Meningitis research focuses on protein C

 

Meningitis strikes like a thief in the night, giving little warning and leaving families to cope with the loss of a loved one. The Department of Health and Children this month launched an immunisation drive against one strain of the disease, Meningitis C. New treatments for those who contract it are also on the way.

Much of the research focuses on a protein found naturally in the body called protein C. It helps to control blood clotting; when protein C levels fall too low dangerous clotting can occur.

Dr Owen Smith, a consultant paediatrician and haematologist at St James's Hospital and a senior lecturer in the Department of Haematology at Trinity College, has done important ground-breaking studies of protein C. He has looked at inherited protein C deficiency and also how its levels can suddenly collapse in blood poisoning or septicemia, particularly that brought on by meningitis.

"It all began when I was training at Great Ormond Street Hospital," he said. He was screening children for an inherited disorder, Pupura fulminans syndrome, which causes severe blood clotting in the skin. The disorder is caused by low levels of protein S which in turn causes a deficiency of protein C.

The two proteins work together to control clotting, he explained. "They prevent you from inappropriate clotting." Without them a person would face a lifelong risk from spontaneous clotting.

Amongst his most frequent early cases on his return to Dublin and St James's were children presenting with meningococcal septicemia. One telling symptom is purple dots on the skin which remain visible when pressed; but these looked very similar to those seen in Purpura fulminans.

This sparked research into the protein C levels in patients with septicemia and he quickly found that, like the inherited cases, these patients were severely deficient in protein C. A lack of the protein in sepsis patients initially caused blood clotting in the skin and eventual organ failure, with a very high risk of death.

He decided to try treating sepsis patients with protein C concentrate and in 1997 he published a paper with colleagues in the Lancet. The early results were dramatic. Twelve patients were treated and none of them died. An average of 50 per cent of patients with sepsis usually die.

Since then much work has been done at the National Centre for Inherited Coagulation Disorders at St James's, in co-operation with the Functional Coagulation Unit at the hospital, Dr Smith said. He also mentioned the contribution of Dr Wendy Livingstone and Dr Barry White at the Thrombosis Haemostasis Laboratory at the Smurfit Institute of Genetics at TCD. Financial support for the work has come from the hospital, the university and also the Health Research Board.

Dr Smith, in his latest research report involving a much larger group of patients, describes how they responded to treatment with protein C. It will be published in a leading scientific journal this December. As with the earlier work, this new research shows administration of protein C can significantly reduce the degree of illness and death from sepsis brought on by meningitis. "The findings are extremely encouraging," he said.

Work on the biochemistry of protein C has also proceeded, he said, and it now emerges that the protein is a powerful anti-inflammatory agent. "Protein C was discovered to be a natural anticoagulant, but it has very potent anti-inflammatory effects. It is inhibiting cytokine release."

Cytokines are key immune system messengers, released in response to injury or infection. They help initiate a cascade of immune and inflammatory responses that would normally help protect the person. But in sepsis this response can spiral out of control.

"We decided to look at protein C and its effects on the cytokine network. We wanted to know how it does it," he said. "The key player in initiating coagulation in sepsis is a molecule called tissue factor." Once expressed it leads to blood clotting, but protein C serves to "down-regulate" tissue factor expression.

What has been learned in these biochemical studies should also help improve treatments for patients with sepsis, Dr Smith added. Patients can be screened to determine how well they will respond to protein C treatment. "We are actually defining the diagnostic variables."

The research, he said, highlighted the benefits of having strong links between scientists conducting research and doctors involved in clinical practice. The initial basic research activities were prompted by findings in patients.

It also showed how apparently minor initial findings could have a major international impact, he added. "Something that happens to a small cohort of patients with meningacoccal septicemia has huge implications for patients in emergency wards around the world."