JP2024532293A - Donor extracellular fluid-based plasma collection - Google Patents

Abstract

The system and method for collecting plasma includes a control circuit configured to control operation of the system, the control circuit configured to receive one or more donor parameters. The control circuit estimates a physiological fluid volume of the donor based at least in part on the one or more donor parameters, and calculates a target volume of a plasma product including raw plasma and an anticoagulant by multiplying the estimated physiological fluid volume by a pre-stored constant. The control circuit controls the system to operate collection and return stages for processing the whole blood into a plasma product until a measured volume of the plasma product in the collection container reaches a target volume of the plasma product.
[Selected Figure] Figure 1

Description

CROSS-REFERENCE TO RELATED APPLICATIONS
This application is related to the prior U.S. Application No. 17/306,099, filed May 3, 2021, U.S. Provisional Application No. 63/140,534, filed January 22, 2021, U.S. Application No. 16/739,441, filed January 10, 2020, International Application No. PCT/US2019/033318, filed May 21, 2019, U.S. Provisional Application No. 62/846,400, filed May 10, 2019, U.S. Provisional Application No. 62/752,480, filed October 30, 2018, and U.S. Provisional Application No. 62/674,144, filed May 21, 2018, all of which are incorporated by reference in their entireties herein. This application claims the benefit of priority to U.S. Provisional Application No. 63/256,762, filed October 18, 2021, U.S. Provisional Application No. 63/244,321, filed September 15, 2021, and U.S. Provisional Application No. 63/236,743, filed August 25, 2021, all of which are incorporated by reference in their entireties herein.

This application relates to systems and methods for performing plasma exchange, and more particularly to plasma exchange systems and methods in which the volume of plasma that can be collected from a particular donor is optimized.

Plasma exchange is an apheresis procedure in which whole blood is drawn from a donor, the plasma is separated and retained from the other cellular blood components (red blood cells, platelets, and white blood cells), and the cellular blood components are returned to the donor. Separation of the plasma from the cellular components can be performed in automated procedures by centrifugation or membrane filtration.

The FDA has issued guidelines for registered blood collecting centers regarding the volume of plasma that can be collected as raw plasma during plasma exchange. (FDA Memo: "Volume Limitations - Automated Collection of Source Plasma (11/4/92)"). The FDA Memo describes an abbreviated plasma volume nomogram that limits the volume (or weight) of pure (or raw) plasma that can be collected from a particular donor to ensure donor safety and comfort.

Because source plasma from multiple donors may be combined, it is advantageous to maximize the volume of pure plasma that can be collected from each individual donor, because even small increases in the volume collected from each individual donor add up to a large increase in the total volume of pooled plasma.

In one embodiment, a system for collecting plasma comprises a reusable component having a control circuit configured to control the operation of the system. The control circuit may be coupled to an input device and configured to receive one or more donor parameters and estimate a physiological fluid volume of the donor based at least in part on the one or more donor parameters. The control circuit may be configured to calculate a target volume of a plasma product including raw plasma and an anticoagulant by multiplying a pre-stored constant by the estimated physiological fluid volume. The control circuit may be configured to control the system to operate a collection phase and a return phase to collect whole blood from the donor, separate the whole blood into a plasma product and a second blood component, and return the second blood component to the donor. The control circuit may be configured to operate the collection phase and the return phase until a measured volume of the plasma product in the collection container reaches a target volume of the plasma product.

In one embodiment, a system for collecting plasma includes a separator configured to separate whole blood into a plasma product and a second blood component including red blood cells, the blood separator having a plasma output port coupled to a plasma line configured to deliver the plasma product to a plasma product collection container. The donor line can be configured to introduce whole blood from a donor into the separator, with flow through the donor line controlled by a first pump. The anticoagulant line can be coupled to an anticoagulant source, with flow through the anticoagulant line controlled by a second pump to combine anticoagulant with the whole blood from the donor based on an anticoagulant ratio. The touch screen can be configured to receive input from an operator. A control circuit can be configured to control operation of the system, the control circuit coupled to the touch screen and configured to receive a weight of the donor. The control circuit can be configured to calculate an extracellular fluid volume of the donor based at least on the weight of the donor and calculate a target volume of the plasma product and/or raw plasma based at least in part on the extracellular fluid volume. The control circuitry may be configured to control the system to operate the collection and return stages to collect whole blood from a donor, separate the whole blood into a plasma product and a second blood component, and return the second blood component to the donor. The control circuitry may be configured to operate the collection and return stages until the volume of the plasma product in the collection container is equal to a target volume of the plasma product and/or raw plasma.

In another embodiment, the method of collecting plasma includes: (a) determining a donor's weight; (b) calculating the donor's extracellular fluid volume based at least in part on the donor's weight; (c) calculating a target plasma volume to be collected based at least in part on the calculated percentage of the donor's extracellular fluid volume; (d) drawing whole blood from the donor via a first line connected to the venous access device and the blood component separation device; (e) introducing an anticoagulant into the drawn whole blood via an anticoagulant line; (f) separating the drawn whole blood into a plasma component and at least a second blood component; (g) collecting the plasma component from the blood component separation device into a plasma collection container; and (h) continuing steps (d) through (g) until a target plasma volume to be collected in the plasma collection container is reached.

In a first aspect of the present disclosure, a system for collecting plasma from a donor is provided, the system comprising: a blood separator for separating whole blood into a plasma product and a second blood component including red blood cells; a donor line for introducing whole blood from the donor into the blood separator; a first pump for controlling flow through the donor line; an anticoagulant line coupled to an anticoagulant source for combining anticoagulant with the whole blood; and a second pump for controlling flow through the anticoagulant line.

A touch screen is provided for receiving inputs from an operator to a controller programmed to control the operation of the system. The controller is configured to control the operation of the system to determine a target volume of plasma product to be collected (TVPP) based on donor weight and donor hematocrit or based on donor weight and height and donor hematocrit, perform a collection and return cycle to collect whole blood from the donor, add anticoagulant to the whole blood at a predetermined ratio (ACR), separate the anticoagulated whole blood into a plasma product and a second component, return the second component to the donor, and stop collection of whole blood from the donor and initiate a final return of the second blood component when the measured volume of plasma product in the plasma collection container reaches the target volume of plasma product.

In a second aspect, the control unit is programmed to calculate i) a target volume of pure plasma (TVP) to be collected based on the donor's weight, and ii) a percentage of anticoagulant in the target volume of plasma product to be collected based on the donor's weight (%AC _TVPP ) based on a predetermined anticoagulant ratio ACR, and the donor's hematocrit, where TVPP=TVP/(1-%AC _TVPP ), and %AC _TVPP is expressed as a fraction.

In a third aspect, the control unit is programmed to calculate the donor's total blood volume (TBV) based on the donor's weight and height, a target volume of pure plasma (TVP) to be collected as a percentage of the TBV, and a percentage of anticoagulant in the target volume of plasma product to be collected (%AC _TVPP ) based on a predetermined anticoagulant ratio (ACR) and donor hematocrit, where TVPP=TVP/(1−%AC _TVPP /100), where %AC _TVPP is expressed as a fraction.

In a fourth aspect, the control unit is programmed to calculate the donor's total blood volume (TBV) based on the donor's weight and height to calculate the donor's body mass index (BMI), TBV=(weight×70)/(√BMI/22) (Lemens' equation). In alternative embodiments, calculations or estimates of total blood volume other than Lemens' equation may be used.

In a fifth aspect, the control unit is programmed to calculate the donor's total blood volume (TBV) based on the donor's weight (Wt), height (Ht) and gender (male or female) as follows: for men, TBV = (0.3669 x ^Ht3 ) + (0.03219 x Wt) + 0.6041; for women, TBV = (0.3561 x ^Ht3 ) + (0.03308 x Wt) + 0.1833, where Ht is in meters and Wt is in kilograms (Nadler's formula).

In a sixth aspect, a method is provided for performing plasma exchange to collect a volume of plasma product (i.e., anticoagulated plasma, VPP) such that a target volume of pure plasma (TVP) in the plasma product is determined based on donor-specific characteristics consistent with donor safety and comfort. In particular, the target volume of pure plasma (TVP) to be collected is based on the donor's weight, or weight and height.

In a seventh aspect, the target volume of pure plasma to be collected (TVP) can be a multiple or fraction of the donor's body weight. Alternatively, the TVP can be a multiple of the donor's total blood volume (TBV), with the donor's TBV being determined based on the donor's weight and height using established methodologies such as the Lemens Equation or Nadler's Formula.

The target volume of plasma product to be collected (TVPP) is established based on the target volume/weight of pure plasma and the percentage of anticoagulant AC in the plasma product (%AC _TVPP ), TVPP=TVP/(1−%AC _TVPP /100), where %AC _TVPP is expressed as a _fraction , based on the AC ratio (ACR) and donor hematocrit.

Once the TVPP is determined, the plasma exchange procedure is initiated, in which whole blood is drawn from the donor, mixed with an anticoagulant in a specific ratio, and then separated into plasma, red blood cells, and other cellular components. Once the TVPP is collected, as determined, for example, by a weighing scale associated with the plasma collection container, the drawing of whole blood from the donor is stopped and the red blood cells and other cellular components are returned to the donor.

In a seventh aspect, in determining the target volume of plasma product to be collected, the donor's hematocrit may be determined prior to the collection phase of each cycle, either by calculation or based on a signal from a sensor or the like indicative of the donor's hematocrit. Additionally, the amount of plasma product in the plasma collection container may be determined, for example, by a weigh scale associated with the plasma collection container or an optical sensor that directly measures volume.

In another aspect, a method is provided for operating a plasma exchange system to collect a plasma product volume that includes the maximum allowable volume/weight of raw plasma according to the limits set forth in the FDA nomogram based on the donor's weight.

To collect the maximum volume/weight of raw plasma allowed by the FDA nomogram, a modified nomogram is provided that utilizes the donor's hematocrit to calculate a target volume/weight of a plasma product having the maximum volume of raw plasma allowed by the FDA nomogram. The calculated volume/weight of raw plasma is compared to the maximum volume/weight of raw plasma allowed by the FDA nomogram. If the calculated volume/weight of raw plasma is less than the maximum allowable volume/weight, the volume/weight of the plasma product collected is adjusted upward by an amount equal to the difference plus the additional amount of anticoagulant added to process the additional volume/weight of plasma from the maximum volume/weight of plasma product allowed by the FDA nomogram.

Therefore, knowledge of the donor's hematocrit and the device's AC ratio is used to determine the volume of additional raw plasma that can be safely collected from the donor consistent with the limits set forth in the FDA nomogram, and then the total volume/weight of the plasma product collected based on the donor's weight as outlined in the FDA nomogram is adjusted accordingly.

The plasma exchange procedure described herein may involve successive cycles of alternating phases, in one phase whole blood is drawn from the donor and plasma is separated and collected; in the other phase separated red blood cells and any other non-RBC cellular components are returned to the donor. The donor's hematocrit changes during the course of the plasma exchange procedure, thus affecting the amount of anticoagulant in the plasma product collected from one cycle to the next.

In a first aspect of the present disclosure, the donor's new hematocrit is determined prior to the start of the subsequent extraction/separation step, and the target volume/weight of the plasma product of the procedure is recalculated prior to the start of each extraction/separation step to ensure that the maximum amount of raw plasma permitted by the FDA nomogram is collected.

In another aspect, a further method is provided for collecting a volume of plasma during an apheresis procedure, the steps of which include determining a donor's total whole blood volume, V _b , determining a volume of raw plasma (V _RP ) that can be taken from the donor based on V _b , and determining a target volume of plasma product (V _PP ) to be collected, where V _PP is equal to the volume of raw plasma (V _RP ) to be collected plus a volume of anticoagulant (V _AC ) added to the V _RP during the apheresis procedure, where V _PP =V _{RP .} x K, where K = (ACR x (1-Hct/100) + 1)/(ACR x (1-Hct/100)), which includes drawing whole blood from a donor based on an established anticoagulant ratio (ACR, defined for anticoagulant-free donor blood as the ratio of the volume of donor blood to the volume of anticoagulant for donor blood) and donor Hct for the procedure, adding an amount of anticoagulant consistent with the ACR to the whole blood, separating a plasma product from the whole blood, and transferring the plasma product to a collection container until the volume of plasma product in the collection container reaches _VPP . Because a plasma exchange procedure consists of multiple extraction/separation and return steps, the _VPP of the procedure is recalculated before each extraction/separation step is started based on the value of the donor's hematocrit determined before the start of each extraction step and the target volume of plasma product adjusted accordingly. Alternatively, _VRP may be determined based on a calculation of the donor's total plasma volume, based on _Vb and the donor's hematocrit.

In another aspect, a method is provided for determining the volume of plasma product (V _PP ) that may be collected during an apheresis procedure, where V _PP is equal to the volume of raw plasma (V _RP ) that may be collected plus the volume of anticoagulant (V _AC ) that is added to the V _RP during the apheresis procedure. The steps of the method include determining the donor's weight (W _kg ) and gender (male or female), determining the donor's hematocrit (Hct), determining the volume of raw plasma (V _RP ) that may be collected based on the donor's weight (W _kg ) and gender (male or female), determining the ratio K between V _PP and V _RP based on the anticoagulant ratio (ACR) and the donor's Hct such that K=V _PP /V _RP , and determining V _PP such that V _PP =V _RP ×K. Also, K=(ACR×(1−Hct/100)+1)/(ACR×(1−Hct/100)). After the V _PP is determined, whole blood is drawn from the donor, anticoagulant is added to the whole blood in an amount consistent with the ACR, the plasma product is separated from the whole blood, and the plasma product is transferred to a collection container. After the desired amount of whole blood has been drawn from the donor, the red blood cells are returned to the donor. The donor's Hct and V _PP are then determined before each collection step.

In a related embodiment, the steps of harvesting and separating are repeated until the volume of plasma product in the collection vessel reaches _VPP .

In a related aspect, the donor's hematocrit after the first collection stage can be calculated by volume balance, assuming that the donor's red blood cell mass is the same at the start of each collection cycle, while the total volume of blood decreases from one cycle to the next by an amount equal to the collected raw plasma. Alternatively, the donor's hematocrit at the start of each collection cycle can be measured with an optical or other sensor.

In further aspects, the volume of raw plasma that may be collected from a particular donor may be determined by any one of several different means. Such means include, for example, the FDA nomogram, which considers only the donor's weight, and modified FDA nomograms that further consider the donor's hematocrit and a portion of the total blood or plasma volume calculated for a particular donor. The total blood or plasma volume may be determined using, for example, Nadler's equation, Gilcher's rules, tables provided by the International Council for Standardization in Hematology (ICSH), or other generally accepted methods that use the donor's height, weight, sex, and age, consistent with donor safety and comfort.

In another aspect, an automated system for separating plasma from whole blood is provided, including reusable hardware components and a disposable kit. The disposable kit further includes: i) a separator for separating whole blood into a plasma fraction and an enriched cell fraction, the separator having an input integrally connected to a blood line for transporting whole blood from a donor to the separator; a plasma output port integrally connected to a plasma collection container by a plasma line; and an enriched cell outlet port integrally connected to a reservoir for receiving enriched cells prior to reinfusion into the donor; ii) a donor line terminating in a venipuncture needle for transporting whole blood from the donor to the blood line; iii) an anticoagulant line integrally connected to the blood line and configured to be connected to a source of anticoagulant for transporting anticoagulant to the donor line; and iv) a reinfusion line for transporting enriched cells from the reservoir to the donor line.

