Thrombocytosis and thrombocythemia

Thrombocytosis is caused by three major pathophysiological mechanisms: (1) reactive or secondary thrombocytosis; (2) familial thrombocytosis; and (3) clonal thrombocytosis, including essential thrombocythemia and related myeloproliferative disorders. Recent work has begun to elucidate the abnormal megakaryocytopoiesis of essential thrombocythemia, which is associated with paradoxically elevated plasma levels of thrombopoietin. The clonal nature of all cases of essential thrombocythemia has been challenged. Thrombotic complications are the major causes of morbidity and mortality in this disease. Indications for platelet cytoreduction and antiplatelet therapy, as well as complications of treatment, are being clarified.     

Thrombocytosis in rheumatoid arthritis: JAK2V617F-positive essential thrombocythemia

Thrombocytosis is an important laboratory finding in rheumatoid arthritis (RA) and it has a correlation with disease activity. Janus kinase 2 valin 617 phenylalanine (JAK2V617F) mutation has gained importance in the diagnosis of myeloproliferative diseases recently. There is no published report in literature on the association between RA and JAK2V617F-positive essential thrombocythemia (ET). In this report, we present a JAK2V617F-positive ET case that had RA. A 57-year-old male patient was diagnosed with RA according to the criteria of American College of Rheumatology (ACR), whose complaint was of pain in the hands and morning stiffness lasting for about 2 h. The patient was evaluated for thrombocytosis because he was in remission and suffering persistent thrombocytosis under treatment. After excluding the causes of secondary thrombocytosis, bone marrow aspiration and biopsy was performed. On peripheral blood and bone marrow PCR examination, the patient was detected to be JAK2V617F positive heterozygously and diagnosed with ET. As a conclusion, mild–moderate thrombocytosis is frequent in RA; however, ET can be diagnosed by JAK2V617F evaluation in peripheral blood in thrombocytosis, especially when platelet count is more than 1 million/ml and when persisting thrombocytosis is detected in RA remission.     

Hemostatic complications in young patients with essential thrombocythemia

PURPOSE: The purpose of this study was to determine the incidence of hemostastic complications in young patients with essential thrombocythemia (ET). PATIENTS AND METHODS: The clinical course of 44 patients under the age of 45 with the diagnosis of ET was reviewed in a retrospective manner. Patients were collected from three medical centers in the United States and Italy: the Brigham and Women's Hospital and the Harvard Community Health Plan, Boston, Massachusetts, and the Ospedali Riuniti di Bergamo, Bergamo, Italy. RESULTS: The overall incidence of hemorrhage or thrombosis, or both, in this group of patients was 39% (17 of 44), with serious complications occurring in 23% (10 of 44). Two patients died of thrombotic events. Neither the presence of symptoms at diagnosis nor any single laboratory parameter proved predictive of clinical sequelae. Treatment with antiplatelet drugs or platelet-lowering agents was not protective. CONCLUSION: We conclude that ET in young patients may result in serious and life-threatening hemostatic problems and consequently that young age is not a favorable prognostic factor in this disease.     

The predictive value of vascular risk factors and gender for the development of thrombotic complications in essential thrombocythemia

 The impact of the cardiovascular risk factors smoking, hypertension, hypercholesterolemia, and diabetes mellitus on the risk of thrombotic complications was evaluated retrospectively in 132 patients with essential thrombocythemia (ET). The median age at diagnosis was 51 years, and the median follow-up time was 65 months. Sixty-three out of 132 patients (48%) had one or more vascular risk factors, whereas 69 patients (52%) had no risk factors. Thirty-two patients were smokers, 27 had hypertension, 21 hypercholesterolemia, and four diabetes mellitus. During the follow-up, 53 patients (40%) had 98 arterial thrombotic events, half of which were disturbances of cerebral circulation. Fifteen patients (11%) experienced 27 venous thrombotic events. The presence of one or more vascular risk factors increased the risk of arterial thrombotic complications. Of the patients, 52% with one or more vascular risk factors and 29% of those without any risk factors had arterial thrombosis (P=0.01). In multivariate analysis the only independent risk factor was smoking (P=0.01). Male gender increased the risk of arterial thrombosis significantly. Thirty-six out of 62 men (58%) but only 17 out of 70 women (24%) had an arterial complication (P<0.001). Smoking had a strong predictive value for the development of arterial complications in women but not in men. Among women 9/15 (60%) of the smokers and 12/82 (15%) of the non-smokers experienced arterial thrombosis (P= 0.002), whereas among men no difference between smokers and non-smokers could be found. According to the present findings, the male gender should be regarded as a risk factor when deciding about the indication for treatment. Smoking should be discouraged especially among women with ET. Received: 28 January 2000 / Accepted: 18 August 2000     

