Note: Descriptions are shown in the official language in which they were submitted.
1 178573
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This is a divisional a~plication of copending
application serial no. 377,362, filed May 12, 1981.
METHOD AND APPARATUS FOR ON LINE FILTRATION REMOVAL
OF MACROMOLECULES FROM A PHYSIOLOGICAL FLUID
This invention relates to pla3mapheresis and
more particularly to the removal of undesirable solutes
from plasma ~n a plasmapheresis process.
BACKGROUND OF T~E INVENTION
. . _
Pla~mapheresis (the removal of blood, separa-
tion of the plasma and the reinfusion of the blood c~
with or without the replacement of the patient'~ plasma
by donor plasma, a plasma ~raction, or other physiologi-
cal solution, is becomi~g more u~eful in the clinical
treatment o~ various disease states. Such disease ~tates
have in common the presence of undesirable ele~ated levels
of plasma solutes. Such solutes (due to their increased
size) cannot be effectively removed by techniques such
as dialyses and hemofiltration. Therefore plasma rémoval
with the infus:ion of physiological solutions is effective
in depleting their concentration. Various disease 8tat~3
reated by plasmapheresis are as follow~.
Myasthenia gravis
Glomeruloneph~itis
Goodpasture's syndrome
Skin diseases
pemphigus
herpes gestationis
Severe asthma
Immune complex diseases
crescentic ~phritis
"` ~ lL76~73
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systemic lupu5 erythemato~us
Wegner'~/polyarteritis
subacute ba~terial endocarditis
' cryoglobulinemia
cutaneous vasculiti~
Diabetic hypertriglyceridemia
Hypercholesterolemia
Macroglobulinemia
- Waldenstrom's syndrome
hypervisco~ity syndromes
paraproteinie~ia~, myeloma
Hematological di~ea3es
hemolytic anemia
red cell agglutinins
auto-antibody lymphocytes
thrombotic thromcocytopenia
purpura
immune ~hrombocytopenia
factor VIII inhibitor
or antibodies
Raynaud' 8 disease and phenomenon
Renal transplantation
Rhe~us incompatibility
Hepatic colna
Hypertension
~otor neurone disease
amyotrophic lateral sclerosis
auto polyneuropathy
Refsum'~ disea3e
Guillain-Barre syndrome
Arthritis
Removal of protein bound toxins
poisons - methyl parathion,
poisonous mushrooms, paraquat
hormones - thyroid
protein bound aluminum - dialysis
dementia
Cancer
Insulin resistant diabetes
While this list is not exhaustive, it exempli-
fies the wide range of diseases a4sociated with biochemi-
cal abnormalities; such biochemical agents being of high
molecular weight.
` `` ~17~573
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At present the number of cases of plasma ex-
change are small and in n~lny instances without controls.
The SUCC~S8 in some case~ i8 quite impressive-
The treatments presently being carried out by5 pla.~mapheresis may be generally grouped into two types:
(1) removal of an abnormal metabolite(s) or toxin(s) and
(2) treatment of a disorder of the immune ~y~tem. Exam-
ples of the fir~t type include hepatic support, hyper-
triglyceridemia, hypercholesterolemia, and the removal
of protein or lipid bound toxins. Examples of the ~econd
type include myasthenia gravi~ glomerulonephritis, macro-
globulinemia~, arthritis, and systemic lupu~ erythema-
to~is.
While in some of ~he diseases there i8 little
known concerning the correlation of the disease with ~he
increa~ed plasma factor~, for other disea~es the factor( 8 )
is known or correlation between the increased factor and
the disease state can be shown as outlined in Table 1 and
Table 2 as follow~.
