M y e l o p ro l i f e r a t i v e D i s o rd e r s Brian Meier,
MD, MA
a
, John H. Burton,
MD
b,
*
KEYWORDS Myeloproliferative disorders Essential thrombocythemia Polycythemia vera Chronic myelogenous leukemia Primary myelofibrosis KEY POINTS The emergency provider (EP) generally encounters myeloproliferative disorders (MPNs) in 1 of 2 ways: as striking laboratory abnormalities of seeming unknown consequence, or in previously diagnosed patients presenting with complications. Rapid hydration, transfusion, cytoreduction, and early hematology consultation can be lifesaving. It is not uncommon for an MPN to initially be considered by the EP after notification from the hospital laboratory that an emergency department patient has an elevated cell count on a complete blood count assay.
INTRODUCTION: NATURE OF THE PROBLEM
It is not uncommon for a myeloproliferative disorder (MPN) to initially be considered by the emergency provider (EP) after notification from the hospital laboratory that an emergency department (ED) patient has an elevated cell count on a complete blood count assay. This finding may take the form of an elevation of a single cell line (eg, red cells, white cells, or platelets). Alternatively, all or multiple cell lines may be elevated in the patient’s laboratory values. When a patient with an elevated cell count presents to the EP, an MPN may often enter the differential diagnosis. Particular consideration should be given to the most common myeloproliferative neoplasms: essential thrombocythemia (ET), polycythemia vera (PV), chronic myelogenous leukemia (CML), and primary myelofibrosis (PMF).1 Myeloproliferative neoplasms are characterized by normal bone marrow with subsequently terminal myeloid expansion in the peripheral blood, leading to pathologically increased numbers of one or more cell lines.2 The entities that are classified as MPNs were first described by Vasquez in 1892. He noted a patient with erythrocytosis and splenomegaly, whom he rightly a Department of Emergency Medicine, Carilion Clinic, 525 Janette Avenue Southwest, Roanoke, VA 24016, USA; b Department of Emergency Medicine, Carilion Clinic, PO Box 13367, Roanoke, VA 24033, USA * Corresponding author. E-mail address: [email protected]
Emerg Med Clin N Am - (2014) -–http://dx.doi.org/10.1016/j.emc.2014.04.014 0733-8627/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
emed.theclinics.com
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suggested as suffering from a hemoproliferative mechanism.3 The entities now known as essential thrombocytopenia and primary myelofibrosis have been described as separate clinical entities. In 1951, Dameshek described these seemingly separate disorders as interrelated and proffered the concept of myeloproliferative syndromes.4 Work over the ensuing 50 years led to great advances in the understanding of the factors that influence hemoproliferation. This culminated in the work by Levine and colleagues3 in 2005, which identified a tyrosine kinase mutation in the common JAK-2 allele. This rendered the best explanation to date as to how these disorders ensue. Since that time, a multitude of other cytogenetic abnormalities have been investigated, none of which have proved to be definitive. DEFINITIONS
In 2008, the World Health Organization altered the classification system of myeloid neoplasms. These entities are now divided into the categories listed in Box 1. The major determination is made between those entities that are considered myelodysplastic from those that are considered myeloproliferative. Myelodysplasia is defined by dysplastic, or abnormal, bone marrow resulting in cytopenia of varying degrees due to intramedullary apoptosis.5 MPNs, in contrast, are notable for normal bone marrow findings with increased cell line count(s) in the peripheral blood.
Box 1 World Health Organization (WHO) classification of myeloproliferative neoplasms Myeloproliferative neoplasms (MPN) Chronic myelogenous leukemia (CML) Polycythemia vera (PV) Essential thrombocythemia, also known as essential thrombocytosis (ET) Primary myelofibrosis (PMF) Chronic neutrophilic leukemia (CNL) Chronic eosinophilic leukemia, not otherwise specified (CEL-NOS) Mast cell disease (MCD) MPN, unclassifiable Myelodysplastic syndromes (MDS) Myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) Chronic myelomonocytic leukemia (CMML) Juvenile myelomonocytic leukemia (JMML) Atypical chronic myeloid leukemia, BCR-ABL–negative (aCML) MDS/MPN, unclassifiable Acute myeloid leukemia (AML) Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1 Data from Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms. Cancer 2009;115(17):3842–7.
Myeloproliferative Disorders
HEMATOPOIESIS
The formation of hematologic cells is a complex process. Although new laboratory techniques in recent years have led to a vastly improved understanding of the mechanisms involved, our knowledge of hematopoiesis remains incomplete. It is believed that the interplay between multiple sources, including both intrinsic and extrinsic factors, produce approximately 2 1011 erythrocytes, 1 1011 leukocytes, and 1 1011 platelets every day.6 In the currently accepted model of hematopoiesis, it is believed that all hematologic cells derive from pleuripotent stem cells found in human bone marrow. As the cells mature, they are influenced by biochemical factors, including growth factors and interleukins, to become either common lymphoid progenitor cells or common myeloid progenitor cells.7 These common progenitors are then further subdivided into granulocyte/macrophage progenitors and megakaryocyte/erythroid progenitors, referred to as colony-forming units (CFUs). These multipotent CFUs then give rise to the progenitors of specific lineages (eg, neutrophils, macrophages, erythrocytes).6 The known factors responsible for growth and differentiation of hematopoietic cells include growth factors and interleukins. Generally, a dysfunction of these proteins or their receptors leads to over- or under-production of specific cell lines. These disruptions lead to the pathology observed in clinical medicine. A brief review of the major signaling molecules is useful in that they can be viewed as current or investigational therapeutics for patients with a myriad of hematologic disorders. These growth and differentiation proteins have been found to act both locally and systemically. They often have cross-reactivity with multiple lineages, work synergistically, and can affect normal and neoplastic cells.6 The major identified proteins responsible for these functions are granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), and thrombopoietin (TPO) (Box 2). It is important to have a general appreciation of the overlap between each of these factors to explain clinical presentations of illness and the transformation that can occur between these disorders over the course of an illness.11
Box 2 Signaling molecules currently used in hematologic therapeutics Granulocyte Colony-Stimulating Factor (G-CSF) Made predominantly by endothelial cells, monocytes, and fibroblasts8 Stimulates granulocyte production and activation Frequently used (Filgrastim) in treatment of neutropenia Erythropoietin (EPO) Produced primarily in the kidneys9 Increased in response to anemia and hypoxia8,9 Commonly used to treat chronic anemia Thrombopoietin (TPO) Synthesized primarily in liver, also in kidney and skeletal muscle6 Increases megakaryocytes and platelets, and to a lesser extent, erythroid precursors10 TPO receptor agonists currently used to treat ITP17 (development of thrombopoietin receptor agonists)
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A BRIEF GENETIC INTERLUDE
The genetic disturbances that lead to overlapping MPNs likely have little relevance to the routine acute management of ED patients. However, new therapeutics are being developed to target these mechanisms and may ultimately affect the fundamental management and prognosis of patients with MPNs. Among the MPNs, CML is unique in that it is strongly associated with a wellrecognized abnormal gene product.12 First discovered by Nowell and Hungerford13 at the University of Pennsylvania in 1960, this abnormal chromosome is now known as the Philadelphia chromosome. Although the exact mechanism of how this chromosomal translocation and its associated gene products lead to CML is uncertain, a few crucial properties have been observed. First, abnormal chromosome signals do not necessarily lead to a surge of stem-cell proliferation. Rather, an increase in downstream differentiation (CFUs) leads to an increase in abnormal, premature cells.14 Second, by binding with the BCR sequences, the ABL1 protein is rendered as an active tyrosine kinase. This allows the developing neutrophils to escape from apoptosis without the normal growth factor input affecting the development of neoplastic cells.15 Last, these neoplastic cells have altered cytoskeleton and adhesion properties that are believed to allow their premature circulation and uncontrolled proliferation.16 Much less is known about the cytogenetic basis of the other myelodysplastic disorders. PATIENT HISTORY Polycythemia Vera
The most common presenting symptoms of PV are nonspecific and indistinguishable from many other diseases, including secondary causes of polycythemia. Although PV is frequently identified by routine laboratory work, approximately 30% of patients have at least one symptomatic complaint at the time of diagnosis. The most common complaints, in decreasing order of frequency, are as follows: headache, weakness, pruritus, dizziness, and diaphoresis.17 Another common complaint, aquagenic pruritus, is itching or burning of the skin, usually after exposure to hot water. This symptom was present in 65% of known patients with PV in a recent survey.18 It is believed that the presence of aquagenic pruritus can distinguish PV from secondary causes of polycythemia.2 A recently published multinational study renders the best insight into the “typical” PV patient.19 This study group, the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT), was composed of 7 centers from Italy, Austria, and the United States. Median age at patient presentation was noted as 61 years of age, although ages ranged from 18 to 95 years. A minority of patients were younger adults with 10% younger than 40. There was no significant difference in the number of men compared with women. The most common presenting complaints for patients with PV were pruritus (36%) and vasomotor symptoms, such as headaches, lightheadedness, and paresthesias (28.5%).19 In addition to generalized symptoms, vascular complications are often initial presenting events for patients with PV. These events can range from microvascular complications, such as erythromelalgia to transient ischemic attacks (TIAs), myocardial infarctions (MIs), and pulmonary emboli (PEs). Erythromelalgia is burning pain, usually in the distal extremities, associated with either erythema or pallor. This is thought to be due to microvascular thrombosis and can progress to ulcerative lesions (Fig. 1).20 Visual disturbances in patients with PV can range from migraines and scintillating scotomata (an enlarging area of visual field translucency with zigzag edges) to
Myeloproliferative Disorders
Fig. 1. Patient with erythromelalgia from PV. (From Fred H, van Dijk H. Images of memorable cases: case 151 [Connexions Web site]. Available at: http://cnx.org/content/m14932/1.3/. Accessed December 4, 2008.)
