Cytoreductive Strategies in Patients with Different Vascular Risk
The most appropriate cytoreductive strategy in the individual patient has to be chosen on the basis of the vascular risk. Most young patients with no vascular history have a low or intermediate vascular risk. Patient older than 65 years with three traditional cardiovascular risk factors and patient with previous vascular event should be considered at the same risk (see Table 10.1).
In the chart reported in Table 10.1, patient assignment to a certain risk level is made by the use of a scoring system. This system has the advantage of considering the impact of age in a more progressive manner than that based on a single threshold level and considers several other cardiovascular risk factors.Also some laboratory disease-related parameters are considered. For example, a high white blood cell count might contribute to change the patient’s risk stratification (Landolfi et al. 2007; Carobbio et al. 2007; Alvarez-Larrán et al. 2007). Multivariate analysis of data from the ECLAP observational study arm in PV patients showed that the risk of arterial thrombosis, particularly of myocardial infarction, was increased in patients with white blood cell count higher than >10 χ 109/L. This increase was statistically significant when WBC was higher than 15 χ 109/L (hazard ratio 1.71; 95% confidence interval 1.10-2.65; P=0.0171) (Landolfi et al. 2007) . Leukocytosis was found a risk factor for thrombosis also confirmed in ET subjects (Carobbio et al. 2007; Gangat et al. 2007).
There is currently no evidence that cytoreduc-tive treatment other than phlebotomy is needed for low- and intermediate-risk PV patients with PV. Cytoreductive therapy for both PV and ET is not curative, and there is little evidence to suggest a favourable effect on thrombosis-free survival. However, this is based on studies of relatively small size, and additional data from large clinical trials are needed. Avoiding cytoreduction is generally recommended also for low-risk ET patients. Thrombotic deaths seem very rare in low-risk ET patients, and there are no data indicating that fatalities can be prevented by starting cytoreduc-tive drugs early. Treatment of intermediate ET risk subjects is quite controversial since the thrombotic risk may not be high enough to justify the use of potentially mutagenic or toxic drugs. The safety of hydroxyurea is still debated while anagrelide is associated with several side effects which include palpitations, congestive heart failure, headache and depression, and its long-term effects are unknown. Also IFN therapy has well-known side effects. Thus, treatment of intermediate-risk subjects must be individualized, with frank discussion with the patient regarding the potential risks and side effects of cytoreductive therapy. An indication to cytoreductive treatment is extreme thrombocytosis (i.e., platelet count >1,500 χ 109/L) or the presence of bleeding symptoms since aspirin use may cause major bleeding in these subjects. Interferon-a is preferred to HU in high-risk women of child-bearing potential.
Interferon is also the first choice in all the subjects intolerant or resistant to HU (Kiladjian et al. 2008). Anagrelide has a potent platelet-reducing activity devoid of leukemogenic potential and may be an alternative to HU in younger patients. Risks and benefits of this drug were evaluated in large retrospective analysis (Fruchtman et al. 2005) and by a randomized clinical trial comparing anagrelide and HU (Harrison et al. 2005) in aspirin-treated ET subjects. This trial showed the superior efficacy of HU, thus indicating that in high-risk patients, anagrelide should be used in subjects resistant or intolerant to HU or in young subjects with intermediate vascular risk.
Secondary Prevention
A large retrospective study by De Stefano et al. analysed a cohort of 494 high-risk patients (235 PV and 259 ET subjects) who had suffered from at least one major thrombotic event (De Stefano et al. 2008) . In this study, arterial thromboses accounted for 69% of thrombotic events, and cerebrovascular accidents were about 39% of these events. The re-thrombosis preferentially occurred in the same district of the first event as observed also in PV subjects followed in the ECLAP observational study (Landolfi et al. 2007). Hereditary thrombophilic states and high leukocyte were found to be associated with a higher risk of recurrence, thrombotic risk being higher in the 2 years after the first thrombotic event and slowly declining thereafter (De Stefano et al. 2008). In patients with first arterial thrombosis, aspirin use was associated with about a quarter of reduction in the risk of recurrence, thus showing a benefit similar to that observed in the general population of patients with previous myocardial infarction or previous cerebrovascu-lar event (Baigent et al. 2009). In fact, in patients with vascular history, aspirin reduces the risk of a vascular event (non-fatal myocardial infarction, non-fatal stroke or vascular death) by approximately one-quarter, this resulting from one-third reduction in non-fatal myocardial infarction, one-quarter reduction in non-fatal stroke and one-sixth reduction in death from a vascular or unknown cause (Baigent et al. 2009) . As reported in Table 10.1. all patients with vascular history should receive HU in addition to aspirin. In patients with very high thrombotic risk or having a recurrence while receiving aspirin, a different and more aggressive antithrombotic treatment may be considered, according to the type of event. Below, we discuss the antithrombotic strategy to be chosen in the secondary prevention of cere-brovascular and cardiovascular events as well as after venous thromboembolism.
