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Data from evaluations and trials conducted at hospitals across North America and Europe consistently show that prophylactic transfusions of activated platelets lead to more transfusions per patient, shorter intervals between transfusions, and more patients requiring massive transfusion support and/or becoming refractory.8 All of these observations are direct indicators that activated platelet transfusions do not lead to the expected clinical outcome, in other words, they do not sufficiently increase the patients’ platelet counts. Instead, prophylactic transfusions of activated platelets lead to increased platelet clearance. The mechanism that is causing this clearance is less clear.

This blog post dives into the immunology section of the ThromboMAP and outlines a hypothesis for the underlying mechanism at play when platelets are cleared. Dr. Maurer previously presented an earlier version of this hypothesis at the 2017 AABB Annual Meeting.

Platelets are immune cells

Over the past decade, an appreciation that platelets do much more than just stop bleeding has gained momentum. As shown in the Blood Vessel section of ThromboMAP, platelets serve as a first line of defense by capturing viruses and identifying/interacting with bacteria and other pathogens.

Figure 1 ThromboMAP

These interactions with pathogens lead to platelet activation.1,2 Following activation, platelets are primed for phagocytosis by macrophages.3,4 Below is a larger image of the Spleen & Liver section which is the primary site of platelet phagocytosis.

Figure 2 – Spleen & Liver section from ThromboMAP

Understanding the immune function of platelets is important as it could explain why transfused platelets often lead to insufficient platelet count increments.

Transfusions of activated platelets as immune stimulators

Activated platelets become opsonized by circulating complement, namely C1q,5 C3b,4 and C4d,6 which is also expected to happen when activated platelets are transfused into thrombocytopenic patients. This process results in the clearance of platelets by macrophages over the course of 6 to 24 hours.7 Whereas HLA antibody mediated refractoriness is associated with very quick clearance of platelets, refractoriness that is not HLA antibody mediated is generally associated with normal 1-hour count increments, followed by very low 24-hour count increments. Importantly, this process can result in the formation of immunological memory that can lead to immediate clearance once antibodies are present. Figure 3 below illustrates the proposed process in which activated platelet transfusions are cleared by complement and macrophages.

Figure 3 – Complement mediated platelet removal after transfusion

In addition to the removal of platelets, macrophages may stimulate B cells to produce antibodies, with or without the help of T cells. The newly acquired targeting of platelets may result in rapid removal of platelets after subsequent transfusions, thereby mimicking the symptoms of HLA mediated refractoriness. Figure 4 shows the end result of this process in which transfused platelets, either activated or non-activated, could be removed from circulation quite quickly following the transfusion.

Figure 4 – Acquired antibody mediated platelet removal after transfusions

Our experience in North American hospitals has shown that complement opsonization and platelet clearance does not occur with every activated transfusion. There are likely a number of additional factors that influence the likelihood of rapid platelet clearance. One such factor is the inflammatory or immunological state of the patient receiving the platelet transfusion.

Preventing the immune stimulation

The mechanism proposed above fits in with our current understanding of the human immune system and strongly suggests that it is important to prevent the transfusion of activated platelets to patients. It is difficult and may be impossible, to understand when a patient is truly vulnerable to becoming refractory. However, ThromboLUX makes is relatively easy to identify activated platelets—which are a catalyst for immune stimulation—and subsequently, prevent them from being transfused.

Share your views – leave a comment

The hypothesis detailed above is largely based on our experience and conversations with experts in immunology. Let us know how it fits in with your experiences by leaving a comment below.

References

  1. Kapur R, Zufferey A, Boilard E, Semple JW. Nouvelle cuisine: platelets served with inflammation. J Immunol 2015;194:5579-87.
  2. Jenne CN, Urrutia R, Kubes P. Platelets: bridging hemostasis, inflammation, and immunity. Int J Lab Hematol 2013;35:254-61.
  3. Hoffmeister KM, Felbinger TW, Falet H, et al. The clearance mechanism of chilled blood platelets. Cell 2003;112:87-97.
  4. Peerschke EI, Yin W, Ghebrehiwet B. Complement activation on platelets: implications for vascular inflammation and thrombosis. Mol Immunol 2010;47:2170-5.
  5. Nording H, Langer HF. Complement links platelets to innate immunity. Semin Immunol 2018;37:43-52.
  6. Peerschke EI, Panicker S, Bussel J. Classical complement pathway activation in immune thrombocytopenia purpura: inhibition by a novel C1s inhibitor. Br J Haematol 2016;173:942-5.
  7. Kim DD, Miwa T, Kimura Y, Schwendener RA, van Lookeren Campagne M, Song WC. Deficiency of decay-accelerating factor and complement receptor 1-related gene/protein y on murine platelets leads to complement-dependent clearance by the macrophage phagocytic receptor CRIg. Blood 2008;112:1109-19.
  8. Data on file, available upon request