anemii pdf 51

Polycythemia Vera Mayo Clin Proc, February 2003, Vol 78174

Mayo Clin Proc. 2003;78:174-194 174 © 2003 Mayo Foundation for Medical Education and Research

Review

Polycythemia Vera: A Comprehensive Review and Clinical Recommendations

From the Division of Hematology and Internal Medicine, Mayo Clinic,Rochester, Minn.

Address reprint requests and correspondence to Ayalew Tefferi, MD,Division of Hematology, Mayo Clinic, 200 First St SW, Rochester,MN 55905 (e-mail: [email protected]).

AYALEW TEFFERI, MD

More than a century has elapsed since the appearance ofthe modern descriptions of polycythemia vera (PV). Dur-ing this time, much has been learned regarding diseasepathogenesis and PV-associated molecular aberrations.New information has allowed amendments to traditionaldiagnostic criteria. Phlebotomy remains the cornerstonetreatment of PV, whereas myelosuppressive agents mayaugment the benefit of using phlebotomy for thrombosisprevention in high-risk patients. Excessive aspirin use iscontraindicated in PV, although the use of lower-dose aspi-rin has been shown to be safe and effective in alleviatingmicrovascular symptoms including erythromelalgia andheadaches. Recent studies have shown the utility of selec-tive serotonin receptor antagonists for treating PV-associ-ated pruritus. Nevertheless, many questions remain unan-swered. What is the specific genetic mutation or alteredmolecular pathway that is causally related to the disease?In the absence of a specific molecular marker, how is aworking diagnosis of PV made? What evidence supportscurrent practice in the management of PV? This articlesummarizes both old and new information on PV; pro-

The clinical phenotype of polycythemia vera (PV)(plethora, engorged veins) was appreciated long be-

fore the disease was formally described by Vaquez1 in 1892and subsequently by Osler2 in 1903.3-7 By 1910, it wasevident that erythrocytosis in PV was often associated withleukocytosis, thrombocytosis, and panmyeloid hyperplasiaof the bone marrow.8-10 The development of myelofibrosisand acute leukemia as part of the natural history of PV wasfirst reported in 1935 and 1938, respectively.11,12

In 1951, Dameshek13 classified PV as a chronic myelo-proliferative disorder (CMPD) along with other relatedmyeloid disorders, including chronic myeloid leukemia(CML) and agnogenic myeloid metaplasia (AMM), be-cause of similarities in both clinical and laboratory fea-tures. Between 1967 and 1981, Fialkow et al14-21 showedthat CMPDs are biologically interrelated on the basis ofbeing clonal stem cell disorders with involvement of bothmyeloid and lymphoid lineage.

Phlebotomy used as treatment of PV was recommendedby Osler22 in the first decade of the 20th century. During

ACE = angiotensin-converting enzyme; ADP = adenosine di-phosphate; AMM = agnogenic myeloid metaplasia; CML =chronic myeloid leukemia; CMPD = chronic myeloprolifera-tive disorder; COPD = chronic obstructive pulmonary dis-ease; EORTC = European Organisation for Research andTreatment of Cancer; EPO = erythropoietin; EPOR = EPOreceptor; ET = essential thrombocythemia; GP = glycopro-tein; IFN- ααααα = interferon ααααα; IGF-1 = insulin-like growth factor1; MMM = myelofibrosis with myeloid metaplasia; 32P = radio-active phosphorus 32; PRTE = post–renal transplant erythro-cytosis; PRV-1 = polycythemia rubra vera-1; PTP = proteintyrosine phosphatase; PV = polycythemia vera; PVSG = Poly-cythemia Vera Study Group; RCM = red blood cell mass;SH2 = Src (family of tyrosine kinases) homology 2; SP =secondary polycythemia; STAT = signal transducer and acti-vator of transcription; TPO = thrombopoietin

poses a modern diagnostic algorithm to formulate a work-ing diagnosis; and provides recommendations for patientmanagement, relying whenever possible on an evidence-based approach.

Mayo Clin Proc. 2003;78:174-194

this early period, external beam irradiation of the spleen,long bones, and vertebrae also was being used in the treat-ment of PV23 until the introduction of intravenous therapywith radioactive phosphorus 32 (32P) by Lawrence24 in1938. By the early 1950s, alkylating agents and antime-tabolites were introduced to the therapeutic armamen-tarium of PV, and the additional benefit of these agents inreducing thrombotic complications was touted.25 However,questions were raised and needed to be resolved about thevalidity of such claims as well as the possible leukemoge-nicity of both 32P and chemotherapeutic agents.26 This andother factors led to the formation of an international Poly-cythemia Vera Study Group (PVSG) in 1967, under theauspices of the National Cancer Institute with Dr Louis R.Wasserman as principal investigator.27 The objectives ofthe PVSG were to describe the natural history of PV andto define optimal therapy through the institution of long-term therapeutic trials. It is reasonable to consider theperiod that started with the PVSG studies as the modern erain PV.

CURRENT DISEASE CLASSIFICATIONDiscordant with the traditional scheme proposed byDameshek,13 current classification systems consider CMLseparate from the other CMPDs because of its specific

Mayo Clin Proc, February 2003, Vol 78 Polycythemia Vera 175

association with the Philadelphia chromosome transloca-tion (bcr-abl tyrosine kinase)28 as well as its unique treat-ment response to both interferon α (IFN-α)29 and imatinibmesylate.30 Therefore, the term chronic myeloproliferativedisorder is currently reserved for only PV, essential throm-bocythemia (ET), and myelofibrosis with myeloid meta-plasia (MMM). However, the CMPDs are joined by CMLand myelodysplastic syndrome as members of a broadercategory of chronic myeloid disorders that also includes afourth category that groups unclassified myeloprolifera-tive/myelodysplastic disorders, chronic myelomonocyticleukemia, juvenile myelomonocytic leukemia, hyper-eosinophilic syndrome, systemic mast cell disease, andchronic neutrophilic leukemia under an operational desig-nation of atypical chronic myeloid disorders (Figure 1).31

All 3 CMPDs, including PV, are characterized by vari-able degrees of bone marrow hypercellularity and atypicalmegakaryocytic hyperplasia and clustering.32 In addition,all 3 disorders may or may not display splenomegaly,leukocytosis, thrombocytosis, and clonal cytogenetic ab-normalities. The clinical distinction among the CMPDs is

Figure 1. Operational classification of the chronic myeloid disorders. *Atypical chronicmyeloid disorders include chronic neutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilic syndrome, systemic mast cell disease, juvenile myelomonocytic leuke-mia, chronic myelomonocytic leukemia, and a chronic myeloid process that displaysoverlapping features of both myelodysplastic syndrome and chronic myeloproliferativedisorder. Reprinted with permission from Tefferi.31 Copyright ©2000 Massachusetts Medi-cal Society. All rights reserved.

made by the demonstration of clonal erythrocytosis inPV,26 substantial bone marrow fibrosis in AMM,31 andclonal thrombocytosis that is not associated with eithererythrocytosis or high-grade myelofibrosis in ET.33,34

Note that currently there is no specific disease marker,molecular or otherwise, for PV or the other CMPDs andthat a working diagnosis is made on the basis of theconstellation of clinical and bone marrow histologicalfindings.

