.Active hemostatic agents include thrombin and the products in which thrombin is associated with passive hemostatic agents and fibrin sealant, while passive hemostatic agents include collagen preparations, gelatin, cellulose and polysaccharides.Active hemostatic agents can be used in association with passive ones (Figure 1, Table 1).
There is a third category of hemostatic agents that includes tissue adhesives and sealants made up of fibrin sealant, ethylene glycol hydrogels, albumin glue with glutaraldehyde and cyanoacrylate, which, when applied onto the site of the bleeding, favor hemostasis by tissue adhesion. 1,5,6Tissue sealants and adhesives are particularly suitable in cases of arterial bleeding and vascular sutures.

Active hemostatic agents
The basic mechanism of action of these agents is to provide a physical structure around the site of the bleeding in which platelets can aggregate, allowing clot to formed.Thrombin has been used to stimulate platelet aggregation and convert fibrinogen into fibrin in the site of the bleeding.Thrombin can be applied as a powder, spray or solution, and is indicated in localized refractory bleeding and in other measures during neurological, orthopedic, cardiac, and vascular prodedures. 1 ena include hypothermia, hemodilution, metabolic acidosis, and inadequate surgical technique.Surgeries involving the spinal cord, as well as heart surgeries with the use of extracorporeal circulation due to high doses of heparin and to hemodilution cause excessive bleeding, and so do procedures in highly vascularized areas.Comparable situations include those that require an approach on friable tissues, reoperations in large areas with adhesion and bleeding on bone surfaces. 2When faced with these situations, local hemostatics, sealants, and tissue adhesives are alternatives to prevent excessive bleeding.

METHODS
The research was conducted on the PubMed database (www.ncbi.nlm.nih.gov/pubmed/) and Google (www.google.com),using the descriptors "topic hemostatic agents, sealants, and tissue adhesives".Many studies were found, but the majority did not refer to the mechanisms of action of local hemostatic agents, sealants, and tissue adhesives.Studies selected for this review were chosen after titles and abstracts resulting from this search were read.Other works included were pertinent to the subject and were found in the references cited in the selected works.

BLOOD COAGULATION
Blood coagulation [2][3][4] is a process that requires coordinated activity of the platelets and coagulation factors for the formation of stable platelets and fibrin clots.Coagulation occurs in primary and secondary pathways.The primary pathway occurs through release of platelets' vasoactive and activating factors in response to injury of the tissue's blood vessels, such as tissue VIIa, IX and X factors.These substances cause temporary vasoconstriction and platelet adhesion to the site of the injury to form a soft plug.In the secondary hemostasis, the activated platelets secrete serotonin, prostaglandin and tromboxane to maintain local vasoconstriction while the coagulation cascade is activated through the release of injured tissue factors resulting in the formation of fibrin and in cross-link and stabilization of the platelet plug.
Coagulation factors are produced in the liver, circulate with the blood inside the vessels and, when these vessels are injured, participate in sequential enzymatic Mechanism of action of topical hemostatic and adhesive tissue agents

Collagen
Collagen, when in contact with the bleeding surface, attracts platelets which adhere to the collagen fibrils, thus promoting degranulation and initiating platelet aggregation that results in thrombi formation in the collagen interstices and initiates formation of the physiological platelet plug. 7,8Microfibrillar collagen is made out of bovine collagen and processed into microcrystals, which can be manipulated to be offered as hemostatic agents as powder, tissues, and foam. 9

Cellulose
Oxidized and regenerated cellulose is a local bioabsorbable hemostatic agent similar to gauze.Cellulose-based products are easy to handle and do not adhere to surgical instruments, unlike collagen-based products.Nevertheless, these products are not biodegradable and should only be used in small amounts. 5,7,8

Gelatin
The characteristics of gelatin allow products that contain it to be used in wounds with irregular contours, which allows them to acquire the contours and geometry of the wound, thereby enlarging and adapting to the wound's format, promoting a mechanical tamponade effect.Thus, the swelling of the gelatin hemostatic agent restrains blood flow and promote a stable matrix around which the clot will form. 2,7,8rombin was initially made of bovine thrombin but is currently available as recombinant human thrombin, developed to reduce the risk of communicable diseases potentially transmitted by human thrombin and to avoid the immune reactions of bovine thrombin. 1However, these modifications sharply raise the price of the product.Thrombin can be more easily applied in combination with passive hemostatic agents, such as gelatin sponges soaked in thrombin. 7

Passive or mechanical hemostatic agents
The basic mechanism of action of mechanical hemostatic agents is to provide a foundation upon which the platelets can aggregate and form a clot hence creating a mechanical barrier to stop the bleeding.Mechanical hemostatic agents are available in various forms and methods of application and these are important factors to determine their efficacy. 7The sponge and wool forms are the most commonly used among surgeons, although wool (microfibrilar) and powder can have electrostatic charge and cause these products to adhere to the surgical instruments and gloves, making them more difficult to handle.

