Coagulation and Transfusion Medicine / Filtration of Plasma
The Effect of Filtration on Residual Levels of Coagulation
Factors in Plasma
Hiba S. Alhumaidan, MD,1 Tracey A. Cheves, MT,1 Stein Holme, PhD,2 and Joseph D. Sweeney, MD1
Key Words: Blood filtration; Clotting factors
DOI: 10.1309/AJCPRRESG7PGIAH5
Abstract
Leukoreduced blood components are commonly
manufactured via filtration. There are specifications
for the residual leukocyte content of any final cellular
blood component but not for residual clotting factors.
Leukoreduced and nonleukoreduced platelet-poor
plasma products were manufactured from filtered vs
unfiltered platelet-rich plasma, respectively, using
platelet leukoreduction filters. The leukoreduced
plasma showed lower levels of factor VIII (75% ± 16%
vs 88% ± 18%, P ≤ .05), factor XI (86% ± 9% vs 96%
± 10%, P ≤ .01) and factor VII (87% ± 14% vs 98%
± 11%, P ≤ .01). No difference was seen with factor
X, factor V, or fibrinogen. Plasma filtered through
a whole blood filter showed a reduction in factor V
(105% ± 12% vs 124% ± 10%, P ≤ .01) but a minimal
reduction in factor VIII (80% ± 5% vs 82% ± 6%, P =
.04). Filtration can alter the residual levels of clotting
factors to a variable extent in manufactured plasma,
most noticeably factors V, VII, VIII, and XI.
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Whole blood donations undergo centrifugation and filtration during the manufacture of different components.1 Prestorage leukoreduction by filtration is a common processing step
that can be performed on whole blood (WB), intermediate
products such as platelet-rich plasma (PRP), or the final blood
product.1,2-4 In recent years, universal leukodepletion of cellular products and, in some countries, acellular components has
become a widespread practice.5 Standards and specifications
exist for the residual cellular content of the final leukoreduced
blood component, though these differ slightly between the
United States and Europe.1,6,7 No current standards exist for
residual leukocytes in leukoreduced plasma products in the
United States. However, the French standard is less than 106/L.8
No specific standards exist regarding the residual clotting factor content for the 2 licensed plasma products manufactured from WB in the United States, fresh frozen plasma
(FFP), and 24-hour frozen plasma (FP24), leukoreduced or
otherwise. However, in Germany the requirement is that the
plasma contains 70% of the original level of factor (F) VIII:C
after thawing and that the concentration of FVIII:C exceed
0.7 IU/mL9. At this time, plasma frozen and manufactured
after storing WB or PRP for 24 hours at room temperature
(24RTFP) is an unlicensed product but could conceivably be
licensed in the future.10
Prestorage filtration of any of these plasma products
will occur if the whole blood is filtered, the PRP is filtered
using an in-line system, or if the platelet-poor plasma (PPP)
is filtered before freezing. Previous studies have examined
the effect of whole blood or RBC filters on the clotting factor
content of the final plasma product, both immediately after
thawing and after storage in the liquid state at 1°C to 6°C.1119 Reports on the effect of plasma filters on plasma proteins
© American Society for Clinical Pathology
Coagulation and Transfusion Medicine / Original Article
are limited,16,17 and to our knowledge, except for 1 report on
a prototype PRP filter, no other reports have described the
effect of platelet filters.19 In a previous report, we examined
the stability of coagulation factors in leukoreduced FFP and
compared it with that of leukoreduced 24RTFP.10 The aim of
this study was to compare prestorage leukoreduced plasma
manufactured using PRP as an intermediate product with
nonleukoreduced plasma to examine whether leukofiltration
had an effect on residual clotting factors and to systematically
evaluate the difference between plasma filtered through a WB
filter and a platelet filter.
