On consults this weekend, I faced a question of whether a patient& #39;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 https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben"> in plt ct
https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉🏼" title="Rückhand Zeigefinger nach rechts (mittelheller Hautton)" aria-label="Emoji: Rückhand Zeigefinger nach rechts (mittelheller Hautton)"> Review of all 5k patients, 1 clinic, 1 yr:
https://abs.twimg.com/emoji/v2/... draggable="false" alt="🔸" title="Kleine orangene Raute" aria-label="Emoji: Kleine orangene Raute">10% of pts with IDA had https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben"> plt
https://abs.twimg.com/emoji/v2/... draggable="false" alt="🔸" title="Kleine orangene Raute" aria-label="Emoji: Kleine orangene Raute">Only 1% of control pts (nl iron) had https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben"> plt
https://abs.twimg.com/emoji/v2/... draggable="false" alt="🔸" title="Kleine orangene Raute" aria-label="Emoji: Kleine orangene Raute">Lower ferritin corr. with higher plt count

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

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In patients with ID-assoc. thrombocytosis, usually mild-moderate https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben"> plt
https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉🏼" title="Rückhand Zeigefinger nach rechts (mittelheller Hautton)" aria-label="Emoji: Rückhand Zeigefinger nach rechts (mittelheller Hautton)"> Series of 100 consec. patients with IDA
https://abs.twimg.com/emoji/v2/... draggable="false" alt="🔹" title="Kleine blaue Raute" aria-label="Emoji: Kleine blaue Raute">Average plt 499k
https://abs.twimg.com/emoji/v2/... draggable="false" alt="🔹" title="Kleine blaue Raute" aria-label="Emoji: Kleine blaue Raute">Only 7% with plt > 1 million
https://www.jstage.jst.go.jp/article/internalmedicine/44/10/44_10_1025/_pdf">https://www.jstage.jst.go.jp/article/i...

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So I& #39;ve shown that iron deficiency is associated with thrombocytosis, but we haven& #39;t discussed causality, and haven& #39;t gotten any closer to answering the question: WHY?

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To answer that, let& #39;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
https://abs.twimg.com/emoji/v2/... draggable="false" alt="↪️" title="Nach rechts zeigender Pfeil mit Haken" aria-label="Emoji: Nach rechts zeigender Pfeil mit Haken"> then to a MK
https://abs.twimg.com/emoji/v2/... draggable="false" alt="↪️" title="Nach rechts zeigender Pfeil mit Haken" aria-label="Emoji: Nach rechts zeigender Pfeil mit Haken"> which flicks off pieces of its cytoplasm to create platelets
https://abs.twimg.com/emoji/v2/... draggable="false" alt="↪️" title="Nach rechts zeigender Pfeil mit Haken" aria-label="Emoji: Nach rechts zeigender Pfeil mit Haken"> 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& #39;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 https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben"> 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 https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben"> in platelets.

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They DID find increased ploidy (DNA replication) of Megakaryocytes in the ID group https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts"> larger MKs https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts"> https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben"> platelet-producing ability.

This suggests that iron deficiency causes https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben"> MK size (via increased DNA replication), and thereby https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben"> Platelets https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4114532/">https://www.ncbi.nlm.nih.gov/pmc/artic...

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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 https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Pfeil nach unten" aria-label="Emoji: Pfeil nach unten"> iron.

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

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So again, why does iron deficiency cause thrombocytosis?

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Now of course that& #39;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 https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben"> platelets.

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We can only postulate here. Xavier et al propose:

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🔹" title="Kleine blaue Raute" aria-label="Emoji: Kleine blaue Raute">Perhaps thrombocytosis might confer a selective advantage in life-threatening hemorrhage (which may be a cause of IDA)?
https://abs.twimg.com/emoji/v2/... draggable="false" alt="🔸" title="Kleine orangene Raute" aria-label="Emoji: Kleine orangene Raute">Perhaps limiting differentiation towards RBCs preserves iron for other necessary functions?

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But that& #39;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