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Neil Blumberg

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Neil Blumberg last won the day on May 28

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    Hematologist/Transfusion Medicine Physician

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  1. Neil Blumberg

    Group O Whole Blood, Low Titer

    The whole blood being used in Pittsburgh is leukoreduced. They have chosen a titer of 50, which I would think is much safer than 200, but who knows? It would nice to have high quality data, or any data whatever, comparing the results with whole blood with similar patients transfused with the usual group O red cells, platelets of whatever group (usually) and AB plasma. I'd speculate that there is no difference because mixing group O red cells with AB plasma gives patients a substantial dose of iatrogenic ABO immune complexes, which we have demonstrated leads to impaired platelet function (in vitro), endothelial damage (unpublished in vitro data) and increased bleeding (observational clinical data). Thus low titer group O whole blood might well be safer than our current practices, which have only been validated not to cause acute massive hemolysis, which is only one of many disastrous clinical outcomes that can result from crossing ABO barriers. Focusing on red cells is fine, but there are other cells in the body that carry ABO antigens (endothelial cells for example) and loads of soluble antigen.
  2. Neil Blumberg

    Group O Whole Blood, Low Titer

    "Stupid question - why is group O whole blood better than group O pack cells and group A thawed plasma? " Not stupid at all. There is no clinical evidence that it is superior or inferior. In fact, no clinical evidence whatever. The main attraction is that it simplifies transfusion in the patients who require red cells, plasma and platelets. One bag instead of three. That it provides better hemostasis is a supposition that may or may not prove to be wrong. It's concerning to me that it's very hard to predict who really needs anything but red cells. One estimate from London is 25% but that includes everyone with an elevated PT/INR and PTT, which are not good tests for predicting bleeding. We examined the last half year of our ED uncrossmatched blood cooler release in our Level 1 trauma center in a medium sized American city. We do not routinely start the massive transfusion protocol with the first cooler (or even the second, unless asked to do so). Of the 230 or so patients, only 2 wound up using more than 8 red cells (0.86%). I suspect this is typical of many university hospitals and almost all smaller teaching hospitals. Hence, no whole blood, no massive transfusion protocol routinely started on arrival, unless requested. I would think that whole blood as the first product to be infused for our patients would harm more patients than help (TRALI, TACO, etc.).
  3. Neil Blumberg

    <4 hour transfusion time limit requirement

    Probably not helpful, but there is not a shred of scientific or clinical evidence for the efficacy and safety of this time limit. Totally expert opinion based upon a group of white haired males (like me) sitting around a table eating tuna fish sandwiches 60 years ago :). We document such stuff for the two regulatory agencies and two accreditation groups we are inspected by. How's that for efficiency? Four inspections.
  4. Neil Blumberg

    blood in free standing ED

    Not to my knowledge. Indeed, I don't believe free standing EDs should have blood available, unless there is no hospital within 20-30 miles and no helicopters are available for transport. I would want patients with life threatening bleeding or anemia to be taken only to a facility with on-site surgical facilities, surgeons, interventional radiology, etc. which are generally not available in free standing EDs. In other words, a fully staffed hospital. I would advocate taking such critically ill patients to the nearest level 1 or 2 trauma center, whenever one can, and bypass the free standing ED.
  5. Neil Blumberg

