CHAPTER 13: POLYCYTHEMIA VERA AND OTHER MYELOPROLIFERATIVE DISEASES

The World Health Organization (WHO) classification of the chronic myeloproliferative diseases (MPDs) includes eight disorders, some of which are rare or poorly characterized (Table 13-1) but all of which share an origin in a multipotent hematopoietic progenitor cell; overproduction of one or more of the formed elements of the blood without significant dysplasia; a predilection to extramedullary hematopoiesis, myelofibrosis; and transformation at varying rates to acute leukemia. Within this broad classification, however, significant phenotypic heterogeneity exists. Some diseases such as chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), and chronic eosinophilic leukemia (CEL) express primarily a myeloid phenotype, while in others 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 consequence of the balanced translocation between chromosomes 9 and 22 (t[9;22][q34;11]), CNL has been associated with a t(15;19) translocation, and CEL occurs with a deletion or balanced translocations involving the PDGFRα gene. By contrast, to a greater or lesser extent, PV, PMF, and ET are characterized by expression of a JAK2 mutation, V617F that causes constitutive activation of this tyrosine kinase that is essential for the function of the erythropoietin and thrombopoietin receptors but not the granulocyte colony-stimulating factor receptor. This essential distinction is also reflected in the natural history of CML, CNL, and CEL, which is usually measured in years, and their high rate of transformation into acute leukemia. By contrast, the natural history of PV, PMF, and ET is usually measured in decades, and transformation to acute leukemia is uncommon in the absence of exposure to mutagenic agents. This chapter, therefore, will focus only on PV, PMF, and ET because their clinical overlap is substantial but their clinical courses are distinctly different. Other chronic myeloproliferative disorders will be discussed in Chap. 14.

PV is a clonal disorder involving a multipotent hematopoietic progenitor cell in which phenotypically normal red cells, granulocytes, and platelets accumulate in the absence of a recognizable physiologic stimulus. The most common of the chronic myeloproliferative disorders, PV occurs in 2 per 100,000 persons, sparing no adult age group and increasing with age to rates as high as 18/100,000. Familial transmission occurs but is infrequent and women predominate among sporadic cases.

ETIOLOGY

The etiology of PV is unknown. Although nonrandom chromosome abnormalities such as 20q and trisomy 8 and 9 have been documented in up to 30% of untreated PV patients, unlike CML, no consistent cytogenetic abnormality has been associated with the disorder. However, a mutation in the autoinhibitory, pseudokinase domain of the tyrosine kinase JAK2—that replaces valine with phenylalanine (V617F), causing constitutive activation of the kinase—appears to have a central role in the pathogenesis of PV.

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 erythropoietin 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. Constitutive activation of JAK2 can explain the erythropoietin-independent erythroid colony formation, and the hypersensitivity of PV erythroid progenitor cells to erythropoietin and other hematopoietic growth factors, their resistance to apoptosis in vitro in the absence of erythropoietin, their rapid terminal differentiation, and their increase in Bcl-X_L expression, all of which are characteristic in PV.

Importantly, the JAK2 gene is located on the short arm of chromosome 9, and loss of heterozygosity on chromosome 9p due to mitotic recombination is the most common cytogenetic abnormality in PV. The segment of 9p involved contains the JAK2 locus; loss of heterozygosity in this region leads to homozygosity for the mutant JAK2 V617F. More than 90% of PV patients express this mutation, as do approximately 50% of PMF and ET patients. Homozygosity for the mutation occurs in approximately 30% of PV patients and 60% of PMF patients; homozygosity is rare in ET. Over time, a portion of PV JAK2 V617F heterozygotes become homozygotes due to mitotic recombination but usually not after 10 years of the disease. PV patients who do not express JAK2 V617F are not clinically different from those who do, nor do JAK2 V617F heterozygotes differ clinically from homozygotes. Interestingly, predisposition to acquire mutations in JAK2 appears to be associated with a specific JAK2 haplotype, GGCC. JAK2 V617F is the basis for many of the phenotypic and biochemical characteristics of PV such as elevation of the leukocyte alkaline phosphatase (LAP) score; however, it cannot solely account for the entire PV phenotype and is probably not the initiating lesion in the three MPDs. First, some PV patients with the same phenotype and documented clonal disease lack this mutation. Second, ET and PMF patients have the same mutation but different clinical phenotypes. Third, familial PV can occur without the mutation even when other members of the same family express it. Fourth, not all the cells of the malignant clone express JAK2 V617F. Fifth, JAK2 V617F has been observed in patients with long-standing idiopathic erythrocytosis. Sixth, in some patients, JAK2 V617F appears to be acquired after another mutation. Finally, in some JAK2 V617F-positive PV or ET patients, acute leukemia can occur in a JAK2 V617F–negative progenitor cell. However, while JAK2 V617F alone may not be sufficient to cause PV, it is essential for the transformation of ET to PV, though not for its transformation to PMF.

