# 38 - 108 Polycythemia Vera and Other Myeloproliferative Neoplasms

### 108 Polycythemia Vera and Other Myeloproliferative Neoplasms

anti-CD52 monoclonal antibody alemtuzumab are especially effec­
tive in younger MDS patients (<60 years old) with more favorable 
IPSS. In a consortium retrospective review, about 50% of patients 
with mainly refractory anemia responded to ATG, usually com­
bined with cyclosporine, particularly patients with hypocellular 
marrow.

HGFs can improve blood counts but, as in most other marrow 
failure states, have been most beneficial to patients with the least 
severe pancytopenia. EPO alone or in combination with G-CSF can 
improve hemoglobin levels, particularly in those with low serum 
EPO levels who have no or a modest need for transfusions. Sur­
vival is improved by EPO and its amelioration of anemia. G-CSF 
treatment alone failed to improve survival in a controlled trial. 
Thrombopoietin mimetics appear to improve platelet counts in 
some patients, but TPO agonists may increase the rate of leukemic 
progression in high-risk MDS. No clear evidence suggests that they 
increase leukemic transformation in low-risk MDS.
Luspatercept, which affects transforming growth factor β–mediated 
suppression of erythropoiesis, has been approved by the FDA for 
anemia in low-risk MDS, particularly those with SF3B1 mutations. 
The FDA has approved ivosidenib, an IDH1 inhibitor, for MDS. 
Venetoclax, a BCL2 inhibitor, is FDA approved for patients with 
AML and has been used in combination with HMA in high-risk 
MDS; however, it remains investigational.
PART 4
Oncology and Hematology
Promising novel agents in trials include targeted therapies (i.e., 
TP53, splicing factor mutations), inflammation pathway inhibitors 
(including inflammasome and interleukin 1 receptor–associated 
kinase), and imetelstat, a telomerase inhibitor. Likely, HMA alone 
will be replaced with HMA combination therapies.
The same principles of supportive care described for aplastic 
anemia apply to MDS. Many patients will be anemic for years. RBC 
transfusion support should be accompanied by iron chelation to 
prevent secondary hemochromatosis.
MYELOPHTHISIC ANEMIAS
Fibrosis of the bone marrow (see Fig. 65-19), usually accompanied by 
a characteristic blood smear picture called leukoerythroblastosis, can 
occur as a primary hematologic disease, called myelofibrosis or myeloid 
metaplasia (Chap. 108), and as a secondary process, called myelophthi­
sis. Myelophthisis, or secondary myelofibrosis, is reactive. Fibrosis can 
be a response to invading tumor cells, usually an epithelial cancer of 
breast, lung, or prostate origin or neuroblastoma. Marrow fibrosis may 
occur with infection of mycobacteria (both Mycobacterium tuberculosis 
and Mycobacterium avium), fungi, or HIV and in sarcoidosis. Intracel­
lular lipid deposition in Gaucher disease and obliteration of the mar­
row space related to absence of osteoclast remodeling in congenital 
osteopetrosis also can produce fibrosis. Secondary myelofibrosis is a 
late consequence of radiation therapy or treatment with radiomimetic 
drugs. Usually the infectious or malignant underlying processes are 
obvious. Marrow fibrosis can also be a feature of a variety of hema­
tologic syndromes, especially chronic myeloid leukemia, multiple 
myeloma, lymphomas, myeloma, and hairy cell leukemia.
The pathophysiology has three distinct features: proliferation of 
fibroblasts in the marrow space (myelofibrosis); the extension of hema­
topoiesis into the long bones and into extramedullary sites, usually the 
spleen, liver, and lymph nodes (myeloid metaplasia); and ineffective 
erythropoiesis. The etiology of the fibrosis is unknown but most likely 
involves dysregulated production of growth factors: platelet-derived 
growth factor and transforming growth factor β have been implicated. 
Abnormal regulation of other hematopoietins would lead to localiza­
tion of blood-producing cells in nonhematopoietic tissues and uncou­
pling of the usually balanced processes of stem cell proliferation and 
differentiation. Myelofibrosis is remarkable for pancytopenia despite 
very large numbers of circulating hematopoietic progenitor cells.
Anemia is dominant in secondary myelofibrosis, usually normocytic 
and normochromic. The diagnosis is suggested by the characteristic 
leukoerythroblastic smear. Erythrocyte morphology is highly abnor­
mal, with circulating nucleated RBCs, teardrops, and shape distortions. 

WBC numbers are often elevated, sometimes mimicking a leukemoid 
reaction, with circulating myelocytes, promyelocytes, and myeloblasts. 
Platelets may be abundant and are often of giant size. Inability to aspi­
rate the bone marrow, the characteristic “dry tap,” can allow a presump­
tive diagnosis in the appropriate setting before the biopsy is decalcified.
The course of secondary myelofibrosis is determined by its etiology, 
usually a metastatic tumor or an advanced hematologic malignancy. 
Treatable causes must be excluded, especially tuberculosis and fungus. 
Transfusion support can relieve symptoms.
■
■FURTHER READING
Arber DA et al: International Consensus Classification of myeloid 
neoplasms and acute leukemias: Integrating morphologic, clinical, 
and genomic data. Blood 140:1200, 2022.
Bernard E et al: Molecular International Prognostic Scoring System 
for myelodysplastic syndromes. NEJM Evid 1:EVIDoa2200008, 2022.
Cazzola M: Myelodysplastic syndromes. N Engl J Med 383:1358, 
2020.
DeFilipp Z et al: Hematopoietic cell transplantation in the manage­
ment of myelodysplastic syndrome: An evidence-based review from 
the American Society for Transplantation and Cellular Therapy 
Committee on Practice Guidelines. Transplant Cell Ther 29:71, 2022.
Gurnari C, Maciejewski JP: How I manage acquired pure red cell 
aplasia in adults. Blood 15;137:2001, 2021.
Hellstrom-Lindberg ES et al: Clinical decision-making and treat­
ment of myelodysplastic syndromes. Blood 142:2268, 2023.
Khoury JD et al: The 5th edition of the World Health Organization 
classification of haematolymphoid tumours: Myeloid and histiocytic/
dendritic neoplasms. Leukemia 36:1703, 2022.
Mustjoki S, Young NS: Somatic mutations in “benign” disease. N 
Engl J Med 384:2039, 2021.
Townsley DM et al: Eltrombopag added to standard immunosuppres­
sion for aplastic anemia. N Engl J Med 376:1540, 2017.
Young NS: Aplastic anemia. N Engl J Med 379:1643, 2018.
Jerry L. Spivak