Predictive values of X-chromosome inactivation patterns and clinicohematologic parameters for vascular complications in female patients with essential thrombocythemia

Essential thrombocythemia (ET) is a heterogeneous disorder in which the clonality of hematopoiesis varies. The clinical significance of clonality status in ET remains to be determined. We used the human androgen receptor gene (HUMARA)-polymerase chain reaction assay to investigate X-chromosome inactivation patterns (XCIPs) and their value in predicting vascular complications in 89 female patients with ET. Fifty-four (68.4%) patients had a clonal pattern of XCIP, and 15 (19.0%) had a polyclonal pattern. The remaining 20 patients had either an ambiguous or a homozygous pattern of XCIP and were therefore excluded from further analysis. Patients with clonal XCIPs were older (P =.029) and were at greater risk for thrombosis (P =.007) than were those with polyclonal XCIPs. We did not find a correlation between the occurrence of hemorrhage and XCIP (P =.492). Advanced age was predictive of thrombosis and hemorrhage. Platelet count did not influence the risk for vascular complications. Hypertension was significantly correlated with thrombotic events (P =.002), whereas diabetes mellitus and hypercholesterolemia were of no predictive value. In a multivariate analysis, age was the significant predictor of thrombosis (P =.030); however, XCIPs (P =.083) and hypertension (P =.073) tended to predict thrombosis. Our results suggest that older patients who have clonal XCIPs or hypertension are at increased risk for thrombosis and should be monitored closely for this complication.     

Leukocyte-platelet interaction in patients with essential thrombocythemia and polycythemia vera

OBJECTIVE: Circulating polymorphonuclear leukocyte (PMN) activation occurs in patients with essential thrombocythemia (ET) and polycythemia vera (PV). We want to define whether this phenomenon plays a role in the formation of circulating PMN-platelet aggregates in these conditions. METHODS: In 80 patients (46 ET and 34 PV) and 50 control subjects, we conducted a flow cytometric analysis to evaluate the levels of PMN-platelet aggregates (defined as the percentage of CD11b-positive PMN coexpressing a platelet-specific marker, i.e., CD42b or CD62P) and the levels of activated PMN and activated platelets. In addition, the in vitro PMN-platelet aggregate formation in response to N-formyl-methionyl-leucyl-phenylalanine (f-MLP)-induced activation of PMN was studied. RESULTS: Significantly high PMN-platelet aggregates in ET and PV patients were found and were associated with increased PMN surface CD11b and surface platelet CD62P expression. In vitro f-MLP stimulation upregulated PMN-CD11b expression and simultaneously increased CD11b/CD42b and CD11b/CD62P aggregates, without affecting platelet surface antigens. In ET patients receiving aspirin, the increments in f-MLP-induced PMN-CD11b and in PMN-platelet aggregates were significantly lower versus ET subjects not treated with aspirin. CONCLUSION: Our data show that in ET and PV patients PMN activation plays an important role in increasing circulating PMN-platelet aggregates and suggest that aspirin treatment may decrease their formation.     

The association of JAK2V617F mutation and leukocytosis with thrombotic events in essential thrombocythemia

OBJECTIVES: The Janus kinase 2 mutation, JAK2 (V617F), and megakaryocytic mutations, MPL (W515L/K), have been identified and correlated with a subtype of essential thrombocythemia (ET) patients. We investigated the frequency of mutations in ET patients and analyzed the relationship with their clinical features. METHODS: Fifty-three ET patients were enrolled in the study. The amplification refractory mutation system was applied for the mutation survey of the JAK2V617F, while the polymerase chain reaction with sequencing was used for the mutation survey of MPLW515L/K. RESULTS: Thirty-five (66%) patients harboring the JAK2 (V617F) mutation, including 3 homozygous and 32 heterozygous changes, but no MPLW515L/K mutation, were found. During follow-up, 17 (32.1%) patients suffered from documented thrombotic events, with 15 having JAK2V617F mutations. Statistical analysis showed that patients with the JAK2 mutation had significantly higher leukocytes, hemoglobin level, and thrombotic event (p = 0.043, p = 0.001, and p = 0.029, respectively). Thrombotic events were also significantly correlated with leukocytosis and older age. CONCLUSIONS: The JAK2V617F mutation was noted in a certain population of ET patients and correlated with leukocytosis, high hemoglobin level, and thrombosis. Therefore, detection of the JAK2V617F mutation can affect not only the diagnosis, but also the management of ET patients.     

