Investigators Perfect New Version of Blood-Regulator Thrombin

ST. LOUIS, June 18 /PRNewswire-USNewswire/ -- In research led by a Saint Louis University investigator, molecular biologists have discovered a way to harness the enzyme thrombin's anti-blood clotting properties. The finding opens the door to new medications that will treat diseases related to thrombosis, the presence of blood clots in blood vessels, which is responsible for nearly a third of all deaths in the U.S.

"Thrombosis is one of the most prevalent causes of fatal disease," said lead researcher Enrico Di Cera, M.D., chair of the department of biochemistry and molecular biology at Saint Louis University School of Medicine. "If we could develop an anti-thrombotic drug that didn't carry a risk of hemorrhage, it would revolutionize the treatment of cardiovascular disease, the leading cause of death in the U.S. and Western world.

"This research carries us closer to that goal."

Blood clotting has long ensured our survival, stopping blood loss after an injury. On the other hand, if triggered in the wrong conditions, clotting can lead to debilitating or fatal conditions like heart attack, stroke and deep vein thrombosis.

Funded by the National Institutes of Health, and published in the June 18, 2010 edition of The Journal of Biological Chemistry (Vol. 285. No. 25), researchers zeroed in on thrombin, a vitamin K-dependent enzyme key to blood coagulation.

An unusual enzyme, thrombin performs distinct and even opposing functions, acting as a pro-coagulant, pro-thrombotic but also as an anti-coagulant factor depending on which target protein - fibrinogen, PAR1 or protein C - becomes activated in the blood. Researchers studied thrombin to decipher the structure-function code that enables this protein to do so many different things.

Tackling this problem far below the level of tissue and organs, molecular biologists looked deep inside the structure, examining thrombin's amino acids to note how they behave and interact with each other.

Using protein engineering, researchers produced mutations in the enzyme's amino acid sequence, carefully taking out pieces and replacing them, a few at a time, to find the exact locations that influence the function of thrombin. Once they found these "hot spots," researchers went even further - trying each of the 20 natural amino acids to see which mutation would allow them to turn on and off the pro-coagulant, pro-thrombotic and anti-coagulant functions.

"We asked the question, what if we can take this enzyme and dissociate the functions, allowing only the function we want?" said Di Cera.

In earlier research, Di Cera's team did just that. They engineered thrombin to promote activity toward protein C - the anticoagulant target protein - and minimize activity toward fibrinogen and PAR1 - the procoagulant and prothrombotic targets.

"In 2000, we engineered a thrombin mutant with potent anticoagulant properties both in vitro and in vivo and we are moving this mutant to a phase I trial," said Di Cera. "In this study, however, we pressed further. We wanted to optimize this mutant to completely abrogate activity toward fibrinogen and PAR1."

"With this research we optimized the mutant so that there is no clotting at all. Furthermore, we generated a new mutant with exclusive prothrombotic activity, thereby demonstrating that the individual functions of thrombin can be dissociated by replacing a single amino acid in the protein."

Once clinical trials are performed, researchers hope to have developed an alternative to heparin, a blood thinner that is used to prevent blood clots and is often used before surgery, but which also causes allergic reactions, dosage challenges and bleeding.

"Heparin is a brute-force remedy that shuts down all thrombin functions, including its beneficial anti-coagulant role," said Di Cera. "Our approach is a new strategy that like a smart bomb only targets the functions we want to turn off."

Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.

No More Hemostase - Marriage from Hell ends

Under the headline "Medafor Shareholders Crush Cryolife" a new article, states ....." Medafor has decided to end its distribution relationship with CryoLife. Over the past 24 months Medafor has supplied CryoLife with its flagship product—a patented absorbable hemostasis powder which promotes rapid clotting. According to CryoLife CEO Anderson, losing the rights to distribute Medafor’s innovative hemostat will cost the company as much as $6 million in lost annual revenues.

It is probably worth noting that in 2009 CryoLife reported a precipitous decline in reported after-tax earnings from $32.9 million (2008) to $8.6 million (2009). CryoLife’s COO stated that losing the Medafor product would materially adversely affect CryoLife.