Polycythemia Vera and 

Other Myeloproliferative 
Neoplasms
The World Health Organization (WHO) classification of the chronic 
myeloproliferative neoplasms (MPNs) includes eight disorders, some 
of which are rare or poorly characterized (Table 108-1) but all of which 
share an origin in a hematopoietic stem cell; overproduction of one or 
more of the formed elements of the blood without significant dysplasia; 
and a predilection to extramedullary hematopoiesis, myelofibrosis, and 
transformation at varying rates to acute leukemia. Within this broad 
TABLE 108-1  World Health Organization Classification of Chronic 
Myeloproliferative Neoplasms
Chronic myeloid leukemia, BCR-ABL–positive
Chronic neutrophilic leukemia
Chronic eosinophilic leukemia, not otherwise specified
Polycythemia vera
Primary myelofibrosis
Essential thrombocytosis
Mastocytosis
Myeloproliferative neoplasms, unclassifiable

classification, however, significant phenotypic heterogeneity exists. 
Some diseases such as chronic myelogenous leukemia (CML), chronic 
neutrophilic leukemia (CNL), and chronic eosinophilic leukemia 
(CEL) express primarily a myeloid phenotype, whereas in other dis­
eases, such as polycythemia vera (PV), primary myelofibrosis (PMF), 
and essential thrombocytosis (ET), erythroid or megakaryocytic 
hyperplasia predominates. The latter three disorders, in contrast to 
the former three, also appear capable of transforming into each other.
Such phenotypic heterogeneity has a genetic basis; CML is the con­
sequence of the balanced translocation between chromosomes 9 and 22 
(t[9;22][q34;11]); CNL has been associated with a mutation of CSF3R 
and a t(15;19) translocation; and CEL occurs with a deletion or bal­
anced translocations involving the PDGFRα usually with the FIP1L1, 
PDGFRβ, FGFR1, and PCM1-JAK2 genes. By contrast, PV, PMF, and 
ET are characterized by driver mutations that directly or indirectly 
constitutively activate JAK2, a tyrosine kinase essential for the function 
of the erythropoietin and thrombopoietin receptors and also utilized 
by the granulocyte colony-stimulating factor receptor. This important 
distinction is reflected in the natural histories of CML, CNL, and CEL, 
which are usually measured in years, with a high rate of leukemic trans­
formation. The natural histories of PV, PMF, and ET, by contrast, are 
usually measured in decades, and transformation to acute leukemia is 
uncommon in the absence of chemotherapy. This chapter focuses only 
on PV, PMF, and ET because their clinical features and driver mutation 
overlap are substantial, although their disease duration and clinical 
manifestations vary.
The other chronic MPNs will be discussed in Chaps. 110 and 115.
POLYCYTHEMIA VERA
PV is a clonal hematopoietic stem cell disorder in which phenotypically 
normal red cells, granulocytes, and platelets accumulate in the absence 
of a recognizable physiologic stimulus. The most common of the MPNs, 
PV occurs in 2.5 per 100,000 persons, sparing no adult age group and 
increasing with age to rates >10/100,000. Familial transmission is infre­
quent, and women under age 50 predominate among sporadic cases.
■
■ETIOLOGY
Nonrandom chromosome abnormalities such as deletion 20q and 
deletion 13q or trisomy 9 occur in up to 30% of untreated PV patients, 
but unlike CML, no consistent cytogenetic abnormality has been asso­
ciated with the disorder. However, a mutation in the autoinhibitory 
pseudokinase domain of the tyrosine kinase JAK2 that replaces valine 
with phenylalanine (V617F), causing constitutive kinase activation, has 
a central role in PV pathogenesis.
JAK2 is a member of an evolutionarily well-conserved, nonreceptor 
tyrosine kinase family and serves as the cognate tyrosine kinase for 
the erythropoietin and thrombopoietin receptors. It also functions as 
an obligate chaperone for these receptors in the Golgi apparatus and 
is responsible for their cell-surface expression. The conformational 
change induced in the erythropoietin and thrombopoietin receptors 
following binding to their respective cognate ligands, erythropoi­
etin or thrombopoietin, leads to JAK2 autophosphorylation, receptor 
phosphorylation, and phosphorylation of proteins involved in cell 
proliferation, differentiation, and resistance to apoptosis. Transgenic 
animals lacking JAK2 die as embryos from severe anemia. Constitu­
tive activation of JAK2, on the other hand, explains the erythropoietin 
hypersensitivity, erythropoietin-independent erythroid colony forma­
tion, rapid terminal differentiation, increased Bcl-XL expression, and 
apoptosis resistance in the absence of erythropoietin that characterize 
the in vitro behavior of PV erythroid progenitor cells.
More than 95% of PV patients express this mutation, as do ∼50% 
of PMF and ET patients. Importantly, the JAK2 gene is located on the 
short arm of chromosome 9, and loss of heterozygosity on chromo­
some 9p involving the segment containing the JAK2 locus over time 
due to mitotic recombination (uniparental disomy) is the most com­
mon cytogenetic abnormality in PV. Loss of heterozygosity in this 
region leads to homozygosity for JAK2 V617F and occurs in ∼60% of 
PV patients and to a lesser extent in PMF but is rare in ET. Most PV 
patients who do not express JAK2 V617F express a mutation in exon 12 

of the gene and are not clinically different from those who do, with the 
exception of a higher frequency of isolated erythrocytosis, nor do JAK2 
V617F heterozygotes differ clinically from homozygotes. Importantly, 
the predisposition to acquire JAK2 mutations appears to be associated 
with a specific JAK2 gene haplotype, GGCC. JAK2 V617F is the basis 
for many of the phenotypic and biochemical characteristics of PV such 
as increased blood cell production and increased inflammatory cyto­
kine production; however, it cannot solely account for the entire PV 
phenotype and is probably not the initiating lesion in any of the MPNs. 
First, PV patients with the same phenotype and documented clonal 
disease can have mutations in LNK, a JAK2 inhibitor, or rarely, calre­
ticulin (CALR), an ER chaperone, since MPN driver mutations are not 
mutually exclusive. Second, ET and PMF patients have the same muta­
tions but different clinical phenotypes. Third, familial PV can occur 
without the mutation, even when other members of the same family 
express it. Finally, in some JAK2 V617F–positive PV or ET patients, 
acute leukemia can occur in a JAK2 V617F–negative progenitor cell, 
suggesting the presence of an ancestral precursor cell.