Correlation of blood counts with vascular complications in essential thrombocythemia: analysis of the prospective PT1 cohort

Essential thrombocythemia, a myeloproliferative neoplasm, is associated with increased platelet count and risk of thrombosis or hemorrhage. Cytoreductive therapy aims to normalize platelet counts despite there being only a minimal association between platelet count and complication rates. Evidence is increasing for a correlation between WBC count and thrombosis, but prospective data are lacking. In the present study, we investigated the relationship between vascular complications and 21 887 longitudinal blood counts in a prospective, multicenter cohort of 776 essential thrombocythemia patients. After correction for confounding variables, no association was seen between blood counts at diagnosis and future complications. However, platelet count outside of the normal range during follow-up was associated with an immediate risk of major hemorrhage (P = .0005) but not thrombosis (P = .7). Elevated WBC count during follow-up was correlated with thrombosis (P = .05) and major hemorrhage (P = .01). These data imply that the aim of cytoreduction in essential thrombocythemia should be to keep the platelet count, and arguably the WBC count, within the normal range. This study is registered at the International Standard Randomized Controlled Trials Number Registry (www.isrctn.org) as number 72251782.     

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.     

Pregnancy complications predict thrombotic events in young women with essential thrombocythemia

Although Philadelphia‐negative myeloproliferative neoplasms (MPNs) occur typically in middle to advanced age, any age group may be affected, posing a challenge for their management during pregnancy when they occur in young females. There is a high incidence of thromboembolic events and pregnancy complications in patients with myeloproliferative neoplasms, and a possible relationship between these complications is a matter of concern. The aim of this article was to correlate thrombosis and pregnancy outcome in 158 females with ET experiencing 237 pregnancies. Seven patients had a thrombotic event before their first pregnancy, one of them ended (14.3%) in a miscarriage. Among the 151 patients with no history of thrombosis before they became pregnant, 40 (26.5%) had a miscarriage (P = NS). Eighteen patients (11.4%) developed major thrombotic complications (12 splanchnic vein, 1 cerebral vein, 2 coronary syndromes, and 3 strokes) after at least one pregnancy (4 uneventful and 14 complicated). The occurrence of thrombosis was significantly more frequent (P < 0.001) in patients with a history of pregnancy complications (28%) than in those experiencing a normal pregnancy and delivery (3.7%). Pregnancy complications in women with ET are associated with a higher risk of subsequent thromboses, so pregnant women with this neoplasm who miscarry need to be carefully monitored. Am. J. Hematol. 89:306–309, 2014. © 2013 Wiley Periodicals, Inc.     

Thrombospondin in essential thrombocythemia

Essential thrombocythemia is a myeloproliferative disorder characterized by frequent bleeding and thrombotic complications. On a molecular level, two abnormalities of platelet thrombospondin have been identified: abnormal glycosylation of the intact 185,000-dalton chain has been detected and a shortened form of the thrombospondin chain is present. We have used two monoclonal antibodies and Lens culinaris lectin to probe the structure of thrombospondin in the platelets from three patients with essential thrombocythemia; one patient with polycythemia vera and two patients with secondary thrombocytosis. The presence of abnormal thrombospondin fragments with molecular weights of 160,000 and 30,000 was detected in the intact platelets and in the supernatant from thrombin-treated platelets, in all of the individuals except one of the secondary thrombocytosis patients. Monoclonal antibody binding studies indicate that both fragments are produced by proteolysis at a single site, which results in the removal of a 30,000- dalton fragment from the NH2-terminal. Lens culinaris lectin-binding studies revealed that some of the carbohydrate moieties of thrombospondin are near this cleavage site. The results are consistent with the hypothesis that the abnormal thrombospondin fragments observed under conditions of increased platelet production are due to increased susceptibility to proteolysis which, in turn, may be due to defective glycosylation.     

