LOCAL HEMOSTATIC AGENTS Peyman Eshghi MD. Pediatric hematologist&oncologist Board member of IPHOS Associate Prof. In SBMU Tehran-2008

" An area of increasing concern is lethal hemorrhage from sites that are not suitable for application of tourniquets or compression dressings." Hasan B. Alam. "Hemorrhage control in the battlefield: Role of new hemostatic agents." Military Medicine, 170(1):63-69.

HEMOSTATIC INTERVENTION Mechanical & physical & thermal methods: compression;ligature ;torniquet; electrocautery,;etc Local & chemical agents: *Fibrin sealents *Absorbable Hemostatic Agents with & without Thrombin : Collagen; Gelatin matrix; Regenerated Oxidized Cellulose; *bone wax *Polymers :glucosamine-containing polymers *Chitosan based dressing *Medicinal plant extract blood stopper *Minerals Systemic coagulation agents: rFVIIa ; antifibrinolytics(transamine;etc.)

Historical background of Chemical hemostatic agents Hippocrates used caustics to achieve hemostasis, At the end of the eighteenth century, carnot introduced gelatin. In 1886 horsley developed a mixture of beeswax, salicylic acid, and almond oil, thus leaving his legacy of “antiseptic wax.” Oxidized cellulose(OC) in 1942 oxidized regenerated cellulose (ORC) was developed in 1960 Gelatin foam(GF) in 1945 Microfibrillar collagen (MFC) was developed in 1970 by hait Chitosan based agents was approved by FDA at 2003 The newest mineral based agent has been introduced by US Army Institute of Surgical Research in 2007 A Plant extract agents was registered in turkey in 2007

Characteristics of an Ideal hemostatic agents for prehospital/battlefield use: (1) capability to stop large vessel arterial and venous bleeding within 2 min of application when applied to an actively bleeding wound through a pool of blood; (2) no requirement for mixing or pre-application preparation; (3) simplicity of application by wounded victim, buddy, or medic; (4) light weight and durable; (5) long shelf life in extreme environments; (6) safe to use with no risk of injury to tissues or transmission of infection; (7) Inexpensive.

Well known hemostatic agents in surgery

Bone wax is a mixture of beeswax (70%) and Vaseline (30%). It is a non-absorbable material,becoming soft and malleable in the hand when warmed. Its hemostatic effect is based on physical rather than biochemical properties It has been used in bone surgeries for a long time; not proper for combat/accident casualty care Complications:Allergic, granuloma,cord compression, infection, interferes with bone healing

Gelatin foam (absorbable gelatin sponge) is made from animal-skin gelatin (denatured collagen) whipped and baked into its sponge form through which nitrogen has been bubbled in during polymerization in order to produce a porous device. The porous structure of the sponge enables it to absorb 45 times it weight in blood. As the sponge fills with blood, platelets come into contact with one another, initiating the clotting cascade. If soaked in thrombin, it directly acts on the coagulation cascade and has an increased hemostatic action. Its effect is probably mostly mechanical on low-pressure bleeders

Microfibrillar collagen (MFC) Adheres tightly to bloody surfaces, with an immediate and complete hemostasis. The hemostatic properties of MFC rely on the promotion of platelet aggregation. Advantages of collagen fleece are fast induction of hemostasis, low tissue reaction, and fast resorption A major disadvantage of using the collagen fleece is difficulty in manipulating the agent during attempts to place it in the area of bleeding This should be applied dry with clean and dry instruments, and pressure with gloved fingers should never be placed, as the MFC would adhere to the glove more than on the hemorrhage site.

Oxidized regenerated cellulose (ORC) Cellulose is first dissolved and then made into a continuous fiber. Never use this soaked in thrombin. The latter, in fact, interferes with its natural action. The greatest use has been for the control of oozing and mild bleeding from broad surfaces, ORC presents multiple mechanisms of action, including physical and mechanical actions in tamponade, swelling and gel formation, conferring hemostasis by decreasing the pH and acting as a caustic and then surface interactions with proteins, platelets, intrinsic and extrinsic pathway activation. One major advantage of oxidized cellulose is its definite and potent action against a wide variety of pathogenic organisms, both in vivo and in vitro.

Chitosan-based dressing Chitosan is a biodegradable,nontoxic,complex carbohydrate derived from chitin(a naturally occuring substance from zeolites): when the deacetylation of chitin is above 70% the generic name” Chitosan” is applied In the form of an acid salt it has a mucoadhesive activity It has a positive charge and it attracts RBCs and Plateletswhich have negative charge. The freeze-dried Dressing augments its sealing action Also offers an antibacterial barrier

CBD;continue It should be applied with pressure for 3 minutes and then release ; can be left on the wound for 48 h ; easily removed by saline without disturbing the clot It can be use even for high flow,high pressure bleeding: combat operations; hemodialysis;etc No complications have been reported > dressings have been distributed in US army It is stiff and the proper size should be applied It is better to use in the areas where torniquets could not be applied Expensive(each bandage package is # 90$)

Clinical resources supporting the use of CBD

Mineral based hemostatic agent a granular combination of a smectite mineral and a polymer (WoundStat) capable of producing hemostasis in the face of high- pressure arterial bleeding Hemostasis is achieved temporarily for a period of at least three hours. originated at Virginia Commonwealth University's Reanimation Engineering Shock Center (VCURES ) for US army

Comparison of a new hemostatic agent to current combat hemostatic agents in a Swine model of lethal extremity arterial hemorrhage.. J Trauma Aug;63(2):276-83; discussion compared the performance of WoundStat (WS) to QuikClot zeolite granules (QCG), HemCon chitosan bandage (HC), Army gauze field bandage (AFB)., and the new QuikClot zeolite Advance Clotting Sponge (ACS) in a lethal vascular injury model. All animals treated with WS survived to 180 minutes and required only a single application No significant difference in survival or survival time ; PostTBL existed between the AFB, QCG, ACS, or HC groups

Folkloric Medicinal Plant Extract Blood Stopper comprises a standardized mixture of the plants Thymus vulgaris, Glycyrrhiza glabra, Vitis vinifera, Alpinia officinarum and Urtica dioica Each of these plants has some effect on the endothelium, blood cells, angiogenesis, cellular proliferation, vascular dynamics and cell mediators, the basic mechanism of action is unknown: Independent of the classic coagulation cascade system, it shows homostatic effect in a protein network environment in a matter of split seconds in vitro and seconds in vivo environments.

continue Therefore it is not only effective on patients with normal haemostatic values, but also on those who are primary and secondary hemostasis defective It is in liquid form Has not especial storage condition Has shown in-vitro anti-bacterial activities

The levels of coagulation factors II, V, VII, VIII, IX, X, XI, and XIII were not affected by BS. Plasma fibrinogen activity and antigen Total protein, albumin, and globulin levels decreased after the addition of ABS. The Journal of International Medical Research2008; 36: 163 – 170