Thrombocytopenia is a common problem in cancer patients. Aside from bleeding risk, thrombocytopenia limits chemotherapy dose and frequency. In evaluating thrombocytopenic cancer patients, it is important to assess for other causes of thrombocytopenia, including immune thrombocytopenia, coagulopathy, infection, drug reaction, post-transfusion purpura, and thrombotic microangiopathy. The incidence of chemotherapy-induced thrombocytopenia varies greatly depending on the treatment used; the highest rates of this condition are associated with gemcitabine- and platinum-based regimens. Each chemotherapy agent differs in how it causes thrombocytopenia: alkylating agents affect stem cells, cyclophosphamide affects later megakaryocyte progenitors, bortezomib prevents platelet release from megakaryocytes, and some treatments promote platelet apoptosis. Thrombopoietin is the main regulator of platelet production. In numerous studies, recombinant thrombopoietin raised the platelet count nadir, reduced the need for platelet transfusions, reduced the duration of thrombocytopenia, and allowed maintenance of chemotherapy dose intensity. Two thrombopoietin receptor agonists now available, romiplostim and eltrombopag, are potent stimulators of platelet production. Although few studies have been completed to demonstrate their ability to treat chemotherapy-induced thrombocytopenia, these agents may be useful in treating this condition in some situations. Chemotherapy dose reduction and platelet transfusions remain the major treatments for affected patients.
Thrombocytopenia is a common problem in patients with cancer. It can result from chemotherapy or radiation treatment, or from the underlying disease itself.
Thrombocytopenia creates a number of problems in the care of a cancer patient. At platelet counts < 10,000/µL, spontaneous bleeding is increased. At platelet counts < 50,000/µL, surgical procedures are often complicated by bleeding. At platelet counts < 100,000/µL, chemotherapy and radiation therapy are administered with caution for fear of worsening the thrombocytopenia and increasing the risk of bleeding. Therapeutic and prophylactic platelet transfusions create the additional risk of infusion complications. Thrombocytopenia can also occur with any infection or adverse drug reaction associated with cancer treatment. Finally, a diagnosis of thrombocytopenia exacerbates the patient’s sense of anxiety and fear beyond that associated with the cancer diagnosis itself.
Clinicians’ responses to thrombocytopenia in a cancer patient vary. Reduction of the dose intensity of chemotherapy or radiation is common; more effective regimens with thrombocytopenic toxicity may be avoided; and treatment may even be precluded. For some patients, treatment of the underlying cause of thrombocytopenia (eg, stopping therapy with the offending antiviral drug) may work. Platelet transfusion is often the only readily available treatment.
With the discovery of thrombopoietin in 1994, great expectations were generated that it would play a role in preventing or treating thrombocytopenia in cancer patients, just as erythropoietin and granulocyte colony-stimulating factor (G-CSF) have played roles in reducing anemia and neutropenia, respectively. The first-generation recombinant thrombopoietins reduced chemotherapy-related thrombocytopenia in early clinical trials, but their subsequent development was halted due to antibody formation against endogenous thrombopoietin. While two second-generation thrombopoietin receptor agonists have now been developed that are potent stimulators of platelet production, neither has yet been tailored for treating thrombocytopenia in patients with cancer.[2,4]
This review will focus on the general approach to, and treatment of, thrombocytopenia in cancer patients, including thrombopoietin treatment in patients receiving non-myeloablative chemotherapy. The use of thrombopoietin in myeloablative settings (stem cell transplantation and induction therapy for acute myeloid leukemia) has recently been discussed.
Clinical Approach to Thrombocytopenia in Patients With Cancer
Although chemotherapy and radiation are the major causes of thrombocytopenia in patients with cancer, other etiologies should be considered in all patients. In general, the following evaluation should be considered when platelet counts are < 100,000/µL.
Is the underlying disease the cause of the thrombocytopenia? Tumor metastatic to bone marrow is common in patients with breast and lung cancer, as well as in those with primary hematologic malignancies such as lymphoma. Many such patients also demonstrate pancytopenia, and these cytopenias generally occur when over 80% of the bone marrow is infiltrated.
Is there an associated immune thrombocytopenia (ITP)? Up to 1% of Hodgkin disease patients,[6,7] 2% to 10% of patients with chronic lymphocytic leukemia,[8-10] and 0.76% (range, 0–1.8%) of patients with other non-Hodgkin lymphomas (NHLs) develop a secondary ITP. These patients respond to steroids, rituximab, splenectomy, and thrombopoietin receptor agonists in the same way as patients with primary ITP, although treatment of the underlying lymphoma may be more effective.
