Primary Thrombocythemia: A Current Perspective

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1 Primary Thrombocythemia: A Current Perspective Tariq I. Mughal Department of Medicine, King Fahad National Guard Hospital, Riyadh, Saudi Arabia Key Words. Primary thrombocythemia Philadelphia negative Interferon Anagrelide c-mpl Abstract. The relationships among thrombocytosis, abnormal platelet aggregation and altered hemostasis in primary thrombocythemia remain poorly understood. Consequently, the appropriate management of asymptomatic patients is controversial and needs to be individualized. For symptomatic patients, conventional therapy, usually hydroxyurea, is directed primarily at lowering the platelet count by suppression of megakaryocyte activity. Recombinant interferon alpha can selectively lower platelet counts and may offer a reasonable alternative. Recent experience with anagrelide is also most promising in both symptomatic and asymptomatic patients. Current thoughts on the pathogenesis and management guidelines are presented here. Nature Primary thrombocythemia (PT) was first described in 1934 as a disease entity characterized by sustained thrombocytosis, in excess of 600 x 109/dl, and an increased risk for bleeding and thrombosis [ 11. The term PT is used interchangeably with the terms essential thrombocythemia, idiopathic thrombocythemia, primary hemorrhagic thrombocythemia, primary thrombohemorrhagic thrombocythemia, thromboblasthemia and piastrinemia [XI. It is the least common of the chronic myeloproliferative disorders (CMD). It arises as a consequence of an acquired clonal defect involving a pluripotential stem cell [6]. Correspondence: Dr. Tariq I. Mughal, Division of Hematology & Oncology, Department of Medicine, King Fahad National Guard Hospital, P.O. Box 22490, Riyadh 11426, Saudi Arabia. Received December 20, 1994; accepted for publication December 20, OAlphaMed Press /95/$5.00/0 Epidemiology The precise incidence of PT is unknown. PT was previously thought to be a relatively rare disease, but, largely due to the increasing use of automation in hematology, it appears to be more prevalent than previously thought [7, 81. Males and females appear to be affected equally [9]. The diagnosis is made most commonly in patients in the fifth decade of life, but it can occur in patients aged 20 to 40 years [9, lo]. There are no known predisposing factors. Neither radiation nor toxic chemicals, often implicated in the etiology of hematological malignancies, appear to play a causative role in PT. No viruses have been associated with it. Pathogenesis In 1981, Fialkow et al. established PT to be a clonal disorder originating in a pluripotential stem cell [6]. It is closely related to the other CMD and is sometimes difficult to distinguish from them, in particular from primary polycythemia. Most patients with PT have normal chromosomes, but a deletion of the long arm of chromosome 21 (21q-) has been reported in some [ 1 I]. At diagnosis, the patient s total platelet count is typically in excess of 1 x 1012/1 and results from a marked increase in platelet production, which averages about six times normal. In vitro culture studies often reveal abnormal myeloid progenitor cells, in particular colony forming units granulocyte-macrophage (CFU-GM), CFU megakaryocyte (CFU-MK), burst forming units erythroid (BFU-E) and CFU-mix, all of which are increased [ 121. Over 80% of patients with PT have spontaneous megakaryocyte and erythroid colony formation in in vitro cultures [13]. Juvonen et al. also STEM CELLS 1995;13:

