Thrombosis in myeloproliferative and myelodysplastic syndromes

Abstract

Myeloproliferative neoplasms (MPNs) and myelodisplastic syndromes (MDs) are clonal disorders caused by mutations of myeloid stem cells. Among MPNs, polycythemia vera and essential thrombocythemia are relatively benign disorders in which arterial and venous thromboses represent the main cause of morbidity and mortality. The natural history of MDs is often complicated by both thromboses and haemorrhages, mainly due to platelet quantitative and quantitative anomalies, as well as to treatment complications. In this short review, we focus the attention on the main aspects of thrombophilia in both disorders.

Keywords:

• Thrombosis
• Myeloproliferative neoplasms
• Myelodisplastic syndromes
• Clonal disorders

Thrombosis in Myeloproliferative Neoplasms

Thrombophilia in subjects with myeloproliferative neoplasms (MPNs) is characterized by an increased incidence in arterial and venous thromboses and by peculiar microcirculatory disturbances.1 Arterial thromboses represent 60–70% of all cardiovascular events and include acute myocardial infarction, cerebral, and peripheral arterial occlusion. Venous thromboembolism is also a frequent complication of MPNs and may involve atypical sites such as abdominal veins or cerebral sinuses. Microcirculatory disturbances are mainly represented by erythromelalgia, headache, dizziness, hearing and visual disturbances, and Raynaud-like phenomena.1,2

Identifying the safest and most effective strategy for reducing the vascular risk of MPNs subjects is critical, particularly in subjects with polycythemia vera (PV) and essential thrombocythemia (ET), in whom thrombotic events can heavily affect life quality and expectancy.2

The pathogenesis of thrombosis in MPNs has been extensively investigated by particularly focusing on the possible contribution of disease related haemostatic abnormalities. However, the mechanisms underlying the thrombotic diathesis of MPNs patients are still largely elusive and, more importantly, the number of large scale studies performed in this specific setting is too limited for investigating the relative role of the various abnormalities.1,2 In addition, the pathogenesis of thrombosis is multifactorial and the type of interplay between haemostatic and other disease-related abnormalities, such as leukocyte count and JAK2^V617F status with individual and environmental factors, remains debated.3

Quantitative and qualitative red blood cell, platelet, and leukocyte abnormalities seem to play a key role in MPN thrombophilia. In PV patients, high shear stress in the vessel wall, due to blood hyperviscosity, accounts for chronic endothelial dysfunction and platelet and leukocyte activation.3 Multivariate analysis of data from the European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) observational study showed that the risk of arterial thrombosis, particularly of myocardial infarction, increased in patients with white blood cell count higher than 10×10⁹/l.4 Leukocytosis as a risk factor for thrombosis was also confirmed in ET subjects.5 For assessing the individual vascular risk, physicians have to rely on approximate and largely subjective estimations and on consensus based recommendations. In any case, since thrombosis represents an important complication of MPNs, an effective antithrombotic strategy has to be adopted as soon as the disorder is diagnosed and, above all, an adequate and individual vascular risk stratification should guide treatment decisions.6

Thus, the antithrombotic strategy is quite different in patients having a low, intermediate, or high vascular risk. This risk stratification mostly relies on age and past thrombotic history. Patients aged <60 years who have no additional risk factors can be considered at low vascular risk, while the presence of diabetes or two other classical cardiovascular risk factors (hypertension, dyslipidemia, obesity) makes the vascular risk intermediate.6,7 The presence of MPNs should raise further attention towards the need for adequately recognizing and treating any modifiable vascular risk factor and for encouraging the patient towards a healthy life style. Particular attention has to be given to smoking habit, which has an important effect on vascular risk and was found to be surprisingly common among PV patients recruited in the ECLAP observational study,4 as well as to patient older than 65 years or with a history of previous thrombosis.

The antithrombotic strategy shall include, in addition to effective intervention on risk factors, treatment of blood hyperviscosity as well as aspirin use in the majority of MPN subjects.

The hypothesis of a high aspirin efficacy in MPNs is supported by both clinical and pharmacological studies.1^–3 The same microvascular disturbances among patients with PV and ET have been attributed to platelet aggregate formation and have been shown to be selectively sensitive to aspirin.2 This evidence has allowed attribution of the pathogenesis of these disturbances and large vessels thrombosis to a thromboxane A2-dependent mechanism. Thromboxane biosynthesis is relatively independent from haematocrit, platelet count, treatment, and clinical history, thus suggesting abnormal in vivo platelet activation selectively sensitive to aspirin.