Bovine albumin and glutaraldehyde
The albumin-glutaraldehyde glue also consists of two separate solutions that are dispensed by a dualchamber syringe system.The solutions are mixed inside the applicator at the time of its use and the crosslinks begin.Glutaraldehyde's covalent molecules connect with the albumin molecules and, when applied, also bind to the proteins of the local bleeding, creating a mechanical seal independent from the body's mechanism of coagulation. 14,15This adhesive is resistant, easy to use, and is more affordable than most.The use of the albumin-glutaraldehyde glue, however, can be associated with tissue injury, embolism and pseudoaneurysm. 16

Polyethylene glycol polymers
Refers to synthetic local hemostatic agents formed by hydrogels that promote organic tissue sealing.When applied to the wound, the product absorbs the fluids and expands, closing the injury and creating pressure on the tissues, thus ceasing the bleeding.The product consists of two polymeric solutions of ethylene glycol and hydrogen chloride and sodium phosphate and sodium carbonate solution.This hemostatic agent is indicated as an adjunct to hemostasis of blood vessels for mechanical sealing of leakage areas 5,17,18 or to diminish or prevent air leakage in lung operations. 19

Cyanoacrylate adhesive
Cyanoacrylate acts by polymerization when in contact with organic proteins that act as catalysts and this reaction produces heat and forms a crust on the surface where applied.This adhesive does not depend on the state of blood coagulation and can be used when there is coagulopathy. 20Its power is identical to that of sutures in keeping the tissues together. 21Cyanoacrylate is bactericidal and bacteriostatic, and in its new formula, the cyanoacrylate glue has minimal tissue toxicity. 22

CONCLUSIONS
There are many local hemostatic agents, tissue sealants, and adhesives currently available (Table 2).The choice for the most suitable agent for a spe-

Polysaccharides
Polysaccharides (Arista AH) are derived from plants and act by blodd dehydration.They act as a sieve causing the blood's solid components to concentrate, increasing the formation of a barrier for the bleeding, and assisting when the activity of platelets and coagulation proteins is normal.Polysaccharides can swell up to 500%. 5 For this reason, this material is not safe in neurological, urological and ophthalmological operations. 5,8

Thrombin Sealant
Thrombin is a natural enzyme with an important role in hemostasis and inflammation.It is derived from prothrombin as a result of the extrinsic and intrinsic pathways of coagulation, and is the foundation for the fibrin clot as it turns fibrinogen into fibrin.Thrombin derived from bovine serum has proved to be very effective, with a strong power to convert fibrinogen into fibrin, to activate platelets and to induce vasoconstriction.However, it has caused immunological reactions. 10Thrombin derived from human plasma has the potential risk of viral disease transmission.For this reason, recombinant thrombin was prepared, but its cost is high. 8,11Thrombin compounds are also available with gelatin and collagen. 8,11,12brin sealant Fibrin sealant is prepared in two syringes, one with fibrinogen concentrate, factor XIII and fibronectin, and the other one with thrombin and tranexamic acid or aprotinin.13 The components of the two syringes are mixed at the time of application.The addition of aprotinin or tranexamic acid contributes to stabilizing the fibrin clot.Fibrinogen is the precursor of fibrin, which represents the basic element of the clot.The transformation of fibrinogen into stable fibrin takes place through the action of thrombin and the factor XIII.The fibrin sealant mimics the final steps of the coagulation cascade autonomously in relation to the mechanism of coagulation. Itis also effective in patients with clotting disorders or for patients receiving heparin or anticoagulants.13,14 Mechanism of action of topical hemostatic and adhesive tissue agents little or no effect in patients using heparin or antiplatelet drugs.In contrast, hemostatic agents based on thrombin or fibrin, because they work in the final stages of coagulation, are indicated if these medicines are used and in case of clotting disorders.It is important to consider that no single hemostatic agent can be effective in all cases of bleeding.cific kind of bleeding depends on the knowledge of their mechanism of action.The use of gelatin should be avoided around nerves and in confined areas because it uses volume increase to create a mechanical barrier to bleeding.Thrombin combined with oxidized cellulose, however, can be used in these circumstances.Collagen, gelatin and cellulose have

Figure 1 -
Figure 1 -Simplified scheme of the coagulation cascade.

Table 1 -
Products grouped in local hemostatic agents, tissue sealants and adhesives

Table 2 -
Product, brand name, manufacturer, and mechanism of action Hemostatic fluid which, when applied to tissues, causes polymerization and hardens.When the material comes into contact with the blood, it begins to join in areas where there is fibrinogen Thrombin + collagen TachoSil Baxter The product is a dry sponge, which can be used in places with active bleeding and acts by releasing coagulation factors