Are MPNs Vascular Diseases?

MYELOPROLIFERATIVE DISORDERS (JJ KILADJIAN, SECTION EDITOR)

Are MPNs Vascular Diseases?

Guido Finazzi & Valerio De Stefano & Tiziano Barbui

Published online: 15 September 2013# Springer Science+Business Media New York 2013

Abstract A high risk of arterial and venous thrombosis is thehallmark of chronic myeloproliferative neoplasms (MPNs), par-ticularly polycythemia vera (PV) and essential thrombocythemia(ET). Clinical aspects, pathogenesis and management of throm-bosis in MPN resemble those of other paradigmatic vasculardiseases. The occurrence of venous thrombosis in atypical sites,such as the splanchnic district, and the involvement of plasmaticprothrombotic factors, including an acquired resistance to acti-vated protein C, both link MPN to inherited thrombophilia.Anticoagulants are the drugs of choice for these complications.The pathogenic role of leukocytes and inflammation, and thehigh mortality rate from arterial occlusions are common featuresofMPN and atherosclerosis. The efficacy and safety of aspirin inreducing deaths and major thrombosis in PV have been demon-strated in a randomized clinical trial. Finally, the Virchow’s triadof impaired blood cells, endothelium and blood flow is sharedboth by MPN and thrombosis in solid cancer. Phlebotomy andmyelosuppressive agents are the current therapeutic options forcorrecting these abnormalities and reducing thrombosis in thisspecial vascular disease represented by MPN.

Keywords Myeloproliferative neoplasms . Thrombosis .

Risk factors . Therapy . Hematologic malignancy

Introduction

Classical chronic myeloproliferative neoplasms (MPNs) includepolycythemia vera (PV), essential thrombocythemia (ET) and

primary myelofibrosis (PMF). These diseases are characterizedby a high frequency of arterial and venous thrombosis, as well asa tendency to transform into post-PVand post-ET myelofibrosisand acute leukemia. The understanding of the MPN pathophys-iology dramatically improved following the description of re-current molecular abnormalities, mainly represented by theV617F mutation in JAK2 exon 14, which involves >95 % ofPVand ≅60–70% of ETand PMF patients [1, 2]. The pattern ofvascular complications in MPN is unique and shares severalclinical and pathogenic aspects with different vascular diseasesthat also involve a high risk of thrombosis, such as inheritedthrombophilia, atherosclerosis and cancer. The aim of thispaper is to review thrombosis in the context of MPN, andespecially its similarities and differences with these well-known thrombophilic conditions.

Inherited Thrombophilia and Venous Thrombosisin MPN

Inherited Thrombophilia

The term thrombophilia describes a tendency to developthrombosis on the basis of inherited or acquired disorders ofblood coagulation or of fibrinolysis toward a prothromboticstate. Deficiencies of antithrombin (AT), protein C (PC), andprotein S (PS) were the first identified causes of inheritedthrombophilia [3, 4], hampering the two main inhibitory co-agulation systems: the inhibition of serine proteases by AT,targeting thrombin and factor Xa, and other coagulation en-zymes, including factors XIIa, XIa, IXa, and VIIa, and theinhibition of non-enzymatic factors VIIIa and Va by the acti-vated PC and its cofactor PS [5, 6]. Such deficiencies are rare,being present in less than 1 % of the general population and inless than 10 % of the patients with venous thromboembolism(VTE) [3, 4]. In the last two decades, two common genepolymorphisms were recognized as additional causes ofhypercoagulability: factor V G1691A Leiden (FVL), whichis resistant to the anticoagulant action of activated protein C,

G. Finazzi (*) : T. BarbuiDivision of Hematology, Ospedale Papa Giovanni XXIII, PiazzaOMS, 1, 24127 Bergamo, BG, Italye-mail: [email protected]

T. BarbuiResearch Foundation, Hospital Papa Giovanni XXIII, Bergamo, Italy

V. De StefanoInstitute of Hematology, Department of Medical Sciences, CatholicUniversity, Rome, Italy

Curr Hematol Malig Rep (2013) 8:307–316DOI 10.1007/s11899-013-0176-z

and prothrombin (PT) G20210A, which is associated withincreased levels of circulating prothrombin [3, 4]. The preva-lence rates of FVL and PT20210A are 5 % and 2–3 % amongindividuals with European ancestry, respectively, and 18 %and 7 % among patients with VTE, respectively [3, 4].