    Volume (Plasma) Reduced Platelet

    "How many techs work in your Blood Bank on a daily basis?" Typically 9-10 on days, 6-7 on evenings and 3-4 on nights, with fewer on holidays and weekend shifts. All are full-time transfusion service only licensed medical technologists. Also 5 supervisory level staff (3 of whom also work at the bench), 2 full-time education/reference specialists, 2 full-time stem cell processing. "How do you keep up with washing units during a surgery? Or do you wash units before the surgery?" We don't. We wash in advance if need be, and if that isn't enough, we do the best we can. Thanks to the fact that manufacturers have focused on apheresis devices and the 2991 and ACP-215 are much older technology, we do not have a closed system. In any case, storing washed red cells for more than a few days would defeat the purpose of removing the supernatant containing free hemoglobin, red cell microparticles, etc. "If they do not use the units, what can you do with them? What is your RBC/PLT unit loss rate (washed but not used?)?" We transfuse 20,000 red cells per year so finding a patient who needs an O or A red cell isn't difficult. Same for platelets. On a typical weekday we transfused 80-100 red cells and 10-20 platelet doses. Essentially no losses. Our platelet outdate rate is consistently about 1-3%, washed or otherwise. Usually these are for scheduled elective transfusions on both inpatients and outpatients. As blood bankers/transfusion service personnel we do many inconvenient things, some quite expensive (CMV serotesting--unnecessary and less clinically valuable than leukoreduction), antigen matching for patients with hemoglobinopathies (quite clinically effective but time consuming and expensive), use of apheresis platelets instead of whole blood platelets (an almost totally unnecessary misuse of donor resources in most cases, additional risk to donors, no clinical advantage of substance, and fabulously expensive). I'd gladly give up apheresis platelets (except for HLA matched) and their cost for universal leukoreduction in the USA and selective washing of ABO minor-incompatible platelets and red cells. The latter on rare occasions kills patients, yet we do nothing about it in most transfusion services, and routinely give group O platelets to non-O recipients. I know these dilemmas are easily ignored and scoffed at, but the facts support these unpopular contentions. I should add that we see perhaps 3-5 platelet transfusion refractory patients per year out of thousands of platelet transfusion recipients. This is a benefit of transfusing only ABO identical platelets and red cells (or washed O's) which our group and Robert Carr of the UK demonstrated 25-30 years ago reduces refractoriness by 2-5 fold in the only randomized trials that exist. We have randomized trial evidence that washed red cells and platelets also contribute to improved long term survival in acute myeloid leukemia patients and reduce inflammation in pediatric cardiac surgery patients. Arguing against washing because it's expensive (it's not really all that expensive compared with apheresis platelets), it's inconvenient (it sure is) andis not "essential" doesn't justify subjecting patients to inferior treatment approaches in our view. Obviously these approaches have not caught on in most places (ABO identical and selective washing) but it's not for lack of data :). Similarly, in our view, transfusing ABO mismatched platelets for our own convenience, inventory purposes and to save outdating does not make sense when there is abundant evidence that this practice seriously harms some patients. Hence, plasma removal by washing when indicated and feasible. Contrary to 75 years or more of practice and tradition, there is no such thing as "universal donor group O red cells" and "universal donor group AB plasma." No patient makes red urine with this approach, and it's necessary when the ABO of the patient isn't known, but patients receiving ABO mismatched platelets use 50% more red cells, develop multi-organ failure more often, have more transfusion reactions and higher mortality rates than patients receiving ABO identical platelets(all observational data, but from multiple centers in surgical patients). O patients receiving AB plasma in large volumes have a 9% increase in mortality rate in Swedish data. We all know of rare case reports of fatal transfusion reactions from group O red cells given to non-O patients. Washed transfusions make these problems go away, in our experience. Is It Time to Reconsider the Concepts of "Universal Donor" and "ABO Compatible" Transfusions? Refaai MA, Cahill C, Masel D, Schmidt AE, Heal JM, Kirkley SA, Blumberg N. Anesth Analg. 2018 Jun;126(6):2135-2138. doi: 10.1213/ANE.0000000000002600. ABO-immune complex formation and impact on platelet function, red cell structural integrity and haemostasis: an in vitro model of ABO non-identical transfusion. Zaffuto BJ, Conley GW, Connolly GC, Henrichs KF, Francis CW, Heal JM, Blumberg N, Refaai MA. Vox Sang. 2016 Apr;110(3):219-26. doi: 10.1111/vox.12354. Epub 2015 Nov 3 Improved outcomes in acute myeloid leukemia patients treated with washed transfusions. Greener D, Henrichs KF, Liesveld JL, Heal JM, Aquina CT, Phillips GL 2nd, Kirkley SA, Milner LA, Refaai MA, Mendler JH, Szydlowski J, Masel D, Schmidt A, Boscoe FP, Schymura MJ, Blumberg N. Am J Hematol. 2017 Jan;92(1):E8-E9. doi: 10.1002/ajh.24585. A randomized trial of washed red blood cell and platelet transfusions in adult acute leukemia [ISRCTN76536440]. Blumberg N, Heal JM, Rowe JM. BMC Blood Disord. 2004 Dec 10;4(1):6. Washing red blood cells and platelets transfused in cardiac surgery reduces postoperative inflammation and number of transfusions: results of a prospective, randomized, controlled clinical trial. Cholette JM, Henrichs KF, Alfieris GM, Powers KS, Phipps R, Spinelli SL, Swartz M, Gensini F, Daugherty LE, Nazarian E, Rubenstein JS, Sweeney D, Eaton M, Lerner NB, Blumberg N. Pediatr Crit Care Med. 2012 May;13(3):290-9. doi: 10.1097/PCC.0b013e31822f173c.
  6. Neil Blumberg

