Page 1320 - Williams Hematology ( PDFDrive )

1294 Part X: Malignant Myeloid Diseases Chapter 84: Polycythemia Vera 1295

or upper abdominal pain secondary to splenic infarcts. Most patients from secondary polycythemia because the red cell mass is increased in
become dependent on transfusions or erythropoietin therapy. 31,75,77,81,107 both disorders. The principal value of red cell mass determination is to
Development of the spent phase is associated with an increased risk distinguish apparent or spurious polycythemia from PV and second-
of leukemic transformation 31,108 ; in the PV Study Group-01 study, the ary polycythemia. 110,111 It could also be useful in distinguishing cases of
incidence of acute leukemia was 24 percent in PV patients with MF, masked PV from ET. The availability of the JAK2 assay has made red
115
compared to 7 percent in those without MF, although it should be noted cell mass determination only rarely important.
that a sizable number of the patients in this study had been treated with
32
78
alkylating agents or P. Therapy, including use of JAK2 inhibitors, is Leukocytes
described in Chap. 86. Absolute neutrophilia occurs in approximately two-thirds of PV
patients. Occasional myelocytes and metamyelocytes are present in
70
LEUKEMIC AND MYELODYSPLASTIC the blood, and considerable degrees of cell immaturity are present in
patients with longstanding, advanced disease. Again, these abnormal-
TRANSFORMATION OF POLYCYTHEMIA VERA ities herald the onset of the spent phase (Chap. 86). Basophilia occurs
Patients with PV have an increased risk of developing leukemia. 71,82 in approximately two-thirds of patients with uncontrolled disease. 31,81,116
117
This contrasts with other nonclonal polycythemic disorders, wherein In PV, the proportion of activated neutrophils is increased, and it is
progression to leukemia is not part of the disease process. Acute leu- possible that neutrophils may be an important factor in PV-associated
kemia, usually myelogenous, is an invariably fatal complication of PV. thrombosis. 118
A European multicenter observational study of 1638 patients reported The leukocyte alkaline phosphatase level is elevated in approxi-
70
a 6.3 percent relative risk of developing leukemia within 10 years after mately 70 percent of patients with PV, but this assay has now become
75
the diagnosis of PV. Different treatments can also influence the risk of largely obsolete.
transformation from PV to leukemia. In the PV Study Group-01 ran-
domized trial, the incidence of acute leukemia at 18 years of followup Platelets
was 1.5 percent on the phlebotomy-only treatment arm, 10 percent on The platelet count is increased in approximately 50 percent of PV patients
the P treatment arm, and 13 percent on the chlorambucil treatment at the time of diagnosis, and in approximately 10 percent of patients
32
9
70
81
arm. In a more recent study of 1638 patients, the risk of transformation it is greater than 1000 × 10 /L. There are no consistent abnormalities
119
to acute myelogenous leukemia (AML) or a myelodysplastic syndrome of thrombopoietin levels in PV patients. A significant proportion of
(MDS) in PV patients also varied by treatment. Treatment-specific risk PV patients first present with isolated thrombocytosis without elevated
of transformation, ordered by increasing risk, was: phlebotomy (haz- hemoglobin, especially if the patient has a reason for iron deficiency,
ard ratio [HR]: 0.91), hydroxyurea (HR: 1.09), interferon (INF)-α (HR: and are sometimes misdiagnosed with essential thrombocythemia. 120
1.24), busulfan (HR: 8.64), pipobroman (HR: 4.32), and P (HR: 8.96). Qualitative platelet abnormalities have been described which may
109
32
Leukemic transformation was not significantly different between phle- play a role in the pathogenesis of thrombotic and hemorrhagic events.
botomy, hydroxyurea, and INF-α treatments. 109 In vitro spontaneous platelet aggregation is accelerated. On the other
Acute leukemia as the terminal PV event may arise from either the hand, patients with MPNs often display a nearly pathognomonic defect
JAK2 V617F -positive clone or, more frequently, from a hematopoietic cell in the primary wave of platelet aggregation induced by epinephrine
that does not carry the JAK2 mutation. 35,47,50 (Chaps. 112 and 121). 121
There are a number of additional platelet abnormalities associ-
ated with PV, including increased platelet thromboxane A genera-
2
LABORATORY FEATURES tion and increased excretion of thromboxane metabolites. Platelet
122
123
124
factor-4 levels are elevated. Platelet survival may be shortened. 124,125
BLOOD FINDINGS Fibrinogen binding after stimulation with a platelet-activating factor is
126
Erythrocytes diminished, and there is reduced expression of the thrombopoietin
20
The hemoglobin concentration, erythrocyte count, and hematocrit are receptor. However, none of these changes are specific for PV. In a pro-
A2
usually increased, and the mean cell volume is usually low-normal or spective study, a PI polymorphism of the platelet glycoprotein IIIa was
127
low in untreated patients, and low in patients who have undergone associated with an increased risk of arterial thrombosis in PV patients,
phlebotomies or had gastrointestinal bleeding episodes. Red cells are although this conclusion remains controversial.
9
hypochromic and microcytic, with morphology characteristic of iron Platelet counts greater than 1000 to 1500 × 10 /L are associated
deficiency. Although increased hemoglobin is generally a diagnostic with progressive decrease of von Willebrand factor (an acquired, type 2
feature of PV, at times the hemoglobin level may be low, normal, or bor- von Willebrand disease) and increased risk of bleeding, but not of
derline, a condition termed “masked” PV. 110–112 thrombosis. 128
The appearance of significant aniso- and poikilocytosis and tear-
drop cells (dacryocytes; Chap. 31) heralds the onset of the spent phase Plasma
129
and post-PV MF (Chap. 86). Serum lysozyme levels are slightly increased in some patients, and
because of increased leukocyte turnover and increased levels of B
12
130
Red Cell Mass Determination binding protein, serum B determination is usually increased. Hype-
12
The Polycythemia Vera Study Group employed the direct determina- ruricemia, a consequence of hyperproliferative myelopoiesis, is fre-
tion of red cell mass as the sine qua non of the diagnosis of PV for all quently encountered. 31
patients entered into their studies. Some believe that even in the rou-
76
tine clinical setting, this procedure should be performed on all patients V617F
to establish a diagnosis of PV. 76,113 Unfortunately, the determination of JAK2 AND EXON 12 MUTATIONS
red cell mass is expensive, requires the use of radioactive isotopes in JAK2 G1849T Creating V617F
patients, and, when performed by the inexperienced, is often inaccu- Mutations within the JAK2 gene cause deregulation of the hemato-
rate. Red cell mass determination is not useful in distinguishing PV poietic process, which is expressed in a wide spectrum of disorders
114
Kaushansky_chapter 84_p1291-1306.indd 1295 9/21/15 11:11 AM