VTE is a common multifactorial disease and is the result ofgene–gene and gene–environment interaction [7]. A simplemodel based on two dichotomous factors (high-risk allele andexposure to an environmental risk factor) is not reliable inmost cases, due to incomplete clinical penetrance of geno-types during life, and to variable age of onset and severity ofthe disease. Moreover, clinical penetrance is modulated alsoby gene–gene interactions and by multiple effects of environ-mental risk factors, acting on the genotype by additive ormultiplicative ways.

There is consistent evidence for a risk gradient for VTE,which is higher in carriers of AT, PC, and PS deficiencies, andthose who are homozygous or carriers of multiple abnormal-ities (high-risk thrombophilia) and moderate in heterozygouscarriers of FVL or PT20210A (mild thrombophilia). In familystudies, the highest incidence of VTE was observed amongcarriers of an AT deficiency, with 0.9–4.0 % per individual-year [8, 9]. The risk for VTE among carriers of an AT, PC, orPS deficiency was 4- to 12-fold greater than that in non-carriers [8, 10]. On the other hand, the incidence of VTEamong the relative carriers of FVL and PT20210Awas lower:0.14–0.67 % per individual-year for FVL [8, 11] and 0.05–0.37 % per individual-year for PT20210A [8, 12].

Venous Thrombosis in MPN

Incidence and Type

Although arterial occlusions represent the major cause ofmortality in PVand ET, venous thrombosis (VT) is a frequentand clinically relevant complication. In the largest epidemio-logical study in PV, (European Collaboration on Low-doseAspirin, ECLAP), pulmonary embolism accounted for 8 % ofall deaths and the cumulative rate of non-fatal thrombosis was3.8 events per 100 persons per year, without difference be-tween arterial and venous types [13]. In prospective studies ofET, the incidence of VTwas approximately 1 % patient-years[14, 15] and in PMF non-fatal VTwas registered in 0.76 % ofpatients per year [16].

A typical complication associated with MPN is splanchnicvein thrombosis (SVT), including Budd-Chiari syndrome(BCS) and portal, splenic or mesenteric vein thrombosis.The prevalence of SVT in MPN ranges between 1 and 23 %[17, 18], and young women seem to be preferentially affected,possibly due to gender-specific factors such as hormonalstatus or contraceptive use [17]. The close relationship be-tween MPN and SVT has been pointed out by the highprevalence of the JAK2 V617F mutation in patients with both

SVT and BCS [19•, 20]. As thrombosis in splanchnic veinsmay be the first clinical manifestation, a careful search forMPN, including the JAK2 V617F mutation, should be carriedout in these patients, even in the presence of normal blood cellcounts [21].

SVT represents an epidemiological link between MPN andinherited thrombophilia since these conditions are the twomost frequent systemic risk factors associated with SVT(Table 1) [22]. Inherited thrombophilia is present in at leastone-third of the patients, and the factor V Leiden or theprothrombin G20210A mutations are the most common mu-tations. A meta-analysis showed a 4-fold and 3-fold increasedrisk of portal vein thrombosis for prothrombin G20210A andfactor V Leiden, respectively [23]. Multiple factors are presentin approximately one-third of patients with BCS and two-thirds of patients with portal vein thrombosis [22].