■
■CLINICAL FEATURES
Although PV is a panmyelopathy, isolated thrombocytosis, leukocy­
tosis, or splenomegaly can be its presenting manifestation, but most 
often, the disorder is first recognized by the incidental discovery of a 
high hemoglobin, hematocrit, or red cell count. With the exception of 
aquagenic pruritus or erythromelalgia, no symptoms distinguish PV 
from other causes of erythrocytosis.
CHAPTER 108
Uncontrolled erythrocytosis causes hyperviscosity, leading to neu­
rologic symptoms such as vertigo, tinnitus, headache, visual distur­
bances, and transient ischemic attacks (TIAs). Systolic hypertension is 
also a feature of the red cell mass elevation. In some patients, venous 
or arterial thrombosis may be the presenting manifestation of PV. Any 
vessel can be affected, but cerebral, cardiac, and mesenteric vessels 
are most commonly involved. Hepatic venous thrombosis (BuddChiari syndrome) is particularly common in young women and may 
be catastrophic if sudden and complete obstruction of the hepatic vein 
occurs; portal vein thrombosis is more common in male PV patients. 
Indeed, PV should be suspected in any woman who develops hepatic 
vein thrombosis, since this is the only type of thrombosis associated 
with JAK2 V617F expression. Digital ischemia, easy bruising, epistaxis, 
acid-peptic disease, or gastrointestinal hemorrhage may occur due to 
vascular stasis or extreme thrombocytosis (>900,000/mL). In the lat­
ter instance, absorption and proteolysis of high-molecular-weight von 
Willebrand multimers by the large platelet mass cause acquired von 
Willebrand’s disease. Erythema, burning, and pain in the extremities, a 
symptom complex known as erythromelalgia, is another complication 
of thrombocytosis in PV due to increased platelet stickiness. Given the 
large turnover of hematopoietic cells, hyperuricemia with secondary 
gout, uric acid stones, and symptoms due to hypermetabolism can also 
complicate the disorder.
Polycythemia Vera and Other Myeloproliferative Neoplasms 
■
■DIAGNOSIS
When PV presents with erythrocytosis in combination with leukocyto­
sis, thrombocytosis, or splenomegaly or any combination of these, the 
diagnosis is apparent. However, when patients present with an elevated 
hemoglobin, hematocrit, and red cell count alone, the diagnostic evalu­
ation is more complex because of the many diagnostic possibilities 
(Table 108-2). Furthermore, unless the hemoglobin level is ≥20 g/dL 
(hematocrit ≥60%), it is not possible to distinguish true erythrocytosis 
from disorders causing plasma volume contraction. This is because 
uniquely in PV, in contrast to other causes of true erythrocytosis, 
there is expansion of the plasma volume, which can mask the elevated 
red cell mass, particularly in women; thus, red cell mass and plasma 
volume determinations are necessary to establish the presence of an 
absolute erythrocytosis and distinguish this from relative erythrocyto­
sis due to a reduction in plasma volume alone (also known as stress or 
spurious erythrocytosis or Gaisböck’s syndrome). Figure 66-18 illustrates 
a diagnostic algorithm for the evaluation of suspected erythrocytosis. 
While an assay for JAK2 or rarely LNK mutations in the presence of 
a normal arterial oxygen saturation appears to provide an alternative

TABLE 108-2  Causes of Erythrocytosis
Relative Erythrocytosis
Hemoconcentration secondary to dehydration, diuretics, ethanol abuse, 
androgens, or tobacco abuse
Absolute Erythrocytosis
Hypoxia
Tumors
Carbon monoxide intoxication
Hypernephroma
High-oxygen-affinity hemoglobin
Hepatoma
High altitude
Cerebellar hemangioblastoma
Pulmonary disease
Uterine myoma
Right-to-left cardiac or vascular shunts
Adrenal tumors
Sleep apnea syndrome
Meningioma
Hepatopulmonary syndrome
Pheochromocytoma
Renal Disease
Drugs
Renal artery stenosis
Androgens
SGLT2 inhibitors
Focal sclerosing or membranous 
glomerulonephritis
Recombinant erythropoietin
Familial (with normal hemoglobin 
function)
Postrenal transplantation
Renal cysts
Erythropoietin receptor mutations
PART 4
Oncology and Hematology
Bartter’s syndrome
VHL mutations (Chuvash polycythemia)
2,3-BPG mutation
PHD2 (EGLN1) and HIF2α (EPAS1) 
mutations
LNK mutations
Polycythemia vera
Abbreviations: 2,3-BPG, 2,3-bisphosphoglycerate; VHL, von Hippel-Lindau.
diagnostic approach to isolated erythrocytosis since red cell mass and 
plasma volume determinations are not usually available, isolated eryth­
rocytosis is uncommon as an initial manifestation of PV, and not every­
one expressing a low JAK2 V617F quantitative mutation allele burden 
(variant allele frequency [VAF] ≤5%) actually has a blood disease. In 
addition, a normal serum erythropoietin level does not exclude the 
presence of PV, but an elevated erythropoietin level is most consistent 
with a secondary cause for the erythrocytosis.
Other laboratory studies that may aid in diagnosis include the red 
cell count, mean corpuscular volume, and red cell distribution width 
(RDW), particularly when the hematocrit or hemoglobin levels are 
<60% or 20 g/dL, respectively. Only three situations cause microcytic 
erythrocytosis: β-thalassemia trait, hypoxic erythrocytosis, and PV. 
With β-thalassemia trait, the RDW is usually normal, whereas with 
hypoxic erythrocytosis or PV, the RDW may be elevated due to associ­
ated iron deficiency. Today, however, the quantitative assay for JAK2 
V617F or JAK2 exon 12 mutations using next-generation sequencing 
technology has superseded the other surrogate tests for establishing the 
diagnosis of PV.
A bone marrow aspirate and biopsy provide no specific diagnostic 
information because these may be normal or indistinguishable from 
ET or PMF. Similarly, no specific cytogenetic abnormality is associated 
with the disease, and the absence of a cytogenetic marker does not 
exclude the diagnosis.
■
■COMPLICATIONS
Many of the clinical complications of PV relate directly to the increase 
in blood viscosity associated with red cell mass elevation and indirectly 
to the increased turnover of red cells, leukocytes, and platelets with the 
attendant increase in uric acid and inflammatory cytokine production. 
The latter also appears to be responsible for some of the constitutional 
symptoms in PV. Peptic ulcer disease can also be due to Helicobacter 
pylori infection, the incidence of which is increased in PV, while the 
pruritus associated with this disorder may be a consequence of mast 
cell activation by JAK2 V617F. A sudden increase in spleen size can 
be associated with painful splenic infarction. Myelofibrosis appears to 