In retrospect, one has to ask the question: What were the guys at CryoLife thinking? Not only is roughly $6 million flushed away but now they will lose one of the strongest product lines."

The full article is available HERE

ProFibrix and CSL Behring Enter Into Fibrinogen and Thrombin Supply Agreement

LEIDEN, The Netherlands and SEATTLE, June 17, 2010 /PRNewswire/ -- ProFibrix B.V., a leader in the development of innovative products for hemostasis and regenerative medicine, today announced that it has entered into an agreement with CSL Behring for the clinical and commercial supply of plasma-based fibrinogen and thrombin, for the manufacturing of Fibrocaps(TM). CSL Behring is a leader in the plasma protein therapeutics industry and a subsidiary of CSL Limited (ASX: CSL), a global biopharmaceutical company headquartered in Melbourne, Australia.
Jaap Koopman, CEO of ProFibrix said: "We are extremely pleased with the supply agreement with CSL Behring. CSL Behring is one of the acknowledged global leaders in the plasma protein therapeutic industry. Importantly, the agreement will enable us to use CSL Behring's fibrinogen and thrombin, approved in markets around the world, as active components in our lead product Fibrocaps. This will offer us a tremendous advantage with regulatory authorities when seeking approval for Fibrocaps."

About Fibrocaps
Fibrocaps is based on a mixture of two essential blood clotting proteins, fibrinogen and thrombin, and is a unique dry powder topical tissue sealant in development to stop bleeding after or during surgery. Fibrocaps is clearly differentiated from existing liquid tissue sealants and hemostats: it is ready for immediate use, is stable at room temperature, and has shown to be safe and efficacious in the first Phase II study conducted in EU. ProFibrix is starting a global Phase II study in the summer of 2010.

Salient Surgical goes Dutch

ccccccccccccccccccccSalient Surgical Technologies Inc. is going Dutch, opening an office in Amsterdam to spearhead its international sales and marketing efforts.
The Portsmouth, N.H.-based company said it's had a presence in Europe since 2001, when it began marketing a line of surgical sealers, but wants to expand that footprint with its Aquamantys electrosurgical cautery system.
Citing positive results from clinical trials of the device in joint replacement and spine procedures, Salient Surgical said it's aiming to make the system the global standard of care for reducing bleeding during surgery.
Earlier this month Salient and Medtronic Inc. (NYSE:MDT) slapped Bovie Medical Corp. (NYSE:BVX) with a patent infringement lawsuit over the technology used in the Aquamantys system.
The lawsuit, filed in the U.S. District Court for Delaware, accuses Bovie Medical of violating a trio of patents licensed to Portsmouth, N.H.-based Salient with its SEER fluid-assisted electrosurgical system. It seeks a jury trial, a permanent injunction on further infringement, damages on lost royalties and legal fees.
Salient, founded as TissueLink Medical in 1999, banked $15 million from its seventh funding roundin January. Its backers include Medtronic — which owns a nearly 9 percent stake in the company — TLM Investors, QuestMark Advisors and the RiverVest Venture Fund.

Animal Products

Following on from the Bleeding Calf Syndrome posting available HERE and other postings available Here regarding risks of animal sourced products.

I have provided further info above provided by DEFRA. To the best of my knowledge only the UK and Scotland are acting to investigate?

You can follow this link for further details also 'This intriguing disease captures the imagination. The VLA will be working with others to help discover the cause.'

I expect manufacturers will focus efforts on recombinant, plant-based technologies.

While our industry battles achieving financial success in the market with the ideal of creating an agent that is:

• of minimized risk
• efficaious
• cost effective,
• easily deliverable
• and applicable to multiple surgeries

The removal of King Pharmaceuticals crown as leader in the multi- $million Thrombin market by Zymogenetics is

a sure indicator as to market preference and acceptance of these benefits. J&J have a human sourced Thrombin following theirpurchase of Omrix.

Certainly reconstituted animal based technologies are facing severe threats currently as the link between zoonotic diseases (animal/human transfer) become more widely known. While BNP (Bleeding Calf Syndrome) transmission is far from clear it should be of concern. The lack of reporting and individual Government action highlight the inadequacies of public protection even with a cursory investigation.

