From OncoLog, November-December 2012, Vol. 57, Nos. 11-12
Research Explores Link Between Thrombocytosis and Cancer
By Kathryn L. HaleHigh platelet counts can be an early indicator of cancer. In fact, about one-third of women with ovarian cancer have an abnormally high platelet count at the time of diagnosis. This paraneoplastic thrombocytosis is also seen in patients with cancers of the gastrointestinal tract, lung, or breast.
While this syndrome has been recognized for many years, its cause, its relationship to the cancer, and its clinical implications—beyond the dangers of blood clots—are unknown.
“We’ve known for a long time that cancer patients are at higher-than-normal risk of developing blood clots,” said Anil K. Sood, M.D., a professor in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center. In the 1860s, the French physician Armand Trousseau observed that patients with cancer were more likely than the general population to have blood clots. This phenomenon came to be known as the Trousseau syndrome or Trousseau sign of malignancy: an unexplained blood clot was a clue to the possible presence of undiagnosed cancer.
Ironically, soon after reporting this sign, Trousseau developed a blood clot in his arm and was later diagnosed with gastric cancer. Dr. Sood saw a similar case firsthand as a medical student, when a mentor’s sudden collapse with a pulmonary embolus was the primary presentation of metastatic colorectal cancer.
A handful of studies have shown that, of people identified randomly as having an unexplained high platelet count, about 40% will have cancer. “A platelet count higher than 450,000/mL is significant and should raise a red flag for the presence of cancer,” Dr. Sood said.
High platelet counts and blood clots have causes other than cancer, of course. Inflammatory, infectious, and autoimmune conditions typically raise platelet counts substantially, as does iron-deficiency anemia. These conditions should be ruled out in any patient with a persistently high platelet count.
“We see this thrombocytosis very consistently in a proportion of cancer patients,” said Dr. Sood, “but we have never known why or what it means. Healthy people have to make about 100 billion platelets every day just to maintain homeostasis. In a person with cancer, that machinery is revved up 5–10 times the normal level. We asked ourselves: how does this come about, and how can we control it? And what implications does it have for diagnosis and perhaps therapy?”
Searching for answers
Dr. Sood and his colleagues in the Departments of Cancer Biology, Experimental Therapeutics, Gynecologic Oncology and Reproductive Medicine, Hematology and Oncology, Pathology, Benign Hematology, Biostatistics, and Leukemia at MD Anderson—along with collaborators from various centers in the United States and the United Kingdom—are working to understand thrombocytosis in patients with ovarian and other cancers. Results of their studies were published in the New England Journal of Medicine in February 2012.
Because they had observed that, among women with ovarian cancer, patients with high platelet counts tended to have worse outcomes, Dr. Sood and his colleagues began their research by reviewing the clinical records of patients treated for primary epithelial ovarian cancer.
“We found that patients with thrombocytosis had more advanced disease, a higher rate of thromboembolic complications, and higher levels of CA-125 (a blood marker of ovarian cancer) than did patients who had normal platelet counts. Patients with thrombocytosis also had significantly faster disease progression and shorter overall survival,” Dr. Sood said. The researchers did not know whether the high platelet counts were a reflection of the extent of disease or other factors.
After ruling out inflammatory conditions and anemia, the researchers began looking for associations between high platelet counts and other blood factors. They found a direct relationship: the higher the platelet count, the higher the circulating level of interleukin-6.
This finding set off a series of experiments. In a mouse model of ovarian cancer, the mice with cancer had significantly higher platelet counts than mice without cancer. Furthermore, high platelet count correlated directly with tumor size and number of metastases. Reducing interleukin-6 production in these mice, with an antibody or small interfering RNA, restored platelet counts to more normal levels.
While this was an exciting finding, Dr. Sood said, “At that point, we could not connect the dots as to why interleukin-6 would be causing high platelet counts. Interleukin-6 is a cytokine, a signaling molecule involved in the production and growth of various immune modulator cells, but it had no known direct connection to platelets.”
“It was amazing,” recalled Dr. Sood. “Among the patients with a high baseline platelet count, the platelet counts returned to the normal range within 2½ weeks of starting treatment with the interleukin-6 antibody. We got very excited. This direct evidence of a clinical link between interleukin-6 and platelet counts drove us to push very hard to figure out the whole pathway.”
