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Chapter 68 The Polycythemias 1087

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unique to any of the MPNs and are associated with AML and MDS. flow are correctable with phlebotomy. Reduction of the hematocrit
Four of these genes—EZH2, ASXL, DNMT3a, and TET2— by relatively small amounts frequently led to substantial improve-
participate in the epigenetic control of transcription and are discussed ments in whole blood viscosity and cerebral blood flow. Some PV
in greater detail in Chapter 70. EZH2 mutations occur in 3% of PV patients apparently still maintain a higher than normal whole blood
patients, 7–16% of PV patients have TET2 mutations, and 5–7% viscosity despite the normalization of the hematocrit, suggesting that
have mutations of DNMT3a; ASXL mutations are rare in PV (<7%). an increase in hematocrit may not be the only factor responsible for
Each of these mutations may precede JAK2V617F, but the converse increased blood viscosity. There appear to be important gender dif-
may also occur. Each of these mutations are far less frequent in PV ferences as related to the location of thromboses in PV patients.
and ET than PMF, supporting that these events may combine to Women appear to have a higher incidence of thromboses within the
generate a more accelerated phase of the classic MPN that phenotypi- abdominal cavity involving the portal, mesenteric, or hepatic vessels
cally presents as MF. In addition to epigenetic regulators, mutations but a comparable rate of other vascular complications. Several groups
in genes that encode proteins that participate in the process of splic- have reported that patients with splanchnic vein thromboses fre-
ing immature mRNA have also been described in MPNs, specifically quently have endothelial cells that are affected by JAK2V617F, sug-
SF3B1, SRSF2, and U2AF1. SF3B1 mutations are mostly found in gesting that in such individuals, their MPN might originate not at
PMF where they cluster within exons 12–16. Alterations in SRSF2 the level of the HSC but rather at the level of a hemangioblast, from
are mostly found in PMF and MPN evolved to AML. U2AF1 muta- which myeloid and endothelial cells originate. Such JAK2V61F-
tions are detected in up to 15% of PMF cases, but are not present in positive endothelial cells have been shown to exhibit a high efficiency
ET or PV patients. IDH1/2, IKZF deletions, NRAS/KRAS, p53 muta- of adhering to normal mononuclear cells, thereby likely leading to an
tions, and RUNX1 mutations rarely occur in PV but are all associated increased risk of thrombosis.
with transformation of an underlying MPN such as PV to acute A number of possible explanations have been suggested for the
leukemia. 18 observed relationship between hematocrit level and the development
of thrombotic events in PV patients. Platelet adhesion and thrombus
The Hypercoagulable State That Characterizes formation on the vascular subendothelium are determined in part by
the rate at which platelets are transported to the vascular surface. In
Polycythemia Vera a polycythemic condition in which increased numbers of RBCs are
present, a greater number of intercellular collisions between RBCs
Thrombosis is a major cause of morbidity and mortality in PV and platelets occurs. These collisions could lead to increased platelet
patients. These thrombotic events are most frequently microcircula- movement in a direction perpendicular to blood flow. This facilita-
tory and arterial, but venous thromboses are also of important clinical tion of platelet transport to the vessel wall may be an important factor
significance. The increased risk for thrombosis can be attributed to in the development of thrombosis. An alternative explanation for the
abnormalities in the vessel wall, blood cell components, and the association between hematocrit level and the risk of thrombosis is
dynamics of blood flow. A number of risk factors for thrombosis have based on the knowledge that blood viscosity is particularly sensitive
been investigated, but most of them are not firmly established. to hematocrit levels. Increased hematocrits lead to increased blood
In the European Collaboration on Low-Dose Aspirin in Polycy- viscosity, in turn leading to increased peripheral vascular resistance
themia Vera (ECLAP) study, the incidence of cardiovascular compli- and an actual reduction in blood flow to a variety of organs, predis-
cations was higher in patients older than 65 years (5.0% of patients posing them to the development of thrombosis. The issue of hemato-
per year; hazard ratio [HR]: 2.0; 95% confidence interval [CI]: crits and thrombosis in PV has been prospectively investigated in an
1.22–3.29; p < .006) or with a history of thrombosis (4.93% of analysis of 1638 patients enrolled in the ECLAP study. In this pro-
patients per year; HR: 1.96; 95% CI: 1.29–2.97; p = .0017). Patients spective study, despite recommendations of maintaining hematocrit
both with a history of thrombosis and older than 65 years had the levels lower than 45%, only 50% of patients achieved this target
highest risk of developing additional cardiovascular events (10.9% of during the follow-up, and 10% had hematocrit levels above 50%.