While Bleeding Calf Syndrome may not pose infection risks via medical devices it exemplifies the public vulnerabilities to weak protection measures from their Governments. This is weak response and is exactly the response delivered that saw vCJD, and Prion borne infections escalate. Harvesting Bovine Materials HERE

New use for old drug could save thousands of lives

A cheap, common drug used to help women with heavy periods could save thousands of lives worldwide, by helping to prevent heavy bleeding after injuries caused in car crashes, shootings, or stabbings.

What do we know already?

Despite advances in surgery and medicine, millions of people die worldwide as a result of injuries caused by accidents and deliberate violence. These types of injuries are usually called 'trauma' by doctors. One of the main causes of death is heavy bleeding.
Heavy bleeding means there's not enough blood carrying oxygen around the body. Organs like the brain and heart stop working without a constant supply of oxygen.
The body's response to trauma injuries is to attempt to keep the blood vessels open, by breaking down blood clots in a process called fibrinolysis. Unfortunately, this can make it hard to stop the bleeding. The same thing happens after surgery, because the body reacts in the same way.
Doctors have used anti-fibrinolytic drugs after surgery for many years, to reduce blood loss. One anti-fibrinolytic drug, tranexamic acid, is cheap and known to be safe. It's also used to help reduce bleeding for women who have heavy periods.
Now researchers have tried using injections of tranexamic acid for people who have serious bleeding from trauma injuries. They carried out a very big study, in 40 countries worldwide, to see whether it would help to prevent deaths from bleeding. Half the people in the study were injected with the drug, and half with saline solution as a placebo.

What does the new study say?

People were less likely to die if they'd had tranexamic acid. In total, 16 percent of people died who'd had the placebo injection, compared with 14.5 percent of people who'd had tranexamic acid. The researchers calculated this could save 100,000 deaths each year worldwide. In the UK, about 1,800 people die each year from bleeding after injury, and the researchers calculate that routine use of tranexamic acid could save the lives of about 280 of these people.
The drug made no difference to the risk of either getting or dying from a complication such as a heart attack, stroke, or blood clot in the lung. That's important, because a drug that works to prevent bleeding might have increased the chances of getting a blood clot that caused this type of problem.
Interestingly, there was little difference in the numbers of patients who needed blood transfusions. About half of people had transfusions, whether or not they'd had tranexamic acid. This might suggest that the benefit of tranexamic acid wasn't purely down to a decrease in bleeding. However, it could also be because more people treated with tranexamic acid lived long enough to receive a transfusion, or simply that it can be hard to tell whether someone needs a transfusion or not.

How reliable are the findings?

The study was a randomised controlled trial, which is the best sort of study for finding out whether a treatment is helpful. The study looked at more than 20,000 patients, and found a clear result that those treated with tranexamic acid were more likely to survive. The results should be very reliable.

Where does the study come from?

The study was carried out by researchers from 40 countries around the world, including countries from Europe, South America, Asia, and Africa. It was published in The Lancet medical journal, owned by the publishing company Elsevier. It was paid for by the UK's Health Technology Assessment programme.

What does this mean for me?

The authors of the study recommend that doctors treating trauma patients should consider using tranexamic acid in cases of heavy bleeding, or where the patient is at risk of heavy bleeding. But writing in a separate article in the same journal, another doctor warns that very high doses of tranexamic acid have been linked to seizures after heart surgery. He says doctors should be cautious, especially if using other types of anti-fibrinolytic drugs.
The proportion of people in the study who died of their injuries may seem high. But that's because many of the injuries happened in parts of the world like rural Africa or India, where it may take longer for accident victims to get good-quality medical care. In a country like the UK, the death rate from injuries is likely to be much lower.

