Postscript

About platelets

Cytoplasmic fragments derived from bone marrow megakaryocytes.
Produced at a daily rate of approximately 10¹¹/day.
Once released into the plasma, they circulate at a concentration of 150–400 x 10⁹/L.
Lifespan of approximately 7-10 days.
Platelets lack a nucleus, but contain:
- Mitochondria (< 10/platelet), which generate energy for:
  - Granule secretion
  - Platelet shape change during activation
- mRNA, ribosomes, endoplasmic reticulum, and Golgi apparatus
- Storage granules
- About 5000 different proteins
- Adhesion and immune receptors
Platelet production:
- Involves:
  - Commitment of hematopoietic stem cells (HSCs) to the megakaryocyte (MK) lineage.
  - Proliferation of the progenitors.
  - MK maturation.
  - Terminal differentiation.
- Controlled primarily by thrombopoietin.

About iron

Iron is critical for:
- Hemoglobin
- Myoglobin
- Mitochondrial function
- DNA replication and repair
- Cellular metabolism and signaling

About iron deficiency anemia

Most common cause of anemia worldwide:
- Reported to account for about 50% of cases.
- Affects over 1.2 billion people worldwide.
Causes include:
- Blood loss (most common)
- Decreased intake (rare):
  - Malnutrition
  - Vegetarians
  - Vegans
- Decreased iron absorption:
  - Celiac sprue
  - Bariatric surgery
  - Atrophic gastritis
- Increased demand:
  - Infancy
  - Adolescence
  - Pregnancy
Characterized by:
- Depletion of body iron stores
- Microcytic hypochromic red blood cells
- Low hemoglobin
Clinical manifestations of iron deficiency per se include:
- Fatigue and weakness
- Pica
- Restless legs syndrome
- Skin and mucosal changes

About thrombocytosis

Defined as a platelet count > 400-450 × 10⁹/L (for more information click here).
May be classified as:
- Primary:
  - 15% of cases.
  - Caused by defect intrinsic to hematopoietic progenitors.
  - Causes include:
    - Essential thrombocythemia
    - Polycythemia vera
    - Primary myelofibrosis
    - Chronic myelogenous leukemia
    - Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) overlap syndromes
    - Myelodysplastic syndrome with del (5q)
- Secondary (reactive):
  - 85% of cases.
  - Caused by disease or condition that results in persistent growth factor-mediated stimulation of otherwise normal megakaryocytes.
  - Causes include:
    - Iron deficiency
    - Infection
    - Malignancy
    - Chronic inflammatory disorders
    - Tissue damage
    - Hemolytic anemia
    - Hemorrhage
    - Intense exercise
    - Postsplenectomy state
    - Postoperative state
    - Rebound from thrombocytopenia
    - Drugs
Prevalence:
- Thrombocytosis reported to be present in:
  - 1.5-2.2% of the adult primary care population.
  - 8% of inpatients.

Iron deficiency and reactive thrombocytosis

Prevalence:
- 13% in a study of 615 subjects.
- 28% in a study of 86 women.
- 33% in a large population of 36,327 patients with iron deficiency anemia.

Platelet counts:
- Thrombocytosis is typically mild-moderate.
- In a study of 615 patients with iron deficiency anemia, those with thrombocytosis (13.3%) had platelet count ranging between 401 x 10⁹/L and 700 x 10⁹/L (median 469 x10⁹/L).
- Extreme thrombocytosis with platelet count > 1,000 x 10⁹/L rarely reported in severe iron deficiency (see case report).
Correlations:
- No correlation found between ferritin and platelet count (Vox Sanguinis. 2017; 112:87–92).
- The following table from a study of women with iron deficiency anemia and thrombocytosis shows correlation between platelet count and MCHC, but not Hb, Hct or MCV.

- Another study of platelet counts in adults with iron deficiency anemia revealed inverse correlations between platelet counts and hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean platelet volume (MPV), platelet distribution width (PDW), and serum iron:

Cause effect:
- Thrombocytosis resolves with iron replacement.
- Thrombocytosis is induced in animal models of iron deficiency:

Iron deficiency causes thrombocytosis, which is reversed by iron replacement therapy in a dose-dependent fashion. (A) Experimental design. Rats were fed an iron-deficient diet (Def) for 6 weeks, and given three injections of ferric carboxymaltose at the doses of 5, 10, or 20 mg/kg body weight (BW, +Fe5, +Fe10, +Fe20, respectively) or placebo (4 mL/kg BW 0.9% NaCl). Animals fed a control diet and given injections of placebo formed the control group (Con). Hematologic parameters were measured weekly from 3 to 6 weeks after the start of the experiment (n=4 per group). (B). Changes in hemoglobin and mean corpuscular volume from 3 to 6 weeks in the different groups of animals. (C) Values of mean corpuscular hemoglobin, hematocrit and platelet count over the course of the experiment. Source.

Mechanisms:
- Previous studies have failed to show an elevation in levels of thrombopoietic cytokines in patients with iron deficiency anemia with or without thrombocytosis, including:
  - Thrombopoietin
  - Erythropoietin (EPO)
  - Leukemia inhibitory factor
  - Interleukin-6
  - Interleukin-11
- One study showed that low iron does not increase megakaryocytic progenitor numbers, but biases the commitment of megakaryocytic (Mk)-erythroid progenitors (MEPs) toward the Mk lineage at the expense of the erythroid lineage in both human and mouse.

Thrombotic risk:
- Rat model of dietary iron deficiency:
  - Iron deficiency is an independent risk factor for the development of venous or arterial thrombosis.
  - Iron deficiency results in hypercoagulability associated with increased platelet and plasma P-selectin (reflecting hyperactivity), and with impaired platelet adhesion and aggregation under shear flow; importantly, all these changes are reversed by iron supplementation.
- In humans:
  - Patients with ischemic stroke or venous thromboembolism (VTE) 1.4 times more likely to have had prior iron deficiency anemia.
  - In one study, thrombotic complications were observed in 16% of iron deficiency anemia patients with thrombocytosis, compared with 8% in IDA without thrombocytosis.

A word about iron deficiency and thrombocytopenia

Iron deficiency may rarely be associated with thrombocytopenia:
- Seen in severe iron deficiency.
- Prevalence:
  - 2.1% in one study of 615 subjects with iron deficiency anemia.
  - 2.3% in another study of 86 women.

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