    Transfusion in surgery pediatric cardiac

    Most patients only need one red cell for surgery, or less. The need for the second is usually emergent and there is insufficient time for washing (takes at least 30 minutes). Just logistics and demographics. Ideally, all patients would receive washed red cells, but there is not yet convincing data that clinical outcomes are improved. There were trends to improved outcomes in our randomized trial (mortality in particular) but the trial was powered to demonstrate that washed red cells reduced post-transfusion reduced inflammation, as measured by IL-6 and CRP, which was conclusively demonstrated.
  7. Neil Blumberg

    Volume (Plasma) Reduced Platelet

    There are no data. When we wash platelets or red cells, the outdate is 24 hours because of the open system (ancient COBE/Terumo type 2991s). Patients do better in terms of key clinical outcomes (mortality, infection, thrombosis) with washed platelets so I'm not concerned about the container, length of storage, etc. Ultimately clinical outcomes are more important than any of those surrogate in vitro markers. We routinely wash to remove incompatible ABO antibody and soluble antigen, FYI. We do not wash red cells more than 21 days of storage due to increased hemolysis, and poorer clinical outcomes with these components (washed >21 days). We currently wash with normal saline, but Plasma-Lyte A (AJCP in press) causes less hemolysis and we will be moving away from normal saline. Hopefully we remove normal saline from use for all transfusion service and clinical uses, due to recent data that normal saline causes increased mortality and renal failure in ICU patients (in NEJM). See references below. A randomized trial of washed red blood cell and platelet transfusions in adult acute leukemia [ISRCTN76536440]. Blumberg N, Heal JM, Rowe JM. BMC Blood Disord. 2004 Dec 10;4(1):6. Providing ABO-identical platelets and cryoprecipitate to (almost) all patients: approach, logistics, and associated decreases in transfusion reaction and red blood cell alloimmunization incidence. Henrichs KF, Howk N, Masel DS, Thayer M, Refaai MA, Kirkley SA, Heal JM, Blumberg N. Transfusion. 2012 Mar;52(3):635-40. doi: 10.1111/j.1537-2995.2011.03329.x. Epub 2011 Sep 2. Washing red blood cells and platelets transfused in cardiac surgery reduces postoperative inflammation and number of transfusions: results of a prospective, randomized, controlled clinical trial. Cholette JM, Henrichs KF, Alfieris GM, Powers KS, Phipps R, Spinelli SL, Swartz M, Gensini F, Daugherty LE, Nazarian E, Rubenstein JS, Sweeney D, Eaton M, Lerner NB, Blumberg N. Pediatr Crit Care Med. 2012 May;13(3):290-9. doi: 10.1097/PCC.0b013e31822f173c. ABO identical and washed blood transfusions as candidate strategies to reduce early mortality in acute promyelocytic leukemia. Sahai T, Henrichs K, Refaai M, Heal JM, Kirkley SA, Schmidt AE, Mendler JH, Masel D, Liesveld J, Aquina C, Blumberg N. Leuk Res. 2017 Nov;62:1-3. doi: 10.1016/j.leukres.2017.09.011. Epub 2017 Sep 23. Improved outcomes in acute myeloid leukemia patients treated with washed transfusions. Greener D, Henrichs KF, Liesveld JL, Heal JM, Aquina CT, Phillips GL 2nd, Kirkley SA, Milner LA, Refaai MA, Mendler JH, Szydlowski J, Masel D, Schmidt A, Boscoe FP, Schymura MJ, Blumberg N. Am J Hematol. 2017 Jan;92(1):E8-E9. doi: 10.1002/ajh.24585. Longer RBC storage duration is associated with increased postoperative infections in pediatric cardiac surgery. Cholette JM, Pietropaoli AP, Henrichs KF, Alfieris GM, Powers KS, Phipps R, Spinelli SL, Swartz M, Gensini F, Daugherty LE, Nazarian E, Rubenstein JS, Sweeney D, Eaton M, Blumberg N. Pediatr Crit Care Med. 2015 Mar;16(3):227-35. doi: 10.1097/PCC.0000000000000320. Transfus Apher Sci. 2018 Feb;57(1):127-131. doi: 10.1016/j.transci.2018.02.021. Epub 2018 Feb 21. 0.9% NaCl (Normal Saline) - Perhaps not so normal after all? Blumberg N1, Cholette JM2, Pietropaoli AP3, Phipps R4, Spinelli SL5, Eaton MP6, Noronha SA7, Seghatchian J8, Heal JM9, Refaai MA9. Crystalloid infusion is widely employed in patient care for volume replacement and resuscitation. In the United States the crystalloid of choice is often normal saline. Surgeons and anesthesiologists have long preferred buffered solutions such as Ringer's Lactate and Plasma-Lyte A. Normal saline is the solution most widely employed in medical and pediatric care, as well as in hematology and transfusion medicine. However, there is growing concern that normal saline is more toxic than balanced, buffered