transient loss of vision.21 Thrombotic presentations are not uncommon in undiagnosed PV. Sources estimate the prevalence of thrombosis at the time of initial diagnosis ranges from 34% to 39%.20 In the IWG-MRT group, arterial thrombosis was the most common thrombotic complication at diagnosis. Arterial thrombosis occurred in 16% of patients, followed by venous thrombus (7.4%) and major hemorrhage (4.2%).19 Thrombotic complications can occur in unusual locations, such as the splanchnic veins, cerebral sinuses, and vena cava. It has been reported that PV accounts for 10% to 40% of all known cases of Budd-Chiari syndrome.20 Essential Thrombocythemia
The incidence of ET is estimated to be 1.0 to 2.5 cases per 100,000 people per year. The disease appears to be more common in women than men. Although it can occur at any age, the incidence of ET increases with age, peaking being between 50 and 70 years.22 The presentation of ET overlaps greatly with other MPNs. It is unique, however, in that an ET diagnosis is based on ruling out other causes of thrombocytosis, including other MPNs.2 Most patients presenting with undiagnosed ET are asymptomatic (from the ET) at presentation, with incidental laboratory findings instigating a further workup. Of the symptomatic patients, the most common symptoms are headache, visual disturbance, and dizziness.2 Vascular complications are also relatively common symptoms. These can range from easy bleeding and bruising, to erythromelalgia, ocular
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migraines, and TIAs.2 Of the more significant vascular complications, thrombosis (w20%) is more common than hemorrhage (10%). Arterial thrombosis is more common than venous thrombosis.23 Similar to PV, thrombosis in unusual locations, such as hepatic vein thrombosis, is a hallmark of ET.2,24 Chronic Myelogenous Leukemia
It is estimated that approximately 15,000 new cases of CML are diagnosed each year in the United States. CML accounts for just less than 1% of all new cancer diagnoses and 32% of all new leukemias.18 The disease has a strong association with a known chromosomal abnormality t (9;22); however, there does not appear to be a strong familial link in this abnormality. The age at initial presentation is 45 to 55 years, although up to one-third of patients are diagnosed after the age of 60. The course of CML has multiple phases that generally occur in the following sequence: chronic phase, accelerated phase, and blast phase. Eighty-five percent of patients are diagnosed in the chronic phase, with up to 50% of patients asymptomatic at the time of diagnosis.25 For patients who do present with symptoms related to CML, the symptoms are often nonspecific, as is the case with other MPNs. Common symptoms of CML include fatigue (34%), bleeding (21%), weight loss (20%), abdominal fullness (15%), and sweating (15%).26 Presentations involving priapism, Sweet syndrome, and splenic infarction have been noted, but are rare.27 Primary Myelofibrosis
PMF is the least common of the MPNs.2 It has a predilection for men older than 50 years and has an annual incidence between 0.5 and 1.5 per 100,000 people.28 The median patient age in one large study was 64, although it has been reported to occur at all ages.29 PMF is characterized by bone marrow fibrosis and extramedullary hematopoiesis. Many PMF clinical findings are related to this pathophysiology. Like other MPNs, an asymptomatic presentation is not uncommon (25%) for newly diagnosed patients with PMF.28 Constitutional symptoms, such as night sweats, fatigue, and weight loss, are more common than in other patients with MPNs.2 Symptoms associated with splenomegaly are also relatively common, including decreased appetite and abdominal fullness. Up to 10% of patients with PMF may present with a thrombotic complication, with the most common being venous thromboembolism (4.5%).30 PHYSICAL EXAMINATION Polycythemia Vera
The most common findings on physical examination for patients with PV are splenomegaly, ruddy cyanosis (facial plethora), hepatomegaly, conjunctival plethora, and hypertension. Other findings are related to the complications of thrombosis and might include excoriations from itching. Splenomegaly has been reported to be present in as many as 70% of patients presenting with PV, although in the IWG-MRT group, splenomegaly was found in 36% of patients.19 Essential Thrombocythemia
The most common physical examination finding in ET is splenomegaly, occurring in approximately 50% of patients at the time of diagnosis.23 Splenomegaly is relatively mild in ET, as opposed to the more marked splenomegaly found in other MPNs.2
Myeloproliferative Disorders
Chronic Myelogenous Leukemia
The physical examination findings in CML are nonspecific and very similar to other MPNs. The most common finding is splenomegaly, followed by hepatomegaly. Findings of lymphadenopathy or myeloid sarcoma are rarer, but if present, signify a much poorer prognosis.31 Primary Myelofibrosis
Although found to some extent in all MPNs, splenomegaly is most prominent in PMF. The spleen is mildly enlarged in 25% of patients, moderately enlarged in 50% of patients, and severely enlarged in the remaining 25%.28 Hepatomegaly is found in two-thirds of patients, usually in association with splenomegaly.28 Other physical examination findings are associated with extramedullary hematopoiesis and include lymphadenopathy, peripheral edema, ascites, and pulmonary edema.28 Imaging and Additional Testing
Many diagnostic studies required to make the definitive diagnosis of MPNs are not routinely performed in the ED setting. These include chromosomal testing, bone marrow analysis, and measurements of specific cytokines. These studies are important for the diagnosis and long-term management of these conditions. Polycythemia Vera
PV often presents as a pan myelocytosis, leading to an increase in white blood cell (WBC) count, hemoglobin (Hgb), and platelets (Box 3).20 In the IWG-MRT group, 49% had a WBC count higher than 10,500 g/mL, whereas 73% had an Hgb greater than 18.5 g/dL, and 53% had platelets greater than 450,000/mL.19 Although an absolute increase in red blood cell (RBC) mass is necessary to confirm a diagnosis of PV, this is rarely required, as it is usually associated with an increase in Hgb. A few circumstances can occur in which an abnormal RBC mass will be present despite a normal Hgb level. These include splenomegaly resulting in an increase in plasma volume, iron deficiency anemia, and acute blood loss anemia.20 Coagulation studies (prothrombin time, activated partial thromboplastin time) are generally normal in patients with
Box 3 WHO criteria for diagnosis of PV Major criteria Hemoglobin greater than 18.5 g/dL in men, 16.5 g/dL in women, or other evidence of increased red cell volume Presence of JAK2 V617F or other functionally similar mutation, such as JAK2 exon 12 mutation Minor criteria Bone marrow biopsy with hypercellularity for age with trilineage growth (panmyelosis) and prominent erythroid, granulocytic, and megakaryocytic proliferation Serum erythropoietin level below the reference range for normal Endogenous erythroid colony formation in vitro Diagnosis requires either both major criteria and 1 minor, or the first major criteria and 2 minor. Data from Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms. Cancer 2009;115(17):3842–7.
