No treatment for low-risk thrombocythaemia:results from a prospective study

Essential thrombocythaemia (ET) is a chronic myeloproliferative disorder characterized by the occurrence of thromboembolic episodes, particularly in patients aged > 60 years or with a previous history of thrombosis, and/or by haemorrhages in patients with an exceedingly high platelet count. In these subgroups of patients the use of cytoreductive therapy is beneficial in terms of risk/benefit ratio. Only limited anecdotal data are available on the thrombotic or haemorrhagic risk and survival in young asymptomatic ET patients with a platelet count < 1500 × 10⁹/l. Therefore the optimal management of these patients is unknown.
To assess the incidence of thrombosis and haemorrhages in this group of patients we carried out a prospective observational study in a cohort of 65 patients with ET, aged < 60 years, with no history of thrombosis or haemorrhage and platelet count < 1500 × 10⁹/l, and in 65 age- and sex-matched controls. Patients were not treated with cytoreductive therapy until the occurrence of thrombosis or haemorrhage. Arterial or venous thrombotic events were objectively documented both in cases and in controls.
The median follow-up was 4.1 years, with an incidence of thrombosis in patients and controls of 1.91 and 1.50 cases/100 patient-years, respectively. The age- and sex-adjusted risk rate ratio was 1.43 (95% CI 0.37–5.4). Only three minor haemorrhagic episodes occurred in patients, with an incidence of 1.12 cases/100 patient-years.
Pregnancy and surgery were not associated with thrombosis in these patients.
We conclude that the thrombotic risk in young ET patients, with no thrombotic history and a platelet count < 1500 × 10⁹/l, is not increased compared to the normal population and that a conservative therapeutic approach should therefore be considered in these patients.     

Indications for lowering platelet numbers in essential thrombocythemia

Essential thrombocythemia (ET), one of the chronic myeloproliferative disorders, exposes individuals to significantly increased risk for thrombohemorrhagic complications. Epidemiologic data indicate that the two most prominent risk factors for thrombosis are age greater than 60 years or a history of or presentation with thrombosis at any age. Age is an important factor in selecting among therapeutic options, as the agents used to treat ET may contribute to acute leukemic transformation and other secondary malignancies. Whether or not hydroxyurea (HU) carries these risks is controversial and unresolved, but the uncertainty is a basis for avoiding it in young patients. Alternatives to HU that have established efficacy in lowering platelet counts in ET are interferon and anagrelide. Both are highly effective in reducing platelet numbers, and are apparently not associated with leukemogenicity or mutagenicity. However, approximately 30% of patients find interferon intolerable for long-term therapy. Anagrelide offers the advantage of oral dosing and long-term effectiveness at managing platelet counts. A recent long-term study of young ET patients treated with anagrelide found that all thrombohemorrhagic events occurred in patients with platelet counts greater than 0.4 × 10⁹/L, adding to the evidence that reduction of platelet counts to normal may be required for optimal control of risk. Semin Hematol 40(suppl 1):22-25. © 2003 Elsevier Inc. All rights reserved.     

Phase III,single-arm study investigating the efficacy,safety, and tolerability of anagrelide as a second-line treatment in high-risk Japanese patients with essential thrombocythemia

Essential thrombocythemia (ET) is usually managed by anti-platelet therapy. European guidelines recommend that patients with ET at high risk of developing thrombohemorrhagic events should be placed on cytoreductive therapy (CRT). In Japan, hydroxycarbamide (HC) is the most widely used CRT; however, treatment options for patients who become intolerant or refractory to initial treatment are limited. This study sought to determine the efficacy, safety, and tolerability of anagrelide in high-risk Japanese adults with ET who were intolerant or refractory to their first-line CRT. Fifty-three patients were enrolled in the study. Of those, 67.9 % had a platelet response (<60 × 10⁴/µL) and 45.3 % achieved normalization of platelet counts (≤40 × 10⁴/µL) on anagrelide therapy. The median time to platelet count response was 98.5 days and the median time to platelet count normalization was 274.0 days. The median daily dose administered was 1.9 mg/day. The most common adverse events observed during anagrelide treatment were anemia, headache, palpitations, and diarrhea. The majority of these were either mild or moderate in severity. Overall, the safety profile of anagrelide in high-risk Japanese patients with ET was consistent with the European Summary of Product Characteristics.     

