The Downside of Platelet Counts
A side effect known as thrombocytopenia impairs blood’s ability to clot.

By Debra Wood, RN

Unable to staunch blood flowing from his skin after a shower and a shave, Robert Carroll sought immediate medical care, but even a week in the hospital failed to correct the problem.

"I just waited for something to happen,” says Carroll, 54, of Falls Church, Virginia. “I was careful and paranoid, but that’s about all I could do.” Carroll’s excessive bleeding resulted from a severe case of thrombocytopenia brought on by the chemotherapy he received to treat chronic lymphocytic leukemia.

Thrombocytopenia is the medical term for a lowering in the number of circulating platelets, which are irregularly-shaped blood cells that clump together and initiate blood clotting. A decline in platelet count hampers the ability of the blood to clot and even minor cuts or bruises can result in significant bleeding that may be difficult to stop.

More specifically, platelets are cells produced by megakaryocytes in the bone marrow and circulate through the body for seven to 10 days. It has been estimated that approximately 1,000 to 3,000 platelets are produced by each megakaryocyte, and normal platelet counts range from 150,000 to 400,000 per microliter.

Thrombocytopenia is diagnosed when a patient’s platelet count dips below 100,000 per microliter. Spontaneous bleeding may occur if the platelet count falls below 20,000 per microliter, and counts below 10,000 per microliter pose a serious threat of life-threatening bleeding, often into the brain or gastrointestinal tract. The most common symptoms of a low platelet count are nosebleeds, bleeding gums while brushing teeth and blood in the urine or stool.

Breast cancer patient Cathy Hughes’ platelet count dropped to 11,000 per microliter as a result of chemotherapy. The 53-year-old from Gilbertsville, New York, had bruises forming all over her body as well as petechiae, tiny collections of blood under the skin that develop when blood leaks from small blood vessels.

"It’s scary when they tell you what can happen because your platelets are so low,” says Hughes, referring to the potential risk of bleeding in various internal organs including the stomach, colon, kidney and brain. “It was so dangerous that I wasn’t to do anything but sit in a chair or stay in bed. That frightened me.”

Causes of Thrombocytopenia

Thrombocytopenia in cancer patients can develop not only as a consequence of chemotherapy or radiation therapy but might also be caused by an infiltration of the cancer cells in the bone marrow. Low platelet counts can also be a result of an autoimmune process by which the body’s immune system attacks platelets. Patients with massive enlargement of the spleen also frequently have low platelet counts, as the spleen can sequester a large number of platelets and prevent them from entering the circulation.

Platelet counts suppressed by chemotherapy agents usually rebound—often within a few days—without treatment, only to plummet again with the next chemotherapy cycle. This reduction in platelet count is usually seen about four to seven days after the start of chemotherapy, and, in most patients, platelet counts will recover to baseline within 10 to 14 days. Aware that platelets may decrease during various treatments, doctors typically monitor blood counts.

A wide variety of chemotherapy drugs, especially when given at high doses, can cause a reduction in platelet counts. Low platelets are associated with most drugs used to treat leukemias and lymphomas, including Cytosar® (cytarabine), Fludara® (fludarabine), cladribine and Velcade® (bortezomib). Many chemotherapy drugs used to treat solid tumors, such as lung and breast cancer, can also cause a decline in platelet counts and include Paraplatin® (carboplatin), Gemzar® (gemcitabine) and Cytoxan® (cyclophosphamide).

The risk of thrombocytopenia with any chemotherapy drug is linked to the dose and schedule of the drug (more frequent administration of higher doses increases the risk) as well as the precise chemotherapy combinations being given and the age and underlying health of the patient. Older patients and those who have received multiple prior therapies are more likely to be at risk for thrombocytopenia with subsequent chemotherapy regimens. Patients with limited bone marrow reserve because of leukemia, myelodysplasia and radiation therapy to the bones are also at risk for developing significant thrombocytopenia.

"Thrombocytopenia frequently either prevents us from giving the full dose of chemotherapy or it delays administration,” says Kenneth Kaushansky, MD, Helen M. Ranney professor and chairman of the department of medicine at the University of California, San Diego School of Medicine. “Numerous studies show either underdosing or delaying on-time administration of chemotherapy reduces cure and beneficial effects.”

