Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Introduction
Top
Polycythemia vera is a clonal
Introduction
disorder arising in a multipotent The pathogenesis of...
hematopoietic progenitor cell that The diagnosis of polycythemia...
The diagnosis of polycythemia...
causes the accumulation of Anecdote as paradigm: the...
Survival with polycythemia...
morphologically normal red cells, Phlebotomy and polycythemia...
white cells, platelets, and their Thrombocytosis and polycythemia...
progenitors in the absence of a The management of polycythemia...
References
definable stimulus and to the
exclusion of nonclonal hematopoiesis.1,2 First described in 1892,3
polycythemia vera is not a new disease and while uncommon, with an
incidence of at least 2 per 100 000,4-6 it is not a rare disease. Yet, after
10 decades of careful clinical and laboratory investigation, the etiology
of polycythemia vera remains unknown and there is no consensus as to
the optimal therapy for the disorder. 7 There is, however, no reason for
this to be so. Although the molecular basis of polycythemia vera remains
elusive, it is the central thesis of this review that the pathophysiology of
polycythemia vera is sufficiently well defined for the provision of a
rational treatment program that prolongs life, alleviates the specific
morbidities associated with the disease, and avoids complications related
to the consequences of the underlying molecular defect. However, for
such an approach to be successful, it is first necessary to recognize the
contradictions between what is actually known about this disease and
how that knowledge has been interpreted and applied clinically, and that
is the purpose of this review.
Figure 1. Relationship
between serum erythropoietin
and hemoglobin in patients
with polycythemia vera
( ), secondary
erythrocytosis ( ) or
relative erythrocytosis (x).
Adapted from Handin et al369
with permission of the
View larger version (11K):
publisher, Lippincott, Williams,
[in this window]
and Wilkins.
[in a new window]
IGF-1
Serum erythropoietin
PRV-1 expression
Clonality assays
The most important omission from the PVSG diagnostic criteria for
polycythemia vera was a requirement for the establishment of clonality.
Unfortunately, however, in contrast to CML, there has been no clinically
applicable clonal assay for polycythemia vera or its companion
myeloproliferative disorders, idiopathic myelofibrosis and essential
thrombocytosis. Nonrandom chromosome abnormalities are not
uncommon in these disorders and in polycythemia vera the most
frequent are trisomies of 1q, 8, 9 or 9p, del13q, del20q, or interstitial
deletions of 13 or 20; occasionally multiple defects are
present. 31,74,101,102 However, there is no consistent or unique
cytogenetic abnormality associated with any of these disorders and at the
time of diagnosis, using conventional cytogenetic techniques, less than
20% of polycythemia vera patients exhibit a cytogenetic abnormality and
many patients never develop one. 74 In this regard, the use of interphase
fluorescence in situ hybridization (FISH) may increase the diagnostic
yield.32 However, bone marrow aspiration is still required for
cytogenetic analysis unless there are numerous primitive cells in the
circulation.
With respect to what the PVSG diagnostic criteria do stipulate, the most
important is elevation of the red cell mass. Admittedly, this criterion
does not establish clonality or even distinguish polycythemia vera from
other disorders that cause erythrocytosis. However, it makes a vitally
important point with respect to the evaluation of a high hematocrit level
in general and polycythemia vera in particular that only direct
measurement of the red cell mass and plasma volume will suffice to
distinguish absolute erythrocytosis from so-called spurious or relative
erythrocytosis due to plasma volume contraction or red cell
redistribution. 109-111 Indeed, it is not hyperbole to state that failure to
appreciate this basic concept has been responsible for more diagnostic
and therapeutic failures in patients with polycythemia vera than any
other single factor. The reason appears to be a lack of understanding of
the pathophysiology of the red mass and plasma volume in disorders
causing erythrocytosis.
