How this doctor is combatting a gravely serious clotting condition

When a 67-year-old man entered the office of Giselle Salmasi, MD, seeking a second opinion about a severe, mysterious blood-clotting condition, she knew she needed to act quickly.

"There was an urgency to find answers," said the Stanford Medicine clinical associate professor of hematology.

It turned out that the man's condition was new to medicine; it had been pinpointed in others only a year earlier by a doctor at the Mayo Clinic. What she was seeing in this patient seemed to match the symptoms and test results that define this new disease. She sent his samples to Rochester, Minnesota, for confirmation.

After testing, the condition -- known as monoclonal gammopathy of thrombotic significance -- was confirmed. Now, it was up to Salmasi to figure out how to treat it. Just six weeks later, she did -- and the patient has now been in remission for eight months.

"He and his family had a remarkable will to continue fighting this recently identified disease," she said. "If he hadn't pushed through and if his family hadn't been keen on trying something new, we wouldn't be here today with a treatment option that works."

Salmasi calls him the index patient for this treatment, the medical term for a disease's first treated individual. He had almost died several times from dangerous clots. The disease, MGTS, was first described by the Mayo Clinic's Anand Padmanabhan, MBBS, PhD, who became Salmasi's collaborator. The two published an article about diagnosing and treating the newly found disease in The New England Journal of Medicine in August.

MGTS is a type of monoclonal gammopathy, a disease in which antibody-producing "factories" in the body called plasma cells start making large amounts of abnormal proteins. The better-known version is monoclonal gammopathy of unknown significance, common in older men. It doesn't usually have symptoms but can develop into multiple myeloma, a type of blood cell cancer.

MGTS, on the other hand, has symptoms. The antibody created by the MGTS plasma cell activates platelets, resulting in blood clots. In the case of this patient, the excessive blood clotting showed up as deep vein thrombosis, pulmonary embolism, abdominal clots and a stroke.

Padmanabhan said he has gratitude for Salmasi's clinical expertise and her ability to "look carefully at this patient who is really sick, might be dying, and ask 'What does he have?'"

"Dr. Salmasi developed a treatment for this disease for the first time," he said. "It's already having an impact way beyond the walls of her institution or her patient. I have shared this paper with multiple other patients I'm following worldwide who are now seeking out and undergoing this treatment."

We spoke with Salmasi about this successful collaboration and its implications for those who might develop MGTS. This interview was edited for clarity and length.

When you first met this patient, what made you think his case might be unusual?

He had had several blood clots that had already resulted in severe outcomes. He had a significant portion of his small bowel removed and nearly died from blood clots in his lungs. Miraculously, he recovered, coming to me about a year later for a second opinion.

The first thing that came to my mind was an autoimmune or spontaneous heparin-induced thrombocytopenia (HIT) syndrome. The hospital and his primary hematologist had ruled out other causes of clotting and low platelets.

He had been on blood thinners and aspirin. But during this time, he had a major stroke (a blood clot in the brain) that resulted in an intensive care unit admission. This was yet another near-fatal clotting event over a short period. So, there was that urgency to find answers.

Dr. Salmasi developed a treatment for this disease for the first time. It's already having an impact way beyond the walls of her institution or her patient.
Anand Padmanabhan

I could see there was something atypical going on. I started speaking to our special research lab about how to do additional testing for atypical spontaneous HIT. Because Stanford Medicine is an academic center, we knew who the right person would be to test this. We had suspected MGTS based on the lab's findings and contacted Anand. That's how it came together so beautifully that we were able to collaborate on this. The patient joined his research study designed to develop ways to diagnose these patients. Our patient tested positive for MGTS.

No other doctors have effectively treated this disease -- how did you figure it out?

This disease is caused by a protein secreted by plasma cells, which are white blood cells. This protein causes massive clotting. It's proving to be one of the worst clotting disorders that has been described. Clearly, blood thinners are not sufficient. This protein is still there, wreaking havoc and causing clots. We have to decrease the levels of that protein. So, we borrowed the treatment approach from therapies for multiple myeloma, which kills plasma cells.

I decided to put him on a standard multiple myeloma regimen, but one that doesn't have clotting as a side effect.

How did the treatment go, and what is his current status?

It can be very hard to propose a multiple myeloma treatment to a patient and their family if you're not confident it will work. Like other cancer treatments, these drugs can have side effects and risks. Thankfully, the patient and his family were brave, rational and intelligent. We talked about several different options, and they were eager to get started with the myeloma regimen. They agreed that, in this case, the benefits far outweighed the risks.

After three cycles of treatment, this protein was completely gone. Anand's lab showed the protein wasn't active or even detectable on more sensitive testing. The patient has finished six cycles of treatment and is on a once-a-month maintenance antibody treatment. He has been in remission for eight months, and it's only been 11 months since he started treatment. He is doing great in his recovery from MGTS.

How common do you think this disease is?

It's hard to know. Anand's publication of the first case came out just a few months before I saw my patient. It was very timely.

I wasn't even fully aware of MGTS at the time. The idea of autoimmune or spontaneous HIT had been described in the literature, but those conditions tend to be transient, while clotting was recurrent over a long time frame in my patient, something I've never seen. We don't have any actual numbers as to how common MGTS is; we're still learning more about it every day.

We're trying to increase awareness. If Anand hadn't just published his case, our patient would be in a very different place. We're trying to get the word out because MGTS can be fatal, and time is of the essence. In many cases, the clotting just continues to get worse over time.

If Anand hadn't just published his case, our patient would be in a very different place. We're trying to get the word out because MGTS can be fatal, and time is of the essence.

Giselle Salmasi

What would you tell someone to look out for if they suspect this? And then what should they or their doctor do?

The most obvious thing to look for is a history of blood clots and low platelet count. MGTS is a type of thrombotic (clot-forming) thrombocytopenia (low platelets): The platelet number in the blood drops because they're used in the blood clots.

Many people will have a blood clot, and the vast majority will not have MGTS. This is not even the only disorder with clotting and low platelets. If the clotting incident is unexplained, severe or recurring, and your doctor rules out other diagnoses, they should test for MGTS. It is prudent to consider this diagnosis when you're left with this combination of clots with low platelets, which does not otherwise make sense.

The other thing to watch out for is ensuring you're doing the right testing for MGTS. I'm fortunate to be at an academic center and working with Anand, who has educated us. Our first-pass HIT testing (chemiluminescence testing) typically misses MGTS. However, other testing they did caught it. If the lab does the wrong test, they will come to the wrong conclusion.

If you suspect MGTS, ensure you're doing the correct testing. If you're a community doctor, contact academic hematologists who can liaise with the right research connections. The testing through Anand's lab is a research test; it won't be widely available for several years.

Illustration (Emily Moskal / Stanford Medicine): Normally, clots begin with platelets clumping on blood vessel walls due to vessel injury. In monoclonal gammopathy of thrombotic significance (MGTS), antibodies (teal) that attach to the PF4 protein (yellow) on platelets (white), trigger clots to form spontaneously in vessels. Clotting factors such as fibrin (pink) and red blood cells then complete the clot and block the vessel, limiting blood flow. With treatment, scientists can help restore normal blood flow by targeting the white blood cells that produce the pathogenic antibodies. Without the antibodies, blood clots do not spontaneously form.