Materials and Methods
These studies were approved by the institutional research
board of The Miriam Hospital (Providence, RI). WB donations were collected from donors who met all American
Association of Blood Banks and US Food and Drug Administration (FDA) criteria into 500-mL containers using citrate
phosphate double dextrose as anticoagulant.1 The initial step
A
was the centrifugation of the WB within 8 hours by a soft spin
(1,900g for 4.5 minutes) using a RC3BP Sorvall Centrifuge
(Fisher Scientific, Pittsburgh, PA) to produce PRP and an
RBC concentrate stored in AS3. Two different manufacturing
schemas were then used.
Schema 1: Leukoreduced Plasma Products
PRP was leukoreduced by inline filtration (Leukotrap
RC-PL, Pall Medical, Covina, CA).2 Two ABO-identical leukoreduced PRPs were then pooled and subsequently divided
into 2 equal aliquots yielding identical pairs of PRP. One of
the paired PRP products was centrifuged within 8 hours on
the day of collection by a hard spin centrifugation (2,350g
for 8 minutes) to produce PPP and platelet concentrate. The
PPP was then frozen at –18°C, yielding leukoreduced FFP.
The second of the paired PRP products was left unagitated
at room temperature for an additional 18 to 24 hours. On the
day after collection, this PRP was centrifuged by a hard spin
centrifugation to PPP and a platelet concentrate. The PPP was
then frozen at –18°C, yielding leukoreduced 24RTFP. This
schema is illustrated in ❚Figure 1A❚.
B
WBD
WBD
WBD
WBD
PRP
PRP
PRP
PRP
8 hours
Pooled
leukoreduced
PRP
Pooled
nonleukoreduced
PRP
Nonleukoreduced Nonleukoreduced
PRP
PRP
Leukoreduced
FFP
Nonleukoreduced
FFP
Leukoreduced
24RTFP
8-24 hours
Leukoreduced Leukoreduced
PRP
PRP
8-24 hours
8 hours
Leukoreduced Leukoreduced
PRP
PRP
Nonleukoreduced
24RTFP
❚Figure 1❚ A schematic representation of both manufacturing processes yielding leukoreduced (A) and nonleukoreduced (B)
plasma products. 24RTFP, plasma frozen after 24-hour room temperature storage; FFP, fresh frozen plasma; PRP, platelet-rich
plasma; WBD, whole blood donation.
© American Society for Clinical Pathology
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Schema 2: Nonleukoreduced Plasma Products
In this schema, the PRP was expressed without passing
through a PRP filter, but all other manufacturing aspects
were identical to schema 1, yielding pairs of nonleukoreduced FFP and nonleukoreduced 24RTFP. This schema is
illustrated in ❚Figure 1B❚.
Both schema 1 and schema 2 manufactured identical
pairs of frozen plasma products for comparative studies that were the subject of previous reports.10,20 Frozen
plasma pairs from both schemas were stored at –18°C for
a minimum of 54 days before testing for schema 1 and 36
days before testing for schema 2. Pairs were then thawed
in a waterbath at 37ºC. Coagulation factor assays were performed on the day of thaw and on day 5 and day 7 of liquid
storage at 1°C to 6°C after thawing.
Plasma Filtration Studies Using WB and Platelet Filters
Five pairs of nonleukoreduced FFP and 24RTFP product from schema 2 were used in this experiment after the
plasma had been frozen for at least 2 months. Paired units
were thawed, pooled, and a sample taken from the pool
(prefiltration sample). Immediately afterwards, the pool
was divided into 2 identical aliquots. One aliquot was filtered using a whole blood filter (WBF3, Pall Medical) and
the second aliquot using a platelet filter (LPS1, Pall Medical). After filtration, the liquid pairs were stored at 1°C to
6°C for 7 days. Postfiltration samples were taken on day
0 (the day of thaw), day 3, day 5, and day 7 for selected
Nonleukoreduced
FFP
clotting factor assays. The post-thaw processing and testing
schema is illustrated in ❚Figure 2❚.
Coagulation Assays
The clotting factor assays performed were prothrombin
time (PT), activated partial thromboplastin time (APTT),
FV, FVII, FVIII, FX, FXI, fibrinogen, antithrombin III
(ATIII), protein C, and free protein S.
