Note: Descriptions are shown in the official language in which they were submitted.
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AUTOMATED COLLECTION SYSTEMS AND METHODS
FOR OBTAINING RED BLOOD CELLS,
PLATELETS, AND PLASMA FROM WHOLE BLOOD
Field of the Invention
The invention relates to centrifugal blood
processing systems and apparatus.
Background of the Invention
Certain therapies transfuse large volumes of blood
components. For example, some patients undergoing
chemotherapy require the transfusion of large numbers of
platelets on a routine basis. Manual blood bag systems
simply are not an efficient way to collect these large
numbers of platelets from individual donors.
On line blood separation systems are today used to
collect large numbers of platelets to meet this demand. On
line systems perform the separation steps necessary to
separate concentration of platelets from whole blood in a
sequential process with the donor present. On line systems
establish a flow of whole blood from the donor, separate out
the desired platelets from the flow, and return the
remaining red blood cells and plasma to the donor, all in a
sequential flow loop.
Large volumes of whole blood (for example, 2.0
liters) can be processed using an on line system. Due to
the large processing volumes, large yields of concentrated
platelets (for example, 4 x 1011 platelets suspended in 200
ml of fluid) can be collected. Nevertheless, a need still
exists to further improve systems and methods for collecting
cellular-rich concentrates, like red blood cells, from blood
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components, in a way that lends itself to use in high
volume, on line blood collection environments, where higher
yields of critically needed cellular blood components like
platelets and red blood cells can be realized.
Summary of the Invention
The invention provides blood processing systems
and methods that separate blood drawn from a donor into red
blood cells and platelets. The systems and methods operate
in first and second modes.
In the first operating mode, the systems and
methods process whole blood and collect platelets. In the
first mode, red blood cells are not concurrently collected,
but are returned to the donor.
In the second operating mode, the systems and
methods process whole blood and concurrently collect red
blood cells along with the associated additional volume of
platelets. During the second mode, no blood components are
returned to the donor.
In one embodiment, the systems and methods also
operate in a third mode. In the third operating mode, the
systems and methods perform a final blood volume trimming
function. During the volume trimming function, a portion of
the collected red blood cell volume can be returned to the
donor. The volume trimming function assures that component
volumes actually collected do not exceed the volumes
targeted for collection.
The invention may be embodied in several forms
without departing from its spirit or essential
characteristics. The scope of the invention is defined in
the appended claims, rather than in the specific description
preceding them. All embodiments that fall within the
meaning and range of equivalency of the claims are therefore
intended to be embraced by the claims. The invention is not
limited to the details of the construction and the
arrangements of parts set forth in the following description
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or shown in the drawings . The invention can be practiced in
other embodiments and in various other ways. The
terminology and phrases are used for description and should
not be regarded as limiting.
Brief Description of the Drawings
Fig. 1 is a diagrammatic view of an on-line blood
processing system;
Fig. 2 is a schematic view of a controller that
governs the operation of the blood processing system shown
in Fig. 1;
Fig. 3 is a diagrammatic view of the blood
processing system shown in Fig. 1 conditioned by the
controller to perform a draw cycle during a non-concurrent
collection mode;
Fig. 4 is a diagrammatic view of the blood
processing system shown in Fig. 1 conditioned by the
controller to perform a return cycle during a non-concurrent
collection mode;
Fig. 5 is a diagrammatic view of the blood
processing system shown in Fig. 1 conditioned by the
controller to perform a concurrent collection mode;
Fig. 6 is a diagrammatic view of the blood
processing system shown in Fig. 1 conditioned by the
controller to perform a blood volume trimming function; and
Fig. 7 is a front view of a blood collection set,
which, in use, receives red blood cells after collection in
the system shown in Fig. 1 for further processing prior to
storage.
Description of the Preferred Embodiments
Fig. 1 shows in diagrammatic form an on line blood
processing system 10 for carrying out an automated blood
collection procedure.
As illustrated, the system 10 comprises a single
needle blood collection network, although a double needle
network could also be used.
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I. System Overview
The system 10 includes an arrangement of durable
hardware elements, whose operation is governed by a
processing controller 18. The hardware elements include a
centrifuge 12, in which whole blood (WB) from a donor is
separated into platelets, plasma, and red blood cells. A
representative centrifuge that can be used is shown in Brown
et al U.S. Patent 5,690,602, which is incorporated herein by
reference.
The hardware elements will also include various
pumps, which are typically peristaltic (designated P1 to
P7) ; and various in line clamps and valves (designated Vl to
V7). Of course, other types of hardware elements may
typically be present, which Fig. 1 does not show, like sole
noids, pressure monitors, and the like.
The system 10 typically also includes some form of
a disposable fluid processing assembly 14 used in associa-
tion with the hardware elements. In the illustrated
embodiment, the assembly 14 includes a processing chamber 16
having two stages 24 and 32. In use, the centrifuge 12
rotates the processing chamber 16 to centrifugally separate
blood components.
The construction of the two stage processing
chamber 16 can vary. For example, it can take the form of
double bags, like the processing chambers shown and
described in Cullis et al. U.S. Patent 4,146,172, which is
incorporated herein by reference. Alternatively, the
processing chamber 16 can take the form of an elongated two
stage integral bag, like that shown and described in Brown
U.S. Patent No. 5,632,893, which is also incorporated herein
by reference.
In the illustrated blood processing system 10, the
processing assembly 14 also includes an array of flexible
tubing that forms a fluid circuit. The fluid circuit
conveys liquids to and from the processing chamber 16. The
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pumps P1-P7 and the valves V1-V7 engage the tubing to govern
the fluid flow in prescribed ways. The fluid circuit
further includes a number of containers (designated C1 to
C5) to dispense and receive liquids during processing.
A controller 18 governs the operation of the
various hardware elements to carry out one or more
processing tasks using the assembly 14. The controller 18
also performs real time evaluation of processing conditions
and outputs information to aid the operator in maximizing
the separation and collection of blood components.