CryoSeal Fibrin Sealant System for Asahi

ThermoGenesis Corp. has made a deal to phase out its production of its CryoSeal wound care product line and license the product to a Japanese distributor.
Asahi Kasei Kurary Medical Co. Ltd. will pay ThermoGenesis $1 million this month so the Rancho Cordova med-tech company will continue to supply CryoSeal while Asahi ramps up production facilities and regulatory approvals in Japan. ThermoGenesis will provide the CryoSeal Fibrin Sealant System for Asahi to distribute in Japan and other Pacific Rim countries for 30 months, at which time Asahi will take over manufacturing.
ThermoGenesis will receive royalty payments on all CryoSeal products Asahi manufactures after the 30 months. Asahi has the option to acquire the CryoSeal line and patent rights any time in the next five years.
ThermoGenesis has enough CryoSeal inventory that it won’t need to engage in any “meaningful” manufacturing in the next 30 months, chief executive officer J. Melville Engle said in a news release.
“The divestiture of CryoSeal is part of our long-term strategy to focus on the development of enabling technologies for the stem cell regenerative medicine market,” Engle said. “This transaction frees up management and corporate resources to address these more strategic market opportunities.”

Spinal Sealant gets CE mark

HyperBranch Medical Technology, Inc. announced today that it has received a CE Mark for Adherus^TM Spinal Sealant. Adherus^TM Spinal Sealant is used in spinal surgeries where a water tight seal is required to prevent cerebrospinal fluid leakage from the dural repair. Prevention of cerebrospinal fluid leaks should benefit the patient in shorter hospital stays and fewer post-surgical complications such as reduced pain and fewer infections. Adherus Spinal Sealant also acts as an adhesion barrier, thereby simplifying subsequent surgeries should the need arise. The unique, single use device is terminally sterilized and can be applied in both Open and MIS procedures through either a 100mm or 150 mm tip. The CE Mark provides regulatory approval for the company to begin sales in Europe and other countries outside the U.S.

“Adherus^TM Spinal Sealant is an easy to use device that complements HyperBranch’s neurosurgical sealant product line. Adherus^TM Dural Sealant, which was first launched in 2009, is currently marketed outside the U.S. for cranial surgery. Adherus^TM Spinal Sealant has negligible swelling, degrades slowly not only provides a watertight seal but also acts as an adhesion barrier to limit scarring, a major advantage if subsequent surgery is required,” said John Conn, President and Chief Executive Officer.

The Adherus^TM products are synthetic hydrogels which polymerize in a moist field, flow optimally depending on the application, and are bio-degradable as the tissue re-establishes itself. The biocompatible composition is stored at room temperature and is delivered through a custom applicator to meet the specific needs of the procedure.HyperBranch Medical Technology, Inc. has now received CE Marks for ocular, cranial, and spinal sealants as well as a hernia mesh fixation product. The Company has completed a U.S. feasibility study and is starting the Pivotal portion of the study this month for the Adherus Dural Sealant. The Spinal product will follow the same approval path in the U.S. The company’s ophthalmic sealant is currently licensed to and marketed by BD Medical.

Scientist has succeeded in producing a replica of human collagen from tobacco plants

A scientist at the Hebrew University of Jerusalem's Robert H. Smith Faculty of Agriculture, Food and Environment has succeeded in producing a replica of human collagen from tobacco plants – an achievement with tremendous commercial implications for use in a variety of human medical procedures.

Natural human type I collagen is the most abundant protein in the human body and is the main protein found in all connective tissue. Commercially produced collagen (pro-collagen) is used in surgical implants and many wound healing devices in regenerative medicine. The current market for collagen-based medical devices in orthopedics and wound healing exceeds US $30 billion annually worldwide.

Currently, commercial collagen is produced from farm animals such as cows and pigs as well as from human cadavers. These materials are prone to harbor human pathogens such as viruses or prions (mad-cow disease). Human cadaver is scarce, and for certain indications possesses serious ethical issues.

Producing human recombinant type I pro-collagen requires the coordinated expression of five different genes. Prof. Oded Shoseyov of the Robert H. Smith Institute of Plant Sciences and Genetics in Agriculture has established the only laboratory in the world that has reported successful co-expression all the five essential genes in transgenic tobacco plants for the production of processed pro-collagen. For this work, Shoseyov was one of the recipients of a Kaye Innovation Award during the Hebrew University Board of Governors meeting in June.

