there are numerous plasma products listed in the circular of information for the use of human blood and blood components , a joint effort of the aabb ( formerly known as the american association of blood banks ) , the america 's blood centers , the fda and the american red cross . this short review will focus on the most commonly used plasma components , fresh frozen plasma ( ffp ) , thawed plasma ( tp ) , and plasma frozen within 24 hours after phlebotomy ( fp24 ) . as the clotting factors in these products are nearly equivalent , the generic term " plasma " will be used throughout this review . ffp is prepared from whole blood donations or is collected by plasmapheresis , and in 2006 it accounted for about 77% of all plasma transfused in the usa . to be labeled as ffp , the plasma must be frozen at -18 or less within 8 hours of collection . by definition ffp there is , however , variability in coagulation factor levels as demonstrated in a study looking at the inr of 20 units of ffp ; the mean inr was 1.1 while the range was 0.9 - 1.3 . this could have ramifications if plasma units with relatively higher inrs are used to try to reverse a recipient 's mildly elevated inr ( see below ) . it is thawed in a 30 - 37 water bath generally when an order for transfusion is received by the blood bank and this step normally takes 20 - 25 minutes . once thawed , the ffp can be kept at 1 - 6 for up to 24 hours without significant loss of clotting factors . if the ffp is not used within 24 hours , it must either be discarded or relabeled as thawed plasma ( tp ) . tp is the product that can result if liquid plasma is maintained at 1 - 6 for more than 1 day ; once ffp has been thawed and refrigerated for more than 24 hours , it can no longer be labeled as " fresh frozen " plasma . instead the thawed unit can be relabeled as tp , and it can continue to be stored in the liquid state at 1 - 6 for up to 4 more days . a recent study demonstrated that for both leukoreduced aphersis or whole blood plasma stored in the liquid state between 2 - 6 , the level of factor viii decreased to approximately 0.40 iu / ml at 28 days of storage . other studies of tp prepared from ffp demonstrated approximately 14 - 55% decreases in factor viii levels at day 5 of storage compared to day 1 [ 6 , 7 ] , but these residual levels , including that of adamts-13 after 5 days of storage , were still well within the therapeutic range [ 8 - 10 ] . the decreases in factor v levels were smaller [ 6 , 8 ] even after 28 days of storage . tp has the advantage of already being in a liquid state thus eliminating the time delay caused by thawing the frozen ffp , and it effectively extends the shelf - life of a unit of plasma that would otherwise have been discarded , thereby reducing wastage of a limited resource . in an effort to reduce the risk of transfusion related acute lung injury ( trali ) from plasma components , many blood centers have limited the collection of plasma from female donors due to their propensity for developing anti - hla alloimmunization after pregnancy . to avoid a shortfall in the plasma supply , there is increasing reliance on the production of plasma from male whole blood donations that have been stored between 8 - 24 hours prior to freezing . this product is known as plasma frozen within 24 hours after phlebotomy ( fp24 ) and in 2006 it accounted for approximately 15% of all the plasma transfused in the usa . the levels of most clotting factors are not significantly diminished compared to regular ffp at the time of thawing [ 7 , 12 - 15 ] , and recently 2 studies have demonstrated that the levels of clotting factors remain hemostatic during 5 days of refrigerated storage of tp prepared from fp24 [ 16 , 17 ] . in one study the levels of v and viii declined to means of 59 and 48 iu / dl , respectively , on storage day 5 , and in the other study the level of protein s ( ps ) was slightly below the reference range by day 5 . demonstrated that fp24 could be prepared from either platelet rich plasma or whole blood donations and stored for up to 7 days at refrigerator temperatures with maintenance of clotting factors at clinically adequate levels . it should be noted , however , that the only currently aabb / fda approved starting material for tp is ffp . furthermore , neither fp24 nor the tp products have been directly compared to ffp in terms of their efficacy in reversing coagulopathies or arresting coagulopathic bleeding , however based on the well preserved coagulation factors there is no a priori reason why these products would be inferior to ffp . the generally cited dose of plasma required to reverse a coagulopathy is 10 - 15 ml / kg . in many institutes , when the inr starts to exceed 1.6 , factor levels begin to drop below 30% which for many of them is the threshold for normal hemostasis ( fig . factor vii has a short half life ( 4 - 6 hours ) thus if plasma is administered more than 8 - 10 hours before the planned procedure , it will have gone through at least 2 half - lives thus reducing its hemostatic efficacy at the time of surgery . 