Myeloid metaplasia
Myelofibrosis
Although it has been argued that the decrease in cerebral blood flow
associated with a high hematocrit level is a physiologic response to
increased oxygenation not increased viscosity,270 the data upon which
this contention are based either actually support the latter process270,271
or fail to substantiate the former since the subjects studied were actually
not sufficiently hyperviscous. 272,273 On the contrary, there are
physiologically sound data indicating that cerebral blood flow like blood
flow elsewhere274 declines independently of oxygen transport when
blood viscosity increases.275
Not only is there compelling evidence that increased blood viscosity due
to an elevated red cell mass is the principal basis for the hypercoagulable
state in polycythemia vera, there is equally strong evidence that
phlebotomy, a venerable practice that was well known in the Hippocratic
era, is the most effective remedy. Unfortunately, it is both an irony and a
tragedy that this is one Hippocratic principle that many hematologists
have been reluctant to embrace wholeheartedly. The reasons are many
but none are clinically tenable or physiologically sound. First, although
phlebotomy was recognized by early clinicians as an effective method of
bringing symptomatic relief to polycythemia vera patients, the adequate
or consistent application of phlebotomy was deterred by the concern that
it would stimulate new blood formation. Thus, in 1928, an authoritative
review of the disease stated "One must conclude that while venesection
is an important and useful in relief in emergency in the treatment of
these patients, it cannot be looked upon in any other light than as a
further, and therefore undesirable stimulant to new blood formation."159
This contention, reaffirmed more than once in modern times in the
absence of any data,87,145,148,290 is, of course, erroneous, since bone
marrow function in polycythemia vera, as in the other myeloproliferative
disorders, is autonomous and erythropoiesis can neither be suppressed by
hyperoxia10,291 nor substantially stimulated by hypoxia292 or
phlebotomy, 12,13,293 and this appears to be true for thrombopoiesis as
well in the absence of anemia. 150,182,293-295
A more serious claim has been that the use of phlebotomy therapy alone
in polycythemia vera results in a high incidence of myelofibrosis,316 a
claim that is difficult to understand except as population specific since it
is contrary to most published experience. For example, in a series of
207 patients followed for more than 10 years, only 4 patients treated
solely by phlebotomy developed myelofibrosis,149 while in another
series of 250 patients, none of the patients treated solely by phlebotomy
developed myelofibrosis.156 Indeed, this experience has been the
rule148,156,163 rather than the exception. As a corollary, the low
incidence of polycythemia vera patients recorded in a published series of
myelofibrosis patients173,175,190,192 as well as the high incidence of
myelofibrosis observed in patients treated with hydroxyurea169 suggest
that this complication is neither frequent nor limited to patients exposed
only to phlebotomy. Furthermore, since myelofibrosis can be a
presenting manifestation of polycythemia vera73,317 and also occurs in
patients exposed to 32P163,189,318 and x-ray therapy,156,163,234 there are
no grounds to implicate venesection as a specific causal factor. An
additional difficulty in this regard, as discussed above, is the definition
of myelofibrosis; a dry tap or increased reticulin is not sufficient for this
purpose.158,179 Finally, implicit in this contention is the notion that
myelofibrosis is deleterious in polycythemia vera, when in fact it is
perfectly compatible with normal bone marrow function, 134,155,181,183 is
a reversible process,168,175,184-186 and has not been shown to impact
adversely on survival.150,174,177 Indeed, failure to recognize
polycythemia vera presenting as myelofibrosis is potentially more
deleterious than the development of myelofibrosis during the course of
the disease.
probably more apparent than real, at least with respect to the phlebotomy
group. In the same fashion, given the lack of attention to reducing blood
viscosity in this disorder, it can be seriously questioned whether a prior
history of thrombosis and advanced age are truly risk factors for
thrombosis in polycythemia vera patients.331 Certainly, neither
chemotherapy nor radiotherapy has proved superior to phlebotomy in
preventing thrombosis but both have proved to be more toxic.244
Furthermore, since polycythemia vera appears to be a
myeloaccumulative disorder rather than a myeloproliferative one, at least
with respect to the erythrocytosis and a disorder that is often indolent
and of long duration, its treatment should be commensurate with that
behavior.