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PV; however, increased erythrocytosis can have an effect on coagulation assessment leading to markedly abnormal values.20 Essential Thrombocythemia
Patients diagnosed with ET will have an elevated platelet count (Box 4). Definitions vary on the specific cutoff for an elevated platelet count. At a minimum, the platelet count will be greater than 450 109/L. In most cases, the platelet count will be greater than 1000 109/L.23 In contrast to PV, the serum Hgb will be normal in patients with ET. The WBC count in patients with ET will typically be normal, although slightly elevated WBC counts may be present.2 Coagulation studies are typically normal. Bleeding time may be increased, although an elevated bleeding time cannot predict the risk of bleeding or thrombotic complications.2 ET is a diagnosis of exclusion. Therefore, no specific laboratory, cytogenetic, or imaging findings are specific to ET. Besides other PMNs, ET must be distinguished from other causes of thrombocytosis. These include inflammation, blood loss, exercise, medications, iron deficiency, hemolytic anemia, and malignancy. For this reason, laboratory tests, such as erythrocyte sedimentation rate, C-reactive protein, iron studies, and peripheral RBC smear are commonly used to distinguish ET from other etiologies of thrombocytosis.2 Chronic Myelogenous Leukemia
CML is suspected in a patient with an increase in the number of leukocytes (Box 5). Generally, this value is greater than 25,000/mL with more than 50% of patients presenting with a WBC count greater than 100,000/mL.27 It has been reported that 100% of patients will have an absolute basophilia and more than 90% will have an absolute eosinophilia.32 Platelet counts are usually increased, and a normochromic, normocytic anemia is generally present as well.31 Although not routinely obtained in the ED, neutrophil alkaline phosphatase is found to be low in patients with CML and can be useful in distinguishing it from PV, pregnancy, and other inflammatory conditions causing an elevation in WBC count (Leukemoid reaction).27 In addition to hematologic findings, there are several laboratory abnormalities frequently encountered in untreated CML. Uric acid is generally 2 to 3 times normal levels in untreated CML. Uric acid levels can be even further increased by initial aggressive treatment, which can lead to urinary tract blockage from precipitates. Serum B12 is usually elevated in CML, often up to 10 times normal levels. This finding
Box 4 WHO criteria for diagnosis of ET Sustained platelet count 450 109/L Bone marrow biopsy specimen demonstrating proliferation of megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes; no significant increase or left-shift of neutrophil granulopoiesis or erythropoiesis Not meeting WHO criteria for PV, PMF, CML, MDS, or other myeloid neoplasm Demonstration of JAK2 V617F or other clonal marker, or in the absence of a clonal marker, no evidence for reactive thrombocytosis Diagnosis requires all 4 elements. Data from Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms. Cancer 2009;115(17):3842–7.
Myeloproliferative Disorders
Box 5 WHO criteria for stage of CML Chronic Phase Diagnosed CML, no features of either accelerated or blast phase Accelerated Phase Blasts greater than 15% in blood or bone marrow Blasts plus progranulocytes greater than 30% in blood or bone marrow Basophilia greater than 20% in blood or bone marrow Platelets less than 100 109 unrelated to therapy Cytogenetic clonal evolution Blast Phase Greater than 20% blasts in blood or bone marrow Extramedullary disease with localized immature blasts Data from Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms. Cancer 2009;115(17):3842–7; and Kantarjian HM, Keating MJ, Smith TL, et al. Proposal for a simple synthesis prognostic staging system in chronic myelogenous leukemia. Am J Med 1990;88(1):1–8.
is because neutrophils contain B12 binding proteins.27 The lactate dehydrogenase level is also elevated in CML, although how these levels affect prognosis in CML has not been demonstrated.33 The final diagnosis of CML requires bone marrow biopsy and cytogenetic testing. Bone marrow findings will reveal increased cellularity with an alteration of the normal erythropoiesis to granulopoiesis.27 Primary Myelofibrosis
Unlike the other PMNs, PMF does not result in the proliferation of a particular line of cells (Box 6). Instead, a variety of abnormalities may exist that suggest the diagnosis Box 6 WHO criteria for diagnosis of PMF Major Criteria Presence of megakaryocyte proliferation and atypia, usually accompanied by reticulin and/or collagen WHO criteria for PV, CML, MDS, or other myeloid neoplasm not met Demonstration of a clonal marker (eg, JAK2 or MPL) Minor Criteria Leukoerythroblastosis Palpable splenomegaly Anemia Increased serum lactate dehydrogenase level Diagnosis requires 3 major and 2 minor criteria. Data from Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms. Cancer 2009;115(17):3842–7.
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and these can vary depending on the stage of disease. A normocytic, normochromic anemia is the most frequently encountered laboratory abnormality.28 The average Hgb measurement is usually between 9 and 12 g/dL,28 with several large studies demonstrating Hgb levels less than 10 g/dL in more than 50% of patients.30,34 WBC counts, although typically normal in patients with PMF, may be markedly abnormal, with one study recording values greater than 25,000/mL in 16% of patients and less than 4000/mL in another 16%.29,34 Serum platelets can be increased or decreased.29 Overall, 10% of patients present with pancytopenia, although this is more common as the disease progresses.28 Other nonspecific laboratory findings include increases in uric acid, lactate dehydrogenase, bilirubin, and alkaline phosphatase, as well as decreases in albumin and cholesterol.28 TREATMENT AND PROGNOSIS Polycythemia Vera
Pruritus is often a major complaint of patients with PV, as it is one of the few symptoms that is not easily treated with suppressive therapy. Pruritus is known to be exacerbated by bathing and skin irritation. No treatment has been shown to be consistently effective. The most commonly used treatment historically has been antihistamines. Antihistamines appear to be effective in approximately 50% of patient encounters.35 More recently, selective-serotonin reuptake inhibitors have been shown to be effective.36 The thrombotic complications of PV present as a wide spectrum of disorders. Thrombotic complications are the most common cause of morbidity and mortality in patients with PV.17 One large study demonstrated that cardiovascular mortality (eg, stroke, MI, PE) accounted for 45% of all deaths in patients with PV. This same study confirmed that age older than 65 and a previous history of thrombosis were the greatest risk factors for future thrombosis.37 Although a common practice is to maintain a patient’s hematocrit and platelet levels within specific parameters, the risk of thrombosis has not been shown to correlate with any particular value.20,38 The index of suspicion for a thrombotic event should be high when treating a patient with PV, especially with patients in high-risk categories. The treatment of an acute thrombus/embolus in PV (or other MPN) does not vary from that of any other patient. Patients presenting with acute coronary syndrome (ACS) still require stenting or thrombolytics.39 The incidence of bleeding in patients with PV ranges from 30% to 40%, varying from minor episodes of epistaxis or gingival bleeding to life-threatening hemorrhage.20 In a large cohort of patients with PV who underwent surgery, there was shown to be increased risk of major hemorrhage during surgery and also an increase in postoperative bleeding.37 There was also a correlation between antithrombotic prophylaxis (aspirin and heparin) and bleeding risk, although how these data translate into bleeding risk in the nonsurgical patient is unclear.40 Hyperviscosity syndrome (HVS), although more common in paraproteinemias, can be caused by any of the MPNs.41 The classic presentation is the combination of mucosal bleeding, visual changes, and neurologic symptoms. Neurologic symptoms can range from headache and vertigo to coma (Box 7).41 HVS should be a consideration in any patient with a known MPN who presents with the previously mentioned complaints. It also should be considered in undiagnosed patients whose initial laboratory tests are suggestive of an underlying MPN. Definitive treatment of hyperviscosity syndrome caused by PV is with plasmapheresis. Before this, ED management also includes rapid hydration, placement of large-bore central venous access, and phlebotomy for severe symptoms. Initial removal of up to 500 mL of
Myeloproliferative Disorders
Box 7 Neurologic manifestations of hyperviscosity syndrome Vertigo Hearing loss Paresthesias Strokelike symptoms Ataxia Generalized stupor Seizures Coma