Pathogenesis: the Role of Plasmatic Prothrombotic Factors

A procoagulant background exists in MPN patients, whopresent with a hypercoagulable state, a subclinical conditiondemonstrated by the alterations of plasma markers of bloodclotting, i.e., thrombin-antithrombin complex, prothrombinfragment 1 + 2, and D-dimer [24]. More recently, the findingof an acquired resistance to activated protein C (APC) hasprovided an important tool to detect the prothrombotic state inMPN patients. By using the thrombin generation assay, an

Table 1 Frequency of systemic risk factors for Budd-Chiari syndromeand portal vein thrombosis (ref. [22])

Risk factors (%) Budd-Chiarisyndrome

Portal veinthrombosis

● Inherited

Antithrombin deficiency 2–5 1–2

Protein C deficiency 2–9 1–9

Protein S deficiency 3–7 1–5

Factor V Leiden 4–26 3–8

Prothrombin G20210A 3–8 3–22

● Acquired

Myeloproliferative neoplasms (MPN) 23–49 6–33

JAK2 V617F (with overt MPN) 57–100 78–100

JAK2 V617F (without overt MPN) 44 27

Antiphospholipid antibodies 1–11 3–13

Behçet’s disease 4–9

Autoimmune diseases 10–13 1–4

Paroxysmal nocturnal hemoglobinuria 2–19 1–2

● Circumstantial*

Oral contraceptives 15–50 15–30

Hormone replacement therapy 14 3

Pregnancy or puerperium 4–16 2–3

* percentage calculated on the number of women

308 Curr Hematol Malig Rep (2013) 8:307–316

APC resistance phenotype has been demonstrated in ET andPV patients, particularly in JAK2 V617F mutation carriers(Fig. 1) [25]. Acquired APC resistance was more frequentlyfound in ET patients with a previous history of thrombosis[26]. A decrease in free PS level seems to be the majordeterminant of APC resistance and can be due to PS cleavageby a protease from platelets [27]. Protein S cleavage wasindeed significantly increased in patients with ETand elevatedplatelet counts, and returned to normal values in ET sub-jects whose platelet counts had stabilized after hydroxy-urea treatment [28].

The results of several studies support the evidence that allhemostatic alterations are worse in the JAK2 V617F mutationcarriers than in the wild-type MPN population [29, 30]. Inter-estingly, the JAK2 V617F mutation was identified in the liverand spleen endothelial cells of patients with BCS [31, 32],suggesting a local prothrombotic state contributing to thepathogenesis of thrombosis in this special vascular district.

Risk Factors

Risk factors for VT in MPN are partially different from thoseobserved for arterial thrombosis, although, for practical rea-sons, these predictors are usually cumulated for a clinicalmanagement plan. In an international study of 891 patientswith ET, multivariable predictors of arterial thrombosis in-cluded age >60 years, thrombosis history, cardiovascular riskfactors including tobacco use, hypertension or diabetesmellitus, leukocytosis, and the presence of JAK2 V617F.Platelet counts higher than 1000 × 109/L were associatedwith a lower risk of arterial thrombosis (P = .007; HR =0.4). In contrast, only male gender predicted venous throm-bosis [33]. In addition, a systematic literature review showed

that JAK2 V617F patients have a 2-fold risk of developingthrombosis both of venous and arterial vessels (OR 2.49 and1.77, respectively) [34]. Notably, the frequency of geneticthrombophilic factors, such as FVL or PT20210A mutations,were higher in MPN cases with venous thrombosis,suggesting the need to perform these tests in youngerpatients with familial or personal history of thrombosis[35–37]. In ET, the presence of both JAK2 V617F andinherited thrombophilia has been reported to increase therisk of thrombosis [37].

Management

VT in MPN should be managed similarly to patients with apersistent risk factor (for instance, inherited thrombophilia)according to current guidelines [38]. In the largest study thatspecifically analyzed the incidence of recurrent thrombosisafter the first venous thromboembolic event in MPN, long-term oral anticoagulation was associated with a 63 % reduc-tion in the risk of recurrence without a significant increase inthe incidence of major bleeding (0.9 % patient-years), ascompared with patients without antithrombotic treatment(1.2 % patient-years) [39].