2 , point a indicates the time at which plasma was reinfused to healthy volunteers who had been orally anticoagulated as part of a study protocol ( see below for further details ) . approximately 8 hours after the plasma infusion ( point c ) the pt began to rise steeply reflecting the end of the plasma 's efficacy . thus transfusing plasma as close to the time of an invasive procedure as possible will produce its maximum hemostatic efficacy . on the other hand once plasma is transfused it , like all blood products , it remains almost entirely in the intravascular space ; unlike crystalloids that distribute themselves between the intra- and extra - vascular spaces , plasma remains nearly entirely in the circulation . this needs to be borne in mind because rapid infusion rates , intended to facilitate the administration of the entire dose of plasma before the start of the surgery , could lead to circulatory ( volume ) overload . the use of plasma in the usa is growing . in 2006 approximately 4 million units were transfused , which is several orders of magnitude higher than in several other developed countries . the indications for plasma transfusion include reversal of a significant coagulopathy in a bleeding patient or one who is about to undergo a surgical procedure , bleeding in the setting of multiple factor deficiencies , or in the rare patient with a deficiency of a factor for which there is no viral - inactivated / recombinant concentrate available . neither its use as a replacement fluid for therapeutic aphersis in thrombotic thrombocytopenic purpura ( ttp ) patients , nor the pharmacological procoagulant agents ( such as rfviia ) that might also be used to reverse a significant coagulopathy will be discussed in this report . the use of plasma as part of fixed ratio rbc : plasma protocols for the resuscitation of trauma patients is controversial and is extensively reviewed in reference . often times the question facing the clinician when trying to decide whether to transfuse plasma is : when is a coagulopathy significant enough for the benefits of plasma transfusion to outweigh its potential adverse events such as trali and volume overload ? to answer this question , 2 important meta - analyses have been performed . segal and dzik analyzed 25 studies of variably coagulopathic patients undergoing a variety of minor procedures including liver biopsy , kidney biopsy , central vein cannulation , paracentesis and others and asked the question , does the peri - operative pt / inr predict the risk of major bleeding during these procedures ? the vast majority of the reports included in this meta - analysis were observational studies , and only 1 was a clinical trial . the authors concluded that the strongest evidence suggesting that the pre - procedure inr does not likely predict the bleeding risk lies with central vein cannulation , although just how coagulopathic patients can be and still tolerate the procedure safely has not been elucidated . as for the literature on the other procedures , the variability in study size and quality makes drawing firm conclusions about the bleeding risk difficult . in 14/25 of the studies included in the meta - analysis , a control group of patients with normal laboratory parameters of coagulation were also included in the report . in these studies , the risk of bleeding between the 2 groups of patients undergoing the same procedure could be estimated . although the confidence intervals of some of these comparisons were relatively large due to the small number of patients in these studies , there was no significant difference in the risk of major bleeding between the patients who underwent these varied procedures with and without coagulopathies . while further study is required , especially for coagulopathic patients undergoing kidney biopsy , overall it would appear that patients with mild coagulopathies undergoing various surgical procedures might not require normalization of their laboratory coagulation parameters with plasma to reduce their risk of bleeding . for further discussion of why the pt / inr does not necessarily predict the risk of peri - operative bleeding , see reference . the second meta - analysis can shed some light on the question , if plasma is administered to peri - surgical patients , does it have a beneficial effect in reducing transfusion requirements or surgical blood loss ? stanworth and colleagues searched various medical publication databases looking exclusively for randomized controlled trials ( rct ) where ffp was the therapeutic intervention . while 57 such trials were identified , 19 were focused on surgical or potentially surgical patients ; there were 11 studies based on cardiovascular surgery in children and adults , 3 studies on liver disease with or without gi bleeding , and 1 study each on warfarin reversal with intracerebral hemorrhage , massive transfusion , hip surgery , hysterectomy , and renal transplantation . in only 12/19 of these studies ( 10 cardiovascular surgery , 1 liver disease , and the lone study on hysterectomy ) did the patients in the control arm receive either no ffp or a colloid volume expander , thus allowing a true evaluation of the effect of the ffp administration . most of these studies concluded that ffp administration did not reduce blood loss or transfusion requirements . to explain why prophylactic plasma administration does not reduce peri - operative bleeding , consider a study of 22 non - trauma patients who received a total of 68 units of ffp ( 500 ml units ) . on average each recipient received approximately 2 units of ffp , and this dose was > 10 ml / kg for each recipient . the average pre - transfusion inr was 1.37 ( range 1.1 - 1.6 ) , and the average decrease in inr was a clinically insignificant 0.03 per unit of ffp transfused . 1 demonstrates a theoretical relationship between pt / inr and the concentration of clotting factors ; a recipient with inr=1.37 would likely have clotting factor concentrations in excess of 50% of normal ( fig . 