The PT and aPTT were measured using an automated
coagulation analyzer and manufacturer’s reagents in a
device that uses optical endpoint for clot detection (MDA
II, TCoag, Wicklow, Ireland). Assays for FV, FVII, FVIII,
FX, and FXI were all conducted using a 1-stage chronometric assay with factor-deficient plasma reagents (Precision BioLogic, Dartmouth, Nova Scotia, Canada) in the
same analyzer. Fibrinogen was measured using the Clauss
method (Fibriquik, TCoag). ATIII and protein C were measured using a chromogenic assay with reagents (Diagnostica
Stago, Parsippany, NJ) in the MDA II. Free protein S assay
was performed using an enzyme-linked immunosorbent
assay (Diagnostica Stago).
Statistical Analysis
Results were entered into an Excel spreadsheet (Microsoft, Redmond, WA), exported into a statistical application
(Epistat, Richardson, TX) and descriptive statistics derived.
Data were analyzed using independent t tests or paired t
tests as appropriate. Pearson correlation coefficient was
Nonleukoreduced
24RTFP
Pooled
nonleukoreduced
plasma
Identical
aliquots
Nonleukoreduced
plasma
Leukoreduction
by filtration
Prefiltration
sample
Nonleukoreduced
plasma
WB
filter
PRP
filter
Leukoreduced
plasma
WB filter
Leukoreduced
plasma
PRP filter
Postfiltration
samples
D0, D3, D5, D7
❚Figure 2❚ A schematic representation of the plasma filtration experiment using whole blood and platelet filters yielding paired
filtered plasma products. 24RTFP, plasma frozen after 24-hour room temperature storage; D0, day of filtration; D3, day 3 of
liquid storage after filtration; D5, day 5 of liquid storage after filtration; D7, day 7 of liquid storage after filtration; FFP, fresh
frozen plasma; PRP, platelet-rich plasma; WB, whole blood.
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© American Society for Clinical Pathology
Coagulation and Transfusion Medicine / Original Article
used in univariant analysis. Statistical significance was
defined as a P value less than or equal to .05.
Results
Sixty WB donations were processed using both manufacturing schemas for a total of 120 plasma products. Ten paired
plasma products (FFP and 24RTFP), 5 group O and 5 group
A, were chosen at random from both schema 1 and schema 2,
then thawed and tested.
❚Table 1❚ shows the comparison of 20 leukoreduced
plasma products (both FFP and 24RTFP) manufactured
using schema 1 with 20 nonleukoreduced plasma products
manufactured using schema 2 (both FFP and 24RTFP). The
data from both product types were combined for clarity after
the initial assessment showed a similar effect of filtration on
both FFP and 24RTFP. On day 0 (day of thaw), all clotting
factor levels, with the exception of FX, FV, and fibrinogen,
appeared reduced in the filtered plasma. The aPTT was
longer in the filtered plasma, reflecting these changes. With
liquid storage, there was a large decline (20%-30%) in factor FV and FVIII:C in both product types, as illustrated in
❚Figure 3❚, with lesser declines in the other clotting factors
(5%-10%). The pattern of differences between the product
types persisted on both day 5 and day 7, with statistical
significance seen with FVIII, FXI, FV, and ATIII on either
of these days and on day 5 with FVII, which may be an
anomalous result related to the phenomenon of cold activation of FVII.