EPIDEMIOLOGYPopulation-based epidemiological studies done in Roches-ter, Minn, have suggested a stable incidence trend for PV ofapproximately 2.3/100,000.35,36 Other studies have reportedeither similar37,38 or lower39-43 incidence figures. A higherdisease incidence has been suggested in persons of Jewishancestry44-48 and among parent-offspring pairs.49,50 Medianage at diagnosis of PV is approximately 60 years with aslight (1.2:1) male preponderance.51 Approximately 7% ofpatients are diagnosed before age 40 years,51 and childrenare rarely diagnosed with PV.52-54


No strong evidence supports disease association withenvironmental exposure,55 although an excess risk has beensuggested in embalmers and funeral directors,56 as well asin persons exposed to benzene,57 petroleum refineries,58

and low doses of radiation.59 In contrast to patients withacute leukemias and CML,60 a high risk of developing PVin atomic-bomb survivors of Hiroshima and Nagasaki hasnot been shown.

PATHOGENETIC MECHANISMSOrigin of the PV Clone

It is now well established that PV is a clonal stem celldisease with trilineage myeloid involvement.16,61 However,some studies have suggested clonal heterogeneity includ-ing clonal involvement of B lymphocytes62 and polyclonalgranulopoiesis in certain patients.63-66 Also, normal he-matopoietic stem cells are known to coexist with clonalstem cells in PV and may gain growth advantage underexperimental conditions.67,68 Regardless, unlike with CML,the clonogenic molecular lesion in PV remains elusive.Recall that cytogenetic studies have played a major role indeciphering the causal genetic mutation in CML.28,69-73

However, karyotypic abnormalities in PV are infrequent(13%-18% in chemotherapy-naïve patients) and nonspe-cific, and they include trisomies of chromosomes 9 and 8and deletions of the long arms of chromosomes 13 and20.74-76 Not surprisingly, these chromosomes were targetedfor further studies that showed cryptic interstitial deletionson chromosome 20q,66 9p chromosomal gains that are notapparent by conventional techniques,77,78 and a high inci-dence of heterozygosity loss involving chromosome 9p.79

Whether further inquiry into these preliminary observa-tions leads to specific pathogenetic information remains tobe seen.

Growth Factor Independence and Hypersensitivityof Erythroid Progenitor Cells

A frequent area of pathogenetic investigation in PVinvolves erythropoietin (EPO) and its relationship to thegrowth of erythroid progenitor cells in affected patients. Ithas been almost 30 years since the initial observation thatin vitro erythroid colony formation in patients with PV mayrequire no additional exogenous EPO, unlike in normalcontrols or in patients with secondary polycythemia (SP).80

However, reports conflict about whether clonal erythroidgrowth in PV is completely independent of EPO81-83 orretains some degree of EPO dependency including hyper-sensitivity.84-86 Regardless, several studies have shown thatthe particular phenomenon is not specific to PV, EPO, orerythroid progenitor cells.

For example, endogenous (ie, without the addition ofexogenous growth factors) erythroid and megakaryocyte

colony formation has been shown not only in PV87 butalso in other CMPDs, including ET88-90 and MMM.88 Simi-larly, growth factor hypersensitivity of clonal progenitorcells has been shown in ET,91 whereas erythroid progenitorcells in PV display growth factor hypersensitivity alsoto insulin-like growth factor (IGF)-1,92 interleukin 3,86,93

granulocyte-monocyte colony-stimulating factor,94 stemcell factor,95 and thrombopoietin (TPO).96 The consistentlyobserved IGF-1 hypersensitivity of erythroid cells in PVhas been attributed to alterations in IGF-1 binding pro-teins.97 Regardless, the phenomena of growth factor in-dependence and hypersensitivity may be nonspecific,intrinsic cell properties that are generic to many clonalprocesses.

Molecular Studies At and Beyond the Level of theEPO Receptor

Signal transducers that are important in physiological,EPO-dependent erythropoiesis involve both enhancingand regulatory molecules and include the EPO recep-tor (EPOR),98,99 Janus kinase 2,100 signal transducers andactivators of transcription (STATs; STAT1, STAT3,STAT5),101-105 Src (family of tyrosine kinases) homology 2(SH2) domain-containing protein tyrosine phosphatases(SH-PTPs; SH-PTP1, SH-PTP2),106 Src,107 phosphoino-sitide 3 kinase,108 and mitogen-activated protein kinasesand their kinases.109 Therefore, a defect in any one of thesemolecules could conceivably underlie EPO-independenterythroid proliferation.

Regarding the EPOR, both its encoding gene and itsstructure have been shown to be intact in PV,110-112 in con-trast to those of some forms of familial polycythemia inwhich EPOR is truncated at the C-terminal as a result ofEPOR gene mutations.113-117 Such modification of theEPOR structure is believed to enhance signal transductionas a result of the loss of a regulatory domain that is nor-mally located distal to the truncation site. It is interestingbut not verified that expression of differentially truncatedEPOR isoforms that result from alternative splicing mayplay a role in the pathogenesis of PV.118

Post–receptor molecular variations that have been re-ported in PV include increased baseline phosphorylation ofthe IGF-1 receptor,119 decreased activity of SH-PTP1,120

increased activity of membrane-associated SH-PTP,121

constitutive activation of STAT3,122 up-regulation of nega-tive control elements of the cell cycle (p16/p14),123 and anabundance of antiapoptotic proteins (Bcl-x

L) in erythroid

precursors.124 Similarly, constitutive activation of phospho-inositide 3 kinase has been shown in EPO-independenterythroid cells that are infected with Friend spleen focus-forming virus.125 Furthermore, mice that genetically lackSH-PTP activity as a result of an SHP-1 null mutation


(motheaten) or deletion of the catalytic domain of SHP-1(motheaten viable) display among other abnormalities aPV phenotype (increased myelopoiesis and growth factorhypersensitivity of myeloid cells including erythroid pro-genitors).126 However, it is currently difficult to formulate aunifying hypothesis on the pathogenesis of PV on the basisof the aforementioned observations because they are oftenisolated, may represent nonspecific events in a clonal cellregardless of cell type, and are not always reproduced byother investigators.97,122,127

TPO and the TPO Receptor in PVThrombopoietin is the key growth factor for physiologi-

cal megakaryocytopoiesis and is essential for plateletproduction.128-132 Normal TPO production is constitutive,133

and circulating TPO is regulated by TPO receptor (c-mpl)–mediated platelet binding, internalization, and catabo-lism.134-138 As such, plasma TPO levels usually are inverselyproportional to total megakaryocyte/platelet mass.139,140

However, in PV and other CMPDs, plasma levels ofTPO are either elevated or normal, despite the associatedincrease in megakaryocyte/platelet mass.141-145 This cur-rently is believed to be the result of a defective TPOclearance caused by an abnormally reduced membraneexpression of c-mpl in PV and other CMPDs. This phe-nomenon was first reported in ET146 and subsequently inPV147 and in other CMPDs.148,149 In ET, the decreasedsurface expression of c-MPL has been associated withreduced c-mpl transcription.146,150 In PV, the particular de-fect was traced to a posttranslational hypoglycosylationof the c-mpl protein with derailment of membrane local-ization.151 Although markedly decreased megakaryocytec-mpl expression may complement morphologic diagno-sis in PV and ET, its pathogenetic relevance remainsunclear.152,153