Shoseyov's invention on has been patented, and the scientific findings behind it were published recently in the journal Biomacromolecules. A company, CollPlant Ltd ., has been established based on patents and technology that were developed in Shoseyov's laboratory. It has raised US$15 million to establish the first commercial molecular farming company in Israel and is already manufacturing collagen-based products that have attracted collaborative commercial interest from companies in the US, Japan Europe and Israel.

Yissum, the technology transfer company of the Hebrew University, is one of the shareholders of CollPlant.. CollPlant is a public company traded in "TASE", and the potential revenue for the Hebrew University from this invention is estimated to reach into the multi-million dollar range.

The Kaye Awards have been given annually since 1994. Isaac Kaye of England, a prominent industrialist in the pharmaceutical industry, established the awards to encourage faculty, staff, and students of the Hebrew University to develop innovative methods and inventions with good commercial potential which will benefit the university and society.

Cow Products - Why ?

Bovine Neonatal Pancytopaenia (BNP) is a newly emerging disease syndrome of calves less than one-month-old which has recently been reported in Britain and Europe.
It is often referred to as calf haemorrhagic disease, haemorrhagic diathesis, bleeding calf syndrome or blood sweating disease.
The first cases of the condition were reported in Germany in 2007.Since then, reports of confirmed cases have slowly risen in a number of European countries while the first confirmed case was recently diagnosed in Ireland and there have been four cases confirmed in Northern Ireland to date.

Typically, the clinical signs in young calves can include excessive bleeding from small abrasions of the skin, or even from injection sites, and the passing of large clots of blood in the dung.

Temperature

Calves affected with the condition normally have a high temperature and become rapidly depressed. In the majority of cases, death follows within 24 to 48 hours (mortality of about 90% is commonly reported), with aggressive veterinary treatment, including blood transfusions, normally providing only a temporary respite for the animal.

The disease syndrome tends to affect single calves in a herd although multiple calves have been affected in some herds in Britain and Germany.

Affected calves tend to be found in larger well-managed herds with a large proportion of affected farms also keeping sheep as well as cattle.

Within countries that have identified cases, a geographical pattern to the occurrence of the disease has not been identified nor has any breed or gender association been established.

On post mortem examination of affected calves, significant damage to the bone marrow has been consistently reported.

The bone marrow is responsible for producing the blood cells. Red blood cells are responsible for transporting oxygen, while white blood cells play a role protecting against infection. Platelets are responsible for blood clotting.

Of these three, the platelets are most severely affected, giving rise to the typical clinical signs of poor clotting and widespread bleeding in the calf.

While the cause of the condition is unknown, there is no evidence that the condition is infectious or that it gives rise to food safety concerns.

The fact that apparently normal calves at birth can develop clinical signs rapidly after consuming colostrum has focused the attention of researchers on colostrum. It is possible that colostrum acts as a vehicle for the introduction into the calf of the agent which damages the bone marrow.

During the 24 hours that follow the birth of an animal, the intestine allows antibodies (a form of defence against disease) which are contained in the colostrum to pass from the gut into the blood stream. This is an important step in the transfer of immunity from the mother to her offspring and plays a vital role in preventing disease in the newborn calf.

It is possible that, in a very small percentage of calves, some of these antibodies target the bone marrow cells, leading to the clinical signs of the disease. Indeed, a similar mechanism is known to cause destruction of blood cells in some newborn foals and piglets. Researchers wish to ascertain whether this is the case in affected calves and, if so, to determine what has changed in the cow or her environment which has led to the occurrence of the condition.

The Department of Agriculture, Fisheries and Food's regional veterinary laboratories are available to assist herdowners and veterinary practitioners with laboratory diagnosis and investigation of any suspicious cases.

The Department has offered to provide free post mortem examinations of any young calf with clinical signs typical of the condition.

While the condition is rare, with minimal losses to date, the Department is always vigilant to the occurrence of novel diseases or novel presentations of existing diseases. Herd owners are asked to notify their veterinary practitioner of any young calves with apparent clotting difficulties.