❚Table 1❚
Coagulation Assay Results in the Filtered (Schema 1) and Nonfiltered (Schema 2) Plasma Unitsa
Day 0
Day 5 Day 7
Assays
Filtered Plasma Nonfiltered Plasma
Filtered Plasma Nonfiltered Plasma
Filtered Plasma Nonfiltered Plasma
PT (11-13.2 sec )
APTT (21-33 sec )
Fibrinogen (150-480 mg/dL)
FV (60%-160%)
FVII (50%-150%)
FVIII (50%-180%)
FX (80%-150%)
ATIII (80%-130%)
FXI (60%-160%)
13.8 ± 0.5
33.9 ± 2.5
258 ± 43
122 ± 13
87 ± 14
75 ± 16
96 ± 10
100 ± 6
86 ± 9
16 ± 1.2
37.5 ± 2.7
253 ± 43
83 ± 11
75 ± 37
51 ± 9
91 ± 11
96 ± 6
84 ± 8
16.4 ± 1.2
39 ± 3
253 ± 41
74 ± 10
76 ± 42
47 ± 9
89 ± 15
94 ± 6
88 ± 13
13.7 ± 0.5
27.6 ± 2.4b
269 ± 25
125 ± 13
98 ± 11b
88 ± 18c
95 ± 9
106 ± 8 b
96 ± 10b
16.2 ± 1.7
30.6 ± 2.7b
257 ± 27
100 ± 19b
99 ± 60
61 ± 10b
95 ± 11
103 ± 8b
97 ± 11b
16.6 ± 2.1
31.6 ± 3.6b
263 ± 27
84 ± 19b
101 ± 51c
59 ± 9b
93 ± 13
102 ± 9b
97 ± 11c
APTT, activated partial thromboplastin time; ATIII, antithromboplastin III; FV, factor V; FVII, factor VII; FVIII, factor VIII; FX, factor X; FXI, factor XI; PT, prothrombin time.
a Coagulation results are from the day of thaw (day 0) and day 5 and day 7 of liquid storage (n = 20). Data were analyzed using independent t tests. Data are the mean ± 1 standard
deviation. Reference ranges are given in parenthesis.
b P ≤ .01, filtered vs unfiltered products.
c P ≤ .05, filtered vs unfiltered products.
B
160
160
140
140
120
120
Factor VIII (%)
Factor V (%)
A
100
80
60
40
100
80
60
40
Filtered plasma
Nonfiltered plasma
20
0
Filtered plasma
Nonfiltered plasma
20
0
Day 0
Day 5
Day 7
Day 0
Day 5
Day 7
❚Figure 3❚ A graphic representation of the decline in factor V (A) and factor VIII (B) in both filtered and nonfiltered thawed
plasma product. Day 0, day of thaw; day 3, day 3 of liquid storage; day 7, day 7 of liquid storage.
© American Society for Clinical Pathology
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❚Table 2❚
Coagulation Assay Results in Pre- and Postfiltered Paired
Plasma Productsa
Postfiltration Day 0
Assays
Prefiltration WB Filter
PRP Filter
FV (60%-160%)
FVIII (50%-180%)
Fibrinogen (150-480 mg/dL) Protein C (78%-170%)
Protein S (60%-140%)
126 ± 12
82 ± 6
316 ± 18
109 ± 19
77 ± 8
105 ± 12b
80 ± 5
309 ± 16
109 ± 21
64 ± 4c
124 ± 10b
76 ± 4c
314 ± 14
109 ± 20
64 ± 8c
FV, factor V; FVIII, factor VIII; PRP, platelet-rich plasma; WB, whole blood.
a Coagulation assays were conducted using WB filter or PRP filter (n = 5). Data were
analyzed using paired t tests. Data are the mean ± 1 standard deviation. Reference
range for normal values are given in parenthesis.
b P ≤ .01, comparing both filters.
c P ≤ .01, comparing pre- and postfiltration products.
