Citrate Effects and Bone Density Changes in Serial Long-

在美国，每年进行大约一百万次血小板去除术，包括NIH输血医学部血小板中心的3,500人。健康的捐献者有资格接受血小板和白细胞分离术，每年最多24次。在血小板去除术期间，将柠檬酸盐抗凝剂添加到血液采集路径中以防止在单采装置中凝血，并在手术期间输注到供体中。与柠檬酸盐给药相关的不良反应很常见，包括由于钙-柠檬酸盐复合物形成引起的急性低钙血症。我科最近的研究表明，血清钙、甲状旁腺素、骨钙素、碱性磷酸酶和维生素D水平也存在变化，并可能在单采后持续长达24小时。除了血小板去除术捐献者外，NIH输血医学部还登记了大约500名白细胞去除术捐献者，他们提供用于体外研究的成分。这些研究性单采程序可能涉及处理两倍于典型血小板单采程序（5升）的血量（10升）。因此，在白细胞去除术期间，给予供体的柠檬酸盐总剂量可能是血小板去除术期间发生的柠檬酸盐总剂量的两倍。白细胞和血小板单采捐献者在参与NIH捐献者计划期间可能会接受100多次单采手术。如果发生或过去曾发生柠檬酸盐相关症状，鼓励献血者在单采前或单采期间口服碳酸钙补充剂。连续、频繁、长期单采献血对全身钙平衡和骨密度的影响尚不清楚。 在这项研究中，我们进行了骨密度测量，（1）在过去10年中在NIH经历了至少50次血小板去除手术的50名长期血小板去除术供体，（2）在过去10年中在NIH经历了至少50次白细胞去除程序的50名长期研究白细胞去除供体，间隔不超过每3周，（3）118名年龄、性别和种族匹配的全血捐献者，他们从未经历过单采，作为NIH单采捐献者的对照组，和（4）21名社区血小板捐献者，他们捐献了至少100次，频率为每2周。还对单采前后柠檬酸盐给药对骨代谢以及体内钙和镁水平的影响进行了全面的实验室评价。 数据表明，单采术诱导甲状旁腺激素的急性增加，伴随着骨钙素的减少，以及C-端肽和维生素D水平的增加。其中一些变化在单采后持续长达14天，变化程度与单采程序的体积有关。在研究和仪器制造商提供的参考人群中，NIH血小板捐献者的骨密度测量值显著高于对照受试者。在NIH白细胞分离供体中观察到对骨密度的不太明显的积极影响，而在社区供体中没有观察到任何益处。NIH单采献血者中骨密度增加的这些效应与甲状旁腺激素以脉动方式而非强直方式释放时的合成代谢效应一致，并且可能与NIH血小板献血者中发现的骨保护素水平增加有关。骨保护素合成可通过每4周周期进行的重复单采捐献来诱导;该分子阻断可诱导骨分解的破骨细胞的活化。这种影响的程度可能受到单采程序的频率和强度（流速）的影响。 研究正在继续评价单采期间预防性静脉钙补充对骨密度标志物的影响。 1. Ronquillo JR，Alvandi F，Reynolds JC，Cecco SA，Wesley RA，Yau YY，Oblitas JM，柯林斯MT，Rehak NN，Leitman SF，Bolan CD.柠檬酸盐对一系列长期单采气味患者骨密度（BMD）的影响输血45：15 A，2005年。

Approximately one million plateletpheresis procedures are performed each year in the U.S., including 3,500 in the Platelet Center of the Department of Transfusion Medicine, NIH. Healthy donors are eligible to undergo plateletpheresis and leukapheresis procedures as often as 24 times per year. During plateletpheresis, citrate anticoagulant is added to the blood collection pathway to prevent clotting in the apheresis device, and is infused into the donor during the procedure. Adverse effects related to citrate administration are common, and include acute hypocalcemia due to the formation of calcium-citrate complexes. Recent studies in our Department indicate that changes in serum calcium, parathormone, osteocalcin, alkaline phosphatase, and vitamin D levels are also present and may be sustained for up to 24 hours after apheresis. In addition to volunteer plateletpheresis donors, the NIH Department of Transfusion Medicine maintains a registry of approximately 500 leukapheresis donors, who provide components for in vitro research use. These research apheresis procedures may involve processing twice as much blood volume (10 liters) as is processed in a typical plateletpheresis procedure (5 liters). Thus during leukapheresis, the total dose of citrate administered to the donor may be twice as great as that which occurs during plateletpheresis. Leukocyte and plateletpheresis donors may undergo more than 100 apheresis procedures during the course of their participation in the donor program at NIH. Donors are encouraged to take oral calcium carbonate supplements before or during apheresis if citrate related symptoms occur or have occurred in the past. The impact of serial, frequent, long-term apheresis donations on total body calcium balance and bone density is unknown. In this study, we performed bone density measurements (DEXA scans) of the wrist, lumbosacral spine, and hip in three cohorts of NIH donors (1) 50 long-term plateletpheresis donors who have undergone at least 50 plateletpheresis procedures at NIH in the past 10 years, at intervals no greater than every 4 weeks (2) 50 long-term research leukapheresis donors who have undergone at least 50 leukapheresis procedures at NIH in the past 10 years, at intervals no greater than every 3 weeks (3) 118 age-, gender-, and race-matched whole blood donors, who have never undergone apheresis, as a control group for NIH apheresis donors, and (4) 21 community platelet donors who have donated at least 100 time, as frequently as every 2 weeks. Comprehensive laboratory evaluations of the effect of citrate administration on bone metabolism and body calcium and magnesium levels before and after apheresis were also performed. The data indicate that apheresis induces an acute increase in parathyroid hormone, accompanied by a reduction in osteocalcin, and an increase in c-telopeptide and vitamin D levels. Some of these changes persist for as long as 14 days after apheresis, with the degree of change related to the volume of the apheresis procedure. NIH platelet donors had significantly higher bone density measurements than control subjects in the study and reference populations provided by the instrument manufacturer. A less marked positive effect on bone density was observed in NIH leukpaheresis donors, while no benefit was observed in community donors. These effects for increased bone density in NIH apheresis donors are consistent with anabolic effects of parathyroid hormone when released in a pulsatile rather than a tonic fashion, and may be related to increased levels of osteoprotegerin found in NIH platelet donors. Osteoprotegerin synthesis may be induced by repeated apheresis donations performed on an every 4 week cycle; the molecule blocks the activation of osteoclast cells which can induce bone breakdown. The degree of this effect is likely to be impacted by the frequency and intensity (flow rate) of apheresis procedures. Studies are continuing to evaluate the impact of prophylactic intravenous calcium supplementation during apheresis on bone density markers. 1. Ronquillo JR, Alvandi F, Reynolds JC, Cecco SA, Wesley RA, Yau YY, Oblitas JM, Collins MT, Rehak NN, Leitman SF, Bolan CD. Citrate effects and bone mineral density (BMD) in serial long-term apheresis odnors. Transfusion 45:15A, 2005.