CHAPTER 118 THROMBOCYTOSIS AND ESSENTIAL THROMBOCYTHEMIA
CHAPTER 118 THROMBOCYTOSIS AND ESSENTIAL THROMBOCYTHEMIA
ANDREW I. SCHAFER
Definition and History
Etiology and Pathogenesis
Essential Thrombocythemia (Clonal Thrombocytosis)
Reactive (Secondary) Thrombocytosis
Bleeding and Thrombotic Complications
Blood and Marrow Findings
Clinical Tests of Hemostasis
Specific Qualitative Platelet Abnormalities
Diagnostic Criteria for Essential Thrombocythemia
Reactive (Secondary) Thrombocytosis
Therapy, Course, and Prognosis
Course and Prognosis
The three major pathophysiological causes of thrombocytosis are (1) clonal, including essential (or primary) thrombocythemia and other myeloproliferative disorders; (2) familial, including rare cases of nonclonal myeloproliferation due to thrombopoietin mutations; and (3) reactive, in which thrombocytosis occurs secondary to a variety of acute and chronic clinical conditions. Essential thrombocythemia is often discovered incidentally on blood counts in asymptomatic individuals and is largely a diagnosis of exclusion. Major causes of morbidity and mortality are bleeding and thrombotic complications, the latter most commonly involving the arterial circulation. Reactive thrombocytosis usually does not cause these complications and does not require treatment. The indications for therapeutic intervention in essential thrombocythemia remain unsettled. Chemotherapy to reduce the platelet count in essential thrombocythemia is generally indicated in patients with previous bleeding or thrombotic episodes or those who are at high risk for such complications. The most commonly used drugs for cytoreduction of the platelet count are hydroxyurea, anagrelide, and recombinant interferon-a. The use of antiplatelet agents is indicated in patients with essential thrombocythemia who have had arterial thrombotic or ischemic problems.
Acronyms and abbreviations that appear in this chapter include: CML, chronic myelogenous leukemia; IL, interleukin.
DEFINITION AND HISTORY
The upper limit of the normal platelet count is generally considered to be between 350,000/µl (350 × 109/liter) and 450,000/µl (450 × 109/liter), varying in different laboratories. The causes of thrombocytosis, in which the platelet count exceeds this upper limit, can be broadly categorized as (1) clonal, including essential thrombocythemia and other myeloproliferative disorders; (2) familial; and (3) reactive, or secondary (Table 118-1).
TABLE 118-1 MAJOR CAUSES OF THROMBOCYTOSIS
Essential (primary) thrombocythemia is one of a group of related chronic myeloproliferative disorders that also includes polycythemia vera, chronic myelogenous leukemia, and myeloid metaplasia with or without myelofibrosis. The earliest descriptions of essential thrombocythemia by di Guglielmo in 1920 and by Epstein and Goedel in 19342 represented, in retrospect, thrombocytosis in association with other disorders. This historical misclassification underscores the diagnostic uncertainty that may occur in patients with thrombocytosis.3 In 1960 essential thrombocythemia was established as a separate disease entity on a clinicopathologic basis.4,5
ETIOLOGY AND PATHOGENESIS
ESSENTIAL THROMBOCYTHEMIA (CLONAL THROMBOCYTOSIS)
As one of the myeloproliferative syndromes, essential thrombocythemia is a clonal disorder of the multipotential hemopoietic stem cell. The clonal nature of essential thrombocythemia was established by the finding of a single glucose-6-phosphate dehydrogenase (G-6-PD) isoenzyme expressed in all blood cell lines of women with thrombocythemia who were coincidentally heterozygous for two types of G-6-PD, enzymes “A” and “B.”6 Furthermore, the same cytogenetic abnormality was found in both the erythroid and the granulocytic precursors of a patient with thrombocythemia.7 More recently, clonality in essential thrombocythemia and the other myeloproliferative disorders was confirmed by X-chromosome inactivation analysis of restriction fragment length polymorphisms (RFLP).8,9 and 10
