Indications for Transfusion 211

brinolytic agents, particularly aprotinin, are being used

more commonly in cardiac surgery. Those agents signifi-
cantly decrease postoperative bleeding and transfusion
requirements, and some cardiac bypass specialists have Patients receiving platelet
suggested that aprotinin may be more effective than plate- inhibitors (such as clopi-
dogrel) or GPIIb/IIIa
lets in facilitating postbypass hemostasis. inhibitors at the time of car-
On the other side of the cardiac bypass equation is the diothoracic surgery may
increasing use of platelet inhibitors, such as clopidogrel, as require platelet transfusions
for several days.
well as GPIIb/IIIa inhibitors, to reduce thrombotic risk in
patients with coronary artery disease. When patients tak-
ing those agents require emergent cardiac surgery, they are
at increased risk of bleeding and may require prolonged
(several days) platelet support. Optimal management of
patients in the setting of cardiac surgery is under study by
several large clinical trials networks.
It is important to note that uremic platelet dysfunction is
not amenable to correction by platelet transfusion because
transfused platelets become “uremic platelets” almost
immediately after infusion. Uremic platelet dysfunction is
Uremic platelet dysfunction
discussed in more detail in Chapter 11: Special Transfu- is not amenable to correction
sion Situations. by platelet transfusion.

Fresh Frozen Plasma

Fresh Frozen Plasma (FFP) contains significant amounts of
all of the coagulation proteins, both procoagulant and
anticoagulant. Thus, FFP is indicated to correct deficien-
cies of coagulation factors for which no specific factor
concentrates are available. Whenever possible, alternative
therapies, such as vitamin K for reversal of warfarin effect,
should be tried first. Factor concentrates are preferable to FFP is generally indicated for
prophylactic use only when
FFP in the case of single-factor deficiencies because such the PT or PTT is 1.5 times the
concentrates are all virus inactivated in some way and, midpoint of normal or
thus, carry far less infectious disease risk than does FFP. higher.
Published guidelines for the prophylactic use of FFP in
patients scheduled for surgery or other invasive procedure
generally focus on PT and/or aPTT values 1.5 times or
more above the midpoint of the reference range for the test
in question. Studies dating back to the 1950s and 1960s
have demonstrated that certain surgical procedures (eg,
cholecystectomy) could be safely performed on patients
taking warfarin with PT values in the therapeutic range.
Later studies likewise demonstrated no increase in bleed-
ing after paracentesis and thoracentesis in patients with a
PT or aPTT up to 1.5 to 2.0 times the midpoint of normal
212 Practical Guide to Transfusion Medicine
PT and aPTT are, at best,
only crude prognosticators of
bleeding risk and some stud-
ies even question whether
they have any utility at all as
predictors.
A PT of 1.5 times midnormal
corresponds to an INR of
2.0, not an INR of 1.5.
range. Another study found PT and aPTT to be good pre-
dictors of surgical bleeding in massively transfused trauma
patients only when the PT or aPTT exceeded 1.5 times the
control value.
Although the figure of 1.5 times midnormal is often
quoted and appears in published guidelines for FFP use,
one must remember that PT and aPTT are, at best, crude
prognosticators of surgical bleeding. Some studies ques-
tion whether they have utility at all as predictors. For
example, in 1980, Ewe studied patients undergoing open
liver biopsy, looking for parameters that correlated with
prolonged liver bleeding time. The author found that none
of the parameters examined, including PT, correlated with
bleeding. A systematic literature review by Segal and Dzik
published in 2005 addressed the issue of whether a pro-
longed PT/international normalized ratio (INR) correlates
with the risk of bleeding at the time of invasive procedures;
the study concluded that there are insufficient data to sup-
port the use of PT/INR to predict bleeding risk.
Burns et al provide a possible explanation for the lack of
correlation between mild to moderately prolonged PT/
aPTT and increased risk of bleeding. When the authors
measured PT or aPTT on two plasma samples, each 50%
deficient in a single (different) coagulation factor, the test
results were within the reference range. However, when
the two 50%-deficient plasma samples were mixed, result-
ing in 75% levels of each factor, the PT and aPTT of the
resulting sample were prolonged—likely reflecting the fact
that the PT and aPTT are designed to be particularly sensi-
tive to simultaneous deficiency of multiple factors.
One important caveat to remember with respect to PT
values is that a PT of 1.5 times midnormal is not the same
as an INR of 1.5. In actuality, an INR of 2.0 typically corre-
sponds to a PT 1.5 times midnormal. This correspondence
makes practical sense if one considers that target ranges
for PT and INR in therapeutic warfarin use are 1.5 to 2.5
times normal for PT, which corresponds to a range of 2.0
to 3.0 for INR.
It is important to note that even when those guidelines
are met, the clinical efficacy of prophylactic FFP remains
in question. A recent systematic review of 57 randomized
controlled trials (RCTs) involving the use of FFP for a vari-
ety of indications concluded that for most clinical situa-
tions there was insufficient RCT evidence to support or
refute the efficacy of treatment with FFP. In response to the
paucity of RCT studies examining the efficacy of FFP in
patients with mildly prolonged PT/INR, the NIH Transfu-
 Indications for Transfusion 213