The first issue with respect to management is diagnosis and it should be
obvious that it is not possible to accurately estimate the red cell mass
from the hematocrit level when polycythemia vera is a diagnostic
consideration and the hematocrit level is less than 60% in a man or 50%
in a woman. Measurement of the red cell mass and plasma volume by
isotope dilution should be a standard of care but unfortunately this
standard is more often honored in the breach than in the observance. In
some locales, bogus medical economics have been allowed to dictate the
availability of these procedures, which can only be seen as an abdication
of our professional responsibilities as hematologists. While elevation of
the red cell mass does not establish the diagnosis of polycythemia vera,
the diagnosis cannot be made in its absence. Even if a clonal assay for
polycythemia vera were available, such an assay would not abrogate the
need for red cell mass and plasma volume determinations in this disease
any more than the HFE assay for hemochromatosis has abrogated the
need for serum transferrin saturation measurements as a guide to both
diagnosis and therapy.
Since few physicians see many of these patients, the concerns described
above emphasize the need to gain greater insight into the natural history
of polycythemia vera and to reinitiate prospective, controlled multicenter
clinical trials using the wisdom gained from such initiatives as the
Cooperative Study of Sickle Cell Disease367 and the PVSG. Until such a
time as those goals are realized, we can do no better than to heed the
advice of William Dameshek, a proponent of phlebotomy therapy in
polycythemia vera: "There seems to be a tendency in medical practice
by no means limited to hematologists to treat almost every condition
as vigorously as possible. In hematology, this consists in attempting to
change an abnormal number whether this number is hemoglobin,
hematocrit, WBC, platelet count to normal values whether the patient
needs it or not!" 238
Footnotes
Submitted December 28, 2001; accepted July 15, 2002.
5. Ania BJ, Suman VJ, Sobell JL, et al. Trends in the incidence of
polycythemia vera among Olmsted County, Minnesota residents, 1935-
1989. Am J Hematol. 1994;47:89-93[Medline].
8. Berlin NI, Lawrence JH, Lee HC. The life span of the red blood cell
in chronic leukemia and polycythemia. Science. 1951;114:385-387.
10. Lawrence JH, Elmlinger PJ, Fulton G. Oxygen and the control of red
cell production in primary and secondary polycythemia: effects on iron
turnover pattern with Fe59 as a tracer. Cardiologia. 1952;21:337-346.
19. Eid J, Ebert RF, Gesell MS, Spivak JL. Intracellular growth factors
in polycythemia vera and other myeloproliferative disorders. Proc Natl
Acad Sci U S A. 1987;84:532-536[Medline].
20. de Wolf JT, Beentjes JA, Esselink MT, et al. In polycythemia vera
human interleukin 3 and granulocyte-macrophage colony-stimulating
factor enhance erythroid colony growth in the absence of erythropoietin.
Exp Hematol. 1989;17:981-983[Medline].
21. Dai CH, Krantz SB, Green WF, Gilbert HS. Polycythaemia vera. III.
Burst-forming units-erythroid (BFU-E) response to stem cell factor and
c-kit receptor expression. Br J Haematol. 1994;86:12-21[Medline].
24. Dai CH, Krantz SB, Sawyer ST. Polycythemia vera. V. Enhanced
proliferation and phosphorylation due to vanadate are diminished in
polycythemia vera erythroid progenitor cells: a possible defect of
phosphatase activity in polycythemia vera. Blood. 1997;89:3574-
3581[Abstract/Free Full Text].
33. Nunez C, Bashein AM, Brunet CL, et al. Expression of the imprinted
tumour-suppressor gene H19 is tightly regulated during normal
haematopoiesis and is reduced in haematopoietic precursors of patients
with the myeloproliferative disease polycythaemia vera. J Pathol.
2000;190:61-68[CrossRef][Medline].
35. Dai CH, Krantz SB, Koury ST, Kollar K. Polycythemia vera. IV.
Specific binding of stem cell factor to normal and polycythemia vera
highly purified erythroid progenitor cells. Br J Haematol. 1994;88:497-
505[Medline].
50. Spivak JL, Ferris DK, Fisher J, et al. Cell cycle-specific behavior of
erythropoietin. Exp Hematol. 1996;24:141-150[Medline].