The reusable hardware components further include: i) a first peristaltic pump for delivering anticoagulant at a controlled rate to the blood line during the collection phase; ii) a second pump for delivering anticoagulated whole blood to the separator during the collection phase and returning concentrated cellular components during the reinfusion phase; iii) a third pump for delivering concentrated cellular components from the separator to the reservoir during the collection phase; iv) clamps associated with each of the blood line, plasma line, and reinfusion line; v) weighing scales for weighing each of the plasma collection container, the reservoir, and the anticoagulant source; and vi) a programmable controller having a touch screen for receiving input from an operator, the programmable controller being configured to receive signals from each of the weighing scales and automatically operate the first pump, the second pump, and the third pump and the clamps to separate the whole blood into a plasma fraction and a concentrated cellular fraction during the collection phase and to return the concentrated cells to the donor during the reinfusion phase. The programmable controller is further configured to determine a target amount of plasma product to be collected in the plasma collection container according to any of the aspects described herein, and to terminate the collection phase upon receiving a signal that the amount of plasma product in the plasma collection container is equal to the target amount of plasma product determined by the controller. In determining the target amount of plasma product to be collected, the controller may be configured to calculate the donor's hematocrit before the collection phase of each cycle. Alternatively, or additionally, the controller may receive a signal from a sensor or the like indicative of the donor's hematocrit. Additionally, the amount of plasma product in the plasma collection container may be determined, for example, by a weigh scale associated with the plasma collection, or an optical sensor that directly measures volume.

Figure 1 is a perspective view of an exemplary plasma exchange device suitable for use in the systems and methods of the present application.

Figure 2 is a perspective view, partially broken away to show detail, of a rotating membrane separator of the type incorporated into a disposable set that can be used in the plasma exchange system of Figure 1.

Figure 3 is a perspective view of the front panel of the plasma exchange system of Figure 1, showing the disposable set components mounted thereon.

Figure 4 is a schematic diagram showing the operation of the plasma exchange system during the collection phase.

Figure 5 is a schematic diagram showing the operation of the plasma exchange system during the reinfusion phase.

Figures 6a and 6b are a flow chart showing the steps of the method used in this application to collect a target volume of pure plasma.

Figure 7 is a table showing the volume of pure plasma based on donor hematocrit that falls within the plasma product volume limits set by the FDA nomogram using a 1:16 ratio of anticoagulant to whole blood.

Figure 8 is a table showing the volume of "unclaimed" pure plasma in a plasma product based on the difference between the values shown in Figure 7 and the maximum volume of pure plasma that can be collected based on the FDA nomogram.

Figure 9 is a table showing the volume of plasma product that can be collected from a donor based on donor weight and hematocrit, resulting in the maximum allowable volume of pure plasma permitted by the FDA nomogram.

FIG. 10 is a table showing inputs to a programmable control unit for performing a hypothetical plasma exchange procedure in accordance with the method of the present application.

Figures 11a and 11b contain a table divided into two parts that shows how the donor's hematocrit increases over the course of a hypothetical plasma exchange procedure based on inputs from the table in Figure 10, resulting in an increase in the total collected volume of plasma product required to collect a target volume of pure plasma.

Figure 12 is a graph showing IgG dilution during plasma exchange.

Figure 13 is a flow chart illustrating a method for collecting plasma using extracellular fluid volume according to another exemplary embodiment.

Figure 14 is a flow chart illustrating a method for collecting plasma using an estimate of physiological fluid volume and a pre-stored constant, according to another exemplary embodiment.

Figures 15A and 15B are charts plotting the percentage of ECFV removed as plasma against the increase in plasma volume achieved on the previous nomogram.

Figure 16 is a table showing the change in plasma collected using fixed Hct values and actual donor Hct.

Figure 17 is a table showing pre-stored constants for different nomograms using fixed Hct values.

Figure 18 is a table showing example nomograms for various different embodiments.

Figure 19 shows example blood volume formulas for various different embodiments.

A more detailed description of the systems and methods according to the present disclosure is provided below. It should be understood that the following description of the specific apparatus and methods is for illustrative purposes and is not exhaustive of all possible variations or applications. Thus, the scope of the disclosure is not intended to be limiting and should be understood to encompass variations or embodiments that may occur to one of ordinary skill in the art. Various aspects of the systems and methods are described in further detail in U.S. Patent Application Publication No. 2020/0147289, which is incorporated herein by reference.

In some embodiments, the target plasma volume to be collected can be set to be a percentage of the donor's extracellular fluid volume, improving consistency of risk across different donors.

In some embodiments, the consistency of the collected plasma product can be improved by setting the target plasma volume to be collected as a percentage of the donor's extracellular fluid volume.

In the context of this application, plasma exchange is performed on an automated system that includes hardware components, generally designated 10, for collecting plasma to be treated as source plasma, and a disposable set, generally designated 12. As described in more detail below with reference to Figures 1-5, the disposable set 12 consists of integrally connected separators, containers, and tubing for transporting blood and solutions within a sterile fluid pathway.

The separator 14, best shown in FIG. 2, has a spinning membrane filter 16 attached to a rotor 18 that rotates within a case 20 to separate the blood into components. A detailed description of the spinning membrane separator is provided in U.S. Pat. No. 5,611,113 to Schondorfer, which is incorporated herein by reference. As will be appreciated, in alternative systems, separation of whole blood may be accomplished by centrifugation. See, for example, U.S. Pat. No. 5,360,542 to Williamson et al.

During plasma exchange, anticoagulated whole blood enters separator 14 through whole blood input port 22. Plasma is separated by a spinning membrane filter and exits plasma output port 24 through plasma line 26 into plasma collection container 28. Enriched cells are pumped out enriched cell output port 30 into reservoir 32 where they remain until reinfused into the donor.

The disposable set 12 also includes tubing lines (donor line 34 terminating at venipuncture needle 36) for introducing whole blood from the donor into the system during collection and returning concentrated cells to the donor during reinfusion, a tubing line (blood line 38) for transporting anticoagulated whole blood to the separator, a tubing line (cell line 40) for transporting concentrated cells to a reservoir, a tubing line (reinfusion line 42) for transporting concentrated cells from the reservoir to the donor line, a tubing line (plasma line 44) for transporting saline (saline line 46), and a tubing line (AC line 48) for transporting anticoagulant.

The hardware components 10 include a programmable control 50 and a touch screen 52 with a graphical user interface ("GUI") for the operator to control the procedure. For example, the GUI allows for entry of any of the following: donor ID, donor gender, donor height, donor weight, donor age, donor hematocrit/hemoglobin, target saline infusion volume (if saline protocol is selected), and target plasma volume. The touch screen 52 also allows the operator to gather status information and handle error conditions.

Three peristaltic pumps are located on the front panel of the hardware component 10, including an AC pump 54, a blood pump 56, and a cell pump 58. The AC pump 54 delivers anticoagulant solution (AC) at a controlled rate into the blood line 38 as whole blood enters the set from the donor. The blood pump 56 pumps anticoagulated whole blood to the separator during the collection phase of the procedure and returns concentrated cellular components and, if necessary, replacement fluid to the donor during the reinfusion phase of the procedure. The cell pump 58 delivers concentrated cellular components from the separator 14 to the reservoir during the collection phase.

The front panel also includes four clamps to which tubing from the disposable set 12 is attached, including a reinfusion clamp 60, a blood clamp 62, a saline clamp 64, and a plasma clamp 66. The reinfusion clamp 60 closes during the collection phase (FIG. 5) to block the reinfusion line (42) and opens during the reinfusion phase (FIG. 5) to allow the blood pump to reinfuse concentrated cellular components from the reservoir 32 to the donor. The blood clamp 62 opens during the collection phase to allow anticoagulated whole blood to be sent to the separator 14 and closes during the reinfusion phase to block the blood line 38. The saline clamp 64 closes to block the saline line 46 during the collection phase and during reinfusion of the separated cellular components. If saline is used as the replacement fluid, the saline clamp 64 opens during the reinfusion phase. The plasma clamp 66 opens during the collection phase to allow plasma to flow into the plasma collection container 28 and closes during the reinfusion phase.

The hardware components 10 include three gravimeters for monitoring the current plasma collection volume (gravimeter 68), AC solution volume (gravimeter 70), and concentrated cellular content volume (gravimeter 72). The system also includes various sensors and detectors, including a venous pressure sensor 74, a separator pressure sensor 76, an optical blood detector 78, and an air detector 80.

The donor is connected to the system throughout the procedure. As shown, the disposable set 12 includes a single venipuncture needle 36 through which whole blood is drawn from the donor in a collection phase (FIG. 4) and enriched cells are returned to the donor in a reinfusion phase (FIG. 5). As noted above, the plasma exchange procedure includes multiple cycles, each cycle having a collection/separation phase followed by a return or reinfusion phase. In the collection phase, whole blood is separated into plasma and enriched cells. The disposable set includes a plasma collection container 28 for receiving the separated plasma and a reservoir 32 for receiving the enriched cells. In the reinfusion phase, enriched cells from the reservoir 32 are reinfused into the donor through the venipuncture needle 36. Plasma exchange performed using a single venipuncture needle 36 may involve multiple cycles of collection and reinfusion.

Returning to FIG. 4, during the collection phase, anticoagulant solution (AC) is pumped at a controlled rate and mixed with the whole blood entering the disposable set 12. The anticoagulated blood is sent to separator 14 where the plasma is separated from the cellular components and sent to plasma collection container 28.

The cellular components are pumped from the separator 14 to the reservoir 32. The collection phase stops when the reservoir 32 reaches the expected volume of concentrated cells or when the target plasma collection volume is achieved.

The reinfusion phase then begins. Referring to FIG. 5, during the reinfusion phase, the blood pump 56 reverses direction and pumps the concentrated cells from the reservoir 32 back through the apheresis needle 36 to the donor. If a saline protocol is selected, saline is returned to the donor as a replacement for the collected plasma, and saline is infused after the final reinfusion phase.

The automated plasma collection device is configured to collect a volume/weight of anticoagulated plasma (i.e., plasma product) having the maximum volume/weight of raw plasma allowed for the donor within the limits set forth in the FDA nomogram. To maximize the volume of raw plasma that constitutes the plasma product, the device is programmed with a nomogram that takes into account the donor's hematocrit. Knowing the donor's hematocrit and the AC ratio of the device, the total volume/weight of the plasma product to be collected can be determined such that the plasma product contains the maximum volume/weight of raw plasma fraction that can be collected from the donor that is consistent with the total volume/weight of raw plasma limits set forth in the FDA nomogram. By programming the calculations into the control unit, the possibility of operator error is reduced compared to calculating the collected volume offline and inputting it into the device.

During plasma exchange, when an anticoagulant is mixed with whole blood taken from a donor, the anticoagulant is uniformly distributed within the pure/unprocessed plasma in the blood, where the volume of pure/unprocessed plasma in the whole blood depends on the hematocrit (Hct) of the whole blood. The following relationship is established:
Red blood cell volume = whole blood volume × Hct/100 [1]
Volume of pure/unprocessed plasma = Volume of whole blood x (1-Hct/100) [2]
When anticoagulant is mixed with whole blood, it is metered in an AC ratio (ACR) of 16 parts whole blood to 1 part AC, or 1 part whole blood to 0.0625 parts AC.
ACR = volume of whole blood/volume of anticoagulant (donor blood does not contain anticoagulant) [3]
(This gives slightly different results than the FDA nomogram, which, as noted above, standardizes the volume of anticoagulant that can be added to a ratio of 1:16 anticoagulant to anticoagulated blood, or 0.06 parts anticoagulant to 1 part anticoagulated blood.)
Volume of anticoagulated blood = Volume of anticoagulant + Volume of whole blood [4]
Combining the equations we get:
Volume of pure/unprocessed plasma = ACR x volume of anticoagulant x (1-Hct/100) [5]
As the red blood cells are returned to the donor:
Volume of collected plasma product = Volume of pure/raw plasma + Volume of anticoagulant [6]
Combining equations [5] and [6], the amount of anticoagulant in a given volume of collected plasma can be calculated.
Volume of anticoagulant = Volume of collected plasma product / (1 + ACR x (1 - Hct/100)) [7]
moreover,
Volume of collected plasma product = Volume of pure/raw plasma x K, where K = (ACR x (1-HCT/100) + 1)/(ACR x (1-HCT/100)) [8]

Given the relationship represented by the above equation, the volume of pure/unprocessed plasma contained within the volume of plasma product permitted under the FDA nomogram can be determined based on the donor's hematocrit. The results of such calculations are shown in FIG. 7, which illustrates the volume of pure/unprocessed plasma based on donor's hematocrit contained within the plasma product volume limits set by the FDA nomogram.

As can be seen with reference to FIG. 7, if the donor weighs 110-149 pounds (the FDA nomogram allows for a maximum plasma product volume of 690 mL) and the donor has a hematocrit of 42 or greater, the volume of raw plasma collected is less than the 625 mL permitted by the FDA nomogram. The situation is similar for donors with a hematocrit of 40 or greater, those weighing 150-174 pounds (the FDA nomogram allows for a maximum plasma collection volume of 825 mL), and those weighing 175 pounds or greater (the FDA nomogram allows for a maximum plasma collection volume of 880 mL).

The table shown in FIG. 8 shows the volume of "unclaimed" raw plasma in the plasma product based on the difference between the values shown in FIG. 7 and the maximum volume of pure/raw plasma that can be collected based on the FDA nomogram. Thus, as shown in the table shown in FIG. 9, the plasma product taken from a particular donor can be adjusted from that listed in the FDA nomogram by an amount corresponding to the amount of "unclaimed" pure/raw plasma listed in FIG. 8 plus the amount of anticoagulant needed to process the additional volume.

Alternatively, the volume of plasma product collected can be calculated by first determining the donor's weight and hematocrit (Hct), determining the volume of raw plasma (V _RP ) that can be collected based on the donor's weight (W _kg ), determining the ratio K between V _PP and V _RP based on the anticoagulant ratio (ACR; 1:16 or 0.0625:1 according to the FDA nomogram) and the donor's Hct, such that K=V _PP /V _RP , and determining V _PP such that V _PP =V _RP ×K, where K=(ACR×(1−Hct/100)+1)/(ACR×(1−Hct/100)).

In yet another method, the volume of plasma product collected (V _PP ) can be calculated by first determining the donor's weight (W _kg ) and hematocrit (Hct), determining the volume of raw plasma (V _RP ) that can be collected based on the donor's weight (W _kg ), determining the volume of anticoagulant (V _AC ) to be added based on the anticoagulant ratio (ACR; 1:16 or 0.06:1 according to the FDA nomogram) and the donor's hematocrit such that V _AC = V _RP × (ACR × (1-Hct/100)), and determining the collected volume such that V _PP = V _RP + V _AC .

In accordance with one aspect of the present disclosure, the automated plasma collection device is configured to collect a volume/weight of plasma product (pure plasma + anticoagulant) with the volume/weight of pure plasma allowed to the donor determined by any of the following:

Referring to Figure 6a, a first method (70) for collecting a target volume of plasma product (TVPP) is shown. In this method, the target volume of plasma product (TVPP) is determined by first calculating a target volume of pure plasma (TVP) to be collected based on the donor's weight (step 72), and then determining the percentage of anticoagulant (%AC _TVPP ) in the target volume of plasma product to be collected based on a predetermined anticoagulant ratio (ACR) and donor hematocrit, where TVPP = TVP / (1 - %AC _TVPP / 100), where %AC _TVPP is expressed as a fraction (step 74). This method does not require any intervening calculations of either the donor's total blood volume or total plasma volume prior to determining the target collection volume of the donor's plasma, although in alternative embodiments such calculations may be included.

Various methods can be used to determine the target volume of pure plasma that can be collected directly from the donor's weight. For example, the donor's weight may be multiplied by an established constant "K ₁ " (such as 10 mL/kg). Alternatively, the donor's weight may be classified into weight categories or ranges (e.g., at least three categories, at least six categories, etc.) and a fixed volume set for each category (the FDA nomogram discussed above classifies donor weight ranges into three categories).

