Patent Description:
Whole blood is made up of various cellular components such as red cells, white cells, and platelets suspended in its liquid component, plasma. Whole blood can be separated into its constituent components (cellular or liquid), and the desired separated component can be administered to a patient in need of that particular component. For example, platelets can be removed from the whole blood of a blood source, collected, and later administered to a cancer patient whose ability to "make" platelets has been compromised by chemotherapy or radiation treatment.

Automated blood separation systems are used to collect large numbers of platelets. Automated systems perform the separation steps necessary to separate platelets from whole blood in a sequential process. Automated systems draw whole blood from the source, separate out the desired platelets from the drawn blood, and optionally return the remaining red blood cells and plasma to the blood source, all in a sequential flow loop. Large volumes of whole blood can be processed using an automated "on-line" system. Due to the large processing volumes, large yields of concentrated platelets can be collected.

Commonly, platelets are collected by introducing whole blood into a centrifuge chamber in which the whole blood is separated into its constituent components, including platelets, based on the size and densities of the different components. This requires that the whole blood be passed through a centrifuge after it is withdrawn from (and, optionally, before one or more separated blood components is returned to) the blood source. Typical blood processing systems thus include a permanent, reusable centrifuge assembly containing the hardware (drive system, pumps, valve actuators, programmable controller, and the like) that pumps and separates the blood, and a disposable, sealed, and sterile fluid processing assembly that is mounted cooperatively on the hardware. The centrifuge assembly spins a disposable centrifuge chamber of the fluid processing assembly during a collection procedure, thereby separating the blood into its constituent components. The separated platelets are typically reconstituted in a liquid storage medium or additive, such as plasma and/or a synthetic storage solution, for storage until needed for transfusion to a patient. Such systems are described for example in <CIT> or <CIT>. <CIT> refers to a system and method for automatically adjusting the operational parameters of blood separation procedures including platelet separation.

For the stored platelets to be suitable for later administration, they must substantially retain their viability and platelet function. A number of interrelated factors may affect platelet viability and function during storage. Some of these factors include the anticoagulant used for blood collection, the method used to prepare the platelets, the type of storage container used, and the medium in which the platelets are stored.

Currently, platelets may be stored for five or even seven days at <NUM>° C. After seven days, however, platelet function may become impaired. In addition to storage time, other storage conditions have been shown to affect platelet metabolism and function, including: pH, storage temperature, total platelet count, plasma volume, agitation during storage, platelet concentration, and the presence of platelet clumps in the final platelet product.

Insofar as the term embodiment or aspect or alternative is used in the following, or features are presented as being optional, this should be interpreted in such a way that the only protection sought is that of the invention claimed and defined in the appended claims.

In one aspect, a disposable processing circuit includes a processing chamber configured to receive a fluid including plasma and platelets and associable with a separation device of a reusable hardware apparatus for separation of platelets from at least a portion of another constituent of a fluid including plasma and platelets. The disposable processing circuit also includes a size exclusion filter in downstream fluid communication with the processing chamber and configured to remove platelet clumps from separated platelets conveyed therethrough from the processing chamber. A platelet storage container is provided in downstream fluid communication with the size exclusion filter and configured to receive filtered platelets from the size exclusion filter, while an additive container is provided in upstream fluid communication with the size exclusion filter.

In another aspect, a method is provided for collecting platelets. The method includes providing a fluid from a fluid source including plasma and platelets, and separating platelets from at least a portion of another constituent of the fluid. The separated platelets are conveyed through a size exclusion filter to remove platelet clumps from the separated platelets, with the filtered platelets being collected in a platelet storage container. An additive is then conveyed through the size exclusion filter and into the platelet storage container.

The embodiments disclosed herein are for the purpose of providing an exemplary description of the present subject matter. They are, however, only exemplary and not exclusive, and the present subject matter may be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting the subject matter as defined in the accompanying claims.

The present disclosure is directed to methods and systems for collecting blood platelets in a platelet storage media or additive. The platelet storage media or additive may be variously configured without departing from the scope of the present disclosure and may include plasma and/or a synthetic storage fluid, which is commonly referred to as a platelet additive solution or "PAS. " Platelet products described herein include the platelet storage media (typically PAS and plasma) and the platelets stored therein. If PAS is used, it typically replaces <NUM>-<NUM>% or more of the plasma in the platelet constituent, thereby decreasing the amount of plasma required to suspend and store the platelets. The use of PAS in addition to plasma as a platelet storage media may be advantageous for a number of reasons (e.g., the reduced incidence of allergic transfusion reactions resulting from platelets stored in PAS), but it should be understood that the term "additive" as used herein encompasses both plasma and non-plasma fluids and combinations thereof unless stated to the contrary.