52. Fairbairn LJ, Cowling GJ, Reipert BM, Dexter TM. Suppression of
apoptosis allows differentiation and development of a multipotent
hemopoietic cell line in the absence of added growth factors. Cell.
1993;74:823-832[Medline].
54. Gregoli PA, Bondurant MC. The roles of Bcl-X(L) and apopain in
the control of erythropoiesis by erythropoietin. Blood. 1997;90:630-
640[Abstract/Free Full Text].
55. Mirza AM, Correa PN, Axelrad AA. Increased basal and induced
tyrosine phosphorylation of the insulin-like growth factor I receptor beta
subunit in circulating mononuclear cells of patients with polycythemia
vera. Blood. 1995;86:877-882[Abstract/Free Full Text].
56. Mirza AM, Ezzat S, Axelrad AA. Insulin-like growth factor binding
protein-1 is elevated in patients with polycythemia vera and stimulates
erythroid burst formation in vitro. Blood. 1997;89:1862-
1869[Abstract/Free Full Text].
58. Solar GP, Kerr WG, Zeigler FC, et al. Role of c-mpl in early
hematopoiesis. Blood. 1998;92:4-10[Abstract/Free Full Text].
59. Borge OJ, Ramsfjell V, Cui L, Jacobsen SE. Ability of early acting
cytokines to directly promote survival and suppress apoptosis of human
primitive CD34+. Blood. 1997;90:2282-2292[Abstract/Free Full Text].
73. Ellis JT, Silver RT, Coleman M, Geller SA. The bone marrow in
polycythemia vera. Semin Hematol. 1975;12:433-444[Medline].
75. Ellis JT, Peterson P, Geller SA, Rappaport H. Studies of the bone
marrow in polycythemia vera and the evolution of myelofibrosis and
second hematologic malignancies. Semin Hematol. 1986;23:144-
155[Medline].
78. Haga P, Cotes PM, Till JA, Minty BD, Shinebourne EA. Serum
immunoreactive erythropoietin in children with cyanotic and acyanotic
congenital heart disease. Blood. 1987;70:822-826[Abstract].
79. Dudley JM, Westwood N, Leonard S, Eridani S, Pearson TC.
Primary polycythaemia: positive diagnosis using the differential response
of primitive and mature erythroid progenitors to erythropoietin,
interleukin 3 and alpha-interferon. Br J Haematol. 1990;75:188-
194[Medline].
82. Turhan AG, Cashman JD, Eaves CJ, Humphries RK, Eaves AC.
Variable expression of features of normal and neoplastic stem cells in
patients with thrombocytosis. Br J Haematol. 1992;82:50-57[Medline].
87. Szur L, Lewis SM, Goolden AWG. Polycythemia vera and its
treatment with radioactive phosphorus. Q J Med. 1959;28:397-424.
96. Moliterno AR, Hankins WD, Spivak JL. Impaired expression of the
thrombopoietin receptor by platelets from patients with polycythemia
vera. N Engl J Med. 1998;338:572-580[Abstract/Free Full Text].
98. Moliterno AR, Silver RT, Spivak JL. A diagnostic assay for
polycythemia vera. Blood. 2001;96:512a.
101. Diez-Martin JL, Graham DL, Petitt RM, Dewald GW. Chromosome
studies in 104 patients with polycythemia vera. Mayo Clin Proc.
1991;66:287-299[Medline].
102. Rege-Cambrin G, Mecucci C, Tricot G, et al. A chromosomal
profile of polycythemia vera. Cancer Genet Cytogenet. 1987;25:233-
245[Medline].
105. Gale RE, Fielding AK, Harrison CN, Linch DC. Acquired skewing
of X-chromosome inactivation patterns in myeloid cells of the elderly
suggests stochastic clonal loss with age. Br J Haematol. 1997;98:512-
519[Medline].
106. Gilbert HL, Acharya J, Pearson TC. Implications for the use of X-
chromosome inactivation patterns and their relevance to the
myeloproliferative disorders. Eur J Haematol. 1998;61:282-
283[Medline].
107. Prchal JT, Sokol L. "Benign erythrocytosis" and other familial and
congenital polycythemias. Eur J Haematol. 1996;57:263-268[Medline].