The anticoagulant ratio (ACR) may be defined in one of two different ways. In the first way, ACR ₁ is the ratio of the volume of whole blood to the amount of anticoagulant (ACR ₁ =WB/AC). In the second way, ACR ₂ is the ratio of the volume of whole blood plus the volume of anticoagulant to the volume of anticoagulant (ACR ₂ =(WB+AC)/AC). When ACR=WB/AC, the percentage of anticoagulant in the target volume of plasma product (%AC _TVPP ) is determined according to the following equation: %AC _TVPP =1/(1+ACR(1-Hct/100)), where Hct is expressed as a percentage. When ACR=(WB+AC)/AC, the percentage of anticoagulant in the target volume of plasma product (%AC _TVPP ) is determined according to the following equation:
%AC _TVPP = 1/(1+(ACR-1)(1-Hct))
The ACR can be expressed as either a ratio or a percentage and can range from 7:1 to 20:1, or about 5% to 14%. An exemplary ACR is 16:1, or 6.25%.

Returning to FIG. 6a, once TVPP has been determined as described above, whole blood is drawn from the donor (step 76) and mixed with anticoagulant based on a predetermined ratio ACR (step 78). The anticoagulated whole blood is then introduced into separator 14 where it is separated into plasma and packed (red blood) cells (step 80). The plasma product (pure plasma and anticoagulant) is collected in plasma collection container 28 (step 82) and the separated red blood cells are collected in reservoir 32. As the plasma product is collected, the volume VPP of the plasma product (pure plasma and anticoagulant) in the plasma container is determined (step 84). When VPP is equal to the target volume (TVPP) of the plasma product, the whole blood collection is stopped and the remaining blood components (such as red blood cells) are returned to the donor (step 86).

Referring to Figure 6b, a second method (90) for collecting a target volume of plasma product TVPP is shown. In this method, the target volume of plasma product (TPPV) is determined by first calculating the donor's total blood volume (TBV) based on the donor's weight and height (step 92), calculating the target volume of pure plasma to be collected (TVP) as a percentage of the TBV (step 94), calculating the percentage of anticoagulant in the target volume of plasma product to be collected (%AC _TVPP ) based on a predetermined anticoagulant ratio (ACR) and hematocrit (step 96), and calculating TVPP = TVP / (1 - %AC _TVPP / 100), where %AC _TVPP is expressed as a fraction (step 98). The %AC _TVPP can be determined as described above in connection with the first method. In this method, it is not necessary to calculate the donor's total plasma volume in order to determine the target collection volume of the donor's plasma.

The donor's plasma volume can be estimated based on the donor's total blood volume, and the volume of plasma that can be collected consistent with donor safety and comfort can be based on this estimate. To estimate the donor's total blood volume, methods utilizing donor parameters can be used. The donor's total blood volume can be determined using one or more of the Lemens Equation (which uses the donor's body mass index to determine total blood volume), Nadler's Equation (which takes into account the donor's height, sex, and weight), Gilcher's Rule of Five (which takes into account sex, weight, and conformation (obese, lean, normal, or muscular)), or the International Council for Standardization in Hematology ("ICSH") standards (which take into account the donor's height, weight, age, and sex) described in British Journal of Hematology 1995, 89:748-56. Other methods for determining the donor's total blood volume can also be used, such as those disclosed in Lemens et al., "Estimating Blood Volume in Obese and Morbidly Obese Patients," Bariatric Surgery, 16, 773-776, 2006.
InBv=70/√(BMIp/22)
where _In Bv is the indexed blood volume, i.e., blood volume per unit mass of the donor, and BMI _p is the donor's body mass index based on the donor's weight and height. The age-dependent regression equation can also be used for the indexed blood volume _In BV at IBW (ideal body weight), as shown below.
_In BV = 90 - 0.4 x age (male), _In BV = 85 - 0.4 x age (female)
Therefore, indexed blood volumes can be calculated based on the donor's gender.

In another embodiment, more than one such method can be used and the average, median, or weighted average of the methods can be taken as the donor's total blood volume. For example, once the donor's total blood volume is determined, the donor's plasma volume can be estimated by multiplying the total blood volume by a constant " _K2 ", where _K2 is equal to (1-donor Hct).

Analysis of demographic, examination, and laboratory data from the 2015-2016 National Health and Nutrition Examination Survey, from which sex, age, height, weight, pregnancy data, and hematocrit were extracted in line with Pearson et al., "Interpretation of red cell volume and plasma volume measured in adults: the International Council for Standardization in Hematology Expert Panel on Radionuclides," British Journal of Hematology, 89:748-756 (1995) (where the ICSH-recommended formula was derived), confirms that for donors with certain characteristics (i.e., underweight women with high hematocrit), up to 36% of the available plasma can be collected within the current regulations. Plasmapheresis with such donors is considered safe, as it is routinely performed without side effects. This suggests that up to 36% of a donor's available plasma can be safely collected by plasmapheresis.

Given that only negative deviations of the donor's true blood volume from the predicted/calculated total blood volume present a potential risk, a further downward adjustment of the collectable volume of plasma may be appropriate, based on consideration of the deviations between the calculated blood volumes as determined by Pearson et al., cited above.

Therefore, the donor's total blood volume (TBV) can be calculated based on the donor's weight (Wt) and height (Ht), and the donor's body mass index (BMI) can be calculated such that TBV=(Wt×70)/√(BMI/22), where BMI=Wt/Ht ² , where Ht is in meters and Wt is in kilograms (Lemens' equation). See "Estimation of Blood Volume in Obese and Morbidly Obese Patients," Lemens et al., Bariatric Surgery 16, 2006, pp. 773-776.

Alternatively, the donor's total blood volume (TBV) can be calculated based on the donor's weight (Wt), height (Ht) and gender (male or female) as follows: for men, TBV = (0.3669 x ^Ht3 ) + (0.03219 x Wt) + 0.6041; for women, TBV = (0.3561 x ^Ht3 ) + (0.03308 x Wt) + 0.1833, where Ht is in meters and Wt is in kilograms (Nadler's formula).

The percentage by which the TBV is multiplied to obtain the TVP (and ultimately the TVPP) is selected to maximize the volume of pure plasma collected from the donor consistent with donor comfort and safety. The percentage range in various embodiments can be about 1%-15%, at least 15%, less than 18%, about 15%-17%, about 12%, about 16% or about 18% of the TBV. The TVPP may also be subject to a maximum collection volume, e.g., 1000 mL or 1050 mL, regardless of the donor's TBV.

An adjustment (V _C ) can be made to the calculated volume of whole blood TBV before calculating the target volume of pure plasma TVP, TVP=0.36(1-Hct)(TBV-V _C ), where V _C =523 mL. It is based on a regression analysis of experimental blood volume data described in Retzlaff et al., "Red Cell Volume, Plasma Volume, and Lean Body Mass in Adult Men and Women," Journal of Hematology, 33, 5:649-667 (1969). There is 95% confidence that the predicted blood volumes of individuals will differ by no more than 20.5%. Thus, a scaling factor of 0.795 can be applied to determine the collectable raw plasma that is 36% of the total plasma volume of the donor above. This will collect 28.6% of the donor's calculated raw plasma volume, consistent with donor safety and comfort.

Returning to FIG. 6b, once the TVPP has been determined (based on the TBV) as described above, whole blood is drawn from the donor (step 100) and mixed with anticoagulant based on a predetermined ratio (step 102). The anticoagulated whole blood is then introduced into separator 14 where it is separated into plasma and packed (red blood) cells (step 104). The plasma product (pure plasma and anticoagulant) is collected in plasma collection container 28 (step 106) and the separated red blood cells are collected in reservoir 32. As the plasma product is collected, the volume of the plasma product VPP (pure plasma and anticoagulant) in the plasma container is determined (step 108). When the VPP is equal to the target volume of the plasma product (TVPP), the whole blood collection is stopped and the remaining blood components (such as red blood cells) are returned to the donor (step 110).

Thus, the collection volume (volume of plasma product) is determined based on the volume of raw plasma volume that can be collected from a particular donor, the donor's hematocrit, and a fixed anticoagulant ratio (ACR). As a result, this method allows for more consistent control of the donor's raw plasma volume, the variable most relevant to donor safety.

In an exemplary method, an operator inputs into the system controller a collection volume of plasma product for a particular donor based on a target volume of raw plasma that can be collected. The target plasma collection volume can be as shown in FIG. 9 based on the donor's weight and hematocrit at the initial collection stage, or by any of the other methods described above. Alternatively, the controller is configured to calculate a target plasma product collection volume for the initial collection stage according to the methods described above, for example, upon the operator inputting either the donor's weight and hematocrit, and/or additional donor-specific information (e.g., donor's sex, height, and age) as required by the methodology used to determine the collectable target volume of plasma that can be collected.

In practice, the operator inputs into the system controller a collection volume of plasma product for a particular donor based on the target volume of raw plasma that can be collected. The target plasma collection volume can be as shown in FIG. 9 based on the donor's weight and hematocrit at the initial collection stage, or by any of the other methods described above. Alternatively, the controller is configured to calculate the target plasma product collection volume for the initial collection stage according to the methods described above, upon the operator inputting, for example, either the donor's weight and hematocrit, and/or additional donor-specific information (e.g., donor's sex, height, and age) as required by the methodology used to determine the collectable target volume of plasma that can be collected.

Preferably, the system administrator initially sets an indication of whether the target collection volume of plasma product (TVPP) is determined by the system (e.g., according to one of the methods described above) or is entered directly into the system by the operator. If the operator enters the TVPP, the system administrator disables the control's ability to calculate the TVPP. The system administrator also sets the AC ratio to be used for all procedures. If the control determines the TVPP, the administrator sets the system to allow either the operator or the donor administrator to enter into the control the appropriate donor-specific characteristics to calculate the TVPP according to one of the methods described above. This system allows donor parameters used for eligibility screening (weight, height, hematocrit, etc.) to be electronically transmitted to the machine, thus avoiding operator error in entering donor parameters. The donor management system can also utilize donor screening measurements, along with the relationship between the volume of pure plasma and the collection volume, to automatically calculate the TVPP to send to the plasmapheresis device's control. Otherwise, the control calculates the TVPP before collection of whole blood from the donor begins. Additionally, if the controller/donor management system calculates the TVPP, the administrator configures the system to allow the operator to enter a TVPP other than the calculated volume. Additionally, the system allows the operator to change the TVPP from the calculated TVPP before or during the procedure if, for example, the estimated time to perform/complete the procedure needs to be reduced for donor comfort or convenience reasons. Upon completion of the procedure, the actual volume of pure plasma collected, and the target volume of plasma (TPV), as well as the actual volume of plasma product collected (VPP) and the target volume (TVPP) are displayed.

As noted above, the plasma exchange procedure may be performed in multiple cycles of collection/harvesting and return/reinfusion phases. If the return/reinfusion phase does not include reinfusion of replacement fluid, the donor's hematocrit will increase with each cycle. Thus, if the target volume of the plasma product is determined based only on the donor's initial hematocrit and does not take into account the donor's increasing hematocrit, the percentage of anticoagulant in the plasma product will be greater (and the volume of raw plasma will be less) than predicted by the initial calculation to determine the target volume of the plasma product. Thus, to ensure that the volume of the plasma product collected contains the maximum volume of raw plasma determined to be collected from a particular donor, the target volume of the plasma product is recalculated periodically throughout the plasma exchange procedure, such as before the start of the collection phase of each cycle, to account for and account for changes in the donor's hematocrit.

Thus, a determination of the target volume of the plasma product is made based on the donor's initial hematocrit. The plasma exchange procedure begins with a first collection phase until a specified volume of whole blood (usually about 500 mL) is collected from the donor. An anticoagulant is added to the whole blood, and the anticoagulated whole blood is separated into plasma product, red blood cells, and other non-RBC blood components. At the end of the first collection phase, the red blood cells and non-RBC blood components are returned to the donor. The current volume of the plasma product to be collected after the first collection phase is determined, for example, by a gravimeter. Then, the current value of the donor's hematocrit is established, a new target volume of the plasma product to be collected is determined, and a second cycle of collection and return phases is performed. The cycle of collection and return phases is repeated until the target volume of plasma product for the plasma exchange procedure is collected, as recalculated before the start of each collection phase. After the final collection phase, the control unit initiates a final red blood cell reinfusion phase, after which the donor is disconnected.

The advantages of performing a plasma exchange procedure with multiple collection/reinfusion cycles according to the above methodology can be seen by reference to FIG. 10 and the tables of FIGS. 11a and 11b. FIG. 10 shows input data for a hypothetical plasma exchange procedure for a donor weighing 190 pounds (86.4 kg) and with an initial hematocrit of 44. With reference to the table of FIG. 1, the simplified FDA nomogram limits the volume of plasma collected from such a donor to 800 mL and the total collected volume of the plasma product to 880 mL. In this example, the FDA nomogram's limitations on the volume of raw plasma that may be collected are for illustrative purposes only. As noted above, other methodologies may be used to determine the amount of raw plasma that may be safely extracted from donors other than those indicated by the FDA nomogram.

The number of collection and reinfusion cycles in a plasma exchange procedure can vary from 3 to 12. In the hypothetical plasma exchange procedure, there are 5 collection and reinfusion cycles, which have been selected for illustrative purposes.

Prior to the start of the first collection cycle, the volume of raw plasma to be collected and the total target volume of plasma product to be collected are determined according to the method described above based on the donor's initial hematocrit. As shown in the first row of the table (Cycle 1 Start), the initial target volume of plasma product to be collected is 889 mL, which is the same as that shown in the table of FIG. 9 for a donor weighing 175 pounds or more and having a hematocrit of 44 to collect the FDA limit of 800 mL of raw plasma from the donor.

During each collection phase, 500 mL of whole blood may be drawn from the donor to which anticoagulant is added in a predetermined ratio (i.e., 1:16), with 31 mL added for each 500 mL collection cycle. The whole blood and anticoagulant are separated into plasma and red blood cell fractions.

During the first return phase (End of Cycle 1 Return), red blood cells and "non-RBC" blood components are returned to the donor, so that at the end of the first return cycle, the donor's hematocrit has increased to 45.6%. The amount of red blood cells in the total blood volume remains the same as at the beginning of the procedure, calculated by the controller based on the blood volume reduced by the amount of raw plasma collected. The controller can also determine a new hematocrit for the next cycle, taking into account the volume of anticoagulant reinfused at each return phase with the red blood cells, and the residual anticoagulant in the donor's whole blood collected from cycle 2 onwards. The volume of raw plasma to be collected for the procedure and the total target volume of the plasma product are then recalculated based on the donor's new increased hematocrit and raw plasma volume. This provides a new total target collection volume of 891 mL.

A second collection phase is then performed, resulting in a total of 430 mL of plasma product, including the 386 mL of raw plasma collected over the first two collection phases (End of Cycle 2 Collection). The red blood cells and "non-RBC" blood components are again returned to the donor, after which the donor's hematocrit is calculated to be 47.2%.

Two more collection phases of 500 mL are performed, each followed by a return phase, in which new values for the volume of raw plasma collected and the total volume of plasma product are determined before the start of each collection phase. As the donor's hematocrit increases, the recalculated target collection volume for the procedure increases to 893 mL (for the third collection phase) and then to 894 mL (for the fourth collection phase). A fifth "mini" collection cycle is performed to raise the volume of collected raw plasma to the 800 mL allowed by the FDA nomogram for the hypothetical donor. The recalculated target collection volume for the plasma product for the fifth collection phase remains at 894 mL.