Treatment indications and choice of a platelet-lowering agent in essential thrombocythemia

The therapeutic strategy in patients with essential thrombocythemia (ET) is a difficult balance between the prevention of bleeding and thrombotic complications and the risks of drug side effects and toxicity. Major bleeding is rare and seems to be related to higher platelet counts. Therefore, a platelet count greater than 1500 x 10(9)/L is generally regarded as an indication for cytoreduction. Thrombotic complications include microvascular occlusive symptoms, which are usually reversible with low-dose aspirin, and large vessel thrombosis. The risk of major thrombosis is higher in patients with ET who are older than 60 years and who have had a previous occlusive event. In this high-risk group, the nonalkylating agent hydroxyurea significantly reduces the rate of vascular complications and has emerged as the treatment of choice. However, the long-term risk:benefit ratio of hydroxyurea remains disputed because its leukemogenic potential has not been ruled out. This holds also for other myelosuppressive agents such as busulfan and pipobroman. Other drugs of particular interest for young patients include recombinant interferon-alpha and anagrelide. Both of these drugs are effective in lowering platelet counts, but their efficacy in reducing clinical complications remains to be demonstrated. Furthermore, interferon and anagrelide have frequent and clinically important side effects. Thus, further clinical studies are required to establish their role in the management of patients with ET.     

Essential thrombocythemia: past and present

Essential thrombocythemia (ET) is a clonal myeloproliferative disorder characterized by sustained increase in platelet number and tendency for thromboembolism. A somatic point mutation that causes a constitutive activation of the JAK2 gene is found in one in two ET patients. ET is more common in women, its incidence being 0.6–2.5/100,000 patient/year and the median age at diagnosis is 65–70 years. ET can affect all age groups, including children (0.09 cases/year), and is often diagnosed in the third–fourth decade of life. Rare cases of familial ET have been reported. Miscarriages are 3–4 times more common among women with ET than in the general population, especially in patients carrying JAK2V617F. Microvascular disturbances are typical of ET, but a major thrombosis (2/3 arterial and 1/3 venous; 1, 2–3% patient/year) is the main cause of morbidity and mortality. Age over 60 years and/or previous thrombosis are validated risk factor for thrombosis. Hemorrhages occur in 0.33% patient/year, mainly in those with a platelet count over 1,500 × 10⁹/L. Progression to myelofibrosis and leukemia is more common in patients carrying the JAK2V617F mutation, and is estimated to occur in 0.16% and 0.12% patient/year, respectively. The ET-related mortality ratio with respect to the general population is 1:1, while for polycythemia vera it is 1.6:1. Low-dose aspirin is useful for microvascular disturbances, and in the primary and secondary prevention of major thrombosis in high-risk patients, but it is not recommended in patients with a platelet count over 1,500 × 10⁹/L. Hydroxyurea is used as first-line treatment in high-risk patients. Other drugs available are alpha-interferon, anagrelide, pipobroman and busulphan.     

A phase III randomized,multicentre, double blind,active controlled trial to compare the efficacy and safety of two different anagrelide formulations in patients with essential thrombocythaemia – the TEAM-ET 2·0 trial

