Apheresis Technology Research Articles

Factors affecting clinical outcomes of continuous and intermittent plasmapheresis in patients with severe hypertriglyceridemia.

Acute hypertriglyceridemia is considered a category III indication for plasmapheresis. The use of plasma as replacement fluid (RF) has been suggested to replace the consumed lipoprotein lipase. Heparin when used as an anticoagulant could possibly release lipoprotein lipase, thereby increasing triglyceride clearance. The impact of RF (albumin vs fresh frozen plasma (FFP) and anticoagulant (ACD-A vs. heparin) on triglycerides following plasmapheresis in 27 patients with severe hypertriglyceridemia (SHTG) was investigated. A paired study of four patients with recurrent SHTG was conducted, evaluating continuous (Optia) versus intermittent flow plasmapheresis (Haemonetics). Shorter procedures positively impacted triglycerides (TG) drop post-sessions p < 0.05. In albumin sessions, patients who used heparin demonstrated significantly greater drop in TG and required less sessions than did those with citrate p < 0.05. In heparin sessions, patients who used albumin demonstrated significantly greater drop in triglycerides and required less sessions than did those with FFP p < 0.05. Three of six patients who used FFP and heparin showed a triglyceride drop of 11.7% following three sessions and a 50% drop with one albumin session. Compared with Haemonetics, Optia removed comparable volumes of plasma in less time, processing smaller blood volumes and using less citrate p < 0.05. Patients demonstrated significantly lower drop in TG and required more sessions with Haemonetics than they did with Optia p < 0.05. Shorter procedure was the main predictor for effective TG clearance. This can be achieved by continuous apheresis technology, particularly when using albumin as RF. TG removal via Optia seems to be optimized by using heparin.

Aggregates in apheresis-derived platelet concentrates: A 5-year single-centre experience.

The phenomenon of aggregates in apheresis-derived platelet concentrates (APCs) has not yet been fully elucidated. Initially, visible aggregates (IVA) usually dissolve within 24 h after collection, but some persist till the end of the shelf life (persistent aggregates, PA). A study conducted at the Croatian Institute of Transfusion Medicine aimed to identify factors that influence the aggregate occurrence in APCs. We conducted a cross-sectional study for the 2018-2022 period and collected data on APCs with IVA. We analysed APCs discarded due to PA separately for two apheresis technologies and compared them to the control group. Significantly more donations were discarded in the IVA group compared with the control group and total number of discarded APCs. A total of 205 APCs were discarded due to PA (14.7% of IVA APCs and 1.27% of all APCs collected). Amicus APCs with PA had a significantly lower platelet count and mean platelet volume. They were obtained by procedures with less anticoagulant used. In contrast to Amicus APCs, Haemonetics APCs with PA had a significantly higher platelet count. None of the donor-related factors examined was predictive of PA. APCs with IVA are more often discarded, not only due to aggregates, but also for impairment of other quality control parameters. Type of apheresis technology, being one of the most common risk factors for IVA, was not confirmed as the main risk factor for PA. There seem to be some donor-related causal factors.

Recent advances in microfluidic cell separation to enable centrifugation-free, low extracorporeal volume leukapheresis in pediatric patients.

