Neoplasias Mieloproliferativas - Emeg Med Clin N Am 2014

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
a b,
Brian Meier, MD, MA , John H. Burton, MD *
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), polycy-
themia 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 path-
ologically 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: JHBurton@carilionclinic.org
Emerg Med Clin N Am 32 (2014) 597–612

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598 Meier & Burton
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 seem-
ingly separate disorders as interrelated and proffered the concept of myeloprolifera-
tive 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 mye-
lodysplastic from those that are considered myeloproliferative. Myelodysplasia is
defined by dysplastic, or abnormal, bone marrow resulting in cytopenia of varying de-
grees 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 599
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 mech-
anisms involved, our knowledge of hematopoiesis remains incomplete. It is believed
that the interplay between multiple sources, including both intrinsic and extrinsic fac-
tors, 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 granu-
locyte/macrophage progenitors and megakaryocyte/erythroid progenitors, referred to
as colony-forming units (CFUs). These multipotent CFUs then give rise to the progen-
itors 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 disrup-
tions 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 synergisti-
cally, 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 gen-
eral appreciation of the overlap between each of these factors to explain clinical pre-
sentations 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)

600 Meier & Burton
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 well-
recognized 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 chromo-
somal 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 down-
stream differentiation (CFUs) leads to an increase in abnormal, premature cells.14 Sec-
ond, 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 com-
plaints, in decreasing order of frequency, are as follows: headache, weakness, pruri-
tus, 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 head-
aches, lightheadedness, and paresthesias (28.5%).19
In addition to generalized symptoms, vascular complications are often initial pre-
senting events for patients with PV. These events can range from microvascular com-
plications, 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

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/. Ac-
cessed December 4, 2008.)
transient loss of vision.21 Thrombotic presentations are not uncommon in undiag-

nosed PV. Sources estimate the prevalence of thrombosis at the time of initial diag-
nosis 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 ac-
counts 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, how-
ever, 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 distur-
bance, and dizziness.2 Vascular complications are also relatively common symptoms.
These can range from easy bleeding and bruising, to erythromelalgia, ocular

602 Meier & Burton
migraines, and TIAs.2 Of the more significant vascular complications, thrombosis

(w20%) is more common than hemorrhage (10%). Arterial thrombosis is more com-
mon 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 fa-
milial 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 asymptom-
atic 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%), abdom-
inal 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, fa-
tigue, and weight loss, are more common than in other patients with MPNs.2 Symp-
toms associated with splenomegaly are also relatively common, including
decreased appetite and abdominal fullness. Up to 10% of patients with PMF may pre-
sent with a thrombotic complication, with the most common being venous thrombo-
embolism (4.5%).30
PHYSICAL EXAMINATION
Polycythemia Vera
The most common findings on physical examination for patients with PV are spleno-
megaly, ruddy cyanosis (facial plethora), hepatomegaly, conjunctival plethora, and hy-
pertension. 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
The most common physical examination finding in ET is splenomegaly, occurring in
approximately 50% of patients at the time of diagnosis.23 Splenomegaly is rela-
tively mild in ET, as opposed to the more marked splenomegaly found in other
MPNs.2


The physical examination findings in CML are nonspecific and very similar to other
MPNs. The most common finding is splenomegaly, followed by hepatomegaly. Find-
ings of lymphadenopathy or myeloid sarcoma are rarer, but if present, signify a much
poorer prognosis.31
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 ex-
amination 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 impor-
tant 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 abso-
lute 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 circum-
stances 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 classifica-
tion system for myeloproliferative neoplasms. Cancer 2009;115(17):3842–7.

604 Meier & Burton
PV; however, increased erythrocytosis can have an effect on coagulation assessment

leading to markedly abnormal values.20
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 im-
aging 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, lab-
oratory 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

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 present-
ing 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.


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 bi-
opsy and cytogenetic testing. Bone marrow findings will reveal increased cellularity
with an alteration of the normal erythropoiesis to granulopoiesis.27
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.


606 Meier & Burton
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 demon-
strating 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 phospha-
tase, 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 exacer-
bated 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 great-
est 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 throm-
bosis has not been shown to correlate with any particular value.20,38 The index of sus-
picion 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 postoper-
ative 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 consider-
ation in any patient with a known MPN who presents with the previously mentioned
complaints. It also should be considered in undiagnosed patients whose initial labo-
ratory tests are suggestive of an underlying MPN. Definitive treatment of hypervis-
cosity 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

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 ma-
jor 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 he-
matocrit 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 compli-
cations 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 trans-
formations, 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.
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 com-
plications. 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 pre-
venting 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, smok-
ing, hypertension).44 Additionally, it has been shown that continued exposure to
platelet levels greater than 1000 109/L is associated with increased risk for throm-
bosis.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 alterna-
tive. Results have been variable in 2 large studies directly comparing the 2 treatments.
Concerns for increased risk of progression to myelofibrosis currently limit the accep-
tance of anagrelide.22

608 Meier & Burton
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 pro-
gression to myelofibrosis.44 As in other MPNs, once transformation into either of these
diseases occurs, prognosis is extremely poor.