2 Mughal 356 observed that, although the existence of spontaneous megakaryocyte formation or the number of spontaneous colonies did not correlate with the platelet count, there was a correlation between complications related to PT and the abnormal colony growth [13]. In PT, in vitro megakaryocyte development is inhibited by human platelet factor 4 (PF4) and'beta-thromboglobulin (BTG) in a way similar to that observed in normal subjects, suggesting that the responsiveness of CFU-MK to PF4 and BTG is normal [ 141. Recently, Li et al. have demonstrated that the proto-oncogene c-mpl is implicated in the pathway of spontaneous megakaryocytopoiesis in patients with PT [ 151. It has also been shown that mpl ligand is a thrombopoietin which appears to be amplified in such patients. These findings require further investigation. The platelets in patients with PT are often functionally abnormal and hyperaggregable. However, it is unclear whether these abnormalities result in an increased risk of bleeding and thrombotic episodes. Clinical Features In developed countries where blood tests are carried out routinely, about 30% of patients, especially those under the age of 40 years, are totally asymptomatic when the diagnosis is made. Symptomatic patients present with anemia, bleeding or thrombosis. The most common site of bleeding appears to be the gastrointestinal tract; rarely skin or mucous membrane bleeding may occur. Thrombotic episodes affect about 30% of all patients, and both venous and arterial thromboses can occur, involving small and large vessels. Arterial thrombi usually involve peripheral vessels, resulting in gangrene, livedo reticularis and erythromelalgia; cerebrovascular thromboses and transient ischemic attacks may also occur. Venous thromboses commonly involve lower extremity vessels and the renal vein. In older patients, the effects of PT appear to be compounded with degenerative vascular diseases, and both bleeding and thrombotic risks are greater. Splenomegaly is present in about 60% of patients. The tip of the spleen is usually less than 5 cm below the costal margin. Fig. 1. Blood film in primary thrombocythemia. There are numerous abnormally large platelets. Laboratory Features The platelet count typically persists in excess of 1 x 1012/1. Peripheral blood films reveal gross abnormalities (Fig. 1). The platelets have a wide variation in size with many large forms (megathrombocytes), platelet aggregates, and megakaryocytic cytoplasm fragments. The platelet anisocytosis results in a high platelet distribution width. The mean platelet volume is usually normal. At diagnosis, most patients have a normal red cell count, hemoglobin and hematocrit, but thereafter many develop microcytic, hypochromic anemia secondary to blood loss from the gastrointestinal tract. A mild degree of leukocytosis with neutrophilia is usually noted. The leukocyte alkaline phosphatase is normal. Bone marrow aspirate is often unsatisfactory due to rapid clotting of the specimen. It reveals megakaryocytic hyperplasia and clumps of aggregated platelets. The trephine sections demonstrate trilineage hyperplasia with adequate iron stores. The megakaryocytes are large with multiple nuclear lobes, and there is an increase in reticulin. Cytogenetic analysis of peripheral blood and marrow is usually normal, though rarely a 21q- abnormality can be observed. The absence of the Philadelphia chromosome predominantly helps in distinguishing PT from chronic myeloid leukemia with thrombocytosis. Moreover, no specific abnormalities, such as BCR-ABL gene, have been described at a molecular level.

3 351 Primary Thrombocythemia: A Current Perspective Abnormalities of platelet aggregation are found in about 50% of patients. Although a wide variety of these abnormalities are seen, the most common are the result of a defective response of platelets to epinephrine and collagen. The bleeding time is often prolonged. Other pertinent laboratory findings include the observation of nucleated red cells and red cells with Howell-Jolly bodies in blood films of some patients who develop autosplenectomy. Serum vitamin Blz and B,,-binding capacity are elevated in 30% of patients. Differential Diagnosis It is prudent to differentiate PT from the other CMD, as well as from the causes of a secondary or reactive thrombocytosis (Table I). A diagnosis of PT is supported by the finding of a persistently elevated platelet count in excess of 1 x 1012/1, splenomegaly, the absence of an increased red cell mass, the absence of the Philadelphia chromosome and the presence of stainable iron on the bone marrow trephine sections [ 161. Philadelphia positive thrombocytosis bears no molecular resemblance to Philadelphia negative primary thrombocythemia and is managed as chronic myeloid leukemia [ 171. In reactive thrombocytosis, the platelet count is usually less than 600 x lo9/] and the, etiology of the primary process can be determined by clinical evaluation. Cases in which there is no obvious cause for a secondary thrombocytosis and the platelet count is between 600 x 109/1 and 1 x 10 2/1 are problematical. Many of these may represent an early stage of PT. In vitro cultures of megakaryocyte and erythroid colonies are often helpful, as the abnormal spontaneous growth seen in most patients with PT is not seen in patients with reactive thrombocytosis. Rarely, other myeloproliferative processes, such as 5q- myelodysplasia, may also present with excessive thrombocytosis. Course of Disease The median survival of patients with PT is around nine years [16]. Most have a protracted course with long remissions during which no specific therapy is usually required. In concordance with other CMD, there is a small risk of Table I. Causes of reactive thrornbocytosis Chronic iron deficiency Chronic inflammatory disorders Acute bleeding Acute inflammation Post-operative Splenectomy and hyposplenism Drugs, e.g., steroids, vincristine Malignancies, e.g., Hodgkin s disease Severe hemolysis Exercise leukemic transformation; the frequency of this is probably less than in other CMD [ 181. Transformation to other CMD, particularly primary polycythemia and myelofibrosis, occurs in 10% to 15% of patients. Patients who present with splenomegaly at diagnosis fare better than those with impalpable spleen. This may be due to the beneficial effect of platelet sequestration within the spleen. Management Most patients who present with symptomatic disease will require specific treatment. Neither the magnitude of thrombocytosis per se, nor the presence of platelet aggregation abnormalities correlates directly with the seventy of bleeding or thrombotic manifestations [ 19, 201. There is, however, a higher incidence of thrombosis among patients who have had a prior thrombotic event 120, 211. It has also been observed that older patients may have an exacerbation of peripheral vascular disease. The precise role of thrombocytosis in the pathogenesis of these complications remains unclear. This, in turn, can often make management decisions difficult. If a patient presents with a life-threatening complication, plateletpheresis is recommended, following which low-dose aspirin therapy is useful. The use of antiplatelet aggregation agents remains controversial, largely due to the small risk of bleeding in patients with abnormal platelet function [22]. This study, however, included patients with primary polycythemia, and other investigators have not observed an increase in the risk of bleeding among patients with PT who are receiving antiplatelet aggregating agents [21, 231. Currently there is substantial enthusiasm for the role of a newer antiplatelet drug, anagrelide

