Chapter 33
Elevated Blood Counts (Case 26)
Marc J. Kahn MD, MBA
Case: A 43-year-old healthy woman presents with upper respiratory symptoms characterized by rhinorrhea, a dry cough, and a headache over a period of 3 days. She presented to her primary-care provider, who diagnosed a viral infection; she was told to drink fluids and take acetaminophen as needed, and was given a decongestant. Two days after her visit, she was called by her physician because the complete blood count (CBC) that had been ordered was abnormal, revealing a white blood cell (WBC) count of 14,600/µL, a hemoglobin of 16.7 g/dL, and a platelet count of 1,432,000/µL. The WBC count differential revealed 80% polymorphonuclear cells, 12% lymphocytes, 5% monocytes, 2% eosinophils, and 1% basophils. On further questioning, she reports some menorrhagia but is otherwise completely asymptomatic. She is very worried that she may have leukemia.
Differential Diagnosis
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Polycythemia vera (PV) |
Essential thrombocytosis (ET) |
Chronic myelogenous leukemia (CML) |
Speaking Intelligently
Whenever a patient is found to have an abnormal CBC, I always review a peripheral blood smear as the next step. Review of the smear is quick and inexpensive, and can greatly help to narrow a differential diagnosis and to plan further diagnostic tests. It is important to educate the patient that in the absence of immature blood cells, acute leukemia is highly unlikely. Because the patient will be referred to a specialist, it is important that the patient understands your reasoning. This is especially important if the patient is referred to a hematologist/medical oncologist in a cancer center.
PATIENT CARE
Clinical Thinking
• In a patient with elevated blood counts, especially an elevated WBC count, it is important to distinguish a problem with cellular differentiation, such as acute leukemia, from a problem with cellular proliferation, such as the myeloproliferative disorders (MPDs).
History
• Patients with ET may additionally have problems with either bleeding or thrombosis.
• Patients with PV may complain of pruritus or headache, and may also present with thrombosis.
Physical Examination
• The physical examination may be normal in patients with MPDs.
• Easy bruisability may be a feature of ET or PV.
Tests for Consideration
| Clinical Entities | Medical Knowledge |
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Polycythemia Vera |
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Pφ |
PV is a clonal disorder characterized by excessive production of red blood cells. PV is strongly associated with acquired mutations of the gene encoding JAK2, an intracellular signaling molecule. The most common mutation, JAK2 V617F, leads to constitutive activation of JAK2, causing erythropoiesis to become independent of erythropoietin. JAK2 V617F is found in over 90% of patients with PV. |
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TP |
Although patients with PV can be asymptomatic, they may complain of headache, pruritus, or fatigue. Shortness of breath, dizziness, and visual changes from increased blood viscosity are also common complaints. Erythromelalgia, burning of the palms and soles, can occur as a result of increased platelets. About 15% of patients may experience arterial or venous thrombosis, manifested as transient ischemic attacks (TIAs), stroke, myocardial infarction (MI), deep venous thrombosis (DVT), and Budd-Chiari syndrome. Epistaxis and gastrointestinal (GI) bleeding can also occur. Patients with PV may be hypertensive, and more than half of patients with PV have splenomegaly. |
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Dx |
Patients with PV have low serum erythropoietin concentrations. The CBC is remarkable for an elevated hematocrit. Platelets and WBCs may also be increased. Serum concentrations of vitamin B12, lactate dehydrogenase (LDH), and uric acid are frequently elevated. Over 90% of patients with PV have the JAK2 V617F mutation. Bone marrow evaluation reveals hypercellularity with erythroid hyperplasia. Marrow fibrosis can also be seen. |
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Tx |
Phlebotomy is the mainstay of therapy in PV to keep the hematocrit less than 45% in men and less than 42% in women. Low-dose aspirin is also recommended to reduce the incidence of thrombosis. Cytoreductive therapy with hydroxyurea or interferon may be used in patients at high risk for thromboembolic disease, such as those over 60 years of age. See Cecil Essentials 48. |
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Pφ |
ET is a clonal disorder characterized by increased numbers of megakaryocytes in the bone marrow and platelets in the circulation. ET is the most common of the MPDs. Between 30% and 50% of patients with ET have the JAK2 V617F mutation. |
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TP |
At least half of patients with ET are asymptomatic at presentation. Because of the increased platelet numbers, most patients with ET eventually experience vasomotor symptoms such as headache, visual disturbance, acrocyanosis, paresthesias, or erythromelalgia. Only about a quarter of patients with ET have palpable splenomegaly. Patients are at increased risk for both arterial and venous thrombotic complications including first-trimester spontaneous abortions. Because of qualitative platelet defects, patients with ET are also at increased risk of bleeding. |
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Dx |
Patients with ET have platelet counts > 600,000/µL without other etiologies for thrombocytosis. Because iron deficiency can cause an elevated platelet count, normal serum ferritin concentrations and stainable iron on marrow biopsy are necessary to make the diagnosis of ET. Detection of either t(9;22) or the BCR/ABL transcript rules out ET in favor of CML. Patients with ET can also have elevations in leukocyte count. |
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Tx |
Patients with ET and platelet counts > 1,500,000/µL, those with a history of thromboembolism, and those older than age 60 years are treated with hydroxyurea as a first-line agent to lower the platelet count. Low-dose aspirin is also used unless bleeding or bruising is exacerbated by the addition of aspirin. Anagrelide is a second-line agent to lower the platelet count. Women of childbearing potential can be treated with interferon-α. Platelet apheresis, along with cytoreductive therapy, may be needed in patients with life-threatening symptoms such as stroke, TIA, MI, or GI bleeding. See Cecil Essentials 48. |