Polycythemia Rubra Vera-1 GeneThe polycythemia rubra vera-1 (PRV-1) gene was re-

cently described as a novel gene that is highly expressed ingranulocytes of patients with PV but not in granulocytes ofnormal controls or of patients with secondary erythrocyto-sis.154 Examination of the open reading frame of thecomplementary DNA that is synthesized from the PRV-1transcript suggested that that particular gene encodes for acell surface receptor with homology to the Ly-6 gene fam-ily that includes the urokinase-type plasminogen activatorreceptor and reactive inhibitor of lysis receptor (CD59).Subsequently, it was shown that the PRV-1 gene washighly homologous to that of human neutrophil antigen-2(CD117), suggesting that the two may not be separategenes but alleles of the same gene.155 PRV-1 expression hasalso been shown in normal bone marrow, granulocyte

colony-stimulating factor stimulated granulocytes, andgranulocytes of some patients with ET or MMM.154 Obvi-ously, more studies are needed to decipher the pathogeneticrelevance of PRV-1 in PV.

Pathogenetic Mechanisms of Thrombosis andBleeding in PV

During the pre-phlebotomy era, thrombosis was the ma-jor cause of death in patients with PV, and the median lifeexpectancy was less than 2 years.156 The marked improve-ment in median survival (≥10 years) with aggressive phle-botomy established the primary role of increased hemat-ocrit in PV-associated thrombosis. How does increasedhematocrit enhance thrombus formation in PV?

In vitro, hematocrit has been shown to be the majordeterminant of whole blood viscosity, especially at lowshear rates.157 However, in vitro observations do not neces-sarily reflect in vivo events because of several confoundingvariables including the different flow dynamics in bloodvessels and the strong relationship between hematocrit andoxygen transport. As a result, the effect of hematocrit on invivo blood viscosity is lower than that suggested by in vitrostudies.157 For example, in vivo, increased hematocrit isassociated with a decreased cerebral blood flow rate,158 notbecause of the change in viscosity but because of thechange in arterial oxygen content.159 Furthermore, althoughvenesection in patients with PV may reduce whole bloodviscosity, it does not necessarily result in improved tissueoxygenation.160 Therefore, the relationship between throm-bosis and high hematocrit in patients with PV represents amore complex scenario with multiple physical and chemi-cal factors.

At low shear rates, which are comparable to flow ratesin large veins, the endothelial displacement of platelets andleukocytes and other proteins from the axial migration ofred blood cells might enhance thrombogenic interactionbetween endothelial cells and platelets.161 A differentmechanism that involves platelets, leukocytes, and redblood cell–derived platelet aggregates such as adenosinediphosphate (ADP) might contribute to thrombosis at high-shear-rate conditions, which are comparable to flow inarterioles and other small vessels. Such aberrations com-bined with decreased flow rates induced by high hematocritvalues might explain the beneficial effect of phlebotomy inpatients with PV.161,162

Phlebotomy substantially reduces but does not abolishthe risk of thrombosis in patients with PV. Therefore, fac-tors other than hematocrit (platelets, leukocytes, endothe-lial cells, coagulation proteins) might contribute to throm-bosis risk in these patients. Although about half of patientswith PV display either thrombocytosis or leukocytosis, therisk of thrombosis in such patients has not been correlated


with either platelet or white blood cell count.163 In con-trast, various potentially thrombogenic, qualitative cell de-fects have been described and include a diminished re-sponse of platelet adenylate cyclase to prostaglandin D

2

(a physiological inhibitor of platelet aggregation),164 anincreased baseline platelet production of thromboxane A

2

(a platelet aggregate),165,166 and abnormal in vivo activationof leukocytes,167 endothelial cells,167,168 and platelets.166,168

Furthermore, previous reports of widespread activation incoagulation proteins,167 reduced levels of physiologic an-ticoagulants (antithrombin III, proteins C and S),169,170 anddecreased fibrinolytic activity171 that in part may be sec-ondary to increased plasma levels of plasminogen activa-tor inhibitor 1172 suggest a baseline pro-thrombotic state inPV.

In a recent study of patients with PV, the presence of thePIA2 allele of platelet glycoprotein (GP) IIIa was associatedwith an increased risk of arterial thrombosis, whereas al-tered polymorphisms in either other platelet GPs (GP Ib,GP Ia) or coagulation proteins (factors II [prothrombin]and V [proaccelerin]) were not detected.173 It was interest-ing but not easily explained to note a statistically signifi-cant correlation in that study between the occurrence of thefactor II G20210A mutation and the presence of microvas-cular disturbances in patients with either ET or PV. Theseevents, which include erythromelalgia (see “MicrovascularDisturbances Including Erythromelalgia” section), previ-ously have been associated with both platelet-mediatedarteriolar inflammation174,175 and increased thromboxaneproduction.176

Pro-hemorrhagic platelet defects in PV include poorplatelet aggregation in response to various platelet agonistsincluding thrombin, ADP, epinephrine, collagen, throm-boxane A

2, and platelet-activating factor177-180; abnormally

low intraplatelet levels of adenine nucleotides and seroto-nin181; reduced platelet factor X–activating activity182; de-fective platelet lipid peroxidation183; impaired binding tofibrinogen as a result of decreased GP IIb/IIIa expres-sion184; and acquired von Willebrand disease.185 Acquiredvon Willebrand disease occurs in more than a third ofpatients with PV and has been associated with a bleedingdiathesis.186,187 Acquired von Willebrand disease in myelo-proliferative disorders is associated with decreased largevon Willebrand factor multimers and increased cleavageproducts of the same, which suggests removal by proteoly-sis.185 Furthermore, because the particular abnormality ischaracteristically associated with extreme thrombocyto-sis188,189 and corrects with platelet count normalization,189 itis believed that the pathogenesis involves abnormal ad-sorption of the large von Willebrand proteins to clonalplatelets, which effectively exposes protein cleavage sitesand enhances proteolysis.190

DIAGNOSISDefinitions

In conventional terminology, polycythemia refers to ei-ther a real (true polycythemia) or spurious (apparent poly-cythemia) increase in erythrocyte volume, ie, red blood cellmass (RCM). True polycythemia may represent either aclonal myeloproliferative disorder (PV) or a nonclonal in-crease in RCM that is often, but not always, mediated byEPO (SP). Apparent polycythemia may result from either areduction in plasma volume (relative polycythemia) or aninaccurate perception of an elevated hemoglobin/hemat-ocrit value that results from not appreciating extreme nor-mal values that exceed the 95th percentile range of refer-ence intervals (Figure 2).191,192 Inapparent polycythemiavera is the converse of apparent polycythemia and indi-cates a true increase in RCM that is masked by a normalhemoglobin/hematocrit value secondary to a concomitantincrease in plasma volume (Figure 2).193

Distinguishing Apparent From True PolycythemiaObviously, familiarity with sex- and race-adjusted nor-

mal values as well as the realization that hemoglobin/hematocrit values in some individuals may fall outside the2 SD range for normal values should prevent unnecessarytesting, including RCM measurements, in many suspectedcases.192 Similarly, most factors that cause plasma volumedepletion (ie, relative polycythemia) are clinically obvious(severe dehydration, diarrhea, vomiting, diuretics use, cap-illary leak syndrome, severe burns, etc) and do not requirespecialized tests for diagnostic confirmation of the relativepolycythemia. Again, it is inappropriate to perform RCMmeasurements in such instances.

