On consults this weekend, I faced a question of whether a patient's thrombocytosis was secondary to iron deficiency or due to a clonal process, and it got me thinking...

Why does iron deficiency (ID) cause thrombocytosis?

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The data clearly support an association between iron deficiency and in plt ct
Review of all 5k patients, 1 clinic, 1 yr:
10% of pts with IDA had plt
Only 1% of control pts (nl iron) had plt
Lower ferritin corr. with higher plt count

https://doi.org/10.1182/blood-2018-99-119352

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In patients with ID-assoc. thrombocytosis, usually mild-moderate plt
Series of 100 consec. patients with IDA
Average plt 499k
Only 7% with plt > 1 million
https://www.jstage.jst.go.jp/article/internalmedicine/44/10/44_10_1025/_pdf

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So I've shown that iron deficiency is associated with thrombocytosis, but we haven't discussed causality, and haven't gotten any closer to answering the question: WHY?

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To answer that, let's start with a quick refresher on platelet maturation.

We start with the multipotent hematopoietic stem cell: this little guy can ultimately become any sort of blood cell the body needs: platelet, RBC, and the full spectrum of WBCs.

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The HSC progresses to a megakaryocyte (MK)/erythrocyte precursor
then to a MK
which flicks off pieces of its cytoplasm to create platelets
that then leave the BM and go out into the bloodstream.

TPO (Thrombopoietin) drives this maturation process.

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Therefore, since TPO leads to more platelets, and iron deficiency leads to more platelets...

Is this the mechanism?

I.e. does decreased iron lead to more TPO and that's why platelets go up?

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In a rat study, Evstatiev et al induced iron deficiency and looked at various cytokine levels over time.

They induced iron deficiency (measured by hepatic iron) and subsequently microcytic anemia + thrombocytosis (compared to control rats) within a matter of weeks.

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HOWEVER, while TPO with time in both groups, TPO levels were similar between groups.

IL-6 and IL-11 (also suggested as involved in IDA thrombocytosis) did rise in week 3 spec. in the ID group, but that rise came after the in platelets.

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They DID find increased ploidy (DNA replication) of Megakaryocytes in the ID group larger MKs platelet-producing ability.

This suggests that iron deficiency causes MK size (via increased DNA replication), and thereby Platelets https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4114532/

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But how does MK growth happen?

In a paper (which was a plenary session at @ASH_hematology ), Xavier et al looked at both mouse and human cell models for iron deficiency and found iron deficiency caused MK/erythrocyte precursors to preferentially develop into MKs.

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AND, the transferrin receptor was upregulated in the Fe-def models, while TFs previously known to regulate erythrocytes and MK maturation were no different.

I.e. MK/RBC progenitor cells shunted towards MKs via transf. receptor sensing iron.

( https://ashpublications.org/blood/article-abstract/134/18/1547/374971/Low-iron-promotes-megakaryocytic-commitment-of)

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So again, why does iron deficiency cause thrombocytosis?

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Now of course that's only one type of answer to "why". One can also ask "why" from an evolutionary standpoint, or "why" only some patients with IDA have platelets.

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We can only postulate here. Xavier et al propose:

Perhaps thrombocytosis might confer a selective advantage in life-threatening hemorrhage (which may be a cause of IDA)?
Perhaps limiting differentiation towards RBCs preserves iron for other necessary functions?

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But that's all for today!

Much acknowledgement to Xavier et al for a beautifully constructed set of experiments and adding greatly to the body of knowledge on this topic.

Hope you all enjoyed this (my first!) tweetorial. Hopefully many more to come!

cc: @AdamRodmanMD @tony_breu