In view of the multipotential stem cell origin of essential thrombocythemia, the reason for its predominant phenotypic expression in the megakaryocyte-platelet lineage is unclear. It may be due to the preferential responsiveness of the abnormal clone to regulatory factors that favor its differentiation into the megakaryocyte-platelet line.11 Alternatively, the mutation(s) may occur in a single multipotential hemopoietic stem cell, the lineage potential of which has become restricted to differentiation primarily into platelets.12
Increased numbers of colony-forming units composed of megakaryocytes (CFU-MEG) have been cultured from the blood or marrow of patients with essential thrombocythemia, compared with control subjects or patients with secondary thrombocytosis.13,14,15,16,17,18 and 19 Furthermore, megakaryocyte colony growth in the absence of exogenously added growth factor is usually present in patients with essential thrombocythemia, although it is unclear if this represents truly autonomous megakaryocytopoiesis or only increased sensitivity of the abnormal thrombocythemia clone to exogenous sources of megakaryocyte colony-stimulating activity.13,14,15,16,17,18,19 and 20 These quantitative changes may be accompanied by abnormal CFU-MEG colony size and nuclear endoreduplication.16
Thrombopoietin,21 the ligand for the megakaryocytic growth factor receptor, c-mpl, the human homolog of the v-mpl (“murine myeloproliferative leukemia virus”), is now recognized as the major humoral regulator of megakaryocytopoiesis and platelet production. While thrombopoietin supports the entire continuum of megakaryocyte development from stem cell to platelet production, other cytokines (e.g., steel factor, IL-3, IL-6, IL-11) also exert actions at different stages, probably in synergy with thrombopoietin (see Chap. 111). Plasma concentrations of thrombopoietin vary inversely with the platelet count in patients with marrow failure.22 Mature platelets themselves appear to have an important role in regulating plasma thrombopoietin levels. Platelets have receptors for thrombopoietin (c-mpl) and remove it from plasma. Thus, in thrombocytopenic states, the high free plasma thrombopoietin levels that result from reduced thrombopoietin binding by the reduced circulating platelet mass should stimulate megakaryocytopoiesis; conversely, in states of thrombocytosis, depletion of free plasma thrombopoietin should decrease megakaryocytopoiesis. In both cases this modulatory mechanism is designed to restore steady-state platelet production. However, unlike the relationship between polycythemia vera and erythropoietin levels, thrombopoietin levels are normal or even elevated in essential thrombocythemia23,24,25 and 26 despite the increased platelet and megakaryocyte mass. The deregulated circulating plasma levels of thrombopoietin in essential thrombocythemia may result from overproduction of endogenous thrombopoietin and/or abnormal thrombopoietin binding and consumption by the defective platelets and megakaryocytes of essential thrombocythemia.27 In support of the latter, the expression of platelet c-mpl has been found to be strikingly reduced in essential thrombocythemia.28
Rare cases of familial occurrence of thrombocytosis have been reported, generally inherited by autosomal dominant transmission. Specific mutations in the thrombopoietin gene, including exon skipping and a single-base deletion in the 5′-untranslated region of the gene, have been described in these families; these mutations lead to markedly elevated plasma thrombopoietin levels.29,30 Thus, these cases are probably nonclonal myeloproliferative disorders. Indeed, it is possible that the inappropriately elevated thrombopoietin levels in some cases of apparently essential thrombocythemia may also be due to thrombopoietin gene mutations.
