Prevention and treatment of thrombotic complications in essential thrombocythaemia: efficacy and safety of aspirin

The efficacy and safety of aspirin in the prevention and treatment of thrombosis in essential thrombocythaemia (ET) was retrospectively analysed in a cohort of 68 ET patients. 41 patients presented with thrombosis, five patients with bleeding; two patients had a paradoxical combination of bleeding and thrombosis at presentation. At presentation, patients with bleeding had significantly higher platelet and leucocyte counts than patients with thrombosis. During long-term follow-up the incidence of thrombosis was significantly reduced in patients receiving aspirin, either as monotherapy or in combination with cytoreduction. However, treatment with aspirin (500 mg/d) was associated with an increase in (minor) bleeding complications. In patients receiving aspirin, bleeding occurred particularly at platelet counts exceeding 1000×10⁹/l. The overall 5- and 10-years survival probability was 93% and 84% respectively, indicating that life expectancy in ET is close to normal. Although our data need confirmation in prospective clinical trials, they suggest that aspirin, particularly in lower doses (100 mg/d), may be a safe antithrombotic agent in ET with an acceptable risk for bleeding, if applied to patients with a platelet count <1000×10⁹/l and/or absence of a bleeding history.     

Anagrelide,a novel platelet lowering option in essential thrombocythaemia: treatment experience in 48 patients in Germany

Abstract: We report on our treatment experience in Germany with anagrelide, a novel platelet lowering agent, in 48 patients (27 females, 21 males) with essential thrombocythaemia. Their age was between 19 and 79 yr when anagrelide therapy was initiated. Sixteen patients were previously untreated, 15 pretreated with hydroxyurea and 17 had multiple pretreatments. Forty-one of the 48 patients had either microvascular, thromboembolic or bleeding complications. About 50% received low dose acetylsalicylic acid as an adjunct. Their platelet count prior to therapy ranged from 850,000/μl to 3,100,000/μl. Eighty-seven per cent of the patients treated with anagrelide were complete hematological responders, while 13% responded only partially or failed to respond. Twelve of our patients (25%) developed short-term (from a few days to a maximum of 4 wk) side effects including headache (most frequent), palpitations, tachycardia or nausea. Eight patients reported long-term (more than 1 month) adverse effects. However, in only 5 of all 48 patients (10%) were these side effects not acceptable so that treatment had to be discontinued. We have now treated patients for up to 7 yr (median maintenance dose 2.5 mg/d). Preliminary evidence suggests that anagrelide mediated platelet count reduction also prevents recurrence of thromboembolic complications. Hence, anagrelide has the potential to become the first-line platelet-lowering treatment in myeloproliferative disorders with high platelet counts.     

Cytoreduction plus low‐dose aspirin versus cytoreduction alone as primary prophylaxis of thrombosis in patients with high‐risk essential thrombocythaemia: an observational study

The effectiveness of low‐dose aspirin in the primary prevention of thrombosis in patients with high‐risk essential thrombocythaemia (ET) treated with cytoreductive drugs is not well established. The risk‐benefit balance of low‐dose aspirin plus cytoreductive therapy compared with cytoreduction alone was retrospectively analysed in 247 patients with high‐risk ET without prior thrombosis. Follow‐up was 763 and 685 person‐years for cytoreduction plus low‐dose aspirin and cytoreduction alone, respectively. The rate of thrombosis was not significantly reduced in patients on cytoreduction plus aspirin (14·4 events per 1000 person‐years) when compared with those on cytoreduction alone (24·8 events per 1000 person‐years; P = 0·2). However, in the subgroup of patients older than 60 years, the addition of low‐dose aspirin was associated with a significantly lower rate of thrombosis (8·6 vs. 29·2 thrombosis per 1000 person‐years for combined treatment and cytoreduction alone, respectively, P = 0·02). The rate of major bleeding was significantly higher with combined therapy than with cytoreduction alone both in the whole series (14·4 vs. 1·4 haemorrhagic events per 1000 person‐years, respectively, P = 0·006) and in the subgroup of patients older than 60 years. In conclusion, low‐dose aspirin benefits high‐risk ET patients older than 60 years receiving cytoreductive therapy as primary prophylaxis of thrombosis.     

