Urokinase

DURING DINNER, ONE OF MY TWIN DAUGHTERS grabbed the ringing phone and announced that Sid was on the line.

* "I've got a 64-year-old woman who had a left hemisphere stroke," Sid said excitedly. "She fell into her husband's arms on the way to a movie. Happened about a half hour ago. She's getting a CT scan."

* "Great," I replied. "I'll be right in. Is Gary on his way?"

* "You bet."

* I turned to my wife and kids. "A lady just had a big stroke. Gotta go in." My wife looked perplexed. "What's so great about that? Why are you smiling?"

* "It just happened," I said. "So we still have a chance to rescue some brain tissue."

* "Go save the lady, Daddy," the girls sang out as I rushed to the car.

* I am one of the neurologists on a team at a university hospital that treats acute stroke patients. Sid is an emergency room physician at my hospital, and Gary is a neuroradiologist who helps us diagnose where the stroke occurred.

Until very recently, doctors have been able to provide little more than supportive care and rehabilitation to stroke patients. Strokes are "brain attacks": just as a heart attack is caused by a blockage in a blood vessel in the heart, strokes are most commonly caused by a blockage in a blood vessel supplying the brain. In both conditions the clogged blood vessel deprives nearby tissues of oxygen and nutrients, causing cells to die. Although clot-dissolving medications are often used to treat heart attacks, only recently have these medications been tried for breaking up the clots that cause strokes. If we acted fast enough, we might be able to prevent long-lasting brain damage. When I got to the emergency room, Sid led me into Mrs. Alberts's curtained partition. He had already told her husband what we had in mind. I introduced myself to Mrs. Alberts. At the sound of my voice, she turned her head and looked toward her husband, who was swaying nervously back and forth on the opposite side of the gurney. Then I stood to the right of Mrs. Alberts, waving my hand as I spoke. She still couldn't locate me. I moved toward Mr. Alberts, shook his hand, and then clasped Mrs. Alberts's left hand. She tried to smile, but only the left side of her mouth responded. Her right arm and leg flopped lifelessly. She could not speak, not even to repeat anything that her husband or I said. Nor could she understand anything we said. When I asked her to point to her nose or snap her fingers, she just shrugged her left shoulder and kept smiling. Mrs. Alberts looked calm and expectant, as if the movie she,d set out to see were about to begin.

Broadly speaking, the brain is organized so that the left hemisphere controls language and the right side of the body, whereas the right hemisphere controls the left side of the body and some kinds of spatial and emotional perception. A stroke in Mrs. Alberts's left hemisphere had disabled her control over the right side of her body and completely obliterated her ability to comprehend speech and to speak.

A deceptively normal-looking CT scan of Mrs. Alberts's brain hung on a light box nearby. It would take hours for the brain swelling that eventually accompanies stroke-related damage to show up. We would have to use other methods to detect the clot's location. But first we needed to know Mrs. Alberts's history.

According to Mr. Alberts, his wife had always been healthy except for an irregular heartbeat. A childhood bout with rheumatic fever had damaged her heart valves and predisposed her to developing the irregularity. That condition slowed blood flow in the left atrium, and when this happens blood clots can form, increasing the risk of stroke. To counteract this effect, Mrs. Alberts had been taking warfarin, an anticoagulant that "thins" the blood.

OVER THE PREVIOUS FlVE YEARS, THIS strategy had partially disabled Mrs. Alberts's clotting proteins. Our lab test results, however, showed that Mrs. Alberts's blood was clotting as if no warfarin were onboard. With her blood now "unthinned," a jellylike clot had formed, and her heart had probably pumped it into one of the main arteries supplying the brain. But Mr. Alberts protested that his wife's level or clotting proteins had been fine when she was tested just two weeks before, prior to a cruise the couple took to Alaska.

"Did she eat differently on the trip than you would at home?" I asked.

He folded his arms over his barrel chest. "Well, we ate more, especially more salad than usual, I suppose."

"How about cauliflower, broccoli, chickpeas, and lettuce?"

