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Chapter 68 The Polycythemias 1091

symptoms can be abolished by reducing the platelet counts to normal Another situation that puts patients with PV and ET at high risk
levels and can be rapidly reversed after the institution of antiplatelet for thrombosis is pregnancy. Maternal and fetal complications have
aggregation therapy but not coumadin. Therefore, the cause of been reported. Specifically, the rate of fetal loss is higher than that of
erythromelalgia appears to be closely linked to abnormal arachidonic the general population.
acid metabolism that occurs within platelets in this disorder. Generalized pruritus occurs in approximately 40% of cases of PV.
Retrospective reviews have revealed a higher than expected number Water contact, such as during showers or bathing, induces attacks of
of patients with PV and pulmonary hypertension. Proposed etiologies intolerable pruritus. There appears to be no clear relationship between
include direct obstruction of pulmonary arteries by circulating the degree of the pruritus and severity of the disease, and 20% of
megakaryocytes, extramedullary hematopoiesis in the pulmonary patients continue to experience itching despite reduction of their
parenchyma, smooth muscle hyperplasia induced by release of PDGF hematocrits to normal levels. Aquagenic pruritus is significantly more
from activated platelets, chronic disseminated intravascular coagula- common among JAK2V617F homozygous patients than heterozy-
tion, and unrecognized recurrent pulmonary emboli. The diagnosis gotes. The degree of pruritus is so severe in some patients that they
of pulmonary hypertension is made, on average, 9.5 years after the are unable to tolerate bathing at all and find it necessary to substitute
diagnosis of the underlying MPN and is associated with a poor gentle skin swabbing or to simply not bathe. The etiology of the
prognosis, with death usually occurring as a result of congestive heart pruritus in PV remains uncertain. Several groups have attempted to
failure or pneumonia. Although anecdotal reports have claimed implicate elevated blood and urine histamine levels in its pathobiol-
improvements in patients’ pulmonary artery pressure with control of ogy. A strong correlation between skin mast cell numbers and the
the underlying disease, others have not found any change in serial severity of itching has been demonstrated, and mast cells in PV have
measurements of 11 patients’ pulmonary arterial pressures despite been shown to be JAK2V617F positive. However, the failure of the
good disease control. Recently, ruxolitinib therapy has been reported pruritus to respond to antihistamine therapy in many patients sug-
to result in improved outcomes, pulmonary and echocardiographic gests that abnormally high histamine levels probably do not constitute
findings, as well as correction of cytokine dysregulation in MPN the sole factor in its development.
patients with pulmonary hypertension. Iron deficiency has also been implicated as a factor contributing
As many as 30–40% of patients with PV experience some sort of to pruritus in PV patients who are almost invariably iron deficient.
hemorrhagic event, which can be relatively trivial, such as epistaxis Iron-substitution therapy has resulted in symptomatic improvement,
or gingival hemorrhage, or can be life-threatening, such as gastro- but this approach is less than optimal because it frequently results in
intestinal hemorrhage or hematomas involving vital organs. The uncontrollable erythrocytosis. Ruxolitinib therapy has been reported
gastrointestinal tract is a frequent site of hemorrhagic complications to be effective in alleviating the patient’s aquagenic pruritis in 80%
because patients with PV are predisposed to portal vein thrombosis of patients.
and resultant variceal bleeding and peptic ulcer disease. Gastroduo- The development of post-PV MF was increased with prolonged
denal erosions and ulcers, and Helicobacter pylori infection are all duration of disease and is directly related to the duration of long-term
significantly more common in PV patients than in control patients follow-up, but the influence of the modality used to treat the initial
with dyspepsia. This may be partly attributable to altered mucosal PV phase of the disease on the rate of transformation to this more
blood flow as a result of increased plasma viscosity or increased his- accelerated form of the disease remains uncertain. Post-PV MF
tamine release caused by peripheral blood basophilia. Cerebral should be considered the natural evolution of PV. Criteria for the
hemorrhage is a common cause of morbidity and mortality. Bleeding diagnosis of post-PV MF have been established (Table 68.2) and can
events frequently occur with the use of aspirin or other nonsteroidal be used as a guide for documenting this transition in disease pheno-
antiinflammatory agents; an association between the hemorrhage and type, which in reality represents a point in the continuum of PV. For
the use of high doses of these platelet-paralyzing drugs has been made patients with disease duration greater than 10 years, the hazard ratio
in almost one-third of such instances. Low-dose aspirin therapy has, was 15.24 (95% CI: 4.22–55.06; p < .0001). The median interval
however, been reported not to lead to an increased incidence of between the diagnosis of PV and the development of post-PV MF is
life-threatening hemorrhagic events. Spontaneous bleeding in patients 13 years. Post-PV MF is characterized by (1) increasing splenomegaly;
with PV is relatively rare, although spontaneous retropharyngeal
hematomas leading to acute upper airway obstruction or hematomas
in the groin or retroperitoneum have been reported.
Patients with PV who undergo surgical procedures are at a very International Working Group for Myelofibrosis
high risk of developing postoperative complications. In one series of TABLE Research and Recommended Treatment Criteria for
68.2
62 major operations on 54 patients with PV, postoperative complica- Post-Polycythemia Vera Myelofibrosis
tions occurred in 49% of patients; 52% of complications were from
hemorrhage, 18% from thrombosis, and 14% from hemorrhage and Required Criteria
thrombosis. The postoperative mortality rate in this patient popula- 1. Documentation of a previous diagnosis of polycythemia vera as
tion was 18%. In another series of 15 patients, five had serious defined by the WHO criteria
complications secondary to thrombosis and hemorrhage. A study by 2. Bone marrow fibrosis grade 2–3 (on 0–3 scale) or grade 3–4 (on
an Italian group retrospectively evaluated 311 surgical interventions 0–4 scale)
in 105 patients with PV and 150 with ET: 24 arterial or venous Additional Criteria (Two Are Required)
thromboses (7.7%), 23 major hemorrhages (7.3%), and five surgery- 1. Anemia or sustained loss of requirement of either phlebotomy (in
related deaths (1.6%) were observed within 3 months of the proce- the absence of cytoreductive therapy) or cytoreductive treatment for
dure. PV patients with uncontrolled erythrocytosis before surgery erythrocytosis
have been shown to have the highest complication rate. Patients with 2. A leukoerythroblastic peripheral blood picture
inadequately controlled disease had a 79% incidence of complica- 3. Increasing splenomegaly defined as either an increase in palpable
tions, but in those with adequate hematologic control before surgery, splenomegaly of ≥5 cm (distance of the tip of the spleen from the
the rate of perioperative and postoperative complications was reduced left costal margin) or the appearance of a newly palpable
to 28%. In addition, the duration of disease control was an important splenomegaly
factor in decreasing surgical risk; a prolonged period of effective 4. Development of ≥one of three constitutional symptoms: >10%
disease control before surgery reduced the complication rate to 5%. weight loss in 6 months, night sweats, unexplained fever (>37.5°C)
Complication rates after surgery can therefore be dramatically reduced WHO, World Health Organization.
by appropriate therapeutic interventions with normalization of blood Adapted from Proposed criteria for the diagnosis of post-polycythemia vera and
counts. The chief deterrent to such an approach has been the failure post-essential thrombocythemia myelofibrosis: A consensus statement from the
by physicians to recognize the risk associated with PV in the surgical international working group for myelofibrosis research and treatment. Leukemia
22:437, 2008.
setting.