The existence of both a chronic and a subtle state ofcontracted plasma volume is controversial.194 In this regard,both Gaisböck syndrome (relative polycythemia associatedwith hypertension and nephropathy)195 and stress poly-cythemia (relative polycythemia associated with emotionalstress)196 are poorly understood, and the general concepthas little foundation. In a series of 109 consecutive RCMand plasma volume measurements performed at the MayoClinic in Rochester, Minn, no patients with relative poly-cythemia were identified.197 In contrast, smoker’s poly-cythemia is real and is secondary to chronic exposure tocarbon monoxide, and the polycythemia resolves with dis-continuation of the habit.198 Again, the use of RCM mea-surements in the aforementioned instances may be unnec-essary in light of the availability of modern diagnostic testsfor differentiating apparent polycythemia from PV.

Secondary PolycythemiaSecondary polycythemia may or may not be EPO medi-

ated (Table 1115,198-224). Erythropoietin-mediated SP may be


Figure 2. The relationship of red blood cell mass and plasma volume in the varieties of poly-cythemias. Hct = hematocrit.

classified into a hypoxia-driven or hypoxia-independentprocess (Table 1). In hypoxia-driven SP (Table 1), theserum EPO level often is increased initially but may returnto within the normal reference range once the hemoglobinlevel has stabilized at a higher level.200,201,225 Hypoxia-inde-pendent EPO production stems from either malignant orbenign tumor tissue (renal cancer, uterine leiomyoma,pheochromocytoma, meningioma, etc)209,212,214,215 or a con-genital process that is believed to result from either anabnormally elevated set point for EPO production216,226,227

or abnormal oxygen homeostasis (Chuvash polycy-themia).217 Often, serum EPO levels are increased in thesehypoxia-independent processes. Chuvash polycythemia isendemic in Russia,228 and the disease gene has been as-signed to chromosome 11 by one group229 and chromosome3 by another.217 The latter study suggests the presence of amutation in the von Hippel-Lindau gene in Chuvash poly-cythemia; interestingly, other patients with germline muta-tions of the von Hippel-Lindau tumor-suppressor genehave experienced SP after treatment with antiangiogenictherapy.230

Other cases of SP may be EPOR mediated,218,231 second-ary to exogenous administration of erythropoietic drugs(EPO, androgen preparation)219,220,232 or related to as yet un-

explained mechanisms (some cases of congenital polycy-themia, post–renal transplant erythrocytosis [PRTE]).221,223,228

Some, but not most, patients221 with autosomal-dominantcongenital polycythemia carry an activating mutation ofthe EPOR gene that results in a C-terminal–truncated re-ceptor that is more efficient in signal transduction, possiblybecause of defective recruitment of regulatory phospha-tases.113,115,116,218 The serum EPO level is usually low in suchpatients. However, mutations of the EPOR are not found inmost patients with autosomal-dominant congenital poly-cythemia.221 Serum EPO levels may be either elevated ornormal in PRTE. The pathogenesis of PRTE may involveEPO hypersensitivity of erythroid progenitor cells224 thatmay or may not be related to the increase in IGF-1 and itsbinding proteins in these patients.233

Diagnosing PVIn 1975, the PVSG published a set of diagnostic criteria

to ensure that patients with SP or apparent polycythemiaare excluded from treatment protocols.234 These criteriarequired the demonstration of increased RCM by bloodvolume measurement using labeled erythrocytes and thedemonstration of normal hemoglobin oxygen saturation. Itis therefore immediately apparent that some patients with


Table 1. Classification of Polycythemia*

Apparent polycythemiaRelative polycythemiaExtreme “high-normal” values

True polycythemiaPolycythemia veraSecondary polycythemia

EPO mediatedHypoxia driven

Central hypoxic processChronic lung disease199

Right-to-left cardiopulmonary vascular shunts200

High-altitude habitat201

Carbon monoxide poisoning202

Smoker’s polycythemia (long-term carbon monoxideexposure)198

Hypoventilation syndromes including sleep apnea203

Peripheral hypoxic processLocalized

Renal artery stenosis204

DiffuseHigh oxygen-affinity hemoglobinopathy

(congenital; autosomal-dominant)205

2,3-Diphosphoglycerate mutase deficiency(congenital; autosomal-recessive)206

Hypoxia independent (pathologic EPO production)Malignant tumors

Hepatocellular carcinoma207,208

Renal cell cancer209

Cerebellar hemangioblastoma210

Parathyroid carcinoma211

Nonmalignant conditionsUterine leiomyomas212

Renal cysts (polycystic kidney disease)213

Pheochromocytoma214

Meningioma215

Abnormally elevated set point for EPO production(congenital)216

Chuvash polycythemia (congenital; abnormal oxygenhomeostasis?)217

EPOR mediatedActivating mutation of the EPOR

Some cases of autosomal-dominant congenitalpolycythemia115,218

Drug associatedEPO doping219

Treatment with androgen preparations220

Unknown mechanismsMost cases of autosomal-dominant congenital polycythemia221

Some forms of autosomal-recessive congenital polycythemia222

Post–renal transplant erythrocytosis223,224

*EPO = erythropoietin; EPOR = EPO receptor.

PV may not fulfill these “study requirements” because (1)their measured RCM value lies at the extreme left tail of theGaussian distribution of RCM values for PV and overlapsthe upper normal values of the reference range; (2) thepathologic baseline RCM value of a specific PV patientmay be lowered to within the normal reference range by asuperimposed iron deficiency or bleeding; or (3) a patientwith PV may also have an unrelated comorbid conditionthat causes hypoxia (eg, a patient can have both PV andchronic lung disease). Furthermore, the other PVSG diag-

nostic criteria (splenomegaly, leukocytosis, thrombocyto-sis, elevated leukocyte alkaline phosphatase, and increasedserum vitamin B

12 level or unbound vitamin B

12 binding

capacity) lack both sensitivity and specificity. Subsequentidentification and clinical application of PV-specific bio-logical parameters have allowed further refinements in theoriginal PVSG diagnostic criteria. Such revised PVSG cri-teria have increased diagnostic accuracy but have addedcomplexity to the diagnostic process.235-237

In the absence of a disease-specific positive marker,such as with CML, it is reasonable to use disease-character-istic biological and histological features to formulate aworking diagnosis of PV. Two such tests that are widelyavailable to routine clinical practice include the determina-tion of serum EPO and the examination of bone marrowhistology. With use of these 2 tests, a diagnostic algorithm(Figure 3), rather than a set of diagnostic criteria, can befollowed to make a working diagnosis of PV. In the pro-cess, the information from RCM determination is seldomrequired. Regarding RCM measurement, it is once againunderscored that (1) a normal-range RCM reading does notrule out the possibility of PV since it misses the PV popula-tion that is distributed at the left extreme tail of theGaussian distribution of RCM values for PV patients; (2)the measurement of RCM in the presence of a hematocritlevel higher than 60% and in the absence of a clinicallyobvious hemoconcentration is a costly redundancy sinceRCM is almost always increased in such cases; and (3) thelikelihood of an otherwise isolated hematocrit level lessthan 60% to be secondary to PV, in the absence of otherPV-related features, is extremely low and can be addressedby more practical and cost-effective biological tests such asserum EPO level (described subsequently). In contrast, ifan upper-normal hematocrit value is associated with a PV-related feature, the diagnosis of PV should be pursued withmore sensitive biological tests, including in some patients abone marrow examination, regardless of the measuredRCM value.

