Elevated Blood Counts (Case 26)
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.
Polycythemia vera (PV)
Essential thrombocytosis (ET)
Chronic myelogenous leukemia (CML)
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.
• 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).
• The peripheral blood smear and WBC differential count are helpful in the case presented, because no immature cells are identified. In this case, acute leukemia is extremely unlikely, and the patient is more likely to have an MPD.
• Agnogenic myeloid metaplasia (AMM) (fibrous tissue increased in the marrow) is also included as an MPD, but unlike the other three disorders, patients usually present with pancytopenia due to marrow replacement with fibrous tissue.
|Clinical Entities||Medical Knowledge|
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.
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.
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.
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.
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.
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.
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.
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.
Chronic Myelogenous Leukemia
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.
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.
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.
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.
a. Erythrocytosis can also be caused by hypoxia (secondary to high altitude, or cardiac or pulmonary disease); high–oxygen affinity hemoglobins, which leads to a shift in the oxygen saturation curve; and erythropoietin-producing tumors (such as pheochromocytoma, hepatic or kidney tumors, or cerebellar hemangiomas); and can occur following renal transplantation or surreptitious use of erythropoietin.
b. Thrombocytosis can also be seen in patients with iron deficiency with blood loss, infections, POEMS syndrome (osteosclerotic myeloma characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), and other inflammatory disorders.