□ EDITORIAL □

Thrombocytosis in Iron Deficiency Anemia

Key words: thrombocytosis, iron deficiency anemia, throm- been implicated as the cause of reactive thrombocytosis.
bosis Several clinical and laboratory observations support the pos-
sible pathogenetic role of elevated IL-6 levels in reactive
thrombocytosis. Tefferi A et al evaluated the discriminatory
value of plasma IL-6 levels in clonal thrombocytosis and in
Thrombocytosis is observed in many disorders and patho- reactive thrombocytosis (1). They showed that IL-6 levels
logical states. An elevated platelet count may be caused by were undetectable in all the patients with clonal thrombo-
a reactive mechanism or it may be the result of autonomous cytosis, whereas they were increased in 60% of the patients
(neoplastic) overproduction. A variety of medical and surgi- with reactive thrombocytosis or clonal thrombocytosis plus
cal conditions can result in reactive thrombocytosis. These reactive thrombocytosis. They suggested that reactive
include infections, inflammatory disorders, malignancies, thrombocytosis is either mediated by high plasma levels of
acute bleeding or hemolysis, rebound phase of thromco- IL-6 or associated with high plasma levels of IL-6 in reaction
cytopenia, iron deficiency anemia and post-splenectomy to a common inflammatory process.
state. On the other hand, autonomous thrombocytosis refers Iron deficiency anemia is a cause of reactive thrombo-
to clonal disorders derived from hematopoietic stem cells. cytosis, and the thrombocytosis is usually mild to moderate
These include essential thrombocythemia, polycythemia degree. In one series, the average platelet count was 499×
vera, chronic myelogenous leukemia, idiopathic myelo- 109 /l, or roughly twice the controls (3). Extreme thrombo-
fibrosis and myelodysplastic syndrome. The most common cytosis is not so common but in one report of 100 consecu-
myelodysplastic syndrome associated with thrombocytosis is tive patients with iron deficiency anemia, platelet counts
the 5q- syndrome. were above 1,000×109/l in 7% of the patients (4). Alteration
As for the frequency, reactive thrombocytosis is much of the bone marrow megakaryocyte count in iron deficiency
more frequent than autonomous thrombocytosis. In a report anemia is not mentioned usually except for two reports (4,
of 91 consecutive patients with a platelet count of more than 5). In these reports, the authors mentioned that the bone mar-
600×109/l, 64 (70%) had reactive thrombocytosis, 20 (22%) row megakaryocyte counts were increased and the plausible
had clonal thrombocytosis, and 7 (8%) had clonal thrombo- explanation of the thrombocytosis might be an increased pro-
cytosis plus reactive thrombocytosis (1). The most common duction of platelets. In this issue, Nagai T et al (6) reported
cause of reactive thrombocytosis was infection, followed by a case of severe iron deficiency anemia with marked
infection & post-surgical, post-surgical, malignancy, thrombocytosis that was complicated by central retinal vein
splenectomy, acute blood loss and iron deficiency anemia in occlusion.
that order. Of the 20 clonal thrombocytosis, the most com-
mon disorder was essential thrombocythemia. Reactive See also p 1090.
thrombocytosis is a much more frequent cause of thrombo-
cytosis than autonomous thrombocytosis even when cases In this case, the platelet count was 1,020×109 /l and the
9
with extreme thrombocytosis (platelet count >1,000×10 /l) authors mentioned that the extreme thrombocytosis was in-
are considered. In one study of 280 patients with extreme volved in the development of central retinal vein occlusion.
thrombocytosis, 231 (82%) had reactive thrombocytosis, 38 Although thrombotic and bleeding events are much less
(14%) had a myeloproliferative disorder and 11 (4%) had likely to occur in association with reactive thrombocytosis
cases of uncertain etiology (2). Of the 231 patients with reac- than autonomous thrombocytosis (2), thrombotic complica-
tive thrombocytosis, the causes were infection (31%), post- tions were occasionally reported in iron deficiency anemia
splenectomy (19%), malignancy (14%), trauma (14%), non- (5, 7).
infectious inflammation (9%), blood loss (6%), uncertain The mechanisms causing reactive thrombocytosis in iron
etiology (4%) and rebound (3%). It is known that the great deficiency anemia are also unknown. There are several re-
majority of platelet counts associated with reactive thrombo- ports to elucidate the mechanisms of the reactive thrombo-
cytosis are less than 1,000×109 /l, however, extreme cytosis from the aspect of thrombopoietic cytokines. Akan et
thrombocytosis of platelet counts greater than or equal to al assayed the serum levels of thrombopoietin, erythro-
1,000×109/l should not be considered rare events (2). poietin, leukemia inhibitory factor, IL-6 and IL-11, but none
Thrombopoietic growth factors including interleukin-6 of these cytokines had any effect on reactive thrombocytosis
(IL-6), tumor necrosis factor-
and thrombopoietin have in iron deficiency anemia (8). Recently, Bilic and Bilic

Internal Medicine Vol. 44, No. 10 (October 2005) 1025

reported that the amino acid sequence homology of thrombo-
poietin and erythropoietin may explain the thrombocytosis in
children with iron deficiency anemia (9). Contrary to this re-
port, however, there are two reports suggesting negative par-
ticipation of erythropoietin and thrombopoietin (10, 11). To
clarify the etiology of thrombocytosis in iron deficiency ane-
mia, further investigation will be necessary.
Kazuo DAN, MD, PhD
Third Department of Internal Medicine, Nippon Medical School,
1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603
References
1) Tefferi A, Ho TC, Ahmann GJ, Katzmann JA, Greipp PR. Plasma
interleukin-6 and C-reactive protein levels in reactive versus clonal
thrombocytosis. Am J Med 97: 374–378, 1994.
2) Buss DH, Cashell AW, O’Connor ML, Richards F 2nd, Case LD.
Occurrence, etiology and clinical significance of extreme thrombo-
cytosis: a study of 280 cases. Am J Med 96: 247–253, 1994.
3) Schloesser LL, Kipp MA, Wenzel FJ. Thrombocytosis in iron-
deficiency anemia. J Lab & Clin Med 66: 107–114, 1965.
1026
4) Kasper CK, Whissell DY, Wallerstein RO. Clinical aspects of iron de-
ficiency. JAMA 191: 359–363, 1965.
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vascular accident. South Med J 76: 662–663, 1983.
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anemia with marked thrombocytosis complicated by central retinal vein
occlusion. Intern Med 44: 1090–1092, 2005.
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associated with severe iron-deficiency anemia and thrombocytosis.
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Thrombopoietic cytokines in patients with iron deficiency anemia with
or without thrombocytosis. Acta Haematol 103: 152–156, 2000.
9) Bilic E, Bilic E. Amino acid sequence homology of thrombopoietin and
erythropoietin may explain thrombocytosis in children with iron defi-
ciency anemia. J Pediatr Hematol Oncol 25: 675–676, 2003.
10) Racke F. EPO and TPO sequences do not explain thrombocytosis in
iron deficiency anemia. J Pediatr Hematol Oncol 25: 919, 2003.
11) Geddis AE, Kaushansky K. Cross-reactivity between erythropoietin
and thrombopoietin at the level of mpl does not account for the
thrombocytosis seen in iron deficiency. J Pediatr Hematol Oncol 25:
919–920, 2003.
Internal Medicine Vol. 44, No. 10 (October 2005)