Platelets for storage may be obtained by separating platelet-rich plasma from a biological fluid including plasma and platelets (including, but not limited to, whole blood). <FIG> and <FIG> show a representative separation system <NUM> useful in the separation and collection of platelets and the delivery of the additive, as described herein. The illustrated separation system <NUM> is similar to the AMICUS® separation system, available from Fenwal, Inc. of Lake Zurich, Illinois, which is an affiliate of Fresenius Kabi AG of Bad Homburg, Germany, and which is described in greater detail in <CIT>; <CIT>; <CIT>; and <CIT>. However, it should be understood that the illustrated separation system <NUM> is merely exemplary and that the configuration of the separation system may vary without departing from the scope of the present disclosure.

The separation system <NUM> of <FIG> and <FIG> includes a hardware component or apparatus <NUM> and a disposable processing kit or circuit <NUM> mounted thereon. The disposable circuit <NUM> includes an access device (e.g., a needle) for accessing the blood or other biological fluid of a fluid source. The disposable circuit <NUM> also includes a plurality of containers for holding fluid (e.g., anticoagulant and saline) and tubing segments defining flow paths for movement of the fluid, its separated constituents, and other fluids through the fluid circuit <NUM>. The illustrated disposable processing circuit <NUM> includes one or more cassettes (shown in <FIG> as three cassettes 16a, 16b and 16c), which interface with a front panel <NUM> of the hardware apparatus <NUM>. Each cassette 16a, 16b, and 16c includes flow paths and valve stations. The front panel <NUM> of the hardware apparatus <NUM> includes a series of valves under the control of a pre-programmed controller of the hardware apparatus <NUM>, which selectively allow and restrict flow through the flow paths of the cassettes 16a, 16b, 16c and ultimately through the tubing segments of the disposable circuit <NUM>.

In the illustrated embodiment, a rotating centrifuge is housed within the hardware apparatus <NUM> to receive a processing chamber <NUM> (<FIG>) of the disposable circuit <NUM>. The illustrated processing chamber <NUM> has first and second stages <NUM> and <NUM> wherein fluid or fluid components are separated under the influence of centrifugal force. While a centrifuge is employed by the illustrated system <NUM>, it is within the scope of the present disclosure for a separator based on a different separation principle to also be used.

The disposable circuit <NUM> further includes a size exclusion filter <NUM> in upstream fluid communication with one or more platelet storage containers <NUM>, such that any fluid flowing into the platelet storage container(s) <NUM> must first flow through the size exclusion filter <NUM>. In the illustrated embodiment, the size exclusion filter <NUM> is in downstream fluid communication with one of the cassettes 16c, thus being interposed between that cassette 16c and the one or more platelet storage containers <NUM>. The size exclusion filter <NUM> is configured to remove platelet clumps from fluid flowing through the size exclusion filter <NUM>. In an alternative embodiment, the size exclusion filter <NUM> may be configured to remove particles greater than the size of a platelet (e.g., red blood cells and white blood cells, along with platelet clumps) from fluid flowing through the size exclusion filter <NUM>. By flowing a platelet-containing substance through the size exclusion filter <NUM>, platelet clumps are prevented from flowing into the platelet storage container(s) <NUM>. This is advantageous for several reasons, as platelet clumps are known to decrease the quality of the stored platelet product (as aggregated products consume more glucose and produce more lactate) and interfere with post-processing steps, such as pathogen inactivation. Additionally, when performing flow cytometry-based enumeration of leukocytes, platelet aggregates (which are naturally autofluorescent) may appear in the leukocyte gate and be incorrectly counted as leukocytes, thereby artificially increasing the reported leukocyte content in the platelet product.

The hardware apparatus <NUM> may include a programmable controller that is pre-programmed with one or more selectable protocols. A user/operator may select a particular processing protocol to achieve a desired outcome or objective, including, for example, to obtain a platelet product having a pre-determined volume. The pre-programmed selectable protocol(s) may be based on one or more fixed and/or adjustable parameters, including, but not limited to, the volume of fluid being processed, the volume of additive used or added to the platelets during processing, the desired platelet concentration and/or the desired platelet yield, the processing time/duration of a given procedure, and/or the desired volume of final platelet product.