The system 10 can be configured to accomplish
diverse types of blood separation processes. Fig. 1 shows
the system 10 configured to carry out an automated procedure
using a single needle 22 to collect from a single donor (i)
a desired yield of concentrated platelets suspended in
plasma (PC)(e.g., upwards to two therapeutic units), which
(if desired) can be provided essentially free of leukocytes,
(ii) a desired volume of concentrated red blood cells (RBC)
(e.g. , upwards to about 200 ml at a hematocrit of about 100%
or upwards to about 230 ml at a hematocrit of about 85%),
which (if desired) can also be provided essentially free of
leukocytes, and (iii) a desired volume (if desired) of
platelet-poor plasma (PPP).
The system 10 can collect various volumes of PC,
PPP, and RBC products as governed by applicable regulations
for allowable blood volumes. For example, in the United
States, component volume iterations that the system 10 can
presently provide include, e.g.:(i) one therapeutic unit
each of PC, PPP, and RBC, or (ii) one therapeutic unit each
of PC and RBC, or (iii) two therapeutic units of PC and one
unit of RBC.
Further details of the operation of the system 10
to achieve these blood processing objectives will be
described later.
II. The System Controller
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The controller 18 carries out the overall process
control and monitoring functions for the system 10 as just
described.
In the illustrated and preferred embodiment (see
Fig. 2), the controller comprises a main processing unit
(MPU) 44. In the preferred embodiment, the MPU 44 comprises
a type 68030 microprocessor made by Motorola Corporation,
although other types of conventional microprocessors can be
used.
In the preferred embodiment, the MPU 44 employs
conventional real time multi-tasking to allocate MPU cycles
to processing tasks. A periodic timer interrupt (for
example, every 5 milliseconds) preempts the executing task
and schedules another that is in a ready state for
execution. If a reschedule is requested, the highest
priority task in the ready state is scheduled. Otherwise,
the next task on the list in the ready state is schedule.
A. Hardware Control
The MPU 44 includes an application control manager
46. The application control manager 46 administers the
activation of a library 48 of control applications. Each
control application prescribes procedures for carrying out
given functional tasks using the system hardware (e.g., the
centrifuge 12, the pumps P1-P7, and the valves V1-V7) in a
predetermined way. In the illustrated and preferred embodi-
ment, the applications reside as process software in EPROM's
in the MPU 44.
An instrument manager 50 also resides as process
software in EPROM's in the MPU 44. The instrument manager
50 communicates with the application control manager 46. The
instrument manager 50 also communicates with low level
peripheral controllers 52 for the pumps, solenoids, valves,
and other functional hardware of the system.
As Fig. ?. shows, the application control manager
46 sends specified function commands to the instrument
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manager 50, as called up by the activated application. The
instrument manager 50 identifies the peripheral controller
or controllers 52 for performing the function and compiles
hardware-specific commands. The peripheral controllers 52
communicate directly with the hardware to implement the
hardware-specific commands, causing the hardware to operate
in a specified way. A communication manager 54 manages low-
level protocol and communications between the instrument
manager 50 and the peripheral controllers 52.
As Fig. 2 also shows, the instrument manager 50
also conveys back to the application control manager 46
status data about the operational and functional conditions
of the processing procedure. The status data is expressed
in terms of, for example, fluid flow rates, sensed
pressures, and fluid volumes measured.
The application control manager 46 transmits
selected status data for display to the operator. The
application control manager 46 transmits operational and
functional conditions to the procedure application A1 and
2 0 the performance monitoring application A2.
B. Operator Interface
In the illustrated embodiment, the MPU 44 also
includes an interactive user interface 58. The interface 58
allows the operator to view and comprehend information
2 S regarding the operation of the system 10. The interface 58
also allows the operator to select applications residing in
the application control manager 46, as well as to change
certain functions and performance criteria of the system 10.
The interface 58 includes an interface screen 60
30 and, preferably, an audio device 62. The interface screen 60
displays information for viewing by the operator in alpha
numeric format and as graphical images . The audio device 62
provides audible prompts either to gain the operator's
attention or to acknowledge operator actions.
35 In the illustrated and preferred embodiment, the
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interface screen 60 also serves as an input device. It
receives input from the operator by conventional touch
activation. Alternatively or in combination with touch
activation, a mouse or keyboard could be used as input
devices.
An interface manager 64 communicates with the
interface screen 60 and audio device 62. The interface
manager 64, in turn, communicates with the application
control manager 46. The interface manager 64 resides as
process software in EPROM's in the MPU 44.
Further details of the MPU 44 and interface 58 are
disclosed in Lyle et al. U.S. Patent 5,581,687, which is
incorporated herein by reference.
C. System Control Functions
In the illustrated embodiment (as Fig. 2 shows),
the library 48 includes at least one system control
application A1. The system control application A1 contains
several specialized, yet interrelated utility functions. Of
course, the number and type of utility functions can vary.
In the illustrated embodiment, a utility function
F1 derives the platelet yield (Yld) of the system 10. The
utility function F1 ascertains both the instantaneous
physical condition of the system 10 in terms of its
separation efficiencies and the instantaneous physiological
condition of the donor in terms of the number of circulating
platelets available for collection. From these, the utility
function F1 derive the instantaneous yield of platelets
continuously over the processing period.
Another utility function F2 relies upon the
calculated platelet yield (Yld) and other processing
conditions to generate selected informational status values
and parameters. These values and parameters are displayed
on the interface 58 to aid the operator in establishing and
maintaining optimal performance conditions. The status
values and parameters derived by the utility function F2 can
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vary. For example, in the illustrated embodiment, the
utility function F2 reports remaining volumes to be
processed, remaining processing times, and the component
collection volumes and rates.
Other utility functions generate control variables
based upon ongoing processing conditions for use by the
applications control manager 46 to establish and maintain
optimal processing conditions. For example, one utility
function F3 generates control variables to optimize platelet
separation conditions in the first stage 24. Another utility
function F4 generates control variables to control the rate
at which citrate anticoagulant is returned with the PPP to
the donor to avoid potential citrate toxicity reactions.
Further details of these and other utility
functions can be found in Brown U.S. Patent 5,676,841, which
is incorporated herein by reference. A summary of various
utility functions relied upon is found at the end of the
Specification.
III. System Operation
In the illustrated embodiment, the system 10 is
conditioned to achieve at least three processing objectives.
The first objective is the collection of a desired yield of
concentrated platelets (PC). The second objective is the
collection of a desired volume of PPP to serve as a storage
medium for the collected PC. The third objective is the
collection of a desired volume of red blood cells (RBC).
