What is TPA and what does
it have to do with stroke?

Blood is essential to human life. It nourishes, it warms, it cools and it cleanses us from the inside. If it leaks out, we are in trouble. If we lose too much, we die. To keep this from happening, blood clots are formed.

But blood clots are not always a good thing. Sometimes they form when there is no danger of bleeding. If so, they may harm rather than protect. They are, in fact, the most common causes of both stroke and heart attack. In order to limit the harmful effects of blood clots, the body needs a way to break them down.

TPA stands for tissue plasminogen activator, a protein that is part of the complex system of checks and balances that regulates blood clotting. Its function is to activate the enzyme plasminogen, which dissolves freshly formed clots. Without such a mechanism, unchecked clotting would cause our blood to congeal. If that happened, we would die just as surely as we would with excessive bleeding.

Only minute amounts of TPA are present in the body at any given time, so it is not possible to draw it out and bank it, as one can with platelets (which are important in the formation of clots). Fortunately for us, remarkably clever people found a way to produce TPA by inserting the gene that codes for it into Chinese hamster ovary cells. Tissue cultures of these cells then became TPA factories, churning out medically useful amounts of the protein. TPA produced by this rearranging of genes is termed r-tPA (“r” for “recombinant”), to distinguish it from the naturally occurring variety.

TPA was first approved for use in treating heart attack in 1987. Clinical trials showed the medication could dramatically reduce death rates in heart attack patients. Nine years later it was approved for use in treating stroke. Stroke patients treated with TPA within three hours of symptom onset were found to have a significantly increased chance of recovering without disability.

It was an important advance, but TPA isn’t a panacea. Overall, for every eight patients treated appropriately with TPA, there will be one additional no-disability outcome. Does this mean that seven of eight patients have a bad outcome? No, it doesn’t. In patients for whom TPA is appropriate, as many as three-out-of-eight will escape death or disability without treatment. TPA winds up increasing the odds of a no-disability outcome to about 50/50 (four-out-of-eight). Of course, this understates the overall benefit of TPA because it does not take into account that treated patients may have some disability, but they probably will have less than they would have without treatment.

Like almost everything else, TPA has a downside, opposite to its upside. The downside is the risk of bleeding. When TPA is given to heart attack victims, the risk is fairly low, less than 1%. In stroke patients, however, the risk of hemorrhaging into the brain is around 6%. When this happens, death and disability are more likely than they would have been had the medication never been given. Yet, even when this is taken into account, TPA still boosts the overall odds of a good outcome by about 30% (as noted, four-in-eight, as opposed to three-in-eight).

The benefit-to-risk ratio for TPA in stroke is not as high as we would wish, but it is judged to be favorable. This was not always so. For years after FDA approval, there was controversy. Two of the professional groups most involved in stroke care found themselves on opposite sides of the issue. Neurologists tended to emphasize the benefit and emergency physicians tended to emphasize the risk. Both sides were aware of the same data, but their interpretations of that data couldn't have disagreed more.

To my knowledge no one has accounted for this difference of opinion. Perhaps it arose in part because the two groups saw stroke from different vantage points, over different time frames. Emergency physicians saw stroke acutely and briefly. Neurologists saw stroke later and over long periods of time. This may have led to a difference in how they viewed the illness. For neurologists, stroke was a terrible thing. For emergency physicians, it may have seemed less terrible.

With time and further experience in using TPA for stroke, the controversy has died down. The two sides have moved closer to a consensus. TPA is endorsed if given in the right way, to the right patient, in the right time frame. In other circumstances it is to be avoided.

Choosing the right patient is the biggest challenge. The time frame for administration of the drug is currently within three hours of symptom onset. Yet, we know that there is nothing fundamental about three hours. Some patients can benefit from TPA well beyond three hours, while others will have no chance of benefit even if they are treated in the first hour. Much depends on the “collateral circulation,” a variable that indicates how much redundancy there is in the circulation to the part of the brain that is at risk because a portion of its blood supply is blocked. People with good collateral circulation can benefit from TPA much later than those with poor collateral circulation.

Unfortunately, there is no reliable way to assess collateral circulation on clinical grounds. Sophisticated physiologic-imaging studies offer the promise that we will be able to confidently measure the collateral circulation in the future, but we are not there yet. Once we do have a better understanding of which patients are likely to benefit, the benefit-to-risk ratio of TPA will doubtless increase.

TPA is not the only way to reopen clot-blocked arteries. Several other drugs have similar mechanisms of action, but none of them is yet FDA-approved for use in stroke. Mechanical means of opening arteries have proven very useful for heart attack patients, and this is now an option for stroke patients as well. Combinations of mechanical and medication treatments are probably the future of acute stroke treatment.