General review

Golde DW, Hocking WG, Koeffler HP, Adamson JW.

Polycythemia: mechanisms and management.
Ann Intern Med. 1981 Jul; 95(1): 71-87.
Description: A review article that describes fundamental concepts in the pathophysiology of erythrocytosis and its effects, including mechanisms that drive eryhtropoiesis, etiologies of secondary erythrocytosis, consequences of elevated red cell mass, and descriptions of specific syndromes. The section describing erythropoietin is somewhat out of date, but the fundamentals are there.
PubMed citation number: 7018337

Primary erythrocytosis

Polycythemia Vera (PV)

General reviews

Spivak JL.

Polycythemia vera: myths, mechanisms, and management.
Blood. 2002 Dec 15;100(13):4272-90. Epub 2002 Aug 08.
Description: A scholarly review that encompasses pathophysiology, diagnosis, clinical course, and treatment. It is an excellent source of references for further reading. It also calls into question many of the characteristics of PV that are generally taught as truisms, but which are based upon anecdote rather than a stringent evidence base. This author argues in favor of measurement of red cell mass as part of the diagnosis of PV (see below).
PubMed citation number: 12393615

Pathophysiology

Prchal JF, Axelrad AA.

Letter: Bone-marrow responses in polycythemia vera.
N Engl J Med. 1974 Jun 13;290(24):1382.
Description: The first of several studies to demonstrate erythropoietin independent erythroid colony formation in vitro in PV. This phenomenon has subsequently been seen in other chronic myeloproliferative disorders and even in normal subjects. Also, there have been reports that, in some PV patients, the erythrocytes are actually hypersensitive to erythropoietin, IGF-1, IL-3, GMCSF, stem cell factor, and TPO. For more detailed references regarding this topic, see the above review articles.
PubMed citation number: 4827655

Adamson JW, Fialkow PJ, Murphy S, Prchal JF, Steinmann L.

Polycythemia vera: stem-cell and probable clonal origin of the disease.
N Engl J Med. 1976 Oct 21;295(17):913-6.
Description: The first of the seminal studies that showed that PV is a clonal stem cell disease. In this study, two women with PV who were heterozygous for the X-linked G-6-PD gene were shown to have circulating erythrocytes, granulocytes, and platelets derived from a clonal stem cell, while their skin fibroblasts were, in contrast, heterozygous.
PubMed citation number: 967201

Swolin B, Weinfeld A, Westin J.

A prospective long-term cytogenetic study in polycythemia vera in relation to treatment and clinical course.
Blood. 1988 Aug;72(2):386-95.
Description: A prospective study of cytogenetic abnormalities in PV patients. They found 17% of patients with abnormalities at presentation (trisomies 1 q, 8, 9, or 9p and deletion of 20q were the most common), while the proportion of cytogenetic abnormalities increased with time, progression to AML, and the use of chemotherapeutic drugs. However, none of these chromosomal abnormalities has yet been identified as etiologic in the pathophysiology of PV.
PubMed citation number: 3401588

Diagnosis

Lamy T, Devillers A, Bernard M, Moisan A, Grulois L, Drenou B, Amiot L, Fauchet R, Le Prise PY.

Inapparent polycythemia vera: an u nrecognized diagnosis.
Am J Med. 1997 Jan; 102(1): 14-20.
Description: Clinical study of 103 patients with PV (according to the PVSG criteria) whose red cell mass was measured. 17% had increased plasma volume with increased red cell mass such that their hematocrits were in the normal range. The authors conclude that red cell mass measurement should be considered in patients with normal hematocrits and other features suggestive of myeloproliferative disorders: leukocytosis, thrombocytosis, hepatic vein thrombosis, or splenomegaly.
PubMed citation number: 9209196

Moliterno AR, Hankins WD, Spivak JL.

Impaired expression of the thrombopoietin receptor by platelets from patients with polycythemia vera.
N Engl J Med. 1998 Feb 26;338(9):572-80.
Description: Recent report of impaired expression of the TPO receptor (c-mpl) by platelets of PV patients. TPO mediated phosphorylation of proteins was deficient in platelets of patients with PV or idiopathic myelofibrosis, but not in patients with other causes of thrombocytosis or erythrocytosis, or in normal patients. The reduction in expression of c-mpl was uniformly associated with this deficiency in phosphorylation. In a subsequent study, it was shown that the c-mpl deficiency is related to defective post-translational processing and that it correlates with disease duration. It was suggested that this may be another marker of disease that could be used for diagnosis.
PubMed citation number: 9475764

Liu E, Jelinek J, Pastore YD, Guan Y, Prchal JF, Prchal JT.

Discrimination of polycythemias and thrombocytoses by novel, simple, accurate clonality assays and comparison with PRV-1 expression and BFU-E response to erythropoietin. Blood. 2003 Apr 15;101(8):3294-301. Epub 2002 Dec 19.
Description: In this article, the authors demonstrate a simple method for determining clonality of hematopoietic cells in myeloproliferative disorders. They report using single stranded conformation polymorphism analysis for 5 genes (3 previously described and 2 new): G6PD, MPP1, IDS, BTK, and FHL1. They compare this assay for monoclonality with in vitro erythropoietin independent erythroid colony formation and PRV-1 RNA expression in patients with PV, other erythrocytosis, and thrombocytoses. All patients with PV showed monoclonality, 10/14 showed statistically significant increased expression of PRV-1, and all showed endogenous erythroid colony formation in contrast to patients with unexplained, congenital, or familial erythrocytosis.
PubMed citation number: 12515724.