crystalloids such as Plasma-Lyte and Lactated Ringer's. Normal saline is the only solution recommended for red cell washing, administration and salvage in the USA, but Plasma-Lyte A is also FDA approved for these purposes. Lactated Ringer's has been traditionally avoided in these applications due to concerns over clotting, but existing research suggests this is not likely a problem. In animal models and clinical studies in various settings, normal saline can cause metabolic acidosis, vascular and renal function changes, as well as abdominal pain in comparison with balanced crystalloids. The one extant randomized trial suggests that in very small volumes (2 l or less) normal saline is not more toxic than other crystalloids. Recent evidence suggests that normal saline causes substantially more in vitro hemolysis than Plasma-Lyte A and similar solutions during short term storage (24 hours) after washing or intraoperative salvage. There are now abundant data to raise concerns as to whether normal saline is the safest replacement solution in infusion therapy, red cell washing and salvage, apheresis and similar uses. In the USA, Plasma-Lyte A is also FDA approved for use with blood components and is likely a safer solution for these purposes. Its only disadvantage is a higher cost. Additional studies of the safety of normal saline for virtually all current clinical uses are needed. It seems likely that normal saline will eventually be abandoned in favor of safer, more physiologic crystalloid solutions in the coming years. N Engl J Med. 2018 Mar 1;378(9):829-839. doi: 10.1056/NEJMoa1711584. Epub 2018 Feb 27. Balanced Crystalloids versus Saline in Critically Ill Adults. Semler MW1, Self WH1, Wanderer JP1, Ehrenfeld JM1, Wang L1, Byrne DW1, Stollings JL1, Kumar AB1, Hughes CG1, Hernandez A1, Guillamondegui OD1, May AK1, Weavind L1, Casey JD1, Siew ED1, Shaw AD1, Bernard GR1, Rice TW1; SMART Investigators and the Pragmatic Critical Care Research Group. BACKGROUND: Both balanced crystalloids and saline are used for intravenous fluid administration in critically ill adults, but it is not known which results in better clinical outcomes. METHODS: In a pragmatic, cluster-randomized, multiple-crossover trial conducted in five intensive care units at an academic center, we assigned 15,802 adults to receive saline (0.9% sodium chloride) or balanced crystalloids (lactated Ringer's solution or Plasma-Lyte A) according to the randomization of the unit to which they were admitted. The primary outcome was a major adverse kidney event within 30 days - a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to ≥200% of baseline) - all censored at hospital discharge or 30 days, whichever occurred first. RESULTS: Among the 7942 patients in the balanced-crystalloids group, 1139 (14.3%) had a major adverse kidney event, as compared with 1211 of 7860 patients (15.4%) in the saline group (marginal odds ratio, 0.91; 95% confidence interval [CI], 0.84 to 0.99; conditional odds ratio, 0.90; 95% CI, 0.82 to 0.99; P=0.04). In-hospital mortality at 30 days was 10.3% in the balanced-crystalloids group and 11.1% in the saline group (P=0.06). The incidence of new renal-replacement therapy was 2.5% and 2.9%, respectively (P=0.08), and the incidence of persistent renal dysfunction was 6.4% and 6.6%, respectively (P=0.60). CONCLUSIONS: Among critically ill adults, the use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction than the use of saline. (Funded by the Vanderbilt Institute for Clinical and Translational Research and others; SMART-MED and SMART-SURG ClinicalTrials.gov numbers, NCT02444988 and NCT02547779 .).
  8. "A relapse would involve both the ABO and the Rh types, would it not?" One can have a relapse with recipient cells, and still have donor cells present, which in this case would be Rh positive, yes? If both donor and recipient types are present (as Malcolm suggests testing) you could have both O+ and A- cells, something we've seen on rare occasions. Sometimes one cannot rely on mixed field typing to explain what's going on clinically. Usually with relapse, the graft is lost, but not always completely. Relapse is usually obvious on peripheral smear and cytogenetics. If the patient had been typed as A+ elsewhere due to the presence of both donor and recipient red cells, the patient might be transfused with A+ cells if that facility did not have a correct history and did not observe mixed field typing. In this situation, we would probably transfuse washed O+ red cells.
  9. Neil Blumberg

