Targeting Hemorrhage: Alternative Storage of Platelets for Hemostatic Transfusion

Platelets are stored at 22°C with agitation because these conditions have been found to improve post-infusion recovery and survival compared to storage at 4°C. The majority of platelet transfusions have classically been for prophylaxis of bleeding in hypoproliferative thrombocytopenia, in which post-transfusion circulation time has been accorded particular importance. Current guidelines for evaluation of platelet products thus focus on parameters associated with recovery and survival instead of measurements of hemostatic properties such as adhesion, aggregation, support of thrombin generation or contribution to clot strength. The underlying assumption is that platelets circulating post-transfusion will be functional in hemostasis. A neglected alternative interpretation of higher post-transfusion circulation time of 22°C-stored platelets is that their ability to adhere to damaged surfaces may be impaired. Since studies of platelet clearance have focused on healthy subjects, the relative contributions of normal clearance vs. adhesion to damaged tissues remain poorly characterized. By contrast, numerous studies have documented the loss of in vitro hemostatic function during 22°C storage. Suggestions that dysfunctional 22°C-stored platelets recover function after transfusion are inadequately substantiated. In addition, bacterial growth risk limits shelf life to 5-7 days, increases costs due to testing requirements, and causes shortages. These constraints on platelet supplies result in non-availability for acutely bleeding patients in the majority of US hospitals that are not major teaching hospitals or Level One Trauma Centers. The results of clinical studies provide evidence that duration of platelet storage and accumulation of functional deficits may adversely affect outcomes in bleeding patients. Alternatives to 22°C-stored platelets are being explored, with evaluation strategies focused on measurement of hemostatic function. Some of the storage approaches currently under development include storage at 4°C, cryo-preservation in DMSO (≤-65°C), and lyophilization. These storage approaches affect platelet function in different ways, but may result in products that support hemostasis and offer improved shelf life and availability. Platelets stored at 4°C were shown in the early 1970's to better support immediate hemostasis in actively bleeding patients than 22°C-stored platelets. Recent data also indicate that 4°C-stored platelets at can be inhibited by physiologic antagonists such as nitric oxide and prostacyclin. These results are consistent with data from two RCTs of 4°C vs. 22°C platelets which did not observe increased rates of thromboembolic complications in the patients treated with 4°C-stored products. The US FDA recognizes cold storage of platelets (1-6°C, without agitation) as an acceptable alternative to 22°C storage. Enhancements to cold storage, such as use of platelet additive solutions (PAS) may further improve functional shelf life. In vitro data suggest that 4°C platelets in PAS may remain hemostatic for 14-21 days. In vivo confirmation of these results could dramatically expand the availability of platelets to the majority of hospitals which currently cannot provide hemostatic resuscitation to bleeding patients. Similarly, cryo-preserved platelets have been shown to be safe and effective and have been in use by some European countries for several decades. Lyophilized platelets are currently entering clinical development and represent another opportunity for increasing shelf life and platelet availability. If one considers that trauma is the number one cause of death in patients under age 46, 90% of pre-hospital preventable deaths are due to bleeding, and approximately 30,000 patients suffer preventable deaths each year in the US due to hemorrhage after injury, improved availability of hemostatic platelets could present a substantial public health benefit.