Thrombocytopenia refers to the presence of abnormally low levels of platelets in the circulating blood. Platelets, or thrombocytes, are a specific kind of blood cell that prevent bleeding. The most common reason that cancer patients experience thrombocytopenia is as a side effect of chemotherapy. When chemotherapy affects bone marrow, the body’s ability to produce platelets, the body’s chief defense against bleeding, is diminished. Platelets normally rush to the site of an injury and work with other blood factors to from a blood clot. Normally, there are billions of platelets in the blood; however certain chemotherapy drugs can lower the platelet count. The fewer platelets an individual has in his/her blood and the longer he/she remains without enough of them, the more susceptible he/she is to bleeding.
Chemotherapy-induced thrombocytopenia typically occurs 6-10 days following administration of the chemotherapy drugs and continues for several days before platelets recover to an appropriate level. Infrequently, cancer patients may also experience thrombocytopenia from other medications or as a consequence of their underlying cancer. When discussing the consequences and management of thrombocytopenia, it is important to distinguish between chemotherapy-induced thrombocytopenia and thrombocytopenia resulting from other causes.
The type and dose of chemotherapy also has an effect on how low the platelet count drops and how long it will take to recover. While receiving chemotherapy, a patient’s blood may be tested frequently to make sure he/she has enough platelets. Thrombocytopenia, or “low platelets”, are terms used to describe a low platelet level in the blood. Fortunately, having a low level of platelets can be corrected for many patients.
Chemotherapy involves the use of drugs to destroy cancer cells. Chemotherapy works by destroying cancer cells that grow rapidly. Unfortunately, chemotherapy also affects normal cells that grow rapidly, such as blood cells forming in the bone marrow, cells in the hair follicles or cells in the mouth and intestines.
When patients experience thrombocytopenia following administration of chemotherapy, they are at risk of certain side effects. Specifically, the fewer platelets in the blood and the longer a patient remains without enough platelets, the more susceptible he/she is to experiencing bleeding. Thrombocytopenia confers a risk of bleeding and the magnitude of risk is closely correlated with the severity and duration of thrombocytopenia. As the platelet count falls below 20,000-50,000; 10,000-20,000; and less than 10,000 cells/µl, the frequency of life-threatening bleeding rises steeply from approximately 5-6% to 10% and 20-40%, respectively. Patients developing thrombocytopenia require treatment with platelet transfusions and occasionally, admission to the hospital, until the platelets return to sufficient levels in the blood to prevent bleeding.
Thrombocytopenia is important for another reason. When patients are treated with chemotherapy, it is for the purpose of destroying cancer cells in order to reduce symptoms from their cancer, prolong their survival or increase their chance of cure. Chemotherapy may be administered as a single drug or in combination with several drugs. The combination of chemotherapy drugs administered to a patient is referred to as a treatment regimen. In a chemotherapy treatment regimen, drugs are administered to patients at a defined dose and according to a specific time schedule. The dose and time schedule of drugs administered in the chemotherapy regimen has been scientifically derived to produce the best chance of survival or cure. When patients develop thrombocytopenia following administration of chemotherapy, doctors may have to delay treatment or reduce the doses of the chemotherapy. Clinical studies have shown for certain diseases that when the dose of therapy is reduced or the treatment cycles prolonged, patients have lower cure rates than if they had been able to receive therapy at the full dose on schedule. Fortunately, there are strategies for the treatment of chemotherapy-induced thrombocytopenia that have been proven to reduce the need for platelet transfusions and help patients receive their treatment on schedule.
A complete blood count (CBC) measures the levels of the three basic blood cells: white cells, red cells and platelets. In the United States, the CBC is typically reported in the following format:
|CBC WITH DIFFERENTIAL|
|White Blood Count||1.5 L||x 10-3/mL||4.0-10.5|
|Red Blood Count||3.50 L||x 10-6/mL||4.70-6.10|
|Polys (absolute)||.34 L||x 10-3/mL||1.8-7.8|
|Lymphs (absolute)||1.0||x 10-3/mL||0.7-4.5|
|Monocytes (absolute)||0.1||x 10-3/mL||0.1-1.0|
|Eos (absolute)||0.1||x 10-3/mL||0.0-0.4|
|Basos (absolute)||0.0||x 10-3/mL||0.0-0.2|
Result column: The result column shows counts that fall within the normal range.
Flag column: The flag column shows counts that are lower (“L”) or higher (“H”) than the normal range.
Reference Interval (or Reference Range) column: The reference interval shows the normal range for each measurement for the lab performing the test. Different labs may use different reference intervals.
White blood cells: White blood cells help protect individuals from infections. The above CBC report shows that the patient’s total white cell count is 1.5, which is lower than the normal range of 4.0-10.5. The low white cell count increases the risk of infection.
Differential: This portion of the CBC shows the counts for the 5 main kinds of white cells, either as percentages (the first 5 counts), or as the absolute number of cells (the second 5 counts).
Absolute neutrophil count: Neutrophils are the main white blood cell for fighting or preventing bacterial or fungal infections. In the CBC report, neutrophils may be referred to as polymorphonuclear cells (polys) or neutrophils. The absolute neutrophil count (ANC) is a measure of the total number of neutrophils present in the blood. When the ANC is less than 1,000, the risk of infection increases. The ANC can be calculated by multiplying the total WBC by the percent of polymorphonuclear cells. For example, this patient’s ANC is .34 = (WBC) 1.5 x 23%.
Red blood cells: Red blood cells carry oxygen from the lungs to the rest of the body. The above CBC report indicates that the patient has a red cell count of 3.5, which is lower than the normal range of 4.70-6.10, and therefore, shown in the flag column.