Thus, as shown in the example above, when the target collection volume of the plasma product is recalculated for each collection step, a target collection volume of 894 mL of plasma product is obtained, which is required to collect the target volume of 800 mL of raw plasma. In contrast, 889 mL of plasma product would be collected if the target collection volume was determined based solely on the donor's initial hematocrit, and 880 mL if the target collection volume was based on the simplified FDA nomogram. In both cases, less than the target volume of 800 mL is collected.

As can be appreciated, the more accurately the donor's hematocrit can be determined, both before and during the procedure, the more likely it is that the target volume of the collected plasma product will contain the maximum volume of raw plasma that can be collected for a particular donor. As noted above, the donor's hematocrit during the procedure is based on the assumption that 100% of the red blood cells withdrawn in each collection cycle are reinfused in each return cycle, along with 100% of the non-RBC cell product and a volume of anticoagulant. However, it has been determined that during the course of the blood separation procedure, interstitial fluid may migrate into the intravascular space, resulting in the recovery of half of the collected volume. See Saito et al., "Interstitial fluid shifts to plasma compartment during blood donation," Transfusion 2013;53(11):2744-50. The shifted interstitial fluid is in addition to the red blood cells, non-RBC cellular products, and anticoagulants that are reinfused at each return stage. Thus, accounting for and accounting for the shift of interstitial fluid provides a more accurate determination of the hematocrit value and therefore the target volume of plasma product that will result in the greatest amount of raw plasma.

The movement of interstitial fluid during plasma exchange has been demonstrated by tracking donor immunoglobulin G (IgG) levels over the course of the plasma exchange procedure. See, for example, Burkhardt et al., "Immunoglobulin G levels during collection of large volume plasma for fractionation," Transfusion 2017;56:417-420. If interstitial fluid had not been moved, the donor's IgG levels would have remained stable over the course of the plasma exchange procedure. However, IgG levels have been shown to decrease, and the amount by which IgG levels decrease is a function of the volume of interstitial fluid moved into the blood system.

Referring to FIG. 12, an empirically developed plot of plasma volume collected (along the X-axis versus IgG concentration (along the Y-axis)) is shown. A 9% drop in donor IgG is seen from a baseline of zero plasma collection (at the start of the procedure) to 200 mL of plasma collection, with an additional 4% drop from 200 mL to 800 mL collection. This is due to a shift in interstitial fluid from approximately 9% of the donor's initial total blood volume (after 200 mL of plasma has been collected) to approximately 13% of the donor's initial total blood volume (after 800 mL of plasma has been collected).

The following relationship between the amount of donor IgG concentration and the volume of collected plasma was established: y=1.0017x ^-0.02 , where y=IgG concentration and x=collected plasma volume. Thus, the percentage of the donor's blood volume displaced by interstitial fluid movement is equal to V _b (1-y), where V _b is the initial volume of the donor's whole blood. Thus, the moved volume of interstitial fluid can be calculated based on the collected plasma volume, and this amount can be added to the volumes of red blood cells, non-RBC cellular products, and anticoagulant reinfused at each return stage to determine the donor's current total blood volume and hematocrit. As can be seen, the controller can be configured to automatically determine the volume of interstitial fluid moved based on the volume of collected plasma and include the moved volume when determining the donor's hematocrit prior to each collection stage.

Alternatively, other methods of directly measuring the donor's hematocrit can be used, such as an optical sensor or, if a centrifuge is used, measuring the volume of red blood cells in the centrifuge.

In some embodiments, changes in donor-specific parameters (e.g., weight, hematocrit, etc.) over time can be used to adjust the target volume of plasma product and/or raw plasma collected for that donor. In some embodiments, accounting for changes may improve donor safety and/or product consistency. In one example, changes in a donor's hematocrit from one donation to another can be used as a surrogate marker of changes in that particular donor's hydration status over time (e.g., between different encounters at a donation center). The controller can be configured to recalculate or adjust the target volume of plasma product and/or raw plasma calculated in a previous donation based on changes in donor weight, hematocrit, etc. in subsequent donations.

In addition, anticoagulant is generally introduced into the disposable kit in a pretreatment step, such as priming the disposable kit, running one or more pre-cycles, or running other pretreatment steps, prior to starting the plasma exchange procedure. To the extent that the anticoagulant used for these purposes is ultimately directed to the plasma product collection container, it can be factored in to determine the volume to be included in the plasma collection container that will result in a target volume of raw plasma to be collected. This can be done, for example, by measuring the weight of a "full" container of anticoagulant and the weight of the container of anticoagulant prior to the start of the first collection cycle, and adding that volume of anticoagulant to the target volume of plasma product. The controller can be configured to automatically perform the steps necessary to account for the anticoagulant introduced into the plasma collection container separately from the anticoagulated plasma.

In another embodiment, a system and method is described for collecting plasma based on the donor's extracellular fluid volume (ECFV). Extracellular fluid refers to the bodily fluid that is outside the donor's cells. In some cases, extracellular fluid may make up approximately one-third of the bodily fluid, with the remaining two-thirds being intracellular fluid. Extracellular fluid may include interstitial fluid, plasma, lymphatic fluid, and transcellular fluid (e.g., cerebrospinal fluid, fluid in the gastrointestinal tract, etc.).

In some embodiments, the consistency of risk across different donors can be improved by setting the target plasma volume to be collected as a percentage of the donor's extracellular fluid volume. Significant donor hypotensive adverse events may correlate with relative ECFV clearance.

In some embodiments, the consistency of the collected plasma product can be improved by setting the target plasma volume to be collected as a percentage of the donor extracellular fluid volume.

In some embodiments, setting the target plasma volume to be collected based on the donor's extracellular fluid volume can provide incremental plasma with significant antihypertensive adverse event (SHAE) rates comparable to other methods of setting the target plasma volume to be collected.

In some embodiments, setting a target plasma volume to collect may be more appropriate given the rapid transport of interstitial water in response to the reduction in plasma volume during donation.

The vascular system contains both extracellular fluid (e.g., plasma) and intracellular fluid (within red blood cells). The extracellular fluid volume (ECFV) is composed of (1) the extravascular fluid volume (ISFV), which is sometimes approximately 20% of body weight, and (2) the intravascular fluid volume, plasma (PV), which is sometimes approximately 4% of body weight. Thus, the ECFV can be estimated as follows:
ECFV (24% of BM) = ISFV (20% of BM) + PV (4% of BM) [9]

Extracellular fluid volume can be estimated or calculated in any of a number of different ways. In one example, the donor's extracellular fluid volume (ECFV) can be based on the donor's weight (BM) and height (H) as follows:
ECFV (L) = 0.02154 x BM ^0.6469 (kg) x H ^0.7236 (cm) [10]
where ECFV is expressed in liters, BM is expressed in kilograms, and H is expressed in centimeters. Bird et al., Appropriate Glomerular Filtration Rate Indexing for Children, J Nucl Med 2003;44:1037-1043 (Bird 2003). Alternative expressions in SI units are:
ECFV (L) = 0.6032 x BM ^0.6469 (kg) x H ^0.7236 (m) [11]
Here, H is expressed in meters.

In another example, the donor's extracellular fluid volume (ECFV) can be based on the donor's weight (W) and height (H) as follows:
ECFV(L)=aW ^b H ^c [12]
where a = 0.0399, b = 0.6065, and c = 0.6217 for women and a = 0.0755, b = 0.6185, and c = 0.4982 for men, weight W is expressed in kilograms, and height H is expressed in centimeters. Bird, N. J. and Peters, A. M., A new gender-specific equation for estimating extracellular fluid volume from adult height and weight, Nuclear Medicine Communications, 42: 58-62 (2021) (Bird 2021).

In another example, the donor's extracellular fluid volume (ECFV) can be based on the donor's body weight (BM) and height (H) as follows:
ECFV (L) = sqrt (BM (kg)) x H (m) [13]
where ECFV is expressed in liters, BM is expressed in kilograms, and H is expressed in meters. Abraham et al., Extracellular Volume and Glomerular Filtration Rate in Children with Chronic Kidney Disease, Clin J Am Soc Nephrol, April 2011 6(4):741-747. In another example, the donor's extracellular fluid volume may be based on body weight (BM) and height (HT) with the following coefficients:
ECFV (L) = 0.96 x BM ^0.51 x H ^0.96 [14]

In another example, extracellular fluid volume can be calculated as extracellular fluid weight (ECFW) based on the donor's body mass (BM) as follows:
ECFW (kg) = 0.135 x BM (kg) + 7.35 kg [15]
where ECFW and BM are expressed in kilograms.

In another example, the donor's extracellular volume (ECFV) can be based on the donor's body weight (BM) and height (H) as follows:
ECFV (L) = 0.0682 x BM ^0.400 (kg) x H ^0.633 (cm) [16]
where ECFV is expressed in liters, BM is expressed in kilograms, and H is expressed in centimeters. Friis Hansen, Body Water Compartments in Children: Changes During Growth and Associated Changes in Body Composition, Pediatrics; Volume 28, Number 2, August 1961. In another example from Friis Hansen, the donor's extracellular fluid volume (ECFV) may be based on body weight alone (BM) as follows:
ECFV(L)=0.583×BM ^0.678 [17]
Here, ECFV is expressed in liters and BM is expressed in kilograms.

In other examples, the extracellular fluid volume may be calculated by first calculating the total body fluid (TBF) volume using any known algorithm, calculating the intracellular fluid (ICF) volume, and subtracting the ICF from the TBF. Other calculations and/or estimates of extracellular fluid are also contemplated.

In any of the formulas for calculating or estimating extracellular fluid volume, the weight used in the formula may be lean body mass instead of total body mass, with appropriate constants. Lean body mass may be the difference between total body mass and fat mass. Lean body mass can be calculated from height and total body mass using formulas such as Bohr, James, and Hume. For example, the Bohr formula is:
For men, eLBM = 0.407W + 0.267H - 19.2 [18]
For women, eLBM = 0.252W + 0.473H - 48.3

Once the amount of extracellular fluid (volume or weight) has been calculated or estimated using one of the above formulas (or another), a percentage of the extracellular fluid volume can be calculated as the target raw plasma volume to be collected. For example, the control circuitry can be configured to calculate the target raw plasma volume to collect as a percentage of the extracellular volume, preferably between about 4% and about 7%, between about 5% and about 6%, at least about 5%, less than about 5.5%, about 5.6% or about 5.25%. The control circuitry may be further programmed to set the target raw plasma volume to collect based on a maximum plasma volume or maximum plasma weight (e.g., 1000 mL or less). In some embodiments, the volume of extracellular fluid may be the primary parameter used to calculate the target raw plasma volume to be collected, although other parameters or equations may be used to ensure that the calculated volume is within an acceptable range.

In some embodiments, the controller may be programmed to calculate the target raw plasma volume to collect using multiple different equations, such as at least two different equations, at least three different equations, etc. The final target raw plasma volume to collect may be based on an average of the target raw plasma volumes from the different equations.

In some embodiments, the ECFV can be calculated or estimated from the extracellular fluid weight.

In one embodiment, a system for collecting plasma may include a separator configured to separate whole blood into a plasma product and a second blood component including red blood cells, the blood separator having a plasma output port coupled to a plasma line configured to deliver the plasma product to a plasma product collection container. The system may include a donor line for introducing whole blood from a donor into the separator, the flow through the donor line being controlled by a first pump. The system may include an anticoagulant line coupled to an anticoagulant source, the flow through the anticoagulant line being controlled by a second pump to mix the anticoagulant with the whole blood from the donor based on an anticoagulant ratio. The system may include a touch screen configured to receive input from an operator and a control circuit configured to control operation of the system. The control circuit may include one or more digital and/or analog circuit components configured or programmed with an algorithm to perform one or more of the aspects described herein. The control circuit may be coupled to the touch screen and configured to receive at least a weight of the donor, and optionally a weight and a height of the donor. The control circuitry may be configured to calculate the donor's extracellular fluid volume (volume or weight) based at least on the donor's body weight. The control circuitry may be configured to calculate a target volume of plasma product and/or raw plasma based at least in part on the extracellular fluid volume, for example, by calculating a numerical percentage or portion of the extracellular fluid volume as a target volume of plasma product or raw plasma. The control circuitry may be configured to control the system to operate the collection and return stages to collect whole blood from the donor, separate the whole blood into a plasma product and a second blood component, and return the second blood component to the donor. The second blood component may be returned to the donor during each return stage. The control circuitry may further be configured to operate the collection and return stages until the amount of plasma product in the collection container is equal to the target volume of plasma product and/or raw plasma.

The control circuitry can be configured to receive the donor's weight and height over the network from a donor management system, which is used for eligibility screening.

The target volume of plasma product and/or raw plasma can be calculated prior to initiating blood collection from the donor.

The control circuitry may be configured to determine whether the amount of raw plasma in the collection container meets a target amount of raw plasma by weighing the amount of plasma product in the collection container and calculating the volume of raw plasma in the collection container based on at least the weight of the plasma product and the percentage of anticoagulant in the collection container.

The anticoagulant ratio may be equal to the volume of whole blood divided by the volume of anticoagulant. The anticoagulant ratio may be equal to the volume of whole blood plus the volume of anticoagulant divided by the volume of anticoagulant. The anticoagulant ratio can be expressed as the reciprocal of these formulas (e.g., 16 parts whole blood to 1 part AC, or 1 part AC to 16 parts whole blood).

The control circuitry can be configured to perform at least three collection and return cycles, and the control circuitry can be configured to determine a volume of whole blood to be collected in a final collection step that is different (e.g., less) than the volume collected in an earlier collection step.

Referring now to FIG. 13, a method of collecting plasma using a plasma collection system as described above will be described. In step 1300, the donor's weight is determined, for example, by receiving the weight on a touch screen input device connected to the system, or by receiving the weight over a network from a donor management system or other remote computer used for donor screening. The donor's height and/or other donor parameters may also be determined in step 1300.

In step 1302, the method includes calculating the donor's extracellular fluid volume based at least in part on the donor's weight, and in an alternative embodiment, on the donor's height. Any of the above formulas may be used alone or together, or other formulas designed to estimate extracellular fluid volume may be used. This calculation may be an estimate or approximation of the donor extracellular fluid.

In step 1304, the method includes calculating a target plasma volume to collect based at least in part on the calculated percentage of the donor extracellular fluid volume. This percentage may be about 5.2%, about 5.4%, about 5.6%, less than about 6.0%, more than about 5.0%, more than about 4%, or other percentages.

At step 1306, the method includes beginning the collection of whole blood from the donor via a first line connected to the venous access device and the blood component separation device. At step 1308, the method includes introducing an anticoagulant into the collected whole blood through the anticoagulant line. At step 1310, the method includes separating the collected whole blood into a plasma component and at least a second blood component (e.g., including red blood cells). A centrifuge, spinning membrane, or other separator may be used. At step 1312, the method includes collecting the plasma component from the blood component separation device into a plasma collection container. In some embodiments, plasma collection may occur simultaneously with the separation at step 1310, such that plasma is separated and continuously deposited in the collection container during the separation process.

At step 1314, the method determines whether the target plasma volume has been achieved. This may be the target plasma product or the target raw plasma. This determination may be made using a volume or weight of either the plasma product or raw plasma calculated from one or more of a gravimeter, pump RPM, flow sensor, estimates, etc. If the target plasma is not reached, the method continues from step 1306 to step 1312 until the target is reached or achieved. At step 1316, the method continues to perform other steps, such as presenting a report of the plasma donation process on the touch screen or other post-processing steps.

Analyses were performed to evaluate the incremental plasma volume and SHAE rate of nomograms based on extracellular fluid volume (ECFV). The nomograms used were as follows:
V _pp =min(φECFV, V _pp.max ) [19]
Here, V _pp.max = 1050 mL and φ is determined. The Bird 2003 equation was used.
ECFV=aW ^b H ^c “20”
where a = 0.02154, b = 0.6469, c = 0.7236. A database of donor populations was used to analyse the amount of plasma volume that could be obtained using the Bird 2003 formula.

