Page 1264 - Hematology_ Basic Principles and Practice ( PDFDrive )

1110 Part VII Hematologic Malignancies

circulating platelets appears to favor the adsorption of larger von The platelet activation observed in ET has also been linked to Src,
Willebrand multimers onto platelet membranes, resulting in their which is a nonreceptor tyrosine kinase particularly abundant in
removal from the circulation and their subsequent degradation. platelets. In thrombin-stimulated platelets, Src kinase is required for
Platelets in patients with ET have been known for a considerable platelet aggregation. This preactivation of Src that is characteristic of
time to be qualitatively abnormal. Although both increased and ET and the related platelet hyperactivity is likely to account for the
decreased platelet reactivity has been described, these findings have hypercoagulable state that is emblematic of ET. Recent in vitro
not been definitively associated with thrombohemorrhagic complica- studies also implicate JAK2V617F-driven heparinase overexpression
tions with two noteworthy exceptions—erythromelalgia, in which in ET as a novel thrombotic mechanism. Heparinase has previously
the prompt relief of symptoms by cyclooxygenase inhibitors provides been shown to complex and enhance the activity of tissue factor,
direct evidence that prostaglandins play a role in the development of resulting in activation of the coagulation cascade.
vascular occlusion, and acquired von Willebrand syndrome, which is Microvascular thrombosis causing digital or central nervous
a major cause of bleeding in patients with ET. system ischemia leads to a variety of clinical syndromes closely associ-
Abnormal platelet aggregation has been reported in 35–100% of ated with ET. The survival of platelets in ET patients with erythro-
patients with ET. The majority of such studies have used conventional melalgia and thrombosis has been shown to be reduced. Thrombosis
platelet aggregation studies performed on platelet-rich plasma. The in this setting is associated with an increased platelet turnover. Treat-
simultaneous measurement of platelet aggregation and adenosine ment of erythromelalgia with aspirin increased mean platelet survival
triphosphate–dense granule release by whole-blood platelet lumiag- from 4.0 ± 0.3 days to 6.9 ± 0.4 days and was associated with a
gregometry has been used to study platelet function in ET patients significant elevation of platelet numbers. These findings suggest that
with the hope of identifying patients at a risk of developing throm- erythromelalgia results from platelet-mediated thrombosis of the
bosis. A prospective analysis of large cohorts of patients has not been arterial microvasculature of the extremities. Complete correction of
performed to confirm the utility of such assays. Platelets derived from this ischemic circulatory defect is associated with the use of platelet
patients with ET and PV have been shown to contain a large propor- cyclooxygenase inhibitors, such as aspirin and indomethacin. Agents
tion of immature platelets that have been recently released from the that do not inhibit platelet cyclooxygenase, such as coumadin, sodium
BM. Such immature platelets have increased hemostatic activity, as salicylate, dipyridamole, sulfinpyrazone, and ticlopidine, are not
demonstrated by a heightened response to thrombin and greater active in the treatment of this disorder.
expression of P-selectin. Hydroxyurea has been shown to be capable One intriguing explanation for the increased risk of thrombosis
of reducing the number of immature platelets in ET, which might in patients with ET has been the observation that the total amount
partly be responsible for the reduced thrombotic risk associated with of thrombin generated on the platelet surfaces of patients with ET is
its use. markedly greater than that generated on the platelet surfaces of
Abnormal aggregation studies have not been successful in predict- normal control participants or patients with reactive thrombocytosis.
ing the incidence of episodes of hemorrhage or thrombosis. In ET, The molecular basis of this abnormality has not been defined.
