CURRENT CLINICAL INTERESTS
Evaluation of the effects of platelet dose on transfusion outcomes
CURRENT RESEARCH INTERESTS
Research on pathophysiologic effects of platelet transfusion
RESEARCH DESCRIPTION
Our research focuses on the pathophysiologic effects of platelet transfusion therapy proceeding from the appropriate collection and storage of platelets for transfusion, to planning effective platelet transfusion therapy, and, finally, to evaluating methods of preventing platelet alloimmunization.
Platelet Storage Studies:
Under a multi-investigator Specialized Center of Clinical Research
Grant from the National Heart, Lung, and Blood Institute of the NIH,
we are evaluating methods of extending platelet storage. Currently,
platelets can only be stored for five days which greatly limits blood
centers ability to provide platelets for transfusions because of
inadequate inventories. There have been two major limitations to
extending platelet storage: 1) the potential for bacterial overgrowth
during storage as platelets are stored at room temperature(22ēC); and
2) as platelets only have a documented in vivo lifespan of 10 days,
does this imply that long-term platelet storage may not be possible?
Fortunately, procedures have recently been developed that allow bacterial testing of platelets pre-release. Therefore, this obstacle to extended platelet storage has now been removed. In addition, studies have suggested that the 10-day lifespan of platelets is not intrinsic to the cell but, rather, the metabolic needs of platelets are greater at the higher body temperature of
37ēC compared to room temperature storage of platelets at 22ēC. This temperature difference may have a substantial effect on in vivo platelet lifespan.
Specifically, we have documented that we can maintain platelet viability at levels at least half of normal values for eight days. However, if platelets are stored in a physiologic solution rather than residual plasma, platelet storage can be extended to
fourteen days. These studies have been done using radiolabeled platelet recovery and survival measurements of autologous stored platelets in normal volunteers. Our next studies will be to transfuse extended stored platelets into thrombocytopenic patients to document the recovery, survival and function of these platelets.
Effective Platelet Transfusion Therapy:
We have used radiochromium-labeled red cell studies to quantitate stool blood loss in thrombocytopenic patients. These studies have suggested that the prophylactic platelet transfusion trigger for platelets can be reduced to at least 10,000 platelets/µl, if not 5,000 platelets/µl, from the previously-accepted trigger of 20,000 platelets/µl. Lowering the transfusion trigger from 20,000 to 10,000 platelets/µl will reduce transfusion costs by 20% to 30%.
The next issue is what is the effect of platelet dose on platelet utilization and post-transfusion hemostasis. Our prior studies in thrombocytopenic patients have demonstrated a direct relationship between platelet count and platelet survival. This suggests that the higher the post-transfusion platelet count, the longer will be the interval between platelet transfusions. However, modeling studies have suggested that frequent lower dose platelet transfusion therapy may result in the utilization of fewer platelet transfusions during a patient’s thrombocytopenic interval.
We have recently been selected as one of 17 trial sites across the U.S. that will be participating in a NHLBI-sponsored Transfusion Medicine/Hemostasis Clinical Trials Network. The platelet dose trial that we had submitted as part of our proposal has been selected as the first study that will be initiated by this new network. This
trial has now completed recruitment, and the result are being
analyzed.
Prevention of Platelet Alloimmunization: We have utilized a dog platelet transfusion model for the last several years to evaluate questions related to platelet alloimmunization. Our most recent studies have suggested that there are at least two different types of white cells that must be removed in order to prevent platelet alloimmunization. One or more of these different alloimmunizing white cells are removed by filtration, but other types of white cells escape filtration but can be removed by centrifugation leukoreduction of the filtered platelets. In addition, following filtration and centrifugation procedures, there remains a residual white cell that is not removed by either of these procedures which, after repeated transfusions, induces tolerance in recipient dogs to standard (unmodified) platelet transfusions as well as skin grafts from some donor dogs.
Our current studies are focused on identifying the alloimmunizing as well as the tolerizing white cells and, in addition, to determine the role of DLA (dog lymphocyte antigen) compatibility between donor and recipient in tolerance induction.
SELECTED PUBLICATIONS
Slichter SJ, Harker LA: Preparation and storage of platelet concentrates. II. Storage variables influencing platelet viability and function.
Br. J. Haematol. 34:403-419, 1976.
Hanson SR, Slichter SJ: Platelet kinetics in patients with bone marrow hypoplasia: Evidence for a fixed platelet requirement.
Blood 66:1105-1109, 1985.
Slichter SJ, Deeg HJ, Kennedy MS: Prevention of platelet alloimmunization in dogs with systemic cyclosporine and by UV-irradiation or cyclosporine-loading of donor platelets.
Blood 69:414-418, 1987.
Ballem PJ, Segal GM, Stratton JR, Gernsheimer T, Adamson JW,
Slichter SJ: Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura: Evidence of both impaired platelet production and increased platelet clearance.
J. Clin. Invest. 80:33-40, 1987.
The Trial To Reduce Alloimmunization To Platelets Study Group: Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions.
N. Engl. J. Med. 337:1861-1869, 1997.
Slichter SJ. Relationship between platelet count and bleeding risk in thrombocytopenic patients.
Trans. Med. Rev. 18:153-167, 2004.
McCullough J, Vesole DH, Benjamin RJ, Slichter
SJ, Pineda A, Snyder E, Stadtmauer EA, Lopez-Plaza I, Coutre S, Strauss RG, Goodnough LT, Fridey JL, Raife T, Cable R, Murphy S, Howard F 4th, Davis K, Lin JS, Metzel P, Corash L, Koutsoukos A, Lin L, Buchholz DH, Conlan MG: Therapeutic efficacy and safety platelets treated with a photochemical process for pathogen inactivation: The SPRINT trial.
Blood 104:1534-1541, 2004.
Slichter SJ, Fish D, Abrams VK, Gaur L, Nelson K, Bolgiano D: Evaluation of different methods of leukoreduction of donor platelets to prevent alloimmune platelet refractoriness and induce tolerance in a canine transfusion model.
Blood 105:847-854, 2005.
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