Second malignancies in patients with essential thrombocythaemia treated with busulphan and hydroxyurea: long-term follow-up of a randomized clinical trial

We have previously demonstrated that hydroxyurea (HU) reduces the rate of vascular complications in patients with essential thrombocythaemia (ET) at high risk of thrombosis. However, the relatively short follow-up (median 27 months) did not enable the evaluation of the risk of developing secondary malignancies. In this study, we report the long-term outcome of the 114 patients included in the trial: 56 patients randomized to receive HU and 58 patients to receive no cytoreductive therapy. Before randomization, 15 patients had been treated with busulphan. During the observation period, 29 patients (50%) shifted from the control to the HU group mainly because of thrombosis. Median follow-up was 73 months (range 3-94). Analysis was by intention to treat and, when indicated, by treatment. When analysed by intention to treat, 46 out of 54 patients (85%) originally randomized in the HU group are alive, compared with 49 of 58 patients (84%) in the control group [not significant (n.s.)]. Five patients (9%) in the HU group and 26 patients (45%) in the control group had thrombosis (P < 0.0001). Seven patients (13%) in the HU group developed secondary acute leukaemia, myelodysplastic syndromes or solid tumours, compared with only one of the control group patients (1.7%) (P = 0.032). The occurrence of secondary malignancies was also analysed by treatment: none of the 20 patients who had never been treated with chemotherapy developed neoplasia vs. three of the 77 patients given HU only (3.9% n.s.) and five of the 15 patients given busulphan plus HU (33% P < 0. 0001). This study showed that: (a) HU reduced the risk of thrombosis in ET patients; (b) the sequential use of busulphan and HU significantly increased the risk of second malignancies; and (c) overall survival was not affected by HU therapy.     

Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia

Despite decades of clinical and laboratory research, relatively little has been accomplished concerning the pathogenesis as well as the identification of risk factors for thrombosis and bleeding in myeloproliferative disorders. In polycythaemia vera, the pro-thrombotic effect of an elevated haematocrit is well established. In contrast, thrombocytosis per se has not been similarly incriminated in essential thrombocythaemia. In both conditions, advanced age and the presence of a prior event identify thrombosis-prone patients. There is increasing evidence to suggest an additional role by leucocytes that might partly explain the antithrombotic effects of myelosuppressive therapy. A substantial minority of affected patients display reduced levels of high molecular weight von Willebrand protein in the plasma during extreme thrombocytosis and it is believed that this might explain the bleeding diathesis of such patients. Recent controlled studies support the therapeutic value of hydroxyurea and aspirin in essential thrombocythaemia and polycythaemia vera, respectively. The current communication will address the incidence, phenotype, pathogenesis, risk factors, prevention, and treatment of both thrombosis and haemorrhage in these disorders.     

Studies of platelet volume, chemistry and function in patients with essential thrombocythaemia treated with Anagrelide

Anagrelide (imidazoquinazolin derivative) is a new compound proposed for the treatment of myeloproliferative disorders. In this study, Anagrelide was given to patients with essential thrombocythaemia (ET) in a compassionate-use protocol. The aim of this study was to test the effect of this drug not only on the platelet count but also on platelet volume, chemistry and function, which has not previously been reported. Thus, in ET, different functional or structural platelet abnormalities were reported: a shortening of the bleeding time, hypoaggregation to several agonists, and in particular a lack of response to adrenalin, an increase in the amount of total platelet glycoprotein IV (or CD36), and an abnormal migration of thrombospondin on electrophoresis. These different parameters were studied before and during therapy with Anagrelide. Although the platelet count was corrected, no functional or chemical abnormality was improved. Furthermore, platelet volume was shown to be constantly increased under Anagrelide. Thus, Anagrelide, in reducing the platelet count, may possibly decrease the risk of thrombosis and haemorrhage. Nevertheless, if the risk of thromboses and/or myelofibrosis is related not only to the platelet count but also to the platelet abnormalities, the persistence of a thrombocytopathy in patients treated with Anagrelide must be taken in consideration. Our data suggest that thromboses and myelofibrosis are clinical end-points which should be included in future large-scale use of Anagrelide.     

