LAUSR

Platelets—essential players in hemostasis—represent major challenges in hematology and transfusion medicine. Demand for platelets remains high in many clinical contexts including hematology-oncology, transplant surgery, cardiac surgery, and trauma medicine. Yet, supply from donors is fragile, especially in the current pandemic, and platelet shelf life is limited to 5–7 days—often only 3–5 days in hospital blood banks after infectious disease testing. “Platelet triage” due to low platelet inventory is unfortunately common and can lead to disruptive delays in surgeries and procedures. While the safety profile of platelets has improved, current technologies still require storage at room temperature, which enables growth of bacteria, and septic transfusion reactions persist. Platelets also contain relatively high plasma volumes ( 300 ml) compared with red blood cells ( 30 ml plasma), so platelets are relatively high-risk products for allergic reactions and transfusionrelated acute lung injury. Additionally, appropriate platelet transfusion thresholds remain unclear in many clinical contexts, platelet quality appears to decrease with time during storage, and the underlying basic platelet biology remains incompletely mapped. At every level, much work remains to be done to improve platelets—a central component therapy in transfusion medicine. In parallel with ongoing efforts to improve standard “liquid” platelet products, alternative therapies are under investigation. For patients who are refractory to platelet transfusions, or in the setting of “platelet triage,” we often reach for noncellular therapies such as the antifibrinolytic agents aminocaproic acid or tranexamic acid, the usage of which continues to expand into new clinical settings. However, antifibrinolytics are not a complete surrogate for platelets. Investigational therapies not yet approved include “synthetic platelets”— noncellular liposomes or microparticles that display platelet proteins involved in hemostasis. Early examples of such technology included fibrinogen-coated albumin microparticles, which were designed to mimic the aggregation function of platelets. More recent synthetic platelet technologies are designed to mimic both the adhesion and aggregation functions of platelets, for example, by displaying von Willebrand factor-binding peptides, collagen-binding peptides, and fibrinogen-mimetic peptides. Such technologies have shown promise in animal models, but to our knowledge have not yet moved into human clinical studies. Human platelets also have functions beyond adhesion and aggregation. The minimal set of defined, purified proteins, lipids, and metabolites that should be included in synthetic platelets to make them maximally beneficial in humans remains unclear, again highlighting fundamental knowledge gaps in this area. In the meantime, an alternative exists—that is, to use donated human platelets as a source of the complex mixture of requisite biomolecules. Freeze-dried (lyophilized) platelets (Thrombosomes) are one such promising alternative to standard liquid platelets. Freeze-dried platelets must be stabilized to prevent collapse during lyophilization. Early versions were stabilized by fixation with paraformaldehyde, but current manufacturing processes have switched to stabilization with trehalose, a disaccharide comprised of two covalently linked molecules of glucose. Lyophilization reduces liquid plasma volumes in this product, but whether this process simply concentrates plasma proteins, including those that could cause allergic transfusion reactions, is unclear. After lyophilization, Thrombosomes are incubated at high temperature (80°C, 24 h) for pathogen reduction, but this treatment could also degrade proteins that are important for the functions of platelets. Thrombosomes have a shelf life of up to 3 years at ambient temperature, and thus could provide a long-term backup product in blood bank inventories for times of low supply (e.g., snowstorms or pandemics). They could also be more readily transported to remote settings (e.g., field aid after natural disasters). Prior to infusion, Thrombosomes are simply and quickly reconstituted (within minutes) in sterile water and then infused through an 18-micron filter. An initial phase 1 human safety evaluation of Thrombosomes showed no serious adverse events, but this small dose-escalation trial included only 10 normal subjects. Further safety and efficacy studies are needed to evaluate Thrombosomes in patients. The study published in this issue of the American Journal of Hematology describes an open-label, phase 1 study of single doses of pooled allogeneic lyophilized platelets in patients with hematologic malignancy, building on positive safety results in healthy volunteers. Three dose levels were given among three cohorts of patients with no Received: 21 December 2021 Accepted: 21 December 2021