platelet aggregation is classically defective in response to epinephrine, Increased numbers of platelet microparticles, as well as increased
adenosine diphosphate (ADP), and collagen but is usually normal platelet–neutrophil and platelet–monocyte complexes, have been
with arachidonic acid and ristocetin. Characteristically, in ET, the observed in patients with ET. Platelet microparticles support throm-
first wave of aggregation is diminished, and the second wave of bin generation and leukocyte activation. Increased numbers of
aggregation is absent in response to epinephrine. Interestingly, prein- platelet microparticles have been associated with the development of
cubation of ET platelets with thrombopoietin partly corrects the vascular thrombosis.
impaired aggregation in response to epinephrine, ADP, and collagen. Recently, in vivo leukocyte activation has been shown to occur in
An acquired form of platelet storage pool disease occurs frequently ET and to be associated with signs of activation of both the coagula-
in ET. Platelet α-granule content and the release of the content of tion cascade and endothelial cells. Such platelet and leukocyte activa-
granules are abnormal, resulting in elevated plasma levels of platelet tion may play a role in the generation of the prethrombotic state that
factor-4 and β-thromboglobulin. characterizes ET. Interestingly, the presence of the JAK2 mutation is
Numerous individual functional platelet abnormalities have been associated with a greater degree of platelet and leukocyte activation.
demonstrated. A defect in the metabolism of arachidonic acid by Activated neutrophils are able to bind platelets, which triggers the
lipoxygenase has been documented, as have decreased numbers of expression of tissue factor, as well as endothelial cell activation and
platelet receptors for prostaglandin D 2 and adrenergic receptors for damage. From a clinical point of view, several studies have demon-
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epinephrine. Platelets from patients with thrombotic episodes have strated that an increased leukocyte count (>11,000 × 10 ) in patients
been found to be capable of increased generation of thromboxanes with ET is an independent risk factor for developing arterial throm-
and to have an increased affinity for fibrinogen. Elevations in bosis, especially myocardial infarction, and is associated with an
β-thromboglobulin and serum thromboxane levels in ET patients are inferior survival rate. Therefore, an important role for leukocytes in
validated indices of enhanced in vivo platelet activation and possibly the pathogenesis of thrombosis in ET is becoming more evident.
thrombin generation. Such abnormalities are not present in patients Direct involvement of endothelial cells of MPN patients by
with secondary thrombocytosis and may provide some explanation JAK2V617F has been reported by several groups, which might lead
for the high incidence of thrombosis associated with ET. The anti- to endothelial dysfunction in subsets of MPN patients, further
thrombotic activity of aspirin has been attributed to its ability to enhancing the thrombotic predisposition to the development of
permanently and selectively inactivate platelet cyclooxygenase-1 splanchnic vein thromboses.
(COX-1), thereby blocking thromboxane biosynthesis. This action
has served as the rationale for the widespread use of aspirin in ET
patients for thrombosis prophylaxis in the absence of valid controlled CLINICAL MANIFESTATIONS
clinical trials. COX-2 has been shown to be overexpressed by the
megakaryocytes and platelets of ET patients; COX-2 can also con- The presenting symptoms of patients with ET are quite variable.
tribute to the enhanced biosynthesis of thromboxanes in ET. Low- Many patients (12–67%) reach medical attention fortuitously as a
dose aspirin can only partially correct this enhanced thromboxane result of the extreme degree of thrombocytosis detected when obtain-
synthesis, likely because of the increased COX-2 activity associated ing a routine blood cell count. Most patients present with symptoms
with the increased rate of platelet generation associated with ET, related to small- or large-vessel thrombosis, or minor bleeding. The
providing the rationale for the use of more aggressive aspirin schedul- thrombotic events at diagnosis and during follow-up occurred at rates
ing or the addition of thromboxane receptor A 2 antagonists to reduce of 10–29% and 8–31%, respectively. In general, arterial events pre-
the incidence of thrombotic events. Although laboratory data indicate dominate over venous events. Presentation with a major bleeding
a rationale for twice-daily dosing of aspirin, prospective clinical data episode is unusual. Neurologic complications are common. Table
for this approach are lacking. 69.1 lists representative neurologic complaints, of which headache