Other objectives may be established, e.g., to collect an
additional volume of PPP for storage.
To achieve these objectives, the utility function
F1 conditions the system 10 to collect and process blood in
at least three different operating modes.
In the first operating mode, the system 10 is
conditioned to process whole blood and collect PC and PPP.
In the first mode, RBC are not concurrently collected, but
are returned to the donor. PPP in excess of that desired may
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also be returned to the donor.
In the second operating mode, the system 10 is
conditioned to process whole blood and concurrently collect
RBC along with the associated additional volumes of PC and
PPP. During the second mode, no blood components are
returned to the donor.
In the third operating mode, the system 10 is
conditioned to perform a final blood volume trimming
function. During the volume trimming function, a portion of
the collected RBC volume, or all or some of the collected
PPP volume, or both, can be returned to the donor. The
volume trimming function assures that component volumes
actually collected do not exceed the volumes targeted for
collection.
At the outset of the processing procedure, the
operator uses the interface 58 to input the desired PC yield
to be collected (Yld~al), the desired RBC volume to be
collected(RBC~oal) , and the desired PPP volume to be collected
( PPP~al ) .
The controller 18 conditions the system 10 to
proceed with blood processing in the first operating mode.
The controller 18 takes into account two processing
variables in commanding a change from the first operating
mode to the second operating mode, and from the second
operating mode to the third operating mode. The first
processing variable is the remaining whole blood volume
needed to achieve the desired platelet yield, or Vb=em (in
ml). The second processing variable is the volume of whole
blood that is needed to be processed to achieve the desired
volume of red blood cells RBC~oa:, or VbRHC~
When Vblem = VbRec. the controller 18 switches from
the first operating mode to the second operating mode. When
Vbrem becomes zero, the controller switches from the second
operating mode to the third operating mode.
(i) Calculating Vbr
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The utility function F2 relies upon the
calculation of Yld by the first utility function F1 to
derive the whole blood volume needed to be processed to
achieve Yld~o~l . During blood processing, the utility function
F2 continuously derives the additional processed volume
needed to achieve the desired platelet yield Vbrem (in ml) by
dividing the remaining yield to be collected by the expected
average platelet count over the remainder of the procedure,
with corrections to reflect the current operating efficiency
rleie
In the illustrated embodiment, the utility
function F2 derives this value using the following
expression:
200, OOOx ( YldGoal-Y-ldcurrent~
~rem- ~ xACDilx (Plt
Pl t Current + Pl t Post
where:
Yld~al is the desired platelet yield (k/~l),
Vbrem is the additional processing volume (ml)
needed to achieve Yld~a~.
Yldcurrent is the current platelet yield (k/~1) ,
calculated by the utility function F1 based upon current
2 0 processing values (as set forth in the Summary that
follows).
~lPlt is the present (instantaneous) platelet
collection efficiency, which can be calculated based upon
current processing values (as set forth in the Summary that
2 5 follows).
ACDil is an anticoagulant dilution factor (as set
forth in the Summary that follows).
Pltcurrent is the current (instantaneous) circulating
donor platelet count, calculated based upon current
30 processing values (as set forth in the Summary that
follows).
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PltPOet is the expected donor platelet count after
processing, also calculated based upon total processing
values (as set forth in the Summary that follows).
(ii) Calculating VbaBc
The utility function F2 derives VbRec based upon
RBC~a" and also by taking into account the donor's whole
blood hematocrit (Hct). The donor's whole blood hematocrit
Hct can comprise a value measured at the outset of the
procedure, or a value that is sensed on-line during the
course of the procedure.
In the illustrated embodiment, Hct is not directly
measured or sensed. Instead, the controller 18 relies upon
an apparent hematocrit value Hb of whole blood entering the
separation chamber. Hb is derived by the controller 18 based
upon sensed flow conditions and theoretical consideration.
The derivation of Hb is described in more detail in the
Summary that follows.
Based upon Hb, the utility function F2 can derive
VbRec using the following expression:
~~Gon! + BZIf
2 o Ill'~~ - H
b
where:
Buf is a prescribed buffer volume, e.g., 20 ml.
In the illustrated embodiment, the utility
function F2 provides a further volume buffer, by rounding up
the calculated volume of VbRHC, a . g . , to the next highest
integer divisible by ten.
In the illustrated embodiment, the utility
function F2 also compares the calculated value of VbRB~ to a
prescribed maximum volume (e.g. , 600 mL) . If VbRB~ equals or
exceeds the prescribed maximum, the utility function F2
rounds the value down to a prescribed lesser amount, e.g.,
to 595 mL.
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(iii) The First Operating Mode
In the first or non-concurrent operating mode, the
system 10 processes whole blood and collects PC and PPP for
storage. During the first mode, RBC and the uncollected
volume of PPP are returned to the donor.
The system 10 shown in Fig. 1 employs one, single
lumen phlebotomy needle 22. During the non-concurrent mode,
the controller 18 operates the system 10 in successive draw
and return cycles. During the draw cycle (Fig. 3), the
controller 18 supplies the donor's WB through the needle 22
to the chamber 16 for processing. During the return cycle
(Fig. 4), the controller 18 returns the RBC and PPP blood
components to the donor through the same needle 22.
In the illustrated embodiment, the system 10 is
configured to enable separation to occur in the chamber 16
without interruption during a succession of draw and return
cycles. More particularly, the system 10 includes a draw
reservoir 66. During a draw cycle (Fig. 3), a quantity of
the donor's WB is pooled in the reservoir 66, in excess of
the volume which is sent to the chamber 16 for processing.
The system 10 also includes a return reservoir 68. A
quantity of RBC collects in the return reservoir 68 during
the draw cycle for periodic return to the donor during the
return cycle (see Fig. 4). During the return cycle, WB is
conveyed from the draw reservoir 66 to the chamber 16 to
sustain uninterrupted separation.
In a draw cycle of the non-concurrent mode Fig.
3), the whole blood pump Pl direct WB from the needle 22
through a first tubing branch 20 and into the draw reservoir
66. Meanwhile, an auxiliary tubing branch 26 meters
anticoagulant from the container C1 to the WB flow through
the anticoagulant pump P3. While the type of anticoagulant
can vary, the illustrated embodiment uses ACDA, which is a
commonly used anticoagulant for pheresis.