Treating Low Platelets

Platelet transfusions represent the best current treatment option for patients with severe thrombocytopenia. Whether to transfuse depends on the patient’s condition and protocols at the treating facility. Transfusions are rarely ordered unless platelets have dropped to 10,000 to 20,000 per microliter, the patient is actively bleeding or the patient needs a surgical procedure.

Doctors may administer the transfusions every couple of days. Transfused platelets do not live as long as naturally produced cells, and, depending upon the number of transfusions needed, cost may become prohibitive (the average cost of platelet transfusions in the United States is more than $500). Transfusion side effects include fever or allergic reactions, the risk of developing an infection from a donor and transfusion-associated lung or circulatory problems.

Neumega® (oprelvekin), approved by the Food and Drug Administration, has been shown effective in preventing severe thrombocytopenia secondary to chemotherapy by as much as 27 percent and decreasing the need for platelet transfusions. The drug, also known as interleukin-11, is a thrombopoietic cytokine that stimulates the proliferation of megakaryocytes. But modest results and adverse reactions, including fluid retention, dilutional anemia and peripheral edema, limit its value.

"It’s too toxic to use in most patients,” says David J. Kuter, MD, clinical director of the Center for Hematology at the Massachusetts General Hospital Cancer Center in Boston and associate professor at Harvard Medical School. “It didn’t work that well and has fallen out of favor because of the side effects.”

In 1994, the natural regulator of platelet production, a hormone termed thrombopoietin, was identified, and physicians envisioned a new approach to treating thrombocytopenia. Researchers investigated the natural hormone and a derivative of it termed megakaryocyte growth and development factor (MGDF) to determine if they might alleviate the need for platelet transfusions in patients with thrombocytopenia. Although initial trials showed modest success, thrombopoietin did not speed up megakaryocyte fragmentation into platelets. This, coupled with immune complications, has led to a re-examination of the approach.

Investigators are now researching the use of small molecules that mimic the action of thrombopoietin on platelet-producing cells but look different from the naturally occurring hormones, so they should not produce antibodies against the body’s natural cells.

AMG 531, an investigational platelet growth factor being developed by Amgen, appears to directly stimulate platelet production by binding to the thrombopoietin receptor and stimulating megakaryocytes to produce platelets. The drug was well tolerated and produced promising results in phase II testing.

GlaxoSmithKline is developing another drug to treat thrombocytopenia called SB-497115. By inducing differentiation and proliferation of megakaryocytes, a phase I trial found the drug not only to be well tolerated, but it also produced an increase in platelet counts. Based on these results, phase II testing is planned.

Bone Marrow Failure States

Low platelet counts also may occur spontaneously and be unrelated to cancer or its treatment. These diseases include aplastic anemia, immune thrombocytopenia purpura and thrombotic thrombocytopenia purpura.

Aplastic anemia refers to a condition in which the body fails to produce sufficient amounts of red and white blood cells and platelets, either because of damage to the bone marrow or from the immune system attacking it. Patients may inherit the condition or develop it, sometimes after exposure to drugs or viruses. Doctors may recommend a bone marrow transplant or drugs designed to suppress the immune system.

The autoimmune condition called immune thrombocytopenia purpura is associated with certain types of cancer, including chronic lymphocytic leukemia, certain lymphomas and small-cell lung cancer. Viral infections and certain medications and antibiotics can also trigger immune thrombocytopenia. The body’s immune system makes antibodies against the platelets, and the platelets are then destroyed in the spleen. Treatment options include steroidal medications, such as prednisone, other drugs to suppress the immune system or removal of the spleen.

Doctors will assess the cause of low platelet counts before recommending treatment. For many cancer patients receiving chemotherapy, monitoring platelet counts becomes a routine part of their care.

Carroll called on The Leukemia & Lymphoma Society (www.lls.org) for more information about his condition, treatment and managing side effects. And Hughes encourages patients to learn more about thrombocytopenia before it becomes a problem that impacts treatment.

"It’s important for people to know before chemotherapy what can happen when platelets are low,” Hughes says. “If I knew in advance, it wouldn’t have been quite so alarming.”