Leukapheresis is a common extracorporeal procedure for leukodepletion and cellular collection. During the procedure, a patient's blood is passed through an apheresis machine to separate white blood cells (WBCs) from red blood cells (RBCs) and platelets (PLTs), which are then returned to the patient. Although it is well-tolerated by adults and older children, leukapheresis poses a significant risk to neonates and low-weight infants because the extracorporeal volume (ECV) of a typical leukapheresis circuit represents a particularly large fraction of their total blood volume. The reliance of existing apheresis technology on centrifugation for separating blood cells limits the degree to which the circuit ECV could be miniaturized. The rapidly advancing field of microfluidic cell separation holds excellent promise for devices with competitive separation performance and void volumes that are orders of magnitude smaller than their centrifugation-based counterparts. This review discusses recent advancements in the field, focusing on passive separation methods that could potentially be adapted to perform leukapheresis. We first outline the performance requirements that any separation method must meet to replace centrifugation-based methods successfully. We then provide an overview of the passive separation methods that can remove WBCs from whole blood, focusing on the technological advancements made in the last decade. We describe and compare standard performance metrics, including blood dilution requirements, WBC separation efficiency, RBC and PLT loss, and processing throughput, and discuss the potential of each separation method for future use as a high-throughput microfluidic leukapheresis platform. Finally, we outline the primary common challenges that must still be overcome for these novel microfluidic technologies to enable centrifugation-free, low-ECV leukapheresis in the pediatric setting.

Increasing the collection flow rate to 2 mL/min is effective and reduces the procedure time in off-line photopheresis.

Extracorporeal photopheresis (ECP) treatment, mostly based on apheresis technology, is used for immunomodulation in various diseases such as cutaneous T-cell lymphoma, graft versus host disease and other (auto)immune disorders. The aim of this study was to collect high cell counts and purity in shorter procedure times using an ECP off-line system with an increased collection flow rate of 2 mL/min to a target volume of 200 mL buffy coat. In this prospective study, data of routinely performed off-line photopheresis treatments were collected and analyzed at the Central Institute for Blood Transfusion & Department of Immunology (ZIB) of the Tirol Kliniken, to assess absolute cell counts and procedure times and to calculate collection efficiencies (CE2). A total of 22 patients participated in this study. The processed blood volume was 4312 mL, the collection time 120 min, overall procedure time 157 min and the absolute cell counts of treated white blood cells (WBC) and mononuclear cells (MNC) were 5.0 and 4.3 × 109 respectively (median values). The calculated CE2 for WBC and MNC was 21.1% and 58.5%, the proportion of treated MNCs of the total number of MNCs present was 55.0%. The data presented in this study show high therapeutically effective cell counts collected with a high MNC purity within a shorter overall collection/procedure time due to an increased collection flow rate.

Therapeutic Thrombocytapheresis as an Important Tool in the Management of Symptomatic Hyperthrombocytosis

Background &amp; Objectives: Hyperthrombocytosis may cause acquired thrombosis-related symptoms and fatal vascular complications. Currently, therapeutic platelet reduction (TPR) with medical therapy remains the mainstay of hyperthrombocytosis management. We encounter patients with high platelet counts with requests for TPR. Here, we share our experience of TPR procedures in patients with symptomatic hyperthrombocytosis due to various underlying etiologies. Methods: The study from January 2013 to October 2020 included 36 patients of hyperthrombocytosis who underwent 82 TPR procedures by apheresis technology. Patient details were obtained from the treatment file and all procedures were performed following recommended instructions and protocol. Statistical analysis was done using the SPSS statistical package. Results: The median age of patients was 53 years with mean hemoglobin, platelet count, plateletcrit, and platelet distribution width of 9.9 g/dL, 1711.3 × 106/mL, 0.57%, and 43.4%, respectively. A total of 26 patients had primary thrombocytosis. The mean TPR procedure time, whole blood volume processed, and anticoagulant used were 162 min, 5070 mL, and 430.3 mL, respectively. The mean reduction of platelets in patients who underwent two and three procedures was 72.4% and 82.7%, respectively (P = 0.003). Conclusion: We conclude that TPR is a useful method in reducing platelet count rapidly in hyperthrombocytosis. It relieves patients of acute symptoms and prevents thrombotic events. The decision to perform TPR should be individualized and based on the clinical scenario, degree of thrombocytosis, and risk factors associated with TPR procedures.

The Japanese Society for Apheresis clinical practice guideline for therapeutic apheresis.