111. Berlin NI, Lewis SM. Measurement of total RBC volume relative to
lean body mass for diagnosis of polycythemia. Am J Clin Pathol.
2000;114:922-926[Medline].
118. Besa EC, Gorshein D, Gardner FH. Androgens and human blood
volume changes: comparison in normal and various anemic states. Arch
Intern Med. 1974;133:418-425[Medline].
122. Campbell A, Emery EW, Godlee JN, Prankerd TAJ. Diagnosis and
treatment of primary polcy-thaemia. Lancet. 1970;1:1074-
1077[Medline].
124. Gibson JG, Seligman A, Peacock WC, et al. The distribution of red
cells and plasma in large and minute vessels of the normal dog,
determined by radioactive isotopes of iron and iodine. J Clin Invest.
1946;5:848-857.
125. Ebert R, Stead EA. Demonstration that the cell plasma ratio of
blood contained in minute vessels is lower than that of venous blood. J
Clin Invest. 1941;20:317-321.
126. Berson S, Yalow RS. The use of K42 or P32 labeled erythrocytes
and I131 tagged human serum albumin in simultaneous blood volume
determinations. J Clin Invest. 1952;31:572-580.
127. Retzlaff JA, Tauxe WN, Kiely JM, Stroebel CF. Erythrocyte
volume, plasma volume, and lean body mass in adult men and women.
Blood. 1969;33:649-661[Medline].
133. Lawrence JH, Berlin NI, Huff RL. The nature and treatment of
polycythemia. Medicine. 1953;32:323-388.
136. Najean Y, Arrago JP, Rain JD, Dresch C. The `spent' phase of
polycythaemia vera: hypersplenism in the absence of myelofibrosis. Br J
Haematol. 1984;56:163-170[Medline].
137. Stead EA, Ebert RF. Relationship of the plasma volume and the cell
plasma ratio to the total red cell volume. Am J Physiol. 1941;132:411-
417.
138. Strumia MM, Strumia PV, Dugan A. Significance of measurement
of plasma volume and of indirect estimation of red cell volume.
Transfusion. 1968;8:197-209[Medline].
142. Fairbanks V. Polycythemia vera: the packed cell volume and the
curious logic of the red cell mass. Hematology. 2000;4:381-
395[Medline].
143. Fairbanks VF, Tefferi A. Normal ranges for packed cell volume and
hemoglobin concentration in adults: relevance to `apparent
polycythemia.' Eur J Haematol. 2000;65:285-296[CrossRef][Medline].
144. Hess CH, Ayers CR, Sandusky WR, et al. Mechanism of dilutional
anemia in massive splenomegaly. Blood. 1976;47:629-644[Abstract].
157. Silverstein MN. The evolution into and the treatment of late stage
polycythemia vera. Semin Hematol. 1976;13:79-84[Medline].
158. Roberts BE, Miles DW, Woods CG. Polycy-thaemia vera and
myelosclerosis: a bone marrow study. Br J Haematol. 1969;16:75-
85[Medline].
160. Tinney WS, Hall BE, Giiffin HZ. The liver and spleen in
polycythemia vera. Proc Staff Meetings Mayo Clin. 1943;18:46-47.
162. Pettit JE, Lewis SM, Williams ED, et al. Quantitative studies of
splenic erythropoiesis in polycythaemia vera and myelofibrosis. Br J
Haematol. 1976;34:465-475[Medline].
166. Rigby PG, Leavell BS. Polycythemia vera. Arch Intern Med.
1960;5:100-105.
171. Johnston JB, Dalal BI, Israels SJ, et al. Deposition of transforming
growth factor-beta in the marrow in myelofibrosis, and the intracellular
localization and secretion of TGF-beta by leukemic cells. Am J Clin
Pathol. 1995;103:574-582[Medline].
177. Pitcock JA, Reinhard EH, Justus BW, Mendelsohn RS. A clinical
and pathological study of seventy cases of myelofibrosis. Ann Intern
Med. 1962;57:73-84.
