BB&T Contributing Editor
Hemostats are used to reduce bleeding during surgical procedures. They work by coagulating blood quickly and accelerating the normal clotting mechanisms. The natural clotting process has been used by manufacturers to design new products that can mimic the body's hemostatic action
Collagen and gelatin (denatured collagen) are used to stimulate the hemostatic cascade. These products tend to be slower-acting than fibrin and thrombin-based products which act later in the cascade to produce immediate hemostatic results.
Synthetic polyanionic materials, such as oxidized regenerated cellulose, and naturally occurring biological polymers, such as chitosan and calcium alginate, are also used as hemostatic agents.
Worldwide sales in topical absorbable hemostats are forecast by MedMarket Diligence (Foothill Ranch, California) to increase from $595 million in 2006 to about $842 in 2011, a 7% compound annual growth rate. The growth will be fueled by an increased incidence of surgery and the need for improved hemostasis products for use in minimally invasive surgical procedures.
The American College of Surgeons (Chicago) has reported that bovine-derived thrombin is used to treat more than 1 million surgical patients each year in the U.S. However, roughly 20% of these patients develop antibodies against bovine coagulation factors than can cross-react with human coagulation proteins and possibly lead to adverse effects, including severe bleeding and thrombosis. rhThrombin was developed as an alternative because of these safety concerns.
Thrombin is a blood factor that is used to control surgical bleeding. Three types of topical thrombin are commercially available: recombinant human, and thrombin that is derived from bovine and human plasmas.
They all have received FDA clearance by submitting Biologics License Applications and have the same indication, for use as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical.
The recombinant human and bovine-derived thrombin can be administered as a spray or in conjunction with an absorbable collagen sponge. Thrombin is used in more than 1 million surgeries each year in the U.S. Han Li, PhD, an analyst at the Stanford Group (New York), projects that the stand-alone thrombin market will reach about $600 million in 2012.
ZymoGenetics (Seattle) is focused on the discovery and development of protein therapeutics for treatment of hemostasis, autoimmune disorders, cancers and other diseases. Recothrom thrombin topical is produced by recombinant DNA technology and is free of human or animal plasma. It is sold as a freeze-dried powder that is reconstituted prior to use.
Recothrom is made by a standard mammalian cell expression process through a contract with Abbott Laboratories (Abbott Park, Illinois). Recothrom was launched in January 2008 and is expected to record sales of $7 million in its first year on the market, well below analysts' initial estimates. Li projects rhThrombin sales of $351 million in 2012.
rhThrombin has safety and manufacturing advantages over plasma-derived products It is not dependent on the availability of blood from animal or human donors and can be scaled-up to meet to supply two to three times the current market size.
ZymoGenetics has a global collaboration with Bayer HealthCare (Leverkusen, Germany) for the marketing of rhThrombin in all countries outside the U.S. The two companies have a co-promotion agreement in the U.S. market. ZymoGenetics recently completed a Phase IIIb open-label safety study in spinal and vascular surgery.
King Pharmaceuticals (Bristol, Tennessee) markets Thrombin-JMI, a topical thrombin of bovine origin, via its Jones Pharma subsidiary. Thrombin-JMI Epistaxis Kit is an intranasal spray delivery device for Thrombin-JMI for use in stopping epistaxes (nosebleeds).
Thrombi-Pad, a hemostat comprising freeze-dried Thrombin-JMI in a gauze pad, is applied topically and is indicated as a trauma dressing for temporary control of moderate to severely bleeding wounds and for the control of surface bleeding from vascular access sites and percutaneous catheters and tubes.
King also markets ThrombiGel, bovine thrombin in a gelatin foam hemostatic pad that is produced by Vascular Solutions (Minneapolis). It is applied topically and is also indicated as a trauma dressing for temporary control of moderate to severely bleeding wounds.
Vascular Solutions is a direct marketer of D-Stat Dry, a gauze pad containing freeze-dried bovine thrombin and D-Stat Flowable that is a combination of liquid thrombin in a collagen matrix.