A container C2 holds saline solution. Another
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auxiliary tubing branch 28 conveys the saline into the first
tubing branch 20, via the in line valve V1, for use in
priming and purging air from the assembly 14 before
processing begins. Saline solution is also introduced again
after processing ends to flush residual components from the
assembly 14 for return to the donor.
The processing controller 18 receives processing
information from a weigh scale 70. The weigh scale 70
monitors the volume of WB collected in the draw reservoir
66. Once the weigh scale 70 indicates that a desired volume
of WB is present in the draw reservoir 66, the controller 18
commands the whole blood processing pump P2 to operate to
continuously convey WB from the draw reservoir 66 into the
first stage 24 of the processing chamber 16 through inlet
branch 36. The controller 18 operates the whole blood pump
P1 at a higher flow rate (at, for example, 100 ml/min) than
the whole blood processing pump P2, which operates
continuously (at, for example, 50 ml/min), so a volume of
anticoagulated blood collects in the reservoir 66. By
monitoring weight using the weigh scale 70, the controller
intermittently operates the whole blood inlet pump P1 to
maintain a desired volume of WB in the draw reservoir 66.
Anticoagulated WB enters and fills the first stage
24 of the processing chamber 16. There, centrifugal forces
generated during rotation of the centrifuge 12 separate WB
into red blood cells (RBC) and platelet-rich plasma (PRP).
A PRP pump P4 operates to draw PRP from the first
stage 24 of the processing chamber 16 into a second tubing
branch 30 for transport to the second stage 32 of the
processing chamber 16. There, the PRP is separated into
platelet concentrate (PC) and platelet-poor plasma (PPP).
The controller 18 optically monitors the location
of the interface between RBC and PRP within the first stage
24 of the processing chamber 16. The controller 18 operates
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the PRP pump P4 to keep the interface at a desired location
within the first stage 24 of the processing chamber 24 . This
keeps a substantial portion of the leukocytes, which occupy
the interface, from entering the flow of PRP.
Optionally, the PRP can also be conveyed through
a filter F to remove leukocytes before separation in the
second stage 32. The filter F can employ filter media
containing fibers of the type disclosed in Nishimura et al
U.S. Patent 4,936,998, which is incorporated herein by
reference. Filter media containing these fibers are
commercially sold by Asahi Medical Company in filters under
the trade name SEPACELL.
The system 10 includes a recirculation tubing
branch 34 and an associated recirculation pump P5. The
processing controller 18 operates the pump P5 to divert a
portion of the PRP exiting the first stage 24 of the
processing chamber 16 for remixing with the WB entering the
first stage 24 of the processing chamber 16. The
recirculation of PRP establishes desired conditions in the
entry region of the first stage 24 to provide maximal
separation of RBC and PRP.
A RBC branch 38 conveys the RBC from the first
stage 24 of the processing chamber 16 to the return
reservoir 68 (which is controlled by valve V3). A weigh
scale 72 monitors the volume of PPP collected in the
container C4.
A PPP branch 40 conveys PPP from the second stage
32 of the processing chamber 16, by operation of the PPP
pump P7. By opening valve V5, all or a portion of the PPP
can be directed to a collection container C4, depending upon
the flow rate of the pump P7. A weigh scale 74 monitors the
volume of PPP collected in the container C4. The PPP that is
not collected flow into the return reservoir 68, where it
mixes with the RBC.
During the second operating mode (which will be
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described later), a relatively large volume of PPP (i.e.,
from about 50~ to 75~ of PPP~~1) will typically be collected
without return to the donor. In anticipation of this, the
controller 16 limits the rate at which PPP is collected
during the first mode. This avoids the collection of a
surplus volume of PPP at the end of the procedure. By
limiting the rate at which PPP is collected during the first
operating mode, the controller 18 reduces the time of the
subsequent blood volume trimming function, thereby reducing
the overall procedure time. The small volume of surplus PPP
also allows the use of higher return flow rates during the
blood volume trimming function, as the amount of
anticoagulant (carried in the PPP) that is returned to the
donor during the blood volume trimming function is reduced.
The controller 18 receives processing information
from the weigh scale 72, monitors the volume of RBC and PPP
in the return reservoir 68. When a preselected volume
exists, the controller 18 shifts the operation of the system
10 from a draw cycle to a return cycle.
In the return cycle (Fig. 4), the controller 18
stops the whole blood inlet pump P1 and anticoagulant pump
P3 and starts a blood return pump P6. A return branch 42
conveys RBC and PPP in the return reservoir 68 to the donor
through the needle 22.
Meanwhile, while in the return cycle, the
controller 18 keeps the WB processing pump P2, the PRP pump
P4, and recirculation pump P5 in operation to continuously
process the WB pooled in the draw reservoir 66 through the
first stage and second stages 24 and 32 of the chamber 16.
When the weigh scale 72 indicates that the
contents of the return reservoir 68 have been conveyed to
the donor, the controller 18 shifts operation of the system
10 to another draw cycle.
The controller 18 toggles between successive draw
and return cycles until Vbrem = Vb~c~ When Vb=em = Vb~~, the
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controller 18 commands a final return cycle, to return the
contents of the return reservoir 68 to the donor. Upon
returning the contents of the return reservoir 68, the
controller 18 switches from the first operating mode to the
second operating mode. (iv) Concurrent Collection
Mode
In a second or concurrent collection mode (Fig.
5) , the controller 18 conditions to system 10 to operate in
a sustained draw cycle, to process whole blood and
concurrently collect the targeted volume of RBC, along with
associated additional volumes of PC and PPP. During the
concurrent collection mode, the controller 18 does not
switch operation of the system 10 to a return cycle. There
is only one sustained draw cycle during the concurrent
collection mode, and no components are returned to the
donor.
During the sustained draw cycle of concurrent
collection mode, the controller 18 avoids the collection of
a large surplus volume of whole blood in the draw reservoir
66. In the illustrated embodiment, the controller 18
achieves this objective by maintaining a smaller flow rate
differential between the whole blood inlet pump P1 and the
whole blood processing pump P2, compared to the differential
maintained during the draw cycle of non-concurrent
collection mode. For example, in the illustrated embodiment,
the whole blood inlet pump P1 is operated at a minimal
differential of, e.g., only 1 mL/min, above the whole blood
processing pump P2.