During a particular processing procedure, the pre-programmed controller may operate the centrifuge and processing chamber <NUM> associated therewith to separate fluid (such as anticoagulated whole blood) into its various components, as well as operate one or more pumps of the hardware apparatus <NUM> to move biological fluid, components of the biological fluid, and non-biological fluids through the disposable circuit <NUM>. This may include, for example, initiating and causing the centrifugal separation of platelet-rich plasma from whole blood (or another biological fluid including plasma and platelets) in the first stage <NUM> of the processing chamber <NUM> and pumping at least a portion of the platelet-rich plasma out of the processing chamber <NUM> via a tubing segment <NUM>. The platelet-rich plasma flows from the tubing segment <NUM> into and through one of the cassettes 16c, with the valves of the hardware apparatus <NUM> being actuated by the controller to direct the flow of platelet-rich plasma through the cassette 16c. The platelet-rich plasma exits the cassette 16c via another tubing segment <NUM> connected to the size exclusion filter <NUM> of the disposable circuit <NUM>, flows through the size exclusion filter <NUM>, and into a platelet storage container <NUM>. The controller may subsequently control one or more pumps of the hardware apparatus <NUM> to pump additive through the size exclusion filter <NUM> (in the same direction of flow experienced by the platelet-rich plasma) to combine with the filtered platelet-rich plasma in the platelet storage container <NUM> as a platelet product. The various processing steps performed by the devices of the hardware apparatus <NUM> under command of the controller may occur separately, in series, simultaneously, or any combination of these.

Once an operator has selected the desired protocol, entered the necessary parameters, and mounted the processing circuit <NUM> to the hardware apparatus <NUM>, collection of platelets may commence with biological fluid being conveyed into and through the processing circuit <NUM>. This may be achieved in any of a number of ways, which may include the controller of the hardware apparatus <NUM> controlling one or more pumps of the hardware apparatus <NUM> to draw fluid into the processing circuit <NUM> from a fluid source, such as a blood bag.

The biological fluid is conveyed through the processing circuit <NUM> and directed through at least one of the cassettes 16a, 16b, 16c (with the controller controlling valves of the hardware apparatus <NUM> to direct flow through the cassette or cassettes) and into the first stage <NUM> of the processing chamber <NUM>. The controller controls the centrifuge of the hardware apparatus <NUM> to rotate about a rotational axis at a rate that is sufficient to cause the platelets of the fluid to separate from another constituent of the fluid. In the illustrated example, platelet-rich plasma is separated from the other constituents of the biological fluid (red blood cells, if the fluid is whole blood) in the first stage <NUM> of the processing chamber <NUM>. The second stage <NUM> of the processing chamber <NUM> is not used in platelet separation and collection in such an embodiment, so it may be loaded with an amount of fluid (e.g., saline) to balance the processing chamber <NUM> and centrifuge during use. However, in other embodiments in which the second stage <NUM> is used (as will be described in greater detail), the second stage <NUM> may remain available for fluid flow and separation (e.g., for the inflow of platelet-rich plasma and the outflow of a separated component, such as platelet-poor plasma).

The platelet-rich plasma exits the first stage <NUM> of the processing chamber <NUM> and is conveyed through a tubing segment <NUM> to one of the cassettes 16c (<FIG>). The other constituents of the fluid exit the first stage <NUM> through a different tubing segment and may be collected for further processing or as a waste product or may be returned to the fluid source. In one embodiment, at least a portion of one of the separated components may remain within the processing chamber <NUM> following separation.

The controller operates selected valves of the hardware apparatus <NUM> to direct flow of the platelet-rich plasma through the cassette 16c and out a second tubing segment <NUM>, with the controller operating a pump <NUM> to convey the platelet-rich plasma into, through, and out the cassette 16c.

The second tubing segment <NUM> includes an inline size exclusion filter <NUM>, which is configured to prevent the flow of platelet clumps and/or particles larger than a platelet, as described previously. Thus, by flowing the platelet-rich plasma through the size exclusion filter <NUM>, platelet clumps and/or particles larger than a platelet (depending on the configuration of the size exclusion filter <NUM>) are prevented from exiting the size exclusion filter <NUM>, thereby improving the quality of the collected platelet product in various ways, which are described above. If platelet clumps are present in a platelet product, it is conventional to "rest" the product, which tends to lead to reduced oxygen levels, thereby promoting glycolysis and a resulting drop in pH.

The size exclusion filter <NUM> could be replaced with a leukoreduction filter, which would also function to remove platelet clumps from the separated platelet-rich plasma. However, it may be preferred to employ a size exclusion filter <NUM> for various reasons. For example, leukoreduction filters tend to be significantly more expensive than size exclusion filters. Additionally, a leukoreduction filter may not be as well-suited to releasing platelets upon the filter being flushed as a size exclusion filter (as will be described in greater detail).