Baxter Bioscience, a division of Baxter Healthcare (Deerfield, Illinois), markets FloSeal, a hemostatic matrix that is hydrated prior to use. It contains gelatin and thrombin made from human plasma.
The fractionation process for extracting and recovering therapeutic proteins from pooled human plasma involves multiple separation steps with decreasing yields. On average, plasma-derived thrombin has a net overall yield of about 15%.
Omrix Biopharmaceuticals (New York) is a biopharmaceutical company that makes biosurgical and immunotherapy products. It was acquired recently by Johnson & Johnson (J&J; New Brunswick, New Jersey). Omrix produces Evithrom thrombin topical, which is marketed in the U.S. by J&J subsidiary Ethicon (Somerville, New Jersey), but is not yet approved in Europe. Ethicon also markets Omrix's Evicel fibrin sealant in the U.S. and in Europe under the Quixil name.
Evithrom is derived from human plasma obtained from screened and tested U.S. donors. It is identical to the thrombin component of Evicel. Evithrom is sold as a frozen liquid and requires less than one minute preparation time in the operating room after thawing. It is applied to the surface of bleeding tissue and may be used in conjunction with an absorbable gelatin sponge.
Omrix is developing an absorbable fibrin patch in collaboration with Ethicon. It is intended for use in stopping mild, moderate and severe bleeding. It acts to stop bleeding in two steps, by serving as an immediate physiological barrier and by utilizing a biological component that promotes the rapid formation of a clot at the site of the wound. It is being evaluated in a Phase II clinical trial on mild-to-moderate bleeding.
Haemacure (Westmount, Quebec) is developing Hemaseel, a topical human thrombin hemostatic agent for use in arresting bleeding during surgical procedures. It is made from human plasma by a patented extraction technology and can be used alone or in combination with passive hemostats such as gelatin. Hemaseel contains one of the clotting proteins in Haemacure's Hemaseel HMN fibrin sealant that is in clinical trials.
Haemacure has instituted major staff reductions and is seeking to raise capital or sell the company.
Collagen and gelatin hemostats
Hemostatic activity is an inherent property of collagen, but is largely dependent on the basic helical structure of this protein. When collagen comes into contact with blood, platelets aggregate on the collagen and release coagulation factors which, together with plasma factors result in the formation of fibrin, and finally in the formation of a clot.
Davol (Cranston, Rhode Island), a division of C.R. Bard (Murray Hill, New Jersey), sells Avitene and Ultrafoam collagen hemostats. Avitene microfibrillar collagen hemostat is available in fibrous (flour) and nonwoven web (sheet) forms. It is used in surgical procedures as an adjunct to hemostasis when control of bleeding by ligature or conventional procedures is ineffective or impractical. It is indicated for all surgical procedures and conforms and adheres to irregular surfaces and can be removed with irrigation and suction.
Ultrafoam is a 100% collagen topical hemostat that is made from Avitene. It is indicated for all surgical procedures and can be used in a dry or wet environment.
Endoavitene is a topical hemostat in a preloaded endoscopic delivery system designed for use in all laparoscopic procedures by passing through 5 mm and 10 mm diameter trocars and cannula.
Integra Lifesciences (Plainsboro, New Jersey) sells Helistat and Helitene absorbable collagen hemostats. Helistat is a sponge and Helitene is in microfibrillar form. They are soft, white, pliable absorbent hemostatic agents and are fabricated from collagen that is obtained from bovine deep flexor (Achilles) tendon.
Superstat (Rancho Dominguez, California) markets the Superstat Collagen Hemostat, a freeze-dried, non-crosslinked, absorbable and modified collagen and calcium chloride. The positive charge of these substances creates an electron sink for hemostasis.
Orthovita (Malvern, Pennsylvania) markets Vita-gel, a composite liquid hemostat used in surgical procedures as an adjunct to hemostasis. It was originally sold as CoStasis and was acquired from Angiotech Pharmaceuticals (Vancouver, British Columbia).