Full-dose heparinization followed by long-life oralanticoagulation therapy that achieves a prothrombin time(PT-INR) in the range of 2.0 to 3.0 is also recommended forSVT, despite the increased risk of gastrointestinal bleeding. Ina survey of the current outcome of portal vein thrombosis in136 patients, 42 (31 %) of which had a myeloproliferativedisorder, anticoagulant therapy reduced the risk of recurrenceor extension of thrombosis by two-thirds without any realincrease in the incidence or severity of bleeding [40]. InBudd-Chiari syndrome, intensive medical management

Fig. 1 Left panel . Resistance to activated Protein C (APC)—expressedas normalized APC sensitivity ratio (nAPCrs)—is increased in patientswith PV and ET compared to controls. Central panel. The nAPCsr isincreased in JAK2V617F carriers compared with noncarriers and was

highest in JAK2V617F homozygous patients. Right panel . The APC-resistant phenotype is inversely correlated and can be due to low freeProtein S (PS) levels. *P < .01 versus controls (ref. [25])

Curr Hematol Malig Rep (2013) 8:307–316 309

including anticoagulation is mandatory, but more aggressiveprocedures, such as trans-jugular intrahepatic portosystemicshunt, angioplasty with or without stenting, surgical shunts,and even in some instances liver transplantation should beconsidered in the most severe cases [41]. Joint managementwith a liver team, follow-up of varices, and advising about theeffects of these procedures on pregnancy are recommended[42••].

Atherosclerosis and Arterial Thrombosis in MPN

Atherosclerosis

Atherosclerosis is a leading cause of death and morbidityworldwide. Advances in basic science have established a fun-damental role for inflammation in mediating all stages of thisdisease, from initiation through progression and, ultimately, thethrombotic complications of atherosclerosis [43]. The disturbedequilibrium of lipid accumulation, immune responses and theirclearance is shaped by leukocyte trafficking and homeostasisgoverned by chemokines and their receptors. These new find-ings provide important links between the risk factors andmechanisms of atherogenesis. Clinical studies have shown thatthis emerging biology of inflammation in atherosclerosisapplies directly to human patients. Elevation in inflammationmarkers predicts the outcomes of patients with acute coronarysyndromes, independently of myocardial damage. In addition,low-grade chronic inflammation, as indicated by levels of theinflammatory marker C-reactive protein (CRP), prospectivelydefines the risk of atherosclerotic complications, thus adding toprognostic information provided by traditional risk factors.Moreover, certain treatments that reduce coronary risk alsolimit inflammation [44]. These new insights into inflammationin atherosclerosis not only increase our understanding of thisdisease, but also suggest novel pathogenic hypotheses for otherdiseases that involve a risk of thrombosis, such as MPN.

Arterial Thrombosis in MPN

Incidence and Type

Arterial thrombosis is themain cause of death inMPN patients.In the ECLAP study on PV, cardiovascular mortalityaccounted for 41 % of all deaths (1.5 deaths per 100 personsper year), mainly due to coronary heart disease (15 % of alldeaths), congestive heart failure (8 %) and non-hemorrhagicstroke (8 %) [13]. In ET, the rate of fatal and non-fatal throm-botic events ranged between 2–4 % patient-years and theincidence of arterial events was two to three times higher thanthat of venous events [14, 15]. In PMF, the overall cumulativerate of cardiovascular death and non-fatal thrombotic compli-cations was 2.23 events per 100 persons per year [16].

Pathogenesis: the Role of Leukocyte and InflammatoryMarkers

Prothrombotic features in MPN include the expression byblood cells of procoagulant and proteolytic properties, thesecretion of inflammatory cytokines, and the expression ofadhesion molecules. In addition to these mechanisms,prothrombotic changes occur in the normal vascular endothe-lium in response to the insults of inflammatory cytokines,hyperviscosity, and leukocyte-derived proteases. Specifically,the upregulation of endothelial adhesion receptors favors theattachment of platelets, erythrocytes and leukocytes to thevascular wall, with subsequent localization of clotting reac-tions and fibrin deposition.