Hydroxyurea treatment reduces haematopoietic progenitor growth and CD34 positive cells in polycythaemia vera and essential thrombocythaemia

The aim of the present work was to investigate the effect of hydroxyurea (HU) treatment on haematopoietic progenitors and CD34 positive (CD34+) cells in patients with polycythaemia vera (PV) and essential thrombocythaemia (ET). Of the PV patients were 10 treated with phlebotomy only and 10 were on HU therapy. Seven ET patients were untreated and 10 received HU. In each subject peripheral blood was obtained for in vitro colony growth, determination of CD34+ cells and plasma erythropoietin (EPO) concentration. The mean number of EPO independent erythroid colonies (EEC) was higher in the group of PV patients on phlebotomy therapy compared to the PV patients treated with HU (74.4 and 8.0 colonies/10(5) cells, respectively) but the difference did not reach statistical significance. The corresponding means for the untreated ET patients and ET patients treated with HU were 13.0 and 1.3 colonies/10(5) cells, respectively, this difference being statistically significant (p = 0.012). The mean EEC for combined groups of PV and ET without myelosuppressive treatment were compared with the results for PV and ET patients on HU therapy; this difference was statistically significant (p = 0.014). The same pattern was observed for total erythroid growth with EPO. The relationship between the concentration of CD34+ cells and total EEC in peripheral blood was statistically significant for both PV (p<0.005) and ET (p<0.01). This finding supports the hypothesis that the level of CD34+ cells in peripheral blood could be used as a proliferation marker in these two myeloproliferative entities. No relationship between plasma EPO and EEC was present. It therefore appears that the reported differences in plasma/serum EPO concentrations between PV patients on phlebotomy treatment compared to patients on myelosuppressive treatment are not likely to be found at the production site for erythrocytes.     

Prognostic utility of spontaneous erythroid colony formation and JAK2 mutational analysis for thrombotic events in essential thrombocythaemia

Background: Thrombotic events in essential thrombocythaemia (ET) are difficult to predict with current risk stratification based on age and prior history of thrombosis. Aims: We aimed to assess the predictive value of the JAK2 V617F mutation (JAK2) and spontaneous erythroid colony (SEC) growth for the development of thrombotic events post diagnosis in patients with ET. Methods: Consecutive patients with ET were retrospectively identified, and clinical and laboratory correlates were evaluated. Thrombotic events were categorized according to their occurrence at or prior to diagnosis (prior thrombosis), and any time post diagnosis of ET (subsequent thrombosis). JAK2 analysis was performed by allele‐specific PCR on whole blood or bone marrow. Results: A total of 62 patients was identified, median age 63 years; 67% (41/61) JAK2‐positive and 47% (25/53) SEC‐positive. Median follow‐up was 33 months (range, 1 to 137). JAK2‐positive patients showed a trend to increased prior thrombosis (27% vs 5%, P= 0.08), and a significant increase in the development of subsequent thrombosis (5‐year event rate 31% vs 6%, P= 0.04), which persisted when stratified for a history of prior thrombosis (P= 0.04). Survival was not affected by JAK2 status. The SEC assay predicted an increased rate of baseline thrombosis (16% vs 0%, P= 0.04), but was not found to be predictive of any subsequent thrombotic events. Conclusions: Patients with ET who are JAK2‐positive by whole blood allele‐specific PCR appear to be at increased risk of thrombotic complications, which is independent of a prior history of thrombosis.     

Multivessel coronary thrombosis, acute myocardial infarction, and no reflow in a patient with essential thrombocythaemia

Essential thrombocythaemia (ET) has been reported rarely to cause coronary thrombosis, but the management is still undefined. A 63 year old woman with multivessel coronary thrombosis, acute myocardial infarction (MI), and no reflow in reperfused coronary artery in association with ET is presented. The patient's platelet count was only moderately raised at the onset of MI, but peripheral blood smear and bone marrow evaluation revealed clumping giant platelets and numerous large hyperploid megakaryocytes. Long term prophylaxis with antiplatelet agents in patients with ET is recommended, even if the platelet count is not largely raised. Cytoreductive treatment may also be effective for secondary prevention when thrombotic complications occur.