CLINICAL FEATURES

Although splenomegaly may be the initial presenting sign in PV, most often the disorder is first recognized by the incidental discovery of a high hemoglobin or hematocrit. With the exception of aquagenic pruritus, no symptoms distinguish PV from other causes of erythrocytosis.

Uncontrolled erythrocytosis causes hyperviscosity, leading to neurologic symptoms such as vertigo, tinnitus, headache, visual disturbances, 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, or mesenteric vessels are most commonly involved. Intraabdominal venous thrombosis is particularly common in young women and may be catastrophic if a sudden and complete obstruction of the hepatic vein occurs. Indeed, PV should be suspected in any patient who develops hepatic vein thrombosis. Digital ischemia, easy bruising, epistaxis, acid-peptic disease, or gastrointestinal hemorrhage may occur due to vascular stasis or thrombocytosis. Erythema, burning, and pain in the extremities, a symptom complex known as erythromelalgia, is another complication of the thrombocytosis of 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.

DIAGNOSIS

When PV presents with erythrocytosis in combination with leukocytosis, thrombocytosis, or both, the diagnosis is apparent. However, when patients present with an elevated hemoglobin or hematocrit alone or with thrombocytosis alone, the diagnostic evaluation is more complex because of the many diagnostic possibilities (Table 13-2). 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. Uniquely in PV, in contrast to other causes for true erythrocytosis, an expanded plasma volume can mask the elevated red cell mass; thus, red cell mass and plasma volume determinations are mandatory to establish the presence of an absolute erythrocytosis and to distinguish this from relative erythrocytosis due to a reduction in plasma volume alone (also known as stress or spurious erythrocytosis or Gaisböck's syndrome). This is true even with the finding of JAK2 V617F mutation because not every patient with PV expresses this mutation but patients without PV do. Figure 2-18 illustrates a diagnostic algorithm for the evaluation of suspected erythrocytosis.

After absolute erythrocytosis has been established, its cause must be determined. An elevated plasma erythropoietin level suggests either a hypoxic cause for erythrocytosis or autonomous erythropoietin production, in which case assessment of pulmonary function and an abdominal CT scan to evaluate renal and hepatic anatomy are appropriate. A normal erythropoietin level, however, does not exclude a secondary cause for erythrocytosis or PV. In PV, in contrast to hypoxic erythrocytosis, the arterial oxygen saturation is normal. However, a normal oxygen saturation does not exclude a high-affinity hemoglobin as a cause for erythrocytosis; documentation of previous hemoglobin levels and a family study are important in this regard.

Other laboratory studies that may aid in diagnosis include the red cell count, mean corpuscular volume, and red cell distribution width (RDW). Only three situations cause microcytic erythrocytosis: β-thalassemia trait, hypoxic erythrocytosis, and PV. With β-thalassemia trait the RDW is normal, whereas with hypoxic erythrocytosis and PV, the RDW is usually elevated due to iron deficiency. Today, an assay for JAK2 V617F has superseded other tests for establishing the diagnosis of PV. Of course, in patients with associated acid-peptic disease, occult gastrointestinal bleeding may lead to presentation with hypochromic, microcytic anemia, masking the presence of PV.