REACTIVE (SECONDARY) THROMBOCYTOSIS
The mechanisms of reactive thrombocytosis are not well defined and are likely to be as complex and diverse as the underlying disorders that cause it. For example, increased megakaryocytopoiesis and thrombocytosis may result from the elevated levels of IL-6 and other cytokines that accompany many inflammatory disorders.31 Catechol-amine-mediated thrombocytosis may result from the release of platelets from the spleen.32,33 Thrombocytosis associated with the conditions listed in Table 118-1 may persist for prolonged periods of time and resolve only with effective treatment for the disorder or elimination of the inciting stimulus. “Rebound” thrombocytosis following recovery from bone marrow suppression generally peaks 10 to 14 days after withdrawal of the offending drug (e.g., alcohol34) or replacement therapy for the cause of thrombocytopenia (e.g., for cobalamin deficiency35). The platelet count may also transiently rise above normal limits with effective treatment for immune thrombocytopenic purpura.36 Following splenectomy for any condition, the platelet count typically rises within the first week to 1,000,000/µl or higher and then gradually returns to normal within about 2 months. Reasons for persistent or extreme postsplenectomy thrombocytosis include persistent anemia or unmasking of previously unrecognized essential thrombocythemia and other myeloproliferative disorders.
In the past, essential thrombocythemia was considered to be the least common of the myeloproliferative disorders, typically affecting patients between the ages of 50 and 70, with an equal sex distribution. However, with frequent inclusion of platelet counts in automated blood analysis, more asymptomatic patients are being uncovered with the incidental finding of thrombocytosis. Furthermore, the diagnosis of essential thrombocythemia is being made increasingly in younger individuals. The disease is occasionally found in childhood,37 and as noted above, rare familial cases have been reported.29,30,38 In contrast to some of the other myeloproliferative disorders, constitutional or hypermetabolic symptoms such as fever, sweats, and weight loss are very uncommon in essential thrombocythemia.
Physical findings are limited usually to mild splenomegaly, which is present in about 40 percent of the patients. Echocardiography may reveal aortic and mitral valvular lesions, including leaflet thickening and vegetations, similar to those described in nonbacterial thrombotic endocarditis.39 The relationship of cardiac valve lesions to thromboembolic complications in essential thrombocythemia is unclear.
BLEEDING AND THROMBOTIC COMPLICATIONS
Bleeding and thrombotic complications are major causes of morbidity and mortality in essential thrombocythemia, as in the other myeloproliferative disorders.40,41,42,43,44 The incidence of these hemostatic complications is unknown; it varies markedly in different series. Some symptomatic patients may exhibit an exclusive pattern of either bleeding or thrombotic problems, whereas others appear to be paradoxically predisposed to both types of complications during the course of their disease. Some studies have suggested that older patients are at markedly increased risk of hemostatic complications,45,46 while younger patients are relatively protected from these problems.47 However, other reports have documented no age-related differences48,49 and have noted serious bleeding and thrombotic episodes in younger patients.50,51
Therapeutic intervention in essential thrombocythemia (see “Therapy, Course, and Prognosis,” below) should be guided by the underlying risk of thrombotic or bleeding complications in any individual patient. Table 118-2 summarizes the emerging consensus of risks of either thrombosis or bleeding, as previously reviewed.52,53,54 and 55 Risks of thrombosis in essential thrombocythemia include a previous history of thrombosis, associated cardiovascular risk factors (e.g., smoking), and probably advanced age. Risks of bleeding in these patients include extreme thrombocytosis (platelet count >2,000,000/µl) and the use of aspirin and possibly other nonsteroidal antiinflammatory drugs. Thrombohemorrhagic complications may occur less frequently in certain populations, such as in China.56
TABLE 118-2 RISKS OF THROMBOHEMORRHAGIC COMPLICATIONS IN ESSENTIAL THROMBOCYTHEMIA
Bleeding complications of essential thrombocythemia are similar in nature to those seen in platelet or vascular disorders, occurring in superficial locations either spontaneously or after minimal trauma. The most common sites of hemorrhage are mucosal and gastrointestinal, although cutaneous, genitourinary tract, and postoperative bleeding are also seen.43 The use of aspirin, which has been found to cause exaggerated prolongations of the bleeding time in patients with myeloproliferative disorders,57 may lead to serious bleeding complications in occasional cases.58
Arterial thrombotic complications occur more frequently than venous thrombosis in essential thrombocythemia, although about 25 percent of all thrombotic events in these patients are deep vein thrombosis of the lower extremities.43 The most common sites of arterial thrombosis in essential thrombocythemia involve the cerebrovascular, peripheral vascular, and coronary arterial circulations. Patients are particularly predisposed to certain specific types of thrombotic events, as described below.