An estimate of φ was calculated by taking the mean plasma volume for this donor set using the previous nomogram (760 mL) and dividing it by the mean ECFV for the donor set calculated using Bird 2003 (16287 mL). Thus,
φ=760/1287=0.047 [21]

The incremental plasma volumes over and above those obtained with the previous nomograms were calculated for each gender separately and for the genders combined for the donor sets with φ=0.0500 and φ=0.0525. The incremental plasma volumes modeled using the ECFV nomogram with φ=0.0525 were 84.6 mL overall, which was nearly identical to the incremental plasma volumes modeled using the donor blood volume nomogram of 86.9 mL (i.e., V _PP =min(0.16×V _DB , V _PPMAX ), V _PPMAX =1050 mL and V _DB =donor blood volume). The incremental plasma volumes modeled using the ECFV nomogram with φ=0.0500 were 48.7 mL overall.

The SHAE rate was also modeled using Kaplan-Meier survival analysis to model the SHAE rate as a function of the percentage of blood volume removed as plasma instead of the traditional time variable. Such analysis was used to predict the SHAE rate based on the ECFV nomograms with φ = 0.0500 and φ = 0.525 separately for female and male donors. The probability of SHAE as a function of the percentage of ECFV removed as plasma was graphed based on the Kaplan-Meier analysis. Given the probability curves, a distribution of the percentage of ECFV removed was generated for the various nomograms. Multiplying the SHAE rate by the percentage of donors in each bin per bin gives the contribution per bin to the overall SHAE rate. Summing these contributions gives the overall modeled SHAE rate. For the FDA 1992 nomogram, modeled SHAE rates were 0.189 for women and 0.048 for men, totaling 0.119, assuming equal proportions of female and male donations. Modeled SHAE rates for the total blood volume nomogram were 0.235 for women and 0.071 for men, totaling 0.153. Modeled SHAE rates for the ECFV nomogram with φ = 0.0500 were 0.171 for women and 0.064 for men, totaling 0.118. Modeled SHAE rates for the ECFV nomogram with φ = 0.0525 were 0.214 for women and 0.071 for men, totaling 0.143. The observed SHAE rates from the database (542 SHAEs in 488,628 procedures) were 0.184 in women, 0.048 in men, and 0.111 overall.

A second similar analysis was performed using the Bird 2021 equation, with ECFVs further based on gender for a population of 1872 normal adults screened for possible kidney donation. The formula [20] was used, with a = 0.0399, b = 0.6064, and c = 0.6217 for women and a = 0.0755, b = 0.6185, and c = 0.4982 for men. The database of donor populations was used to analyze ECFV distribution by gender and gender combined. The distribution of the percentage of ECFV removed as plasma for the FDA 1992 nomogram was then graphed. The previous nomogram and the ECFV nomogram using the Bird 2021 equation were then used to obtain incremental plasma volumes of φ = 0.052, φ = 0.054, and φ = 0.056 for each gender separately and gender combined. The incremental plasma volumes (mL) modeled using the ECFV nomogram with φ = 0.052 were -20.0 in women, 82.6 in men, and 31.4 overall. The incremental plasma volumes modeled using the ECFV nomogram with φ = 0.054 were 7.20 in women, 111.5 in men, and 59.5 overall. The incremental plasma volumes modeled using the ECFV nomogram with φ = 0.056 were 34.1 in women, 138.3 in men, and 86.3 overall, which was in good agreement with the incremental plasma volumes modeled using the donor blood volume nomogram of 86.9 mL.

In this second analysis, the percentage of donations predicted to increase or decrease pure plasma donation volume compared to the previous nomogram was calculated. With the ECFV nomogram using Bird 2021 and φ = 0.052, 29.15% of women, 81.26% of men, and 55.26% of the total were predicted to increase pure plasma volume donation. With the ECFV nomogram using Bird 2021 and φ = 0.054, 43.95% of women, 94.63% of men, and 69.33% of the total were predicted to increase pure plasma volume donation. With the ECFV nomogram using Bird 2021 and φ = 0.056, 60.59% of women, 99.21% of men, and 79.94% of the total were predicted to increase pure plasma volume donation.

Kaplan-Meier survival analysis was also used to model SHAE rates as a function of the percentage of blood volume removed as plasma instead of the traditional time variable. Such analysis was used to predict SHAE rates based on ECFV nomograms using φ = 0.052, φ = 0.054, and φ = 0.056 separately for female and male donors using Bird 2021. The probability of SHAE as a function of the percentage of ECFV removed as plasma was graphed based on Kaplan-Meier analysis. Given the probability curves, distributions of the percentage of ECFV removed were generated for the various nomograms. Multiplying the SHAE rate by the percentage of donors in each bin per bin gives the contribution per bin to the overall SHAE rate. Summing these contributions gives the overall modeled SHAE rate. For the FDA 1992 nomogram, the modeled SHAE rates were 0.189 for women and 0.048 for men, totaling 0.119, assuming equal proportions of female and male donations. The modeled SHAE rates for the previous total blood volume nomogram were 0.240 for women and 0.072 for men, totaling 0.156. The modeled SHAE rates for the ECFV nomogram with φ = 0.052 were 0.133 for women and 0.064 for men, totaling 0.098. The modeled SHAE rates for the ECFV nomogram with φ = 0.054 were 0.170 for women and 0.073 for men, totaling 0.122. The modeled SHAE rates for the ECFV nomogram with φ = 0.056 were 0.208 for women and 0.073 for men, totaling 0.141. The observed SHAE rates from the database (542 SHAEs in 488,628 procedures) were 0.184 in women, 0.048 in men, and 0.111 overall.

A second analysis using the Bard 2021 formula predicted slightly lower ECFV values, therefore a higher %ECFV was used to obtain the desired incremental plasma volume of approximately 85 mL. The formula _Vpp = min(0.056 x ECFV, 1050)) met its objectives.

In the third analysis, the percentage difference in ECFV values (PECFV) between the Bird 2021 formula for females (ECFV_F) and the formula for males (ECFV_M) was calculated across the entire donor population of the donor database using donor weight and height, regardless of sex. Thus,
PECFV=100×(ECFV_F-ECFV_M)/ECFV_M [22]
A histogram was generated. In all cases, the female formula produced ECFV values approximately 5% lower than the male formula. Therefore, when selecting an ECFV for a particular donor regardless of gender,
ECFV=ECFV_F [23]
Without reference to the actual sex of the donor as an input, a slightly lower ECVF and a slightly lower (more conservative) pure plasma volume are selected. This formula may be used when the sex of the donor is not determined, or in other embodiments.

Now referring to FIG. 14, systems and methods for collecting plasma according to additional embodiments are described. Any of the structures and features described above can be used with additional embodiments, such as venipuncture needles, separators, donor lines, anticoagulant lines, calculations, etc. The input device can be configured to receive input data from an operator (e.g., via a touch screen, a nearby smartphone, etc.). The input device can be configured to receive input data over a network from a remote computer, such as a server computer configured to access and/or store donor data (e.g., donor ID, donor weight, donor height, blood donation history, digital image of donor, etc.) for multiple donors.

In step 1400, a control circuit of a reusable hardware component (e.g., plasma exchange machine, apheresis machine, etc.) is configured to receive donor parameters from one or more input devices, such as a touch screen, a keyboard, a wireless or wired network interface circuit, etc. The donor parameters may include one or more of parameters indicative of characteristics such as donor weight, donor height, donor body mass index, donor sex, donor extracellular fluid volume, donor intracellular fluid volume, donor blood volume, donor plasma volume, donor body surface area, or other donor physiological, biological, or other characteristics.

The control circuitry may be configured to estimate (step 1402) a physiological fluid volume of the donor based at least in part on one or more donor parameters. The estimation may be performed using one or more equations, such as the Bird 2003 equation, the Bird 2021 equation, the Lemens equation, the Nadler equation, or other equations. The physiological fluid volume may include one or more of donor blood volume, donor plasma volume, donor extracellular fluid volume, donor intracellular fluid volume, donor water volume, etc. The amount of fluid may be volume, weight, or other amount.

At step 1404, the control circuitry may be configured to calculate a target volume of raw plasma and plasma product including anticoagulant by multiplying a pre-stored constant by the estimated physiological fluid volume. The pre-stored constants may be programmed into the reusable components and/or control circuitry of the system during manufacturing and/or during software or firmware updates. The pre-stored constants may be calculated or estimated, as described below.

In one example, if the physiological fluid volume is an extracellular fluid volume, the pre-stored constant may be about 0.06125 for female donors, about 0.062715 for male donors, at least about 0.050, less than about 0.064, and/or other constants. In another example, if the physiological fluid volume is an extracellular fluid volume, the pre-stored constant may be about 0.06275 for female donors and about 0.06284 for male donors. See also FIG. 17. In yet another example, the pre-stored constant may be the same for both male and female donors, e.g., 0.06257 if an Hct of 36 is used for both male and female donors. One or more of these constants may be used when making the estimate using the Bird 2021 formula.

In another example, if the physiological fluid volume is total plasma volume, the pre-stored constant may be about 0.285 for female donors, about 0.3135 for male donors, at least about 0.25, less than about 0.34, or other constants. In another example, the pre-stored constant may be about 0.3192 for female donors, about 0.3197 for male donors, at least about 0.25, less than about 0.34, and/or other constants. In yet another example, the pre-stored constant may be the same for both male and female donors, e.g., 0.3183 if an Hct of 36 is used for both male and female donors.

In another example, if the physiological fluid volume is the total blood volume of the donor, the pre-stored constant may be about 0.16 for female donors, about 0.66 for male donors, at least about 0.10, less than about 0.75, or other constants. In another example, the pre-stored constant may be about 0.1761 for female donors, 0.1764 for male donors, at least about 0.10, less than about 0.75, and/or other constants. In yet another example, the pre-stored constant may be the same for both male and female donors, e.g., 0.1756 if an Hct of 36 is used for both male and female donors.

In some embodiments, the pre-stored constants may be different for male and female donors. The donor's gender may be one of the donor parameters received from the input device. The control circuitry may be configured to calculate the target plasma product to collect using male pre-stored constants for male donors and female pre-stored constants for female donors. Alternatively, one pre-stored constant may be used for both male and female donors.

At step 1406, the control circuitry may be configured to control the system to operate the collection and return steps to draw whole blood from a donor, introduce an anticoagulant (step 1408), separate the whole blood into a plasma product and a second blood component (step 1410), and return the second blood component to the donor. The plasma product is collected in a collection vessel (step 1412). The plasma product includes both raw plasma from the donor and anticoagulant provided from the anticoagulant source and processed through the separator.

At step 1414, the control circuitry is configured to measure the amount of plasma product including raw plasma and anticoagulant collected in the container. In one embodiment, the container is weighed to determine the weight of the collected plasma product, which is then converted to a volume of the plasma product. In another embodiment, other measuring devices may be used, such as an optical sensor, a pump rotation sensor or counter, or other devices.

At step 1416, the control circuitry determines whether the measured amount of plasma product in the collection container meets the target amount of plasma product calculated at step 1404 above. This determination is made at any of a number of stages in the collection process, such as at preset intervals (e.g., every 1 second, every 5 seconds during collection), in response to specific events (e.g., end of a collection and/or return cycle, start of a collection and/or return cycle), and/or at other times during processing. Once the target plasma product, including raw plasma and anticoagulant, is achieved, processing proceeds to step 1418 and performs other steps, such as stopping the pump, calculating and/or reporting the results of the procedure, and transmitting a collection report to a remote computer over a network.

The processes of FIG. 14 may be performed in the order shown, or in other embodiments, in a different order. In one example, the target volume of plasma product may be calculated prior to initiating whole blood collection. In another example, the target volume of plasma product may be calculated after initiating whole blood collection. In another example, the control circuitry may be configured to first estimate the donor's physiological fluid volume and then multiply that volume by a constant.

In some embodiments, donor hematocrit is not used in step 1416 or to determine when the measured amount of plasma product meets the target amount of plasma product. Instead, a constant that is not the donor's actual hematocrit may be used in place of the actual hematocrit to determine when the measured amount of plasma product meets the target amount of plasma product. In other embodiments, a constant may not be used to represent the donor's hematocrit.

In some embodiments, the actual donor hematocrit is not used in calculating the target amount of plasma product in step 1404 or otherwise. Instead, a constant (e.g., a minimum donor Hct set by a regulatory agency, an average donor Hct across a given donor population, etc.) may be used, or no constant may be used.

During plasma collection from a donor, the total plasma product (aka the total collected volume of pure or raw plasma and anticoagulant) can be affected by the ratio of anticoagulant used in processing the whole blood and the hematocrit of the donor. The factor F is the dilution factor of the anticoagulant and can be defined as:
F=1+1/R(1-H) [24]
where R is the anticoagulant ratio (such as 16:1, expressed in this formula as 16), H is the donor hematocrit, expressed in this formula as a decimal, such as 0.38, which represents 38% Hct. F can be used to determine the volume of raw plasma based on the volume of plasma product collected.
Volume of raw plasma = Volume of plasma product / F [25]
For example, if the plasma product volume is 900 mL, R is 16, and H is 50%, then F=1.125 and the volume of raw plasma collected will be 800 mL.

In one embodiment using the Bird 2021 system,
ECFV = f (weight, height, sex) [26]
where ECFV is the extracellular fluid volume, which according to the Bard 2021 formula is a function of the donor's weight, height, and sex.
F=f(ac_ratio, Hct) [27]
The factor F shown in equation [24] is a function of ac_ratio or R and Hct or H. Further, as shown in equation [25], volume of plasma product = volume of raw plasma x F. Therefore,
Volume of plasma product = f (weight, height, sex) x % x F (ac_ratio, Hct) [28]
If the target volume of raw plasma is x% of the ECFV (e.g., 5.6% as in one example above).

However, in another example, Hct can be omitted from equation [28] and replaced with a constant C.
Volume of plasma product = f (weight, height, sex) x % x F (ac_ratio, C) [29]

An analysis was conducted to determine the value of the constant C. Using a database of donor populations, the plasma volumes obtained using equation [28] (using actual donor Hct) and equation [29], which uses the mean hematocrit of donors in the donor population as the constant C instead of actual donor Hct, were analyzed. The analysis also determined the plasma volumes obtained using equation [28] using actual donor Hct and equation [29] using the minimum donor hematocrit assigned by the regulatory agency as the constant C instead of Hct.

Figure 16 is a table showing the results of the analysis. Using the mean donor Hct (42.6% for women and 46.2% for men) instead of actual Hct would have resulted in negligible changes in mean collected volume (0.1 mL less for women and 0.3 mL less for men). Using the minimum Hct instead of actual Hct would have resulted in 6.4 mL less mean total collected volume for women and 12.9 mL less for men. The mean raw plasma volume was also calculated and resulted in negligible changes (0.07 mL less for women and 0.25 mL less for men using mean Hct). The mean raw plasma volume using minimum Hct would have resulted in 5.8 mL less for women and 11.6 mL less for men. Combining genders, the mean total collected volume was calculated to be 0.20 mL less for both genders using mean Hct and 9.62 mL less for both genders using minimum Hct. The raw plasma volume for both sexes was calculated to be 0.2 mL less when using the mean Hct and 8.7 mL less when using the minimum Hct.