To further assure that only a slight buffer volume
of whole blood is maintained in the draw reservoir 66 during
the sustained draw cycle of concurrent collection mode, the
weight scale 70 toggles the whole blood inlet pump P1 and
anticoagulant pump P3 off whenever the sensed volume of
blood in the draw reservoir 66 exceeds a specified minimum
buffer amount , e.g., 5 g.
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During the sustained draw cycle of concurrent
collection mode, red blood cells are directed into a
collection container C4, via the valve V4, which is opened
for this purpose (return valve V3 is closed, so no RBC
collect in the return reservoir 68) . A weigh scale 108
monitors the weight of the collection container C4.
An associated volume of PC collects in the second
stage 32 of the chamber 16, while the associated volume of
PPP collects in the collection container C3 (through the
operation of the PPP pump P7 and valve V5, which is opened) .
Valve V3 is closed , so no PPP collects in the return
reservoir 68.
The controller 18 continuously derives Vbrem during
the sustained draw cycle of concurrent collection mode. When
Vb=em becomes zero, the controller 18 terminates the
concurrent collection mode.
(iv) Blood Volume Trimming Function
In the illustrated embodiment ( see Fig . 6 ) , at the
end of the concurrent collection mode, the controller 18
assesses the volumes of RBC and PPP that have been
collected, using weigh scales 108 and 74, respectively.
If the volume of RBC collected exceeds RBC~oal, the
controller 18 commands the system 10 to enter a return cycle
to return the excess RBC volume to the donor from the
collection container C4, through the branch path 43 (valve
V6 being opened) , and into the return path 42 (valve V2
being closed), by operation of the in-line return pump P6.
Likewise, if the volume of PPP collected exceeds
PPP~al, the controller 18 commands the system 10 to enter a
return cycle to return the excess PPP volume to the donor
from the collection container C3, through the branch path 45
(valve V7 being opened and valve V5 being closed), and into
the return path 42, by operation of the in-line return pump
P6.
At the end of the blood volume trimming function,
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the controller 18 commands a saline re infusion operation to
return residual blood in the system 10 to the donor, along
with a prescribed fluid replacement volume.
(v) Post Collection Processing
(1) PPP
The retention of PPP can serve multiple purposes,
both during and after the component separation process.
The retention of PPP serves a therapeutic purpose
during processing. PPP contains most of the anticoagulant
that is metered into WB during the component separation
process. By retaining a portion of PPP instead of returning
it all to the donor, the overall volume of anticoagulant
received by the donor during processing is reduced. This
reduction is particularly significant when large blood
volumes are processed. The retention of PPP during
processing also keeps the donor's circulating platelet count
higher and more uniform during processing.
The system 10 can also derive processing benefits
from the retained PPP. For example, the system 10 can, in an
alternative recirculation mode, recirculate a portion of the
retained PPP, instead of PRP, for mixing with WB entering
the first compartment 24. Or, should WB flow be temporarily
halted during processing, the system 10 can draw upon the
retained volume of PPP as an anticoagulated "keep-open"
fluid to keep fluid lines patent. In addition, at the end of
the separation process, the system 10 can draw upon the
retained volume of PPP as a "rinse-back" fluid, to resuspend
and purge RBC from the first stage compartment 24 for return
to the donor through the return branch 42.
(2) PC
After the separation process, the system 10 also
operates in a resuspension mode to draw upon a portion of
the retained PPP to resuspend PC in the second stage 24 for
transfer and storage in the collection containers) C5.
Resuspension and transfer of PC to the collection containers
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C5 can be accomplished manually or on line.
Preferable , the container ( s ) C5 intended to store
the PC are made of materials that, when compared to DEHP-
plasticized polyvinyl chloride materials, have greater gas
permeability that is beneficial for platelet storage. For
example, polyolefin material (as disclosed in Gajewski et al
U.S. Patent 4,140,162), or a polyvinyl chloride material
plasticized with tri-2-ethylhexyl trimellitate (TEHTM) can
be used.
( 2 ) RBC
In the illustrated embodiment (see Fig. 7), a
disposable collection set 76 is provided to process the RBC
volume collected for storage.
The set 76 includes a transfer path 78. The
transfer path 78 has a sealed free end 80 designed to be
connected in a sterile fashion to a sealed tube segment 82
on the RBC collection container C4 (see Fig. 7). Known
sterile connection mechanisms (not shown) like that shown in
Spencer U.S. Patent 4,412,835 can be used for connecting the
transfer path 78 to the tube segment 82. These mechanisms
form a molten seal between tubing ends, which, once cooled,
forms a sterile weld.
A first bag 84 communicates with the transfer path
78 through a length of sample tubing 86. The first bag 84
contains a red blood cell additive solution S, e.g., SAG-M
or ADSOL~ Solution (Baxter Healthcare Corporation).
Following coupling of the collection set 76 to the RBC
collection container C4, a conventional in-line frangible
cannula 106 in the sample tubing 86 is opened, and the red
blood cell additive solution S is transferred from the first
bag 84 into the collection container C4 for mixing with the
collected RBC volume. The mixture of additive solution and
RBC can then be transferred back into the first bag 84.
Residual air in the first bag 84 can be vented
into an in-line air venting chamber 88, which communicates
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with the transfer path 78. At the same time, an aliquot of
the collected RBC volume present in the first bag 84 can be
expressed into the sample tubing 86.
The tubing 86 preferably carries an identification
code 90 which is identical to a code 90 printed on or
otherwise applied to the first bag 84. The tubing 86 is
then closed with a conventional snap-apart seal, and the
first bag 84 is detached from the collection set 76 for
storing the RBC volume. The tubing 86 can be further sealed
in segments, using conventional tube sealers, to isolate
multiple samples of the RBC for analysis and cross-matching.
The set 76 also includes a second bag 92, which
communicates with the transfer path 78 downstream of the
first bag 84 through a branch path 94. The branch path 94
includes an in-line filter 96. The in-line filter 96
carries a filtration medium 98 that selectively removes
leukocytes from red blood cells. The filter can comprise,
e.g., a R-3000 Red Blood Cell Filter (Asahi Medical).