A third tubing segment <NUM> is connected to the downstream end of the size exclusion filter <NUM> to direct the filtered platelet-rich plasma into a platelet storage container <NUM>. In the illustrated embodiment, the third tubing segment <NUM> includes a joint <NUM>, which splits the third tubing segment <NUM> into two branches <NUM> and <NUM>, each having an associated platelet storage container <NUM>. In other embodiments, there may be only one platelet storage container <NUM> or more than two platelet storage containers <NUM>.

When all of the platelet-rich plasma to be filtered has passed through the size exclusion filter <NUM>, the controller reconfigures the valves of the hardware apparatus <NUM> to define a different flow path through the cassette 16c (<FIG>). The new valve configuration defines a flow path through the cassette 16c between a tubing segment <NUM> connected to an additive container <NUM> (<FIG>) and the second tubing segment <NUM>. The additive container <NUM> may be integrally formed with the remainder of the processing circuit <NUM> as part of a closed system or may be separately provided and connected to the circuit <NUM> (using a sterile docking port or spiked connector, for example) prior to use.

In one embodiment, the additive container <NUM> is provided with an amount of a synthetic PAS, but it is also within the scope of the present disclosure for the additive container <NUM> to be empty at the start of the procedure. In such an embodiment, plasma separated from the fluid in the processing chamber <NUM> (e.g., in the second stage <NUM>) is directed into the additive container <NUM>, with the plasma serving as an additive. According to yet another embodiment, a plurality of additive containers may be provided, with at least one including a synthetic PAS and at least another one being configured to receive separated plasma.

Regardless of the nature of the additive, the controller operates one or more of the pumps of the hardware apparatus (illustrated in <FIG> as a single pump <NUM>) to convey additive through the tubing segment <NUM>, into and through the cassette 16c, and out of the cassette 16c via the second tubing segment <NUM>. The additive flows through the size exclusion filter <NUM> and into the platelet storage container(s) <NUM>, where it mixes with the filtered platelet-rich plasma as a final platelet product. If a plurality of additive containers are provided, additive from the different containers may be sequentially or simultaneously conveyed through the size exclusion filter <NUM>. Flushing the size exclusion filter <NUM> with the additive improves platelet recovery in the final platelet product by displacement of platelet-rich plasma with the additive and may also break up platelet clumps that may be present in the size exclusion filter <NUM>, thereby increasing platelet yield.

With a suitable amount of additive in the platelet storage container(s) <NUM>, the procedure may end or continue with additional processing (e.g., pathogen inactivation of the final platelet product).

It should be understood that the foregoing procedure is particular to the system <NUM> of <FIG> and <FIG>, but that the present disclosure is not limited to this particular method or a procedure employing such a system. In other embodiments, any of a number of phases of the preceding procedure may vary without departing from the scope of the present disclosure, provided that the separated platelets are conveyed through a size exclusion filter <NUM>, followed by additive being conveyed through the size exclusion filter <NUM> to loosen clumped platelets and flush them into a location where the additive and flushed platelets are mixed with the filtered platelets.

For example, according to one variation of the preceding exemplary procedure, platelets may pass through both stages <NUM> and <NUM> of the processing chamber <NUM> before being conveyed through the size exclusion filter <NUM>.

As described above with respect to the single stage procedure, once an operator has selected the desired (double stage) protocol, entered the necessary parameters, and mounted the processing circuit <NUM> to the hardware apparatus <NUM>, collection of platelets may commence with biological fluid being conveyed into and through the processing circuit <NUM>.

The biological fluid is conveyed through the processing circuit <NUM> and directed through at least one of the cassettes 16a, 16b, 16c (with the controller controlling valves of the hardware apparatus <NUM> to direct flow through the cassette or cassettes) and into the first stage <NUM> of the processing chamber <NUM>. The controller controls the centrifuge of the hardware apparatus <NUM> to rotate about a rotational axis at a rate that is sufficient to cause the platelets of the fluid to separate from another constituent of the fluid (e.g., platelet-rich plasma being separated from red blood cells, if the fluid is whole blood) in the first stage <NUM> of the processing chamber <NUM>.

The separated platelets exit the first stage <NUM> via the tubing segment <NUM> and flow to one of the cassettes 16c, as in the single stage procedure. However, rather than being directed through the cassette 16c and then through the size exclusion filter <NUM> (as in <FIG>), the controller instead operates a pump 34a and selected valves of the hardware apparatus <NUM> to direct flow of the platelets out of the cassette 16c via a tubing segment <NUM> leading into the second stage <NUM> of the processing chamber <NUM> (<FIG>). As the platelets are being conveyed into the second stage <NUM>, the other constituents of the fluid may exit the first stage <NUM> through a different tubing segment and may be collected for further processing or as a waste product or may be returned to the fluid source.