be part of the natural history of the disease but is a reactive, reversible 
process that does not itself impede hematopoiesis and by itself has no 
prognostic significance in PV. In ∼15% of patients, however, myelofi­
brosis is associated with hematopoietic stem cell failure, manifested by 
substantial extramedullary hematopoiesis in the liver and spleen and 
transfusion-dependent anemia. Organomegaly can cause significant 
mechanical discomfort, portal hypertension, and progressive cachexia.
Although the incidence of acute myeloid leukemia is increased in 
PV, the incidence of acute leukemia in patients not exposed to chemo­
therapy or radiation therapy is very low. Interestingly, chemotherapy, 
including hydroxyurea, has been associated with acute leukemia in 
JAK2 V617F–negative hematopoietic stem cells (HSCs) in some PV 
patients. Erythromelalgia is a curious syndrome of unknown etiology 
associated with thrombocytosis, primarily involving the lower extremi­
ties and usually manifested by erythema, warmth, and pain of the 
affected appendage and occasionally digital infarction. It occurs with a 
variable frequency and is usually responsive to salicylates. Some of the 
central nervous system symptoms observed in patients with PV, such 
as ocular migraine, appear to represent a variant of erythromelalgia.
Left uncontrolled, erythrocytosis can lead to thrombosis involving 
vital organs such as the liver, heart, brain, or lungs. Patients with mas­
sive splenomegaly are particularly prone to thrombotic events because 
the associated increase in plasma volume masks the true extent of the 
red cell mass elevation measured by the hematocrit or hemoglobin 
level. A “normal” hematocrit or hemoglobin level in a PV patient with 
massive splenomegaly should be considered indicative of an elevated 
red cell mass until proven otherwise.
TREATMENT
Polycythemia Vera
PV is generally an indolent disorder, the clinical course of which 
is measured in decades, and its management should reflect its 
tempo. Thrombosis due to erythrocytosis is the most significant 
complication and often the presenting manifestation; maintenance 
of the hemoglobin level at ≤140 g/L (14 g/dL; hematocrit <45%) 
in men and ≤120 g/L (12 g/dL; hematocrit <42%) in women is 
mandatory to avoid thrombotic complications. Phlebotomy serves 
initially to reduce hyperviscosity by reducing the red cell mass 
to normal while further expanding the plasma volume. Periodic 
phlebotomies thereafter serve to maintain the red cell mass within 
the normal range and induce a state of iron deficiency that prevents 
accelerated reexpansion of the red cell mass. In most PV patients, 
once an iron-deficient state is achieved, phlebotomy is usually 
only required at 3-month intervals. Neither phlebotomy nor iron 
deficiency increases the platelet count relative to the effect of the 
disease itself, and neither thrombocytosis nor leukocytosis is cor­
related with thrombosis in PV, in contrast to the strong correlation 
between erythrocytosis and thrombosis. The use of salicylates to 
prevent thrombosis in PV patients is potentially harmful not only if 
the red cell mass is not controlled by phlebotomy, but also due to an 
increased incidence of bleeding, particularly in patients over age 60.
Anticoagulation is indicated when a thrombosis has occurred, 
and the newer oral anticoagulants may be preferable to a vitamin K 

antagonist since they do not require monitoring. Asymptomatic 
hyperuricemia (<10 mg/dL) requires no therapy, but allopurinol 
should be administered to avoid further elevation of the uric acid 
when chemotherapy is used to reduce splenomegaly or leukocytosis 
or to treat pruritus. Generalized pruritus intractable to antihistamines 
or antidepressants such as doxepin can be a major problem in PV; 
the JAK1/2 inhibitor ruxolitinib, pegylated interferon α (IFN-α), 

psoralens with ultraviolet light in the A range (PUVA) therapy, and 
hydroxyurea are other methods of palliation. Asymptomatic throm­
bocytosis requires no therapy unless the platelet count is sufficiently 
high to cause bleeding due to acquired von Willebrand’s disease, 
but bleeding in this situation is not usually spontaneous and is 
responsive to tranexamic acid or ε-aminocaproic acid. Symptomatic 
splenomegaly can be treated with either ruxolitinib or pegylated

IFN-α. Both ruxolitinib and pegylated IFN-α target the involved 
HSCs in PV and are not mutagenic; hydroxyurea does not target 
the involved HSCs in PV and is mutagenic. Furthermore, pegylated 
IFN-α allows only biweekly administration and produced complete 
hematologic and molecular remissions in ∼20% of PV patients. 
Anagrelide, a phosphodiesterase inhibitor, can reduce the platelet 
count and, if tolerated, is preferable to hydroxyurea because it lacks 
marrow toxicity and is also protective against venous thrombosis, 
whereas hydroxyurea is not. However, chronic anagrelide therapy 
is cardiotoxic and nephrotoxic, particularly in older PV patients.
A reduction in platelet number may be necessary for the treat­
ment of erythromelalgia or ocular migraine if salicylates are not 
effective or if the platelet count is sufficiently high to increase the risk 
of hemorrhage but only to the degree that symptoms are alleviated. 
Alkylating agents and radioactive sodium phosphate (32P) are leuke­
mogenic in PV, and their use should be avoided. If a cytotoxic agent 
must be used, hydroxyurea is preferred, but this drug does not pre­
vent either thrombosis or myelofibrosis in PV, is itself leukemogenic, 
and should be considered as a short-duration therapy. Previously, 
PV patients with massive splenomegaly unresponsive to reduction 
by chemotherapy or IFN required splenectomy. However, with the 
introduction of the nonspecific JAK1/2 inhibitor ruxolitinib, it has 
been possible in the majority of patients with PV complicated by 
myelofibrosis and myeloid metaplasia to reduce spleen size while 
at the same time alleviating constitutional symptoms and pruritus 
due to cytokine release while reducing the phlebotomy requirement. 
However, in contrast to PMF, PV patients have a more chronic 
course; in contrast to other malignancies, PV patients have a low 
rate of mutation accumulation, and the acquisition of deleterious 
mutations such as TP53 mutations as detected by next-generation 
sequencing is usually associated with leukemic transformation. Since 
hydroxyurea antagonizes TP53 and also causes del17p, leading to 
TP53 haploinsufficiency, its chronic use should be constrained in PV.
Ruxolitinib has also been demonstrated in a phase 3 clinical 
trial to be effective in PV patients without myelofibrosis who are 
intolerant or refractory to hydroxyurea or best available supportive 
therapy. Three other JAK2 inhibitors, fedratinib, pacritinib, and 
momelotinib, have been approved for treatment of PV patients 
with myelofibrosis in whom ruxolitinib treatment failed or who 
were intolerant to the drug. In some PV patients with end-stage 
disease, pulmonary hypertension may develop due to fibrosis or 
extramedullary hematopoiesis. A role for bone marrow transplanta­
tion, either allogeneic or haploidentical, in PV has not been defined.
Most patients with PV can live long lives without functional 
impairment when their red cell mass is effectively managed with 
phlebotomy alone. Chemotherapy is never indicated to control the 
red cell mass in PV, but when venous access is an issue, ruxolitinib 
or pegylated IFN is the preferred therapy. Interestingly, hepcidin 
production is suppressed, but not absent in PV, and a hepcidin 
agonist has been shown to reduce phlebotomy requirements in PV.
■
■PRIMARY MYELOFIBROSIS
Chronic PMF (other designations include idiopathic myelofibrosis, 
agnogenic myeloid metaplasia, or myelofibrosis with myeloid metaplasia) 
is a clonal HSC disorder associated with mutations in JAK2, MPL, or 
CALR, and characterized by marrow fibrosis, extramedullary hema­
topoiesis, variable suppression of hematopoiesis, and splenomegaly. 
PMF is the least common MPN, and establishing its diagnosis in the 
absence of a specific clonal marker is difficult because myelofibrosis 
and splenomegaly are also features of both PV and CML. Furthermore, 
myelofibrosis and splenomegaly also occur in a variety of benign and 
malignant disorders (Table 108-3), many of which are amenable to 
specific therapies not effective in PMF. In contrast to the other MPNs 
and so-called acute or malignant myelofibrosis, which can occur at any 
age, PMF primarily afflicts men in their sixth decade or later.
■
■ETIOLOGY
Nonrandom chromosome abnormalities such as 9p, 20q−, 13q−, 
trisomy 8 or 9, or partial trisomy 1q are common in PMF, but no 