The first step in the diagnostic evaluation of PV is todetermine whether this diagnosis should be suspected. Thediagnostic possibility of PV may be entertained only if (1)the hemoglobin/hematocrit level is higher than the 95thpercentile of the normal distribution adjusted for sex andrace, (2) there is a documented increase in the hemoglobin/hematocrit level above the baseline for an individual pa-tient, regardless of where the specific hematocrit level lieswithin the reference range, or (3) a PV-related feature(thrombocytosis, leukocytosis, microcytosis from iron de-ficiency, splenomegaly, aquagenic pruritus, unusual throm-bosis including Budd-Chiari syndrome, erythromelalgia)accompanies a borderline-high hematocrit value. Other-wise, a repeated blood test in 3 months should suffice.


Figure 3. A practical algorithm for the diagnosis of polycythemiavera (PV). Specialized testing includes bone marrow immunohis-tochemistry for the thrombopoietin receptor (c-mpl), reverse tran-scriptase-polymerase chain reaction for neutrophil expression ofthe polycythemia rubra vera-1 gene, and spontaneous erythroidcolony assay. *Note that most PV can be diagnosed by clinicaland bone marrow histological parameters and does not requirespecialized testing. Furthermore, none of the 3 specialized tests candifferentiate PV from other myeloproliferative disorders, and theirsensitivity and specificity in distinguishing PV from secondary orapparent polycythemia have not been tested rigorously in an ad-equate number of prospective, well-designed studies that includeenough patients to make statistically valid conclusions. A limitednumber of such studies support the usefulness of these specializedtests in complementing, but not substituting for, other diagnosticprocedures.

Serum erythropoietin

Low

PV diagnosisprobable

Bone marrowbiopsy

Histologycharacteristic

for PV?

PV

Yes No

PV

Specializedtesting*

Notconsistent

with PV

PV diagnosispossible

Evaluate forsecondary

polycythemia

Normal High

Reevaluatein 3 mo

ConsistentwithPV

In the presence of one of the aforementioned three sce-narios, it is reasonable to start the diagnostic work-up bydetermining the serum EPO level (Figure 3). In general,serum EPO levels are low in PV, even in the presence oftreatment with phlebotomy (Figure 4).238-241 However, se-rum EPO levels also can be low in other CMPDs includingET241-243 and rare cases of congenital polycythemia withactivating mutation of the EPOR.115 Therefore, a low serumEPO level is highly suggestive but not diagnostic of PV(estimated specificity of >90%).244 In contrast, the serumEPO level may lie within the reference range in patientswith a definite diagnosis of PV (a sensitivity of a low serumEPO level for PV is estimated to be <70%) (Figure 4).244,245

However, PV is unlikely to be associated with an increasedserum EPO level.244 Therefore, PV remains a diagnosticconsideration in the presence of either a low or normalserum EPO level.

The next step is bone marrow examination with cytoge-netic studies (Figure 3). Bone marrow histology, to theexperienced hematopathologist, often reveals characteris-tic changes that include hypercellularity, increased numberof megakaryocytes including cluster formation, the pres-ence of giant megakaryocytes and pleomorphism in mega-karyocyte morphology, mild reticulin fibrosis (in 12% ofpatients), and decreased bone marrow iron stores.246 Incontrast, cytogenetic studies disclose abnormalities (triso-mies of chromosomes 9 and 8 and deletions of the long armsof chromosomes 13 and 20) in only 13% to 18% of patientsat diagnosis and hence have limited diagnostic value.74-76

In equivocal cases, which should constitute no morethan 10% of the patients seen in routine clinical practice,additional specialized tests may be necessary to confirmthe working diagnosis of PV. Combined with a bonemarrow morphologic assessment, the demonstration ofmarkedly decreased megakaryocyte expression of the TPOreceptor (c-mpl) supports the diagnosis of PV.147,152 Simi-larly, a recent study has suggested the possibility of using aperipheral blood neutrophil assay for PRV-1 expression todistinguish PV (high expression) from SP (not detect-able).154 Finally, although their value in distinguishing PVfrom SP has been shown in both prospective247 and retro-spective248 studies, I rarely use spontaneous (endogenous)erythroid colony assays for the diagnosis of PV because oftheir limited availability and the need for considerableexpertise. Furthermore, as is the case with c-mpl immuno-histochemistry, a negative test result does not necessarilyexclude a diagnosis of PV.248

MANAGEMENTDisease manifestations in PV that require treatment fallinto 2 major categories, life threatening and non–lifethreatening. Life-threatening manifestations of PV include

increased hematocrit, vascular events, and clonal evolutioninto MMM and acute leukemia. Non–life-threatening com-plications of PV include constitutional symptoms, mi-crovascular disturbances, and aquagenic pruritus.


Prevention and Treatment of Life-ThreateningComplications in PV

Aggressive phlebotomy and modern supportive care areprimarily responsible for the currently observed markedimprovement in the median survival of patients (>10 years)initially treated with phlebotomy alone.51 Earlier reportssuggested a median survival of less than 2 years innonphlebotomized patients with PV.12,156,249 Furthermore,in a cohort of 250 patients seen between 1933 and 1961, amedian survival of less than 4 years was documented inpatients treated with nonaggressive venesection, and thecause of death in most of these patients was thromboticcomplications.156 Aggressive phlebotomy defined as main-taining the hematocrit level at lower than 45% was sug-gested on the basis of a retrospective study of PV thatshowed a progressive increase in the incidence of vascularocclusive episodes at hematocrit levels higher than 44%.250

This contention is supported by other studies that showedsuboptimal cerebral blood flow in ranges of hematocritvalues between 46% and 52%.158 Because of the physi-ological difference in hematocrit values between the sexesas well as among different races,251-253 it is reasonable,although not evidence based, to target an even lower he-matocrit level (42%) in women and African Americans.Nevertheless, phlebotomy in any patient, and especially inthose with cardiovascular disease, should be performed un-der careful conditions with appropriate and monitored fluidreplacement to avoid both hypotension and fluid overload.254

Observations From Randomized Studies.—The first2 randomized studies of PV were run concurrently by the

PVSG26,163,255 and the European Organisation for Researchand Treatment of Cancer (EORTC).256-258 Between 1967and 1974, the PVSG study randomized 431 patients withactively proliferating PV to treatment with either phle-botomy alone or phlebotomy supplemented with either oralchlorambucil (10 mg/d for 6 weeks followed by a 30-dayrest and similar daily treatment every other month) orintravenous 32P (2.3 mCi/m2) (ie, a 3-arm study). Between1967 and 1978, the EORTC randomized 293 patients totreatment with either 32P (0.5-1.0 mCi/10 kg body weight)or oral busulfan (4-6 mg/d for 4-6 weeks).