Leukocytes have a central role in the inflammatory re-sponse and in the activation of the blood coagulation system[45]. In particular, the release of proteolytic enzymes (i.e.,elastase, cathepsin G) and reactive oxygen species (ROS),and the increased expression of CD11b on their surfaces canactivate/damage platelets and endothelial cells and impairsome coagulation proteins [46]. In patients with ET and PV,the occurrence of leukocyte activation is demonstrated by thedetection of specific phenotypic changes (increments inmembrane-associated CD11b) and increased plasma concen-trations of granule-derived proteases (i.e., elastase andmyeloperoxidase) [45, 46]. The adhesion of platelets to leu-kocytes and the formation of platelet-leukocyte aggregatesmediate the cross-talk between platelets, neutrophils andmonocytes (Fig. 2) [24, 47]. Data suggest that aspirin mayinhibit the interaction between neutrophils and platelets [48].

The association of elevated inflammatory markers withthrombosis in MPN has been demonstrated. In a study of244 patients with PV and ET, increased levels of CRP(>3 mg/L) correlated with age (P=0.001), phenotype (poly-cythemia vera vs. essential thrombocythemia, P=0.006), car-diovascular risk factors (P=0.012) and JAK2 V617F alleleburden greater than 50 % (P=0.003). The major thrombosisrate was significantly and independently increased in patientswith high levels of C-reactive protein (OR. 2.61 P=0.01),indicating that the highest levels of this biomarker doubledthe risk of thrombosis [49].

Risk factors

Currently, the classification of patients with either PVor ET ina “high-risk” or “low-risk” category for thrombotic complica-tions is based on increasing age and previous history ofthrombosis [42••]. More recently, leukocytosis was found tobe an independent risk factor for arterial thrombosis, particu-larly in acute coronary disease (Table 2) [33, 50]. PV patientswith WBC count >15,000 × 109/L, compared to those withWBC count <15,000 × 109/L, had a significant (70 %) in-crease of myocardial infarction [51]. Three large cohort


studies in ET reported that an increased baseline leukocytecount was an independent risk factor for both thrombosis andinferior survival [52–54]. ElevatedWBC count that developedduring follow-up was also correlated with major thrombosis(P< .05) [55].

Management

LowDose Aspirin The efficacy and safety of low-dose aspirin(100 mg daily) in PV was assessed in the ECLAP double-blind, placebo-controlled, randomized clinical trial [56]. Inthis study, 532 PV patients were randomized to receive100 mg aspirin or placebo. After a follow-up of about 3 years,data analysis showed a significant reduction of a primary,combined end-point including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and major venous

thromboembolism (relative risk 0.4 (95 % CI: 0.18-0.91),P=0.0277).

In ET, the efficacy of aspirin has not been tested in random-ized clinical trials. Low-dose aspirin (100 mg daily) controlsmicrovascular symptoms such as erythromelalgia and tran-sient neurological and ocular disturbances. A retrospectivestudy has suggested that antiplatelet therapy reduces the inci-dence of venous thrombosis in JAK2-positive patients and therate of arterial thrombosis in patients with associated cardio-vascular risk factors [57]. Interestingly, a recent study hasshown that the effect of once-daily low-dose aspirin inET is shorter-lasting through faster renewal of plateletcyclooxygenase-1 and suggests that impaired platelet inhibi-tion can be rescued by modulating the aspirin dosing intervalrather than the dose [58]. This new concept deserves to bevalidated in prospective studies, but prescribing low-dose

Fig. 2 Mechanisms promotingthe interaction of platelets,neutrophils and monocytes andthe production of prothromboticsubstances. ADP adenosinediphosphate GP glycoprotein, ILinterleukin, LAP leukocytealkaline phosphatase, LPSlipopolysaccharide, TNF tumornecrosis factor, TX thromboxane(ref. [47])

Table 2 Sites of thrombosis according to leukocytosis at diagnosis in 657 patients with ET (ref. [53])