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 suspi-
cion 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. Hy-
droxyurea can be instituted for patients with WBC count greater than 80 109/L. Allo-
purinol 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 pre-
sentation 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 complica-
tions 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 appro-
priate to start empiric broad-spectrum antibiotics and obtain blood cultures; however,
a true infection is rarely present.48 Early ED management focuses on aggressive hy-
dration, 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 initi-
ated after a discussion with a hematologist/oncologist. All patients with hyperleukocy-
tosis will require admission.
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

Table 1
Summary of emergent complications and associated treatments
Diagnosis Presentation ED Management Definitive Treatment

PV with Hct >60% Neurologic symptoms, Fluid resuscitation Plasmapheresis
or hyperviscosity visual disturbances, Central venous access Long-term
syndrome mucosal bleeding Phlebotomy: cytoreductive
250–500 mL over therapy
1–2 h with NS
replacement
Hyperleukocytosis/ Similar to HVS Fluid resuscitation Leukapheresis
leukostasis pulmonary Central venous access Induction
symptoms Hydroxyurea chemotherapy
Fever 1–2 g PO q6
Broad-spectrum
antibiotics
Thrombosis Chest pain (PE/ACS) Anticoagulation/ —
Abdominal pain intervention per
(Budd-Chiari) usual protocol
Extremity pain/
swelling (DVT)
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 pa-
tients 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 (<4.0 109/L)
Constitutional symptoms of fever, sweating, or weight loss at the time of diagnosis
Proportion of blast cells in the blood (1%)
Data from Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary
myelofibrosis based on a study of the international working group for myelofibrosis research
and treatment. Blood 2009;113(13):2895–901.

610 Meier & Burton
SUMMARY
The EP generally encounters MPNs in 1 of 2 ways: as striking laboratory abnormalities

of seeming unknown consequence, or in previously diagnosed patients presenting
with complications. The course of patients with MPNs is highly variable, but major
complications can arise. Emergent conditions related to hyperviscosity need to be
recognized early and treated aggressively. Rapid hydration, transfusion, cytoreduc-
tion, and early hematology consultation can be lifesaving. Likewise, although manage-
ment is not altered, a high index of suspicion for thrombotic complications is required in
patients with known PMNs as these are a significant cause of morbidity and mortality.
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M y e l o p ro l i f e r a t i v e

INTRODUCTION: NATURE OF THE PROBLEM

It is not uncommon for a myeloproliferative disorder (MPN) to initially be considered by

Emerg Med Clin N Am 32 (2014) 597–612

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suggested as suffering from a hemoproliferative mechanism.3 The entities now

 Myeloproliferative neoplasms (MPN)

Descargado para Daniela Alonso (dalonso2@fucsalud.edu.co) en University Foundation of Health

The formation of hematologic cells is a complex process. Although new laboratory

Granulocyte Colony-Stimulating Factor (G-CSF)

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A BRIEF GENETIC INTERLUDE

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transient loss of vision.21 Thrombotic presentations are not uncommon in undiag-

Descargado para Daniela Alonso (dalonso2@fucsalud.edu.co) en University Foundation of Health

migraines, and TIAs.2 Of the more significant vascular complications, thrombosis

Chronic Myelogenous Leukemia

Descargado para Daniela Alonso (dalonso2@fucsalud.edu.co) en University Foundation of Health

Chronic Myelogenous Leukemia

Imaging and Additional Testing

Descargado para Daniela Alonso (dalonso2@fucsalud.edu.co) en University Foundation of Health

PV; however, increased erythrocytosis can have an effect on coagulation assessment

Chronic Myelogenous Leukemia

 Sustained platelet count 450 109/L

Diagnosis requires all 4 elements.

Descargado para Daniela Alonso (dalonso2@fucsalud.edu.co) en University Foundation of Health

is because neutrophils contain B12 binding proteins.27 The lactate dehydrogenase

Diagnosis requires 3 major and 2 minor criteria.

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TREATMENT AND PROGNOSIS

Descargado para Daniela Alonso (dalonso2@fucsalud.edu.co) en University Foundation of Health

Descargado para Daniela Alonso (dalonso2@fucsalud.edu.co) en University Foundation of Health

Chronic Myelogenous Leukemia

Descargado para Daniela Alonso (dalonso2@fucsalud.edu.co) en University Foundation of Health

Diagnosis Presentation ED Management Definitive Treatment

 Age older than 65

Descargado para Daniela Alonso (dalonso2@fucsalud.edu.co) en University Foundation of Health

The EP generally encounters MPNs in 1 of 2 ways: as striking laboratory abnormalities

Descargado para Daniela Alonso (dalonso2@fucsalud.edu.co) en University Foundation of Health

15. Bedi A, Zehnbauer B, Barber J, et al. Inhibition of apoptosis by BCR-ABL in

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Descargado para Daniela Alonso (dalonso2@fucsalud.edu.co) en University Foundation of Health

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Myeloproliferative neoplasms (MPN)

Sustained platelet count 450 109/L

Age older than 65