Featured Research

from universities, journals, and other organizations

Natural molecule indirectly prevents stable clot formation

Date:
February 2, 2011
Source:
The Scripps Research Institute
Summary:
A scientist has identified a new role for a natural signaling molecule in preventing blood clot formation. The molecule could become a target for the development of novel and cost-effective treatments for blood clotting diseases such as Hemophilia A.

A scientist from The Scripps Research Institute has identified a new role for a natural signaling molecule in preventing blood clot formation. The molecule could become a target for the development of novel and cost-effective treatments for blood clotting diseases such as Hemophilia A.

The findings, from a study by Scripps Research Assistant Professor Laurent O. Mosnier, were published in a recent edition of Journal of Biological Chemistry.

The study focused on Platelet Factor 4 -- a small cytokine (intracellular signaling molecule) released during platelet aggregation.

Based on Platelet Factor 4 effects on another coagulation protein, it was thought that Platelet Factor 4 could potentially stimulate activation of thrombin-activatable fibrinolysis inhibitor (TAFI) -- an enzyme (soluble protein) that protects clot longevity, making clots last longer and preventing excess bleeding; TAFI is like a hardener that is added to the mortar used between the bricks in a brick wall, without which the mortar would never completely solidify, and the wall would never be solid.

The new study, however, found exactly the opposite role for Platelet Factor 4 -- inhibition of TAFI activation.

For Mosnier, this finding led to a radical idea -- sequestering Platelet Factor 4 using such molecules as heparin derivatives could improve clot stability. Heparin -- a highly sulfated or negatively charged glucoseaminoglycan (polysaccharide or sugar derivative) -- is a commonly used anticoagulant. Mosnier, however, was able to modify the compound to have the reverse effect and aid in blood clotting in laboratory tests.

"The idea of using heparin to prevent bleeding in kids [who have bleeding tendencies] would be outrageous because that would just greatly accelerate bleeding," said Mosnier, "Our trick, however, was to modulate heparin's anticoagulant properties. This opens up new possibilities."

Converting Heparin from an Anticoagulant into a Non-Anticoagulant

Heparin's anticoagulant activity is derived from a specific pattern of nitrogen- and oxygen-linked sulfation (or simply negative charges) that is recognized by anti-thrombin -- the inactivator of coagulation. However, in addition to binding to anti-thrombin heparin also binds to Platelet Factor 4, which is glittered with positive charge, and they attract one another like magnets.

Mosnier found heparin's anticoagulant activity could be prevented, and its Platelet Factor 4 binding selected for, by selectively removing the N-linked sulfations (and further acetylation). This effectively prevented heparin from being recognized by anti-thrombin and allowed it to instead take the Platelet Factor 4 out of the equation. This resulted in prevention of clot breakdown (fibrinolysis), by allowing TAFI to do its job.

To test the effectiveness of the modified heparin derivatives in enhancing clot stability, Mosnier employed a functional assay called a "clot lysis assay." Using a light scattering technique, plasma was used to generate a clot, which was degraded. Further modulation of the conditions allowed measurement of clot stability via TAFI activation. Mosnier found that, indeed, the modified-version heparin promoted clot stability.

Toward a Cheaper, Cost-Effective Treatment for Hemophilia A

An optimistic Mosnier admits his new discovery is in its infancy, but hopes it may one day provide an alternative treatment for bleeding conditions such as Hemophilia A.

Hemophilia A, which affects 1 in 5,000 males, is an X-linked genetic bleeding disorder whereby there is a reduced amount or activity of factor VIII. This results in the unstable clots, lacking fibrin -- a fibrous clot-forming protein. Currently, the treatment for Hemophilia A is prophylactically taking factor VIII as a medicine to improve clotting. Unfortunately, immunity against factor VIII is a significant side effect.

Mosnier hopes that modification of heparin -- which is cheaper than factor VIII and already used clinically -- could one day stabilize clots in these patients.

"The next step is to see if the modified compound will improve bleeding complications in the Hemophilia mouse," said Mosnier. "We are still a long way from claiming anything clinically."

His optimism is contagious, however, and it is an exciting time for science in the Mosnier lab.

This research was funded by a "Pathway to Independence Grant," which enabled the establishment of the Mosnier Lab, from the National Institute of Health (NHLBI Grant HL087618).


Story Source:

The above story is based on materials provided by The Scripps Research Institute. Note: Materials may be edited for content and length.


Journal Reference:

  1. L. O. Mosnier. Platelet Factor 4 Inhibits Thrombomodulin-dependent Activation of Thrombin-activatable Fibrinolysis Inhibitor (TAFI) by Thrombin. Journal of Biological Chemistry, 2010; 286 (1): 502 DOI: 10.1074/jbc.M110.147959

Cite This Page:

The Scripps Research Institute. "Natural molecule indirectly prevents stable clot formation." ScienceDaily. ScienceDaily, 2 February 2011. <www.sciencedaily.com/releases/2011/02/110201084147.htm>.
The Scripps Research Institute. (2011, February 2). Natural molecule indirectly prevents stable clot formation. ScienceDaily. Retrieved August 2, 2014 from www.sciencedaily.com/releases/2011/02/110201084147.htm
The Scripps Research Institute. "Natural molecule indirectly prevents stable clot formation." ScienceDaily. www.sciencedaily.com/releases/2011/02/110201084147.htm (accessed August 2, 2014).

Share This




More Health & Medicine News

Saturday, August 2, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Texas Quintuplets Head Home

Texas Quintuplets Head Home

Reuters - US Online Video (Aug. 1, 2014) After four months in the hospital, the first quintuplets to be born at Baylor University Medical Center head home. Linda So reports. Video provided by Reuters
Powered by NewsLook.com
Ebola Patient Coming to U.S. for Treatment

Ebola Patient Coming to U.S. for Treatment

Reuters - US Online Video (Aug. 1, 2014) A U.S. aid worker infected with Ebola while working in West Africa will be treated in a high security ward at Emory University in Atlanta. Linda So reports. Video provided by Reuters
Powered by NewsLook.com
Ebola Vaccine Might Be Coming, But Where's It Been?

Ebola Vaccine Might Be Coming, But Where's It Been?

Newsy (Aug. 1, 2014) Health officials are working to fast-track a vaccine — the West-African Ebola outbreak has killed more than 700. But why didn't we already have one? Video provided by Newsy
Powered by NewsLook.com
Study Links Certain Birth Control Pills To Breast Cancer

Study Links Certain Birth Control Pills To Breast Cancer

Newsy (Aug. 1, 2014) Previous studies have made the link between birth control and breast cancer, but the latest makes the link to high-estrogen oral contraceptives. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins