Blood Podcast: Review Series on Platelet Heterogeneity

Host: American Society of Hematology
Date: December 11, 2025
Guests: Dr. Craig Morrell, Dr. Larry Freilinger, Dr. Leo Nicolai
Episode Theme: Exploring the latest advances and research on platelet heterogeneity—from their origins and functions to implications for disease and clinical practice.

Episode Overview

This special bonus episode of the Blood Podcast reviews emerging research on platelet heterogeneity, featuring conversations with three leading experts and authors of recent review articles in Blood. The discussion delves into what makes platelets diverse, the implications for disease, and new techniques to characterize platelet subpopulations. The conversation is rich in cutting-edge science, offering insights for researchers and clinicians alike.

Key Discussion Points & Insights

1. Defining Platelet Heterogeneity

• Host Dr. Beth Battinelli sets the stage: Platelets vary not only in site of origin but also in content, receptor expression, and function. This variability has consequences for disease and therapy. [00:25]
• Dr. Craig Morrell underscores platelets’ classical role in hemostasis—thrombus formation and stopping bleeding—but highlights newer roles:
  • Platelet involvement in immune response (recruitment and activation of white blood cells).
  • Diversity in megakaryocyte populations (in bone marrow and beyond) produces platelets with distinct RNA expression and potential phenotypes.
  • Emerging evidence of extramedullary platelet production (lung, spleen).
    Quote:

  "We also are starting to understand that there's other locations outside the bone marrow that are capable of producing platelets, including the lung and the spleen." (Dr. Morrell, 01:49)

2. Known Platelet Subpopulations & Functional Differences

• Dr. Leo Nicolai introduces the concept of subpopulations:
  • Aggregatory platelets (form clots).
  • Procoagulant platelets (facilitate coagulation via specific activation pathways).
  • Secretory platelets.
  • Young/reticulated platelets (detected by high RNA content, associated with higher thrombosis risk and reactivity).
    Quote:

  "There's a subpopulation of young platelets in the blood... associated with cardiovascular events, thrombosis risk, and they seem to be more active, more reactive to stimuli." (Dr. Nicolai, 03:30)

3. Platelet Age and Its Effects

• Dr. Larry Freilinger responds on aging and subpopulation:
  • Platelets are larger and richer in RNA at birth; with age, they lose membrane, surface proteins, and RNA.
  • At any given time, individual variation in size and marker density creates a spectrum of subtypes. Quote:

  "So RNA levels change over time, size changes over time, quantity of surface marker can change over time. But even within an individual... there's high variation in platelet size and... surface marker density." (Dr. Freilinger, 04:40)

4. Procoagulant Platelets and Disease Implications

• Dr. Nicolai explains the importance of procoagulant platelets, primarily explored in mouse models:
  • Specific pathways (mitochondrial proteins, TMEM16F scramblase) control this function.
  • Blocking procoagulant platelets reduces thrombosis and protects from strokes, but may increase bleeding in some inflammatory contexts.
  • Human disease (Scott syndrome) illustrates the clinical impact, with patients showing only mild bleeding. Quote:

  "It is the crucial link between thrombosis and platelet-mediated thrombosis and coagulation. And we now also see that it's a link to inflammation." (Dr. Nicolai, 08:11)

5. Megakaryocyte Location and Platelet Production Dynamics

• Dr. Morrell discusses mouse models revealing the dynamics of platelet origin:
  • Baseline: lung-derived platelets contribute ~10% of circulating platelets.
  • Under stress (thrombocytopenia, infection), lung megakaryocyte contribution increases.
  • Lung megakaryocytes have subpopulations that are unusually long-lived, perhaps serving as a reserve.
  • Spleen’s role (during sepsis): produces platelets with higher immune function (e.g., more CD40 ligand). Quote:

  "The lung might be a reservoir to kind of help make that gap ... between bone marrow making platelets and other sources making platelets." (Dr. Morrell, 10:02)
  "The lung megakaryocytes are very immune differentiated ... because the lung tissue environment is very different than the bone marrow." (Dr. Morrell, 11:39)

6. Emerging Techniques for Platelet Characterization

• Dr. Freilinger presents advances in high-dimensional flow cytometry:
  • Spectral flow cytometry using 16+ markers can profile individual platelets’ surface protein expression.
  • Heterogeneity is more dynamic than fixed subtypes; the environment and disease can shift platelet function.
  • Bringing these discoveries into clinical diagnostics is challenging: standardization, rarity of relevant diseases, and cost are hurdles. Quote:

  "With a panel that has 16 different probes... you get a much better idea of what that platelet is all about." (Dr. Freilinger, 13:11)
  "But getting these into the clinic is going to require a lot of effort and standardization." (Dr. Freilinger, 14:28)

7. Therapeutic Targeting of Platelet Subpopulations

• Host Dr. Battinelli raises the issue: If environments shape platelet subtypes, how can therapies target one group without affecting others?
• Dr. Freilinger suggests tuning signaling pathways, e.g., shift function towards immune modulation vs. hemostasis. Quote:

  "...if there is a way to tone down one pathway versus another... that would allow you to guide the platelets more towards, say, maybe an immune phenotype versus a hemostatic phenotype." (Dr. Freilinger, 15:55)

• Dr. Morrell advocates targeting the specific drivers rather than the platelets themselves, possibly even for designing “custom” platelets in culture for clinical needs. Quote:

  "...targeting the drivers versus the product, because it's going to be so hard ... to target a particular type, but rather the drivers themselves." (Dr. Morrell, 16:25)

• Dr. Nicolai adds targeting should occur at disease sites (such as a ruptured plaque), lessening the need to distinguish origin or initial phenotype. Quote:

  "...if you are specific enough and you just inhibit this one function that doesn't play a role, for example, in bleeding so much ... then it may be not so important where these platelets originally came from ..." (Dr. Nicolai, 17:06)

Notable Quotes & Memorable Moments

• On the breadth of platelet diversity:

  "Platelets are indeed quite heterogeneous, not only in their function, but also in their characterization." (Dr. Battinelli, 17:52)

• On the clinical utility of new technologies:

  "The inclusion of these markers in clinical studies is an interesting question, and I'd really like to see that move forward." (Dr. Freilinger, 13:49)

• On evolutionary implications:

  "What was the evolutionary pressure that came to develop these [extramedullary megakaryocytes]?... Looks like all organisms have these extramedullary megakaryocytes." (Dr. Morrell, 12:23)

Timestamps for Key Segments

• Platelet heterogeneity concept intro: [00:25–01:49]
• Functional and known subtypes (Nicolai): [02:43–04:14]
• Platelet age and subpopulation markers (Freilinger): [04:24–05:44]
• Procoagulant platelets in disease (Nicolai): [06:27–08:40]
• Megakaryocyte location & stress response (Morrell): [09:08–12:39]
• Flow cytometry & future clinical application (Freilinger): [12:59–15:03]
• Therapeutic challenges & speculation (All): [15:03–17:44]
• Summary & concluding thoughts: [17:44–18:45]

Conclusion

This episode provides a deep dive into the multifaceted world of platelet heterogeneity. The experts clarify how understanding the diversity in platelet origins, functions, and markers could pave the way for bespoke therapies in thrombosis and inflammation, as well as open new avenues for research and diagnostics in hematology. The conversation remains candid about current technological and conceptual limitations, but is optimistic about future breakthroughs.

For more on this topic, the reviewed articles can be accessed via bloodjournal.org.