Blood Donors and MPD
Date: Sat, 1 Feb 1997 12:53:02 -0500
From: Norm Freeburg <nfreeburg@CYBERUS.CA>
Subject: blood donors/MPD
I was asked about the reference I made to blood donors in the review of Dr.
Silver's article (again, there was nothing about the blood donations in Dr.
Silver's article). The articles:
"Myeloproliferative disease in patients with a history of multiple
blood donations: a report of 8 cases" in Haematologica 1994, issue 79, by
Randi, et al.
"Analysis of the mechnism of anagrelide-induced thrombocytopenia in
humans" publ. in Blood, April 1992, issue 79 (8), by Mazur, et al.
Let me mention the statement in the second article first. The article states
that they used (for purposes of testing anagrelide) frequent blood donors
because frequent blood donors typically have higher concentrations of
circulating CFU-meg in their blood. CFU-meg are the megakaryocyte
colony-forming progenitor blood cells. In other words, they are committed
stem cells. Stem cells develop into all of our blood cells - red, white, and
platelet (megakaryocyte), but these cells were already "committed" to being
megakaryocytes, so blood donors typically have more of these "committed" to
platelet cells, than non-blood donors.
In the FIRST article - in an Italian hospital/medical school, in a five-year
period they had 44 cases of MPD (using the PVSG criteria). Eight of these
44 turned out to have been regular blood donors (3-PV, 5-ET) which is over
18%. In a control group of 61 patients with non-MPD thrombocytosis (in
other words - high platelets but secondary, not primary), only slightly over
3% were regular blood donors. No other factor was found in common in the
MPD group except the blood donating. They had not been "sent" to give blood
because of a high hematocrit. All presented at diagnosis with high
platelets; all apparently had had normal platelet levels before beginning to
donate. There was variation in the number of years before developing MPD,
but all were giving blood frequently.
The article does not conclude that phlebotomies stimulate the
mechanisms involved in differentiation, etc., but they do mention it as a
possibility. The other is that the blood donations triggered the onset of
latent MPD disease.
Norm and I were interested in the article because of the statistics on
phlebotomy-only progressing to myelofibrosis. It is usually explained by
the fact that phlebotomy-only does nothing to actually suppress the
overproduction (differentiation? - whatever). (Silver says it doesn't
control myelopoiesis, especially megakaryocytopoiesis - Najean says it
doesn't control myeloid hyperplasia.) I'm totally guessing here - but I
suppose that the higher concentrations of CFU-meg found in blood donors is
considered a reactive response - BUT, that does NOT explain the stats in the
Italian article where only 3% of those with REACTIVE thrombocythemia had
been blood donors and 18% of the PRIMARY thrombocythemia were blood donors.
So may I throw out some questions here - related, or unrelated, to the above
- I haven't a clue!!! Most have to do with thrombopoietin - hormone (mostly
produced in liver, I think) that is a "stimulator" for stem cells to become
megakaryocytes (differentiate), to mature into platelets, and to be released
into the blood stream. (At first when discovered they thought it only had to
do with maturation & release of the already committed megakaryocytes.)
Thrombopoietin (Tpo) is a "newcomer" in the field of genetic engineering -
only recently cloned in the lab.
Is elevated thrombopoietin (Tpo) the mechanism that causes reactive
thrombocytosis in iron-deficiency (or blood loss) anemia? (I did find an
article that said Tpo was elevated in aplastic anemia, but couldn't find an
answer about iron-deficient thrombocytosis.)
And, is it believed to be elevated Tpo after a phlebotomy that can
cause a reactive platelet rise?
Is the later-developing high platelets in PV ever considered to be
reactive thrombocytosis from iron-deficiency? And.....
Have any of you out there had your Tpo levels checked? Thinking
particularly about PV patients who have had that increase in platelets as a
later course of the disease.
Are they using Tpo diagnostically for primary/secondary
thrombocytosis? Is there a distinction in the levels? (As usually they look
for erythropoietin to be elevated in secondary polycythemia, but low in
primary - vera.)
What role (if any) does Tpo have in platelet-derived growth factor
(PDGF) and transforming growth factor beta (TGF-beta)? (These are known to
be involved in marrow fibrosis.)
Is the platelet-rebound problem seen sometimes with HU and
anagrelide, reactive in nature? Do Tpo levels play a part?
Could agents taken to lower platelet-levels, which themselves
produce anemia, be counter-productive if this anemia causes reactive
thrombocytosis? (Or can this type of anemia produce thrombocytosis? Lots of
other considerations, obviously, when needing to lower platelets!)
AND, since Tpo can actually promote growth of progenitor stem cells
that ARE NOT YET COMMITTED to becoming megakaryocytes (platelets), COULD
something (like a phlebotomy??) that elevated Tpo levels, ALSO CAUSE A RISE
IN OTHER BLOOD CELLS COUNTS (besides platelets)?
The last question comes out of one of our "mouse" studies that Robert
suggested we look at. The article is "Thrombopoietin, but not
erythropoietin promotes viability and inhibits apoptosis (cell death) of
multipotent murine (mouse) hematopoietic progenitor cells in vitro (test
tube)" in Blood,Oct 1996. The question is strictly mine (not from the
article) though the fact that Tpo influences stem cells that are not just
committed to be platelets IS the point of the article.
It's probably "wishful" thinking on my part; I was just trying to
figure out a way that Norm's "messed up" white blood cells could be caused
by his iron-deficiency rather than the disease itself. (Actually his WBC's
are normal now, on the interferon.) I did the same thing when he was
diagnosed - trying to figure out how he could have secondary polycythemia
instead of P-vera.
Any thoughts or answers are appreciated!! Norm has not had real
high platelets so the thrombopoietin-reactive thrombocytosis stuff is new to
us. (I did notice one article where a case of iron-deficient reactive
thrombocytosis caused a platelet level of 1.6 million - usually they don't
consider above 1 million as reactive?) And a couple more thoughts -
autoimmune disease is a cause of reactive thrombocytosis (such as rheumatoid
arthritis), but some articles did see some overlap with primary
thrombocytosis. Also, that reactive thrombocytosis is not considered to have
the same thrombotic risk, so it could be significant if some rise in
platelets in MPD IS reactive in nature. (Though in the case of PV, one still
has the progression to fibrosis to consider.)
Best to all,
Ruth
NOTE: Since this original posting, two articles that implicate Tpo
with myelofibrosis have come to my attention. They are :
THROMBOPOIETIN-RESPONSIVE ESSENTIAL THROMBOCYTHEMIA WITH MYELOFIBROSIS
publ. in British Journal of Haematology, May 1997, vol. 97(2).
and A MODEL OF MYELOFIBROSIS AND OSTEOSCLEROSIS IN MICE INDUCED BY
OVEREXPRESSING THROMBOPOIETIN; REVERSAL OF DISEASE BY BONE MARROW
TRANSPLANTATION by Yan, et al., publ. in Blood, July 1996, vol. 88(2).
Dr. Silver stated that they were beginning to do research in this area
with Malcom Moore, co-discoverer of G-CSFa (a growth colony-stimulating
factor).
|