Most of the diseases for which apheresis therapy is indicated are intractable and rare, and each patient has a different background and treatment course prior to apheresis therapy initiation. Therefore, it is difficult to conduct large-scale randomized controlled trials to secure high-quality evidence. Under such circumstances, the American Society for Apheresis (ASFA) issued its guidelines in 2007, which were repeatedly revised until the latest edition in 2019. The ASFA guidelines are comprehensive. However, in the United States, a centrifugal separation method is mainly used for apheresis, whereas the mainstream procedure in Japan is the membrane separation method. The target diseases and their backgrounds are different from those in Japan. Due to these differences, the direct adoption of the ASFA guidelines in Japanese practice creates various problems. One of the features of apheresis in Japan is the development of treatment methods using hollow-fiber devices such as double filtration plasmapheresis (DFPP) and selective plasma exchange and adsorption-type devices such as polymyxin B-immobilized endotoxin adsorption columns. Specialists in emergency medicine, hematology, collagen diseases/rheumatology, respiratory medicine, cardiovascular medicine, gastroenterology, neurology, nephrology, and dermatology who are familiar with apheresis therapy gathered for this guideline, which covers 86 diseases. In addition, since apheresis therapy involves not only physicians but also clinical engineers, nurses, dieticians, and many other medical professionals, this guideline was prepared in the form of a worksheet so that it can be easily understood at the bedside. Moreover, to the clinical purposes, this guideline is designed to summarize apheresis therapy in Japan and to disseminate and further develop Japanese apheresis technology to the world. As diagnostic and therapeutic techniques are constantly advancing, the guidelines need to be revised every few years. In order to ensure the high quality of apheresis therapy in Japan, both the Japanese Society for Apheresis Registry and the guidelines will be inseparable.

Apheresis at the National Institutes of Health: A unique nursing experience

The National Institutes of Health (NIH) Clinical Center (CC) is the largest hospital in the world dedicated entirely to clinical research. For over 50 years, NIH scientists have been involved in the development and refinement of apheresis technology that is essential for new and emerging clinical applications of immunotherapy and personalized medicine. NIH investigators have studied the structure and function of blood cells, looking for characteristics that can be exploited to create these new and innovative therapies. Since the very beginning, NIH apheresis nurses have played a pivotal role in providing the raw materials needed for these innovations. The NIH CC Department of Transfusion Medicine (DTM) provides essential services to support investigators and patients when apheresis nurses collect Hematopoietic Progenitor Cells (HPCs), lymphocytes, platelets, plasma and granulocytes from patients and donors enrolled in clinical research protocols at NIH. While balancing patient safety needs, regulatory requirements and research protocol integrity, DTM apheresis nurses face unique challenges.

Overview of Cellular Immunotherapies within Transfusion Medicine for the Treatment of Malignant Diseases.

Over the years, transfusion medicine has developed into a broad, multidisciplinary field that covers different clinical patient services such as apheresis technology and the development of stem cell transplantation. Recently, the discipline has found a niche in development and production of advanced therapy medicinal products (ATMPs) for immunotherapy and regenerative medicine purposes. In clinical trials, cell-based immunotherapies have shown encouraging results in the treatment of multiple cancers and autoimmune diseases. However, there are many parameters such as safety, a high level of specificity, and long-lasting efficacy that still need to be optimized to maximize the potential of cell-based immunotherapies. Thus, only a few have gained FDA approval, while the majority of them are studied in the context of investigator-initiated trials (IITs), where modern, academically oriented transfusion centers can play an important role. In this review, we summarize existing and contemporary cellular immunotherapies, which are already a part of modern transfusion medicine or are likely to become so in the future.

Blood apheresis technologies – a critical review on challenges towards efficient blood separation and treatment

This review article critically assesses materials engineering advances across blood separation technologies which addresses operating challenges such as surface fouling and material biocompatibility.