The results from the PVSG study favored treatment withphlebotomy alone with a median survival of 12.6 yearscompared with 10.9 and 9.1 years for treatment with 32Pand chlorambucil, respectively (P=.008). The difference insurvival was attributed to an increased incidence of acuteleukemia in patients treated with chlorambucil or 32P com-pared with those treated with phlebotomy alone (13.2% vs9.6% vs 1.5% for 13-19 years).163,259 Furthermore, 3.5% ofthe patients treated with chlorambucil developed large celllymphoma, and incidences of gastrointestinal and skin can-cers increased in patients treated with either chlorambucilor 32P.260

Additional observations from the PVSG study includedthe following: (1) a significantly higher incidence ofthrombotic events in the first 3 years in patients treatedwith phlebotomy alone, (2) a lack of correlation betweenthrombosis and either platelet count or hematocrit value,and (3) a significant association between thrombosis riskand patients either older than 70 years or with a history ofthrombosis. In addition, in patients treated with phle-botomy alone, thrombosis risk was associated with an in-creased frequency of phlebotomy (maintenance phle-botomy of more than once every 3 months).

The results from the EORTC study favored busulfan to32P for both first remission duration (median, 4 years vs 2years) and overall survival (10-year survival rates of 70%vs 55%; P=.02). At a median follow-up of 8 years, therewere no significant differences in the risks of leukemictransformation (2% vs 1.4%), nonhematologic malignancy(2.8% vs 5%), vascular complications (27% vs 37%), ortransformation into MMM (4.8% vs 4.1%) between thebusulfan and 32P arms, respectively.257

In an effort to reduce the risk of thrombosis associatedwith treatment by phlebotomy alone, the PVSG initiatedanother randomized study in 1977 in which treatment withintravenous 32P (2.7 mCi/m2) plus phlebotomy was com-pared with treatment with phlebotomy plus high-dose aspi-rin (900 mg/d) in combination with dipyridamole (225 mg/d).261 Results showed that the addition of antiplateletagents, at the specific doses used, had no benefit in terms ofthrombosis prevention but increased the risk of gastrointes-

10.1-12.0

12

14

16

18

20

10

8

6

4

2

012.1-14.0 14.1-16.0 16.1-18.0 >18.0

Hemoglobin (g/dL)

EPO (mU/mL)<2.92.9-15.1>15.1

No.

of pa

tient

s

Figure 4. Serum erythropoietin levels in 42 unselected patientswith polycythemia vera. EPO = erythropoietin. Reprinted withpermission from Blackwell Publishing.244


tinal bleeding. However, a more recent randomized studyof PV (112 patients) using a much lower dose of aspirin (40mg/d) showed no increased bleeding diathesis.262 Further-more, the results of the PVSG aspirin study may have beeninfluenced by the fact that 27% of the patients randomizedto the phlebotomy-aspirin-dipyridamole arm had a historyof thrombosis compared with 13% in the other arm. It ishoped that an ongoing European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study willfurther clarify the role of low-dose aspirin in the treatmentof PV.

Other randomized studies of PV have compared hy-droxyurea with pipobroman (a significant difference favor-ing pipobroman in the incidence of transformation intoMMM but no difference in survival, incidence of thrombo-sis, or the rate of leukemic conversion)263 and compared 32Palone with 32P plus hydroxyurea (no difference in survival,incidence of thrombosis, or risk of transformation intoMMM, but 32P alone was associated with significantly fewerincidences of both acute leukemia and other cancers).264

The findings from these randomized studies indicatethat chlorambucil and 32P significantly shorten the survivalof patients with PV.255,257 The findings also suggest thatother cytoreductive agents including hydroxyurea, busul-fan, and pipobroman may not have similar detrimentaleffects on survival and maintain the apparently nonspe-cific, antithrombotic benefit of myelosuppressive ther-apy.257,263,265 Whether hydroxyurea, busulfan, and pipobro-man increase the underlying risk of acute leukemia in PVwhen used alone with phlebotomy is currently unknown,and this issue can be addressed definitively only in thesetting of a controlled, randomized study. However, theseagents might contribute to leukemogenicity if used withother leukemogenic drugs.264,266

Observations From Nonrandomized Studies.—Al-though the use of chlorambucil or 32P was associated withinferior survival, it resulted in a significantly reduced rateof early thrombotic complications compared with that inpatients treated with phlebotomy alone.255 This led to theexploration of presumably less leukemogenic drugs to re-duce the risk of thrombosis. In a nonrandomized study bythe PVSG, treatment with hydroxyurea was associated witha lower incidence of early thrombosis compared with ahistorical cohort treated with phlebotomy alone (6.6% vs14% at 2 years).265,267 Similarly, the incidence of acuteleukemia compared with a historical control treated witheither chlorambucil or 32P was significantly lower (5.9% vs10.6% vs 8.3%, respectively, in the first 11 years of treat-ment).163,268 A limited survey of other clinical trials that usedsingle-agent hydroxyurea in PV revealed leukemic conver-sion rates of 1% (100 patients treated for 3-216 months)269

and 5.6% (71 patients treated for 1.5-15 years).270

Many studies have reported the use of pipobroman as asingle agent in PV.266,271-273 In one of these studies involving163 patients, the drug was effective in more than 90% ofthe patients, and median survival exceeded 17 years.271 Inthe first 10 years, the incidences of thrombotic events,acute leukemia, MMM, and other malignancies were 16%,5%, 4%, and 8%, respectively. In this group, female sexand age older than 65 years were significantly associatedwith thrombosis.

In addition to the information from an aforementionedrandomized study that included a treatment arm with busul-fan alone,257 other single-arm studies have reported thetherapeutic value of busulfan in PV.274,275 In 65 busulfan-treated patients with PV monitored between 1962 and1983, overall median survival was 11.1 years; in patientswhose disease was diagnosed before the patients were age60 years, overall median survival was 19 years.274 Only 2patients (3%) treated with busulfan alone developed acuteleukemia.