1 , point b ) . from the experience with patients with single clotting factor deficiencies such as hemophilia a and b , levels of clotting factors > 30% are sufficient for normal hemostasis . thus the recipients with an inr=1.37 were unlikely to have bled excessively even in the absence of plasma transfusion , and the slight reduction in inr did not confer any improvement in the recipient 's hemostatic potential . furthermore , given that some ffp units can have inrs approaching that of these recipient 's , it is not surprising that the decreases in the post - transfusion inrs were quite modest . abdel - wahab and colleagues studied ffp recipients from a wide variety of hospital wards , and with and an assortment of clinical diagnoses . in this retrospective study , 324 ffp units were transfused to 121 recipients who had relatively low pre - transfusion inrs , 1.1 - 1.85 , and who had post - transfusion inrs performed within 8 hours of the transfusion ( the approximate therapeutic duration of plasma ) . once again , only small median reductions in the post - transfusion pt and inr were seen ; 0.20 seconds and 0.07 , respectively . only 1 of the 324 recipients completely corrected their pt and inr , and only 15% of patients corrected their pt / inr to 50% of normal . it is not surprising that patients with lower inrs ( 1.1 - 1.5 ) were no more likely to correct their coagulation parameters than those with slightly higher inrs ( 1.5 - 1.85 ) , and these authors did not find a correlation between the magnitude of the change in the inr and the dose of ffp administered ; recipients of 1 unit of ffp were no more likely to correct their inr by 50% than those who received 2 units . the latter finding can be explained by considering that 1 unit of ffp ( approximately 225 ml ) , when administered to a 70 kg recipient , translates into a dose of 3.2 ml / kg . receipt of 2 units of ffp by a 70 kg recipient would amount to a dose of 6.4 ml / kg - both doses are significantly below the recommended 10 - 15 ml / kg of plasma to correct a coagulopathy . furthermore , each recipient in this study received on average 2.7 units of ffp , and assuming each recipient weighed 70 kg , the average dose of ffp would only have been 8.7 ml / kg . thus the low rate of correction could be attributable to the small volume of ffp transfused . additionally , consider that the plasma volume of a 70 kg recipient with a hct of 0.40 is approximately 3,000 ml . transfusing 450 ml of plasma ( 2 regular units ) would increase the concentration of clotting factors by 15% ; according to fig . 1 , a 15% increase in clotting factors in a recipient with an inr of 1.5 would only amount to a small decrease in their inr ( fig . 1 , point c ) . a recipient with an inr=1.5 still has a considerable reserve of clotting factors and a slight increase in their concentration is unlikely to be important for hemostasis . this might also explain the popular perception of the success of prophylactically administering plasma to recipients with modestly elevated inrs ; when these patients tolerate the surgical procedure without excessive bleeding , this positive outcome is attributed to the administration of the plasma . in reality , these recipients were unlikely to have had a coagulopthic bleed owing to their significant reserve of clotting factors ( even with their slightly elevated inr ) . another study of plasma recipients in canada also found a minimal inr response when mildly coagulopathic patients were transfused with small quantities of ffp . a study of patients with liver cirrhosis who were transfused with ffp was performed in 2 parts : a retrospective review of the charts of 80 patients who received ffp to reverse a pt prolonged by > 3 seconds , and a prospective analysis of 20 patients who received ffp with the same laboratory abnormality . the indications for ffp ranged from pre - procedure prophylaxis , acute bleeding , or prophylactic reversal of a prolonged pt in non - bleeding recipients . the etiology of the cirrhosis in the majority of these patients was either alcohol use or a combination of hepatitis c and alcohol use . these investigators found only a small number of ffp recipients who corrected their pt to within 3 seconds of normal after ffp transfusion ( 12/100 ) . interestingly , the 2 recipients with the highest pre - transfusion pts who received 6 units of ( pt=23.8s and 22.9s ) ffp demonstrated on average a 9.75s reduction in their pt after transfusion . the 2 recipients with the lowest pt who also received 6 units of ffp ( both had pt=15.5s ) both demonstrated only a 0.4s reduction after transfusion . while the authors did not convert pt into inr , a pt=15.5s roughly translates into an inr of approximately 1.3 - 1.5 depending on the sensitivity of the pt reagent , once again indicating that in patients with a relatively mild coagulopathy , minimal correction is expected after plasma transfusion . it might be hypothesized that the low rates of pt / inr correction after plasma infusion is related to the fact that the patients in these clinical studies have been quite sick . however , a different type of study evaluating the recovery of factor vii in normal ffp compared to a pathogen inactivated ( s-59+uva light ) form of ffp in healthy volunteers showed a similar magnitude of pt correction as the earlier studies . in this study , 27 healthy volunteers donated approximately 2.5 l of autologous plasma over time and were then administered warfarin to deplete their levels of vitamin k - dependent clotting factors , which includes factor vii . after they were anticoagulated to inrs between 1.5 - 2.0 they were