Unstimulated apheresis for chimeric antigen receptor manufacturing in pediatric/adolescent acute lymphoblastic leukemia patients

Autologous unstimulated leukapheresis product serves as starting material for a variety of innovative cell therapy products, including chimeric antigen receptor (CAR)-modified T-cells. Although it may be reasonable to assume feasibility and efficiency of apheresis for CAR-T cell manufacture, several idiosyncrasies of these patients warrant their separate analysis: target cells (mononuclear cells [MNC] and T-cells) are relatively few which may instruct the selection of apheresis technology, low body weight, and, hence, low total blood volume (TBV) can restrict process and product volume, and patients may be in compromised health. We here report outcome data from 46 consecutive leukaphereses in 33 unique pediatric patients performed for the purpose of CD19-CAR-T-cell manufacturing. Apheresis targets of 2×109 MNC/1×109 T-cells were defined by marketing authorization holder specification. Patient weight was 8 to 84 kg; TBV was 0.6 to 5.1 L. Spectra Optia apheresis technology was used. For 23 patients, a single apheresis sufficed to generate enough cells and manufacture CAR-T-cells, the remainder required two aphereses to meet target dose and/or two apheresis series because of production failure. Aphereses were technically feasible and clinically tolerable without serious adverse effects. The median collection efficiencies for MNC and T-cells were 53% and 56%, respectively. In summary, CAR apheresis in pediatric patients, including the very young, is feasible, safe and efficient, but the specified cell dose targets can be challenging in smaller children. Continuous monitoring of apheresis outcomes is advocated in order to maintain quality.

Short- and long-term effects of lipoprotein apheresis on plasma hormones in patients with therapy-resistant dyslipidemia

Background and aimsLipoprotein apheresis (LA) is a highly effective method to improve the clinical and metabolic situation in patients with therapy-resistant disorders of lipid metabolism. Cholesterol is the substrate for the synthesis of all steroid hormones. If repeated massive reduction of LDL-cholesterol may interfere with human adrenal steroidogenesis, and could become clinically relevant is unknown, so far. Thus, the aim of this study was to determine possible short- and long-term effects of LA on blood plasma levels of ACTH, cortisol, aldosterone, DHEAS, renin and testosterone. MethodsIn total, 39 patients, treated with one of four LA techniques were studied: 1. Lipid Filtration (LF; n = 7), 2. Dextran Sulfate Adsorption (DSA; n = 7), 3. Membrane Filtration Optimised Novel Extracorporeal Treatment (MONET; n = 8), and 4. Direct Absorption of Lipoproteins (DALI; n = 15). Hormone levels were analyzed before and after five LA sessions with an interval of 20 weeks covering a total observation time of two years. In addition patients were comprehensively characterized by clinical and laboratory data. ResultsPatients treated with LA revealed an acute reduction of steroid hormones and ACTH, independent of apheresis technology but no long-term insufficiency in steroidogenesis was observed. Plasma renin levels were stable in LF patients and were highly elevated in patients under DSA, MONET and DALI apheresis throughout the observation period. ConclusionsIn summary, these data suggest that although different LA techniques considerably differ in their acute effects on hormone levels during LA, they did not alter long-term hormone levels sustainably.

Current state of apheresis technology and its applications

Apheresis is at the forefront of therapeutic approaches for an increasing number of indications caused by formation of pathologic antibodies treated by therapeutic plasma exchange, or through the use of red cell exchanges to overcome complications secondary to sickle cell crises. Likewise, the number of hematopoietic stem cell transplants has continued to grow annually and this is the direct result of the expansion of apheresis collections. Over the years a number of apheresis platforms have been utilized, but as one of the oldest and most widely used systems, the COBE Spectra, has ceased to be used therapeutically and at blood centers for donations there is an active search to find suitable systems that will replace it and have the versatility to perform as many procedures as possible. Computer innovations have made it possible with current apheresis technology to obtain more real-time information of the procedure which permits the operator to adjust parameters not only to optimize the specific procedure but also to safeguard against potential adverse events. The focus of this review is to go over available clinical data describing the operation, outcomes and applications of apheresis platforms, and discuss those systems that are likely to meet clinical demands and those of blood donation centers.