In one embodiment, the minimum Hct can be used as the constant C. In another embodiment, the average Hct across a given population can be used as the constant C. The average Hct of the donor population may be initially unknown. Furthermore, the minimum Hct is a conservative estimate assigned by the regulatory agency (FDA). For lower Hct donors, using the average Hct will result in more plasma being collected than using the actual Hct. Selecting the minimum Hct as the constant C is a more conservative estimate to optimize donor safety. Analysis shows that using the minimum Hct as the constant C will result in collecting, on average, about 10 mL less plasma than using the actual donor Hct. To accommodate the difference of 10 mL, it was proposed to increase x% in equation [29] to recover at least a portion of the 10 mL. To determine the amount by which to increase x%, an analysis of the incremental plasma volume achieved in the 1992 FDA nomogram was performed on the donor population using the donor's actual Hct and the minimum Hct. The results are plotted based on the percentage (mL) of extracellular fluid removed as plasma and are shown in accompanying FIG. 15A. For the desired target range of incremental plasma volume above the 1992 FDA nomogram 85±3 mL, a percentage of 5.65% is selected as fitting within the target range when using min Hct instead of actual donor Hct. In other words, the 5.60% percentage of ECFV that meets the target range when using actual donor Hct increases by 0.05% to 5.65% when using min Hct to maintain plasma increments above the previous 1992 FDA nomogram within the target of 85±3 mL. SHAE rates are also calculated for several data points, with a 5.65 point SHAE rate estimated to be 0.269%-0.300%.

In Figure 15B, an analysis of incremental plasma volume achieved across the 1992 FDA nomogram to determine the amount to increase x% was performed for a population of donors using donor actual Hct and Hct inputs of 38 for females/39 for males and 36 for females/36 for males. Results are plotted based on the percentage (mL) of extracellular fluid removed as plasma and are shown in attached Figure 15B. For the desired target range of incremental plasma volume above 85±3 mL of the 1992 FDA nomogram, a percentage of 5.70% was selected as fitting within the target range when using Hct inputs of 36 for females and 36 for males instead of actual donor Hct. In other words, to maintain plasma increments above the previous 1992 FDA nomogram within the 85±3 mL target range, the percentage of ECFVs meeting the target range when using actual donor Hct increased from 5.60% to 5.70% when using 36 Hct. SHAE rates were also calculated for several data points, and the SHAE rate for the 5.70 percentage points is estimated to be 0.294%.

In various embodiments, as shown in FIG. 17, the ECFV fraction may be selected from values of at least about 0.055% and/or less than about 0.0575%. The total plasma volume fraction may be at least about 0.25 and/or less than about 0.35. The total blood volume fraction may be at least about 0.12 and/or less than about 0.24.

In one embodiment, equation [29] above can be expressed as follows:
Volume of plasma product = f (weight, height, sex) x FH (x%, ac_ratio, C) [29.1]

where FH is a pre-stored constant that is a function of the percentage of ECFV to be collected and other variables previously defined. If ac_ratio is set to 16, constant C is set to the minimum Hct for male donors of 39 and the minimum Hct for female donors of 38 (set by regulatory agency), and x% is set to 5.65% of the increase rate, the equation becomes:
Volume of plasma product = f (weight, height, sex) x FH (constant) [30]
Plasma product volume _f = ECFV × 0.6125 (female) [31]
Plasma product volume _m = ECFV × 0.62715 (male) [32]
In this case, the pre-stored constants used in the method shown in Figure 14 are 0.6125 for female donors and 0.62715 for male donors. In alternative embodiments, a single constant may be used for both genders, which may be the average of the two constants, or the lower of the two constants, or another constant.

In an alternative embodiment, as shown in FIG. 17, x% can be set to an increase percentage of 5.70% with Hct set to 39 for male donors and 38 for female donors (see nomogram ECFV21-5.7-1050-H38/39). The physiological volume fraction (% of ECFV taken as target plasma product) is 0.057 or 5.70%. The AC coefficient F in equation [27] is 1.1008 for female donors and 1.1025 for male donors. The pre-stored constant C is 0.06275 for female donors and 0.06284 for male donors, resulting in a collection volume of 866 mL for females and 1049 mL for males.

According to another embodiment, Hct can be set to a constant 36 for both male and female donors as shown in Figure 17 (see nomogram ECFV21-5.70-1050-H36/36). The physiological volume fraction (% of ECFV taken as target plasma product) is 0.057 or 5.70%. The AC coefficient F in equation [27] is 1.0977. The pre-stored constant C is 0.06257 for both male and female donors, resulting in a collection volume of 864 mL for females and 1044 mL for males.

One advantage is that by using pre-stored constants, as described in the analysis above and in the method of FIG. 14, one can proceed without needing actual donor Hct. Between donor weight, height, and Hct, donor Hct has the greatest potential error with the method determined for each donor. Assigning a fixed Hct as the minimum Hct (e.g., 39 for men and 38 for women) offers the advantage of a passive approach, resulting in a safer estimate of plasma collection. Additionally, calculation of the target plasma product may be easier, require less processing power and time, thereby improving the operation of the control circuitry, and/or may be less prone to error, since a pre-stored constant for the donor is multiplied with the estimated ECFV of the plasma. The target plasma product may be 10.0% more for female donors and 10.2% more for male donors compared to the previous nomogram, e.g., increasing the target plasma product from 1000 mL to 1100 mL for female donors and from 1000 mL to 1102 mL for male donors.

The analysis performed demonstrated that the plasma collection algorithm can calculate the target plasma product to be collected without using actual donor Hct in the calculation of donor physiological fluid and/or without using actual donor Hct in the comparison of collected plasma product to the target plasma product. The analysis also demonstrated that in some embodiments, the percentage of ECFV volume collected can be increased from 5.60% to 5.65% or 5.70% with an acceptable SHAE rate, achieving the goal of increasing the raw plasma yield volume by approximately 85 mL over the 1992 FDA nomogram.

In some embodiments, the plasma collection device control circuitry can be configured to calculate a target plasma product, including raw plasma and anticoagulant, by multiplying the donor's estimated physiological fluid volume by a constant.

In some embodiments, the plasma collection device control circuitry can be configured to calculate the target plasma product, including raw plasma and anticoagulant, by multiplying the donor's estimated physiological fluid volume by constants only, not variables.

In some embodiments, the plasma collection device control circuitry may be configured to calculate a target plasma product that includes raw plasma and anticoagulant using the donor's estimated physiological fluid volume and predetermined constants in the calculation, but not the anticoagulant ratio in the plasma, which is pre-provided with a pre-defined constant.

In some embodiments, the pre-stored constants may be predetermined or pre-calculated by the plasma collection device manufacturer and programmed into the plasma collection device memory during manufacture. The pre-stored constants may be calculated based on one or more of a target percentage of physiological fluid volume (x%), an anticoagulant ratio (R), and a constant C used in place of actual donor Hct, a minimum donor Hct per regulatory rule, an average donor Hct across a given donor population, or other constants.

In the analysis performed above, the target range for improved plasma collection over the previous nomogram may have been 85±3 mL, but other target ranges for improved plasma collection may be used, such as at least 30 mL, at least 60 mL, less than 100 mL, less than 120 mL, etc., to reach the target percentage of physiological fluid volume.

According to another embodiment, a method for collecting plasma may include receiving one or more donor parameters selected from donor weight, donor height, donor body mass index, and donor gender. Any one or more of these donor parameters may be received from a user input device (e.g., touch screen, keyboard, etc.) coupled to the plasma collection device or from another input device, such as a network interface circuit, configured to receive donor parameters from a remote computer, such as a donor management system used for donor screening, donor recruitment, and/or other functions. In some ECFV equations, only weight may be used. In other ECFV equations, weight and height may be used. In still other ECFV equations, weight, height, and gender may be used.

The method may further include estimating a donor physiological fluid volume based at least in part on one or more donor parameters. The estimated donor physiological fluid volume may be selected from a group including total blood volume, total plasma volume, extracellular fluid volume, intracellular fluid volume, interstitial fluid volume, intercellular fluid volume, lymphatic volume, and/or other fluid volumes expressed in various units, such as volume, weight, area (e.g., body surface area). Any of the above-mentioned formulas or other available formulas, such as Remens, Bird 2003, Bird 2021, may be used to estimate one or more donor physiological fluid volumes. The donor physiological fluid volume may be calculated by the plasma collection machine as part of the plasma collection procedure for a particular donor.

The method may further include calculating a target volume of plasma product to be collected by multiplying the estimated donor physiological fluid volume by a pre-stored constant. The pre-stored constant may be determined during product development and programmed into the plasma collection device, e.g., firmware or other memory, during manufacturing. In some embodiments, the calculation may only involve multiplying the estimated donor physiological fluid volume by a pre-stored constant to arrive at the target volume of plasma product to be collected. In other embodiments, other coefficients may be used in the calculation. The pre-stored constant may be a pre-calculated constant (during product development, on a remote server computer, or even on the plasma collection device itself) based on a predetermined percentage (e.g., x%) of physiological fluid volume, a specific anticoagulant ratio (R) expressed as a ratio, fraction, decimal, or otherwise, and/or a donor Hct value or a constant (C) that is a surrogate for the donor Hct value.

When the physiological fluid is ECFV, the pre-stored constant may be greater than about 0.050 and/or less than about 0.064 or less than about 0.06257.

As shown in FIG. 17, the pre-stored constants can be at least about 0.28 and/or less than about 0.34, or about 0.0.3183, where the physiological fluid volume is the total plasma volume of the donor and Hct is set to 36 for both male and female donors. If Hct is set to 38 for female donors and 39 for male donors, the pre-stored constants can be about 0.3192 for female donors and about 0.3197 for male donors.

17, if the physiological fluid is the donor's total blood volume and Hct is set to 36 for both male and female donors, the pre-stored constant may be at least about 0.10 and/or less than about 0.20, or about 0.1756. If Hct is set to 38 for female donors and 39 for male donors, the pre-stored constant may be about 0.1761 for female donors and about 0.1764 for male donors.

Other constants are contemplated. In various embodiments, any of the pre-stored constants described in FIG. 17 or values described elsewhere herein may be within a range of at least about 50%, at least about 75%, less than about 150%, and/or less than about 200% of the indicated value. For example, if the donor's physiological fluid volume is ECFV and Hct is set to 36 for male and female donors, the pre-stored constant may be at least about 0.3128 (50% of the indicated value: 0.06257), at least about 0.04692 (75% of the indicated value: 0.06257, etc.), less than about 0.07508, and/or less than about 0.12514. For example, different embodiments may contemplate other values of Hct (at least about 33 Hct for male and/or female donors, less than about 45 Hct for male and/or female donors), other values of AC ratio (15:1, 16:1, 17:1, etc. (AC volume + whole blood volume)/(whole blood volume) or (AC volume/whole blood volume)), and/or other values of physiological fluid volume ratio (less than about 7.5% of ECFV, greater than or equal to about 4.5% of ECFV), whereby other predetermined constants may be used based on desired collection volume, desired SHAE percentage, etc.

The method may further include drawing whole blood from a donor via a venous access device to a blood component separation device. The calculations and estimations described above may be performed prior to drawing the whole blood, during drawing the whole blood, and/or after drawing of the whole blood has begun. The method may include introducing an anticoagulant to the drawn whole blood, separating the drawn whole blood into a plasma product comprising raw plasma and the anticoagulant and at least a second blood component (e.g., red blood cells), and collecting the plasma product from the blood component separation device in a plasma collection container.

The method may further include determining whether the collected plasma product (including raw plasma and anticoagulant) has reached a target amount of plasma product to be collected. This determination may be made at various points during the processing of the blood from collection to mixing with anticoagulant, separation, and returning the red blood cells to the donor. This determination may be made by receiving a signal from a weighing scale that weighs the plasma product collection container. The determination may include converting the weight of the plasma product to a volume of the plasma product. The determination may include comparing the measured volume of the plasma product to a target amount of plasma product to be collected. The determination may include determining that the collected plasma product has reached the target amount of plasma product to be collected when the collected plasma product is equal to or approximately equal to the target amount of plasma product or a value derived from the target amount of plasma product.

The control circuitry of the plasma collection machine can be programmed with one or more of a number of different nomograms. The nomograms may be based on the percentage or fraction of the donor's blood volume (BV), plasma volume (PV), extracellular fluid volume (ECFV), or weight removed as plasma (W). These nomograms can be expressed as follows:
V _PP = minimum (φ _BASE , _N V _BASE , V _{PP, MAX, M} ) [33]
where _V is the target volume of pure (or raw) plasma, the subscript BASE refers to the nomogram criteria above (PV, BV, ECFV or W), φ is the percentage of the donor base volume, _V is the maximum pure plasma volume, and the subscripts N and M refer to the particular values of φ and _V . Exemplary formulas for calculating BV and ECFV are provided above (e.g., Lemens, Bird 2003, Bird 2021, etc.). Plasma volume can be calculated as follows:
V _P = (1-H) V _B [34]
where H is the donor Hct (or the minimum or average Hct across a set of donors). Body weight can be measured in kilograms.

The control circuitry can be programmed with any nomogram with one or more characteristics, such as a baseline (PV=plasma, BV=blood, EDFV03=Bard 2003, ECFV21=Bard 2021, W=body weight), a percentage of the baseline volume removed as plasma (100φ _BASE ), a maximum pure plasma volume (V _PP,MAX ) and/or additional data such as expected Hct. The plasma collection system control circuitry can be programmed with any one or more of the nomograms shown in FIG. 18, which can use one or more of the formulas described above. For example, the nomogram designation PV-28.0-1000 indicates a nomogram based on a target raw plasma of 28.0% (not to exceed 1000 mL) of the total donor plasma volume. Nomogram designation ECFV21-5.70-1050 indicates a nomogram based on a target pure plasma of 5.70% of the donor extracellular fluid volume, not to exceed a maximum of 1050 mL pure plasma, using the Bard 2021 equation. As another example, nomogram designation ECFV21-5.70-1050-H38/39 indicates a nomogram based on a target pure plasma of 5.70% of the donor extracellular fluid volume, not to exceed a maximum of 1050 mL pure plasma, using the Bard 2021 equation, taking the hematocrit as the minimum acceptable value (38% for females and 39% for males) to calculate the collection volume.

As shown in FIG. 18, for the nomogram designated as -H38/39, the hematocrit can be taken as the minimum acceptable value (38% for females and 39% for males). For the one designated as -H36/36, a fixed hematocrit of 36% can be used regardless of gender. V _PP can be first assessed using the nomogram. The collected volumes (pure plasma and anticoagulant) can then be calculated assuming these fixed hematocrits. Again as shown in FIG. 18, the nomogram designated as ECFV21-5.60-1050-Female(3) can use the Bird2021 equation for females for all donors, male and female. For the nomogram designated as -H AVG, the collected volumes (pure plasma and anticoagulant) can be calculated using the average hematocrit for females and males. This amounts to 42.6% for males and 46.2% for females for one set of donors.

The original 1992 nomogram and the optimized nomogram are based on donor weight applied in stages. The nomogram, listed as weight (body volume) in FIG. 18, uses body weight continuously according to equation [33] under the assumption that body density is about 1.0 g/mL. φ _BASE can be expressed in milliliters per kilogram of body weight (9.90 mL/kg body weight). φ _BASE can also be expressed as a percentage of volume (in this case 0.99% and 1.00%). Other values of φ _BASE are contemplated, such as at least about 8 mL/kg, at least about 9 mL/kg, less than about 10.5 mL/kg, less than about 12.0 mL/kg, etc.

18, V _PP,MAX can be at least about 1000 mL, at least about 950 mL, at least about 800 mL, less than about 1050 mL, less than about 1100 mL, less than about 1200 mL, etc. Any of the nomograms described herein can include an upper limit V _PP,MAX .