Klippel S, Strunck E, Temerinac S, Bench AJ, Meinhardt G, Mohr U, Leichtle R, Green AR, Griesshammer M, Heimpel H, Pahl HL.

Quantification of PRV-1 mRNA distinguishes polycythemia vera from secondary erythrocytosis.
Blood. 2003 Nov 15;102(10):3569-74. Epub 2003 Jul 31.
Description: The authors describe a quantitative RT-PCR assay for the measurement of PRV-1 mRNA levels. PRV-1, a novel member of the urokinase-type plasminogen activator receptor (uPAR) superfamily, had been previously shown by the same group to be overexpressed in mature peripheral blood granulocytes from patients with PV. In this more recent study, they determined PRV-1 expression in 71 patients with PV (according to the WHO diagnostic criteria), 11 patients with secondary erythrocytosis, and in 80 healthy controls. PV patients expressed significantly higher amounts of PRV-1 (P < .0001). Because there was no overlap between the PRV-1 expression in PV patients and the others, the authors conclude that the assay has a very high sensitivity and specificity for the diagnosis of PV in their population.
PubMed citation number: 12893745

Treatment

Pearson TC, Wetherley-Mein G.

Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia.
Lancet. 1978 Dec 9;2(8102):1219-22.
Description: Retrospective review of thrombotic risk factors in PV patients (method of diagnosis not stated) that suggests that the risk of thrombosis rises rapidly with hematocrit above a value of 44% in men. Based on this reference, it has been fairly widely accepted that the therapeutic goal of phlebotomy in PV should be a hematocrit of 45% (though it is not necessarily widely adhered to, see Streiff MB, Smith B, Spivak JL. The diagnosis and management of polycythemia vera in the era since the Polycythemia Vera Study Group: a survey of American Society of Hematology members' practice patterns. Blood. 2002 Feb 15;99(4):1144-9.). Of Note, there was also a 1.5 times higher risk of thrombosis in those with platelet counts above 400,000/ml, though this trend was not statistically significant. Also note that this study was only in men with PV. It has been suggested that a lower hematocrit should be the goal in women and possibly in African Americans.
PubMed citation number: 82733

Berk PD, Goldberg JD, Silverstein MN, Weinfeld A, Donovan PB, Ellis JT, Landaw SA, Laszlo J, Najean Y, Pisciotta AV, Wasserman LR.

Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy.
N Engl J Med. 1981 Feb 19;304(8):441-7.
Description: This is the report of the first major randomized clinical trial in PV performed by the Polycythemia Vera Study Group (PVSG-01). In it, patients were randomized to treatment with phlebotomy alone, chlorambucil, or 32P. In the latter two groups, there was increased incidence of acute leukemia, as compared to the group treated with phlebotomy alone.
PubMed citation number: 7005681

Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T

European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. Efficacy and safety of low-dose aspirin in polycythemia vera.
N Engl J Med. 2004 Jan 8;350(2):114-24.
Description: Landmark randomized clinical trial evaluating the prophylactic use of low dose aspirin in patients with PRV (the ECLAP trial). In it, patients with neither clear indication for, nor clear contraindication against, treatment with aspirin were randomized to low dose aspirin or placebo. There was no increase in hemorrhage seen with the aspirin therapy, so aspirin was deemed to be safe in the treatment of PV patients. The authors also conclude that there was a reduced risk of thrombosis in the group treated with aspirin (see also the editorial in the same issue of the journal, page 99 for an alternate interpretation).
PubMed citation number: 14711910

Congenital and familial erythrocytoses

Kralovics R, Prchal JT.

Congenital and inherited polycythemia.
Curr Opin Pediatr. 2000 Feb;12(1):29-34.
Description: A review article that summarizes the characteristics of the various congenital erythrocytoses, including primary familial and congenital polycythemia (PFCP), high-affinity hemoglobins, methemoglobinemia, 2,3-BPG deficiency, Chuvash polycythemia, and familial and childhood PV. It can serve as a source of references for further reading.
PubMed citation number: 10676771

Secondary erythrocytosis

A comprehensive review of all forms of secondary erythrocytosis is beyond the scope of this reading list. For more information, see any respected textbook.

Vlahakos DV, Marathias KP, Agroyannis B, Madias NE.

Post-transplant erythrocytosis.
Kidney Int. 2003 Apr;63(4):1187-94. Review.
Description: A review of epidemiology, clinical characteristics, complications, mechanisms, and treatment of post-renal transplant erythrocytosis.
PubMed citation number: 12631334

Fakhouri F, Grunfeld JP, Hermine O, Delarue R.

Angiotensin-converting enzyme inhibitors for secondary erythrocytosis.
Ann Intern Med. 2004 Mar 16;140(6):492-3.
Description: Brief letter reporting the successful use of ACE inhibitors for treatment of erythrocytosis in cystic kidney disease with references to similar reports in COPD and high altitude associated erythrocytosis.
PubMed citation number: 15023727

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