Erythromelalgia and Digital Microvascular Ischemia Erythromelalgia is characterized by intense burning or throbbing pain in a patchy distribution in the extremities, most prominently involving the feet.59,60,61 and 62 The pain tends to be exacerbated by heat, exercise, and dependency and to be relieved by cold exposure and elevation of the extremity. It is often accompanied by warmth, duskiness, and mottled erythema of the involved areas, sometimes resembling livedo reticularis. Erythromelalgia may be occasionally confused with Raynaud syndrome, reflex sympathetic dystrophy, shoulder-hand syndrome, or causalgia.62 Histopathologic examination of biopsies of the affected areas typically shows arterial endothelial swelling, fibromuscular intimal proliferation, and vascular occlusion caused predominantly by platelet thrombi.63,64
Signs of digital microvascular ischemia, primarily involving the toes, may develop in essential thrombocythemia independently of erythromelalgia. Painful vascular insufficiency may progress to frank gangrene and necrosis of the digits unless treatment is promptly instituted. Since thrombosis involves the small vessels, physical examination usually reveals normal peripheral pulses, and arteriography shows patent major vessels.65 Erythromelalgia and digital ischemia in patients often respond promptly and dramatically to aspirin and reduction of the elevated platelet count.65,66 and 67
Cerebrovascular ischemia A wide spectrum of neurologic manifestations in essential thrombocythemia may be caused by cerebrovascular ischemia.43,68,69,70,71,72 and 73 Central nervous system involvement may take the form of nonspecific symptoms, such as headache and dizziness; a vague sense of a decrease in mental acuity; or focal neurologic signs, such as anterior or posterior cerebral artery transient ischemic attacks, seizures, or retinal artery occlusion. Ischemic stroke may be the presenting manifestation of essential thrombocythemia.74 As in the digital ischemia syndromes, cerebrovascular ischemia may be relieved by aspirin and platelet reduction.
Recurrent Abortions and Fetal Growth Retardation Multiple placental infarctions, presumably caused by platelet thrombi, may result in placental insufficiency in some pregnant women with essential thrombocythemia.75,76 This may lead to recurrent spontaneous abortions, fetal growth retardation, premature deliveries, or abruptio placentae.75,76,77 and 78 These serious consequences have led to the use of aspirin during pregnancy in women with essential thrombocythemia.77 However, the successful outcome of pregnancy in the absence of any specific therapy79,80 and the lack of clinical trials to evaluate treatment modalities make specific recommendations difficult. No correlation has been found between the outcome of the pregnancy and the degree of maternal thrombocytosis, presence of disease complications, or specific therapy for thrombocythemia. To reduce the risk of maternal or neonatal bleeding complications, aspirin should be avoided for at least one week prior to delivery. Pregnancy does not adversely affect the natural history of essential thrombocythemia.81
Hepatic and Portal Vein Thromboses The myeloproliferative disorders are the most frequently identifiable underlying etiologies in patients who present with hepatic vein thrombosis (Budd-Chiari syndrome).82,83 The incidence of myeloproliferative disorders associated with either hepatic or portal vein thrombosis may, in fact, be underestimated; such patients have been shown to have erythropoietin-independent erythroid colony growth in marrow cultures, a diagnostic marker of a stem cell abnormality, even in the absence of any overt clinical or hematologic manifestations of a myeloproliferative disorder.83,84 and 85 Hepatic and portal vein thromboses are most commonly associated with polycythemia vera, but a number of cases associated with essential thrombocythemia have also been described.42
BLOOD AND MARROW FINDINGS
Untreated patients with essential thrombocythemia have platelet counts that may range from only slightly above the normal limits to several million per microliter. Some patients may have mild leukocytosis and mild anemia. Platelet morphology on blood films shows large, pale blue staining, hypogranular platelets, and occasional nucleated megakaryocyte fragments that may have a lymphoblastoid appearance. Increased platelet turnover in essential thrombocythemia is indicated by the finding of increased reticulated platelets (young platelets) in the circulation, which can be detected by flow cytometric analysis of platelet RNA. While both the percentage and the absolute number of reticulated platelets in blood are elevated in patients with essential thrombocythemia compared with healthy individuals, it is unclear whether or not this finding can distinguish essential thrombocythemia from secondary (reactive) thrombocytosis.86,87