Most recently, IFN-α276 and anagrelide277 were added tothe therapeutic armamentarium for PV. Interferon α hasbeen shown to control erythrocytosis in approximately76% of the patients receiving subcutaneous drugs in dosesranging from 4.5 to 27 million U per week (usual dosage is3 million U subcutaneously 3 times a week).276,278,279 Asimilar degree of benefit is appreciated in terms of reduc-tion in spleen size or relief from intractable pruritus.Anagrelide is an oral imidazoquinazoline derivative thatinhibits platelet aggregation at concentrations higher thantherapeutic drugs but displays a species-specific platelet-lowering effect in humans at therapeutic concentrations.280

Anagrelide is capable of substantially reducing the plateletcount in more than 80% of patients with PV.281

In summary, the results from single-arm studies supportthose from randomized studies and show that pipobromanand busulfan are valuable treatment agents for PV andmight be considered alternatives to hydroxyurea. Pipobro-man currently is unavailable in the United States. It isunclear what value is gained by substituting the aforemen-tioned traditional cytoreductive agents with the newerdrugs (ie, IFN-α and anagrelide), especially in view of thenewer drugs’ unfavorable toxicity and cost profile (Table2).282 Furthermore, a recent retrospective study of PVshowed no evidence of a favorable effect in bone marrowfiber content after treatment with IFN-α.283

Current Treatment Recommendations.—The main-stay of therapy for all patients with PV is phlebotomy tokeep the hematocrit level below 45% in white men and theappropriate corresponding values for females and those ofother races.158,250,284,285 In addition to treatment with aggres-sive phlebotomy, cytoreductive chemotherapy should beconsidered in patients who are at high risk for thrombosis


Table 2. Clinical Properties of Drugs Initially Considered for the Treatment of Polycythemia Vera

Hydroxyurea Interferon α Pipobroman*

Drug class Antimetabolite Biological agent Alkylating agentMechanism of action Myelosuppressive Myelosuppressive MyelosuppressiveHalf-life, metabolism ≈4 h, renal excretion Kidney metabolized Insufficient informationStarting dosage 500 mg twice a day orally 5 million U 3 times a week 1 mg/kg per day orally

subcutaneouslyTime before onset of

action (approximate) 3-5 d 3 wk 28 dFrequent adverse effects Anemia, neutropenia, Flulike symptoms, fatigue, Delayed cytopenia

oral and skin ulcers, anorexia, weight loss,hyperpigmentation, alopecianail changes

Infrequent adverse effects Leg ulcers, nausea, Confusion, depression, Nausea, rash,diarrhea, fever, elevated autoimmunity, abdominal cramps,liver function test results hyperlipidemia diarrhea, hemolysis

*Not available in the United States but widely used in Europe.

(Tables 3 and 4).163 In older patients, my current choice ofchemotherapy is hydroxyurea (initial dosage of 500 mgtwice a day) or busulfan (initial dosage of 4 mg/d). Adverseeffects of hydroxyurea that might necessitate the use of analternative agent include neutropenia and mucocutaneouschanges (Table 2 and Figure 5). With use of busulfan,potental toxicity to the lungs (pulmonary fibrosis)286-288 andto bone marrow (aplasia),289 although infrequent, should berecognized. Using intermittent treatment with drug holi-days and withholding treatment of impending cytopeniaare recommended.

In younger but high-risk patients, I sympathize with theconcern over possible drug leukemogenicity associatedwith long-term therapy with either hydroxyurea or busul-fan but inform patients that there is no hard evidence tosupport this concern. Regardless, IFN-α (initial dosage of 3million U subcutaneously 3 times a week) is a reasonablealternative in this instance (Table 4).278 I also prefer the useof IFN-α in women of childbearing age because of thetheoretical risk of teratogenicity associated with the othercytoreductive agents279,290 and in the presence of intractablepruritus.291

Because 32P-associated leukemia in PV peaks after 7years of treatment, it is reasonable to advocate the use of 32P

in elderly patients with issues of treatment compliance andconvenience, especially if life expectancy is less than 10years (intravenous 32P at 2.3 mCi/m2 to be repeated every 3months if necessary).163

The lack of evidence that correlates thrombocytosis withthrombosis in PV argues against the potential therapeuticvalue of anagrelide in PV. A randomized, controlled study isnecessary to define the role of anagrelide in the treatment ofPV. Similarly, no current evidence suggests that eitheranagrelide or IFN-α modifies the risk of disease transforma-tion into either MMM or leukemia.283 Therefore, I currentlydo not recommend the routine use of anagrelide for PV.

Under current treatment strategies, the incidences oftransformation into MMM or acute leukemia in the firstdecade of disease are estimated at 10% and 5%, respec-tively.163 The risk beyond the first decade increasesprogressively.292

Treatment of Non–Life-Threatening Complicationsin PV

Microvascular Disturbances Including Erythromel-algia.—Microvascular disturbances in PV and relateddisorders are believed to represent a transient inflamma-tion-based occlusive phenomenon that is a result of inter-action between clonal platelets and the endothelium ofarterioles. The corresponding clinical manifestations in-clude headache, light-headedness, transient neurologic orocular disturbances, tinnitus, atypical chest discomfort,paresthesias, and erythromelalgia (painful and burning sen-sation of the feet or hands associated with erythema andwarmth).

Erythromelalgia is an extremely rare disease,293 andmost cases are not associated with myeloproliferative dis-orders.294,295 Two thirds of patients with erythromelalgiamay have no identifiable comorbid condition (primaryerythromelalgia), whereas the remaining third may have

Table 3. Risk Stratification in Polycythemia Vera

Risk category Risk factors

Low risk Age younger than 60 y and no history ofthrombocytosis and platelet count lower than1500 × 109/L

Indeterminate risk Age younger than 60 y and no history ofthrombocytosis and either platelet count higherthan 1500 × 109/L or the presence ofcardiovascular risk factors

High risk Age 60 y or older or a positive history ofthrombosis


Table 4. Treatment of Polycythemia Vera

Women ofRisk category Age <60 y Age ≥60 y childbearing age

Low risk Phlebotomy alone ± low-dose Not applicable Phlebotomy alone ± low-doseaspirin* aspirin*

Indeterminate risk Phlebotomy alone† Not applicable Phlebotomy alone†

High risk Phlebotomy + hydroxyurea or Phlebotomy + hydroxyurea + Phlebotomy + interferon α +interferon α + low-dose aspirin* low-dose aspirin* low-dose aspirin*

*Not evidence based.†Use of aspirin is discouraged if the platelet count is >1000 × 109/L but is encouraged otherwise.

associated various clinical conditions or factors (secondaryerythromelalgia) including diabetes, autoimmune diseasesincluding systemic lupus erythematosus, drugs (calciumchannel blockers, ergot derivatives), and myeloproliferativedisorders.295 In a retrospective series of 168 patients witherythromelalgia, only 15 had an associated myeloprolifera-tive disorder (9 with PV, 4 with ET, and 2 with CML).294

The characteristic occurrence of erythromelalgia in PVhas been recognized for several decades, and the estimatedincidence is approximately 3%.296,297 The syndrome is oftenassociated with thrombocythemia, and the pathogenesismay involve platelet-mediated endothelial cell injury thatresults in inflammation and transient thrombotic occlusionby platelet aggregates.174,175,298 Some studies have suggesteda pathogenetic role for thromboxane-mediated platelet acti-vation,176 which is consistent with the efficacy of treatmentwith low-dose aspirin (81 mg/d).299 Aspirin producesprompt (within hours) alleviation of symptoms in mostpatients with PV-associated erythromelalgia. However,normalization of platelet count with cytoreductive therapymay be necessary in certain patients who do not respondwell to aspirin (A.T., unpublished data).