Anagrelide is an established treatment option for essential thrombocythaemia (ET). A prolonged release formulation was developed with the aim of reducing dosing frequency and improving tolerability, without diminishing efficacy. This multicentre, randomized, double blind, active-controlled, non-inferiority trial investigated the efficacy, safety and tolerability of anagrelide prolonged release (A-PR) over a reference product in high-risk ET patients, either anagrelide-naïve or -experienced. In a 6 to 12-week titration period the individual dose for the consecutive 4-week maintenance period was identified. The primary endpoint was the mean platelet count during the maintenance period (3 consecutive measurements, day 0, 14, 28). Of 112 included patients 106 were randomized. The mean screening platelet counts were 822 × 10⁹/l (95% confidence interval (CI) 707–936 × 10⁹/l) and 797 × 10⁹/l (95% CI 708–883 × 10⁹/l) for A-PR and the reference product, respectively. Both treatments effectively reduced platelet counts, to mean 281 × 10⁹/l for A-PR (95% CI 254–311) and 305 × 10⁹/l (95% CI 276–337) for the reference product (P < 0·0001, for non-inferiority). Safety and tolerability were comparable between both drugs. The novel prolonged-release formulation was equally effective and well tolerated compared to the reference product. A-PR provides a more convenient dosing schedule and will offer an alternative to licensed immediate-release anagrelide formulations.     

Impact of leukocytosis on thrombotic risk and survival in 532 patients with essential thrombocythemia: a retrospective study

Established risk factors for thrombosis in essential thrombocythemia (ET) include age (≥60 years) and previous vascular events. Recently, also leukocytosis has been proposed in risk stratification of ET patients. We report a retrospective study on 532 ET patients followed for a median of 7.6 years. Sixty-four patients (12%) developed 95 thrombotic events during follow-up. Together with the high-risk condition, a white blood cell (WBC) value above 11 × 10⁹/L, corresponding to the fourth percentile value, significantly correlated with a higher thrombotic risk (p = 0.033) by Cox proportional hazards. Moreover, the cumulative risk of thrombosis was significantly higher in high-risk patients with WBC >11 × 10⁹/L. JAK2 V617F mutation did not correlate with thrombosis. Overall, 123 (23%) patients died. Three independent parameters were noted as prognostic factors for survival in multivariate analysis: age >60 years, leukocytosis >11 × 10⁹/L, and hemoglobin level below normal values. Based on these parameters, three groups of risk were defined, with significantly different survivals. Baseline leukocytosis correlated with a higher thrombotic risk in high-risk patients and identified a cohort of patients with worse survival.     

Thrombosis in thrombocythemic Ph‐ myeloproliferations is associated with higher platelet count prior to the event: results of analyses of prothrombotic risk factors from a registry of patients treated with anagrelide

Controversies still exist regarding definition of the thrombotic risks in Ph‐ (BCR/ABL1‐) myeloproliferative disorders with thrombocythemia (MPD‐T). Platelet counts at diagnosis are currently not taken as a risk factor of thrombosis. In our cohort of 1179 patients with MPD‐T, prospectively registered for anagrelide treatment, we found that the median platelet count prior to the thrombotic event was significantly higher than at time points without any ensuing thrombosis (453 vs. 400 × 10⁹/L, P < 0.001), albeit higher platelet counts at diagnosis tended to be connected with fewer thrombotic events (in contrast to WBC counts at diagnosis). The JAK2^V617F mutation predicted both arterial and venous events, while age >65 yr, hypertension, diabetes mellitus, smoking, elevated triglyceride and homocysteine levels predicted arterial events only. For venous events, the specific thrombophilic risk factors (factor V ‘Leiden’ and others), antiphospholipid antibodies, and elevated factor VIII levels played a major role. During anagrelide treatment (± aspirin), we documented a decrease in both venous (6.7‐fold) and arterial events (1.8‐fold), while bleeding (mostly minor events) increased twofold compared to history. Our results suggest that keeping platelet counts at low levels may be a meaningful therapeutic measure to prevent thrombosis, although their counts at diagnosis lack any prognostic value.     

Open-label, dose-titration and continuation study to assess efficacy, safety, and pharmacokinetics of anagrelide in treatment-naïve Japanese patients with essential thrombocythemia