TABLE 108-3  Disorders Causing Myelofibrosis
MALIGNANT
NONMALIGNANT
Acute leukemia (lymphocytic, 
myelogenous, megakaryocytic)
HIV infection
Hyperparathyroidism
Renal osteodystrophy
Systemic lupus erythematosus
Tuberculosis
Vitamin D deficiency
Thorium dioxide exposure
Gray platelet syndrome
Chronic myeloid leukemia
Hairy cell leukemia
Hodgkin’s disease
Primary myelofibrosis
Lymphoma
Multiple myeloma
Myelodysplasia
Metastatic carcinoma
Polycythemia vera
Systemic mastocytosis
cytogenetic abnormality specific to the disease has been identified. 
JAK2 V617F is present in ∼55% of PMF patients, and mutations in 
the thrombopoietin receptor, MPL, occur in ~4%. Most of the rest 
have mutations in the calreticulin gene (CALR) that alter the carboxyterminal portion of the protein, permitting it to bind and activate MPL 
while presenting it at the cell surface. The degree of myelofibrosis and 
the extent of extramedullary hematopoiesis are not related. Fibrosis in 
this disorder is associated with overproduction of transforming growth 
factor β and tissue inhibitors of metalloproteinases and thrombopoi­
etin, while osteosclerosis is associated with overproduction of osteo­
protegerin, an osteoclast inhibitor. Marrow angiogenesis occurs due 
to increased production of vascular endothelial growth factor. Impor­
tantly, fibroblasts in PMF are polyclonal and not part of the neoplastic 
clone but can be induced by it to produce inflammatory cytokines.
CHAPTER 108
Polycythemia Vera and Other Myeloproliferative Neoplasms 
■
■CLINICAL FEATURES
No signs or symptoms are specific for PMF. Many patients are asymp­
tomatic at presentation, and the disease is often detected by the dis­
covery of splenic enlargement and/or abnormal blood counts during a 
routine examination. In contrast to its companion MPN, night sweats, 
fatigue, and weight loss are common presenting complaints. A blood 
smear will show the characteristic features of extramedullary hemato­
poiesis: teardrop-shaped red cells, nucleated red cells, myelocytes, and 
promyelocytes; myeloblasts may also be present (Fig. 108-1). Anemia, 
usually mild initially, is common, whereas the leukocyte and platelet 
counts are either normal or increased, but either can be depressed. 
Mild hepatomegaly may accompany splenomegaly but is unusual in its 
FIGURE 108-1  Teardrop-shaped red blood cells indicative of membrane damage 
from passage through the spleen, a nucleated red blood cell, and immature myeloid 
cells indicative of extramedullary hematopoiesis are noted. This peripheral blood 
smear is related to any cause of extramedullary hematopoiesis.

FIGURE 108-2  This marrow section shows the marrow cavity replaced by fibrous 
tissue composed of reticulin fibers and collagen. When this fibrosis is due to a 
primary hematologic process, it is called myelofibrosis. When fibrosis is secondary 
to a tumor or a granulomatous process, it is called myelophthisis.
PART 4
Oncology and Hematology
absence; isolated lymphadenopathy should suggest another diagnosis. 
Both serum lactate dehydrogenase and alkaline phosphatase levels can 
be elevated. Marrow is usually inaspirable due to the myelofibrosis 
(Fig. 108-2), and bone x-rays may reveal osteosclerosis. Exuberant 
extramedullary hematopoiesis can cause ascites; portal, pulmonary, or 
intracranial hypertension; intestinal or ureteral obstruction; pericardial 
tamponade; spinal cord compression; or skin nodules. Splenic enlarge­
ment can be sufficiently rapid to cause splenic infarction with fever and 
pleuritic chest pain. Hyperuricemia and secondary gout may ensue.
■
■DIAGNOSIS
While the clinical picture described above is characteristic of PMF, 
all of these clinical features can be observed in PV or CML. Massive 
splenomegaly commonly masks erythrocytosis in PV, and reports of 
intraabdominal thrombosis in PMF most likely represent instances of 
unrecognized PV. In some PMF patients, erythrocytosis has developed 
during the course of the disease. Importantly, because many other dis­
orders have features that overlap with PMF but respond to distinctly 
different therapies, the diagnosis of PMF is one of exclusion, which 
requires that the disorders listed in Table 108-3 be ruled out.
The presence of teardrop-shaped red cells, nucleated red cells, 
myelocytes, and promyelocytes establishes the presence of extramedul­
lary hematopoiesis, while the presence of leukocytosis, thrombocytosis 
with large and bizarre platelets, and circulating myelocytes suggests the 
presence of an MPN as opposed to a secondary form of myelofibrosis 
(Table 108-3). Marrow is usually inaspirable due to increased marrow 
reticulin, but marrow biopsy will usually reveal a hypercellular mar­
row with trilineage hyperplasia and, in particular, increased numbers 
of megakaryocytes in clusters and with large, dysplastic nuclei. A 
small number of PMF patients with a low JAK2 V617F mutation allele 
burden (≤25%) have a faster time to anemia and leukopenia and a 
shortened survival. However, there are no specific bone marrow mor­
phologic abnormalities that distinguish PMF from the other MPNs. 
Splenomegaly due to extramedullary hematopoiesis may be sufficiently 
massive to cause portal hypertension and variceal formation. In some 
patients, exuberant extramedullary hematopoiesis dominates the clini­
cal picture.
An intriguing feature of PMF is the occurrence of autoimmune 
abnormalities such as immune complexes, antinuclear antibodies, 
rheumatoid factor, or a positive Coombs’ test. Whether these represent 
a host reaction to the disorder or are involved in its pathogenesis is 
unknown. Cytogenetic analysis of the blood is useful both to exclude 
CML and for prognostic purposes, because the development of com­
plex karyotype abnormalities portends a poor prognosis in PMF. It is 
thought that impaired expression of the cytokine CXCL4 is responsible 
for the markedly increased number of circulating CD34+ cells in PMF 