Hemoglobin (Hb or Hgb): Hemoglobin is the part of the red cell that carries the oxygen. The above CBC report indicates that the patient’s Hb count is 10.8, which is below the normal range of 14.0-18.0. The hematocrit (HCT), another way of measuring the amount of Hb, is also low. This means that the patient has mild anemiaand may be starting to notice symptoms.
These three ranges will vary depending on age and gender. For women, they will be lower than those shown here. For example, the Hb reference interval for a woman is 12.0-16.0.
Platelets: Platelets are the cells that form blood clots that stop bleeding. The above CBC report indicates that the platelet count for this patient is low.
Chemotherapy-induced thrombocytopenia occurs because the chemotherapy drugs have destroyed many of the normal rapidly dividing cells in the bone marrow responsible for platelet production. Naturally occurring substances called cytokines exist in the body to regulate certain critical functions at the cellular level. One group of cytokines is commonly referred to as blood cell growth factors. Blood cell growth factors are responsible for stimulating the cells in the bone marrow to produce more blood cells.
A blood cell growth factor that is approved by the U.S. Food and Drug Administration (FDA) for the prevention of chemotherapy-induced thrombocytopenia is Neumega® (oprelvekin). Neumega helps the bone marrow create more platelets and has been demonstrated in clinical studies to prevent thrombocytopenia and decrease the need for platelet transfusions in patients at high risk for developing thrombocytopenia. The most common side effect observed with Neumega is fluid retention or edema. This symptom persists while Neumega is being used and is reversible within a few days of discontinuation of Neumega.
The most common way to treat thrombocytopenia is with platelet transfusions. Transfusions only temporarily correct thrombocytopenia and are associated with complications.
Platelet Transfusion: The goal of a platelet transfusion is to prevent or stop bleeding. Traditionally, the assessment of a patient for a platelet transfusion was based on a clinical “trigger” value, which is a laboratory value below which a transfusion was automatically prescribed. However, transfusions are associated with complications. It is important to carefully evaluate all options when considering a platelet transfusion, as the benefits should outweigh the risk or complications of transfusion.
Although improvements have lowered the risk of transfusion-transmitted complications, the only way to effectively eliminate the risk is to avoid exposure to allogeneic blood. Despite the risks, platelet transfusions are common treatments for thrombocytopenia associated with cancer and chemotherapy.
Complications of Platelet Transfusion: Patients receiving platelet transfusions are at risk for several reactions that range from mild allergic reactions to life-threatening anaphylaxis. Febrile reactions are the most common, occurring in 1 in every 100 transfusions, but most are not a significant clinical problem. Clinically, the most significant complications are the immunomodulatory effects of alloimmunization, immunosuppression and graft-versus-host disease (GVHD), all of which are rare.
Infectious Complications: Patients receiving platelet transfusions are at risk for bacterial, parasitic and viral infections. Bacterial infections are estimated to occur in 1 of every 2,500 transfusions and viral infections occur in approximately 1 in every 3,000. Fear of infection with the human immunodeficiency virus (HIV) has caused the most concern, although the risk per transfusion is relatively low (1 in 225,000 transfusions). All blood components are tested for HIV antibodies; however, there is a period of time after HIV exposure before antibodies can be detected in the blood. To address this issue, intense donor screening is being used and more sensitive assays are being developed.
Patients receiving an allogeneic transfusion are at greater risk for lethal infection for the hepatitis viruses than from HIV. It is estimated that hepatitis results from approximately 1 in every 3,000 transfusions.
The reduction in the frequency and severity of thrombocytopenia and its associated complications has resulted from scientists developing a better understanding of the basic biology of bone marrow blood cell production and from participation in clinical studies designed to evaluate strategies directed at reducing thrombocytopenia and its complications. Currently, there are several strategies aimed at improving the prevention and management of thrombocytopenia.
New blood cell growth factors: Several new blood cell growth factors are being developed and evaluated in clinical studies for the purpose of improving chemotherapy-induced thrombocytopenia.
AMG 531 is an investigative agent that stimulates the body to produce platelets and thus reduce or reverse thrombocytopenia. Researchers associated with the AMG 531 in Myelodysplastic Syndrome Study Group conducted a clinical trial to evaluate AMG 531 among patients with myelodysplastic syndrome (MDS) who had thrombocytopenia. This trial included 28 patients, nine of whom had to receive platelet transfusions to reduce thrombocytopenia.
61% of patients had an elevated level of platelets following therapy with AMG 531.
Nearly half of the patients maintained elevated levels of platelets for eight or more weeks.
The researchers concluded that AMG 531 appears to provide promising activity among patients with MDS who have thrombocytopenia. Ultimately, AMG 531 may significantly reduce the need for platelet transfusions and prevent bleeding in this group of patients. Future clinical trials are planned to further evaluate AMG 531 in this setting.
Peripheral blood stem cells: Stem cells responsible for the production of platelets can be collected in large quantities from the peripheral blood. Delivery of peripheral blood stem cells following very high doses of chemotherapy has been demonstrated to result in more rapid platelet recovery than with stem cells collected from bone marrow. Many doctors have begun evaluating the use of peripheral blood stem cells to support multiple cycles of dose intensive chemotherapy alone or in combination with Neumega® or other blood cell growth factors for the purpose of reducing the frequency and severity of thrombocytopenia and its complications.
Kantarjian HM, Giles FJ, Fenauz P, et al. Evaluating safety and efficacy of AMG 531 for the treatment of thrombocytopenic patients with myelodysplastic syndrome (MDS): Preliminary results of a Phase 1-2 study. Proceedings from the 2007 annual meeting of the American Society of Clinical Oncology. Abstract 7032.