A bone marrow aspirate and biopsy provide no specific diagnostic information since these may be normal or indistinguishable from ET or PMF, and unless there is a need to exclude some other disorder, these procedures need not be done. Although the presence of a cytogenetic abnormality such as trisomy 8 or 9 or 20q– in the setting of an expanded red cell mass supports a clonal etiology, no specific cytogenetic abnormality is associated with PV, 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 cytokine production. The latter appears to be responsible for constitutional symptoms, while peptic ulcer disease may be due to Helicobacter pylori, and the pruritus associated with this disorder may be a consequence of basophil activation by JAK2 V617F. A sudden increase in spleen size can be associated with 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 some patients, however, the myelofibrosis is accompanied by significant extramedullary hematopoiesis, hepatosplenomegaly, and transfusion-dependent anemia, which are manifestations of stem cell failure. The organomegaly can cause significant mechanical discomfort, portal hypertension, and progressive cachexia. Although the incidence of acute nonlymphocytic leukemia is increased in PV, the incidence of acute leukemia in patients not exposed to chemotherapy or radiation is low, and the development of leukemia is related to the development of extramedullary hematopoiesis, hepatosplenomegaly, and transfusion-dependent anemia or exposure to chemotherapy. Importantly, chemotherapy alone, including hydroxyurea, has been associated with acute leukemia that develops in JAK2 V617F–negative stem cells. Erythromelalgia is a curious syndrome of unknown etiology associated with thrombocytosis, primarily involving the lower extremities and usually manifested by erythema, warmth, and pain of the affected appendage and occasionally digital infarction. It occurs with a variable frequency in MPD patients 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.

If left uncontrolled, erythrocytosis can lead to thrombosis involving vital organs such as the liver, heart, brain, or lungs. Patients with massive splenomegaly are particularly prone to thrombotic events because the associated increase in plasma volume masks the true extent of the red cell mass elevation as 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.

Chronic PMF (other designations include idiopathic myelofibrosis, agnogenic myeloid metaplasia, or myelofibrosis with myeloid metaplasia) is a clonal disorder of a multipotent hematopoietic progenitor cell of unknown etiology characterized by marrow fibrosis, extramedullary hematopoiesis, and splenomegaly. PMF is the least common chronic MPD, and establishing this 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 13-3), many of which are amenable to specific therapies not effective in PMF. In contrast to the other chronic MPDs and so-called acute or malignant myelofibrosis, which can occur at any age, PMF primarily afflicts men in their sixth decade or later.

ETIOLOGY

The etiology of PMF is unknown. Nonrandom chromosome abnormalities such as 9p, 20q– 13q– trisomy 8 or 9, or partial trisomy 1q are common, but no cytogenetic abnormality specific to the disease has been identified. JAK2 V617F is present in approximately 50% of PMF patients, and mutations in the thrombopoietin receptor Mpl occur in about 5%. The degree of myelofibrosis and the extent of extramedullary hematopoiesis are also not related. Fibrosis in this disorder is associated with overproduction of transforming growth factor β and tissue inhibitors of metalloproteinases, while osteosclerosis is associated with overproduction of osteoprotegerin, an osteoclast inhibitor. Marrow angiogenesis occurs due to increased production of vascular endothelial growth factor. Importantly, fibroblasts in PMF are polyclonal and not part of the neoplastic clone.

CLINICAL FEATURES

No signs or symptoms are specific for PMF. Many patients are asymptomatic at presentation, and the disease is usually detected by the discovery of splenic enlargement and/or abnormal blood counts during a routine examination. However, in contrast to its companion MPDs, night sweats, fatigue, and weight loss are common presenting complaints. A blood smear will show the characteristic features of extramedullary hematopoiesis: teardrop-shaped red cells, nucleated red cells, myelocytes, and promyelocytes; myeloblasts may also be present (Fig. 13-1). Anemia, usually mild initially, is the rule, while the leukocyte and platelet counts are either normal or increased, but either can be depressed. Mild hepatomegaly may accompany the splenomegaly but is unusual in the absence of splenic enlargement; isolated lymphadenopathy should suggest another diagnosis. Both serum lactate dehydrogenase and alkaline phosphatase levels can be elevated. The LAP score can be low, normal, or high. Marrow is usually inaspirable due to the myelofibrosis (Fig. 13-2), and bone radiographs 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 enlargement 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 earlier is characteristic of PMF, all of the clinical features described can also be observed in PV or CML. Massive splenomegaly commonly masks erythrocytosis in PV, and reports of intraabdominal thromboses in PMF most likely represent instances of unrecognized PV. In some patients with PMF, erythrocytosis has developed during the course of the disease. Furthermore, since many other disorders 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 13-3 be ruled out. A diagnostic algorithm has been proposed but does not distinguish one disease causing myeloid metaplasia from another.