TABLE 108-4  Three Current Scoring Systems for Estimating Prognosis 
in PMF Patients
RISK FACTOR
IPSS (2009)a
DIPSS (2010)b
DIPSS PLUS (2011)c
Anemia (<10 g/dL)
X
X
X
Leukocytosis (>25,000/μL)
X
X
X
Peripheral blood blasts (≥1%) X
X
X
Constitutional symptoms
X
X
X
Age (>65 years)
X
X
X
Unfavorable karyotype
X
Platelet count (<100,000/μL)
X
Transfusion dependence
X
aBlood 113:2895, 2009. bBlood 115:1703, 2010. cJ Clin Oncol 29:392, 2011.
Note: The Dynamic International Prognostic Scoring System (DIPSS) was developed 
to determine if the International Prognostic Scoring System (IPSS) risk factors 
identified as important for survival at the time of primary myelofibrosis (PMF) 
diagnosis could also be used for risk stratification following their acquisition 
during the course of the disease. One point is assigned to each risk factor for 
IPSS scoring. For DIPSS, the same is true, but anemia is assigned 2 points. The 
DIPSS Plus scoring system represents recognition that the addition of unfavorable 
karyotype, thrombocytopenia, and transfusion dependence improved the DIPSS 
risk stratification system for which additional points are assigned (Table 108-5). 
More recent studies suggest that mutational analysis of the ASXL1, EZH2, SRSF2, 
and IDH1/2 genes further improves risk stratification for survival and leukemic 
transformation (Leukemia 27:1861, 2013), as can cytogenetic abnormalities 
(Leukemia 32:1631, 2018). These prognostic scoring systems are not accurate for 
risk assessment in polycythemia vera or essential thrombocytosis patients who 
have developed myelofibrosis (Haematologica 99:e55, 2014).
(>15,000/μL) compared to PV patients, unless they too develop extra­
medullary hematopoiesis.
Importantly, ∼55% of PMF patients, like patients with its companion 
MPNs, express the JAK2 V617F mutation, often as homozygotes. Such 
patients are usually older and have higher hematocrits than patients 
with MPL (4%) or CALR (36%) mutations; PMF patients expressing 
an MPL mutation tend to be more anemic and have lower leukocyte 
counts than JAK2 V617F–positive patients. Somatic mutations (due to 
deletions [type 1] or insertions [type 2]) in exon 9 of CALR have been 
found in a majority of patients with PMF who lack mutations in either 
JAK2 or MPL. In some studies, type 1 mutations, the most common 
CALR mutation in PMF, had a survival advantage compared to JAK2 or 
MPL mutations but not with respect to leukemic transformation. PMF 
patients who lack a known MPN driver mutation (triple-negative) 
appear to have the worst prognosis.
■
■COMPLICATIONS
Survival in PMF varies according to specific risk factors at diagnosis 
(Tables 108-4 and 108-5) but is much shorter than in PV and ET 
patients. The natural history of PMF is one of increasing marrow fail­
ure with transfusion-dependent anemia and increasing organomegaly 
due to extramedullary hematopoiesis. As with CML, PMF can evolve 
from a chronic to an accelerated phase with constitutional symptoms 
and increasing marrow failure. About 10% of patients spontaneously 
transform to an aggressive form of acute leukemia for which therapy is 
usually ineffective. Additional important prognostic factors for disease 
acceleration during the course of PMF include the presence of complex 
TABLE 108-5  IPSS and DIPSS Risk Stratification Systems
NUMBER OF RISK FACTORS
RISK CATEGORIESa
IPSS
DIPSS
DIPSS PLUS
Low

Intermediate-1

1–2

Intermediate-2

3–4
2–3
High
≥3
>4
4–6
aThe corresponding survival curves for each risk category can be found in the 
references cited in the footnotes of Table 108-4.
Abbreviations: DIPSS, Dynamic International Prognostic Scoring System; IPSS, 
International Prognostic Scoring System.

cytogenetic abnormalities, thrombocytopenia, and transfusion-dependent 
anemia. Mutations in the ASXL1, EZH2, SRSF2, and IDH1/2 genes have 
been identified as risk factors for early death or transformation to acute 
leukemia, as have complex cytogenetic abnormalities, and have proved 
to be more useful for PMF risk assessment than the clinical scoring 
systems.
TREATMENT
Primary Myelofibrosis
No specific therapy exists for PMF. The causes for anemia are mul­
tifarious and include ineffective erythropoiesis uncompensated by 
splenic extramedullary hematopoiesis, hemodilution due to sple­
nomegaly, splenic sequestration, blood loss secondary to throm­
bocytopenia or portal hypertension, folic acid deficiency, systemic 
inflammation, and autoimmune hemolysis. Neither recombinant 
erythropoietin nor androgens such as danazol have proven to be 
consistently effective as therapy for anemia. Erythropoietin may 
worsen splenomegaly and will be ineffective if the serum erythro­
poietin level is >125 mU/L. Given the inflammatory milieu that 
characterizes PMF, glucocorticoids can ameliorate anemia as well as 
constitutional symptoms such as fever, chills, night sweats, anorexia, 
and weight loss, and combining these with low-dose thalidomide has 
proved effective as well. Thrombocytopenia can be due to impaired 
marrow function, splenic sequestration, or autoimmune destruction 
and may also respond to low-dose thalidomide and prednisone.
Splenomegaly is by far the most distressing and intractable prob­
lem for PMF patients, causing abdominal pain, portal hypertension, 
easy satiety, and cachexia, whereas surgical removal of a massive 
spleen is associated with significant postoperative complications 
including mesenteric venous thrombosis, hemorrhage, rebound 
leukocytosis and thrombocytosis, and hepatic extramedullary 
hematopoiesis with no amelioration of either anemia or thrombo­
cytopenia when present. For unexplained reasons, splenectomy also 
increases the risk of blastic transformation.
Splenic irradiation is, at best, temporarily palliative and associ­
ated with a significant risk of neutropenia, infection, and subsequent 
operative hemorrhage if splenectomy is attempted. Allopurinol can 
control significant hyperuricemia, and bone pain can be alleviated 
by local irradiation. Pegylated IFN-α can ameliorate fibrosis in 
early PMF, but in advanced disease, it may exacerbate bone mar­
row failure. The JAK1/2 inhibitor ruxolitinib has proved effective 
in reducing splenomegaly and alleviating constitutional symptoms 
in a majority of advanced PMF patients while possibly prolonging 
survival, but in some patients, ruxolitinib is associated with RAS 
mutations. Although anemia and thrombocytopenia are its major 
side effects, these are dose-dependent, and with time, anemia 
stabilizes, and thrombocytopenia may improve. Fedratinib, a new 
tyrosine kinase inhibitor with anti-FLT3 activity, has proved useful 
in patients with disease refractory to ruxolitinib. Two other JAK2 
inhibitors have been approved for PMF therapy, pacritinib, which is 
useful when thrombocytopenia is present, and momelotinib, which 
may be useful in improving red cell production.
In some patients, hypomethylating agents such as azacytidine 
or decitabine in combination with high-dose ruxolitinib have been 
used to control the disease or prepare patients for bone marrow 
transplantation. Transformation to acute leukemia in PMF, like PV 
or ET, is usually refractory to treatment.
Allogeneic bone marrow transplantation is the only curative 
treatment for PMF and should be considered in younger patients 
and older patients with high-risk disease; nonmyeloablative con­
ditioning regimens permit hematopoietic cell transplantation to be 
extended to older individuals.
ESSENTIAL THROMBOCYTOSIS
ET (other designations include essential thrombocythemia, idiopathic 
thrombocytosis, primary thrombocytosis, and hemorrhagic thrombocy­
themia) is a clonal hematopoietic stem cell disorder associated with 