    Transfusion in surgery pediatric cardiac

    The rationale for irradiation is that congenital cardiac anomalies are associated with immune deficiency syndromes. Some of these are not easy to diagnose in the first months or even first few years of life. Our own policy is for infants and younger children (<5 years of age) to transfuse only irradiated, ABO identical red cells and the first red cell is washed. We only wash red cells <21 days of age because of data that washed red cells are associated with less inflammation and clinical complications if of shorter storage (<21 days), but greater inflammation and poorer clinical outcomes if >28 days of storage. Pediatr Crit Care Med. 2015 Mar;16(3):227-35 Despite the long standing policy of using "fresher" red cells for these patients, the safest red cells are probably about 10-21 days of storage according to our data and meta-analyses of the randomized trials. Fresher red cells are associated with a higher incidence of post-operative infections, the major cause of morbidity and mortality in this population. I would never transfused red cells <7-10 days old to any patient at this point in time. We have some mechanistic data that is as yet unpublished that the mechanism is dysregulation of oxidation/reduction in freshly collected red cells. Blood. 2016 Jan 28;127(4):400-10 Washed red cells reduce the risk of post-operative inflammation in the only published randomized trial and there is also a trend towards reduced mortality in the washed arm of the study. This may be controversial but it's the only data we have to go on, certainly the only randomized trial. Pediatr Crit Care Med. 2012 May;13(3):290-9.
  10. Are you sure someone didn't transfuse this patient elsewhere with A positive red cells? Sometimes patients relapse and another hospital transfuses them according to their current type (which may have been mixed field with no anti-A). The vast majority of transplant patients in similar situations do not make anti-A. The graft is presumably tolerized by all the A antigen present on non-lymphohematopoietic cells and in soluble form (even in non-secretors). Worth getting a history in these instances.
  11. Neil Blumberg

    Can leuko-reduce prevent GVHD

    "Did leukoreduction not work? Or are we still fighting the same complications because some of the US still has not adopted universal leukocyte reduction? Leukocyte reduction seems to have helped our patients a lot." The short (sort of) answer is that while leukoreduction reduces acute transfusion reactions, likely including TRALI and TACO, reduces alloimmunization to white cell and red cell alloantigens, reduces the risk of GVHD, reduces the risk of organ failure due to inflammation, etc. it does not completely abrogate these risks. Platelet transfusions still cause inflammatory type reactions in about 1% of transfusions due to soluble mediators in the plasma such as IL-6 and CD40L. There is still lots of stored plasma in red cells and, in particular, platelets, allogeneic antigen, both soluble and cell associated, mediators such as VEGF, CD40L, IL-6, etc. that are not removed by leukoreduction at the time of manufacture. The red cells and platelets deteriorate and release mediators such as free hemoglobin, free heme, platelet granule contents, etc. that are both biologically and clinically active, causing some of these complications even after leukoreduction. There are some residual viable white cells, if not irradiated, so even minimal amounts of allogeneic white cells may have effects. We don't know. Then there is the routine, inventory driven, unfortunate use of ABO non-identical plasma and cells that creates immune complexes that almost certainly cause bleeding, endothelial damage and inflammation. Iatrogenic immune complex disease, if you will, that contributes to cellular damage and organ injury. Thus there are still plenty of candidate mediators for harm. Nonetheless, I would suggest leukoreduction is the most important advance in transfusion practice since the invention of serologic testing (Coombs test) and infectious disease testing to prevent hemolytic reactions and viral disease transmission respectively. It is our speculation, and we have randomized trial evidence in acute leukemia and pediatric cardiac surgery, that removal of stored supernatant immediately prior to transfusion by washing, along with leukoreduction and ABO identical can strikingly improve clinical outcomes by reducing immunomodulation and inflammation. When ABO identical red cells or platelets are not available, we remove 95% of the supernatant from group O red cells or platelets for non-O patients. References on request.
  12. Neil Blumberg