The rotation of the processing chamber <NUM> within the centrifuge causes the platelets entering the second stage <NUM> of the processing chamber <NUM> to be further concentrated by separating them from another fluid component. For example, if the fluid flowing into the second stage <NUM> is platelet-rich plasma, concentrated or pelleted platelets are separated from (platelet-poor) plasma. The fluid component separated from the platelets may flow out of the second stage <NUM> while platelets continue to accumulate in the second stage <NUM>. In one embodiment, platelet-poor plasma (as the fluid component separated from the platelets in the second stage <NUM>) is conveyed out of the second stage <NUM> and into a plasma or additive container, which may correspond to the additive container <NUM> or a different container.

Eventually (e.g., once the desired amount of platelets have been accumulated in the second stage <NUM> or once a predetermined amount of fluid has been processed), the controller may transition to a phase in which the platelets in the second stage <NUM> are resuspended. The platelets may be resuspended using platelet-poor plasma separated from the platelets during the preceding phase, a synthetic PAS, or a different fluid or combination of fluids.

The resuspended platelets are then conveyed out of the second stage <NUM> of the processing chamber <NUM> and into the cassette 16c via a tubing segment <NUM> of the processing circuit <NUM>. The controller operates selected valves of the hardware apparatus <NUM> to direct flow of the resuspended platelets through the cassette 16c and out the second tubing segment <NUM> (<FIG>), with the controller operating a pump <NUM> to convey the resuspended platelets into, through, and out the cassette 16c.

The resuspended platelets pass through the size exclusion filter <NUM> of the second tubing segment <NUM>, the third tubing segment <NUM>, and the joint <NUM> and one of the branches <NUM> and <NUM> (if provided), to a platelet storage container <NUM>, as described above with respect to the platelet-rich plasma in the single stage procedure. Passing separated platelets through a size exclusion filter <NUM> is particularly advantageous when the separated platelets comprise resuspended platelets because doing so removes platelets clumps resulting from incomplete resuspension of the concentrated platelets.

When all of the resuspended platelets to be filtered have passed through the size exclusion filter <NUM>, the controller reconfigures the valves of the hardware apparatus <NUM> to define a different flow path through the cassette 16c. The new valve configuration defines a flow path through the cassette 16c between the tubing segment <NUM> connected to the additive container <NUM> and the second tubing segment <NUM> (as in <FIG>) or between some other source of additive (e.g., a separate plasma container) and the second tubing segment <NUM>.

The controller operates one or more of the pumps of the hardware apparatus <NUM> to convey additive from the additive source, into and through the cassette 16c, and out of the cassette 16c via the second tubing segment <NUM>. The additive flows through the size exclusion filter <NUM> and into the platelet storage container(s) <NUM>, where it mixes with the filtered resuspended platelets as a final platelet product. If a plurality of additive containers are provided, additive from the different containers may be sequentially or simultaneously conveyed through the size exclusion filter <NUM>. As described previously, flushing the size exclusion filter <NUM> with the additive improves platelet recovery in the final platelet product by displacement of resuspended platelets with the additive and may also break up platelet clumps that may be present in the size exclusion filter <NUM>, thereby increasing platelet yield.

Claim 1:
A disposable processing circuit (<NUM>) configured for use in combination with a reusable hardware apparatus (<NUM>) including a separation device, the processing circuit (<NUM>) comprising:
a processing chamber (<NUM>) configured to receive a fluid including plasma and platelets and associable with said separation device of said reusable hardware apparatus (<NUM>) for separation of platelets from at least a portion of another constituent of a fluid including plasma and platelets;
a size exclusion filter (<NUM>) in downstream fluid communication with the processing chamber (<NUM>) and configured to remove platelet clumps from separated platelets conveyed therethrough from the processing chamber (<NUM>);
a platelet storage container (<NUM>) in downstream fluid communication with the size exclusion filter (<NUM>) and configured to receive filtered platelets from the size exclusion filter (<NUM>); and
an additive container (<NUM>) in upstream fluid communication with the size exclusion filter (<NUM>), wherein the disposable processing circuit defines a fluid flow path extending from the processing chamber (<NUM>) to the platelet storage container (<NUM>), with the fluid flow path including the size exclusion filter (<NUM>) and not including a leukoreduction filter.