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2080 Part XII: Hemostasis and Thrombosis Chapter 121: Acquired Qualitative Platelet Disorders 2081

neuropathic components. 297,298 It has been difficult to predict the risk of erythromelalgia or with digital or cerebrovascular ischemia. 231,232,298,322
bleeding or thrombosis in an asymptomatic patient, but an increase in However, the evidence to date remains largely anecdotal, and aspirin
229
leukocyte count 221,232,235 or the number of reticulated platelets in patients can exacerbate a bleeding tendency in patients with myeloproliferative
with thrombocytosis, thought to reflect an increase in platelet turnover, neoplasms, particularly in those individuals with acquired von Wille-
299
has been associated with an increased risk for thrombosis. Vascu- brand syndrome or with World Health Organization (WHO)-defined
lar complications are also more likely to occur in patients older than prefibrotic myelofibrosis masquerading as essential thrombocythe-
60 years of age and, most importantly, in patients with other cardiovas- mia. 221,301,303,323 Consequently, even though a single, daily, low-dose
cular risk factors, such as diabetes, hypertension, hyperlipidemia and aspirin is recommended for thromboprophylaxis in essential thrombo-
obesity. 221,300–303 cythemia, a risk-adapted approach is advised. 221,305 In addition, because
platelet volume and turnover may be enhanced in essential thrombo-
Therapy cythemia and polycythemia vera, the platelets of some individuals may
Therapy should be risk-adapted and considered for symptomatic not achieve total COX-1 inhibition with a single daily dose of aspirin.
patients, for patients with a history of thrombosis or bleeding, for In such circumstances, 12-hour dosing may be considered, although
those with standard cardiovascular risk factors, for patients older than this protocol has not been formally evaluated in a prospective clinical
60 years of age, and for individuals about to undergo surgery. Readers trial. 324,325
are referred to expert recommendations for a summary of the treatment In a double-blind, placebo-controlled study of 518 patients with
of essential thrombocythemia and polycythemia vera, with particular polycythemia vera who were judged to have no contraindications to
relevance to risk factors for hemostasis and thrombosis (Chaps. 84 and daily low-dose (100 mg) aspirin, subjects in the aspirin arm exhibited a
85). 221,232,301,303–306 Treatment includes phlebotomy to correct the poly- reduced risk of nonfatal arterial and venous cardiovascular end points.
cythemia and maintenance of a normal red cell mass, with the goal to Although aspirin was well-tolerated, there was no effect of aspirin on
307
326
achieve a hematocrit of less than 45 percent, 235,307,308 as well as therapy overall and cardiovascular mortality. As has been noted, this study
of the underlying disorder. 228,232,309,310 Platelet count reduction to less population was heavily pretreated to normalize the platelet count,
than 400 × 10 /L in patients with thrombocytosis, either by platelet- although some individuals may have had residual elevations in red cell
9
pheresis or cytoreductive agents, has been considered to be a target mass. Consequently, the safety and efficacy of aspirin as observed in this
value associated with clinical improvement in patients with essential study may not be relevant to all patients with polycythemia vera.
thrombocythemia. 228,302,311 Pregnant women with essential thrombocythemia or polycythe-
Effective cytoreductive agents include the ribonuclease reductase mia vera pose special challenges because of an apparent increased risk
inhibitor hydroxyurea, interferon-α (most recently the pegylated of unsuccessful pregnancy, thrombotic or bleeding complications, and
312
form of interferon alfa-2a), and anagrelide. 301,311,313,314 In a prospective, potential teratogenicity of hydroxyurea. 305,327 In essential thrombocythe-
randomized trial of 114 “high-risk” individuals with essential thrombo- mia, the risk of first trimester miscarriages may be higher among women
328
cythemia who were either older than 60 years of age or had a previous with the JAK2 (V617F) mutation. Although evidence-based recom-
history of thrombosis, hydroxyurea significantly reduced the incidence mendations are not available, Barbui and Finazzi recommend a risk-
312
of new thrombosis from 24.0 to 3.6 percent. Anagrelide, an imidazo- adapted approach to management in pregnancy. High-risk women are
quinazoline derivative, is thought to decrease platelet counts by impair- defined as those with previous major bleeding or thrombotic episodes,
315
ing megakaryocyte maturation. Anagrelide has essentially no effect previous pregnancy complications, or a platelet count greater than
329
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on red and white cell counts and is not known to be leukemogenic. 1500 × 10 /L. Low-risk individuals are recommended to be main-
Nevertheless, 10 to 20 percent of patients experience neurologic, gas- tained at a hematocrit of less than 45 percent and to receive aspirin,
trointestinal, and cardiac side effects, in particular fluid retention, often 100 mg/day during pregnancy and low-molecular-weight heparin, 4000
necessitating discontinuation of the drug. 314,316,317 When hydroxyurea U/day for 6 weeks after delivery. Interferon-α, rather than aspirin, is
and anagrelide were compared head-to-head in a randomized trial of considered if there has been previous major bleeding or if platelets
9
809 patients with essential thrombocythemia (all of whom were tak- are greater than 1500 × 10 /L. High-risk patients are recommended to
ing aspirin), subjects in the anagrelide group showed an increased rate receive low-molecular-weight heparin throughout pregnancy.
of arterial thrombosis, major bleeding, and transformation to myelo-
fibrosis relative to the group treated with hydroxyurea; however, the LEUKEMIAS AND MYELODYSPLASTIC
anagrelide group showed a relative decreased rate of venous throm-
318
bosis. Progression to myelofibrosis despite treatment with anagre- SYNDROMES
lide has also been observed in a phase II study. However, in a newer, Clinical and Laboratory Features
319
although relatively small, randomized, phase III study of 259 previously The most frequent cause of bleeding in patients with leukemia or a myel-
untreated high-risk patients with essential thrombocythemia, anagre- odysplastic syndrome is thrombocytopenia. However, abnormal platelet
lide was found to be noninferior to hydroxyurea in the prevention of function in vitro has been described in acute myelogenous leukemia,
320
arterial or venous thrombotic complications. It should be noted that and in some patients this may be clinically significant. In acute myel-
this study used a long-lasting anagrelide drug that is not currently avail- ogenous leukemia and its variants, platelets may be larger than normal,
able in the United States. During an episode of acute bleeding in the abnormally shaped, and exhibit a marked variation in the number of
chronic myeloproliferative neoplasms, DDAVP infusion may temporar- granules. There may be decreased aggregation and serotonin release in
ily improve hemostasis if the patient has an acquired storage pool defect response to ADP, epinephrine, or collagen, decreased surface P-selectin
or acquired von Willebrand syndrome. 252,321 In the case of acquired von expression in response to platelet activation via the PAR-1 thrombin
Willebrand syndrome, cytoreduction to reduce the platelet count may receptor, and decreased platelet procoagulant activity. These functional
also ameliorate the process, although this may take time and require abnormalities may be caused by either acquired storage pool deficiency
more temporizing interventions including DDAVP or factor VIII/VWF or a defect in the process of platelet activation through one or more
concentrates. 234 signaling pathways. 330–334 These defects are intrinsic to the platelet and
Low-dose aspirin (~80 to 100 mg/day) may be useful in patients probably relate to the fact that the megakaryocytes from which platelets
with essential thrombocythemia and thrombosis, particularly those with were derived originated from a leukemic stem cell. Indeed, in a familial

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