    Can leuko-reduce prevent GVHD

    While I would not use leukoreduction as the primary method of preventing transfusion associated graft versus host disease in high risk patients, there is evidence that it reduces the incidence of this complication in patients not conventionally thought to be immunosuppressed. These data are from the UK haemovigilance reports. Lymphocytes are not killed by irradiation, but they cannot successfully proliferate, which is necessary for graft versus host disease to occur. These UK data make one wonder what the heck the USA experts (AABB and FDA) are thinking in not mandating universal leukoreduction 20 years after it was implemented in France, UK, Canada, etc. So little cost, so many benefits. Three FDA committees have voted overwhelmingly that universal leukoreduction is clinically sound policy. No action. Many pleas to the AABB. No action. This is one of the most cost-effective and important innovations in transfusion safety in the last half century. It reduces suffering, morbidity and mortality. It's cheap and easy. The impact of universal leukodepletion of the blood supply on hemovigilance reports of posttransfusion purpura and transfusion-associated graft-versus-host disease. Williamson LM, Stainsby D, Jones H, Love E, Chapman CE, Navarrete C, Lucas G, Beatty C, Casbard A, Cohen H. Transfusion. 2007 Aug;47(8):1455-67.
  13. Neil Blumberg

    Eluates on babies with positive DATs

    No eluates, ever on neonates. Won't change therapy in any way. There are essentially no cases of autoimmune red cell disease in neonates, and the only source of IgG is mom. If we didn't have a maternal specimen, or a history from the birthing facility I suppose we might do one, but there's really no clinical mileage in doing so.
  14. Neil Blumberg

    5 Day Plasma

    Don't believe you need a variance or validation. Just relabel the product before 24 hours is up. The product is liquid plasma, not FFP after 24 hours.
  15. Neil Blumberg

    Anticoagulant in Frozen Plasma affecting INR reversal?

    The INR is a largely useless predictor of bleeding risk except for those on coumadin/warfarin, and not so good a predictor in those patients. It is known that the range of 2-3 is a reasonably safe and effective one for anti-coagulation to prevent recurrent thrombosis (usually DVT or PE). Beyond that, INR numbers like 6 or 12 tell us next to nothing except that factor VII is quite low, which may or may not be clinically important. The INR of liquid plasma or FFP is around 1.6-1.8, and is not affected by the citrate anticoagulant, since exogenous excess calcium is added in the performance of the INR. INRs of 1.5 to about 2.0 are not associated with substantial increases in bleeding, either spontaneous or procedure related, and do not need to be corrected at all, in my view, and this opinion is supported by an extensive observational literature. FFP will not correct such an INR in any case, and thus represents risk without benefit. Medical specialty society recommendations for INRs of 1.5 prior to procedures are without any evidence support whatever, and represent old, no longer valid expert opinion. If an INR needs correction for any reason, factor concentrates are more effective and less likely to harm the patient than FFP. FFP should never be used to reverse warfarin/coumadin in my opinion, because of these efficacy and safety issues. Unfortunately factor concentrates are also much more expensive than plasma/FFP. However, this considers only the cost of the product, not the cost of any clinical complications such as thrombosis, volume overload, ICU admission, etc., not to mention death, all of which are more likely with plasma/FFP. Meta-analyses of randomized trials of FFP vs. factor concentrate, demonstrate that FFP is associated with a two fold mortality increase. 'Nuf said. One ICU admission for a few days can balance the increased costs of factor concentrates for the overall health system. Factor concentrates, preferably II, VII, IX, X concentrates that also contain some protein S and C; in the USA=Kcentra; in Europe=Beriplex are preferred over three factor concentrates, but both are superior to FFP.

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