The river of life – protein C disease case study

Daniel C. Weaver

Slowly at first, ever so slowly it began, creeping as stealthily as a cat through her mind. At first she noticed little lights flickering at the edge of her vision. Angela ignored them, like the little floaters in our eyes that slip out of sight when we glance at them quickly. But these strange lights flickered with no relation to movement. They came and went, came and went, until one day the flickers became flares and then just as quickly vanished. These were Angela’s first symptoms, but only some years later did we know.

I am a pathologist in Jasper, a town of 10,030 embedded in the soft folds of southern Indiana. The town is known for its German heritage, its hardwood, and its Catholic church, St. Joseph’s. Hewn over a century ago from the surrounding hills of sandstone and hardwood, St. Joseph’s rises nearly 100 feet from floor to groined nave. The bright green tiled roof marked with crosses is held aloft by 14 yellow poplar timbers three feet in diameter, now wrapped in a blanket of sandstone. On the east side of the church stands our watchtower, a sandstone sentinel holding six tons of iron bells. When the wind is right, I can hear the peal of the bells in the hospital.

I ran into Angela at our blood-draw station over a decade ago. A thin woman in her early twenties, she sat in a chair with her right leg propped up. I knew her already; she was a clerk on the third floor. I said, “Hello. What brings you here?”

“My leg. It’s swollen. Dr. Kay thinks it’s a clot.”

Dr. Kay was an obstetrician. “I didn’t know you were pregnant.”

“Twelve weeks,” replied Angela.

“Well, congratulations. I’ll take a look at your blood and see what it tells me.”

Later that day I began my journey into Angela’s blood, into the complex river of her life. Blood is composed of three cell types and a multitude of proteins and small molecules. It flows out of the heart, through the aorta into ever-diverging arteries and arterioles, to empty finally into a network of channels known as the capillary bed. Here, along 60,000 miles of tortuous canals, occur the exchanges of oxygen and carbon dioxide that keep us alive.

Our blood cleans and nurtures the trillions of cells in our bodies. It brings in the oxygen we need and carts away the carbon dioxide waste we excrete. It fights bacterial invaders, attacks traitorous cancer cells, and feeds us with sugars, fats, and proteins. Once the blood has fed and washed our cells, it flows from the capillary bayous out into the venules and veins, and then returns to the heart and lungs. The exchanges occur without the river’s ever leaving its banks. But even if the blood vessels are breached by a nick or a cut, blood is capable of one other remarkable feat: it clots.

I began my examination of Angela’s blood. A single drop of blood, smeared across a glass slide and highlighted with red and blue stains, can tell quite a tale. Abnormal, misshapen, or fractured blood cells can be a sign of leukemia, anemia, malaria, babesiosis, or any of the hundreds of other diseases that show up in the blood. But Angela’s blood was strangely silent. The numbers of cells, their types and shapes, were all perfectly normal. I didn’t see anything that would explain why she had formed a clot–a thrombus–in her leg vein.

I called Dr. Kay and told him I saw nothing unusual in Angela’s blood. Her condition was most likely related to her pregnancy. Perhaps her increased estrogen levels were somehow affecting blood flow, or perhaps the pressure of the developing fetus on the pelvic veins was slowing blood flow from the leg to the heart, creating prime conditions for clot formation, or thrombosis. The absence of clear-cut findings was not surprising, I thought, given the little we know about why some patients experience inappropriate clot formation.

Later, though, my thoughts returned to Angela. She did not have any of the risk factors that can slow down blood flow and set the stage for clot formation. She was not obese, she was not immobile or sedentary, she had not had recent surgery or cancer. She was in such an early stage of her pregnancy that I doubted the developing fetus could be impinging on her pelvic veins. Perhaps something else was up. Perhaps Angela had a defect in her clotting mechanism.

Clotting is one of biology’s most complex and dynamic events. More than two dozen proteins and other factors regulate the mechanics of the process. Some initiate clotting, while others limit how big a clot will get. If we did not keep a tight rein on the clotting mechanism, a simple paper cut could end up clotting all the body’s ten pints of blood. But if blood did not clot, we could ooze to death from tender gums.

Later the next day I called Dr. Kay and suggested we test Angela’s blood for abnormalities in the proteins that rein in clot formation. On the following day we sent fresh vials of Angela’s blood to Washington University in St. Louis for additional analysis.

There are at least three major proteins in the blood that serve as brakes on clotting–protein S, protein C, and antithrombin III. If any of these are absent, defective, or too few in number, spontaneous blood clots can form. Once formed, they can stop the flow of blood to an organ and damage it.

A few days later Angela was worse. An ultrasound examination revealed that clots were forming in both of her femoral veins, the large vessels that carry blood through the thighs on its way back to the heart. She was confined to bed to prevent the clots from moving upward.

Within a few more days we had the results of the blood analysis. Angela had only 45 percent of the normal levels of protein C. We had the answer for her thrombosis.

Protein C deficiency is one of several inherited clotting disorders. Most patients who suffer from the deficiency don’t experience symptoms until their late teens or early twenties. We don’t really know why. We do know that protein C deficiency has a distinct predilection for appearing first during pregnancy. And we do know that it runs in families. In fact, Angela’s aunt had suffered from thrombophlebitis, an inflammation of the veins that often accompanies thrombosis.