7.1 to 10 × 109/LWhite Blood Cells* More than 10 × 109/LWhite Blood Cells*

HR (95 % CI) p HR (95 % CI) p

Major thrombosis 2.21 (1.05–4.65) 0.036 3.27 (1.54–6.95) 0.002

Arterial thrombosis 2.07 (0.83–5.20) 0.121 3.12 (1.20–8.08) 0.019

Myocardial infarction 5.82 (0.64–53.2) 0.118 8.08 (1.00–65.5) 0.050

Stroke/TIA 0.88 (0.29–2.67) 0.824 1.32 (0.42–4.11) 0.631

Venous thrombosis 1.40 (0.49–4.04) 0.534 2.51 (0.86–7.29) 0.092

Multivariable analysis adjusted for center, gender, standard cardiovascular risk factors, hemoglobin, hematocrit and platelet count

Statistically significant values are in bold

*Reference category: WBC ≤ 7 × 109 /L


aspirin twice daily to prevent severe arterial thrombotic recur-rence in MPN is now suggested [59].

Statins According to the evidence briefly reviewed herein, theuse of statins in the management of MPN has been advocated[60]. Recent in vitro data showed that statins induce apoptosisand inhibit JAK2 V617F-dependent cell growth. Statin treat-ment inhibited erythropoietin-independent erythroid colonyformation of primary cells from MPN patients, but had noeffect on erythroid colony formation from healthy individuals[61]. However, no clinical trials with statins in MPN patientshave been performed so far.

Cancer, Thrombosis and MPN

Cancer and Thrombosis

A relationship between cancer and thrombosis has been rec-ognized for almost 150 years, and each year brings additionaldata that confirms this association [62, 63]. Furthermore, alarge proportion of the terminal events in neoplastic diseasecases are thrombotic, leading to the hypothesis that cancer is aprothrombotic disease [64, 65]. Such thrombosis may occur inarteries and/or veins and, although the interest is more fre-quently focused on VT, approximately 25 % of thrombosiscases in cancer patients are arterial. Perhaps the oldest andmost dominant theory of the pathophysiology of thrombosis isthat of Virchow, which has three separate but overlappingparts: the contents of the blood, the blood vessel wall, andblood flow [66]. Indeed, patients with various cancers fre-quently demonstrate abnormalities in each component ofVirchow’s triad, leading to a prothrombotic or hypercoagulablestate. The mechanisms are likely to be multiple and, probably,synergistic. For example, tumor cells may be directlyprothrombotic, inducing thrombin generation, while normalhost tissues may stimulate (or be stimulated to) prothromboticactivity as a secondary response to the cancer. Nevertheless,Virchow’s triad gives us the opportunity to dissect and identifydifferent aspects of the causes of thrombosis.

Pathogenesis of Thrombosis in MPN: the Role of Virchow’sTriad

Blood Cells and Blood Flow

Abnormalities of blood cells arising from the clonal prolifer-ation of hematopoietic stem cells in MPN involve both quan-titative and qualitative changes that characterize the switch ofthese cells from a resting to a procoagulant phenotype.

The prothrombotic mechanisms of an increased number ofred blood cells have been clearly demonstrated in PV [67].Elevated hematocrit levels can increase the thrombotic risk by

multiple pathways. Under the low shear rates, as in the venousbed, a major thrombotic role is played by hyperviscosity,while at high shear rates, the rise of red blood cell massdisplaces platelets toward the vessel wall, thus facilitatingshear-induced platelet activation and enhancing platelet–platelet interactions. In addition, in ET and PV, biochemicalchanges in the cell membrane and intracellular content of redblood cells have been reported, leading to the formation of redblood cell aggregates and impaired blood flow [68]. Recently,in PV patients, an abnormal adhesion of red blood cells to thesub-endothelial protein laminin, due to the phosphorylation ofLu/BCAM by a JAK2 V617F pathway, has been shown [69].