blood over 1 to 2 hours with normal saline replacement can be performed without major hemodynamic consequence (see Box 7). If further phlebotomy is required, an additional 500 to 1000 mL may be removed over the ensuing 24 hours with a goal hematocrit of less than 55%. The addition of low-dose aspirin (81 mg) also can be considered.42 Hematologic transformation and solid tumor formation are the other major complications of PV. In a large study, 3.5% of patients had hematologic transformation, whereas 4.3% had transformation into solid organ tumors.37 Of the hematologic transformations, approximately two-thirds of patients transformed into myelofibrosis, whereas one-third evolved into acute myelogenous leukemia (AML). Mortality due to hematologic transformation and solid organ tumor formation represented 13.0% and 19.5% of all deaths, respectively.37 Proposed risk factors for the transition to myelofibrosis include duration of disease and age.37,43 Age older than 70 years appears to be a risk factor for developing AML. The use of cytoreductive drugs other than hydroxyurea and interferon appears to confer the greatest risk of developing AML.37 EPs should be cognizant that the diseases often overlap and patient courses are rarely consistent. Essential Thrombocythemia
The management of ET is very similar to that of PV. The 2 main aims of treatment include treating the common vasomotor symptoms and preventing thrombotic complications. The mainstay of treatment is low-dose aspirin. In addition to microvascular symptoms, such as erythromelalgia, the use of low-dose aspirin also is useful in preventing more significant complications.22 The use of more aggressive therapy to reduce the risk of thrombosis is restricted to groups at higher risk for these complications. Risk factors associated with increased risk for thrombosis include age older than 60, history of thrombosis, presence of a JAK2 mutation, and the usual coronary artery disease risk factors (eg, diabetes, smoking, hypertension).44 Additionally, it has been shown that continued exposure to platelet levels greater than 1000 109/L is associated with increased risk for thrombosis.2 In patients with these risk factors, the primary therapy is hydroxyurea. The side effects of hydroxyurea include increased infection risk, leukopenia, and anemia.45 For this reason, another agent, anagrelide, has recently been investigated as an alternative. Results have been variable in 2 large studies directly comparing the 2 treatments. Concerns for increased risk of progression to myelofibrosis currently limit the acceptance of anagrelide.22
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Overall, the risk of thrombotic complications as a result of ET is less than that of PV. In a large multicenter study, 12% of patients with ET had a thrombotic complication during the follow-up period (mean follow-up 6.2 years).44 The overall risk of leukemic or myelofibrotic transformation is relatively low compared with other MPNs. In this multicenter trial, 1% of patients developed an acute leukemia, whereas 4% had progression to myelofibrosis.44 As in other MPNs, once transformation into either of these diseases occurs, prognosis is extremely poor. Chronic Myelogenous Leukemia
Given that the diagnosis of CML requires bone marrow biopsy, it is not likely that EPs will render the diagnosis of CML in the ED. The EP should refer patients with a suspicion of CML to a specialist for consultation. CML is characterized by 3 distinct stages that generally occur in succession: chronic, accelerated and blast phases (see Box 5). The criteria for each of these stages are somewhat variable.46 Most undiagnosed patients with CML seen in the ED setting will present in the chronic phase of disease. Initial treatment for these patients will be symptomatic. Hydroxyurea can be instituted for patients with WBC count greater than 80 109/L. Allopurinol is often instituted to minimize the complications associated with high uric acid produced during tumor lysis.47 Therapy initiated in the ED will typically be under the direction of a consulting hematologist/oncologist. Once the diagnosis of CML is made, the hematologist/oncologist will generally initiate therapy with a tyrosine kinase inhibitor. The major complication of CML is related to the progression of disease, with the final stage being a blast crisis. Patients can either present undiagnosed in this stage, which is rare, or present with symptoms related to progression of known disease. The presentation and management of acute leukemia and blast crisis is covered elsewhere in the issue and will be only briefly discussed here. Hyperviscosity can be due to increases in any hematologic cell line. When WBCs are the culprit, it is often referred to as hyperleukocytosis and leukostasis. Although rare in the chronic phase of CML, hyperleukocytosis and leukostasis warrant special mention, as mortality can reach 20% to 40%.48 In addition to the common triad of mucosal bleeding, neurologic symptoms, and visual changes, pulmonary complications represent a significant number of deaths due to hyperleukocytosis.48 Historically, hyperleukocytosis has been defined by WBC count greater than 100 109; however, complications from leukostasis may arise with WBC counts substantially lower than this.48 Nearly all patients with hyperleukocytosis will present with fever. It is appropriate to start empiric broad-spectrum antibiotics and obtain blood cultures; however, a true infection is rarely present.48 Early ED management focuses on aggressive hydration, central venous access, and prompt cytoreduction. Hydroxyurea, 1 to 2 g orally every 6 hours, should be started when the diagnosis is first made (Table 1). Further cytoreduction with induction chemotherapy and/or leukapheresis can be initiated after a discussion with a hematologist/oncologist. All patients with hyperleukocytosis will require admission. Primary Myelofibrosis
Other than bone marrow transplant, treatments for PMF focus on symptomatic relief and prevention of disease progression. Similar to PV and ET, hydroxyurea is the most commonly used medication. Hydroxyurea in PMF is used to treat a myriad of symptoms, including hepatosplenomegaly, night sweats, weight loss, and anemia.28 Other treatments, less frequently encountered in the ED, including EPO, thalidomide, and interferon-alpha, have been shown to be efficacious in certain populations. These
Myeloproliferative Disorders
Table 1 Summary of emergent complications and associated treatments Diagnosis
Presentation
ED Management
Definitive Treatment
PV with Hct >60% or hyperviscosity syndrome
Neurologic symptoms, visual disturbances, mucosal bleeding
Fluid resuscitation Central venous access Phlebotomy: 250–500 mL over 1–2 h with NS replacement
Plasmapheresis Long-term cytoreductive therapy
Hyperleukocytosis/ leukostasis
Similar to HVS pulmonary symptoms Fever
Fluid resuscitation Central venous access Hydroxyurea 1–2 g PO q6 Broad-spectrum antibiotics
Leukapheresis Induction chemotherapy
Thrombosis
Chest pain (PE/ACS) Abdominal pain (Budd-Chiari) Extremity pain/ swelling (DVT)
Anticoagulation/ intervention per usual protocol
—
Abbreviations: ACS, acute coronary syndrome; DVT, deep venous thrombosis; ED, emergency department; Hct, hematocrit; HVS, hyperviscosity syndrome; NS, normal saline; PE, pulmonary emboli; PO, by mouth; PV, polycythemia vera; q, every.
agents are not universally effective in improving symptoms and are best managed by a hematologist/oncologist.2 The course and prognosis of PMF is less favorable than that of ET and PV. Five-year survival is 40% compared with healthy age-matched controls. The median survival time for patients with PMF is approximately 69 months.2 The most common cause of death is transformation into acute leukemia. The overall incidence of thrombotic complication is less than 10%, which is lower than both ET and PV.29 Several risk factors have been noted to be associated with decreased survival in patients with PMF (Box 8). These factors are frequently used to assess the prognosis of patients diagnosed with PMF. Survival has been shown to range from 135 months in patients with none of these risk factors, to as low as 27 months in individuals with 3 or more risk factors.29
Box 8 Risk factors associated with decreased survival in patients with PMF Age older than 65 Hemoglobin less than 10 g/dL Exaggerated leukocytosis (>25 109/L) or leukopenia (
MD, MA
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b,
*
KEYWORDS Myeloproliferative disorders Essential thrombocythemia Polycythemia vera Chronic myelogenous leukemia Primary myelofibrosis KEY POINTS The emergency provider (EP) generally encounters myeloproliferative disorders (MPNs) in 1 of 2 ways: as striking laboratory abnormalities of seeming unknown consequence, or in previously diagnosed patients presenting with complications. Rapid hydration, transfusion, cytoreduction, and early hematology consultation can be lifesaving. It is not uncommon for an MPN to initially be considered by the EP after notification from the hospital laboratory that an emergency department patient has an elevated cell count on a complete blood count assay.