Lymphocyte apheresis for chimeric antigen receptor T-cell manufacturing in children and young adults with leukemia and neuroblastoma.

The first step in the production of chimeric antigen receptor T cells is the collection of autologous T cells using apheresis technology. The procedure is technically challenging, because patients often have low leukocyte counts and are heavily pretreated with multiple lines of chemotherapy, marrow transplantation, and/or radiotherapy. Here, we report our experience of collecting T lymphocytes for chimeric antigen receptor T-cell manufacturing in pediatric and young adult patients with leukemia, non-Hodgkin lymphoma, or neuroblastoma. Apheresis procedures were performed on a COBE Spectra machine using the mononuclear cell program, with a collection target of 1 × 109 total mononuclear cells per kilogram. Data were collected regarding preapheresis and postapheresis blood counts, apheresis parameters, products, and adverse events. Ninety-nine patients (ages 1.3-25.7 years) and 102 apheresis events were available for analysis. Patients underwent apheresis at a variety of absolute lymphocyte cell counts, with a median absolute lymphocyte count of 944 cells/μL (range, 142-6944 cells/μL). Twenty-two patients (21.6%) had absolute lymphocyte counts less than 500 cells/μL. The mononuclear cell target was obtained in 100% of all apheresis harvests, and chimeric antigen receptor T-cell production was possible from the majority of collections (94%). Mononuclear cell collection efficiency was 65.4%, and T-lymphocyte collection efficiency was 83.4%. Ten patients (9.8%) presented with minor adverse events during the 102 apheresis procedures, with one exception of a severe allergy. Mononuclear cell apheresis for chimeric antigen receptor T-cell therapy is well tolerated and safe, and it is possible to obtain an adequate quantity of CD3+ lymphocytes for chimeric antigen receptor T-cell manufacturing in heavily pretreated patients who have low lymphocyte counts.

What is the role of apheresis technology in stem cell transplantation?

Since the demonstration that hematopoietic cells are present in circulating blood, peripheral blood stem cell transplantation (PBSCT) has become an area of interest. The invention of growth factors such as the granulocyte colony-stimulating factor (G-CSF) and the availability of apheresis techniques allowed the wide application of peripheral blood stem cells (PBSC) in both autologous and allogeneic hematopoietic stem cell transplantation settings. It has been since 1986 that clinically introduced, peripheral blood stem cells replaced bone marrow as a stem-cell source to nearly 100% in the autologous and to approximately 75% in the allogeneic transplantation setting. During this period of time, remarkable development occurred in both stem cell mobilizing agents (i.e. CXCR4 antagonists) and apheresis techniques. Currently, apheresis technology is being increasingly used in not only for collection of PBSC or blood product support, but also for treatment and/or prevention of several transplantations related complications. Apheresis technology also allows to manipulate stem cells and thus provides opportunity to curative treatment of certain diseases.

Apheresis technology correlates with bacterial contamination of platelets and reported septic transfusion reactions.

Apheresis technology to collect platelet (PLT) components differs among devices. We evaluated the relationship of the plateletpheresis device with bacterial contamination and reported septic transfusion reactions. Plateletpheresis was performed using Amicus (Fenwal, a Fresenius Kabi Company) or Trima (Trima Accel, TerumoBCT) from 2010 to 2014. All donations used inlet-line sample diversion and were tested by quality control (QC; Day 1) aerobic culture. Rates of bacterial contamination and septic reactions to PLTs were calculated for both devices. During the 5-year study period, plateletpheresis collections using Amicus and Trima devices totaled 1,486,888 and 671,955 donations, respectively. The rate of confirmed-positive bacterial cultures of apheresis PLT donations was significantly higher with Amicus than with Trima (252 vs. 112 per 106 donations [odds ratio {OR}, 2.3; 95% confidence interval {CI}, 1.8-2.9]). Septic transfusion reactions were caused by 30 apheresis PLT units from 25 contaminated Amicus procedures and three apheresis PLT units from three contaminated Trima procedures. The overall rate of septic reactions was significantly higher with apheresis PLT components collected with Amicus than with Trima (16.8 vs. 4.5 per 106 donations [OR, 3.8; 95% CI, 1.1-12.5]). All apheresis PLT components implicated in septic transfusion reactions had negative QC culture results incubated through Day 5 (i.e., false negatives). Apheresis technology affects bacterial contamination of plateletpheresis collections. The device-specific, higher rate of confirmed-positive bacterial culture results also correlated with a significantly higher rate of reported septic transfusion reactions to apheresis PLTs.