He nodded yes. "They're supposed to be healthy for you."

All these foods are fine, but they are also high in vitamin K. Since warfarin works by inhibiting the formation of blood-clotting proteins that depend on vitamin K, eating vitamin K-rich foods may counteract its effect. Mrs. Alberts had probably suffered a stroke because she had loaded up with too many veggies.

Mr. Alberts and I stepped into the hall-way and met with the Albertses' son and daughter. I explained that if we acted quickly, we might be able to restore blood flow to their mother's left hemisphere before irreversible damage occurred. Gary would have to perform an arteriogram, a delicate procedure in which a thin plastic catheter is inserted into a large artery in the thigh and threaded up through the aorta into the brain's arteries. Once the catheter was in place, he would inject a dye that would show up white on an Xray, revealing the pattern of the brain's blood supply. If the arteriogram turned up a clot blocking a major brain artery, as we suspected, Gary would inject a clot-dissolving drug called urokinase into the clot

Urokinase has been available for 30 years to treat heart attack patients, but its use in treating stroke and that of heart attack drugs such as tissue plasminogen activator--is still experimental. About half the time urokinase or other anticlotting drugs are injected into the brain, they fail to break up a clot. They can also produce serious side effects. The catheter or even the drug itself may dislodge the clot or material from the blood vessel wall and cause another stroke. The drugs may also cause bleeding in the brain by hindering the function of blood-clotting proteins.

"What are the alternatives?" Mrs. Alberts's daughter asked.

"The best available treatment is to support her blood pressure, prevent medical complications such aspneumonia, and hope that the clot dissolves on its own, or that other blood vessels in the brain can compensate for the blocked artery," I answered. "We are also doing a study of another drug to see if it can protect brain cells if given within the first six hours after stroke. The trial is designed so that your mother could be assigned a placebo or the trial drug. She can take part no matter what you decide about the urokinase."

"What are the chances that the clot will disappear without risking the urokinase?" the son asked.

"There's a natural balance between the clotting proteins that prevent us from bleeding too much when we suffer a cut and the clot-dissolving proteins that prevent blood from making clots, called thromboses, in our body," I said. "So the clot in your mother's brain could spontaneously melt away. If that happens very soon after the stroke, patients sometimes improve quickly--so quickly that some neurologists call the recovery the 'spectacular shrinking deficit, The problem with waiting is that only about 50 percent of the clots that reach the brain from the heart will break up on their own within three or four days after a stroke. Even if they do, brain tissue will have perished by then. Unless blood flow is restored within about six hours, neurons will die."

They looked at each other and then at me. We were complete strangers, thrown together during a crisis. "Most folks--and many doctors-don't realize that a stroke can be managed as urgently as a heart attack," I added. "When we have the opportunity to try to dissolve the clot, we recommend going for it." They agreed that we should try the urokinase. So did their family doctor.

Mrs. Alberts's stroke was just 70 minutes old when the arteriogram revealed a clot blocking the large middle cerebral artery, which feeds much of the left hemisphere. Gary gently stabbed the clot with the tip of the soft, flexible catheter tubing and ran the urokinase through the catheter into the clot. Every few minutes, he squirted in a little dye to see if the blocked blood vessel had opened. Between injections, I reexamined Mrs. Alberts. After more than half an hour, nothing had changed. She remained paralyzed on her right side and mute. The clot had resisted all of Gary's efforts. We had to give up before Mrs. Alberts got so much of the urokinase that she,d start bleeding into other parts of the brain.

I sent Mrs. Alberts to the intensive care unit with one of my neurology residents while Sid and I, barely able to conceal our disappointment, gave the bad news to the family. They agreed to allow Mrs. Alberts into the clinical trial of the experimental drug we had mentioned earlier. Neither Sid nor I considered this much of a consolation prize.

When I finally returned home, my kids were in bed and about to fall asleep. "Did you save the lady's brain?" they asked.

"Still working on it."