TABLE 108-6  Causes of Thrombocytosis
Tissue inflammation: collagen vascular 
disease, inflammatory bowel disease
Hemorrhage
Malignancy
Iron-deficiency anemia
Infection
Surgery
Myeloproliferative disorders: polycythemia 
vera, primary myelofibrosis, essential 
thrombocytosis, chronic myelogenous 
leukemia
Rebound: Correction of vitamin B12 
or folate deficiency, post-ethanol 
abuse, postsplenectomy
Myelodysplastic disorders: 5q– syndrome, 
idiopathic refractory sideroblastic anemia
Hemolysis
Postsplenectomy or hyposplenism
Familial: Thrombopoietin 
overproduction, JAK2, CALR, or 
MPL mutations
mutations in JAK2 (V617F), MPL, or CALR and manifested clinically by 
overproduction of platelets without a definable cause. ET has an incidence 
of 1–2/100,000 and a distinct female predominance. Canonical MPN 
driver mutations distinguish 90% of ET patients from the more common 
nonclonal, reactive forms of thrombocytosis (Table 108-6); mutationnegative ET patients may have either uncommon MPL mutations, JAK2 
V617F expression limited to the platelets, or a hereditary form of throm­
bocytosis. Once considered a disease of the elderly and responsible for 
significant morbidity due to hemorrhage or thrombosis, it is now clear 
that ET can occur at any age in adults and often without symptoms or dis­
turbances of hemostasis. There is an unexplained female predominance 
in contrast to PMF or the reactive forms of thrombocytosis where no sex 
difference exists. Because no specific clonal marker is available, clinical 
and laboratory criteria have been proposed to distinguish ET from other 
MPNs, which may also present initially with isolated thrombocytosis but 
have differing prognoses and therapies (Table 108-6). These criteria are 
useful in identifying disorders such as CML, PV, PMF, or myelodysplasia, 
which can masquerade as ET. Furthermore, as with “idiopathic” erythro­
cytosis, nonclonal benign forms of thrombocytosis exist (e.g., hereditary 
overproduction of thrombopoietin and those with noncanonical JAK2 
driver mutations) that are not widely recognized because we currently 
lack diagnostic assays. Approximately 50% of ET patients express JAK2 
V617F, 30% CALR (both type 1 and type 2), and 8% MPL mutations. ET 
patients lacking a canonical MPN driver mutation usually have a benign 
prognosis.
CHAPTER 108
Polycythemia Vera and Other Myeloproliferative Neoplasms 
■
■ETIOLOGY
Megakaryocytopoiesis and platelet production depend on thrombo­
poietin and its receptor MPL. As in the case of early erythroid and 
myeloid progenitor cells, early megakaryocytic progenitors require 
the presence of interleukin 3 (IL-3) and stem cell factor for optimal 
proliferation in addition to thrombopoietin. Their subsequent terminal 
development is also enhanced by the chemokine stromal cell-derived 
factor 1 (SDF-1). Interestingly, terminal megakaryocyte maturation 
and platelet production do not require thrombopoietin.
Megakaryocytes are unique among hematopoietic progenitor cells 
because reduplication of their genome is endomitotic rather than 
mitotic and promoted by thrombopoietin. Unlike erythropoietin, 
thrombopoietin is produced only in the liver but has important func­
tions in the bone marrow where it functions to maintain hematopoi­
etic stem cells quiescent in their endosteal niches; once released from 
their niches, thrombopoietin promotes the proliferation of these cells 
in the sinusoidal niches. Like plasma erythropoietin and its target 
erythroblasts, an inverse correlation exists between the platelet count 
and plasma thrombopoietin. However, unlike erythropoietin, throm­
bopoietin is only constitutively produced and the plasma thrombopoi­
etin level is controlled by the size of the platelet and megakaryocyte 
progenitor cell pools. Also, in contrast to erythropoietin, but like 
its myeloid counterparts, granulocyte and granulocyte-macrophage 
colony-stimulating factors, thrombopoietin not only enhances the 
proliferation of its target cells but also enhances the reactivity of their 
end-stage product, the platelet. Paradoxically, in the three MPNs,

expression of the thrombopoietin receptor, MPL, is impaired and 
plasma thrombopoietin is increased despite the increased number of 
megakaryocytes and platelets.