Critical updates in the 7th edition of the American Society for Apheresis guidelines

The 7th edition of the American Society for Apheresis (ASFA) guidelines was composed by an international physicians committee, and includes 14 new diseases, and 2 new indications for diseases described in the former guidelines. Several indications have either changed names or were excluded from this edition. The guidelines are developed after taking into account documented evidence, either supporting or negating use of apheresis technology in the treatment of diseases. Based on this evidence, the committee revises, updates and includes or excludes disease entities/indications in the guidelines. This article describes the revisions to the 7th edition of the ASFA guidelines, in a comprehensive manner.

Mobilization of hematopoietic stem cells with the novel CXCR4 antagonist POL6326 (balixafortide) in healthy volunteers\u2014results of a dose escalation trial

BackgroundCertain disadvantages of the standard hematopoietic stem and progenitor cell (HSPC) mobilizing agent G-CSF fuel the quest for alternatives. We herein report results of a Phase I dose escalation trial comparing mobilization with a peptidic CXCR4 antagonist POL6326 (balixafortide) vs. G-CSF.MethodsHealthy male volunteer donors with a documented average mobilization response to G-CSF received, following ≥6 weeks wash-out, a 1–2 h infusion of 500–2500 µg/kg of balixafortide. Safety, tolerability, pharmacokinetics and pharmacodynamics were assessed.ResultsBalixafortide was well tolerated and rated favorably over G-CSF by subjects. At all doses tested balixafortide mobilized HSPC. In the dose range between 1500 and 2500 µg/kg mobilization was similar, reaching 38.2 ± 2.8 CD34 + cells/µL (mean ± SEM). Balixafortide caused mixed leukocytosis in the mid-20 K/µL range. B-lymphocytosis was more pronounced, whereas neutrophilia and monocytosis were markedly less accentuated with balixafortide compared to G-CSF. At the 24 h time point, leukocytes had largely normalized.ConclusionsBalixafortide is safe, well tolerated, and induces efficient mobilization of HSPCs in healthy male volunteers. Based on experience with current apheresis technology, the observed mobilization at doses ≥1500 µg/kg of balixafortide is predicted to yield in a single apheresis a standard dose of 4× 10E6 CD34+ cells/kg from most individuals donating for an approximately weight-matched recipient. Exploration of alternative dosing regimens may provide even higher mobilization responses.Trial Registration European Medicines Agency (EudraCT-Nr. 2011-003316-23) and clinicaltrials.gov (NCT01841476)

Pediatric Therapeutic Apheresis: A Critical Appraisal of Evidence.