As noted above, serum thrombopoietin levels are generally normal or even elevated in clonal thrombocythemia; thrombopoietin levels do not correlate with platelet count in these patients. Serum thrombopoietin levels are also usually elevated in reactive thrombocytosis, and it is not clear whether or not this test can discriminate these patients from those with essential thrombocythemia.24,25 Plasma levels of IL-6 and C-reactive protein are low or undetectable in clonal thrombocythemia, while they may be elevated in secondary thrombocytosis, which often accompanies acute and chronic inflammatory states.31
Pseudohyperkalemia may be found in patients with extreme thrombocytosis or leukocytosis. It is diagnosed in thrombocytosis states when the serum potassium concentration exceeds the plasma potassium concentration and is caused by the release of intracellular potassium during the process of blood clotting in vitro.88
Marrow pathology in essential thrombocythemia characteristically reveals increased cellularity with megakaryocytic hyperplasia. There are frequently giant megakaryocytes with increased ploidy that occur in clusters.89,90 Significant dysplasia of the megakaryocytes is unusual, but large masses of platelet debris (“platelet drifts”) are typically seen in marrow samples.91 Most patients with essential thrombocythemia have no cytogenetic abnormalities using conventional techniques.92 However, some patients who otherwise meet the diagnostic criteria of essential thrombocythemia are found to have the Philadelphia chromosome on cytogenetic analysis of the marrow.93 Such patients generally do not have pronounced leukocytosis or other characteristic clinical features of CML. However, the natural history of their disease is more like that of CML than that of essential thrombocythemia. Some patients with essential thrombocythemia are found to have the bcr/abl gene rearrangement in the absence of the Philadelphia chromosome, although the clinical implications of this are not clear at present.94
CLINICAL TESTS OF HEMOSTASIS
The bleeding time is prolonged in fewer than 20 percent of patients with essential thrombocythemia.40,72,78 This test generally does not correlate with the degree of thrombocytosis or specific platelet function abnormalities and it has not been found to predict reliably either a bleeding or a thrombotic tendency in patients with essential thrombocythemia.95,96 and 97
The platelet aggregation abnormalities in patients are variable. Reduced platelet responses to collagen, ADP, and arachidonic acid occur in less than one-third of cases.42 A characteristic aggregation abnormality is complete loss of platelet responsiveness to epinephrine. In contrast to platelet release defects (e.g., storage pool deficiency or aspirinlike defect), in which only the second wave of platelet aggregation is absent, even the primary wave of epinephrine-stimulated aggregation is often lost in essential thrombocythemia. An abnormal epinephrine-induced platelet response is the most frequent and sometimes the only abnormality on aggregometry; this unusual abnormality is also observed in other myeloproliferative disorders.40,42,72,78 Some patients have platelet hyperaggregability or spontaneous aggregation in vitro.72,98,99 and 100
SPECIFIC QUALITATIVE PLATELET ABNORMALITIES
A wide array of specific morphological, biochemical, and metabolic platelet defects has been described in patients with essential thrombocythemia.41 These abnormalities, shown in Fig. 118-1, include acquired von Willebrand disease,101,102 and 103 reduced a-adrenergic receptors associated with absent aggregation to epinephrine,104 acquired storage pool disease,97,105,106,107 and 108 impaired membrane procoagulant activity,95,109 selective deficiency of 12-lipoxygenase,110,111 abnormal membrane glycoproteins,112,113 increased Fc receptors,114 and reduced prostaglandin D2 receptors.115 Only some of these abnormalities are specific for the myeloproliferative disorders, and none of them have been directly demonstrated to be pathogenetically linked to clinical hemostatic complications.
