TYPES OF HEMOSTATIC AGENTS USED IN VASCULAR SURGERY

TYPES OF HEMOSTATIC AGENTS USED IN VASCULAR SURGERY

More than 51 million surgical operations are performed annually. In order to provide hemostasis during surgical procedures, effective management of the bleeding is necessary to get positive results. During natural process of human hemostasis, a thrombotic response involving a complex interaction between coagulation and fibrinolytic factors as well as platelets and vessel wall occurs to endothelial damage. Hemostasis involves two stages. Primary stage is a cellular stage which is started with endothelial damage. Next, blood flow is slowed down through vasoconstriction. The vasoconstriction is followed by the adhesion of the inflammatory effector platelet cells and the formation of a loose aggregated plug containing platelets and fibrinogen. In the secondary stage, the soft plug is stabilized with a clot formation. Platelets maintaining vasoconstriction and a reduction in blood flow via release of serotonin and thromboxane facilitate this stage. Coagulation cascade turns plasma-soluble fibrinogen into insoluble fibrin through thrombin. At the same time, cross-linking of fibrin monomers resulted with formation of stable clot is initiated via converting factor XIII to factor XIIIa.

When the surgeons provide rapid hemostasis, the following benefits are expected: shorter operation time, reduction of transfusion requirement, better management of anticoagulated patient, and general improvement in patient recovery time.

Hemostatic agents, sealants and adhesives are utilized to improve hemostasis and they provide many advantages in vascular surgery. The importance of hemostasis has accelerated the development of new agents such as oxidized regenerated cellulose (ORC), porcine gelatin, bovine collagen, polysaccharide spheres and thrombin. These agents are quite varied in their action mechanism, chemical structure, ease of implementation, adhesion to wet or dry tissues, immunogenicity and cost. Hemostatic agents are mainly categorized into three types: hemostats, sealants, and adhesives. Furthermore, hemostats are also sub-divided as mechanical, active and flowable hemostats. Sealants are known as fibrin and synthetic sealants. Adhesives are sub-categorized as cyanoacrylate or as albumin and glutaraldehyde.

1. Hemostats

a. Mechanical

Mechanical agents (also called passive substances) are generally thought to be the most effective for small amounts of bleeding and they create a barrier to stop blood flow and a surface that permits blood to clot more rapidly. These mechanical hemostatic agents have been utilized in vascular surgery more than 50 years. At the beginning of twentieth century, hemostasis was maintained through clamps, clips, sutures, cauterization or direct compression. New mechanical agents have been recently developed such as gelatin, collagen and ORC materials for vascular surgery.

• Gelatin: Gelatin is known as hydrocolloid which is made of acid partial hydrolysis of porcine based collagen converted into foam and then dried. It could be found as sponge and powder forms. Although it could be utilized alone, it is also possible to use it with the combination of topical thrombin. Gelatin has a capability to absorb the blood 40 times of its weight and it might enlarge up to 200% of its initial sizes. It is possible to cut the dry sponge form into any size and any shape. It should be applied dry or it should be applied directly to the bleeding site with a single pressure. Gelatin could be left in place and its absorption time is between 4 and 6 weeks. It could not be utilized as intravascularly since it has some safety issues such as “overswelling” when it is applied at small areas.
• Collagen: Collagen hemostats are made from bovine skin. In order to provide a matrix for clot formation and to increase platelet aggregation, degranulation, and the release of clotting factors, they are tightly bound to the blood surface and therefore further increase clot formation. It is very effective on patients with low platelet numbers and it is also effective to control arterial bleeding. Even though it is more expensive than porcine gelatin, hemostasis is achieved in 1-5 minutes. It could be easily removed through irrigation and suction. It reduces the rebleeding and the requirement of multiple applications. When it is left in place, it is expected to be absorbed in 8-10 weeks. The main problems with bovine collagen are swelling and allergic reaction. Therefore, it is not recommended to use collagen hemostats in the areas on which they may apply pressure. Bovine collagen should not be used in patients having sensitivities and allergy to bovine origin materials.
• Oxidized regenerated cellulose: ORC products are made from plant derived alpha-cellulose. They could be found as single or multiple sheets, as absorbable knitted fabric and could be in low or high density. They are stored at room temperature, ready to use and have a capacity to absorb the blood 7-10 times of its weight. They act in intrinsic way resulting in contact and platelet activation. When they are absorbed, a gelatin like mass is created and they help clotting. ORC hemostats are mainly utilized in order to control capillary, venous and small arterial bleeding. They should be applied dry. Their absorption time is 4-8 weeks. They are not recommended to be used at closed areas or for bleeding resulted from large arteries due to the risk of swelling.