The mixture of red blood cells and additive
solution can be transferred from the collection bag C4 to
the second bag 92 through the in-line filter 96, by-passing
the first bag 84. In this way, the set 76 provides red
blood cells essentially free of leukocytes, suitable for
long term storage.
An air venting path 100 extends from the second
bag 92 to the transfer path 78, bypassing the in-line filter
96. By opening a conventional break-away cannula 106 in the
path 100, residual air in the second bag 92 can be vented
through the path 100 into the in-line air venting chamber
88. A one-way valve 104 in the path 100 allows air and
liquid flow in the path 100 away from the bag 92, but not in
the opposite direction.
At the same time, an aliquot of the collected RBC
present in the second bag 92 can be expressed into the
venting path 100. The venting path 100 carries an
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identification code 102 which is identical to a code 102
printed on or otherwise applied to the second bag 92. The
venting path 100 and branch path 94 can be closed with a
conventional snap-apart seal, to allow detachment of the
second bag 92 from the transfer path 78. The path 100 can
also be sealed in segments, to provide multiple samples of
the RBC for analysis and cross-matching.
The collection set 76 provides the flexibility to
provide a red blood cell product suitable for long term
storage, which is either non-leukocyte reduced or leukocyte
reduced before storage.
IV. Summary of Various Processing Utility
Functions
A. Deriving Platelet Yield
The utility function F1 makes continuous
calculations of the platelet separation efficiency (r~plt) of
the system 10. The utility function F1 treats the platelet
separation efficiency r~Pt1 as being the same as the ratio of
plasma volume separated from the donor's whole blood
relative to the total plasma volume available in the whole
blood. The utility function F1 thereby assumes that every
platelet in the plasma volume separated from the donor's
whole blood will be harvested.
The donor's hematocrit changes due to
anticoagulant dilution and plasma depletion effects during
processing, so the separation efficiency r~Plt does not remain
at a constant value, but changes throughout the procedure.
The utility function F1 contends with these process-
dependent changes by monitoring yields incrementally. These
yields, called incremental cleared volumes (~ClrVo1), are
calculated by multiplying the current separation efficiency
r~Pit bY the current incremental volume of donor whole blood,
diluted with anticoagulant, being processed, as follows:
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Eq (1)
D Cl rVo1=ACDi 1 x ~1 Pi r"~ VDLProc
where:
~Volpro~ is the incremental whole blood volume
being processed, and
ACDil is an anticoagulant dilution factor for the
incremental whole blood volume, computed as follows:
Eq (2)
ACDi1= AC
AC+ 1
where:
AC is the selected ratio of whole blood volume to
anticoagulant volume (for example 10:1 or "10"). AC may
comprise a fixed value during the processing period.
Alternatively, AC may be varied in a staged fashion
according to prescribed criteria during the processing
period.
For example, AC can be set at the outset of
processing at a lesser ratio for a set initial period of
time, and then increased in steps after subsequent time
periods; for example, AC can be set at 6:1 for the first
minute of processing, then raised to 8:1 for the next 2.5 to
3 minutes; and finally raised to the processing level of
10:1.
The introduction of anticoagulant can also staged
by monitoring the inlet pressure of PRP entering the second
processing stage 32. For example, AC can be set at 6:1
until the initial pressure (e.g. at 500 mmHg) falls to a set
threshold level (e.g. , 200 mmHg to 300 mmHg) . AC can then be
raised in steps up to the processing level of 10:1, while
monitoring the pressure to assure it remains at the desired
level.
The utility function F1 also makes continuous
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estimates of the donor's current circulating platelet count
(Plt~ir~) . expressed in terms of 1000 platelets per microliter
(~1) of plasma volume (or k/~1) . Like r~Plt, Plt~;r~ will change
during processing due to the effects of dilution and
depletion. The utility function F1 incrementally monitors
the platelet yield in increments, too, by multiplying each
incremental cleared plasma volume OClrVol (based upon an
instantaneous calculation of r~Plt) by an instantaneous
estimation of the circulating platelet count Plt~;r. The
product is an incremental platelet yield (Dyld), typically
expressed as e" platelets, where e" - .5 x 10" platelets (ell
.5 x 1011 platelets) .
At any given time, the sum of the incremental
platelet yields DYld constitutes the current platelet yield
Yldc"rren« which can also be expressed as follows:
Eq (3)
D Cl r'Vol X Pl t cur
Yldcurrent-Yldold 100, 000
where:
Yldola is the last calculated Yld~"r=e"t~ and
Eq (4)
4 Cl rVo1 x Pl t current
~Yld=
100,000
where:
Pltcurrent is the current (instantaneous) estimate
of the circulating platelet count of the donor.
~Yld is divided by 100,000 in Eq (4) to balance
units.
The following provides further details in the
derivation of the above-described processing variables by
the utility function F1.
(i) Deriving Overall Separation
Efficiency
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The overall system efficiency r~Plt is the product
of the individual efficiencies of the parts of the system,
as expressed as follows:
Eq (5)
~plt ~lstSepX~2ndSepX~Anc
where:
~llgtseP is the ef f iciency of the separation of PRP
from WB in the first separation stage.
rl2ndSep 1S the efficiency of separation PC from PRP
in the second separation stage.
r~,~,~ is the product of the efficiencies of other
ancillary processing steps in the system.
1. First Stage Separation
Efficiency ~l,csap
The utility function F1 derives r~lstSep continuously
over the course of a procedure based upon measured and
empirical processing values, using the following expression:
Eq (6)
__ ~P
~ SeP ( 1 _ Hb ) Qb
where:
Qb is the measured whole blood flow rate (in
ml/min) .
Qp is the measured PRP flow rate (in ml/min).
Hb is the apparent hematocrit of the
anticoagulated whole blood entering the first stage
separation compartment . Hb is a value derived by the utility
based upon sensed flow conditions and theoretical
considerations. The utility function F1 therefore requires
no on-line hematocrit sensor to measure actual WB
hematocrit.