INTRODUCTION: NATURE OF THE PROBLEM
It is not uncommon for a myeloproliferative disorder (MPN) to initially be considered by the emergency provider (EP) after notification from the hospital laboratory that an emergency department (ED) patient has an elevated cell count on a complete blood count assay. This finding may take the form of an elevation of a single cell line (eg, red cells, white cells, or platelets). Alternatively, all or multiple cell lines may be elevated in the patient’s laboratory values. When a patient with an elevated cell count presents to the EP, an MPN may often enter the differential diagnosis. Particular consideration should be given to the most common myeloproliferative neoplasms: essential thrombocythemia (ET), polycythemia vera (PV), chronic myelogenous leukemia (CML), and primary myelofibrosis (PMF).1 Myeloproliferative neoplasms are characterized by normal bone marrow with subsequently terminal myeloid expansion in the peripheral blood, leading to pathologically increased numbers of one or more cell lines.2 The entities that are classified as MPNs were first described by Vasquez in 1892. He noted a patient with erythrocytosis and splenomegaly, whom he rightly a Department of Emergency Medicine, Carilion Clinic, 525 Janette Avenue Southwest, Roanoke, VA 24016, USA; b Department of Emergency Medicine, Carilion Clinic, PO Box 13367, Roanoke, VA 24033, USA * Corresponding author. E-mail address: [email protected]
Emerg Med Clin N Am - (2014) -–http://dx.doi.org/10.1016/j.emc.2014.04.014 0733-8627/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
emed.theclinics.com
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suggested as suffering from a hemoproliferative mechanism.3 The entities now known as essential thrombocytopenia and primary myelofibrosis have been described as separate clinical entities. In 1951, Dameshek described these seemingly separate disorders as interrelated and proffered the concept of myeloproliferative syndromes.4 Work over the ensuing 50 years led to great advances in the understanding of the factors that influence hemoproliferation. This culminated in the work by Levine and colleagues3 in 2005, which identified a tyrosine kinase mutation in the common JAK-2 allele. This rendered the best explanation to date as to how these disorders ensue. Since that time, a multitude of other cytogenetic abnormalities have been investigated, none of which have proved to be definitive. DEFINITIONS
In 2008, the World Health Organization altered the classification system of myeloid neoplasms. These entities are now divided into the categories listed in Box 1. The major determination is made between those entities that are considered myelodysplastic from those that are considered myeloproliferative. Myelodysplasia is defined by dysplastic, or abnormal, bone marrow resulting in cytopenia of varying degrees due to intramedullary apoptosis.5 MPNs, in contrast, are notable for normal bone marrow findings with increased cell line count(s) in the peripheral blood.
Box 1 World Health Organization (WHO) classification of myeloproliferative neoplasms Myeloproliferative neoplasms (MPN) Chronic myelogenous leukemia (CML) Polycythemia vera (PV) Essential thrombocythemia, also known as essential thrombocytosis (ET) Primary myelofibrosis (PMF) Chronic neutrophilic leukemia (CNL) Chronic eosinophilic leukemia, not otherwise specified (CEL-NOS) Mast cell disease (MCD) MPN, unclassifiable Myelodysplastic syndromes (MDS) Myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) Chronic myelomonocytic leukemia (CMML) Juvenile myelomonocytic leukemia (JMML) Atypical chronic myeloid leukemia, BCR-ABL–negative (aCML) MDS/MPN, unclassifiable Acute myeloid leukemia (AML) Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1 Data from Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms. Cancer 2009;115(17):3842–7.
Myeloproliferative Disorders
HEMATOPOIESIS
The formation of hematologic cells is a complex process. Although new laboratory techniques in recent years have led to a vastly improved understanding of the mechanisms involved, our knowledge of hematopoiesis remains incomplete. It is believed that the interplay between multiple sources, including both intrinsic and extrinsic factors, produce approximately 2 1011 erythrocytes, 1 1011 leukocytes, and 1 1011 platelets every day.6 In the currently accepted model of hematopoiesis, it is believed that all hematologic cells derive from pleuripotent stem cells found in human bone marrow. As the cells mature, they are influenced by biochemical factors, including growth factors and interleukins, to become either common lymphoid progenitor cells or common myeloid progenitor cells.7 These common progenitors are then further subdivided into granulocyte/macrophage progenitors and megakaryocyte/erythroid progenitors, referred to as colony-forming units (CFUs). These multipotent CFUs then give rise to the progenitors of specific lineages (eg, neutrophils, macrophages, erythrocytes).6 The known factors responsible for growth and differentiation of hematopoietic cells include growth factors and interleukins. Generally, a dysfunction of these proteins or their receptors leads to over- or under-production of specific cell lines. These disruptions lead to the pathology observed in clinical medicine. A brief review of the major signaling molecules is useful in that they can be viewed as current or investigational therapeutics for patients with a myriad of hematologic disorders. These growth and differentiation proteins have been found to act both locally and systemically. They often have cross-reactivity with multiple lineages, work synergistically, and can affect normal and neoplastic cells.6 The major identified proteins responsible for these functions are granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), and thrombopoietin (TPO) (Box 2). It is important to have a general appreciation of the overlap between each of these factors to explain clinical presentations of illness and the transformation that can occur between these disorders over the course of an illness.11
Box 2 Signaling molecules currently used in hematologic therapeutics Granulocyte Colony-Stimulating Factor (G-CSF) Made predominantly by endothelial cells, monocytes, and fibroblasts8 Stimulates granulocyte production and activation Frequently used (Filgrastim) in treatment of neutropenia Erythropoietin (EPO) Produced primarily in the kidneys9 Increased in response to anemia and hypoxia8,9 Commonly used to treat chronic anemia Thrombopoietin (TPO) Synthesized primarily in liver, also in kidney and skeletal muscle6 Increases megakaryocytes and platelets, and to a lesser extent, erythroid precursors10 TPO receptor agonists currently used to treat ITP17 (development of thrombopoietin receptor agonists)
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A BRIEF GENETIC INTERLUDE
The genetic disturbances that lead to overlapping MPNs likely have little relevance to the routine acute management of ED patients. However, new therapeutics are being developed to target these mechanisms and may ultimately affect the fundamental management and prognosis of patients with MPNs. Among the MPNs, CML is unique in that it is strongly associated with a wellrecognized abnormal gene product.12 First discovered by Nowell and Hungerford13 at the University of Pennsylvania in 1960, this abnormal chromosome is now known as the Philadelphia chromosome. Although the exact mechanism of how this chromosomal translocation and its associated gene products lead to CML is uncertain, a few crucial properties have been observed. First, abnormal chromosome signals do not necessarily lead to a surge of stem-cell proliferation. Rather, an increase in downstream differentiation (CFUs) leads to an increase in abnormal, premature cells.14 Second, by binding with the BCR sequences, the ABL1 protein is rendered as an active tyrosine kinase. This allows the developing neutrophils to escape from apoptosis without the normal growth factor input affecting the development of neoplastic cells.15 Last, these neoplastic cells have altered cytoskeleton and adhesion properties that are believed to allow their premature circulation and uncontrolled proliferation.16 Much less is known about the cytogenetic basis of the other myelodysplastic disorders. PATIENT HISTORY Polycythemia Vera
The most common presenting symptoms of PV are nonspecific and indistinguishable from many other diseases, including secondary causes of polycythemia. Although PV is frequently identified by routine laboratory work, approximately 30% of patients have at least one symptomatic complaint at the time of diagnosis. The most common complaints, in decreasing order of frequency, are as follows: headache, weakness, pruritus, dizziness, and diaphoresis.17 Another common complaint, aquagenic pruritus, is itching or burning of the skin, usually after exposure to hot water. This symptom was present in 65% of known patients with PV in a recent survey.18 It is believed that the presence of aquagenic pruritus can distinguish PV from secondary causes of polycythemia.2 A recently published multinational study renders the best insight into the “typical” PV patient.19 This study group, the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT), was composed of 7 centers from Italy, Austria, and the United States. Median age at patient presentation was noted as 61 years of age, although ages ranged from 18 to 95 years. A minority of patients were younger adults with 10% younger than 40. There was no significant difference in the number of men compared with women. The most common presenting complaints for patients with PV were pruritus (36%) and vasomotor symptoms, such as headaches, lightheadedness, and paresthesias (28.5%).19 In addition to generalized symptoms, vascular complications are often initial presenting events for patients with PV. These events can range from microvascular complications, such as erythromelalgia to transient ischemic attacks (TIAs), myocardial infarctions (MIs), and pulmonary emboli (PEs). Erythromelalgia is burning pain, usually in the distal extremities, associated with either erythema or pallor. This is thought to be due to microvascular thrombosis and can progress to ulcerative lesions (Fig. 1).20 Visual disturbances in patients with PV can range from migraines and scintillating scotomata (an enlarging area of visual field translucency with zigzag edges) to
Myeloproliferative Disorders
Fig. 1. Patient with erythromelalgia from PV. (From Fred H, van Dijk H. Images of memorable cases: case 151 [Connexions Web site]. Available at: http://cnx.org/content/m14932/1.3/. Accessed December 4, 2008.)