For each of the nomograms listed in FIG. 18, the target used as the goal for completing plasma donation to the donor may be calculated as a target pure plasma or a target plasma product (pure plasma or raw plasma and anticoagulant). For each of the nomograms listed in FIG. 18, the calculation of the target plasma product may use one or more of the following: actual donor hematocrit, fixed donor hematocrit (e.g., 36, 38, 39), the same or different fixed hematocrits for female and male donors, the average of donor hematocrit across the donor population, or other values.

In various embodiments, the control circuitry of the plasma collection device may be configured to estimate the donor's physiological fluid volume using any of the nomograms described in FIG. 18 based at least in part on one or more donor parameters. Additionally, the control circuitry may be configured to calculate a target volume of plasma product including raw plasma and anticoagulant by multiplying the estimated physiological fluid volume by a pre-stored constant, the pre-stored constant being determined based on the respective nomogram described in FIG. 18.

As shown in FIG. 19, the donor's total blood volume (and/or total plasma volume) can be calculated or estimated using any of the models shown based on weight (W), height (h) and/or age (A). Feldshuh, J. and Y. Enson, "Prediction of Normal Blood Volume: Relationship Between Blood Volume and Body Habit," Circulation, 56(4):605-612 (1977). Harley, P. J., "Red Cell and Plasma Volumes in Normal Adults," Journal of Nuclear Medicine, 16(1):46-52 (1975). Nadler, S. B. et al., "Prediction of Blood Volume in Normal Adults," Investigative Surgery, 51(2):224-232 (1961). T. C. and Pearson, et al., "Interpretation of Measured Red Cell Volume and Plasma Volume in Adults: Expert Panel on Radionuclides of the International Council for Standardization in Hematology," British Journal of Hematology, 89:748-756 (1995). J. A. Retzlaff et al., "Red Cell Volume, Plasma Volume, and Lean Body Mass in Adult Men and Women," Journal of Blood Cell Counting and Testing, 33(5):649-667 (1969); Wenesland, R. et al., "Red Cell, Plasma, and Blood Volume in Healthy Men by Radioactive Chromium (Cr51) Cell Tagging," when used, body surface area S is calculated by the following formula:
S=0.007184W ^0.245 h ^0.725 [34]
where W is weight in kilograms and h is height in centimeters. Dubois, D. and E. F. Dubois, "Formula for estimating approximate surface area when height and weight are known," Archives of Internal Medicine, 17:863-871 (1916). The equation for surface area (S) can be written as:
S=aW ^b h ^c +d [35]
Here, d = 0.
Therefore, any model that simply scales S by some factor can be expressed in the same mathematical form as shown in the bottom table of FIG. 19 (the formula for calculating blood volume based on weight and height).

Additional embodiments of the methods and systems disclosed herein are described below.

In a first embodiment, a system for collecting plasma is provided. The system includes a separator configured to separate whole blood into a plasma product and a second blood component including concentrated cells. The separator has a plasma output port coupled to a plasma line configured to deliver the plasma product to a plasma product collection container. The system includes a donor line configured to introduce whole blood from a donor into the separator, the donor line having a flow through the donor line controlled by a first pump, an anticoagulant line coupled to an anticoagulant source, the flow through the anticoagulant line controlled by a second pump to mix anticoagulant with the whole blood from the donor based on an anticoagulant ratio, an input device configured to receive input from an operator and/or from a remote computer via a network, and a control circuit configured to control operation of the system. The control circuit is coupled to the input device and configured to receive one or more donor parameters, estimate a physiological fluid volume of the donor based at least in part on the one or more donor parameters, and calculate a target volume of a plasma product including raw plasma and an anticoagulant by multiplying a pre-stored constant by the estimated physiological fluid volume. The control circuit is configured to control the system to operate the collection and return stages to collect whole blood from the donor, separate the whole blood into a plasma product and a second blood component, and return the second blood component to the donor. The control circuit is further configured to operate the collection and return stages until a measured volume of the plasma product in the collection container reaches a target volume of the plasma product.

The second embodiment includes the first embodiment, where the control circuit is configured not to use the donor's hematocrit when determining when the measured amount of plasma product meets the target amount of plasma product.

The third embodiment includes the first embodiment, where the control circuit is configured not to use the donor's hematocrit in calculating the target amount of plasma product.

The fourth embodiment includes the first embodiment, where the estimated physiological fluid volume is an extracellular fluid volume.

The fifth embodiment includes the fourth embodiment, where the pre-stored constant is between about 0.050 and about 0.064.

A sixth embodiment includes the fourth embodiment, wherein the control circuit is configured to calculate the donor's extracellular fluid volume based on the donor's weight (W), height (H) and gender, ECFV=0.0399× ^W0.6065 × ^H0.6217 for females and ECFV=0.0755× ^W0.6185 × ^H0.4982 for males.

The seventh embodiment includes the first embodiment, where the estimated physiological fluid volume is the total plasma volume.

The eighth embodiment includes the seventh embodiment, where the pre-stored constant is between about 0.25 and about 0.34.

The ninth embodiment includes the first embodiment, where the estimated physiological fluid volume is the total blood volume.

A tenth embodiment includes the ninth embodiment, where the pre-stored constant is between about 0.10 and about 0.75.

An eleventh embodiment includes the first embodiment, where the pre-stored constants are different for male and female donors, and donor gender data is received from an input device and used to select between the male pre-stored constants and the female pre-stored constants.

A twelfth embodiment includes the first embodiment, in which the donor's weight and height are received over a network from a donor management system, which is used for eligibility screening.

A thirteenth embodiment includes the first embodiment, wherein the target amount of plasma product is calculated prior to initiating blood collection from the donor.

A fourteenth embodiment includes the first embodiment, wherein the control circuit is configured to measure the amount of raw plasma and plasma product including anticoagulant in the collection container using a weighing scale.

In a fifteenth embodiment, a method for collecting plasma is provided, the method including: (a) receiving one or more donor parameters selected from donor weight, donor height, donor body mass index, and donor gender; (b) estimating a donor physiological fluid volume based at least in part on the one or more donor parameters, the estimated donor physiological fluid volume being selected from total blood volume, total plasma volume, and extracellular fluid volume; and (c) calculating a target volume of a plasma product to be collected, the target volume of the plasma product including raw plasma and anticoagulant, the target volume of the plasma product being calculated by multiplying the estimated donor physiological fluid volume by a pre-stored constant. (d) drawing whole blood from a donor to a blood component separation device via a venous access device; (e) introducing an anticoagulant into the drawn whole blood; (f) separating the drawn whole blood into a plasma product containing raw plasma and an anticoagulant and at least a second blood component; (g) collecting the plasma product from the blood component separation device into a plasma collection container; (h) determining whether the collected plasma product containing raw plasma and an anticoagulant has reached a target amount of the plasma product to be collected; and (i) continuing steps (d) to (h) until the collected plasma product has reached the target amount of the plasma product to be collected.

A sixteenth embodiment includes the fifteenth embodiment, wherein the estimated donor physiological fluid volume is the donor's extracellular fluid.

A seventeenth embodiment includes the sixteenth embodiment, where the pre-stored constant is between about 0.05 and about 0.07.

An eighteenth embodiment includes the seventeenth embodiment, where the pre-stored constants include a first constant for use with male donors and a second constant, different from the first constant, for use with female donors.

The nineteenth embodiment includes the fifteenth embodiment, except that the donor's actual hematocrit is not used to estimate the donor's physiological fluid volume, and the donor's actual hematocrit is not used to calculate the target volume of plasma product to be collected.

In a twentieth embodiment, a system for collecting plasma is provided. The system includes a blood separator configured to separate whole blood into a plasma product and a second blood component comprising concentrated cells, the blood separator having a plasma output port coupled to a plasma line configured to deliver a plasma product comprising raw plasma and an anticoagulant to a plasma product collection container, a donor line configured to introduce whole blood from a donor into the blood separator, the donor line having a flow through the donor line controlled by a first pump, an anticoagulant line coupled to an anticoagulant source, the flow through the anticoagulant line controlled by a second pump to mix the anticoagulant with the whole blood from the donor based on an anticoagulant ratio, an input device configured to receive input from an operator, and a control circuit programmed to control operation of the system, the control circuit being connected to the input device and configured to control at least The system is programmed to receive a donor's weight, estimate the donor's physiological fluid volume based at least in part on the donor's weight without using the donor's actual hematocrit, determine a target volume of a plasma product including raw plasma and an anticoagulant as a predetermined percentage of the donor's physiological fluid volume without using the donor's actual hematocrit, collect whole blood from the donor, separate the whole blood into a collected plasma product and a second blood component, and control the system to operate a collection step and a return step to return the second blood component to the donor, the control circuitry being programmed to perform the collection step and the return step at least three times, the control circuitry being configured to compare the amount of collected plasma product with the target volume of the plasma product, and continue processing the whole blood until the amount of collected plasma product reaches the target volume of the plasma product.

In a twenty-first embodiment, a system for collecting plasma is provided. The system includes a separator configured to separate whole blood into a plasma product and a second blood component including concentrated cells, the blood separator including a plasma output port coupled to a plasma line configured to deliver the plasma product to a plasma product collection container, a donor line configured to introduce whole blood into the separator, the donor line having flow through the donor line controlled by a first pump, an anticoagulant line coupled to an anticoagulant source, the anticoagulant line having flow through the anticoagulant line controlled by a second pump to mix anticoagulant with the whole blood from the donor based on an anticoagulant ratio, an input device configured to receive input from an operator, and a flow control device configured to control operation of the system. and a control circuit coupled to the input device and configured to receive a weight of the donor, calculate the donor's extracellular fluid volume based at least on the weight of the donor, and calculate a target volume of the plasma product and/or raw plasma based at least in part on the extracellular fluid volume; and the control circuit configured to control the system to operate the collection and return stages to collect whole blood from the donor, separate the whole blood into a plasma product and a second blood component, and return the second blood component to the donor, where the control circuit is further configured to operate the collection and return stages until the volume of the plasma product in the collection container meets the target volume of the plasma product and/or raw plasma.

In a twenty-second embodiment, the control circuitry includes the system of the twenty-first embodiment, configured to receive donor weight and height over a network from a donor management system, the donor management system being used for eligibility screening.

A twenty-third embodiment includes the system of the twenty-first embodiment, in which a target amount of plasma product and/or raw plasma is calculated prior to initiating blood collection from the donor.

A twenty-fourth embodiment includes the system of the twenty-first embodiment, wherein the control circuitry is configured to determine whether the amount of raw plasma in the collection container meets a target amount of raw plasma by weighing the amount of plasma product in the collection container and calculating the volume of raw plasma in the collection container based on at least the weight of the plasma product and the percentage of anticoagulant in the collection container.

A twenty-fifth embodiment includes the system of the twenty-first embodiment, wherein the control circuitry is configured to calculate the donor's extracellular fluid volume as extracellular fluid volume (ECFV) based on the donor's weight (W), height and gender, such that for women, ECFV = 0.0399 x W ^0.6065 x H ^0.6217 , and for men, ECFV = 0.0755 x W ^0.6185 x H ^0.4982 .

A twenty-sixth embodiment includes the system of the twenty-first embodiment, wherein the control circuitry is configured to calculate a target volume of plasma product and/or raw plasma by calculating a percentage of the donor's extracellular fluid volume.

A twenty-seventh embodiment includes the system of the twenty-first embodiment, in which the control circuitry is configured to perform at least three collection and return cycles, and the control circuitry is configured to determine a volume of whole blood to be collected in a final stage that is different from the volume collected in an earlier collection stage.

A twenty-eighth embodiment includes the system of the twenty-first embodiment, wherein the control circuitry is configured to calculate the donor's extracellular fluid volume (ECFV) based on the donor's body weight (BM) and height (H), as follows: ECFV(L) = 0.02154 x BM ^0.6469 (kg) x H ^0.7236 (cm).

A twenty-ninth embodiment includes the system of the twenty-first embodiment, where the control circuitry is configured to calculate the donor's extracellular fluid volume as an extracellular fluid volume (ECFV) based on body weight (BM) and height (H), such that ECFV(L) = √(BM(kg)) x H(m).

A 30th embodiment includes the system of the 21st embodiment, and the control circuitry is configured to calculate the donor's extracellular fluid volume as extracellular fluid weight (ECFW) based on the donor's body weight (BM), such that ECFW (kg) = 0.135 x BM (kg) + 7.35 kg.

In a thirty-first embodiment, a method of collecting plasma is provided. The method includes: (a) determining a donor's weight; (b) calculating the donor's extracellular fluid volume based at least in part on the donor's weight; (c) calculating a target plasma volume to be collected based at least in part on the calculated percentage of the donor's extracellular fluid volume; (d) drawing whole blood from the donor through a first line connected to the venous access device and the blood component separation device; (e) introducing an anticoagulant through the anticoagulant line into the drawn whole blood; (f) separating the drawn whole blood into a plasma component and at least a second blood component; (g) collecting the plasma component from the blood component separation device into a plasma collection container; and (h) continuing steps (d) through (g) until a target plasma volume to be collected in the plasma collection container is reached.

A thirty-second embodiment includes the method of the thirty-first embodiment, wherein the target plasma volume to be collected is a target raw plasma volume.

A thirty-third embodiment includes the method of the thirty-first embodiment, in which the donor's extracellular fluid volume is calculated as the extracellular fluid volume (ECFV) based on the donor's body weight (BM) and height (H): ECFV(L) = 0.2154 x BM 0.6469 (kg) x H 0.7236 (cm).

A thirty-fourth embodiment includes the method of the thirty-first embodiment, where the control circuitry is configured to calculate the donor's extracellular fluid volume as an extracellular fluid volume (ECFV) based on the weight (W), height (H), and sex of the donor, such that ECFV = 0.0399 x W0.6065 x H0.6217 for females and ECFV = 0.0755 x W0.6185 x H0.4982 for males.

A thirty-fifth embodiment includes the method of the thirty-first embodiment, in which the donor's extracellular fluid volume is calculated as extracellular fluid weight (ECFW) based on the donor's body weight (BM), ECFW (kg) = 0.135 x BM (kg) + 7.35 kg.

A thirty-sixth embodiment includes a system for collecting plasma is provided, the system including a blood separator configured to separate whole blood into a plasma product and a second blood component including concentrated cells, the blood separator having a plasma output port coupled to a plasma line configured to deliver the plasma product to a plasma product collection container, the blood separator including a donor line configured to introduce whole blood from a donor into the blood separator, flow through the donor line being controlled by a first pump, an anticoagulant line, the anticoagulant line coupled to an anticoagulant source, flow through the anticoagulant line being controlled by a second pump to mix anticoagulant with the whole blood from the donor based on an anticoagulant ratio, an input device configured to receive input from an operator, and a programmable logic device configured to control operation of the system. and a control circuit connected to the input device and programmed to control the system to receive at least the weight of the donor, estimate the donor's extracellular fluid volume based on the weight of the donor, determine a target volume of the plasma product and/or raw plasma based at least in part on the donor's extracellular fluid volume, and operate a collection step and a return step to collect whole blood from the donor, separate the whole blood into the plasma product and a second blood component, and return the second blood component to the donor, the control circuit being programmed to perform the collection step and the return step at least three times, and the control circuit being programmed to perform a final collection step by collecting a volume of whole blood less than the volume of whole blood collected in the previous collection.

A thirty-seventh embodiment includes the system of the thirty-sixth embodiment, where the control circuitry is programmed to receive the donor's height, sex, and hematocrit (Hct) over a network from a donor management system used for eligibility screening.

A thirty-eighth embodiment includes the system of the thirty-sixth embodiment, wherein the control circuitry is further configured to operate the collection and return phases until the volume of raw plasma (VRP) in the collection container is equal to a target volume of raw plasma, the volume of raw plasma (VRP) being based on the measured volume of plasma product (VPP).