200. Berk PD, Goldberg JD, Silverstein MN, et al. Increased incidence
of acute leukemia in polycythemia vera associated with chlorambucil
therapy. N Engl J Med. 1981;304:441-447[Abstract].
206. Reimer RR, Hoover R, Fraumeni JF, Young RC. Acute leukemia
after alkylating-agent therapy of ovarian cancer. N Engl J Med.
1977;297:177-181[Abstract].
220. Neu LT, Shuman MA, Brown EB. Polycythemia vera and acute
leukemia. Ann Intern Med. 1975;83:672-673[Medline].
229. Lundberg WB, Farber LR, Cadman EC, Skeel RT. Spontaneous
acute leukemia in polycythemia vera. Ann Intern Med. 1976;84:294-
295[Medline].
233. McDonnell JM, Beschorner WE, Staal SP, Spivak JL, Mann RB.
Richter's syndrome with two different B-cell clones. Cancer.
1986;58:2031-2037[Medline].
236. Tinney WS, Hall BE, Giffin HZ. The prognosis of polycythemia
vera. Proc Staff Meetings Mayo Clin. 1945;20:227-230.
253. Barabas AP, Offen DN, Meinhard EA. The arterial complications
of polycythaemia vera. Br J Surg. 1973;50:183-187.
254. Wasserman LR, Balcerzak SP, Berk PD, et al. Influence of therapy
on causes of death in polycythemia vera. Trans Assoc Am Physicians.
1981;94:30-38[Medline].
259. Wells RE, Merrill EW. Influence of flow properties of blood upon
viscosity-hematocrit relationship. J Clin Invest. 1962;41:1591-1598.
261. Begg TB, Hearns JB. Components in blood viscosity: the relative
contribution of haematocrit, plasma fibrinogen and other proteins. Clin
Sci. 1966;31:87-93[Medline].
264. Cobb LA, Kramer RJ, Finch CA. Circulatory effects of chronic
hypervolemia in polycythemia vera. J Clin Invest. 1960;39:1722-1728.
266. Wanless IR, Peterson P, Das A, et al. Hepatic vascular disease and
portal hypertension in polycythemia vera and agnogenic myeloid
metaplasia: a clinicopathological study of 145 patients examined at
autopsy. Hepatology. 1990;12:1166-1174[Medline].
269. York EL, Jones RL, Menon D, Sproule BJ. Effects of secondary
polycythemia on cerebral blood flow in chronic obstructive pulmonary
disease. Am Rev Respir Dis. 1980;121:813-818[Medline].
271. Wade JP. Transport of oxygen to the brain in patients with elevated
haematocrit values before and after venesection. Brain. 1983;106:513-
523[Abstract].
273. Wade JP, du Boulay GH, Marshall J, et al. Cerebral blood flow,
haematocrit and viscosity in subjects with a high oxygen affinity
haemoglobin variant. Acta Neurol Scand. 1980;61:210-215[Medline].
276. Chien S, Usami S, Taylor HM, Lundberg JL, Gregersen MI. Effects
of hematocrit and plasma proteins on human blood rheology at low shear
rates. J Appl Physiol. 1966;21:81-87[Medline].
277. Turitto V, Weiss H. Red blood cells: their dual role in thrombus
formation. Science. 1976;207:541-543.
280. Dintenfass L. Viscosity of the packed red and white blood cells.
Exp Mol Pathol. 1965;4:597-605[Medline].
284. Posan E, Ujj G, Kiss A, et al. Reduced in vitro clot lysis and release
of more active platelet PAI-1 in polycythemia vera and essential
thrombocythemia. Thromb Res. 1998;90:51-56[CrossRef][Medline].
285. Jensen MK, de Nully BP, Lund BV, Nielsen OJ, Hasselbalch HC.
Increased platelet activation and abnormal membrane glycoprotein
content and redistribution in myeloproliferative disorders. Br J
Haematol. 2000;110:116-124[CrossRef][Medline].
287. Murphy S, Davis JL, Walsh PN, Gardner FH. Template bleeding
time and clinical hemorrhage in myeloproliferative disease. Arch Intern
Med. 1978;138:1251-1253[Medline].