The presence of teardrop-shaped red cells, nucleated red cells, myelocytes, and promyelocytes establishes the presence of extramedullary hematopoiesis, while the presence of leukocytosis, thrombocytosis with large and bizarre platelets, and circulating myelocytes suggests the presence of an MPD as opposed to a secondary form of myelofibrosis (Table 13-3). Marrow is usually not aspirable due to increased marrow reticulin, but marrow biopsy will reveal a hypercellular marrow with trilineage hyperplasia and, in particular, increased numbers of megakaryocytes in clusters and with large, dysplastic nuclei. However, there are no characteristic morphologic abnormalities of the bone marrow that distinguish PMF from the other chronic MPDs. Splenomegaly due to extramedullary hematopoiesis may be sufficiently massive to cause portal hypertension and variceal formation. In some patients, exuberant extramedullary hematopoiesis can dominate the clinical 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 result. Whether these represent a host reaction to the disorder or are involved in its pathogenesis is unknown. Cytogenetic analysis of blood is useful both to exclude CML and for prognostic purposes because complex karyotype abnormalities portend a poor prognosis in PMF. For unknown reasons, the number of circulating CD34+ cells is markedly increased in PMF (>15,000/μL) compared with the other chronic MPDs unless they too develop myeloid metaplasia.

Importantly, approximately 50% of PMF patients, similar to patients with its companion myeloproliferative disorders PV and ET, express the JAK2 V617F mutation, often as homozygotes. Such patients had a poorer survival in one retrospective study but not in another, in which they were found to be older and to have higher hematocrits than patients who were JAK2 V617F negative. Patients with an MPL mutation tend to be more anemic than those without this mutation.

COMPLICATIONS

Survival in PMF varies according to specific clinical features (Table 13-4) but is shorter than in patients with PV or ET. The natural history of PMF is one of increasing marrow failure with transfusion-dependent anemia and increasing organomegaly due to extramedullary hematopoiesis. As with CML, PMF can evolve from a chronic phase 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. Important prognostic factors for disease acceleration include anemia; leukocytosis; thrombocytopenia, the presence of circulating myeloblasts, older age; the presence of complex cytogenetic abnormalities; and constitutional symptoms such as unexplained fever, night sweats, or weight loss.

Essential thrombocytosis (other designations include essential thrombocythemia, idiopathic thrombocytosis, primary thrombocytosis, and hemorrhagic thrombocythemia) is a clonal disorder of unknown etiology involving a multipotent hematopoietic progenitor cell manifested clinically by overproduction of platelets without a definable cause. ET is an uncommon disorder, with an incidence of 1–2/100,000 and a distinct female predominance. No clonal marker is available to consistently distinguish ET from the more common nonclonal, reactive forms of thrombocytosis (Table 13-5), making its diagnosis difficult. Once considered a disease of the elderly and responsible for significant morbidity due to hemorrhage or thrombosis, with the widespread use of electronic cell counters, it is now clear that ET can occur at any age in adults and often without symptoms or disturbances of hemostasis. There is an unexplained female predominance in contrast to PMF or the reactive forms of thrombocytosis in which no sex difference exists. Because no specific clonal marker is available, clinical criteria have been proposed to distinguish ET from the other chronic MPDs, which may also present with thrombocytosis but have differing prognoses and therapies (Table 13-5). These criteria do not establish clonality; therefore, they are truly useful only in identifying disorders such as CML, PV, or myelodysplasia, which can masquerade as ET, as opposed to actually establishing the presence of ET. Furthermore, as with "idiopathic" erythrocytosis, nonclonal benign forms of thrombocytosis exist (e.g., hereditary overproduction of thrombopoietin) that are not widely recognized because we currently lack adequate diagnostic tools. Approximately 50% of ET patients carry the JAK2 V617F mutation, but its absence does not exclude the disorder.