Apheresis technology has progressed significantly over the last 50-60 years from a predominately blood donation-based procedure to one that now includes a variety of therapeutic modalities. The last 25 years also has seen an increase in the number of diseases treated by therapeutic apheresis (TA) modalities. Because of ethical considerations, therapeutic modalities are often vetted first in adult populations before establishing utility in pediatric patients. TA is no different. The majority of published studies involve adult patients. Pediatric apheresis studies are traditionally retrospective, single-center experiences, single case reports, or case series. To confirm this, we evaluated the peer-reviewed published literature to assess the level of evidence of clinical pediatric apheresis studies published in the last 21 years. Adverse events experienced by pediatric patients undergoing TA procedures and procedural modifications necessary to accommodate pediatric patients receiving TA were also explored. Consideration was given to differences in disease outcomes in pediatric vs adult patients and evolution of TA treatment indications. A systematic search of the literature yielded >1000 pediatric apheresis publications. Only 370 articles specifically assessed TA in the treatment of a pediatric disease. Of those, the majority (98%) were single-center experiences, single case reports, or case series. The remaining 2% were prospective cohort studies or randomized controlled trials. This first formal assessment of the pediatric apheresis literature confirms the findings of previous anecdotal reports and expert opinion.

Detection of bacterial contamination in apheresis platelets: is apheresis technology a factor?

Apheresis platelet (AP) contamination may be influenced by manufacturing methods because bacteria are subject to the same forces that permit separation of blood cells. This study assesses whether apheresis technology influences in-process detection of bacterial contamination. Blood Systems, Inc. (BSI) and New York Blood Center (NYBC) use Amicus and Trima devices to collect APs. Manufacturing (arm disinfection and in-line diversion) was consistent for both devices in the study period. Detection was performed using BacT/ALERT. True-positive (TP) rates were calculated and significance testing was performed using chi-square tests separately for BSI and NYBC. For BSI, multivariable logistic regression analysis was also performed to identify factors associated with TP results. For BSI, there were 49 TPs in 354,946 donations (1.4/10,000): 2.5 per 10,000 for Amicus and 1.0 per 10,000 for Trima (p < 0.05). Multivariable logistic regression analysis showed significant association between TP and devices (odds ratio, 2.8; 95% confidence interval [CI], 1.01-8.0) and for one collection region. For NYBC, there were 18 TPs in 161,840 donations (1.1/10,000): 2.1 per 10,000 for Amicus and 0.4 per 10,000 for Trima (p < 0.05). The TP rate was significantly higher in Amicus collections than in Trima collections at NYBC and BSI. These results do not allow for conclusions regarding the relative clinical risk of PLTs collected by Amicus and Trima. Future evaluations of component quality and clinical outcomes should consider different collection technologies.

Plasma and Plasma Protein Product Transfusion: A Canadian Blood Services Centre for Innovation Symposium.

Plasma obtained via whole blood donation processing or via apheresis technology can either be transfused directly to patients or pooled and fractionated into plasma protein products that are concentrates of 1 or more purified plasma protein. The evidence base supporting clinical efficacy in most of the indications for which plasma is transfused is weak, whereas high-quality evidence supports the efficacy of plasma protein products in at least some of the clinical settings in which they are used. Transfusable plasma utilization remains composed in part of applications that fall outside of clinical practice guidelines. Plasma contains all of the soluble coagulation factors and is frequently transfused in efforts to restore or reinforce patient hemostasis. The biochemical complexities of coagulation have in recent years been rationalized in newer cell-based models that supplement the cascade hypothesis. Efforts to normalize widely used clinical hemostasis screening test values by plasma transfusion are thought to be misplaced, but superior rapid tests have been slow to emerge. The advent of non-vitamin K-dependent oral anticoagulants has brought new challenges to clinical laboratories in plasma testing and to clinicians needing to reverse non-vitamin K-dependent oral anticoagulants urgently. Current plasma-related controversies include prophylactic plasma transfusion before invasive procedures, plasma vs prothrombin complex concentrates for urgent warfarin reversal, and the utility of increased ratios of plasma to red blood cell units transfused in massive transfusion protocols. The first recombinant plasma protein products to reach the clinic were recombinant hemophilia treatment products, and these donor-free equivalents to factors VIII and IX are now being supplemented with novel products whose circulatory half-lives have been increased by chemical modification or genetic fusion. Achieving optimal plasma utilization is an ongoing challenge in the interconnected worlds of transfusable plasma, plasma protein products, and recombinant and engineered replacements.