Early the next morning, I found Mrs. Alberts surveying the hospital bustle from her glass-enclosed ICU room. The vision in her right visual field had returned. She welcomed me, the left corner of her mouth lifting into a half-smile.

"Hey, how do you feel?" I asked.

I did a double take when she answered, "Okay." I then asked her to repeat a few simple words and phrases. After a few attempts, she could repeat single words such as "dog," though she couldn't yet manage short phrases such as "I walk the dog." When I asked her simple questions, she could answer yes or no, but she could not yet express her thoughts. Her right arm was still paralyzed, but she had regained a flicker of motion in her right foot and hip.

A test that measures blood flow through the large brain arteries revealed that the clot had broken up. The urokinase may have hastened the blood's natural clot-dissolving mechanisms, but there was no way to know for sure. What we were able to tell from a magnetic resonance imaging scan was that most of Mrs. Alberts's left hemisphere had been spared, so blood flow had probably resumed soon enough to rescue much of the oxygen-deprived tissue. But there was an area the size of a quarter deep in the left hemisphere that had sustained at least some damage. This region helps coordinate movement and some linguistic abilities.

The next morning Mrs. Alberts took me by the hand and said, "I hope you're okay" and hugged me. She could name a few items that I pointed to, including her nose and my tie, but called the picture of a glove "a hat" and a bird's feather "a pole." And she could quickly and smoothly repeat several phrases with only an occasional mix-up of consonants. Other skills were also returning. She could lift her right leg above the bed and wiggle her toes. The shrinking of the deficit was almost spectacular.

A FEW DAYS LATER, MRS. ALBERTS was ready to start therapy with our rehabilitation team. Their aim would be to improve the use of the brain pathways that had been partially spared from injury and try to retrain neighborhoods of brain cells and parts of the widespread networks that help carry out language and movement. The physical and occupational therapists would also help her learn ways to compensate for disabilities that kept her from taking care of herself

At first, the physical therapist had to hold Mrs. Alberts steady and swing her right leg when she took a step. Two weeks later Mrs. Alberts was walking on her own, moving cautiously, like some one picking her way across a slippery, iced-over pond. After another week she could walk with just an ankle brace and a cane, with only a slight limp. She could even lift her right arm to reach out, though her fingers twitched uselessly when she tried to grip something. Mrs. Alberts had learned to dress, eat, and bathe with some supervision, despite her weakness and lack of fine motor skills. And she could correctly name 9 of the 20 pictures I showed her.

"When do . . . When do we . . . " She gave me her gosh-darn look of frustration and sighed. "When is home?" she blurted. "Oh, I did it!"

"Good work," I cheered. "You'll be well enough to leave in a few days. Your husband is getting some equipment for the apartment, and the therapists want to spend a bit more time training him to help you get around."

"I love . . . all of you," she said. At a follow-up visit three months later, Mrs. Alberts was able to raise her right arm overhead and open and close her hand slowly. Her movements were painstaking and deliberate, as if powered by a mechanical crank rather than a finely tuned power source. She walked with a slight limp, but she no longer needed a brace or a cane. And she could correctly name 16 of the 20 pictures I had shown her in the hospital. Although the struggle to speak sometimes left her in tears, she said the words were beginning to come more easily.

Mrs. Alberts's rapid recovery may have been helped by our experimental use of urokinase to break up the clot. But the result of a single experience is not enough to change established clinical practice. Only large clinical trials that compare treated patients with untreated patients can tell for sure whether a particular drug will actually help a patient recover. Those tests depend not only on the support of drug companies but also on the cooperation of many patients and physicians. We later learned that the experimental drug we had given Mrs. Alberts in the framework of a clinical trial involving 500 patients had been no more effective than a placebo.

"How's the nice lady who had a stroke?" asked one of my daughters.

"Going on a cruise with her grandchildren," I said. On this trip she would carry a list of foods rich in vitamin K.

"Cool," chimed the twins. Spectacular, I thought.

COPYRIGHT 1996 Discover
COPYRIGHT 2004 Gale Group