ATH: A Novel Heparin-Based Anticoagulant Presented By: ATTWILL Medical Solutions Inc.

Thrombosis Problem in Catheters Of the over 7 million Central Venous Access devices (CVADs) placed annually in the USA catheter occlude due to thrombosis is the most common non-infection related complication The occurrence of catheter related thrombosis affects 33% to 59% of indwelling catheters As much as 25% of all of all CVADs fail because of thrombosis related occlusions

Why Clots are an Issue Clotting in catheters precipitates the need for intervention which may include dangerous chemical dissolution of the clot or removal of the therapeutic device; Surgical clotting may lead to thromboembolism and stroke during surgery and/or post-operatively;

Cost Catheter Failure due to Thrombosis without preventative measures Cost Item Amount Total number of Catheter 7,000,000 25% failure due to occlusion 1,750,000 Cost of Catheter replacement $1,388 Total Cost of Catheter failures without preventative treatment $2,429,000,000

Comparison of Saving by each Technology Technology cost Failure Rate/ number of Failures Cost of Failures $1,388 per Catheter + Savings Catheter alone 7,000,000 25% 1,750,000 $2,429,000,000 TPA @ $8.75, 7 per line (21days) $61,250,000 4.5% $437,220,000 $1,930,530,000 Valves @ $29.75, 7 per line (21 days) $208,250,000 2.25% $218,610,000 $2,002,214,000 Heparin @ $1.35, 21 per line (21 days) $198,450,000 $1,914,780,000 ATH @ $1.75, 21 per line (21 days) $257,250,000 0.10% $9,716,000 $2,162,034,000

What is Thrombosis and Thrombin? Thrombosis is the formation of a blood clot (thrombus) inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot, because the first step in repairing it (hemostasis) is to prevent loss of blood. Thrombin is a coagulation protein that is present in the blood of humans and other animals. It is a key protein in thrombogensis It catalyzes the conversion of fibrinogen to fibrin and activates procoagulant factors V, VIII, XI, and XIII. Thrombin also activates platelets, regulates endothelial cell function, and has a host of direct actions on other cells.

Initiating The Process of Thrombosis

What are Heparin and ATIII? Heparin is an anticoagulant (blood thinner) that prevents the formation of blood clots. Heparin is used to treat and prevent blood clots in the veins, arteries, or lung. Heparin is also used before surgery to reduce the risk of blood clots. Heparin is a commercial preparation of heparin sulfate, and binds anti-thrombin and thrombin, thereby catalyzing the thrombin-AT reaction. Antithrombin is the most important natural inhibitor of the coagulation cascade, accounting for approximately 80% of the thrombin inhibitory activity in plasma. Thrombin binds to heparin in a non-specific manner and slides along the chain until it encounters the bound AT.

Heparin and Antithrombin

What is ATH ? Permanently bonded antithrombin and heparin; Unlike UFH, all heparin in ATH is active; This leads to a greater than 4X activity over commercial heparin; Consequently, ATH contains no inactive heparin chains which can cause adverse effects such as; clot growth, non-specific protein binding and cannot reduce platelet activity.

Comparing ATH and Heparin(AT) as Anti-Coagulants CHARATERISTIC ATH Heparin(AT) When used as Lock Solution can Impart Anti-coagulant Characteristics to Catheter inner Lumen surface  Reduces Existing Clot Mass/Size Attaches to Polyurethane without need for excessive or special processing Turns Clot Surface into Anticoagulant Surface 100% of bound agent is active Very Low Concentrations Required to make Actively Thrombo-resistant Surface Effective against all molecules in the Clotting Cascade Surface Activity Stable and Durable in Aggressive Conditions Requires Exogenous Circulating AT to Become Active  Can Cause Bleeding Inhibits Resting Platelet Initial Responses to Injury

Heparin Coated ATH A C Un-coated SEM’s of 30 day explanted catheter segments from rabbit study showing fibrin sheath and large thrombi in (A) Heparin Coated and (B) non-coated catheter segments. ATH coated catheters (C) show no accumulation Of fibrin sheath, thrombus or platelets B

Size of markets for potential uses of ATH Application Statistics Venous Access Catheters 7,000,000 catheters in the USA Number of Surgical procedures in the US 51.4 million procedures per year Likely to get a blood clot 1% Total number of preventable clots 514,000 Total amount of heparin sold in the US per year $3.1 billion

Acute 4 Hr. Aspiration Study Samples were implanted in rabbits maintained under general anesthesia, blood was aspirated into the catheters and held for 2.5 minutes then re-injected and the catheter flushed. This cycle was repeated until the catheter clotted or for a maximum of 4 hours. catheters were then explanted and observed.

Chronic Rabbit Study Explant Implanted samples were tunneled and tips placed in the right atrium, catheters were accessed 2X a day and remained patent for the length of the study (106 days). There was no anticoagulant used during the study.