transient loss of vision.21 Thrombotic presentations are not uncommon in undiagnosed PV. Sources estimate the prevalence of thrombosis at the time of initial diagnosis ranges from 34% to 39%.20 In the IWG-MRT group, arterial thrombosis was the most common thrombotic complication at diagnosis. Arterial thrombosis occurred in 16% of patients, followed by venous thrombus (7.4%) and major hemorrhage (4.2%).19 Thrombotic complications can occur in unusual locations, such as the splanchnic veins, cerebral sinuses, and vena cava. It has been reported that PV accounts for 10% to 40% of all known cases of Budd-Chiari syndrome.20 Essential Thrombocythemia
The incidence of ET is estimated to be 1.0 to 2.5 cases per 100,000 people per year. The disease appears to be more common in women than men. Although it can occur at any age, the incidence of ET increases with age, peaking being between 50 and 70 years.22 The presentation of ET overlaps greatly with other MPNs. It is unique, however, in that an ET diagnosis is based on ruling out other causes of thrombocytosis, including other MPNs.2 Most patients presenting with undiagnosed ET are asymptomatic (from the ET) at presentation, with incidental laboratory findings instigating a further workup. Of the symptomatic patients, the most common symptoms are headache, visual disturbance, and dizziness.2 Vascular complications are also relatively common symptoms. These can range from easy bleeding and bruising, to erythromelalgia, ocular
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migraines, and TIAs.2 Of the more significant vascular complications, thrombosis (w20%) is more common than hemorrhage (10%). Arterial thrombosis is more common than venous thrombosis.23 Similar to PV, thrombosis in unusual locations, such as hepatic vein thrombosis, is a hallmark of ET.2,24 Chronic Myelogenous Leukemia
It is estimated that approximately 15,000 new cases of CML are diagnosed each year in the United States. CML accounts for just less than 1% of all new cancer diagnoses and 32% of all new leukemias.18 The disease has a strong association with a known chromosomal abnormality t (9;22); however, there does not appear to be a strong familial link in this abnormality. The age at initial presentation is 45 to 55 years, although up to one-third of patients are diagnosed after the age of 60. The course of CML has multiple phases that generally occur in the following sequence: chronic phase, accelerated phase, and blast phase. Eighty-five percent of patients are diagnosed in the chronic phase, with up to 50% of patients asymptomatic at the time of diagnosis.25 For patients who do present with symptoms related to CML, the symptoms are often nonspecific, as is the case with other MPNs. Common symptoms of CML include fatigue (34%), bleeding (21%), weight loss (20%), abdominal fullness (15%), and sweating (15%).26 Presentations involving priapism, Sweet syndrome, and splenic infarction have been noted, but are rare.27 Primary Myelofibrosis
PMF is the least common of the MPNs.2 It has a predilection for men older than 50 years and has an annual incidence between 0.5 and 1.5 per 100,000 people.28 The median patient age in one large study was 64, although it has been reported to occur at all ages.29 PMF is characterized by bone marrow fibrosis and extramedullary hematopoiesis. Many PMF clinical findings are related to this pathophysiology. Like other MPNs, an asymptomatic presentation is not uncommon (25%) for newly diagnosed patients with PMF.28 Constitutional symptoms, such as night sweats, fatigue, and weight loss, are more common than in other patients with MPNs.2 Symptoms associated with splenomegaly are also relatively common, including decreased appetite and abdominal fullness. Up to 10% of patients with PMF may present with a thrombotic complication, with the most common being venous thromboembolism (4.5%).30 PHYSICAL EXAMINATION Polycythemia Vera
The most common findings on physical examination for patients with PV are splenomegaly, ruddy cyanosis (facial plethora), hepatomegaly, conjunctival plethora, and hypertension. Other findings are related to the complications of thrombosis and might include excoriations from itching. Splenomegaly has been reported to be present in as many as 70% of patients presenting with PV, although in the IWG-MRT group, splenomegaly was found in 36% of patients.19 Essential Thrombocythemia
The most common physical examination finding in ET is splenomegaly, occurring in approximately 50% of patients at the time of diagnosis.23 Splenomegaly is relatively mild in ET, as opposed to the more marked splenomegaly found in other MPNs.2
Myeloproliferative Disorders
Chronic Myelogenous Leukemia
The physical examination findings in CML are nonspecific and very similar to other MPNs. The most common finding is splenomegaly, followed by hepatomegaly. Findings of lymphadenopathy or myeloid sarcoma are rarer, but if present, signify a much poorer prognosis.31 Primary Myelofibrosis
Although found to some extent in all MPNs, splenomegaly is most prominent in PMF. The spleen is mildly enlarged in 25% of patients, moderately enlarged in 50% of patients, and severely enlarged in the remaining 25%.28 Hepatomegaly is found in two-thirds of patients, usually in association with splenomegaly.28 Other physical examination findings are associated with extramedullary hematopoiesis and include lymphadenopathy, peripheral edema, ascites, and pulmonary edema.28 Imaging and Additional Testing
Many diagnostic studies required to make the definitive diagnosis of MPNs are not routinely performed in the ED setting. These include chromosomal testing, bone marrow analysis, and measurements of specific cytokines. These studies are important for the diagnosis and long-term management of these conditions. Polycythemia Vera
PV often presents as a pan myelocytosis, leading to an increase in white blood cell (WBC) count, hemoglobin (Hgb), and platelets (Box 3).20 In the IWG-MRT group, 49% had a WBC count higher than 10,500 g/mL, whereas 73% had an Hgb greater than 18.5 g/dL, and 53% had platelets greater than 450,000/mL.19 Although an absolute increase in red blood cell (RBC) mass is necessary to confirm a diagnosis of PV, this is rarely required, as it is usually associated with an increase in Hgb. A few circumstances can occur in which an abnormal RBC mass will be present despite a normal Hgb level. These include splenomegaly resulting in an increase in plasma volume, iron deficiency anemia, and acute blood loss anemia.20 Coagulation studies (prothrombin time, activated partial thromboplastin time) are generally normal in patients with
Box 3 WHO criteria for diagnosis of PV Major criteria Hemoglobin greater than 18.5 g/dL in men, 16.5 g/dL in women, or other evidence of increased red cell volume Presence of JAK2 V617F or other functionally similar mutation, such as JAK2 exon 12 mutation Minor criteria Bone marrow biopsy with hypercellularity for age with trilineage growth (panmyelosis) and prominent erythroid, granulocytic, and megakaryocytic proliferation Serum erythropoietin level below the reference range for normal Endogenous erythroid colony formation in vitro Diagnosis requires either both major criteria and 1 minor, or the first major criteria and 2 minor. Data from Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms. Cancer 2009;115(17):3842–7.