4 Mughal 3.58 [ Anagrelide is a quinazolin derivative that inhibits platelet aggregation by interfering with cyclic adenosine monophosphate (CAMP) phosphodiesterase and the formation of arachidonate metabolites. In addition, it specifically inhibits megakaryocyte maturation. Current data suggest that anagrelide administered orally at a dose of 2 mg/day results in about a 50% reduction in the platelet count by one month. Major toxic effects at this dose level include migrainelike headaches, nausea, arrhythmias; rarely, cardiac failure may develop. Concomitant use of anagrelide with other antiplatelet agents must be avoided as the risk for bleeding may increase. Conventional platelet-lowering therapies include hydroxyurea and busulfan. Hydroxyurea remains the most commonly used drug and is reasonably successful in maintaining a satisfactory platelet count. Busulfan use carried a risk of development of secondary malignancies and may also hasten leukemic transformation of PT; it should therefore best be avoided. Over the past decade several studies have explored the use of recombinant interferon alpha (IFN) as a nonleukemogenic alternative therapy for patients with symptomatic PT [ These studies were initiated following the encouraging responses to IFN in controlling thrombocytosis associated with chronic myeloid leukemias [3 1, 321. Moreover, in vitro studies have demonstrated a dose-dependent suppression of CFU-GM, CFUmix, BFLJ-E and CFU-MK by IFN [33]. Currently it is not clear if spontaneous megakaryocyte colony formation is also inhibited. Giles et al. treated 18 patients, 14 of them newly diagnosed, with symptomatic PT with IFN 3-5 MU/day administered S.C. [28]. The platelet counts were selectively lowered with relief of symptoms in all patients; all 14 newly diagnosed patients had a greater than 50% decrease in platelet count by day 28. Giralt et al. have reported their experience in treating 13 patients with symptomatic PT, six of them newly diagnosed [29]. Responses were noted in nine patients (61%), including two patients who had normalization of their platelet counts. Mughal has treated 12 such patients, 11 of whom were previously untreated [30]. Six patients had relief of their symptoms, and the platelet counts decreased by about 50% by day 60. In all these studies the regimen of S.C. IFN was well-tolerated, and favorable responses were observed in most patients, whether previously treated or untreated. The precise role of IFN in this disease remains undefined at present. Several studies which are underway should clarify the role of IFN. Treatment of asymptomatic patients remains highly controversial. Most physicians recommend low-dose aspirin therapy. Anagrelide will probably be the drug of choice if current studies confirm its efficacy and if side-effects are mild. Until our understanding of PT increases and other risk factors are identified, therapy for patients with asymptomatic PT should be individualized. There are several groups in whom the risks of the disease appear to be higher and therapy to control the thrombocytosis is therefore important. These include pregnant patients and patients who require neurosurgery. Among pregnant patients with PT there is a high incidence of miscarriage and fetal growth retardation. It is often appropriate to offer these patients plateletpheresis followed by low-dose aspirin. Conclusions Although there are several types of systemic therapies currently available, none has the potential to offer long-term cure to patients with PT. The two principal new agents, IFN and anagrelide, are both active and efficient. Anagrelide, in particular, has been studied in asymptomatic individuals with PT and appears to be very effective with acceptable toxicity. However, the roles of these agents are not fully established, and randomized studies are needed. Acknowledgments The author is grateful to Ms. Betty Atkinson, for typing this manuscript. References Epstein E, Goedel A. Hamorrhagische thrombocythamia bei vascularer schrumpfmilz. Virchows Arch (Path01 Anat) 1934;293:233. Reid J. Haemorrhagic thrombocythemia. Lancet 1940;ii: Holst JE. Hemorrhagical thrombocythemia. Acta Med Scand 1948;130:

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