b. Active

Active hemostats include thrombin enzyme catalyzing the transformation of fibrinogen to fibrin which is the final part of blood clotting. FDA approved topical thrombin enzyme to utilize it in surgery to provide hemostasis at the end of 1970’s. Since then, thrombin has been purified from bovine, human and recombinant resources. The first thrombin utilized had bovine origin but it is complicated to use it due to the formation of antibodies which cross-react with human coagulation factors. In order to decrease this risk, human thrombin is utilized with the combination of gelation sponges. On the other hand, it is risky to utilize human thrombin since it may result in transmission of blood-borne pathogens.

c. Flowable

This category could be further sub-divided into two classes: porcine gelatin products (it could be combined with three thrombins: bovine, human or rhThrombin) and bovine collagen products packaged with human plasma thrombin. Flowable hemostats are known as the most effective one among hemostats.

2. Sealants

a. Fibrin Sealants

Fibrin sealants are made from human and/or animal blood products which mimic the last part of coagulation cascade during clot formation. Freeze dried clotting protein (e.g. fibrinogen) and thrombin combination are found in separate vials. They interact to form stable clot during application. The preparation and the application of fibrin sealant is a little complicated. While fibrinogen is solubilized in water, thrombin is solubilized in a dilute CaCl₂ solution. Next, two solutions are transferred into double-barreled syringes in order to facilitate the combination of both solutions when they are applied. Some sealants include two additional components: human blood factor XIII and aprotinin inhibiting the enzymes damaging blood clot.

Some studies suggest that they effect the surgical outcomes positively. The main advantages of fibrin sealants are low infection rate, shorter operation time and reduction in blood lose.

b. Synthetic Sealants

Synthetic sealants contain polyethylene glycol (PEG) polymers and at least one additional ingredient. These agents are known as biodegradable agents acting as both fluid barrier and hemostatic agents. They rapidly construct an adhesive bond and they degrade in 1-6 weeks. Synthetic sealants are more expensive than other hemostatic agents.

3. Adhesives

Adhesive hemostatic agents are mainly utilized in cardiovascular surgery as a part of typical hemostatic measures.

a. Cyanoacrylate

Cyanoacrylates require low amount of moisture to affect adhesion although most of the adhesives require moisture evaporation. Due to the intensive inflammatory response when it is applied to the non-cutaneous surfaces, it used to be utilized externally until recent time. The main surgical purpose of cyanoacrylates was the closure of skin incisions. Cyanoacrylates have been utilized in treatment of varicosities for more than 20 years. It was first utilized in endoscopic intravenous injections of peptic varicosities.

b. Albumin and glutaraldehyde

Albumin and glutaraldehyde tissue adhesive has been utilized as a supportive treatment for the hemostasis of large vessels. It strongly bonds to tissue in 2-3 minutes with excellent strength. In order to help sealing of the separating layers of the aortic wall, it is mainly utilized in complicated cardiac repairs (e.g. dissection of aortic aneurysms).

Resource: Vyas, K. S., & Saha, S. P. (2013). Comparison of hemostatic agents used in vascular surgery. Expert Opinion on Biological Therapy, 13(12), 1663–1672. https://doi.org/10.1517/14712598.2013.848193