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Chronic Myelogenous Leukemia |
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Pφ |
CML is characterized by the balanced translocation t(9;22), also called the Philadelphia chromosome. This translocation leads to a fusion gene, BCR/ABL, which functions as a tyrosine kinase. The BCR/ABL protein acts in a number of cellular pathways to promote proliferation of myeloid cells. BCR/ABL is also able to inhibit apoptosis. Over time, the leukemic clone of CML acquires additional abnormalities, which leads to acceleration into a blast phase, characterized clinically as an acute leukemia. |
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Almost all patients with CML present in a chronic phase characterized by an elevated WBC count and elevated platelets. The peripheral WBC count is predominantly myeloid cells without a significant number of blasts. Almost half of patients with CML are asymptomatic at presentation. Most patients with CML have splenomegaly. Thrombotic or hemorrhagic complications are uncommon until blast crises occur; thrombocytopenia leads to purpura and bleeding. |
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Dx |
Demonstration of t(9;22) by cytogenetics or BCR/ABL by PCR is required for the diagnosis of CML. Granulocytosis, thrombocytosis, and basophilia may be present on the peripheral smear; in the chronic phase, <10% blasts are seen on the peripheral smear. In the accelerated phase, blast counts are between 10% and 19%. In the blast phase, acute myeloid or, less commonly, acute lymphoblastic leukemia is seen with ≥20% blasts. Serum LDH and uric acid are increased. |
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Tx |
Treatment for CML has changed since the introduction of the novel tyrosine kinase inhibitor, imatinib. A complete hematologic remission is seen in >90% of CML patients in chronic phase and >30% of CML patients in accelerated or blast phase who are treated with imatinib. Allogeneic stem cell transplantation is reserved for patients who fail to respond to imatinib. Over time, imatinib resistance can develop. Allogeneic transplantation or use of dasatinib, a second-generation tyrosine kinase inhibitor, can be employed in patients who are no longer responding to imatinib. See Cecil Essentials 48. |
Practice-Based Learning and Improvement: Evidence-Based Medicine
Title
Efficacy and safety of low-dose aspirin in polycythemia vera
Authors
Landolfi R, Marchiolo R, Kutti J, et al.
Institution
Catholic University School of Medicine, Rome, Italy
Reference
N Engl J Med 2004;350:114–124
Problem
Increased arterial and venous thrombosis in patients with PV
Intervention
Low-dose aspirin (100 mg/day) vs. placebo
Outcome/effect
Low-dose aspirin was associated with a reduction in nonfatal MI, nonfatal stroke, pulmonary embolism, major venous thrombosis, and death from cardiovascular disease (relative risk, RR = 0.40, P = 0.03) when compared with placebo in patients with PV. There was no significant increased incidence of bleeding in the aspirin group.
Historical significance/comments
Historically, the use of aspirin in asymptomatic patients with PV has been controversial because of the potential risk of increased bleeding complications in treated patients. This is the first randomized, double-blind, placebo-controlled trial to show efficacy of low-dose aspirin in patients with PV.
Interpersonal and Communication Skills
Patients with MPDs are frequently referred to specialists in hematology/oncology because they have a “cancer,” a term that causes significant emotional distress for patients and their families. Although MPDs are indeed cancers in that they are clonal, it often helps to let patients know that “all cancers are different” and the patient’s prognosis is related to his or her specific disorder. CML, for example, is clearly a cancer and leukemia, but the physician can offer hope to patients and their families by informing them of the high efficacy and low toxicity of the tyrosine kinase inhibitors in the treatment of CML. For patients with PV and ET, it may be emphasized that the natural history of the disease can be quite good. Although honesty with patients and families is essential, the physician should try to find ways to plant seeds of hope in discussions of prognosis and treatment.
Professionalism
Dilemmas in Clinical Trials: Follow Ethical Principles
As more and more tyrosine kinase inhibitors become available for treating diseases such as CML, there will be increased interest in placing suitable patients into clinical trials involving these drugs. As with any clinical trial, specific ethical principles must apply: (1) All clinical trials must be properly registered with, and reviewed by, an appropriate human subject committee and an institutional review board; (2) patients entered into a clinical trial must receive information advising them of the possible risks and benefits of the therapy, and must provide informed consent; (3) patients must be informed that their medical records pertinent to the trial may be made available to outside data-monitoring committees including the US Food and Drug Administration (FDA); and (4) patients must be provided with contact information should they have any questions or concerns about their participation in the clinical trial.
Systems-Based Practice
Be Aware of Community Resources to Help Patients Obtain Medications
Although quite effective for the treatment of CML, imatinib and dasatinib are expensive medications. Additionally, because they are oral medications taken at home, inpatient hospital insurance benefits may not cover the costs associated with their use. As such, for patients with CML and inadequate outpatient prescription coverage, affording proper therapy could be a problem. In this case it is often necessary to pursue programs offered through the pharmaceutical companies so as to get patients the medications they need at reduced or no cost. Additionally, hospital social workers can sometimes assist in finding community resources to help make necessary medications available to patients who cannot otherwise afford them.