Although anagrelide is widely used for the treatment of essential thrombocythemia (ET) in the USA and Europe, it is not licensed in Japan. Existing literature has reported differences in polymorphism and activity of CYP1A2 in Japanese and non-Japanese ethnic groups, which may alter anagrelide metabolism. We intended to identify the optimum dosage of anagrelide in treatment-naïve Japanese patients with ET and assess its long-term safety and efficacy. Twelve patients with ET and a platelet count of ≥80 × 10⁴/μL were enrolled. Anagrelide was administered at an initial dose of 0.5 mg/day (weeks 1–4), then increased to 1.0 mg/day (weeks 5–8). During the following maintenance (weeks 9–52) and continuation periods (weeks 53–104), the dose was adjusted according to patient safety data and to maintain target platelet counts (<60 × 10⁴/μL). Increasing the dose led to a decrease in mean platelet count, and target platelet counts were maintained in 11 patients. Adverse events were mild or moderate, and none led to discontinuation. This cohort of Japanese patients exhibited higher pharmacokinetic exposures of anagrelide and its active metabolite than those previously documented in non-Japanese patients. These differences were modest, suggesting specific dosing regimens for Japanese patients are not required.     

Should a platelet limit of 600 × 109/l be used as a diagnostic criterion in essential thrombocythaemia? An analysis of the natural course including early stages

In order to evaluate the natural history of essential thrombocythaemia (ET), clinical data and prognostic factors of 143 patients with ET were retrospectively analysed (mean observation time 6.1 ± 4.6 years). In 42 patients the early phase of the disease with initial platelet counts between 250 and 600 × 10⁹/l was assessed. In most early cases, ET was suggested by clinical symptoms (79%) and increased megakaryopoiesis (95%) with abnormal megakaryocytes in bone marrow histology (n = 34) and cytology (n = 5). Other myeloproliferative disorders and reactive thrombocytosis were excluded according to the diagnostic criteria of the Polycythemia Vera Study Group. During follow-up of the 38 early cases not treated cytoreductively at diagnosis, the platelet counts increased to >600 × 10⁹/l in 28 patients (74%) and remained between 450 and 600 × 10⁹/l in 10 patients (26%). In primarily asymptomatic patients (n = 46) with initial platelet counts above (n = 37) and below 600 × 10⁹/l (n = 9) the rates of increase of symptomatic patients were similar at about 7% per year. No influence of the initial platelet count on survival was seen in multivariate analysis of prognostic factors which included all 143 cases. Survival was mainly influenced by the rate of ET-related complications during follow-up (P = 0.002). Analysing the influence of cytoreductive therapy on symptom-free survival, platelet reduction benefited patients under 60 years (19 cytoreductively treated v 65 untreated patients, P = 0.075). The results demonstrate the possible clinical relevance of the early stages of ET and suggest that the features of pathologic megakaryopoiesis in the bone marrow are a more reliable diagnostic criterion than a definite platelet limit. Therefore, further therapeutic studies should include all stages of the disease and all age groups.     

JAK2<Superscript>V617F</Superscript> positive early stage myeloproliferative disease (essential thrombocythemia) as the cause of portal vein thrombosis in two middle-aged women: therapeutic implications in view of the literature

The present study describes portal vein thrombosis (PVT) in two women as the first and single presenting symptom of latent or masked myeloproliferative disease (MPD). Essential thrombocythemia (ET) was suspected by a sustained increase in platelet count (>400 × 10⁹/l) and slight splenomegaly on echogram. ET could be diagnosed by the presence of large platelet in peripheral blood smear, an increase in clustered large megakaryocytes in bone marrow smear and the presence of the JAK2^V617F mutation. A subsequent biopsy specimen was consistent with the diagnosis of true ET. In patients with a first episode of splanchnic vein thrombosis (SVT), analysis of any venous thrombophilic risk factors as well as a JAK2^V617F mutation status indicative for MPD is warranted. Administration of heparin followed by oral anticoagulation with vitamin K antagonists is the treatment of choice in patients with SVT. Anticoagulation therapy combined with low-dose aspirin and proper treatment of the MPD is recommended in patients with SVT associated with the JAK2^V617F mutation.     