The utility function F1 derives Hb based upon the
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following relationship:
Eq ('1 )
H be ( Qb Qp)
b
b
where:
Hrb~ is the apparent hematocrit of the RBC bed
within the first stage separation chamber, based upon sensed
operating conditions and the physical dimensions of the
first stage separation chamber. As with Hb, the utility
function F1 requires no physical sensor to determine Hrb~,
which is derived by the utility function according to the
following expression:
Eq (8)
_i
H be - 1 - ( ~ ( qb-qp) ) k;1
gAK SY
where:
qb is inlet blood flow rate (cm3/sec) , which is a
known quantity which, when converted to ml/min, corresponds
with Qb in Eq (6).
qP is measured PRP flow rate (in cm'/sec), which
is a known quantity which, when converted to ml/min
corresponds with QP in Eq (6).
~i is a shear rate dependent term, and SY is the
red blood cell sedimentation coefficient (sec). Based upon
empirical data, Eq (8) assumes that ~i/SY=15.8x106 sec-1.
A is the area of the separation chamber (cm2) ,
which is a known dimension.
g is the centrifugal acceleration (cm/secZ) , which
is the radius of the first separation chamber (a known
dimension) multiplied by the rate of rotation squared S2z
(rad/secz) (another known quantity).
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k is a viscosity constant - 0.625, and x is a
viscosity constant based upon k and another viscosity
constant a = 4.5, where:
Eq (9)
k+2 [ k+2 ] k'1-1. 272
K=
a k+1
Eq (8) is derived from the relationships expressed
in the following Eq (10):
Eq (10)
H
H be ~ 1 Hrbc) (k+1~ ~ bqb
gAK SY
set forth in Brown, The PhYSics of Continuous Flow
Centrifugal Cell Separation, "Artificial Organs" 1989;
13(1):4-20)). Eq (8) solves Eq (10) for Hrbc.
2. The Second Stage
Separation Efficiency
2adSep
The utility function Fl also derives ~ZndSep
continuously over the course of a procedure based upon an
algorithm, derived from computer modeling, that calculates
what fraction of log-normally distributed platelets will be
collected in the second separation stage 32 as a function of
their size (mean platelet volume, or MPV), the flow rate
(Qp), area (A) of the separation stage 32, and centrifugal
acceleration (g, which is the spin radius of the second
stage multiplied by the rate of rotation squared S2z).
The algorithm can be expressed in terms of a
function, which expressed ~l2ndseP in terms of a single
dimensionless parameter gASp/Qp,
where:
Sp = 1.8 X 10-9 MPV2~' (sec) , and
MPV is the mean platelet volume (femtoliters, fl,
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or cubic microns), which can be measured by conventional
techniques from a sample of the donor' s blood collected
before processing. There can be variations in MPV due to use
of different counters. The utility function therefore may
include a look up table to standardize MPV for use by the
function according to the type of counter used.
Alternatively, MPV can be estimated based upon a function
derived from statistical evaluation of clinical platelet
precount PItPRE data, which the utility function can use.
The inventor believes, based upon his evaluation of such
clinical data, that the MPV function can be expressed as:
MPV (fl) ~ 11.5 - 0.009P1tPRE (k/(tl)
3. Ancillary Separation
Efficiencies ~
r~""~ takes into account the ef f iciency ( in terms of
platelet loss) of other portions of the processing system.
r~""~ takes into account the efficiency of transporting
platelets (in PRP) from the first stage chamber to the
second stage chamber; the efficiency of transporting
platelets (also in PRP) through the leukocyte removal
filter; the efficiency of resuspension and transferral of
platelets (in PC) from the second stage chamber after
processing; and the efficiency of reprocessing previously
processed blood in either a single needle or a double needle
configuration.
The efficiencies of these ancillary process steps
can be assessed based upon clinical data or estimated based
upon computer modeling. Based upon these considerations, a
predicted value for r~,u,~ can be assigned, which Eq (5) treats
as constant over the course of a given procedure.
B. Deriving Donor Platelet Count (Plt~irc)
The utility function F1 relies upon a kinetic
model to predict the donor's current circulating platelet
count Plt~ir~ during processing. The model estimates the
donor's blood volume, and then estimates the effects of
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dilution and depletion during processing, to derive Plt~;r~,
according to the following relationships:
Eq (11)
Plt~tr~= [ (Dilution) xPltpre] - (Depletion)
where:
Pltpre is the donor's circulating platelet count
S before processing begins (k/~l), which can be measured by
conventional techniques from a sample of whole blood taken
from the donor before processing. There can be variations
in PltPre due to use of different counters (see, e.g.,
Peoples et al., "A Multi-Site Study of Variables Affecting
Platelet Counting for Blood Component Quality Control,"
Transfusion (Special Abstract Supplement, 47th Annual
Meeting), v. 34, No. 10S, October 1994 Supplement). The
utility function therefore may include a look up table to
standardize all platelet counts ( such as, PltP=e and Pltpost,
described later) for use by the function according to the
type of counter used.
Dilution is a factor that reduces the donor's
preprocessing circulating platelet count PltP~e due to
increases in the donor's apparent circulating blood volume
caused by the priming volume of the system and the delivery
of anticoagulant. Dilution also takes into account the
continuous removal of fluid from the vascular space by the
kidneys during the procedure.
Depletion is a factor that takes into account the
depletion of the donor' s available circulating platelet pool
by processing. Depletion also takes into account the
counter mobilization of the spleen in restoring platelets
into the circulating blood volume during processing.
1. Estimating Dilution
The utility function F1 estimates the dilution
factor based upon the following expression:
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Eq (12)
Prime+ 2ACD -PPP
Dilution=1-
DonVol
where:
Prime is the priming volume of the system (ml).
ACD is the volume of anticoagulant used (current
or end-point, depending upon the time the derivation is
made ) ( ml ) .
PPP is the volume of PPP collected (current or
goal) (ml).
DonVo1 (ml) is the donor's blood volume based upon
models that take into account the donor's height, weight,
and sex. These models are further simplified using
empirical data to plot blood volume against donor weight
linearized through regression to the following, more
streamlined expression:
Eq (13)
Don Vol=1024+5lWgt(rz=0.87)
where:
Wgt is the donor's weight (kg).