sion Medicine/Hemostasis Clinical Trials Network has

embarked on a large multicenter RCT designed to com-
pare transfusion of FFP with no treatment in patients
undergoing invasive hepatic procedures with a preproce-
dure INR of 1.3 to 1.9. That study is ongoing.
Two final points merit mention. First, FFP is not effective
at correcting INRs that are only minimally elevated, largely
because the correlation between PT or aPTT and coagula-
tion factor levels is nonlinear, particularly at factor levels FFP is not effective in cor-
below 30% (which corresponds to mild-to-moderate pro- recting INRs that are only
longation of PT). Second, when the INR of FFP units was minimally elevated.
measured, INRs as high as 1.3 were noted—not surprising
given that FFP is a biological product collected from clini-
cally healthy donors, some of whom will have lower levels
of coagulation factors than others. Thus, one cannot
expect FFP to “normalize” only minimally prolonged INR
values because the product itself might have a comparably
“prolonged” INR, if one were measured on the contents of
the bag. Indeed, a study published in 2006 found that
when FFP was transfused to patients with INR measure-
ments between 1.1 and 1.85, fewer than 1% of patients
exhibited complete correction of INR and only 15% cor-
rected halfway to normal.
In any event, if FFP is to be used, the timing and dose FFP should be transfused
should be carefully considered. If correction of a mark- immediately before it will be
edly abnormal PT or aPTT is required before surgery, needed because some fac-
tors (especially Factor VII)
FFP should be given immediately before the patient is have very short in-vivo half-
called to the operating room, not the night before. Sev- lives (3-5 hours).
eral coagulation factors have very short half-lives, and if
FFP is given 8 hours preoperatively, those factors will be
largely gone from the circulation by the time surgery
begins. In particular, Factor VII has a biologic half-life of
3 to 5 hours, meaning that very little Factor VII will
remain after 8 hours.
Likewise, the dose should be based on the patient’s size,
with a common rule of thumb being to begin by infusing
10 mL/kg of recipient body weight and then measuring
posttransfusion PT, aPTT, or both 15 to 30 minutes after
infusion. If substantial correction of the coagulopathy has
not taken place, further FFP can be given. Because a unit An appropriate initial dose of
FFP is 10 mL/kg. This dose
of FFP has a volume of approximately 200 mL, an appro- should raise the factor levels
priate starting dose for a 70-kg patient would be 3 to 4 by about 25% unless the
units. Patients with liver failure may require substantially patient is bleeding or con-
suming factor in some other
higher starting doses because they are incapable of pro- way (eg, DIC).
ducing any coagulation proteins, most of which are pro-
duced in the liver. Some authorities recommend a starting
dose of 20 mL/kg for liver failure patients.