Thrombotic complications in essential thrombocythemia (ET): clinical facts and biochemical riddles

Hemostatic complications which can occur in the arterial or venous vasculature or in the microcirculation are the major causes of morbidity and mortality in patients with ET. In order to prevent these complications, often platelet reductive drugs are used. These agents are by themselves potentially toxic, i.e. may cause leukemia or cardiac side effects. In order to avoid these adverse effects, a better understanding of the mechanism of thrombus formation which is causative in ET is mandatory. Unfortunately, until now, no biomarkers have been identified which allow the estimation of the risk of thrombotic complications. Platelet number is not a good predictor per se since thrombotic complications can occur in some patients at low platelet numbers whereas others do not encounter a thrombosis even at very high platelet levels. On the other hand, lowering of the platelet count usually results in symptomatic improvement. In ET, morphological alterations of the megakaryocyte in the bone marrow and the circulating platelets are observed: megakaryocyte nuclei show a staghorn appearance, circulating platelets are characterized by anisocytosis and giant size. Functional studies indicate that these anatomically altered platelets function abnormally. When platelets are analyzed with a platelet function analyzer (PFA-100, which uses cartridges that measure how well a patient's platelets adhere and aggregate to form a platelet plug in the first phase of thrombus formation), in many patients with ET, closure time using collagen/ADP and collagen/epinephrine cartridges is prolonged. This seems paradoxical since these patients do not show an increased bleeding time. These results indicate that either receptors and/or consecutive signaling events are abnormal in ET platelets. Proteomic analysis of platelets of ET patients has revealed individual differences but not yet led to the identification of disease-specific proteins. Moreover, the search for alternative risk factors (factor V Leiden, prothrombin gene polymorphism, etc.) has not provided evidence for the contribution of these factors to the generation of the thrombotic risk in ET patients. In summary, despite intensive research over several decades, relatively little is known about the pathogenesis and risk factors for thrombosis in ET. I expect that this conference will contribute to the development of new strategies to identify patients at risk for hemostatic complications.     

Treatment of essential thrombocythemia

PURPOSE: Essential thrombocythemia (ET) is a myeloproliferative syndrome that rises many therapeutic problems. This affection is rarely life threatening, but hemorrhagic and thrombotic complications must be prevented when possible. The rarity of these complications makes difficult the assessment of treatment efficiency. Few randomised clinical trials were done, and treatment often rests on retrospective studies. The potential toxicity of treatments, their leukemogenicity in particular, rises a decisional problem for young patients. We propose to review available data in order to propose the most rational treatment for each patient. CURRENT KNOWLEDGE AND KEY POINTS: After numerous years when we only disposed of retrospective studies, non-randomised prospective studies or isolated case-reports, two randomised trials allows us to more precisely define ET treatment. The first trial proved the efficiency of the hydroxyurea-aspirin association in the prevention of thrombotic events in high-risk patients. The second trial signalled to our attention the increased risk of bleeding of the association anagrelide-aspirin, with also the possibility of increased appearance of myelofibrosis. FUTURE PROSPECTS AND PROJECTS: New perspectives in the treatment of ET will require to get more insights in the role of hydroxyurea and anagrelide in particular by longer follow-up. But not less important is a better definition of the thrombosis risks (who has to be treated?) and also of the diagnostic groups since ET can, in some particular cases, be misdiagnosed with polycythemia vera or idiopathic myelofibrosis.     

Neurological disorders in essential thrombocythemia

Patients with essential thrombocythemia often complain of various subjective neurological symptoms. This prospective study aims to assess their incidence and response to therapy. Among 37 consecutive patients with essential thrombocythemia, 11 presented with neurological symptoms. Among them 4 had thrombotic events, 7 complained of transient or fluctuating subjective symptoms, and one had both. Brain magnetic resonance imagery failed to detect any substratum in patients with subjective symptoms. JAK2V617F mutation was found in 9 of 11 patients with neurological symptoms versus 14 of 26 patients without symptoms. Ten patients received low-dose aspirin for these symptoms: complete resolution was observed in 3, improvement with persisting episodes in 2, and resistance to aspirin in 2 patients, in whom addition of cytoreductive therapy became necessary to resolve those disabling symptoms. In this prospective cohort, 30% of patients with essential thrombocythemia presented neurological symptoms. Aspirin was fully efficient in only 30% of cases. JAK2V617F mutation could be a risk factor for such symptoms.