Platelets in MPN patients circulate in an activated sta-tus, as assessed by the detection of increased expression ofsurface P-selectin and Tissue Factor [48, 70, 71], and bythe increased fraction of platelets phagocytosed by circu-lating neutrophils and monocytes [72]. Enhanced in vivoplatelet activation is further suggested by the finding ofincreased levels of platelet activation products both in theplasma (i.e., beta-thromboglobulin and Platelet Factor 4) andurine (i.e., thromboxane (Tx) A2 metabolites 11-dehydro-TxB2 and 2,3-dinor-TxB2) [73]. Activated platelets providea catalytic surface for the generation of thrombin, whichfurther amplifies their own activation. Accordingly, in ETand PV patients the thrombin generation induced by plateletswas found to be increased and associated with platelet activa-tion, particularly in carriers of the JAK2 V617Fmutation [74].

Endothelium

Several factors may perturb the physiological state of endothe-lium in MPN patients and turn it into a pro-adhesive andprocoagulant surface. In particular, reactive oxygen speciesand intracellular proteases released by activated neutrophilscan induce detachment or lysis of endothelial cells, affectingfunctions involved in thromboregulation [24]. High levels ofcirculating endothelial cells (resting, activated, apoptotic, andcirculating precursor endothelial cells) are measured in MPN[75–77]. In addition, high circulating levels of endothelial acti-vation markers, such as thrombomodulin, selectins and vonWillebrand Factor (vWF) are released and favor the formationof cellular aggregates [78, 79]. Finally, the decrease in endoge-nous nitric oxide (NO) production, a physiologic negative feed-back mechanism for thrombus propagation, vascular hemody-namics, and interactions of leukocytes and platelets with endo-thelial cell, further contributes to the procoagulant scenario [79].

Management: Cytoreduction as an Antithrombotic Therapy

Phlebotomy

Phlebotomy is the recommended main tool to control hemat-ocrit (HCT) in PV patients. The optimal target of HCT levels


for reducing vascular events has been a matter of debate. In arecent large-scale, multicenter randomized clinical trial (Cyto-PV), 365 JAK2 V617F PV patients were assigned to receiveeither more intensive therapy to maintain a HCT target of lessthan 45 % or a less intensive treatment with HCT target 45–50%. After a median follow-up of 31months, the primary endpoint of cardiovascular death and major thrombosis wasrecorded in 5 of 182 patients in the low-hematocrit group(2.7 %) and 18 of 183 patients in the high hematocrit group(9.8 %) (hazard ratio in the high-hematocrit group, 3.91;P = 0.007) (Fig. 3) [80••]. This study demonstrates that highHCT levels are associated with four times higher rates ofthrombotic events and supports the importance of a strictcontrol of hematocrit to prevent thrombosis in PV.

Hydroxyurea (HU)

HU is an antimetabolite that prevents DNA synthesis and wasintroduced in the therapy of PV and ET to reduce thrombosiswithout increasing the risk of leukemia. The antithromboticefficacy of this drug in ET was demonstrated in a seminal,randomized clinical trial showing that HU reduced the rate ofthrombotic events mainly represented by cerebral transientischemic attacks [81]. Interestingly, HU’s antithrombotic ef-fect may highlight additional mechanisms of action besidespan myelosuppression, including qualitative changes in leu-kocytes, decreased expression of endothelial adhesion mole-cules and enhanced nitric oxide generation [82]. Studies fromnational registries and prospective analysis failed to attribute aclear leukemogenic risk to HU [83, 84•, 85], but it should beemphasized that this risk may appear after a long-term expo-sure to this drug. It is wise to adopt a cautionary attitude and toconsider carefully the use of this agent in young subjects andin those previously treated with other myelosuppressiveagents or carrying cytogenetic abnormalities [42••].