Therapeutic effectiveness of ranimustine chemotherapy for elderly essential thrombocythemia*

Background: We studied the clinical effectiveness of ranimustine (MCNU) chemotherapy for essential thrombocythemia (ET). Methods: MCNU chemotherapy was carried out in 14 ET patients who were 60 years of age or older, including six men and eight women. Their ages ranged between 61 and 88 years (median age: 73 years). The patients’ mean platelet count before the treatment was 1.157 ± 0.284 × 10⁶/µL. Five of the studied patients had experienced a thrombotic episode, and one had a profuse epistaxis. Patients were treated mainly by intravenous administration of MCNU. In 12 patients, the platelet count was controlled to a level less than 500 × 10³/µL, while in two patients, it was controlled to less than 700 × 10³/µL. Results: Cerebral infarction occurred in only one patient during or after MCNU therapy. Even in the cases in which thrombosis had occurred before MCNU treatment, further thrombotic events occurred in only one case. In the patient with a profuse epistaxis, bleeding improved during treatment and normal platelet count was maintained after chemotherapy. Conclusion: It was suggested that MCNU chemotherapy may be useful for the prevention of complications in elderly ET patients.     

What is the standard treatment in essential thrombocythemia

The treatment of patients with essential thrombocythemia (ET) should be based primarily on the expected risk of major thrombotic complications. Although the specific values chosen for separating different risk categories are in part arbitrary, the following recomendations can be made. Young asymptomatic subjects with platelet counts below 1,500x10(9)/L are at lower risk and can be followed untreated. However, it should be emphasized that thrombotic events can also occur in a small percentage of these lower-risk cases. Low-dose aspirin (100-300 mg/day) should be given to patients with symptoms of microvascular occlusion, such as erythromelalgia or transient neurological attacks, and avoided in those with bleeding manifestations. The risk/benefit of low-dose aspirin in the primary prevention of thrombosis in asymptomatic patients remains uncertain. For high-risk patients (age >60 years, or platelet count >1,500x10(9)/L, or previous thrombosis), hydroxyurea, plus aspirin in the case of thrombosis, is the treatment of choice because its efficacy in preventing thrombotic complications has been proven in a randomized clinical trial. However, the possible long-term leukemogenicity of this drug, as well as that of other effective cytoreductive agents such as busulphan and pipobroman, remains a major concern. Anagrelide and interferon could overcome this worry but their efficacy has been hitherto demonstrated only in lowering the platelet count. Controlled clinical studies showing a benefit in preventing thrombotic and hemorrhagic complications are urgently needed.     

Target hematologic values in the management of essential thrombocythemia and polycythemia vera

Treatment of essential thrombocythemia (ET) and polycythemia vera (PV) is aimed at preventing vascular complications, which are the main cause of morbidity and mortality in these diseases. Over the years, clinical trials have demonstrated that the incidence of thrombosis and bleeding can be reduced by controlling the blood cell counts, but the target hematological levels have varied across the studies. In this article, we review the evidence supporting the use of predefined target hematologic values for the management of ET and PV in routine clinical practice. At present, the recommended target hematocrit in PV is below 45%, regardless of the patients' risk profile. Concerning platelet counts, no direct correlation has been demonstrated with thrombotic risk in either ET or PV. Thus, although cytoreductive treatment reduces the rate of vascular complications in high‐risk patients, no particular threshold of the platelet counts has been shown to be more protective against thrombosis. Extreme thrombocytosis is a risk factor for bleeding, particularly when aspirin or anagrelide are given. Leukocytosis at baseline or during follow‐up appears to be a risk factor for thrombosis, mostly in high‐risk patients. However, the clinical benefit of strictly controlling this parameter is not yet established. Finally, standardized definitions of response to cytoreductive treatment in ET and PV have recently been published. Nevertheless, they have been produced to compare the efficacy of new therapies in clinical trials, whereas its relevance in clinical practice has been questioned in retrospective studies showing that such response definitions do not correlate with the patients' clinical outcome.     