Charting the pathway
Dr. Sood and his colleagues hypothesized that interleukin-6 produced by the tumor or the host stimulates the production of some other factor that in turn stimulates platelet production. To test this hypothesis, the researchers returned to mouse models. They looked at the spleens and bone marrow, the most important centers of blood cell production and development. In mice with cancer, the spleens had extraordinarily high levels of megakaryocytes, the precursors of platelets.
A study of human tissue confirmed this finding. The researchers found high levels of megakaryocytes in bone marrow specimens from women with ovarian cancer. In blood samples from a larger group of ovarian cancer patients with thrombocytosis, analysis of 10 factors known to promote platelet production identified two factors that were significantly elevated in the patients with thrombocytosis: interleukin-6 and thrombopoietin.
Thrombopoietin is synthesized in the liver, and little is known about the effects of cancer on its production. On the basis of published data indicating that interleukin-6 stimulates thrombopoietin synthesis, the group developed a model to explain high platelet counts in cancer: interleukin-6 produced by the tumor stimulates production of thrombopoietin by the liver, which stimulates overproduction of megakaryocytes and platelets by the bone marrow, leading to thrombocytosis.
While visiting the University of Cincinnati, Dr. Sood met a researcher who had developed a mouse strain that lacked the interleukin-6 receptor in the liver. As hypothesized, these mice failed to develop thrombocytosis when ovarian cancer cells were implanted into them because the interleukin-6 produced by their tumors could not signal the increase in thrombopoietin that stimulates platelet production. “This was proof that interleukin-6 plays a major role in cancer-related thrombocytosis,” said Dr. Sood.
These findings were supported by clinical data from women with ovarian cancer. An analysis of normal liver tissue from patients who had undergone resection of liver metastases showed elevated levels of thrombopoietin. Furthermore, patients who had low plasma levels of interleukin-6 survived significantly longer than those with higher levels.
In addition to exploring how cancer drives thrombocytosis, Dr. Sood and his colleague Vahid Afshar-Kharghan, M.D., an associate professor in the Department of Benign Hematology, have looked at how platelets affect tumors. Their results support published data suggesting that platelets promote tumor progression. In a mouse model of ovarian cancer, reducing platelet levels by 50% with an antiplatelet antibody inhibited tumor growth by 50% and increased apoptosis (programmed tumor cell death) by a factor of four compared with controls. By implicating platelets in tumor growth, this finding closed the loop suggested by the tumor interleukin-6/hepatic thrombopoietin/ thrombocytosis pathway. The mechanisms by which platelets promote tumor growth are not fully known, however, and are a focus of ongoing work.
The researchers also found abundant platelets in the ascitic fluid surrounding ovarian tumors in mice, indicating that platelets are active in the tumor microenvironment. Thus, the cancer platelet interaction is more complex than suggested by early findings. This suggestion in turn implies that there might be more than one approach to treating cancer-related thrombocytosis.
Testing new treatments
One approach to treating thrombocytosis in patients with cancer is to reduce the production of interleukin-6. The interleukin-6 antibody siltuximab, which is being tested by Dr. Sood’s colleagues in the United Kingdom, is one means of doing this. The antibody not only reduces platelet counts in patients but also depletes levels of the growth factors produced by platelets; this finding suggests siltuximab could boost the effectiveness of chemotherapy. In the U.K. trial, the antibody stopped tumor growth in some patients. In a mouse model of ovarian cancer, treatment with paclitaxel and siltuximab reduced tumor growth by over 90% compared with controls, significantly more than either agent alone.
Dr. Sood also mentioned the recent well-publicized findings that people who regularly take aspirin, which disrupts platelet function, have lower rates of cancer and generally less aggressive cancers. While this was initially explained by aspirin’s anti-inflammatory effect, thinking has started to shift to its antiplatelet effect. This is supported by clinical evidence that cancer patients who receive heparin (an anticoagulant that reduces platelet activation) to prevent clots live longer than similar patients not receiving heparin. These antithrombotic agents may have antitumor effects that are just starting to be recognized.
It is not clear yet what any of these findings will mean for cancer patients. What is clear is the potential for long-term clinical benefits for cancer patients who develop thrombocytosis. Since publishing the initial results, Dr. Sood has received correspondence from many oncologists applauding his efforts to explain and treat this very common phenomenon. Dr. Sood expects that the work being done in his laboratory and elsewhere on paraneoplastic thrombocytosis will shed light not only on the potentially serious blood clots that frequently accompany cancer but also on the cancer itself.
For more information, call Dr. Anil Sood at 713-745-5266.
FURTHER READINGStone RL, Nick AM, McNeish IA, et al. Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med 2012; 366:610-618.