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patients per year; HR: 4.35; 95% CI: 2.95–6.41; p < .0001). These These different hematocrit values were not associated with different
data confirm previous findings that increasing age and history of thrombotic outcomes as assessed using univariate and multivariable
thrombosis are the two most important prognostic factors for the analysis. However, in a recent prospective randomized clinical trial of
development of vascular complications. 365 patients with PV, it was shown that patients with hematocrit
This information does not negate the increased incidence of maintained at less than 45% had a lower incidence of cardiovascular
thrombotic incidents also observed in younger patients with this events compared with patients whose hematocrits were maintained
disorder. In a series of 58 PV patients younger than 40 years of age, at 45–50% (4.4% vs. 10.9%; p = .02). The group with lower hema-
a disturbingly high incidence of life-threatening thrombotic events tocrit also had lower death rates from cardiovascular events or major
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was observed. In fact, seven of the 10 patients in this series who died thrombosis. This study confirmed the need for strict hematocrit
during the period of observation died from thrombotic events—four control in PV patients.
from Budd-Chiari syndrome (BCS), one from a pulmonary embo- Additional factors have been implicated in the development of
lism, and two from cerebral thrombosis. Therefore, although a sig- thrombosis in PV patients. Almost all patients with PV are iron
nificant factor, preexisting atherosclerotic disease is not the sole deficient. Decreased RBC deformability has been said to accompany
etiologic factor in the genesis of thrombosis in PV. Analysis of the iron deficiency, leading to increased blood viscosity and a decreased
ECLAP study identified smoking in addition to older age as an ability of RBCs to pass through small-bore polycarbonate filters. This
important risk factor for major thrombosis. A retrospective study of increased membrane stiffness, however, might be counterbalanced by
450 patients with PV demonstrated that hypertension and tobacco the effect of a reduced RBC size on the adherence of blood platelets
use were associated with arterial thrombosis (p < .02) and diabetes to arteriolar subendothelium. RBC size is a major determinant of
mellitus was associated with venous thrombosis (p = .002). platelet adherence, with larger RBCs leading to increased platelet
The principal hemorrheologic abnormality in PV is an elevated adherence and smaller RBCs to decreased platelet adherence. Whether
whole blood viscosity. The blood viscosity in PV is higher than that the increased membrane stiffness associated with iron deficiency is
of normal control participants at all shear rates. In a retrospective counterbalanced by the decreased platelet adherence associated with
analysis of PV patients with histories of vascular thrombosis, a strong smaller RBCs is yet to be determined.
correlation in univariate analysis between hematocrit level and the Inflammation may be another predictor of thrombosis in patients
development of thrombotic episodes, including many cerebrovascular with PV. In a retrospective study patients with increased inflamma-
occlusions, was demonstrated. Cerebral blood flow is reduced in tion as evidenced by an increased C-reactive protein (CRP) had
patients with PV in whom the hematocrit level is 53–62%. These significantly greater risk for thrombosis based on a multivariant
abnormalities were observed even in patients with hematocrits at the analysis that adjusted for age, sex, ET, or PV diagnosis, cardiovascular
lower levels of normal, that is, 46–52%. Reductions in cerebral blood risk factors, and JAK2V617F mutation status.