Interferon Alpha (IFN-alpha)

IFN-alpha was considered for the treatment of patientswith MPN since this agent suppresses the proliferation ofhematopoietic progenitors, has a direct inhibiting effect onbone marrow fibroblast progenitor cells, and antagonizesthe action of platelet-derived growth factor, transforminggrowth factor-beta and other cytokines, which may beinvolved in the development of myelofibrosis [86]. TwoPhase II studies in PV have shown that pegylated interfer-on alpha-2a therapy led to a high rate of hematologicresponse and reduced the malignant clone as quantitatedby the percentage of the mutated allele JAK2 V617F, withgood tolerability [87, 88]. However, whether this drug ismore efficacious than HU in reducing the rate of vascularevents remains to be demonstrated in clinical trials thatare underway.

Fig. 3 Time to the primary end-point (death from cardiovascularcauses or thrombotic events)among 365 PV patients with ahigh (45–50 %) or low (<45 %)hematocrit target enrolled in theCYTO-PV clinical trial (ref.[80••])

Table 3 Risk-adapted therapy in PV and ET (ref. [42••])

1. Risk stratification.

At least one of the following defines high-risk patients:

- Age above 60 years

- Previous major thrombotic or hemorrhagic complication

2. Therapy

Low-risk patients

- PV: target hematocrit below 45 % plus aspirin 100 mg/day

- ET: aspirin 100 mg/day if arterial thrombosis or microcirculatorysymptoms are present

- PVand ET: life-long oral anticoagulation (PT-INR 2.0–3.0) ifvenous thrombosis

High-risk patients

As above, plus myelosuppressive therapy:

- Hydroxyurea or PEG-Interferon as first choice

- Anagrelide in resistant or intolerant ET patients


Anagrelide

Anagrelide, a member of the imidazoquinazolin compounds,has a potent platelet reducing activity devoid of leukemogenicpotential and has been compared to HU in two randomizedclinical trials. The first included 809 ET patients, diagnosedaccording to PVSG criteria and all treated with aspirin,100 mg/day [14]. Compared to HU, patients in the anagrelidearm showed an increased rate of arterial thrombosis, majorbleeding and myelofibrotic transformation, but a decreasedincidence of venous thrombosis. In the second, 259 previouslyuntreated, high-risk WHO-diagnosed ET patients were ran-domized [15]. During the total observation time of 730patient-years, there was no significant difference betweenthe anagrelide and hydroxyurea groups regarding incidencesof major arterial and venous thrombosis and severe bleedingevents. Disease transformation into myelofibrosis or second-ary leukemia was not reported. Anagrelide is currently rec-ommended as second-line therapy in high-risk ET patientsresistant or intolerant to hydroxyurea [42••].

Current Recommendations and New Drugs

Current recommendations for the management of PV and ETare summarized in Table 3. Nevertheless, the advent of a newgeneration of drugs with JAK2 inhibitory activity should betaken into consideration. These agents have been found to beeffective for the treatment of disease-related splenomegaly orsymptoms in adult patients with myelofibrosis [89, 90]. How-ever, no data are so far available on the efficacy in preventingthrombotic complications, which remain the primary goal oftherapy in PV and ET.

Conclusion

This review shows that MPN can actually be seen as a “vascu-lar disease”, considering its common clinical features and path-ogenic pathways with paradigmatic conditions that involve ahigh risk of thrombosis, such as inherited thrombophilia, ath-erosclerosis and cancer. A better understanding of the physio-pathological basis of thrombophilia inMPN can help to identifymore efficient predictors and to optimize the therapeutic ap-proach to thrombosis in this disease.

Acknowledgments Dr. Barbui and Dr. Finazzi are supported by a grantfrom Associazione Italiana per la Ricerca sul Cancro (AIRC, Milano)“Special Program Molecular Clinical Oncology 5x1000” to AGIMM(AIRC287 Gruppo Italiano Malattie Mieloproliferative) (project #1005).

Compliance with Ethics Guidelines

Conflict of Interest Guido Finazzi declares that he has no conflict ofinterest.

Valerio De Stefano has received research support from Shire, andpayment for the development of educational presentations includingservice on speakers bureaus from Shire and Novartis.

Tiziano Barbui has received honoraria fromNovartis for serving on anadvisory board.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

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Are MPNs Vascular Diseases?

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