Secondary Prevention of Cerebrovascular Events
In this paragraph, we will not discuss the use of thrombolytic therapy in acute stroke. We have no data about these treatments in MPNs subjects. However, in selected cases, according to current guidelines, the use of thrombolytic drugs such as recombinant tissue plasminogen activator (r-TPA), streptokinase, or urokinase might be safe also in these patients.
In acute ischemic stroke, in the absence of contraindications, clinicians should administer aspirin therapy (initial dose of 150-325 mg followed by 75-100 mg/die) (Albers et al. 2008). The use of aspirin within 48 h of stroke onset can reduce both stroke recurrence risk and mortality (Sandercock et al. 1997; Chen et al. 1997), while there is no evidence that early treatment with anticoagulants decreases mortality.
Moreover, it is reasonable that PV or ET patients with stroke should also begin HU in order to minimize their risk (starting dose 500 mg twice per day). The dose of HU is aimed to keep platelet count lower than 400 χ 109/L and leukocyte count higher than 2 χ 109/L.As in general population, also in MPNs, subjects with stroke, oral anticoagulation can be suggested only in case of concomitant atrial fibrillation with rheumatic heart disease, prosthetic heart valves, or intrac-ardiac thrombus, documented intraluminal thrombus, or arterial dissections (Albers et al. 2008). Aspirin may be used safely in combination with low-dose heparin also for deep venous thrombosis prophylaxis. In fact, venous thrombosis is a frequent complication of stroke, with about 5% of early deaths attributed to pulmonary embolism (Collins et al. 1994).
In general population, the combination of aspirin 25 mg and extended-release dipyridamole 200 mg twice daily, and clopidogrel 75 mg/die are all acceptable options for secondary prevention stroke or TIA. However, in MPNs, aspirin use seems to have an efficacy on cerebral isch-emic events not found in other clinical conditions, and this may be related to the suggested role of thromboxane hyperproduction in the thrombotic tendency of these patients. In PV and ET patients with history of cerebrovascular disease, aspirin use was found associated with a 67% reduction in the risk of recurrence (De Stefano et al. 2008). However, in patients having a stroke recurrence under aspirin treatment, the combination of aspirin with dipyridamole or the use of clopidogrel can be considered.
Secondary Prevention in Acute Coronary Syndromes
Antithrombotic therapy is a mainstay in the management of patients with acute coronary artery disease. As in general population, PV and ET patients with acute coronary syndrome should be treated with aspirin initially at a dose 160-200 mg and then indefinitely at a dose of 75-100 mg/die in the absence of contraindication. In all patients, aspirin should be associated with clopidogrel at a daily dose of 75 mg, and this dual treatment should be continued for at least 12 months (Becker et al. 2008) . In case of allergy to aspirin, only clopidogrel can be prescribed. Moreover, ACE inhibitors and beta-blockers have to be continued indefinitely in all patients, and clinicians have to assess fasting lipid profile within 24 h of hospital-ization and initiate lipid-lowering medication to maintain low-density lipoprotein cholesterol lower than 100 mg/dL. For patients with a large anterior myocardial infarction, significant heart failure, intracardiac thrombus shown by transtho-racic echocardiography, atrial fibrillation, and with a history of a thromboembolic event, we suggest the combined use of moderate-intensity (INR, 2.0-3.0) oral VKA plus low-dose aspirin (<100 mg/day) for at least 3 months after acute coronary event. All these recommendations are based on studies performed in the general population. In MPNs, patients with coronary syndromes, an aggressive pharmacological cytoreduction is also recommended since several findings indicate that hydroxyurea is very effective in secondary prevention of coronary syndromes (Harrison et al. 2005; De Stefano et al. 2008).