Has there been a recent infection? While infection may produce consumptive coagulopathies (eg, disseminated intravascular coagulation [DIC]), some bacteria release neuraminidase that actually reduces platelet survival by removing the sialic acids coating platelets and thereby increasing their clearance by the Ashwell-Morell receptor in the liver.[11,12] Viral infection (eg, with cytomegalovirus) in compromised patients may inhibit bone marrow production of platelets. Such thrombocytopenias improve with adequate treatment of the infection.
Has the patient received a new medication? Heparin-induced thrombocytopenia should be considered. Antibiotics (eg, vancomycin, linezolid) and antiviral agents (eg, ganciclovir[15,16]) commonly induce thrombocytopenia by direct bone marrow toxicity or drug-dependent antibody clearance.[13,17]
Has there been a recent transfusion? Post-transfusion purpura (PTP) is a rare complication of transfusion of red blood cells (RBCs) and platelets, with the platelet count usually dropping below 10,000/µL. PTP occurs in the 1% of patients who lack the common platelet antigen PLA1, also known as human platelet antigen (HPA)-1a, and in this group, PTP usually is observed in women previously sensitized by pregnancy. Upon transfusion of HPA-1a–positive platelets into sensitized HPA-1a–negative patients, antibody destroys the transfused platelets, and by a still unclear mechanism also destroys the patient’s own HPA-1a–negative platelets. This under-recognized complication of transfusion responds readily to intravenous immunoglobulin (IVIG).
Does the patient have a coagulopathy? In addition to infection, some tumors (eg, gastric and pancreatic adenocarcinomas) can produce chronic DIC.[18,19] Such thrombocytopenic patients usually have elevated D-dimer and low fibrinogen levels, but often have minimally prolonged prothrombin time and partial thromboplastin time. Treatment of chronic DIC is often difficult. Heparin may improve the coagulopathy, but most patients do not improve without effective treatment of the underlying tumor.
Is there a chemotherapy- or transplant-related thrombotic microangiopathy? Mitomycin-C and gemcitabine have been found to induce endothelial injury, with a resultant thrombotic microangiopathy whose major manifestation is renal failure and thrombocytopenia; this is best referred to as a chemotherapy-related hemolytic uremic syndrome. These patients usually have normal activity levels of the protein ADAMTS13 but have abundant schistocytes in the peripheral blood smear and an elevated lactate dehydrogenase level; most improve with supportive care and discontinuation of the chemotherapy. Plasma exchange, rituximab, or steroids are not indicated. It is unclear whether complement inhibition with eculizumab is of benefit.
When was the last chemotherapy or radiation therapy administered? The platelet has a normal lifespan of 8 to 10 days. After many types of chemotherapy, the platelet count generally starts to drop by day 7 and reaches its nadir at day 14, with a gradual return back to baseline by day 28 to 35 (Figure 1).  Depending upon the dose and duration of radiation therapy, the onset of thrombocytopenia is generally at days 7 through 10. The duration of thrombocytopenia is longer, and sometimes continues for 30 to 60 days.
What chemotherapy was given? The incidence, severity, and duration of thrombocytopenia vary with the chemotherapy regimen. Most non-myeloablative chemotherapy regimens were developed to minimize thrombocytopenia and the need for platelet transfusions. Thus, most standard regimens are associated with relatively low rates of dose-limiting thrombocytopenia; when thrombocytopenia occurs, it is often of short duration (4 to 6 days). Most patients respond well to platelet transfusion. In a recent review of different chemotherapy regimens in 614 patients with solid tumors, a platelet count < 100,000/μL was seen in 21.8% of all subjects; these were unaccompanied by other cytopenias in 6.2%. Grade III thrombocytopenia (platelet count, 25,000–49,000/μL) was seen in 3.6% and grade IV thrombocytopenia (platelet count, < 25,000/μL) in 3.3%. Thrombocytopenia occurred in 82% of those receiving only carboplatin, and in 58%, 64%, and 59% of those receiving combination therapies with carboplatin, gemcitabine, or paclitaxel, respectively. In an analysis of 43,995 patients receiving 62,071 chemotherapy regimens, 6.5% had grade III and 4.1% had grade IV thrombocytopenia with platinum-based regimens; 3.0% had grade III and 2.2% grade IV thrombocytopenia with anthracycline-based regimens; 7.8% had grade III and 3.4% grade IV thrombocytopenia with gemcitabine-based regimens; and 1.4% had grade III and 0.5% grade IV thrombocytopenia with taxane-based regimens. Among the 10,582 regimens for which data were available, platelet transfusions occurred in 2.5% of patients (in 1.0% of those treated with platinum-based regimens, 0.6% of those who received anthracycline-based treatment, 1.8% of patients treated with gemcitabine-based therapy, and 0.3% of those who received taxane-based treatment). The Table provides an overview of the reported frequencies of thrombocytopenia associated with various current chemotherapy regimens.
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