Clinical Impact

Activated vs. Non-Activated

 

Platelets can be classified as Activated or Non-Activated. Recent ThromboLUX studies and beta-testing sites have shown that Activated Platelets do not perform as well as Non-Activated platelets for prophylactic transfusion. This is may be explained by the unintended immunomodulatory effects Activated platelets seem to have in certain oncology patients. Conversely, Activated Platelets have been shown to be very active in hemostasis and are beneficial to bleeding patients receiving therapeutic transfusions. Currently, the activation status of platelets for transfusion is unknown – visual inspection and product age are not sufficient criteria – which makes providing the best patient care challenging. Several years of inventory screening with ThromboLUX has shown that about 30-50% of all platelet transfusions in hospital inventory contain Activated Platelets*.

Activated Platelet Implications for HemOnc

Transfusions of Activated Platelets to hematology-oncology patients can have unintended consequences. It has been shown that transfusions of Activated Platelets are more likely to lead to reduced platelet count increments than non-activated platelets1. An association between refractoriness and transfusions of Activated Platelets has also been observed, especially if patients are febrile at the time of transfusion*. These findings formed the basis for quality improvement initiatives in hospitals. When hematology-oncology patients exclusively received Non-Activated Platelets a significant reduction in average transfusions per patient was observed. The poor survival of Activated Platelets after transfusion might be explained by complement-mediated clearance by macrophages.

In addition to the implications of activated platelets on platelet refractoriness, a growing body of literature is suggesting activated platelets may interfere with certain immunotherapies. It was shown that activated platelets contain various upregulated factors, suggesting that platelets may be highly immunomodulatory. Specifically, TGFβ2, IL-63, CD40L4, and complement5 are found in conjunction with activated platelets. This serves to add complexity to the treatment of already very complex patients.

Platelet Refractoriness

Platelet refractoriness is a huge issue. It is estimated that 15-25% of prophylactic platelet recipients become refractory6-8. Platelet refractoriness is typically defined as two or more consecutive failed platelet transfusions. In other terms, platelet refractoriness is persistent thrombocytopenia despite transfusion. This means there is a mechanism of accelerated platelet clearance occurring in the patient.

Some of the platelet clearance mechanisms are well established like HLA mediated and drug-induced platelet removal. It’s become apparent that there is an additional form of immune refractoriness that’s based on the innate immune system. The leading hypothesis is that transfusions of Activated Platelets result in complement-mediated opsonization and platelet removal. The clinical observation is an insufficient platelet count increment within 24 hours of transfusion. Furthermore, opsonized platelets can interact with the adaptive immune system leading to antibody formation and fast removal of platelets from subsequent transfusions within 1 hour.

 

Solutions to Refractoriness

When a patient is identified as refractory the go-to solution is HLA matched or cross-matched platelets. However, only up to one-third of refractory cases or less can be attributed to alloimmunization9. The remaining refractory cases are typically referred to as “non-immune” refractoriness. A major portion of these “non-immune” cases may, in fact, be complement-mediated as discussed above. 

By excluding Activated Platelets from transfusion to hematology-oncology patients the chance of complement-mediated immune refractoriness is drastically reduced. This helps to explain why hospitals see a substantial drop in the number of patients requiring massive platelet transfusion support once the ThromboLUX System is implemented.

Activated Platelets for Therapeutic Transfusions

Therapeutic transfusions to actively bleeding patients such as trauma and surgical patients have fundamentally different requirements than prophylactic transfusions given to hematology-oncology patients. Emerging data suggest that Activated Platelets may be beneficial in therapeutic transfusions10.

References

1 – Maurer-Spurej, E., Labrie, A., Pittendreigh, C., Chipperfield, K., Smith, C., Heddle, N., . . . Barnett, M. (2009). Platelet quality measured with dynamic light scattering correlates with transfusion outcome in hematologic malignancies. Transfusion, 49(11), 2276-2284.

2 – Rachidi, S., Metelli, A., Riesenberg, B., Wu, B. X., Nelson, M. H., Wallace, C., . . . Li, Z. (2017). Platelets subvert T cell immunity against cancer via GARP-TGFbeta axis. Sci Immunol, 2(11). doi:10.1126/sciimmunol.aai7911

3 – Muylle, L., Joos, M., Wouters, E., De Bock, R., & Peetermans, M. E. (1993). Increased tumor necrosis factor alpha (TNF alpha), interleukin 1, and interleukin 6 (IL-6) levels in the plasma of stored platelet concentrates: relationship between TNF alpha and IL-6 levels and febrile transfusion reactions. Transfusion, 33(3), 195-199.

4 – Stolla, M., Refaai, M. A., Heal, J. M., Spinelli, S. L., Garraud, O., Phipps, R. P., & Blumberg, N. (2015). Platelet transfusion – the new immunology of an old therapy. Front Immunol, 6, 28. doi:10.3389/fimmu.2015.00028

5 – Peerschke, E. I., Yin, W., & Ghebrehiwet, B. (2010). Complement activation on platelets: implications for vascular inflammation and thrombosis. Mol Immunol, 47(13), 2170-2175. doi:10.1016/j.molimm.2010.05.009

6 – Legler, T. J., Fischer, I., Dittmann, J., Simson, G., Lynen, R., Humpe, A., . . . Kohler, M. (1997). Frequency and causes of refractoriness in multiply transfused patients. Ann Hematol, 74(4), 185-189.

7 – Slichter, S. J., Davis, K., Enright, H., Braine, H., Gernsheimer, T., Kao, K. J., . . . Woodson, R. (2005). Factors affecting posttransfusion platelet increments, platelet refractoriness, and platelet transfusion intervals in thrombocytopenic patients. Blood, 105(10), 4106-4114

8 – Hod, E., & Schwartz, J. (2008). Platelet transfusion refractoriness. Br J Haematol, 142(3), 348-360. doi:10.1111/j.1365-2141.2008.07189.x

9 – Trial to Reduce Alloimmunization to Platelets Study, G. (1997). Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. N Engl J Med, 337(26), 1861-1869. doi:10.1056/NEJM199712253372601

10 – Cap, A. P. (2016). Platelet storage: a license to chill! Transfusion, 56(1), 13-16. doi:10.1111/trf.13433

* – Unpublished data; publications in preparation