Polycythemia, a review
Robert asked sometime back if someone could review the new Messinezy article-
"Polycythemia" in Molecular Aspects of Medicine, April 1996. I enjoyed the
article (actually, it is a chapter in what is book/journal) - it was very
thorough and up-to-date.(I like to see lots of articles from the '90's used
as references.) As the title indicates - the article includes all the
polycythemias, but the major portion is about primary polycythemia (vera)
and , therefore, pertinent to us.
A brief discussion of the clonal origin is give. Research indicates survival is poorer IF an abnormal chromosome is found at diagnosis (also see"Chromosome Studies in 104 Patients With PV" in Mayo Clinical Proceedings, issue 66, 1991). Most PV'ers DON'T show this initially, though the incidence increases with progression to MF (etc.) and not just in those receiving chemo. Clonality testing for PV is not yet well enough developed to be useful in diagnosis. A 20q chromosome abnormality is found in some and this does include a tumor suppressor gene.
The problem and methods of diagnosis are discussed further. Most PV is still diagnosed by the PVSG criteria (modified). Better method is needed. - bone marrow - not really of great value in diagnosis says Messinezy
- erythropoietin (Epo) levels - Messinezy thinks valuable for diagnosis (I am prejudiced against them since Norm's rise after plebotomies - apparently not fitting the "norm")
- endogenous erythroid colonies (EEC) - still used, particularly for diagnosis between primary and secondary polycythemia, but may depend on the culture medium used.
- other growth factors and the response to them by erythroid precursers in PV patients are being tested
- erythropoietin receptor (EPO-R) - (This gets into the research mentioned to us by Dr. Jerry Spivak at Johns Hopkins.) The EPO-R gene has been located on chromosome 19p and abnormalities have been discovered in a family with congenital PV. However, other similar families did NOT show the same abnormality.
(Messinezy states that even if the EPO-R gene itself is not faulty, it may still play a part - the abnormality may lie in some area such as the signal pathways between EPO and its receptor (EPO-R).)
A caution - EPO-R abnormality, says Messinezy, would NOT explain raised granulocyte or platelet counts typical of PV. Messinezy states that all PV patients may not display the same molecular defect. This may also be why it will be difficult to FIND a definitive diagnostic test (reminding us again of the research at Johns Hopkins).
- ultrasound splenic sizing and computerized tomography of the spleen are also mentioned briefly as diagnostic tools that some have used.
Clinical features are mentioned briefly and then an interesting section on progression to MF and acute leukemia. This is where Messinezy states that there is enough (evidence) to suggest that controlling platelet count & proliferation should be a part of the therapy of PV, not only to reduce thrombotic episodes but also, possibly, to reduce progression to MF. The possible role of platelet-derived growth factor (PDGF) in MF is also mentioned. (Robert earlier gave us a review of an article from Leukemia and Lymphoma, 1995 - "TGF-beta and Megakaryocytes in the Pathogenesis of Myelofibrosis in Myeloproliferative Disorders.)
He also brings up the interesting possibility, not a new idea though, that perhaps all MF patients have had an earlier proliferation stage even if unrecognized.
Management section is next - what about an initial-phase raised platelet count? Aspirin, P32, busulphan, hydroxyurea (HU), interferon, and anagrelide are all briefly covered.
My take on his review of the available treatments? It may not matter in older patients which is used - P32, busulphan, or HU (he doesn't mention pipobroman), though venesection (phlebotomy) alone is not the recommendation (consistent with other literature), but the question of therapy in younger patients is more uncertain. HU differs from radiation & alkylating drugs and is, hopefully, less leukemogenic (HU acts by blocking DNA synthesis, not killing cells???). Interferon (IFN) is mentioned promisingly because it is not mutagenic, has produced positive chromosome changes, and is believed to antagonize PDGF (platelet-derived growth factor). Anagrelide is also mentioned hopefully - it inhibits megakaryocyte (platelet) maturation further down the line. Major side effects are cardiovascular, not known to be leukomegenic. Messinezy muses that it would be nice to know if anagrelide prevents PDGF release (and, therefore, might affect progression to MF. It does not alter the number or morphology of megakaryoctyes in the bone marrow - see "Anagrelide: a review...." in Drugs, issue 47, 1994.) He does not go very deep into what constitutes greater risk of thrombotic events, etc., nor reference much of the literature which attempts to identify possible factors.
Messinezy concludes with a section on secondary polycythemia (elevated
hematocrit due to more erythropoietin) and then relative (apparent) polycythemia
(elevated hematocrit due to a low plasma volume). Some of the mechanisms
involved in this stress polycythemia (relative) are mentioned - obesity
(hypertension along with it), smoking can fit in here as well as with secondary
polycythemia, AND (a new one for me) acute alcohol consumption. He mentions
the complexities between secondary & relative polycythemia. Some things
- cardio/pulmonary included - may raise the Epo AND lower the plasma volume.
Although phlebotomies may be indicated for secondary & relative
polycythemias, not necessarily at the same (lower) hematocrit levels as with
PV AND myelosuppression (drugs) are NOT indicated.