FIGURE 118-1 Structural, biochemical, and metabolic abnormalities of platelets in essential thrombocythemia. At top is a schematic of a transected vessel wall; at bottom is a schematic of a single platelet. Abbreviations: PGD2, prostaglandin D2; b-TG, beta-thromboglobulin; AA, arachidonic acid; CO, cyclooxygenase; 12-LO, 12-lipoxygenase; PGG2 and PGH2, prostaglandins G2 and H2; TxA2, thromboxane A2; 12-HETE and 12-HPETE, 12-hydroxy- and hydroperoxy-5,8,10,14-eicosatetraenoic acid. (Reprinted with permission from Schafer.42)
DIAGNOSTIC CRITERIA FOR ESSENTIAL THROMBOCYTHEMIA
There are no tests that can be used to establish the diagnosis of essential thrombocythemia with certainty. The disease remains largely a diagnosis of exclusion. For these reasons, a set of diagnostic criteria for essential thrombocythemia (Table 118-3) has been proposed.116 The minimum platelet count of 600,000/µl to establish the diagnosis of essential thrombocythemia has been subsequently challenged.117 Thrombocythemia-related complications may occur in individual patients with only slight thrombocytosis or even with platelet counts in the upper normal range, and the natural history of these early stage essential thrombocythemia patients is comparable to that of patients who meet the original diagnostic criteria.117
TABLE 118-3 DIAGNOSTIC CRITERIA FOR ESSENTIAL THROMBOCYTHEMIA
Most of the diagnostic criteria listed in Table 118-3 were designed to differentiate essential thrombocythemia from other myeloproliferative disorders associated with thrombocytosis. Polycythemia vera with thrombocytosis can usually be readily distinguished from essential thrombocythemia by the finding of erythrocytosis and an elevated red cell mass. This disease may be masked by concomitant iron deficiency, which can further increase the platelet count, but a trial of iron therapy in such cases typically raises the hematocrit to polycythemic levels. As noted above, chronic myelogenous leukemia with associated thrombocytosis is sometimes misdiagnosed as essential thrombocythemia until its diagnostic cytogenetic or DNA abnormality is revealed. Myeloid metaplasia and myelofibrosis are characterized by more marked, frequently massive, splenomegaly; furthermore, in contrast to essential thrombocythemia, the blood film in myelofibrosis typically shows myelophthisic or leukoerythroblastic changes and the marrow biopsy shows fibrosis. Despite these characteristic distinctions in clinical presentation, however, some myeloproliferative disorders represent “overlap” syndromes that cannot be clearly categorized. Finally, essential thrombocythemia cannot be diagnosed without excluding possible causes of reactive (or secondary) thrombocytosis.
Reactive (Secondary) Thrombocytosis
A large number of diverse processes have been associated with reactive thrombocytosis (see Table 118-1). While many of these are active systemic diseases which dominate the clinical picture in these patients, in some individuals subclinical disorders (e.g. occult cancer) may be responsible for the secondary thrombocytosis. In the latter cases, reactive thrombocytosis is particularly difficult to distinguish from essential thrombocythemia.