302. Humphrey PR, Michael J, Pearson TC. Red cell mass, plasma
volume and blood volume before and after venesection in relative
polycythaemia. Br J Haematol. 1980;46:435-438[Medline].
304. Rakita L, Gillespie DG, Sancetta SM. The acute and chronic effects
of phlebotomy on general hemodynamics and pulmonary functions of
patients with secondary polycythemia associated with pulmonary
emphysema. Am Heart J. 1965;70:466-475[Medline].
307. Weisse AB, Moschos CB, Frank MJ, et al. Hemodynamic effects of
staged hematocrit reduction in patients with stable cor pulmonale and
severely elevated hematocrit levels. Am J Med. 1975;58:92-
98[Medline].
308. Milligan DW, MacNamee R, Roberts BE, Davies JA. The influence
of iron-deficient indices on whole blood viscosity in polycythaemia. Br J
Haematol. 1982;50:467-471[Medline].
309. Hutton RD. The effect of iron deficiency on whole blood viscosity
in polycythaemic patients. Br J Haematol. 1979;43:191-199[Medline].
311. Moore DF, Sears DA. Pica, iron deficiency, and the medical
history. Am J Med. 1994;97:390-393[Medline].
314. Yip R, Mohandas N, Clark MR, et al. Red cell membrane stiffness
in iron deficiency. Blood. 1983;62:99-106[Abstract].
315. Aarts PA, Bolhuis PA, Sakariassen KS, Heethaar RM, Sixma JJ.
Red blood cell size is important for adherence of blood platelets to artery
subendothelium. Blood. 1983;62:214-217[Abstract].
329. Tartaglia AP, Goldberg JD, Berk PD, Wasserman LR. Adverse
effects of antiaggregating platelet therapy in the treatment of
polycythemia vera. Semin Hematol. 1986;23:172-176[Medline].
332. Berger S, Aledort LM, Gilbert HS, Hanson JP, Wasserman LR.
Abnormalities of platelet function in patients with polycythemia vera.
Cancer Res. 1973;33:2683-2687[Medline].
335. Schlemper RJ, van der Maas AP, Eikenboom JC. Familial essential
thrombocythemia: clinical characteristics of 11 cases in one family. Ann
Hematol. 1994;68:153-158[Medline].
336. Eyster ME, Saletan SL, Rabellino EM, et al. Familial essential
thrombocythemia. Am J Med. 1986;80:497-502[Medline].
339. Buss DH, Cashell AW, O'Connor ML, Richards F, Case LD.
Occurrence, etiology, and clinical significance of extreme
thrombocytosis: a study of 280 cases. Am J Med. 1994;96:247-
253[Medline].
350. van Genderen PJ, Budde U, Michiels JJ, van Strik R, van Vliet HH.
The reduction of large von Willebrand factor multimers in plasma in
essential thrombocythaemia is related to the platelet count. Br J
Haematol. 1996;93:962-965[Medline].
351. van Genderen PJ, Prins FJ, Lucas IS, et al. Decreased half-life time
of plasma von Willebrand factor collagen binding activity in essential
thrombocythaemia: normalization after cytoreduction of the increased
platelet count. Br J Haematol. 1997;99:832-836[Medline].
354. Michiels JJ, Koudstaal PJ, Mulder AH, van Vliet HH. Transient
neurologic and ocular manifestations in primary thrombocythemia.
Neurology. 1993;43:1107-1110[Abstract].
360. Prentice TC, Berlin NI, Lawrence JH. Effect of therapy on blood
volume, blood pressure, and spleen size in polycythemai vera. Arch
Intern Med. 1952;89:584-590.
367. Gaston M, Rosse WF. The cooperative study of sickle cell disease:
review of study design and objectives. Am J Pediatr Hematol Oncol.
1982;4:197-201[Medline].
368. Conley CL. Polycythemia vera: diagnosis and treatment. Hosp Prac.
1987;22:181-210.
369. Handin RI, Lux SE, Stossel TP. Blood: Principles and Practices of
Hematology 2nd ed. Philadelphia, PA: Lippincott, Williams, and
Wilkins; 2002.