Management of Pruritus in PV.—Generalized pruri-tus that is often exacerbated by a hot bath is a characteristicfeature of PV. In a single institutional study of 397 con-secutive patients with PV, a history of pruritus was docu-mented in 48% either at diagnosis or at a later stage of thedisease.300 Pruritus may be the most agonizing aspect of PVand may result in sleep deprivation and interference withvarious social and physical activities.301

Information is conflicting regarding the pathogeneticrole of both histamine302-304 and mast cells304,305 in PV-associated pruritus. Regardless, conventional treatment of-ten includes antihistamines,306,307 and responses have beenboth unpredictable and variable.300

Platelets and their contents have also been implicated inthe pathogenesis of pruritus associated with PV. Accord-ingly, an early double-blind crossover study had suggesteda benefit for aspirin therapy, and the proposed mechanismwas inhibition of platelet release of pruritogenic amines

including prostaglandins and serotonin.301 Interestingly, arecent study showed a response rate higher than 80% inPV-associated pruritus treated with paroxetine, a selectiveserotonin reuptake inhibitor.308

A recent study suggested a significant correlation be-tween active pruritus and low mean corpuscular volumethat implied a potential pathogenetic role for iron defi-ciency.300 Likewise, previous reports have suggested thatiron deficiency might be pathogenetically contributory andthat iron replacement may benefit some patients with PV-associated pruritus.309-311 However, iron replacement ther-apy has not been consistently effective in the treatment ofPV-associated pruritus,304 and its indiscriminate use in thiscontext is discouraged.

Other treatment modalities that have been used in PV-associated pruritus include IFN-α,291,312-314 psoralen photo-chemotherapy,315-317 and cholestyramine.318 The results ofseveral studies indicate that IFN-α may reduce pruritus in upto 81% of affected patients. The mechanism of action inIFN-α–induced alleviation of pruritus is unclear but may berelated partly to the decreased need for phlebotomy, whichresults in a lesser degree of iron deficiency.300,313

My current recommendation for treating patients withPV associated with intractable pruritus is to use IFN-α in

Figure 5. Nail pigmentation as a result of treatment with hydroxy-urea. Reprinted with permission from Elsevier Science.33


high-risk patients and paroxetine in low-risk patients whootherwise do not require cytoreductive therapy.

DIAGNOSIS AND TREATMENT OF SPAlthough an increased serum EPO level is highly sugges-tive of SP, a normal level does not exclude the possibil-ity.244 Therefore, regardless of the serum EPO level, iffamily history suggests a congenital cause, it is essential tomeasure P

50 (oxygen pressure at 50% hemoglobin-oxygen

saturation). A low P50

would be consistent with either a highoxygen-affinity hemoglobinopathy205 or 2,3-diphospho-glycerate mutase deficiency.206 Other types of congenitalpolycythemia may be inherited in either an autosomal-dominant or autosomal-recessive fashion and may displayhigh, normal, or low serum EPO levels.222 If low serumEPO levels are displayed, the possibility of mutations inthe EPO receptor should be included in the differentialdiagnosis.115

In acquired SP, initial laboratory tests should include themeasurement of arterial hemoglobin-oxygen saturation andthe carboxyhemoglobin level, especially in smokers. In theabsence of a central hypoxic state, renal vascular studiesshould be performed to rule out the possibility of renalartery stenosis.204,319,320 Imaging studies of the kidney, liver,and central nervous system may be considered when eitherthe aforementioned studies are unrevealing or the patienthas a persistently elevated serum EPO level. Patientsshould always be questioned about the use of androgenpreparations: oral, transdermal, or intramuscular.220,321,322

Regarding EPO doping, immunoblotting techniques havebeen developed to differentiate endogenous EPO from ex-ogenously administered recombinant EPO.232

Specific management of SP depends on the underlyingcause and should take into account the balance between thephysiological benefit of an increased hematocrit level andthe possible impairment of oxygen delivery to tissues as aresult of increased whole blood viscosity. In cyanotic con-genital heart disease, aggressive phlebotomy should beavoided because of the potential risk of stroke.323-325 Adetrimental effect of overzealous phlebotomy may also beexpected in patients with high oxygen-affinity hemoglo-binopathy.326 In both of these conditions, judicious phle-botomy to a hematocrit level of 60% is reasonable, mayalleviate symptoms of hyperviscosity, and may providesome hemodynamic improvement.327,328 Similarly, gradedphlebotomy in chronic obstructive pulmonary disease(COPD) to a hematocrit range of 55% to 60% may improveboth exercise tolerance and cardiac function.329-333

Post–renal transplant erythrocytosis is distinctly associ-ated with an increased risk of thrombosis.223 Fortunately,both angiotensin-converting enzyme (ACE) and angio-tensin II receptor inhibitors are effective in lowering he-

matocrit levels in PRTE.334 The mechanism of action isunknown. Recent data suggest that angiotensin II promoteserythropoiesis and that ACE inhibition may induceapoptosis in erythroid precursor cells.335,336 Also, ACE inhi-bition has been shown to reduce hematocrit levels inCOPD-associated SP.337 In addition, treatment with the-ophylline has been shown to lower hematocrit levels inboth COPD and PRTE.338,339

CONCLUSIONSThe fundamental pathogenetic processes in PV remain in-adequately defined. Most investigators agree that PV repre-sents a clonal stem cell disease and that the resultant clonalmyeloproliferation displays altered behavior in terms ofboth sensitivity to a multitude of hematopoietic growthfactors and expression of a variety of cellular and mem-brane molecules. However, none of the currently discussedbiological processes regarding the pathogenesis of PV aredisease specific and none have been particularly insightfulin further advancing the current state of the science. Agenomic approach that uses global analyses of genes aswell as protein expression may provide an alternative andmore effective method of deciphering the pathogenesis ofPV and related disorders.340

In routine clinical practice, it is more practical to use adiagnostic algorithm instead of diagnostic criteria to makea working diagnosis of PV. In this regard, the measurementof RCM is seldom necessary and can be replaced easily byan accurate interpretation of the observed hematocrit levelwithin the context of the clinical presentation as well as theuse of PV-related biological markers. Some PV-relatedbiological markers, such as serum EPO concentration, areused to help clinicians decide on further diagnostic work-up.244 Other biological markers, such as bone marrow ex-amination, are used to confirm the diagnosis.246 Often, thediagnosis is made on the basis of clinical and bone marrowfindings, and it is not necessary to perform specialized testssuch as endogenous erythroid colony assays,248 bone mar-row c-mpl immunostains,152 or determination of granulo-cyte PRV-1 expression.154 In equivocal cases, any of the 3specialized tests, depending on test availability, may beused for further clarification.

It is important to separate non–life-threatening fromlife-threatening disease manifestations in PV. The formerinclude microvascular disturbances that are often con-trolled with low-dose aspirin, as well as aquagenic pruritus,which recently was shown to respond to selective serotoninreuptake inhibitors. Life-threatening complications of PVinclude thrombosis and disease transformation into MMMor acute leukemia. To date, no controlled and reproducibletreatment has been shown to influence disease transforma-tion in PV. Therefore, it is unwarranted to suggest that any


one of the currently available treatment agents is of provenbenefit in this regard. Furthermore, it is unnerving to wit-ness the increasing use of new cytoreductive agents in PVwith no evidence of their superiority over conventionaltherapy for thrombosis prevention. High priority should begiven for the development of randomized studies to selectthe “best” drug, from the standpoint of both toxicity andefficacy, among the currently available cytoreductiveagents.

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