B
140
140
120
120
100
100
Factor VIII (%)
Factor V (%)
A
❚Table 2❚ shows the results of the filtration studies
using the WB and platelet filters. Both filters caused a small
decrease in protein S, and the platelet filter caused a small
decrease in FVIII:C. A statistically insignificant reduction
in fibrinogen was evident, which was similar to the differences observed in Table 1. Of particular note was the 20%
to 30% reduction in FV after filtration using the WB filter,
which was not seen with the platelet filter. During liquid
storage to day 7, fibrinogen remained stable but levels of
FV, FVIII:C, and protein C declined. These changes are
illustrated in ❚Figure 4❚. FV showed a gradual decrease
of about 40% to day 7 after filtration, but the difference
between the 2 filtered products reduced with liquid storage
was not statistically significant after day 3. FVIII:C showed
a more abrupt decline between day 0 and day 3, with little or
no change after day 3. Protein C was stable until day 3, and
80
60
40
WB filter
PRP filter
20
60
40
WB filter
PRP filter
20
0
0
Prefiltration
D0
D3
D5
Prefiltration
D7
C
D0
D3
D5
D7
D
140
140
120
120
100
100
Protein C (%)
Free Protein S (%)
80
80
60
40
WB filter
PRP filter
20
0
Prefiltration
D0
D3
D5
D7
80
60
40
WB filter
PRP filter
20
0
Prefiltration
D0
D3
D5
D7
❚Figure 4❚ A graphic representation of clotting factors V (A), VIII (B), free protein S (C), and protein C (D) before and after
filtration and up to 7 days of liquid storage. D0, day of filtration; D3, day 3 of liquid storage after filtration; D5, day 5 of liquid
storage after filtration; D7, day 7 of liquid storage after filtration; PRP, platelet-rich plasma; WB, whole blood.
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© American Society for Clinical Pathology
Coagulation and Transfusion Medicine / Original Article
then declined by about 10%. Protein S showed a decline of
approximately 13% after filtration for both filter types, but
levels increased after liquid storage to prefiltration levels
by day 5 to day 7, possibly representing dissociation of free
protein S from protein S bound to C4B-binding protein.
Discussion
Our results show that leukoreduction filters have a variable effect on the residual clotting factor content of manufactured plasma products. No statistically significant differences were observed with FX, fibrinogen, or protein C; small
changes were observed with ATIII and protein S; and larger
differences were observed with FVII, FXI, and FVIII. In the
case of FV, a significant decrease was observed only with the
WB filter. The mechanism of these changes is unclear but is
unlikely to be solely because of simple protein attachment to
a foreign surface. The proprietary coating of these polyester
filter surfaces is probably a contributing factor, which confers
a degree of selectivity in clotting factor adherence.
Nine previous reports, mostly from Europe, have
addressed changes in clotting factors after the leukofiltration
of either WB or plasma. Heiden et al11 studied the effect of
WB filters from 5 different manufacturers, 4 of which were
polyester filters and 1 was a polyurethane filter. No statistically significant reductions in clotting factors were observed
after filtration. Kretzschmar et al,12 using a polyurethane WB
filter, documented a postfiltration increase in aPTT and an
associated decline in FVIII:C, but this was only significant
after the plasma was stored at room temperature for 18 hours
before processing. Williamson et al,13 using WB filters,
assessed filtration after either warm (room temperature) or
cold (1°C-6°C) storage and showed a reduction of FV (30%)
with filtration. A reduction in FVIII was observed with WB
filtration only after warm storage for 2 to 4 hours before processing. Solheim et al14 used a WB filter and demonstrated
a lower but more stable FV and FVIII in the filtered product
after thawing and attributed this to platelet retention on the
WB filter with subsequent activation and binding of FV.
Runkel et al15 studied 2 different WB filters, a positively
charged polyester filter and an uncharged polyester filter.
Postfiltration fibrinogen, FV, and FVIII:C levels were measured and were found to be not different from those of a
control population, but no prefiltration samples were tested.
Cardigan et al16 evaluated the effect of 5 WB filters and 2
plasma filters on the residual clotting factors of leukoreduced
FFP. Statistically significant losses in factors V, VIII, IX, XI,
and XII were observed with 2 of the 5 WB filters. One of
the WB filters appeared to cause an increase in FV, another
WB filter an increase in fibrinogen; both were attributed
to release from platelet alpha granules. The plasma filters
© American Society for Clinical Pathology
showed a variable reduction in FVIII, FIX, and FXI. Of note,
there was no effect on FV using the 2 plasma filters. Chabanel et al17 studied 4 different plasma filters and the effect on
plasma manufactured from filtered WB or nonfiltered WB.