The clonal nature of ET was established by analysis of glucose-6-

phosphate dehydrogenase isoenzyme expression in patients hemizy­
gous for this gene. Although thrombocytosis is its principal manifesta­
tion, like the other MPNs, the hematopoietic stem cell is involved in 
ET. Furthermore, a number of families have been described in which 
ET was inherited, in one instance as an autosomal dominant trait. In 
addition to ET, PMF and PV have also been observed in such kindreds.
■
■CLINICAL FEATURES
Clinically, ET is most often identified incidentally when a platelet 
count is obtained during the course of a routine medical evaluation. 
Occasionally, review of previous blood counts will reveal that an 
elevated platelet count was present but overlooked for many years. 
No symptoms or signs are specific for ET, but these patients can have 
hemorrhagic and thrombotic tendencies expressed as easy bruising 
for the former and microvascular occlusive events for the latter such 
as erythromelalgia, ocular migraine, or a TIA. Physical examination is 
generally unremarkable. Splenomegaly is indicative of another MPN, 
in particular PV, PMF, or CML.
Anemia is unusual, but a mild neutrophilic leukocytosis is not. 
The blood smear is most remarkable for the number of platelets pres­
ent, some of which may be very large. The large mass of circulating 
platelets may prevent the accurate measurement of serum potassium 
due to release of platelet potassium upon blood clotting. This type of 
hyperkalemia is a test tube artifact and not associated with electrocar­
diographic abnormalities. Similarly, arterial oxygen measurements can 
be inaccurate unless thrombocythemic blood is collected on ice. The 
prothrombin and partial thromboplastin times are normal, whereas 
abnormalities of platelet function such as a prolonged bleeding time 
and impaired platelet aggregation can be present. However, despite 
much study, no platelet function abnormality is characteristic of ET, 
and no platelet function test predicts the risk of clinically significant 
bleeding or thrombosis.
PART 4
Oncology and Hematology
The elevated platelet count may hinder marrow aspiration, but 
marrow biopsy usually reveals megakaryocyte hypertrophy and hyper­
plasia, as well as an overall increase in marrow cellularity. If marrow 
reticulin is increased, another diagnosis should be considered. The 
absence of stainable iron demands an explanation because iron defi­
ciency alone can cause thrombocytosis, and absent marrow iron in the 
presence of marrow hypercellularity is a feature of PV.
Nonrandom cytogenetic abnormalities occur in ET but are uncom­
mon, and no specific or consistent abnormality is notable, even those 
involving chromosomes 3 and 1, where the genes for thrombopoietin 
and its receptor, MPL, respectively, are located.
■
■DIAGNOSIS
Thrombocytosis is encountered in a broad variety of clinical disorders 
(Table 108-6), in many of which inflammatory cytokine production 
is increased. The absolute level of the platelet count is not a useful 
diagnostic aid for distinguishing between benign and clonal causes of 
thrombocytosis. About 50% of ET patients express the JAK2 V617F 
mutation. When JAK2 V617F is absent, cytogenetic evaluation is man­
datory to determine if the thrombocytosis is due to CML or a myelo­
dysplastic disorder such as the 5q– syndrome or sideroblastic anemia. 
Because the BCR-ABL translocation can be present in the absence of 
the Ph chromosome, and because the BCR-ABL reverse transcriptase 
polymerase chain reaction is associated with false-positive results, 
fluorescence in situ hybridization (FISH) analysis for BCR-ABL is the 
preferred assay in patients with thrombocytosis in whom a cytogenetic 
study for the Ph chromosome is negative. CALR mutations (type 1 or 
type 2) are present in 30% and MPL mutations are present in 8% of 
ET patients who do not have a JAK2 mutation. Anemia and ringed 
sideroblasts are not features of ET, but they are features of idiopathic 
refractory sideroblastic anemia with the SF3B1 mutation, and in 
some of these patients, thrombocytosis occurs in association with 
expression of JAK2 V617F, CALR, or an MPL mutation. Significant 

splenomegaly should suggest the presence of another MPN such as PV 
or PMF, because splenomegaly can mask the presence of erythrocyto­
sis. Importantly, what appears to be ET can evolve into PV (usually in 
women with JAK2 V617F) or PMF (usually in men with type 1 CALR 
mutations) after a period of many years due to clonal evolution or 
succession. There is sufficient overlap of the JAK2 V617F neutrophil 
allele burden between ET and PV that this test cannot be used as a dis­
tinguishing diagnostic feature with the exception that, in ET, the quan­
titative JAK2 V617F neutrophil allele is never greater than 50%, and 
importantly in this regard, 64% of JAK2 V617F–positive ET patients 
in one study actually were found to have PV when red cell mass and 
plasma volume determinations were performed. Claims that ET and 
PV form a biological continuum are unfounded as these disorders have 
different gene expression profiles and different natural histories.
■
■COMPLICATIONS
Perhaps no other condition in clinical medicine has caused otherwise 
astute physicians to intervene inappropriately more often than throm­
bocytosis, particularly if the platelet count is >1 × 106/μL. It is com­
monly believed that a high platelet count causes thrombosis; however, 
no controlled clinical study has ever established this association, and 
in patients younger than age 60 years, the incidence of thrombosis 
was not greater in patients with thrombocytosis than in age-matched 
controls, and tobacco use appears to be the most important risk factor 
for thrombosis in ET patients.
To the contrary, very high platelet counts are associated primarily 
with hemorrhage due to acquired von Willebrand’s disease. This is not 
meant to imply that an elevated platelet count cannot cause symptoms 
in an ET patient, but rather that the focus should be on the patient, not 
the platelet count. For example, some of the most dramatic neurologic 
problems in ET are migraine-related and respond only to lowering of 
the platelet count, whereas other symptoms such as erythromelalgia 
respond simply to platelet cyclooxygenase-1 inhibitors such as aspirin 
or ibuprofen, without a reduction in platelet number. Still others may 
represent an interaction between an atherosclerotic vascular system 
and a high platelet count, and others may have no relationship to 
the platelet count whatsoever. Recognition that PV can present with 
thrombocytosis alone as well as the discovery of previously unrecog­
nized causes of hypercoagulability (Chaps. 121 and 122) make the 
older literature on the complications of thrombocytosis unreliable.
TREATMENT
Essential Thrombocytosis
Survival of ET patients is not different than the general population 
regardless of their driver mutation. An elevated platelet count in 
an asymptomatic patient without cardiovascular risk factors or 
tobacco use requires no therapy. Indeed, before any therapy is initi­
ated in a patient with thrombocytosis, the cause of symptoms must 
be clearly identified as due to the elevated platelet count. When 
the platelet count rises above 1 × 106/μL, a substantial quantity of 
high-molecular-weight von Willebrand multimers are removed 
from the circulation and destroyed by the enlarged platelet mass, 
resulting in an acquired form of von Willebrand’s disease. This can 
be identified by a reduction in ristocetin cofactor activity. In this 
situation, aspirin could promote hemorrhage. Bleeding in this situ­
ation is rarely spontaneous and usually responds to tranexamic acid 
or ε-aminocaproic acid, which can be given prophylactically before 
and after elective minor surgery.
Plateletpheresis is at best a temporary and inefficient remedy 
that is rarely required. Importantly, ET patients treated with 32P or 
alkylating agents are at risk of developing acute leukemia without 
any proof of benefit; combining either therapy with hydroxyurea 
increases this risk. If platelet reduction is deemed necessary on the 
basis of symptoms refractory to salicylates alone, pegylated IFN-α, 
the quinazoline derivative anagrelide, or hydroxyurea can be used 
to reduce the platelet count, but none of these is uniformly effec­
tive or without significant side effects. Hydroxyurea and aspirin