Risks and benefits of a low-dose aspirin were assessed by the ECLAP study.8 This trial randomized 532 PV subjects to receive aspirin (100 mg) or placebo. After a follow-up of about 3 years, data analysis showed a significant reduction (risk ratio: 0·41) of major thromboses (both arterial and venous) without a significant increase in haemorrhagic complications in the aspirin group. The high aspirin efficacy and the uniform sensitivity of all events to this agent support the hypothesis of a key role of platelet thromboxane in the pathogenesis of PV thrombophilia.8

Aspirin at low doses (75–100 mg/day) is currently used in all subjects having no contraindication to this agent.

In very low-risk subjects, risks and benefits of low-dose aspirin should be carefully balanced. In these patients, a decision on aspirin use has to be taken after considering history of bleeding, gastrointestinal symptoms, and other factors which may influence the thrombotic and/or haemorrhagic risk. These factors, in the particular setting of ET subjects, include the JAK2 status, the platelet count, and the presence of microcirculatory symptoms, generally sensitive to aspirin. In any case, aspirin is indicated in patients at intermediate risk and is strongly recommended in subjects at higher risk levels.

An accurate evaluation of the vascular risk has to be used particularly for tailoring the cytoreductive intervention in each patient. Treatment of blood hyperviscosity has to be a primary objective in PV subjects. Recent findings have raised the issue that probably treatment might safely target values higher than those generally accepted. While waiting for future studies, it seems prudent to recommend, as rational targets, haematocrit values of 0·42 and 0·45 in female and male subjects, respectively.1,6

Past thrombotic history has an important predictive role in patients with PV and ET. Recurrences generally occur in the same district of the first vascular event, so strategies for secondary prevention could be differentiated according to the type of the first event. In the general population secondary prevention of venous thrombosis relies on short- or long-term anticoagulation, while secondary prevention of arterial events is largely based on aspirin. The latter may be associated to clopidogrel in acute coronary syndrome or to dipyridamole after ischaemic stroke or transient ischaemic attack. Whether these recommendations can also apply to PV and ET patients is currently unclear.

The search for new antithrombotic strategies for PV and ET subjects has undoubtedly become a priority for future research. Early recognition of MPNs and wider use of aspirin and cytoreduction have likely contributed to lower the incidence of thrombotic events. However, thrombotic recurrence in patients with thrombotic history remains unacceptably high. This calls for the adoption of more aggressive antithrombotic or cytoreductive strategies or for the search for novel treatment approaches.1

Most investigators place much expectation on JAK2 inhibition as a rational approach for targeting an important mechanism leading to uncontrolled cell growth and possibly involved in the pathogenesis of the haemostatic imbalance. Several pharmaceutical companies have developed JAK2 inhibitors which are now under study. Whether they can effectively control cell proliferation might be established soon. However, the safety of these inhibitors and their capacity to reduce disease progression and thrombotic complications will require long-term studies. While waiting for the development of such promising new therapeutic tools, every effort has to be made for optimizing the use of available drugs.

Thrombosis in Myelodysplastic Syndromes

Myelodysplastic syndromes (MDs) are one of the most common haematological malignancies in Western countries.9 These neoplasms included five categories: refractory anaemia (RA), RA with ring sideroblasts, RA with excess of blasts, RAEB ‘in transformation’, and chronic myelomonocytic leukemia. Causes of death in MDS patients are usually related to the consequences of the leukaemic evolution or to clinical events outside leukemia, such as cardiac failure, infection, haemorrhage and hepatic cirrhosis.9 MD patients have a low baseline risk of thrombosis due to the high frequency of thrombocytopenia and severe anaemia. However, most patients are old and typically affected by several comorbid diseases, including vascular complications. Moreover, the possible role of central venous catheters and red cell transfusions in MD thrombophilia has to be considered. In MD patients, the burden of thrombotic events does not seem much higher than that of general population, but the weight of some treatments in increasing the thrombotic risk is under investigation.10,11 The vascular risk seems to increase significantly when chemotherapeutic drugs such as thalidomide or lenalidomide are used in association with erythropoiesis-stimulating agents, which do not seem to increase the thrombotic risk when used alone.12 However, no clinical trials are available and retrospective studies are quite limited in size.