2. Estimating Depletion
The continuous collection of platelets depletes
the available circulating platelet pool. A first order
model predicts that the donor's platelet count is reduced by
the platelet yield (Yld) (current or goal) divided by the
donor's circulating blood volume (DonVol), expressed as
follows
Eq (14)
Dep1= 100, 000 Yld
DonVo1
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where:
Yld is the current instantaneous or goal platelet
yield (k/~.1). In Eq (14), Yld is multiplied by 100,000 to
balance units.
Eq (14) does not take into account splenic
mobilization of replacement platelets, which is called the
splenic mobilization factor ( or Spleen). Spleen indicates
that donors with low platelets counts nevertheless have a
large platelet reserve held in the spleen. During
processing, as circulating platelets are withdrawn from the
donor's blood, the spleen releases platelets it holds in
reserve into the blood, thereby partially offsetting the
drop in circulating platelets. The inventor has discovered
that, even though platelet precounts vary over a wide range
among donors, the total available platelet volume remains
remarkably constant among donors. An average apparent donor
volume is 3.10 ~ 0.25 ml of platelets per liter of blood.
The coefficient of variation is 8.1%, only slightly higher
than the coefficient of variation in hematocrit seen in
normal donors.
The mobilization factor Spleen is derived from
comparing actual measured depletion to Depl (Eq ( 14 ) ) , which
is plotted and linearized as a function of PltPre. Spleen
(which is restricted to a lower limit of 1) is set forth as
follows:
Eq (15)
Spleen= [2.25-0. 004P1tPre] >_1
Based upon Eqs (14) and (15) , the utility function
derives Depletion as follows:
Eq (16)
Depletion= 100,000Y1d
Sp1 eenx DonVol
C. Real Time Procedure Modifications
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The operator will not always have a current
platelet pre-count PltPre for every donor at the beginning of
the procedure. The utility function F1 allows the system to
launch under default parameters, or values from a previous
procedure. The utility function F1 allows the actual
platelet pre-count PltPIe, to be entered by the operator
later during the procedure. The utility function F1
recalculates platelet yields determined under one set of
conditions to reflect the newly entered values. The utility
function F1 uses the current yield to calculate an effective
cleared volume and then uses that volume to calculate the
new current yield, preserving the platelet pre-count
dependent nature of splenic mobilization.
The utility function F1 uses the current yield to
calculate an effective cleared volume as follows:
Eq (17)
100, 000xDonVolXYld
Cl rV01= currea t
ACD+ PPP x 50, 000x Yld~urrent
[DonVol-Prime- ] Preold
3 2 Spleenold
where:
ClrVo1 is the cleared plasma volume.
DonVol is the donor's circulating blood volume,
calculated according to Eq (13).
Yld~rent is the current platelet yield calculated
according to Eq (3) based upon current processing
conditions.
Prime is the blood-side priming volume (ml).
ACD is the volume of anticoagulant used (ml).
PPP is the volume of platelet-poor plasma
collected (ml).
Preola is the donor's platelet count before
processing entered before processing begun (k/~1).
Spleenola is the splenic mobilization factor
calculated using Eq (16) based upon Preoia.
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The utility function F1 uses ClrVo1 calculated
using Eq ( 17 ) to calculate the new current yield as follows
Eq (18)
DonVol-Prime- 'BCD + PPP
3 2 ClrVolXPreNew
YldNew- [ ClrVo1 ] ~ 100, 000
DonVol +
2 X Spl eenNew
where:
PreNew is the revised donor platelet pre-count
entered during processing (k/~.1).
YldNeW is the new platelet yield that takes into
account the revised donor platelet pre-count PreNew~
ClrVo1 is the cleared plasma volume, calculated
according to Eq (17).
DonVol is the donor's circulating blood volume,
calculated according to Eq (13), same as in Eq (17).
Prime is the blood-side priming volume (ml) , same
as in Eq (17).
ACD is the volume of anticoagulant used (ml) , same
as in Eq (17).
PPP is the volume of platelet-poor plasma
collected (ml), same as in Eq (17).
SpleenNew is the splenic mobilization factor
calculated using Eq (15) based upon PreNeW~
D. Remaining Procedure Time
The utility function F2 can also calculate
remaining collection time (trem) (in min) as follows:
Eq (19)
Vb
- rem
rem
b
where:
Vbrem is the remaining volume to be processed,
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calculated using Eq (19) based upon current processing
conditions.
Qb is the whole blood flow rate, which is either
set by the user or otherwise derived by the controller 18.
E. Plasma Collection
The utility function F2 adds the various plasma
collection requirements to derive the plasma collection
volume (PPP~al) (in ml) as follows:
Eq(20)
PPP =PPP +PPP +PPP +PPP +PPP
Goal PC Source Reinfuse Waste CollCham
where:
PPPp~ is the platelet-poor plasma volume selected
for the PC product, which can have a typical default value
of 250 ml, or be otherwise calculated by the controller 18
based upon current processing conditions.
PPPgource is the platelet-poor plasma volume
selected for collection as source plasma.
PPPWaste is the platelet-poor plasma volume selected
to be held in reserve for various processing purposes
(Default = 30 ml).
PPPcollcham is the volume of the plasma collection
chamber (Default = 40 ml).
PPPxeinfuse is the platelet-poor plasma volume that
will be reinfusion during processing.
F. Plasma Collection Rate
The utility function F2 calculates the plasma
collection rate (QPPp) (in ml/min) as follows:
Eq (21)
PPPGoal PPPCurrent
QPPP
rem
where:
PPP~al is the desired platelet-poor plasma
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collection volume (ml).
PPPcurrent is the current volume of platelet-poor
plasma collected (ml).
t=em is the time remaining in collection,
calculated using Eq (19) based upon current processing
conditions.
G. Total Anticipated AC Usage
The utility function F2 can also calculate the
total volume of anticoagulant expected to be used during
processing (ACDEna) (in ml) as follows:
Eq (22)
ACD =ACD QbX trem
End current 1 +AC
where:
ACD~urre~e is the current volume of anticoagulant
used (ml).
AC is the selected anticoagulant ratio,
Qb is the whole blood flow rate, which is either
set by the user or otherwise calculated by the controller 18
based upon current processing conditions.
trem is the time remaining in collection,
calculated using Eq (19) based upon current processing
conditions.
Various features of the inventions are set forth
in the following claims.