1 ~76~'~3
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TABT ~ 1
IMMUNOLOGICAL DISOR~ERS TREATED BY PI~SMAPHERESIS
Disease Increased Factor(~) or
Abnormality __
Myasthenia gravis Antibody ~pecific for acetyl-
S choline receptor
Renal transplant rejection (Antibody to glomerular ba~e-
(ment membrane
Goodpasture'~ syndrome ~Antibody to basement membrane
(of lung
10 Rhesus incompatibility Anti-D-antibody
Systemic lupus erythema- DN~ antibodies and immun~
tosua complexes of DNA
Glomerulonep~ritis Immune complexe~ or auto-
antibodie~
15 Macroglobulinemia IgM and hyperviscosity
(Waldenstrom's syndrome)
Pemphigu~ vulgaris IgG anti~odies
Asthma bronchitis IgE
Myeloma Myeloma globulin
~o Raynaud's disease and Macroglobulin, i~creased vis-
pnenomena c08ity
~hrombocytopenic purpura Immunocomplex
~ancer ~ 2 globulines,
f?_globulins, ~ -l-antitryp-
sin, ceruloplasmin, orosomu-
coid, haptoglobin, IgA
Breast cancer Circulating immune complex
Polyneuropathy Antibodies to myelin
Rheumatoid arthritis "Serum factor"
30 Diabetes Autoantibodies to insulin
receptor
Autoimmune hemolytic Antibody to R~C
- . anemia
1 176573
TABLE 2
METABOLXC DISORDERS TREATED BY PLASMAPHERESIS
Disease Increa3ed Factor(Q) or
AbnormalitY
5 Hepatic coma Metabolic factors (bilirubin)
Refsum's disease Phytanic acid (bound to lipo-
proteins)
PoisOnings Protein bound drug
Dialysis dementia Protein bound aluminum
10 Hypertriglyceridemia Triglycerideq and hypervis-
cosity
Hypercholesterolemia Choles~erol
Amyt~ophic lateral Cytotoxic factors, immune
15 ~clerosis complexes suspected
Listed are various diseases for which increased
levels of antibodies or macrom~lecules exist and for
which plasmapheresis has been useful by its reduction of
these substances. For example, in myasthenia gravis,
antibodies specific for the acetycholine receptors are
elevated. ~emoval of these antibodies by pla~mapheresi6
shows improvement in the patients. ~n macroglobulinemia,
there is an increased level of gamma globulin. Reducing
this level by plasmaphçre3i~ is clinically effective.
The conventional method of plasmapheresi~
employs a cell centri~uge involving bulky and expensive
equipment which is not portable and is very co~tly, and
carries with it potential hazards. Namely, essential
plasma products are lost that are not being replenished
in the substitution fluids and the potential exists for
acquiring hepatitis. In addition, the effectiveness of
5 7 3
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the procedure is limited due to the limited removal
that can be accomplished in discarding a limited volume.
If conventional plasmapheresis were to be accepted for
the treatment of many of these diseases there would be
created a greater need for plasma products than could be
met nationally. Obviously, to take advantage of pla~mz-
pheresis in treating these diseases, new techniques mu~t
be developed for removal of the plasma "toxins".
A ma~or improvement would be to develop "on-
line" removal systems to remove the "toxin" in question
and to return the treated plasma back to the patient. The
advantage~ are quite obvious. The recent development o~
membrane systems for the on-line removal of plasma from
whole blood has added impetus to the development work.
Extracorporeal treatment of plasma generated by either
membrane plasma separators or centrifuges has been carried
out by either specific or non-specific sorbents such a
activated charcoal, nonionic or ionic resins and immobil-
ized proteins, cells or tissue.
In many of the disease states multiple biochemi-
cal abnormalities exist, and due to the nature of the
abnormal substances involved, multiple sorbent sy~tems
may be required. Such developments will take ~any year~.
Therefore due ~o the nature of the substances (larger
25 molecular weights of generally over 100,000 daltons) or
the nature of the disease state, where the specific macro-
molecule that is causative for the symptoms of the disease
is not defined, the more general approach of removing all
molec~les ovex a specific molecular weight can be chosen.
Mem~ran~s having a molecular cutoff of about 100;000 dal-
tons are chosen as they can pass albumin thereby negat-
ing the need to infuse this plasma product as is done by
the conventional plasmapheresis process.
1 :L76~73
Therefore it is an object of the invention to
provide a plasmapheresis method and apparatus for removing
macromolecules of predetermined size from a plasma solution.
In a process aspect of the invention there is
provided a method of removing macromolecules from a stream
of physiological solution including: forming from the
stream of a physiological solution a separated stream
containing macromolecules, then using a membrane filter
having a porosity to remove macromolècules of predetermined
size out of the separated stream, to produce the filtered
separated stream substantially free of macromolecules of
the predetermined size, and further including the step of
adding a complexing agent to the separated stream before
it is filtered by the membrane filter, the method being
continuous.
mgJ~ - 7 -
5 7 3
In an apparatus aspect of the invention there
is provided an apparatus for removing macromolecules
from a patient's physiological solution comprising; plasma
separation means for dividing a physiological solution
containing macromolecules into a concentrated cellular
element stream and a plasma stream, filter means in fluid
flow communication with the plasma separation means for
receiving the plasma stream therefrom and filtering such
plasma stream to remove macromolecules of a predetermined
size therefrom, fluid flow communication means for
receiving the filtered plasma stream from the filter means
and for receiving the concentrated cellular element
stream and combining the two last-named streams to form
a processed stream substantially free of macromolecules
of the predetermined size for return to the patient, a
complexing agent being added to the plasma stream before
it is filtered by the filter means to promote macromolecules
formation.
mg~ 8 -
1 176573
Other objects and advantages of the invention
will be apparent from the following description taken in
conjunctio~ with the drawings whereino
BRIEF DESCRIPTION OF THE DRAWINGS
FIGURE 1 is a schematic flow diagram illustrat-
ing the method and apparatus of the invention;
FIGURE 2 is a schematic flcw diagram similar to
FIGURE 1, but showing a modification thereof: -
. FIGURE 3 is a chart showing albumin retention
in a plasma solution filtered by the method and apparatus
shown in FIGURE l; and
FIGURE 4 i~ a chart showing the cryo-protein
~removal in the same plas~a solution used in the FlGUR~ 3
chart and employing the method and apparatu~ show~ in
FIGURE 1.