For all MPN patients with previous acute coronary syndromes, the use of HU and low-dose aspirin (75-100 mg/die) is mandatory. Although there is no convincing evidence of a differential efficacy of aspirin and hydroxyurea in the various arterial districts, patients with previous myocardial infarction should be treated with these two agents with a possible indication to a more aggressive use of hydroxyurea in subjects with previous myocardial infarction and persistent leukocytosis. In fact, in a prospective study performed from GIMEMA-MPD Group (De Stefano et al. 2008), a multivari-ate analysis showed that cytoreduction was independently effective in preventing recurrence of thrombosis and reduced the risk by 47%. This efficacy resulted more pronounced in patients with a first coronary syndrome, in which there was a 70% reduction in the risk of a recurrence of coronary event (De Stefano et al. 2008). In addition, leukocytosis was found associated with a high risk of MI recurrence (Landolfi et al. 2007).
For patients with previous large anterior MI, significant heart failure and atrial fibrillation, the combined use of moderate-intensity (INR, 2.0-3.0) oral VKA plus low-dose aspirin (<100 mg/day) for at least 3 months after the MI can be suggested.
Finally, one should consider the possibility that in patients at very high vascular risk, the association of aspirin with clopidogrel might be continued for more than the recommended 12 months.
Secondary Prevention of Venous Thromboembolism
Treatment of venous thrombosis in PV and ET patients should not differ from that recommended in the general population (Hirsh et al. 2008; Geerts et al. 2008) where unfractionated heparin, low molecular weight heparins, or fondaparinux are used whenever a rapid anticoagulation is needed, and oral anticoagulants are the treatment of choice beyond the acute phase.
Low molecular weight heparins, in comparison to unfractionated heparin, have a more predictable anticoagulant activity since a variable resistance to unfractionated heparin may arise from increased heparin clearance, elevations in fibrinogen or factor VIII levels and elevations of heparin-binding proteins in plasma. Among these proteins, one has to consider the role of platelet factor 4, which is likely to be more abundantly released in patients with thrombocytosis and/or increased platelet activation (Gayoso 1999). This might support the preferential use of low molecular weight heparins in MPN subjects (Landolfi et al. 2008) .
Unfractionated heparin is preferred in patients with renal failure or in case of low molecular weight heparins unavailability. Acute treatment with heparins has to be initiated as soon as possible with oral anticoagulant and continued until INR is >2.0 for at least 24 h.
In the general population, oral anticoagulation is continued for at least 3 months. Longer treatment durations are recommended in cases of recurrence or in presence severe of a major throm-bophilic condition. Myeloproliferative neoplasms are one of such states, but decisions on optimal treatment duration have to consider additional variables such as the treatment of underlying disease as well as the location of thrombosis. Deep vein thrombosis of lower limbs in patients with unrecognized disease or in subjects not receiving chemotherapy can be treated by cytoreduction and a short-term anticoagulation (3-6 months) followed by low-dose aspirin. In fact, differently from general population, in patients with MPNs, aspirin seems efficacious also in venous throm-boembolism (Landolfi et al. 2004; De Stefano et al. 2008). Therefore, in case of a first venous thrombosis, an indefinite use of aspirin could be acceptable as an alternative strategy after a limited period of oral anticoagulant therapy.
Long-term treatment of VTE manifesting in patients receiving chemotherapy and aspirin may be more controversial.
Cytoreduction in patients with first venous thrombosis resulted associated with about a 30% reduction in the risk of recurrence (De Stefano et al. 2008). In PT-1 trial HU, aspirin-treated patients seemed to show a lower efficacy in preventing venous thromboembolism compared to anagrelide (Harrison et al. 2005) .
Concluding Remarks
The search for new antithrombotic strategies for PV and ET subjects has undoubtedly become a priority for future research. Early recognition of the myeloproliferative disorder and wider use of aspirin and cytoreduction have likely contributed to lower the incidence of thrombotic events. However, thrombotic recurrences in patients with thrombotic history remain unacceptably high. Physicians’ awareness of such a high risk needs to be increased in order to avoid an overestima-tion of the neoplastic risk of hydroxyurea in high-risk young subjects and/or of the bleeding risk of patients with gastrointestinal symptoms. In addition, in very high-risk patients, the association of hydroxyurea and aspirin, which is currently viewed as an aggressive treatment, does not seem well suited to the patients’ risk level. This calls for the adoption of more aggressive antithrom-botic or cytoreductive strategies or for the search for novel treatment approaches.