reinfused with 1 l of either their unaltered plasma or their plasma after it had undergone pathogen inactivation after one final dose of warfarin ( fig . this dose of plasma was on average 12 ml / kg for all study participants . the investigators then measured a series of pharmacokinetic parameters of factor vii , along with a pt . immediately prior to ffp administration , the average pt was 15 seconds , and within 1 hour after ffp administration , it had dropped to approximately 13 seconds ( fig . this 2 second decrease in pt represents only about 50% correction compared to the average pre - anticoagulation baseline pt of 11.5 seconds . at the end of the study period , all volunteers were given oral vitamin k which resulted in a complete reversal of their pt prolongation which should serve as a reminder that in situations when reversal of a coagulopathy is not urgent , non - human source medications such as vitamin k could be employed ( fig . 2 , point d ) . interestingly , while only 15% of the sick patients in the study by abdel - wahab et al . corrected their pt / inr by 50% , the average pt correction by the healthy volunteers in this study was 50% . this 50% correction of the pt could have been predicted from fig . 1 : again , if the average plasma volume of the healthy recipients was 3,000 ml , and they received 1,000 ml of ffp , then their clotting factors should have been increased by 33% . a 33% increase in clotting factors is consistent with a decrease of about 2 seconds ( from 15 to 13 seconds ) ( fig . 1 , from point b to d ) . while these healthy volunteers   received on average about 3 ml / kg more ffp than those reported by abdel - wahab et al . , perhaps other factors are involved in determining a recipient 's propensity to correct their pt / inr after plasma infusion . furthermore , holland et al . demonstrated that some patients with mildly prolonged inrs ( 1.3 - 1.6 ) will effect some degree of correction without plasma therapy by simply having their underlying diseases treated and receiving supportive care . another way to consider the effect of transfusing plasma to patients with an elevated inr is to remember that the response of a patient who is otherwise stable ( i.e. , not bleeding ) depends mostly on the pretransfusion inr . 3 which is based on an equation derived from a clinical study of 140 adults who received jumbo apheresis plasma units ( 500 ml ) . these patients were not involved in trauma , not in the operating room , did not have dic and were not treated with prothrombin complex concentrates ( pcc ) . clearly the largest reductions in the inr are predicted to occur in recipients with the highest starting inrs ; in theory as the inr falls below 1.5 , continued transfusion with plasma is predicted to effect only a small and clinically insignificant change in the inr . at an inr1.5 the recipient is being exposed to all the adverse risks of plasma therapy without any clinical benefit . perhaps the currently employed dose of plasma to reverse coagulopathies is insufficient to effect a significant reduction in the pt / inr . a small welsh study extensively evaluated the laboratory parameters of hemostasis including factor levels , pt and ptt in icu patients before and after receiving a median dose of either 12.2 ml / kg ( n=10 ) or 33.5 ml / kg ( n=12 ) of ffp . they found much larger increases in the post - transfusion factor levels and decreases in the pt and ptt ( especially the ptt ) in the recipients of the higher dose of ffp . while this study did not investigate the clinical impact of higher levels of clotting factors or lower pt and ptt values on these recipients , it is possible that the currently recommended dose of 10 - 15 ml / kg is insufficient to reverse a coagulopathy . based on clotting factor levels , ffp , tp and fp24 are equivalent products for reversing significant coagulopathies . emerging evidence suggests that many peri - operative patients with slightly elevated pt / inrs do not suffer from major bleeding at a higher rate than those without coagulopathies , although further study is required to delineate when correction is required . the generally employed threshold for plasma transfusion is inr1.6 because at higher values the concentrations of clotting factors begin to approach critical levels where hemostasis might be negatively affected . administration of plasma to recipients with an inr1.5 is unlikely to produce a clinical benefit and unnecessarily exposes patients to the risks of plasma transfusion . the routine administration of small quantities of plasma to peri - operative patients with minor coagulopathies probably confers very little hemostatic benefit and potentially subjects the recipients to numerous adverse reactions including volume overload and trali ; conversely , higher doses of plasma than are currently recommended might be necessary to reverse a significant coagulopathy .
although traditionally fresh frozen plasma ( ffp ) has been the product of choice for reversing a significant coagulopathy , the modern blood bank will have several different plasma preparations which should all be equally efficacious in reversing a significant coagulopathy or arresting coagulopathic bleeding . 
 emerging evidence suggests that for a stable patient , transfusing plasma for an inr1.5 does not confer a hemostatic benefit while unnecessarily exposing the patient to the risks associated with plasma transfusion . this review will discuss the various plasma products that are available and present some of the current literature on the clinical uses of plasma 
 .