Page 1242 - Hematology_ Basic Principles and Practice ( PDFDrive )

1088 Part VII Hematologic Malignancies

Thrombocytosis and qualitative platelet abnormalities occur fre- stimulate the activation of endothelial cells and platelets, and induce
quently and are likely to be important contributory factors to the the release from activated leukocytes reactive oxygen species as well
development of thrombosis. Some investigators have implicated as proteases that are capable of impairing a number of hemostatic
uncontrolled thrombocytosis as a cause of thrombosis in these processes. Platelet–leukocyte aggregates are increased in number in
patients, but this relationship has not been confirmed by others. PV and are associated with an increased propensity to thrombose. In
Increased plasma and urinary thromboxane production has been addition, the prothrombotic state in PV has been attributed to an
linked to increased platelet activation in these patients. A low-dose acquired resistance to the naturally occurring anticoagulant, protein
aspirin regimen selective for inhibition of platelet cyclooxygenase has C, which is associated with reduced levels of protein S. The loss of
been found to suppress increased thromboxane production in vivo protein S in PV patients is especially profound in those with a high
and to clinically benefit patients with PV. Furthermore, elevated levels JAK2V617F allele burden, but its cause remains unknown, although
of serum VEGF and plasma TPO have been observed in patients with some have speculated that it is the consequence of the degradation
PV. These growth factors have been shown to lead to platelet of protein S by the increased levels of neutrophil elastase.
activation. JAK2V617F allele burden has also been implicated as a potential
Despite conflicting data, no clear clinical relationship between risk factor for thrombosis. In a prospective study of 173 patients with
platelet number or function and the incidence of hemorrhage or PV that were followed for a median of 24 months, patients with a
thrombosis in PV patients has been delineated. An argument in favor JAK2V617F allele burden of >75% had a sevenfold increased risk of
of a role of elevated platelet numbers in the genesis of thrombosis in thrombosis compared with patients with an allele burden of <25%.
PV and ET is the observation in patients with ET that a reduction However, another prospective study comparing patients with an allele
of excessive platelet numbers with the use of hydroxyurea is associated burden of <50% versus <50% did not confirm the association
with a reduction in the risk of developing thrombotic events. between JAK2V617F allele burden and thrombotic risk. In a retro-
However, this should not be taken as evidence that the reduction in spective study of 186 patients with MPN, individuals harboring the
developing additional vascular events was caused by platelet count JAK2V617F mutation were at highest risk for VTE. JAK2 allele
normalization alone; very likely, it may be related to the suppression burdens higher than 20% identified patients with a sevenfold
by hydroxyurea of each of three myeloid lineages. In line with this increased risk of VTE but not arterial thrombosis. More studies are
interpretation are the results of a randomized study performed by the needed to clearly establish higher JAK2V617F allele burden as a risk
Medical Research Council in the United Kingdom (PT-01) in which factor for thrombosis.
patients with ET were randomized to receive either hydroxyurea or Clearly, the thrombotic tendencies in PV are multifactorial and
anagrelide therapy. This study showed that hydroxyurea therapy in the future it is likely that the thrombotic risk will be assessed on
rather than anagrelide, a selective platelet number-reducing drug, was an individual basis, taking into account many of the factors men-
associated with a reduction in the number of arterial thrombotic tioned previously.
events, especially in JAK2V617F patients. In this study the rate of
thrombosis in PV patients during follow-up did not vary according
to different platelet numbers. Select patients with PV have, however, Polycythemia Vera and the Risk of Hemorrhage
been afforded prompt resolution of vascular complications such as
erythromelalgia or TIAs after institution of platelet antiaggregating Patients with PV are also at an increased risk of developing life-
agents or cytoreduction. It is important to emphasize that erythro- threatening hemorrhagic complications. Abnormalities in platelet
melalgia does not resolve in PV patients with phlebotomy alone or function and number have been implicated as the cause of this
with anticoagulation, but requires the use of platelet antiaggregating hemorrhagic tendency. Qualitative platelet abnormalities frequently
agents or reduction of platelet numbers. What distinguishes the found in these patients include platelet hypofunction, as demon-
clinical courses of these patients from those of others is unknown. strated by defective in vitro platelet aggregation, acquired storage pool
These reports, coupled with the knowledge of abnormal thromboxane disease, and platelet membrane defects, and increased platelet reactiv-
metabolism of platelets in PV, provide substance to the belief that ity, as demonstrated by enhanced platelet aggregation, increased
platelets contribute to the generation of the thrombotic and hemor- plasma β-thromboglobulin levels, and shortened platelet survival.
−1
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rhagic tendencies observed in PV. Although a number of clinical With platelet counts greater than 1000 × 10 L , the development
assessments of platelet function have been used to identify patients of acquired von Willebrand syndrome has been reported and is associ-
who are potentially at a high risk of developing a life-threatening ated with life-threatening hemorrhagic episodes.
hemorrhagic or thrombotic event, the results of these studies to date
have been very disappointing. It appears that the etiology of throm-
bosis and hemorrhage in PV is multifactorial, and that the available Post-Polycythemia Vera Myelofibrosis and Acute
tools are inadequate to identify patients at highest risk. Myeloid Leukemia
An elevation of WBC number occurs in 50–60% of PV patients,
which may also have a detrimental effect on the rheology of the A major cause of morbidity and mortality in PV results from the
microcirculation in PV. An analysis of the ECLAP database showed transition from the polycythemic phase of the disease to post-PV MF
6
−1
that a baseline WBC count above 15,000 × 10 L was associated and to acute leukemia. Post-PV MF is characterized by cytopenias,
with the development of major arterial events, mainly myocardial MF, and extramedullary hematopoiesis. In a variety of MPNs, the
infarction. A retrospective study of 459 patients with PV showed a fibroblastic component of the BM has been shown not to be directly
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significant association between baseline leukocyte count >15 × 10 /L involved in the malignant process but to be a reactive event to the
and venous thrombotic events during a median follow up of 64 neoplastic clone. Several investigators have suggested that the release
months. Similar results were shown in two additional studies in of growth factors, particularly VEGF, fibroblast growth factor, trans-
patients with ET. Activated leukocytes may release proteases and forming growth factor-β, lipocalin, and tumor necrosis factor-α from
oxygen radicals that alter endothelial cells and platelets so as to favor myeloid cells are responsible for the marrow fibroblastic proliferation,
the development of a prothrombotic state. A series of markers of increased marrow microvessel density, osteosclerosis, as well as the
leukocyte activation, including expression of membrane CD11b and systemic symptoms observed in patients with PV-related MF. Whether
leukocyte alkaline phosphatase antigen, cellular elastase content, the use of any particular therapeutic agents for treatment of PV
plasma elastase levels, and myeloperoxidase levels, are elevated in accelerates the development of PV related MF remains hotly debated,
patients with PV. Limited and conflicting data are available as to although it is well established that the use of alkylating agents such
whether or not there is a correlation between the presence of platelet– as piprobroman or chlorambucil increases the risk of developing acute
leukocyte interactions and thrombotic events. Increased expression of leukemia. It remains a source of debate if treatment with hydroxyurea
leukocyte adhesion molecules increases the adhesion of leukocytes to increases the risk of developing MF or AML. The bulk of evidence
platelets and the endothelium. These cell-to-cell interactions does not support a clear leukemogenic role for this drug that is the