Damaged veins heal faster with heparin treatment, laboratory study finds

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The findings, made in laboratory mice, add more evidence to support the aggressive anti-clot efforts now under way at American hospitals and nursing homes. Those efforts are aimed at preventing many of the 300,000 deaths that occur each year when clots break free of vein walls and travel to the lungs.

The new study, published in the March issue of the Journal of Vascular Surgery, looked at the impact of low-molecular weight heparin, or LMWH, a form of anti-clotting medication that is often given to hospitalized patients. It's different from the unfractionated form of heparin that has recently been the subject of safety concerns.

Researchers from the U-M Section of Vascular Surgery created venous clots in laboratory mice, and studied how the size of the clot, the damage inflicted on the vein wall, and the natural repair process in the cells of the vein wall changed over time. Some of the mice received LMWH before the clot was formed, while others received it afterward. Another group of mice received no heparin.

"Mice that received LMWH before their clot formed went on to experience a much faster and more complete healing process, compared with those that received LMWH only after the clot was formed and those that didn't receive the drug," says senior author Peter Henke, M.D., an associate professor of vascular surgery. "And among those that received LMWH only after the clot was formed, the mice that got treated the soonest after clot formation healed the fastest and the most completely."

The experiments, performed in U-M's Conrad Jobst Vascular Surgery Research Laboratory, simulated a human condition called deep-vein thrombosis, or DVT. That's the term for blood clots that form in the veins of the lower limbs, clinging to and damaging the vein wall. When such clots break free and travel to the lungs, they're called pulmonary embolisms or PEs.

A million Americans each year suffer DVTs, many of them during a hospital stay - and many of them without symptoms. About half go on to develop a PE, which causes sudden symptoms and must be treated immediately. Still, more than half of PE patients will die - making the condition one of the most preventable causes of death among hospitalized patients.

LMWH is increasingly prescribed to hospitalized patients who might be at risk of developing DVTs and PEs, especially older people, surgical patients, and people with a personal or family history of clotting problems. DVTs are especially likely to form in legs that are immobile for long periods of time, that have been injured, or that have poor circulation. Cancer patients, pregnant women, and overweight people are also at higher risk of developing one.

As the body's own repair mechanisms break down the clot, they often leave behind a small patch of damaged vein wall that is never fully repaired, and interferes with the vein's ability to push blood back up to the heart - a situation called chronic venous insufficiency. The damaged area may also be more hospitable for future clot formation.

LMWH helps encourage the breaking up of clots, and prevents new ones from forming. So, the U-M researchers, led by Henke and former U-M medical student Daria Moaveni, M.D., set out to see how the cells of the vein wall, or endothelium, react to a DVT when the drug is present.

First, they studied the "natural history" of DVTs by performing detailed molecular analyses of the vein wall tissue in the area of a clot after one, four and 14 days.

They found that the clots grew over the first four days, then began to shrink as the body's repair mechanisms kicked in. Using a special stain, the researchers could see endothelial cells and vascular smooth muscle cells dying off immediately after clot formation, and then saw new ones growing in the vein lining in the clot-damaged area.

Then, the researchers induced DVTs in the three groups of mice in the heparin experiment. The mice that received LMWH before the DVT formed had the fastest endothelial repair, followed by those that received LMWH soon after the DVT was induced. The biggest difference was seen at four days after the DVT formed, but by day 14 the two heparin-treated groups of mice had about the same extent of repair. The pre-treated mice had the greatest recovery of the vein wall lining.

Using real-time polymerase chain reaction tests, the researchers were also able to look at patterns of gene expression in harvested veins in culture. As with the cell staining, they saw signs that the pre-treated mice reacted in a way that suggested fastest recovery.

While the new results can't immediately be translated into human patients, they do help illuminate the process by which LMWH works - including the advantages of pre-treatment in at-risk patients, or early treatment of patients in whom a DVT has formed.

"Hospitalized patients who are on prophylactic heparin can still develop clots, but these results suggest that having heparin 'on board' can lessen the long-term impact of a DVT," says Henke. "At the same time, our findings also suggest that rapid heparin treatment after a DVT forms is important for long-term healing." This conclusion is supported by a previous U-M study, published in Thrombosis and Haemostasis in 2007, showing that the longer a clot is in contact with a vein, the worse the damage.

Now, the team is studying the proteins in the vein wall that are involved in promoting endothelial health and regeneration after an injury or other insult. They're also working on the clinical level to increase the appropriate use of preventive measures among patients hospitalized at U-M. A new standardized risk-factor assessment tool is now in use among all surgical patients, and will soon be used in all U-M hospital patients, to determine which patients need prophylaxis the most.

University of Michigan Health System