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PV; however, increased erythrocytosis can have an effect on coagulation assessment leading to markedly abnormal values.20 Essential Thrombocythemia
Patients diagnosed with ET will have an elevated platelet count (Box 4). Definitions vary on the specific cutoff for an elevated platelet count. At a minimum, the platelet count will be greater than 450 109/L. In most cases, the platelet count will be greater than 1000 109/L.23 In contrast to PV, the serum Hgb will be normal in patients with ET. The WBC count in patients with ET will typically be normal, although slightly elevated WBC counts may be present.2 Coagulation studies are typically normal. Bleeding time may be increased, although an elevated bleeding time cannot predict the risk of bleeding or thrombotic complications.2 ET is a diagnosis of exclusion. Therefore, no specific laboratory, cytogenetic, or imaging findings are specific to ET. Besides other PMNs, ET must be distinguished from other causes of thrombocytosis. These include inflammation, blood loss, exercise, medications, iron deficiency, hemolytic anemia, and malignancy. For this reason, laboratory tests, such as erythrocyte sedimentation rate, C-reactive protein, iron studies, and peripheral RBC smear are commonly used to distinguish ET from other etiologies of thrombocytosis.2 Chronic Myelogenous Leukemia
CML is suspected in a patient with an increase in the number of leukocytes (Box 5). Generally, this value is greater than 25,000/mL with more than 50% of patients presenting with a WBC count greater than 100,000/mL.27 It has been reported that 100% of patients will have an absolute basophilia and more than 90% will have an absolute eosinophilia.32 Platelet counts are usually increased, and a normochromic, normocytic anemia is generally present as well.31 Although not routinely obtained in the ED, neutrophil alkaline phosphatase is found to be low in patients with CML and can be useful in distinguishing it from PV, pregnancy, and other inflammatory conditions causing an elevation in WBC count (Leukemoid reaction).27 In addition to hematologic findings, there are several laboratory abnormalities frequently encountered in untreated CML. Uric acid is generally 2 to 3 times normal levels in untreated CML. Uric acid levels can be even further increased by initial aggressive treatment, which can lead to urinary tract blockage from precipitates. Serum B12 is usually elevated in CML, often up to 10 times normal levels. This finding
Box 4 WHO criteria for diagnosis of ET Sustained platelet count 450 109/L Bone marrow biopsy specimen demonstrating proliferation of megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes; no significant increase or left-shift of neutrophil granulopoiesis or erythropoiesis Not meeting WHO criteria for PV, PMF, CML, MDS, or other myeloid neoplasm Demonstration of JAK2 V617F or other clonal marker, or in the absence of a clonal marker, no evidence for reactive thrombocytosis Diagnosis requires all 4 elements. Data from Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms. Cancer 2009;115(17):3842–7.
Myeloproliferative Disorders
Box 5 WHO criteria for stage of CML Chronic Phase Diagnosed CML, no features of either accelerated or blast phase Accelerated Phase Blasts greater than 15% in blood or bone marrow Blasts plus progranulocytes greater than 30% in blood or bone marrow Basophilia greater than 20% in blood or bone marrow Platelets less than 100 109 unrelated to therapy Cytogenetic clonal evolution Blast Phase Greater than 20% blasts in blood or bone marrow Extramedullary disease with localized immature blasts Data from Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms. Cancer 2009;115(17):3842–7; and Kantarjian HM, Keating MJ, Smith TL, et al. Proposal for a simple synthesis prognostic staging system in chronic myelogenous leukemia. Am J Med 1990;88(1):1–8.
is because neutrophils contain B12 binding proteins.27 The lactate dehydrogenase level is also elevated in CML, although how these levels affect prognosis in CML has not been demonstrated.33 The final diagnosis of CML requires bone marrow biopsy and cytogenetic testing. Bone marrow findings will reveal increased cellularity with an alteration of the normal erythropoiesis to granulopoiesis.27 Primary Myelofibrosis
Unlike the other PMNs, PMF does not result in the proliferation of a particular line of cells (Box 6). Instead, a variety of abnormalities may exist that suggest the diagnosis Box 6 WHO criteria for diagnosis of PMF Major Criteria Presence of megakaryocyte proliferation and atypia, usually accompanied by reticulin and/or collagen WHO criteria for PV, CML, MDS, or other myeloid neoplasm not met Demonstration of a clonal marker (eg, JAK2 or MPL) Minor Criteria Leukoerythroblastosis Palpable splenomegaly Anemia Increased serum lactate dehydrogenase level Diagnosis requires 3 major and 2 minor criteria. Data from Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms. Cancer 2009;115(17):3842–7.
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and these can vary depending on the stage of disease. A normocytic, normochromic anemia is the most frequently encountered laboratory abnormality.28 The average Hgb measurement is usually between 9 and 12 g/dL,28 with several large studies demonstrating Hgb levels less than 10 g/dL in more than 50% of patients.30,34 WBC counts, although typically normal in patients with PMF, may be markedly abnormal, with one study recording values greater than 25,000/mL in 16% of patients and less than 4000/mL in another 16%.29,34 Serum platelets can be increased or decreased.29 Overall, 10% of patients present with pancytopenia, although this is more common as the disease progresses.28 Other nonspecific laboratory findings include increases in uric acid, lactate dehydrogenase, bilirubin, and alkaline phosphatase, as well as decreases in albumin and cholesterol.28 TREATMENT AND PROGNOSIS Polycythemia Vera
Pruritus is often a major complaint of patients with PV, as it is one of the few symptoms that is not easily treated with suppressive therapy. Pruritus is known to be exacerbated by bathing and skin irritation. No treatment has been shown to be consistently effective. The most commonly used treatment historically has been antihistamines. Antihistamines appear to be effective in approximately 50% of patient encounters.35 More recently, selective-serotonin reuptake inhibitors have been shown to be effective.36 The thrombotic complications of PV present as a wide spectrum of disorders. Thrombotic complications are the most common cause of morbidity and mortality in patients with PV.17 One large study demonstrated that cardiovascular mortality (eg, stroke, MI, PE) accounted for 45% of all deaths in patients with PV. This same study confirmed that age older than 65 and a previous history of thrombosis were the greatest risk factors for future thrombosis.37 Although a common practice is to maintain a patient’s hematocrit and platelet levels within specific parameters, the risk of thrombosis has not been shown to correlate with any particular value.20,38 The index of suspicion for a thrombotic event should be high when treating a patient with PV, especially with patients in high-risk categories. The treatment of an acute thrombus/embolus in PV (or other MPN) does not vary from that of any other patient. Patients presenting with acute coronary syndrome (ACS) still require stenting or thrombolytics.39 The incidence of bleeding in patients with PV ranges from 30% to 40%, varying from minor episodes of epistaxis or gingival bleeding to life-threatening hemorrhage.20 In a large cohort of patients with PV who underwent surgery, there was shown to be increased risk of major hemorrhage during surgery and also an increase in postoperative bleeding.37 There was also a correlation between antithrombotic prophylaxis (aspirin and heparin) and bleeding risk, although how these data translate into bleeding risk in the nonsurgical patient is unclear.40 Hyperviscosity syndrome (HVS), although more common in paraproteinemias, can be caused by any of the MPNs.41 The classic presentation is the combination of mucosal bleeding, visual changes, and neurologic symptoms. Neurologic symptoms can range from headache and vertigo to coma (Box 7).41 HVS should be a consideration in any patient with a known MPN who presents with the previously mentioned complaints. It also should be considered in undiagnosed patients whose initial laboratory tests are suggestive of an underlying MPN. Definitive treatment of hyperviscosity syndrome caused by PV is with plasmapheresis. Before this, ED management also includes rapid hydration, placement of large-bore central venous access, and phlebotomy for severe symptoms. Initial removal of up to 500 mL of