A thirty-ninth embodiment includes the system of the thirty-sixth embodiment, in which the control circuitry is configured to calculate the donor's extracellular fluid volume as the extracellular fluid volume (ECFV) based on the donor's body weight (BM) and height (H), as follows: ECFV (L) = 0.02154 x BM 0.6469 (kg) x H 0.7236 (cm).

A fortieth embodiment includes the system of the thirty-sixth embodiment, where the control circuitry is configured to calculate the donor's extracellular fluid volume as an extracellular fluid volume (ECFV) based on the donor's body weight (BM) and height (H), such that ECFV(L) = √(BM(kg)) x H(m).

In a forty-first embodiment, a method for collecting plasma is provided in which the plasma product is collected in multiple collection stages during which separated red blood cells are reinfused into the donor. The method includes a) determining a volume of whole blood ( _Vb ) and hematocrit (Hct) of the donor; b) determining a volume of raw plasma ( _VRP ) that can be collected from the donor; c) determining a volume of plasma product ( _VPP ) that can be collected, where the plasma product comprises the volume of raw plasma plus a volume of anticoagulant; d) collecting whole blood from the donor; e) introducing an anticoagulant at a specific ratio (ACR) to the collected whole blood; f) separating the collected whole blood into a plasma product and a second component comprising red blood cells; g) collecting the plasma product in a plasma collection container; h) returning the red blood cells to the donor after a desired amount of whole blood has been collected from the donor; and i) determining the donor's Hct and _VPP before each collection step.

A forty-second embodiment includes the forty-first embodiment, wherein steps d) through i) are continued until the measured volume of plasma product in the collection vessel is equal to V _PP .

In a forty-third embodiment, a method for collecting plasma is provided in which a plasma product is collected in multiple collection stages during which separated red blood cells are reinfused into a donor, the method comprising: a) determining a volume of whole blood (V _b ) and hematocrit (Hct) of a donor, b) determining a volume of raw plasma (V _RP ) that can be collected from the donor based on V _b , c) determining a volume of anticoagulant V AC to be added to V _RP based on an anticoagulant ratio (ACR) and the donor's Hct such that V _AC = V _RP × (ACR × ₍ 1−Hct)), and d) determining a volume of plasma product (V _PP ) that can be collected, where the plasma product is the volume of raw plasma (V _RP ) and the volume of anticoagulant (V _{AC )} . ) e) collecting whole blood from the donor; f) introducing an anticoagulant at a specific ratio (ACR) into the collected whole blood; g) separating the collected whole blood into a plasma product and a second component comprising red blood cells; h) collecting the plasma product in a plasma collection container; i) returning the red blood cells to the donor after a desired amount of whole blood has been collected from the donor; and j) determining the donor's Hct and _VPP prior to each collection step.

A forty-fourth embodiment includes the forty-third embodiment, wherein steps d) through j) are continued until the measured volume of plasma product in the collection vessel is equal to V _PP .

A forty-fifth embodiment includes any of the forty-third and forty-fourth embodiments, wherein _Vb is determined based on one or more donor-specific characteristics including donor weight, height, sex, age, and morphology.

In a forty-sixth embodiment, a method is provided for collecting a volume of plasma product (V _PP ) in an apheresis procedure, in which the plasma product is collected in multiple collection stages during which separated red blood cells are reinfused into the donor, where V _PP is equal to the volume of raw plasma (V _RP ) available from the donor plus a volume of anticoagulant (V _AC ) added to the V _RP during the apheresis procedure. The steps of the method include a) determining the donor's weight (W _kg ) and sex (male or female); b) determining the donor's hematocrit (Hct); c) determining the volume of raw plasma (V _RP ) that can be collected based on the donor's weight (W _kg ) and sex (male or female); d) determining the ratio K between V _PP and V _RP based on the anticoagulant ratio and the donor's Hct such that K=V _PP /V _RP ; and e) determining the ratio V _PP =V _RP ×K. The method includes determining the donor's Hct and target _VPP ; f) drawing whole blood from the donor; g) introducing an anticoagulant at a specific ratio (ACR) into the drawn whole blood; h) separating the drawn whole blood into a plasma product and a second component comprising red blood cells; i) collecting the plasma product in a plasma collection container; j) returning the red blood cells to the donor after a desired amount of whole blood has been drawn from the donor; and k) determining the donor's Hct and target _VPP before each collection step.

A forty-seventh embodiment includes the forty-sixth embodiment, wherein steps c) through k) are repeated until the measured volume of plasma product in the collection container is equal to V _PP . Preferably, K=V _PP /V _RP =(ACR×(1−Hct/100)+1)/(ACR×(1−HCT/100)).

In a forty-eighth embodiment, a method is provided for collecting a volume of plasma product (V _PP ) in an apheresis procedure, in which the plasma product is collected in multiple collection stages during which separated red blood cells are reinfused into the donor, where V _PP is equal to the volume of raw plasma that can be collected from the donor (V _RP ) plus the volume of anticoagulant (V _AC ) that is added to the V _RP during the apheresis procedure. The steps of the method are: a) determining the donor's weight (W _kg ) and sex (male or female); b) determining the donor's hematocrit (Hct); c) determining the volume of raw plasma (V _RP ) that can be collected based on the donor's weight (W _kg ) and donor's sex (male or female); d) determining V _AC to be added to V _RP based on the anticoagulant ratio (ACR) and donor Hct such that V _AC = V _RP × (ACR × (1−Hct)); and e) determining V _PP = V _RP + V _AC . The method includes: determining _{the Hct} and VPP of the donor; f) drawing whole blood from the donor; g) introducing an anticoagulant at a specific ratio (ACR) into the drawn whole blood; h) separating the drawn whole blood into a plasma product and a second component comprising red blood cells; i) collecting the plasma product in a plasma collection container; j) returning the red blood cells to the donor after a desired amount of whole blood has been drawn from the donor; and k) determining the donor's Hct and _VPP before each collection step.

A forty-ninth embodiment includes the forty-eighth embodiment, wherein steps d) through k) are continued until the measured volume of plasma product in the collection vessel is equal to V _PP .

A fiftieth aspect includes any of the forty-eighth and forty-ninth embodiments, wherein the _VRP is determined by establishing a _VRP for each of a plurality of donor weight ranges and selecting the _VRP for the weight range that includes the donor weight. The donor weight ranges can be divided into three categories: 110-149 pounds, 150-174 pounds, and 175 pounds or greater.

In a fifty-first embodiment, V _RP =K ₁ ×W _kg .

In a fifty-second embodiment, V _RP is less than or equal to 28.6% of (1-Hct)×(V _b ).

In a fifty-third embodiment, V _b is determined using one of Nadler's equation, Gilcher's five rules, the ICSH standard, and other commonly accepted methodologies.

In a fifty-fourth embodiment, V _RP =W _kg x 10 mL/kg.

In a fifty-fifth embodiment, if donor parameters are used to estimate the donor's total blood volume (V _b ), then V _RP =K ₂ ×V _b .

In a fifty-sixth embodiment, an automated system for separating plasma from whole blood is provided, including reusable hardware components and a disposable kit. The disposable kit further includes: i) a separator for separating whole blood into a plasma fraction and an enriched cell fraction, the separator having an input integrally connected to a blood line for transporting whole blood from a donor to the separator; a plasma output port integrally connected to a plasma collection container by a plasma line; an enriched cell outlet port integrally connected to a reservoir for receiving enriched cells prior to reinfusion into the donor; ii) an anticoagulant line integrally connected to the blood line and configured to be connected to a source of anticoagulant for transporting anticoagulant to the donor line; iii) a saline line configured to be attached to a source of saline for transporting saline to the blood line; and iv) a reinfusion line for transporting enriched cells from the reservoir to the donor line. The reusable hardware components further include: i) a first peristaltic pump for delivering anticoagulant at a controlled rate to the blood line during the collection phase; ii) a second pump for delivering anticoagulated whole blood to the separator during the collection phase and returning concentrated cellular components during the reinfusion phase; iii) a third pump for delivering concentrated cellular components from the separator to the reservoir during the collection phase; iv) clamps associated with each of the blood line, plasma line, reinfusion line, and saline line; v) weigh scales for weighing each of the plasma collection container, the reservoir, and the anticoagulant source; and vi) a programmable controller comprising a touch screen for receiving input from an operator, the programmable controller being configured to receive signals from each of the weigh scales and automatically operate the first pump, the second pump, and the third pump and the clamps to separate the whole blood into a plasma fraction and a concentrated cellular fraction during the collection phase and to return the concentrated cells to the donor during the reinfusion phase. The programmable controller is further configured to determine a weight of the plasma fraction to be collected in the plasma collection container according to any of the aspects described herein, and to terminate the collection phase upon receiving a signal from a weighing scale of the plasma collection container for the plasma collection container equal to the weight of the plasma fraction determined by the controller. In determining the target amount of plasma product to be collected, the controller may be configured to calculate the donor's hematocrit prior to the collection phase of each cycle. Alternatively, or additionally, the controller may receive a signal from a sensor or the like indicative of the donor's hematocrit. Additionally, the amount of plasma product in the plasma collection container may be determined, for example, by a weighing scale associated with the plasma collection. In one embodiment, the separator includes a spinning membrane separator.

While the present application describes calculating the target raw plasma and/or plasma product based on total blood volume, total plasma volume, extracellular fluid volume, and/or other parameters, in alternative embodiments, the target raw plasma and/or plasma product may be calculated based on one or more other donor parameters, such as intracellular fluid volume, interstitial fluid volume, tissue fluid volume, intravascular fluid volume, cerebrospinal fluid volume, total body water volume, lymph volume, transcellular fluid, effective circulating volume, or other donor parameters. The target raw plasma and/or plasma product may further be calculated or determined based at least in part on electrolyte components, such as cations and anions, such as sodium, potassium, calcium, chloride, bicarbonate, and/or phosphate.

It will be understood that the described embodiments are illustrative of some of the applications of the principles of the present subject matter. Numerous modifications may be made by those skilled in the art without departing from the spirit and scope of the claimed subject matter, including combinations of features individually disclosed or claimed herein. For these reasons, the scope of the claims should not be limited to the above description, but should be as set forth in the following claims.

Claims (20)

1. A system for collecting plasma, comprising:
a separator configured to separate whole blood into a plasma product and a second blood component comprising concentrated cells, the separator having a plasma output port coupled to a plasma line configured to deliver the plasma product to a plasma product collection container;
a donor line configured to introduce whole blood from a donor into the separator, the flow through the donor line being controlled by a first pump;
an anticoagulant line coupled to an anticoagulant source, flow through the anticoagulant line being controlled by a second pump to mix anticoagulant with whole blood from a donor based on an anticoagulant ratio;
an input device configured to receive input from an operator and/or from a remote computer over a network;
and a control circuit configured to control operation of the system;
the control circuitry is coupled to the input device and configured to receive one or more donor parameters, estimate a physiological fluid volume of the donor based at least in part on the one or more donor parameters, and calculate a target volume of a plasma product including raw plasma and an anticoagulant by multiplying the estimated physiological fluid volume by a pre-stored constant;
the control circuitry is configured to control the system to operate a collection stage and a return stage to collect whole blood from a donor, separate the whole blood into a plasma product and the second blood component, and return the second blood component to the donor;
The control circuitry is further configured to operate the collection and return steps until a measured amount of plasma product in the collection container reaches a target amount of plasma product. The system of claim 1, wherein the control circuit is configured to not use donor hematocrit when determining when the measured amount of plasma product meets the target amount of plasma product. The system of claim 1, wherein the control circuitry is configured to not use donor hematocrit in calculating the target amount of plasma product. The system of claim 1, wherein the estimated physiological fluid volume is an extracellular fluid volume. The system of claim 4, wherein the pre-stored constant is between about 0.050 and about 0.064. The system of claim 4, wherein the control circuitry is configured to calculate the donor's extracellular fluid volume based on the donor's weight (W), height (H) and gender, ECFV = 0.0399 x W ^0.6065 x H ^0.6217 for women and ECFV = 0.0755 x W ^0.6185 x H ^0.4982 for men. The system of claim 1, wherein the estimated physiological fluid volume is total plasma volume. The system of claim 7, wherein the pre-stored constant is between about 0.25 and about 0.34. The system of claim 1, wherein the estimated physiological fluid volume is total blood volume. The system of claim 9, wherein the pre-stored constant is between about 0.10 and about 0.75. The system of claim 1, wherein the pre-stored constants are different for male and female donors, and donor gender data is received from the input device and used to select between male pre-stored constants and female pre-stored constants. The system of claim 1, wherein the donor's weight and height are received over the network from a donor management system, which is used for eligibility screening. The system of claim 1, wherein the target amount of the plasma product is calculated prior to initiating blood collection from the donor. The system of claim 1, wherein the control circuitry is configured to measure the amount of plasma product, including raw plasma and anticoagulant, in the collection container using a weighing scale. 1. A method for collecting plasma, comprising:
(a) receiving one or more donor parameters selected from donor weight, donor height, donor body mass index, and donor gender;
(b) estimating a donor physiological fluid volume based at least in part on one or more of said donor parameters, wherein the estimated donor physiological fluid volume is selected from total blood volume, total plasma volume, and extracellular fluid volume;
(c) calculating a target amount of plasma product to be collected, the target amount of plasma product including raw plasma and anticoagulant, the target amount of plasma product being calculated by multiplying an estimated donor physiological fluid volume by a pre-stored constant;
(d) drawing whole blood from a donor via a venous access device to a blood component separation device;
(e) introducing an anticoagulant into the collected whole blood;
(f) separating the collected whole blood into a plasma product comprising unprocessed plasma and an anticoagulant and at least a second blood component;
(g) collecting the plasma product from the blood component separation device in a plasma collection container;
(h) determining whether the collected plasma product, including raw plasma and anticoagulant, reaches a target amount of plasma product to be collected;
(i) continuing steps (d) through (h) until the collected plasma product reaches a target amount of plasma product to be collected. The method of claim 15, wherein the estimated donor physiological fluid volume is the donor's extracellular fluid. The method of claim 16, wherein the pre-stored constant is between about 0.05 and about 0.07. The method of claim 17, wherein the pre-stored constants include a first constant for use with male donors and a second constant, different from the first constant, for use with female donors. 16. The method of claim 15, wherein the donor's actual hematocrit is not used to estimate the donor's physiological fluid volume, and the donor's actual hematocrit is not used to calculate the target volume of plasma product to be collected. 1. A system for collecting plasma, comprising:
a blood separator configured to separate whole blood into a plasma product and a second blood component comprising packed cells, the blood separator having a plasma output port coupled to a plasma line configured to deliver a plasma product comprising raw plasma and an anticoagulant to a plasma product collection container;
a donor line configured to introduce whole blood from a donor into the blood separator, the flow through the donor line being controlled by a first pump;
an anticoagulant line coupled to an anticoagulant source, the flow through the anticoagulant line being controlled by a second pump to mix the anticoagulant with the whole blood from the donor based on an anticoagulant ratio;
an input device configured to receive input from an operator;
and a control circuit programmed to control the operation of the system;
the control circuitry is connected to the input device and is programmed to control the system to receive at least a donor's weight, estimate the donor's physiological fluid volume based at least in part on the donor's weight without using the donor's actual hematocrit, determine a target volume of a plasma product including raw plasma and an anticoagulant as a predetermined percentage of the donor's physiological fluid volume without using the donor's actual hematocrit, collect whole blood from the donor, separate the whole blood into a collected plasma product and a second blood component, and operate a collection and return step to return the second blood component to the donor;
the control circuit is programmed to perform the collection and return steps at least three times;
The control circuit is configured to compare the amount of collected plasma product to a target volume of plasma product and continue processing of the whole blood until the amount of collected plasma product reaches the target volume of plasma product.

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