Plasma filtered from nonfiltered WB had a higher FVIII and
von Willebrand factor; a mild reduction in FVIII, FIX, and
FXI was observed with 1 of the 4 filters; and a significant
decrease was observed in FIX and FXI with another. Snyder
et al18 studied only postfiltration samples on the day of processing and 6 and 12 months later. No time-related differences with frozen storage were seen, and because prefiltration
samples were not taken, no filter effect could be assessed. To
our knowledge, the study by Dzik et al19 is the only previous
report on the effect of PRP filtration on clotting factors, and
this report found no reduction in the concentration of clotting
factors. The results are clearly heterogeneous, which is likely
related to the type of product filtered (WB or plasma), the
type of filter used, and the time or temperature of product
storage before processing, in addition to possible unknown
variability related to the filtration process.
Our results show similarity to these previously published
studies. Factor X and protein C are both vitamin K–dependent
glycoproteins, and the oligosaccharide chains could cause an
electrostatic repulsion from the negatively charged coated
polyester surfaces, which restricts adherence. FXI is largely
bound to high-molecular-weight kininogen, which has an
affinity for negatively charged surfaces, and which explains
the loss of this protein. FVII attaches to tissue factor in vivo;
it is possible that cell membrane fragments containing tissue
factor or surface-attached monocytes expressing tissue factor
could explain any decrease observed. No clear explanation
can be found for the loss of FVIII, but this appears more variable and is inconsistent. The loss of FV with the WB filter is
more intriguing because the difference in FV activity appears
to decrease with liquid storage (Figure 4). FV is known to
exist in plasma as 2 isoforms that differ in glycosylation in
the C2 domain at position N2181.21 The glycosylated form is
designated FV1 and the nonglycosylated form FV2. FV1 has
decreased binding affinity for negatively charged phospholipids but also less prothrombinase activity. Alteration in the
ratio of FV1 to FV2 by a relatively selective binding of the
FV2 isoform to the WB filter could explain the difference. If
the FV1 isoform is more stable ex vivo, this difference would
be attenuated with liquid storage, as observed.
Our study has some important limitations. First, we
studied only filters from a single manufacturer and the results
may not be generalizable to other filter types. Second, our
assays were limited and not all clotting factors or anticoagulant proteins were studied. Third, we studied PPP filtration
through WB and platelet filters, which would not occur in
practice. Nevertheless, our results are similar to those of previously published reports, thus lending credence to the data
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with the exception of protein S, which has shown postthaw
instability in other reports.22 These observations may have
manufacturing and clinical implications. From a manufacturing perspective, any reduction in FVIII:C could have implications because FVIII:C is still acquired from plasma in the
manufacture of plasma-derived concentrates. From a clinical
perspective, the reduction in FV with the WB filter and the
reduction in FXI with the platelet filter may have implications
for plasma dosing. No concentrate is available for either of
these factors in the United States; plasma is used as a source
of FV in both hereditary FV deficiency and the acquired
coagulopathies of liver disease, disseminated intravascular
coagulation, and hemodilution coagulopathy and as a source
of FXI in the treatment of FXI deficiency (hemophilia C).
Although plasma dosing is inexact, the type of plasma product
transfused (filtered vs nonfiltered) does not appear to have
received any attention in the clinical outcome of trials involving plasma transfusion.23
In conclusion, leukoreduction filters influence the protein content of the manufactured plasma product. This aspect
appears to have received minimal attention in the United
States and may be important for the future design and overall
performance characteristics of these filters. Furthermore, the
change in FV and FVIII between day 5 and day 7 is minimal
and the extension of liquid storage to day 7 has the potential
to reduce wastage of thawed plasma product.
From the 1Blood Bank and Transfusion Medicine Research Unit, The
Miriam Hospital, Providence, RI; and 2Pall Medical, Covina, CA.
This study was supported by a grant from Pall Medical,
Covina, CA.
Dr Sweeney has received honoraria and grant support from
Pall Medical; Dr Holme is an employee of Pall Medical.
Address reprint requests to Dr Sweeney: Coagulation and
Transfusion Medicine, The Miriam Hospital, 164 Summit Ave,
Providence, RI 02906; [email protected].
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