ETIOLOGY

Megakaryocytopoiesis and platelet production depend on thrombopoietin 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 development is also enhanced by the chemokine stromal cell–derived factor 1 (SDF-1). However, megakaryocyte maturation requires thrombopoietin.

Megakaryocytes are unique among hematopoietic progenitor cells because reduplication of their genome is endomitotic rather than mitotic. In the absence of thrombopoietin, endomitotic megakaryocytic reduplication and, by extension, the cytoplasmic development necessary for platelet production are impaired. Like erythropoietin, thrombopoietin is produced in both the liver and the kidneys, and an inverse correlation exists between the platelet count and plasma thrombopoietic activity. Like erythropoietin levels, plasma levels of thrombopoietin are controlled largely by the size of its progenitor cell pool. 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. In addition to its role in thrombopoiesis, thrombopoietin also enhances the survival of multipotent hematopoietic stem cells.

The clonal nature of ET was established by analysis of glucose-6-phosphate dehydrogenase isoenzyme expression in patients hemizygous for this gene; by analysis of X-linked DNA polymorphisms in informative female patients; and by the expression in patients of nonrandom, although variable, cytogenetic abnormalities. Although thrombocytosis is its principal manifestation, like the other chronic MPDs, a multipotent hematopoietic progenitor 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 some 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 occlusions for the latter such as erythromelalgia, ocular migraine, or TIAs. Physical examination is generally unremarkable except occasionally for mild splenomegaly. Massive splenomegaly is indicative of another MPD, 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 present, 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 laboratory artifact and not associated with electrocardiographic abnormalities. Similarly, arterial oxygen measurements can be inaccurate unless thrombocythemic blood is collected on ice. The prothrombin and partial thromboplastin times are normal, while 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.

The elevated platelet count may hinder marrow aspiration, but marrow biopsy usually reveals megakaryocyte hyperplasia and hypertrophy, 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 deficiency 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 uncommon, and no specific or consistent abnormality is notable, even those involving chromosomes 3 and 1, in which the genes for thrombopoietin and its receptor Mpl, respectively, are located.

DIAGNOSIS

Thrombocytosis is encountered in a broad variety of clinical disorders (Table 13-5) in many of which production of cytokines 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 mandatory to determine if the thrombocytosis is due to CML or a myelodysplastic disorder such as the 5q- syndrome. Because the bcr-abl translocation can be present in the absence of the Ph chromosome, and because 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. Anemia and ringed sideroblasts are not features of ET, but they are features of idiopathic refractory sideroblastic anemia, and in some of these patients, the thrombocytosis occurs in association with JAK2 V617F expression. Massive splenomegaly should suggest the presence of another MPD, and in this setting a red cell mass determination should be performed because splenomegaly can mask the presence of erythrocytosis. Importantly, what appears to be ET can evolve into PV or PMF after a period of many years, revealing the true nature of the underlying MPD. There is sufficient overlap of the JAK2 V617F neutrophil allele burden between ET and PV that this cannot be used as a distinguishing diagnostic feature; only a red cell mass and plasma volume determination can distinguish PV from ET, and importantly in this regard, 64% of JAK2 V617F–positive ET patients actually were found to have PV when red cell mass and plasma volume determinations were performed.

COMPLICATIONS

Perhaps no other condition in clinical medicine has caused otherwise astute physicians to intervene inappropriately more often than thrombocytosis, particularly if the platelet count is >1 × 10⁶/μL. It is commonly believed that a high platelet count causes intravascular stasis and 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 control participants.

To the contrary, very high platelet counts are associated primarily with hemorrhage due to acquired von Willebrand 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, while 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 unrecognized causes of hypercoagulability (Chap. 21) make the older literature on the complications of thrombocytosis unreliable.