Keywords: essential thrombocythaemia; thrombosis; coronary artery; no reflow     

Incidence, clinical features and outcome of essential thrombocythaemia in a well defined geographical area

In an attempt to characterise the clinical features, incidence and outcome of essential thrombocythaemia (ET) we report our experience in a large unselected series of patients from a well defined region. All new cases of ET in the County of Copenhagen were registered during the period 1977-98. We identified 96 cases of ET, yielding an age- and sex-adjusted annual incidence rate of 0.59/100.000 and a point-prevalence at last follow up of 11/100.000. The overall incidence rate was 0.31 and 1.00 per 100.000 population during the consecutive periods 1977-89 and 1990-98, respectively, corresponding to a 3.2-fold increase. Median age at diagnosis was 67 yr (females 68 yr, males 66 yr, range 18-87 yr), and the female to male (F/M) ratio was 2.6:1. At diagnosis, 52% of the patients displayed no ET-related symptoms and were discovered fortuitously by a routine platelet count. Forty-eight percent presented with thrombohaemorrhagic phenomena, of which microvascular disturbances of the central nervous system (CNS), extremities and skin were most frequently observed (23%). Compared to patients diagnosed after 1989, patients diagnosed before 1990 had a significantly higher mean platelet count, white blood cell (WBC) count, lactate dehydrogenase (LDH) value and alkaline phosphatase value. With a median follow up of 70 months, 5-yr survival was 76%, significantly lower than the expected survival of an age- and sex-matched control group (p = 0.0052). Thirty-seven patients experienced a total of 55 thrombohaemorrhagic events during follow-up, corresponding to an incidence of thrombosis and microvascular disturbances or haemorrhage of 8.1% per pt-yr and 2.5% per pt-yr, respectively. The number of patients experiencing thrombosis or microvascular disturbances was significantly higher among the 29 patients who never received acetylsalicylic acid (ASA) compared to the 67 patients who received ASA during follow up (45% vs. 21%; p = 0.017). This study provides population-based data suggesting the benefit of treatment with low-dose ASA in a non-selected population of patients with ET.     

Pipobroman is safe and effective treatment for patients with essential thrombocythaemia at high risk of thrombosis

Essential thrombocythaemia (ET) is a disease associated with an elevated risk of thrombosis. This study evaluated the efficacy and safety of pipobroman (PB) in the long-term control of ET patients who had, at diagnosis, one or more of the following currently known risk factors for thrombosis or haemorrhage (high-risk patients): age > 60 years, history of thrombosis or haemorrhage, platelets >1000 x 10(9)/l. From 1978 to 2000, with a median follow-up of 10 years, 118 previously untreated high-risk ET patients (median age 62 years, range 25-82), were treated with PB at the starting dose of 0.8-1 mg/kg/d. All patients reached a platelet count <600 x 10(9)/l and 91% achieved a platelet count <400 x 10(9)/l. During follow-up, 13 patients had thrombosis, with a 10-year cumulative risk of 14%. Acute myeloid leukaemia, myelofibrosis and solid tumours occurred in three, two and seven patients with a 10-year cumulative risk of 3%, 2% and 7% respectively. Actuarial survival at 20 years was 64% and the standardized mortality ratio was 1.1 (95% CI: 0.7-1.7), not statistically different from the general population (P = 0.54). Age was associated with a higher risk of death (P = 0.00009) and thrombosis (P = 0.003). The duration of PB treatment did not correlate with the occurrence of second malignancies. This study, with a median follow-up of 10 years, demonstrates that pipobroman is effective and well tolerated. The low cumulative 10-year risk of thrombosis, leukaemia and solid tumours indicates that pipobroman is an adequate treatment for patients with high risk ET.     

Relationships between thrombohemorrhagic complications and platelet function in patients with essential thrombocythaemia

Three subgroups have been distinguished in essential thrombocythaemia (ET) patients, on the basis of clinical and laboratory findings. ET patients with bleeding incidents had smaller platelet volume, lower concentrations of beta-thromboglobulin and platelet factor 4 in their plasma, 10%, 26%, and 26% lower compared to patients without complications, respectively. ATP secretion from platelets of bleeders, clotters, and "no-complications" ET patients was found to be 75%, 36%, and 45%, respectively, lower than in healthy people. Spontaneous platelet aggregation appeared to be normal in about 90% of ET patients with no complications and in all bleeders but only in 35% patients with clotting incidents. All bleeders had abnormal agonist-evoked aggregation assays. Among remaining ET patients 30%-60% displayed normal values of different evoked aggregation tests. Thus, clinically distinguished group of bleeding ET patients may be differentiated from other subgroups on the basis of laboratory findings.