Patients with reactive thrombocytosis generally do not have splenomegaly, unless enlargement of the spleen results from the underlying disease. It is now recognized that extreme thrombocytosis (platelet count >1,000,000/µl) by no means excludes a reactive or secondary process as its etiology. In fact, in a review of 280 consecutive hospitalized patients with reported platelet counts of greater than 1,000,000/µl, 82 percent were found to have reactive thrombocytosis and only 14 percent had myeloproliferative disorders.118 Platelet morphology and platelet function are typically normal in reactive thrombocytosis, in contrast to essential thrombocythemia. In general, reactive thrombocytosis, even when extreme, does not cause thrombotic or bleeding complications and hence does not require treatment (see “Therapy, Course, and Prognosis,” below).
THERAPY, COURSE, AND PROGNOSIS
The therapeutic options described below are designed specifically for patients with clonal thrombocytosis (essential thrombocythemia and thrombocytosis associated with other myeloproliferative disorders), not for those with secondary or reactive thrombocytosis. Many reports have attempted to link reactive thrombocytosis with thrombotic complications; however, the thrombotic events in these cases can be usually attributed to the underlying systemic disease (e.g., cancer, postoperative state) rather than to the secondary thrombocytosis per se. One exception might be the increased risk of thrombosis in patients who develop thrombocytosis following splenectomy for hemolytic anemias, most notably thalassemia, that are incompletely resolved by the surgical procedure.119,120 While it is important to identify and attempt to treat the underlying systemic disease, there is no convincing evidence that either therapy to reduce the platelet count or antiplatelet therapy is beneficial in patients with reactive thrombocytosis.
The pivotal therapeutic decision in essential thrombocythemia is whether or not treatment is required to reduce the elevated platelet count. This issue is controversial because of the paucity of prospective, controlled trials to determine the impact of platelet cytoreduction on morbidity and mortality in clonal thrombocythemia.
Although an association has been suggested between the platelet count in thrombocythemia and the occurrence of thrombotic complications,73 most retrospective studies have failed to support such a correlation.42,43,46,48,72,121 Nevertheless, one prospective study of “high-risk” patients with essential thrombocythemia (age over 60 and/or previous episodes of thrombosis) found that control of the platelet count to levels below 600,000/µl with hydroxyurea significantly reduced the incidence of thrombotic episodes over a median follow-up period of 27 months.54 In contrast to the unsettled indications for prophylactic platelet cytoreduction in asymptomatic patients with essential thrombocythemia, there is general consensus that lowering the platelet count in patients with active or recurrent bleeding or thrombosis may result in symptomatic improvement. The indication for prompt cytoreduction is particularly strong in patients who have microvascular digital65,66 or cerebrovascular71 ischemia syndromes.
When reduction of the platelet count is indicated, plateletpheresis122,123 and 124 is generally reserved for selected cases of acute and threatening thrombotic and hemostatic problems. Reduction of the platelet count by this method is transient and may be followed by a rebound increase in the thrombocytosis. Radiophosphorus and alkylating agents (e.g., melphalan, busulfan) have been largely abandoned because of their leukemogenic potential.125
Hydroxyurea, a nonalkylating myelosuppressive agent, is highly effective as initial therapy for essential thrombocythemia. Doses required to control thrombocytosis are generally 10 to 30 mg/kg per day. Blood counts should be checked within 7 days of initiating therapy and monitored frequently thereafter, since hydroxyurea can cause rapid myelosuppression. Maintenance doses should be individually adjusted according to blood counts. Continuous, orally administered daily treatment with this drug reduces the platelet count to less than 500,000/µl within 8 weeks in 80 percent of patients and provides long-term control without severe marrow toxicity or serious side effects.126 Painful but reversible leg ulceration may occur with long-term treatment with hydroxyurea.127 Hydroxyurea was not initially considered to be leukemogenic, although a statistically insignificant trend to an increased incidence of acute leukemia with its use was noted by the Polycythemia Vera Study Group.128 The leukemogenic potential of hydroxyurea, although not as great as with radiophosphorus or alkylating agents, has been confirmed in more recent studies129,130; this is an important consideration in deciding on long-term use of this drug in younger patients with essential thrombocythemia.