Anagrelide in the treatment of thrombocythemia essential (ET)

Essential thrombocythaemia (ET), the most often occurring myeloproliferative disorder is a clonal malignant disorder arising from stem cell. The course of the disease is complicated by some severe thrombotic events and far less commonly by haemorrhagic phenomena. Treatment of ET consist of antiplatelet drugs (e.g. aspirin) and lowering platelet count (hydroxyurea or interferon alpha). Anagrelide (anagrelide hydrochloride) is an imidazoquinazoline derivative which lowers platelet count probably by inhibiting thrombopoiesis and reduces platelet aggregation. The aim of the study was to evaluate the efficacy and side effects of anagrelide in patients with ET refractory to prior treatment with hydroxyurea. Anagrelide (Agrylin or Thromboreductin) was used in 40 patients with ET from Jan. 1999 to June. 2003. Out of 40 patients, there were 29 females and 11 males, (median age 52.0 +/- 14.25 years; range, 21-72). Median follow up was 23 months (range, 8 to 54 months). Anagrelide in the average dose of 2,0 mg (range, 1,0-3,5 mg) reduced platelet count in all patients. Median time of response was 3-4 weeks. Complete remission (platelet count < or =450 G/l) achieved 22 persons (55%) and partial remission 17 persons, and only one patient had platelet count slightly above 600 G/l (627 G/l). There was a significant (p < 0.05) reduction in platelet count from a mean of 1136.05 +/- 295.09 G/l to 480.98 +/- 72.26 G/l (56%) Despite platelet count reduction <500 G/l in 3 patients reappeared symptoms of low extremities deep venous thrombosis and in one transient ischaemic cerebral stroke was found. Hemoglobin level in a single case was lower than 12 g/dL (10.8 g/dL), and neither leukopenia nor disturbances of hepatic or renal function were observed. During the first two months of treatment with anagrelide some mild and transient side effects were noticed, eg. headache in 10 (25%), fluid retention in 8 (20%), palpitations in 4 (10%), and diarrhoea in 2 (5%) patients, but all of them continued therapy. Achieved platelet count reduction allowed in 2 ET patients safe performance of planned surgery (cholecystectomy, partial thyroidectomy) and in 1 balloon coronary angioplasty. Anagrelide proved to be an effective drug for of ET patients refractory to hydroxyurea.     

Essential thrombocythemia: A retrospective analysis of 39 cases

Thirty-nine Chinese patients presenting as essential thrombocythemia (ET) were analyzed retrospectively. The median age at presentation was 69 years and the M:F ratio was 1.35:1. At diagnosis, 33 cases (84%) were asymptomatic and the diagnosis was made incidentally, while 3 cases (8%) presented with small vessel, and 2 cases (5%) with large vessel, thrombosis. One patient (3%) presented with minor bleeding. The platelet count ranged from 0.9-34 × 10¹²/1. Of 12 karyotypes done, 2 cases were abnormal, both showing the Philadelphia (Ph) chromosome. First-line therapy was radiophosphorus (³²P) in 3 cases, melphaian in 20 cases, and hydroxyurea in 12 cases; 4 cases did not receive specific therapy. During the follow-up (mean = 4 years), no thrombotic or bleeding episodes were observed. One patient with the Ph chromosome underwent blastic transformation. These results indicate that bleeding and thrombosis occur significantly less in Chinese patients than in Western patients. The Ph chromosome appears to be a bad prognostic indicator. Because of the very low incidence of complications and good prognosis, the authors believe that cytoreductive therapy is best achieved by the use of hydroxyurea instead of alkylating agents or radiophorphours, as the latter agents are potentially leukemogenic. © 1995 Wiley-Liss, Inc.     

Correlation between leukocytosis and thrombosis in Philadelphia-negative chronic myeloproliferative neoplasms

The evidence that leukocytes may contribute to the pathogenesis of thrombosis in Chronic Myeloproliferative Neoplasms is increasing but not definitive. To further enforces whether an increased leukocyte count is associated with thrombosis and whether this effect can be modulated by cytoreductive therapy, we analyzed the clinical course of 187 patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET) followed at two Italian Institutions over a period of 7 years. The association was measured at diagnosis or before thrombotic events: a multivariable analysis was carried out using data at baseline and time-dependent covariates. We found that white blood cells (WBC) count above 9.5 × 10⁹/L at diagnosis (baseline analysis) was associated with thrombosis during the follow-up (Hazard Ratio [HR] of 1.8, p 0.03). At the time-dependent analysis, therapy with hydroxyurea (HU), lowering by 35% the baseline WBC level, reduced such strength of association giving a HR of 1.3 (p value non significant). We found a trend between WBC level and thrombosis in untreated low-risk patients (RR of 1.9, 95% CI 0.9 to 3.1); in high-risk patients treated with HU this correlation was clearly lost (RR 1.1, 95% CI 0.2 to 2.7). Finally, we could not identify the presence of JAK2 ^V617F as a risk factor for thrombosis. Properly designed prospective studies should corroborate such results.     