Myeloproliferative Disorders
Box 7 Neurologic manifestations of hyperviscosity syndrome Vertigo Hearing loss Paresthesias Strokelike symptoms Ataxia Generalized stupor Seizures Coma
blood over 1 to 2 hours with normal saline replacement can be performed without major hemodynamic consequence (see Box 7). If further phlebotomy is required, an additional 500 to 1000 mL may be removed over the ensuing 24 hours with a goal hematocrit of less than 55%. The addition of low-dose aspirin (81 mg) also can be considered.42 Hematologic transformation and solid tumor formation are the other major complications of PV. In a large study, 3.5% of patients had hematologic transformation, whereas 4.3% had transformation into solid organ tumors.37 Of the hematologic transformations, approximately two-thirds of patients transformed into myelofibrosis, whereas one-third evolved into acute myelogenous leukemia (AML). Mortality due to hematologic transformation and solid organ tumor formation represented 13.0% and 19.5% of all deaths, respectively.37 Proposed risk factors for the transition to myelofibrosis include duration of disease and age.37,43 Age older than 70 years appears to be a risk factor for developing AML. The use of cytoreductive drugs other than hydroxyurea and interferon appears to confer the greatest risk of developing AML.37 EPs should be cognizant that the diseases often overlap and patient courses are rarely consistent. Essential Thrombocythemia
The management of ET is very similar to that of PV. The 2 main aims of treatment include treating the common vasomotor symptoms and preventing thrombotic complications. The mainstay of treatment is low-dose aspirin. In addition to microvascular symptoms, such as erythromelalgia, the use of low-dose aspirin also is useful in preventing more significant complications.22 The use of more aggressive therapy to reduce the risk of thrombosis is restricted to groups at higher risk for these complications. Risk factors associated with increased risk for thrombosis include age older than 60, history of thrombosis, presence of a JAK2 mutation, and the usual coronary artery disease risk factors (eg, diabetes, smoking, hypertension).44 Additionally, it has been shown that continued exposure to platelet levels greater than 1000 109/L is associated with increased risk for thrombosis.2 In patients with these risk factors, the primary therapy is hydroxyurea. The side effects of hydroxyurea include increased infection risk, leukopenia, and anemia.45 For this reason, another agent, anagrelide, has recently been investigated as an alternative. Results have been variable in 2 large studies directly comparing the 2 treatments. Concerns for increased risk of progression to myelofibrosis currently limit the acceptance of anagrelide.22
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Overall, the risk of thrombotic complications as a result of ET is less than that of PV. In a large multicenter study, 12% of patients with ET had a thrombotic complication during the follow-up period (mean follow-up 6.2 years).44 The overall risk of leukemic or myelofibrotic transformation is relatively low compared with other MPNs. In this multicenter trial, 1% of patients developed an acute leukemia, whereas 4% had progression to myelofibrosis.44 As in other MPNs, once transformation into either of these diseases occurs, prognosis is extremely poor. Chronic Myelogenous Leukemia
Given that the diagnosis of CML requires bone marrow biopsy, it is not likely that EPs will render the diagnosis of CML in the ED. The EP should refer patients with a suspicion of CML to a specialist for consultation. CML is characterized by 3 distinct stages that generally occur in succession: chronic, accelerated and blast phases (see Box 5). The criteria for each of these stages are somewhat variable.46 Most undiagnosed patients with CML seen in the ED setting will present in the chronic phase of disease. Initial treatment for these patients will be symptomatic. Hydroxyurea can be instituted for patients with WBC count greater than 80 109/L. Allopurinol is often instituted to minimize the complications associated with high uric acid produced during tumor lysis.47 Therapy initiated in the ED will typically be under the direction of a consulting hematologist/oncologist. Once the diagnosis of CML is made, the hematologist/oncologist will generally initiate therapy with a tyrosine kinase inhibitor. The major complication of CML is related to the progression of disease, with the final stage being a blast crisis. Patients can either present undiagnosed in this stage, which is rare, or present with symptoms related to progression of known disease. The presentation and management of acute leukemia and blast crisis is covered elsewhere in the issue and will be only briefly discussed here. Hyperviscosity can be due to increases in any hematologic cell line. When WBCs are the culprit, it is often referred to as hyperleukocytosis and leukostasis. Although rare in the chronic phase of CML, hyperleukocytosis and leukostasis warrant special mention, as mortality can reach 20% to 40%.48 In addition to the common triad of mucosal bleeding, neurologic symptoms, and visual changes, pulmonary complications represent a significant number of deaths due to hyperleukocytosis.48 Historically, hyperleukocytosis has been defined by WBC count greater than 100 109; however, complications from leukostasis may arise with WBC counts substantially lower than this.48 Nearly all patients with hyperleukocytosis will present with fever. It is appropriate to start empiric broad-spectrum antibiotics and obtain blood cultures; however, a true infection is rarely present.48 Early ED management focuses on aggressive hydration, central venous access, and prompt cytoreduction. Hydroxyurea, 1 to 2 g orally every 6 hours, should be started when the diagnosis is first made (Table 1). Further cytoreduction with induction chemotherapy and/or leukapheresis can be initiated after a discussion with a hematologist/oncologist. All patients with hyperleukocytosis will require admission. Primary Myelofibrosis
Other than bone marrow transplant, treatments for PMF focus on symptomatic relief and prevention of disease progression. Similar to PV and ET, hydroxyurea is the most commonly used medication. Hydroxyurea in PMF is used to treat a myriad of symptoms, including hepatosplenomegaly, night sweats, weight loss, and anemia.28 Other treatments, less frequently encountered in the ED, including EPO, thalidomide, and interferon-alpha, have been shown to be efficacious in certain populations. These
Myeloproliferative Disorders
Table 1 Summary of emergent complications and associated treatments Diagnosis
Presentation
ED Management
Definitive Treatment
PV with Hct >60% or hyperviscosity syndrome
Neurologic symptoms, visual disturbances, mucosal bleeding
Fluid resuscitation Central venous access Phlebotomy: 250–500 mL over 1–2 h with NS replacement
Plasmapheresis Long-term cytoreductive therapy
Hyperleukocytosis/ leukostasis
Similar to HVS pulmonary symptoms Fever
Fluid resuscitation Central venous access Hydroxyurea 1–2 g PO q6 Broad-spectrum antibiotics
Leukapheresis Induction chemotherapy
Thrombosis
Chest pain (PE/ACS) Abdominal pain (Budd-Chiari) Extremity pain/ swelling (DVT)
Anticoagulation/ intervention per usual protocol
—
Abbreviations: ACS, acute coronary syndrome; DVT, deep venous thrombosis; ED, emergency department; Hct, hematocrit; HVS, hyperviscosity syndrome; NS, normal saline; PE, pulmonary emboli; PO, by mouth; PV, polycythemia vera; q, every.
agents are not universally effective in improving symptoms and are best managed by a hematologist/oncologist.2 The course and prognosis of PMF is less favorable than that of ET and PV. Five-year survival is 40% compared with healthy age-matched controls. The median survival time for patients with PMF is approximately 69 months.2 The most common cause of death is transformation into acute leukemia. The overall incidence of thrombotic complication is less than 10%, which is lower than both ET and PV.29 Several risk factors have been noted to be associated with decreased survival in patients with PMF (Box 8). These factors are frequently used to assess the prognosis of patients diagnosed with PMF. Survival has been shown to range from 135 months in patients with none of these risk factors, to as low as 27 months in individuals with 3 or more risk factors.29
Box 8 Risk factors associated with decreased survival in patients with PMF Age older than 65 Hemoglobin less than 10 g/dL Exaggerated leukocytosis (>25 109/L) or leukopenia (