Anagrelide is effective in platelet cytoreduction in essential thrombocythemia, and is now an alternative first-line therapy. This quinazoline derivative can be given orally and reduces platelet counts by inhibiting marrow megakaryocyte maturation.131,132 The recommended starting dose is 0.5 mg q.i.d. or 1 mg b.i.d., with dosage adjustments made at weekly intervals when needed. The dose required to control the platelet count in average-sized adults is approximately 2.0 to 3.0 mg/day.133 The time to 50 percent reduction in the platelet count after the start of anagrelide therapy is approximately 11 days. Anagrelide reduces the platelet count without affecting the white blood count, although a small reduction in the hematocrit may be seen. Platelet counts are well controlled while patients are taking the drug, but its discontinuation leads to a rapid rise in the platelet count in most patients. Important adverse reactions that have been noted include neurologic and gastrointestinal symptoms, palpitations, and fluid retention.133,134
Recombinant interferon-a has also been demonstrated to be effective therapy for essential thrombocythemia.135,136,137 and 138 This drug suppresses proliferation of the abnormal megakaryocyte clone and results in a decrease in megakaryocyte size and ploidy during therapy. Platelet counts are reduced to the normal or near-normal range in most patients within 1 month of starting interferon therapy. An effective regimen has been to initially administer interferon subcutaneously at a dose of 3,000,000 units daily, with doses subsequently adjusted according to individual tolerance and response.139,140,141 and 142 Thereafter, suppression of the platelet count can be maintained for several years using lower doses of interferon administered by subcutaneous injection three times per week.139,141 Relapse of the thrombocytosis occurs after discontinuation of interferon.141 Severe flulike side effects are not infrequent but generally can be ameliorated by reduction of the interferon dose and by the use of acetaminophen. Interferon therapy is often accompanied by some reduction in the white blood count as well as the platelet count, but generally no effect on the hematocrit is noted. Although it is nonleukemogenic, the toxicity and cost associated with the long-term use of interferon-a make it unlikely to be used as first-line therapy in “low-risk” patients with essential thrombocythemia.143
Aspirin may be highly effective adjunctive therapy in patients with essential thrombocythemia who have recurrent thrombotic complications, particularly digital or cerebrovascular ischemia. Aspirin (but not warfarin) improves the increased platelet turnover and the clinical symptoms of erythromelalgia.144 However, aspirin may also cause marked prolongation of the bleeding time and the unpredictable occurrence of serious bleeding in some patients with thrombocythemia.57,58 A short-term pilot study using low-dose (40 mg daily) aspirin in polycythemia vera patients showed no excess bleeding complications,145 and larger trials of low-dose aspirin in myeloproliferative disorders are under way.146 The use of aspirin in patients with essential thrombocythemia is controversial at present, with some recommending caution40 but others recommending routine use to prevent thrombosis unless patients have a specific contraindication, such as a history of bleeding.
COURSE AND PROGNOSIS
The major causes of morbidity and mortality in essential thrombocythemia are thrombosis and hemorrhage. In rare cases, essential thrombocythemia may transform to another myeloproliferative disorder as part of the natural history of the disease.147 Although the other myeloproliferative disorders have the potential, to a greater or lesser degree, to spontaneously convert to acute leukemia, this association is less clear in essential thrombocythemia.135,148 The use of radiophosphorus or alkylating agents, and probably also hydroxyurea, to treat essential thrombocythemia is likely to enhance the leukemic potential of the disease. A high proportion of patients with essential thrombocythemia who develop acute myeloid leukemia and myelodysplastic syndromes with hydroxyurea treatment have chromosome 17p deletions and other characteristics of the 17p– syndrome.130 The survival curve for patients with essential thrombocythemia has been shown to be similar to that of a normal age-matched population.149
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