Vitagel contains a suspension of collagen and thrombin of bovine origin. It is combined with the patient's own plasma and is delivered from a double-barreled syringe. The resultant fibrin/collagen clot stems bleeding and provides a matrix for healing.
Orthovita also sells Vitasure, a plant-based absorbable hemostat that is supplied under a non-exclusive agreement by Medafor (Minneapolis).
Xemax Surgical Products (Napa, California) sells Collatene, a microfibrillar collagen hemostat used in dental surgery and for guided tissue regeneration.
Pharmacia, a subsidiary of Pfizer (New York), markets Gelfoam, an absorbable gelatin hemostat. It is a sterile, compressed and pliable surgical sponge prepared from specially treated purified gelatin solution. It is capable of absorbing and holding within its meshes many times its weight of whole blood. When implanted in tissues, Gelfoam is completely absorbed in four to six weeks. It liquefies in two to five days when applied to bleeding nasal, rectal or vaginal mucosa.
Johnson & Johnson Wound Management (Somerville, New Jersey, a division of Ethicon, markets the Surgicel line of absorbable hemostats that are made from oxidized regenerated cellulose. They include Surgicel, Surgicel Fibrillar and Surgicel NU-KNIT. They can be cut to size for use in endoscopic procedures and are used adjunctively in surgical procedures to assist in the control of capillary, venous and small arterial hemorrhage when ligation and other conventional methods of control are impractical or ineffective.
The company also sells Surgifoam absorbable porcine gelatin hemostats in powder and sponge forms, and Surgiflo hemostatic matrix comprised of Surgifoam, to which is added sterile saline solution and is fitted with an applicator tip for delivery onto a bleeding site.
Instat is an absorbable bovine collagen hemostat in a sponge-like pad, and Instat MCH is a microfibrillar collagen hemostat.
Alltracel Pharmaceuticals (Dublin, Ireland) was acquired by HemCon Medical Technologies (Portland, Oregon) in May 2008. It has a research operation in the Czech Republic and manufacturing facilities in Shenzhen, China.
SealOn is a biodegradable oxidized cellulose hemostat that is sold to the consumer market as a spray, plaster, powder, nasal sponge, blotter, patch and dressing. The base material is oxidized cellulose obtained from cotton. A calcium salt of oxidized cellulose is the active ingredient. The product stops capillary bleeding and minor arterial and venous hemorrhages. When contacted with blood, the material causes a "foreign-body" surface reaction to platelets, co-activates the initial coagulation stage and accelerates the polymerization of fibrinogen.
Alltracel's professional and military hemostats are branded m-doc (micro-dispersed oxidized cellulose) and are sold in a variety of forms, as a spray, powder, impregnated plaster, nasal impregnated polyvinyl alcohol sponge and a non-adhering dressing.
Alltracel has a joint venture with Elmarco (Prague, Czech Republic), which has a nanotechnology manufacturing process called Nanospider.
LifeScience Plus (Santa Clara, California) produces BloodSTOP and BloodSTOP iX, water soluble hemostatic gauze products made from cellulose. BloodSTOP is used externally and is made from oxidized cellulose. BloodSTOP iX is used primarily internally and is made from etherized regenerated cellulose.
It is distributed at retail by NutraMax Products (Gloucester, Massachusetts). The BloodStop name also is used by Biolife (Sarasota, Florida) for its hemostat that is sold at retail in drug stores
HemCon Medical Technologies produces the HemCon hemostatic bandage that is fabricated from chitosan (poly-N-acetylglucosamine), a naturally occurring and biocompatible polysaccharide that is obtained from chitin, a marine biopolymer obtained from the exoskeleton of shrimp.
Chitosan has a positive charge and attracts red blood cells and platelets which have a negative charge. The red blood cells create a seal over the wound as they are drawn into the bandage, forming a tight seal. The HemCon bandage does not contain human proteins or clotting factors and has been shown to act as an effective barrier against bacteria, including MRSA.