Fortunately, most people with protein C deficiency do well. Though every patient with the disorder has inherited at least one defective gene encoding protein C, very few have symptoms. Indeed, one large study turned up protein C deficiency in one of 200-300 individuals, but the disease caused medical problems in only about one in 20,000. Why clinical problems are so rare is unknown, but it may be that genetic variations in blood chemistry allow some people to get by with lower levels of protein C.

Now that we had a diagnosis, we needed to reduce Angela’s risk of clot formation with anticoagulants. The only suitable anticoagulant for pregnant women is heparin, which cannot cross the placenta. After two weeks of treatment, the clots broke up and normal blood flow returned. The swelling in Angela’s legs went down and she could walk without pain. Although a second ultrasound turned up some narrowing in her femoral veins, Angela seemed much better. We crossed our fingers and hoped.

In the thirty-ninth week of her pregnancy, Angela delivered a healthy baby girl. Four days later, her legs were swelling and inflamed. This was a clear sign that blood clots were forming in her deep pelvic veins, impeding blood flow. Angela remained in the hospital for six weeks while we treated her with anticoagulant drugs. Eventually we were able to send her home.

For the next four years Angela did relatively well. She had two more incidents of clotting in her legs, which we were able to treat.

Then, one late May, she came to our emergency room with acute shortness of breath. A chest scan revealed that her right lung was not receiving normal blood flow. Angela probably had a clot in one of the arteries carrying blood to her lungs. We hospitalized her and began to hunt for the clot source. Clots in the pulmonary artery usually do not form there; they form elsewhere in the body, such as the pelvic veins, and then pass through the heart to the lungs. We searched her legs,and pelvis but found nothing. Then, in the right side of her heart, where blood is received from the body and pumped out to the lungs, we found a clot, a huge clot that if dislodged would flow out of the heart into the forking of the pulmonary arteries and stop blood flow to the lungs. Angela would die before we could do anything.

After talking to her husband, we referred Angela to the university hospital in St. Louis. A few days later, surgeons there opened her heart and removed the clot from the right atrium, one of the two muscular chambers of the heart’s right side.

After she returned to Jasper, she came to the lab every month or so to have her blood drawn. She became, as do many patients with a chronic disorder, an excellent student of her disease. She asked me once about her daughter, Clara, and whether she should be tested. I said no, not at the time. Clara had only a 50-50 chance of carrying a defective protein C gene, I explained, and even if she had the disorder, there was no treatment for her condition. Moreover, she would not be likely to experience any symptoms until her middle to late teens. I could see no reason to label a child with an inherited disorder when she might never suffer any effects. I reminded Angela that most patients with protein C deficiency do well. Most patients do not suffer as she had. It was then that Angela told me about the lights.

“They’re back,” Angela said.

“What’s back?” I asked.

“The lights, the lights I saw as a child. I saw them again last night.”

“What lights?” I asked.

“The lights that I see in my eyes. They’re like flickers or flashes that just come and go and come and go.” She paused and said, “I think I know what they are now. They’re clots, and they’re in my brain, aren’t they, Dr. Weaver?”

I mumbled a reply: “I really can’t answer that, Angela. I just don’t know.”

Two years later–six years after I’d first peered into Angela’s blood–I got the phone call I feared would someday come. Angela had died. Dr. Kay was requesting an autopsy.

The autopsy is the physician’s final act. It is the parting of the flesh, the opening of the cavities, the removal of the organs for inspection, first with the fingertips, then with the eyes. A portion of each organ is saved for later analysis under the microscope. As I held Angela’s heart, I felt the firmness in the right atrium. When I opened the heart, I saw a fractured clot. In her lungs, I found its remnant, wedged between the two pulmonary arteries. The great rivers of life had been dammed. For Angela, it was a quick death.

The next week I finished my examination of Angela. Each organ, under the microscope, has its own special hue. The brain is a delicate soft pink, the color of cotton candy on the Fourth of July. As I scanned across Angela’s visual cortex, I saw little gray flecks that I suspected were scars. Although the physician in me does not know what they represent, the man in me believes that those scars were the source of Angela’s flickering lights.

It has been 11 years now since I began my journey into Angela’s blood. Her husband is remarried. I see him and his wife and Clara at church, in St. Joseph’s. As near as I can tell, everything seems all right. But Clara is just now nearing the danger zone, and the family has not tested her blood. I cannot blame them.

I still follow the literature on protein C disease, and we are beginning to get a clearer picture of genetic risk factors. Insufficient amounts of protein C are not the only problem. In 1993 investigators in the Netherlands discovered that 10 to 30 percent of patients with thrombotic disease have sufficient levels of protein C. In these patients, the problem lies in a defect in a regulatory protein that normally binds protein C.

Unfortunately, treatment of thrombotic disorders remains primitive. But there is hope. The genes for many clotting proteins have been isolated. Some patients, mainly infants born with two defective protein C genes, are being treated successfully with purified synthetic protein C. The science of clotting has been moving fast. For the Claras of this world, however, the race remains–between the speed of molecular research and the biology of their inheritance.

Meanwhile, here beneath the oaks and the poplars, in the rolling hills of Indiana, hills rounded with time, we do all that we can. We wait, we watch, we listen. And we pray.

COPYRIGHT 1997 Discover

COPYRIGHT 2004 Gale Group

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