Rezidivierende Lungenarterienembolie und koronare Thrombose bei Thrombozythämie

Essential thrombocythemia (ET) is an entity of chronic myeloproliferative neoplasms (MPN) with onset in old age. A diagnosis by exclusion is based on molecular and non-molecular criteria. Platelet count, bone marrow histology and Janus kinase2 (JAK 2) status are required for diagnosis confirmation (WHO criteria). Complex disorders of platelet and hemorheological function and the JAK 2 mutation dominate the variable disease with thrombotic and hemorrhagic complications. Age, platelet count and thrombotic/hemorrhagic events represent high risk criteria. The use of anagrelide (cytoreductive) needs cardiac risk assessment and monitoring due to potential cardiac side effects.     

Romiplostim for the management of perioperative thrombocytopenia

Thrombocytopenic patients requiring invasive surgery have few options to improve their platelet count preoperatively. This is a single‐centre, retrospective review of thrombocytopenic patients receiving the thrombopoietin receptor agonist romiplostim perioperatively to allow for surgical interventions. Patient characteristics, romiplostim use, and surgical and safety outcomes (bleeding, thrombosis, transfusions) were collected and analysed. Forty‐seven patients underwent 51 surgical procedures (ranging from total hip arthroplasty to open cardiac surgery) with romiplostim support. Thrombocytopenia aetiologies included immune thrombocytopenia, chronic liver disease, haematological malignancy, drug‐related thrombocytopenia, and hereditary thrombocytopenia. Median (range) platelet counts improved, from 47 × 10⁹/l (9–120 × 10⁹/l) at romiplostim initiation to 164 × 10⁹/l (28–603 × 10⁹/l) at the time of surgery (P < 0·0001). A dose of 3 μg/kg per week for 2 doses increased the platelet count to >100 × 10⁹/l in 79% of patients within 14 days. In 96% of cases, surgery proceeded on schedule without delay or cancellation. Four patients had bleeding events unrelated to thrombocytopenia and 1 patient developed deep venous thrombosis. Six patients required red cell transfusion and 3 patients required platelet transfusion perioperatively. In conclusion, romiplostim was effective in increasing platelet counts to allow surgery to proceed safely and on schedule. Bleeding and thromboembolic events were within acceptable limits for this surgical population.     

Markers of endothelial and in vivo platelet activation in patients with essential thrombocythemia and polycythemia vera

We investigated endothelial and in vivo platelet activation in a cohort of 52 patients with essential thrombocythemia (ET) and polycythemia vera (PV) before and after cytoreductive treatment, 22 healthy controls, and 17 patients with acute cerebrovascular ischemia (ACVI) and normal platelet counts. We measured platelet expression of CD62P and CD63 antigens and levels of soluble vascular cell adhesion molecule 1 (sVCAM-1). We found increased in vivo platelet activation in all patients with ET and PV, both before and after cytoreductive treatment, compared with controls. In patients with arterial thrombosis, platelet expression of CD62P, and in patients with erythromelalgia, expression of both markers was higher compared with expression in patients without thrombotic complications. In patients with ET and PV before and after treatment, sVCAM-1 expression was increased compared with expression in controls but also compared with expression in patients with ACVI and normal platelet counts. In patients with arterial thrombosis and erythromelalgia, in vivo platelet activation correlated with the level of sVCAM-1. Our findings indicated that in vivo platelet activation reflects intrinsic platelet defects in patients with ET and PV, persists after cytoreductive treatment, and results in endothelial damage, probably through release of angiogenic factors and/or activation of white blood cells.