The HemCon bandage has historically been sold for hemorrhage control by the military in the U.S., UK and Germany. Bleeding is the leading cause of battlefield mortality.
ChitoFlex is used as a packing to stop the bleeding of deep wounds caused by shrapnel or small arms fire. It is comprised of the same materials and technology as the HemCon bandage as is used by the military, medical first responders and healthcare professionals. The company has expanded into the civilian market with new bandages designed for emergency medical professionals and with the HemCon dental dressing for use by dentists and oral surgeons to stop bleeding after tooth extractions.
HemCon is exploring the use in its chitosan-based dressings of the Nanospider technology from Alltracel Pharmaceutical, which it acquired in May 2008.
HemCon has an agreement with Cardinal Health (Dublin, Ohio) for marketing a line of hemorrhage-control bandages to hospitals and surgery centers.
Abbott Vascular (Redwood City, California), a subsidiary of Abbott Laboratories, manufactures the Chito-Seal hemostasis pad for use in the management of bleeding wounds such as vascular access sites and percutaneous catheters or tubes. The pad is coated with chitosan gel.
Similar products are made by Marine Polymer Technologies (Danvers, Massachusetts), which markets the Syvek Patch, a freeze-dried chitosan pad for vascular access hemostasis following femoral vascular catheterization procedures, and Syvek NT for the management of bleeding wounds such as vascular access sites, percutaneous catheters or tubes and surgical debridement.
Scion Cardiovascular (Miami) markets the Clo-Sur Plus P.A.D., a chitosan-based topical hemostat that also carries the claim of a bacterial barrier. It supplies Medtronic (Minneapolis) with the Clo-Sur P.A.D., which lacks an antimicrobial claim.
Starch Medical (San Jose, California) has received the CE mark for its PerClot polysaccharide hemostatic system and its StarFoam absorbable polysaccharide hemostat. PerClot is composed of an absorbable plant-based polymer. It contains no thrombin, collagen or other human or animal components. It is intended for use in controlling capillary, venous and arterial bleeding in surgical procedures. StarFoam is a hemostatic foam or wafer. Its application features a "press and release" technique.
Medafor (Minneapolis) markets Arista AH, an absorbable, plant-based hemostatic powder. The same product is being sold as M Patch in Europe. The microporous polysaccharide hemispheres (MPH) rapidly dehydrate blood and promote clotting on contact. It is sold in a ready-to-use applicator and is absorbed one to two days after application to the wound site.
The product is sold as Hemostase MPH to the cardiovascular and vascular markets under an exclusive distribution with CryoLife (Kennesaw, Georgia), as the Stasys Patch to interventional cardiologists under a non-exclusive agreement with Medrad Interventional/Possis (Minneapolis), and as Vitasure to the orthopedic market under a non-exclusive agreement with Orthovita.
Z-Medica (Wallingford, Connecticut) produces QuikClot, an absorbent hemostatic agent. It is a zeolite (inert mineral obtained from lava rocks) that is left in a wound until bleeding has stopped. QuikClot and QuickClot ACS+ are granular products that are sold to the military and law enforcement.
The company also sells to the consumer market with QuickClot Sport and QuickClot Sport Silver (an antibacterial product and the only commercial hemostat that contains silver ions) for use by athletes, and QuickClot 1st Response for use by EMS personnel and first responders. These products are comprised of beads contained within a gauze sponge.
TZ Medical (Portland, Oregon) manufactures Neptune, a topical pad prepared from calcium alginate that facilitates hemostasis after catheterization.
Biolife produces PRO QR (Quick Relief) powder, a hemostat for minor external bleeding from wounds and procedures. The product comprises tiny beads that are composed of a potassium/iron oxyacid salt and a hydrophilic polymer (polystyrene divinylbenzene). The potassium salt reacts with blood to quickly form a protective matrix but does not enter the bloodstream.
It is sold by the bottle for use in emergency rooms to stop external bleeding. The company also markets QR, single-use blister packs for the consumer market for stopping nosebleeds and bleeding from minor wounds.