In the drawings, like numhers and letters are
used to identify like and similar parts throughout the
several views.
DE~INITIONS:
Crvoprecipitates: Ser~m globulins that
precipitate or gel on cooling at low tem-
peratures (4-35C) and redissolve on warming
,.~.
`: I ;176573
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CrYoqlobulins: Homogenous proteins that have
become physically altered (myeloma, mixture~
of immunoglobulins (as IgG and (IgM, sr Lmmune
complexes (as antigen and antibody), possible
with complement (as in SLE) Mol. Wt. 100,000 -
1,800,000
Macromolecules: Molecules of 100,000 daltons
molecular weight or higher
The use of the artificial Xidney, blood oxy-
genators, and artificial joints is well recognized today.
However, for a variety o~ disease states, application of
the techniques of extracorporeal circulation and mechani-
cal or mass transfer support are becoming more recognized.
Significant advances have been made in the axeas o~ cardiac,
pancreatic and liver support in recent years. Within the
past decade, with the availability of the continuous ~low
blood cell centrifuges, many different disease states,
mostly of an Lmmunological nature, have been investigated
in response to plasma exchange.
For many of the diseases, the nonspecific removal
of plasma factoxs has correlated with improvements in the
disease state. Problems with this conventional methodolo-
gy in chronic applications are the limited removal re-
lated to the volume o exchange and dilution by the required
inusion solution, the requirement for plasma products
and the potential hazards of such infusions, and the need
'for bulky and expensive capital equipment. The removal
of the specific plasma factors as antibodies, immune
complexes, and immunoglobulins by specific agents as
sorbents may be desirable; however, in most disease
states the etiology is not known.
In most immunologically related disease states
the presence and abnormal concentration of plasma factors
: I ~.76573
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greater than t~e molecular weight of albumin, suggests
the application of membrane filtration. In practic~,
plasma is separated on-llne from whole blood in an extra-
corporeal circuit. The plasma which contains the molecules
S of interst i~ then filtered through a membrane filter
which reject~ those macromolecules greater than albumin
and allows albumin and the smaller size plasma solute3
to pas~ and be returned to the patient. The return of
the albumin o~viates the requirement for infusion of large
volumes o~ donor plasma. Such techniques are presently
being applied clinically in the treatment of rheumatoid
arthritis and certain other disease states.
Plasma exchange has been shown to be effective
in the treatment of various diseases, including the immu-
nologically based disease states. This technique, however,has severe limitations in chronic applications, such as
limited removal related to the volume of exchange and dilu-
ti~n by the infusion solution and the requirement for plas-
ma products. Removal of the macromolecules as immune
complexes by specific sorbents in most cases re~uire~ ex-
tensive development work. The nonspecific removal of
macromolecules by membrane filtration makes the treatment
simpler and more universal in application.
In practice, plasma i8 separated on-line fro~
whole blood. The plasma which contain~ the macromolecules
is then filtered through a membrane filter which rejects
the macromolecules and passes the albumin and smaller
size plasma solutes which are reinfùsed into the patient.
With rheumatoid arthritis plasma and membranes of nominal
pore size of 0.1 microns, over 9P~ passage of albumin was
achieved with greater than 25~ rejection in a single pass
of rheumatoid factor and Clq binding immune complexes.
In certain immunologically related disease states, the
1 ~76573
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increased levels of cryoprecipitates containing antigen
and or antibody in the form of immune complexes with or
without complement sugge~ts that their removal could be
therapeutic. Modification of the on-line pla~ma ~iltra-
S tion circuit i5 made to include a heat exchanger to coolthe plasma to below 10C before filtr~tion. Using rheuma-
toid arthritis plasma with cryoprecipitate concentrations
of greater than 5 tLme~ normal, reductions to concentra-
tions below normal values were achieved in single pa~
with over 90~ passage of albumin.
The technique~ of on-line plasma filtration
th~ough select membranes and t~e cooling of placma to
promote qel formation of abnormal plasma proteins to maxi-
miz~ their removal are simple and easy to apply. They do
not requLre the infusion of expensive plasma products.
~ Referring to the drawings, FIGURE 1 illu~trates
the method and apparatu~ of the invention as applied to the
filtration of biood, although it wil~ be understood that
any other type of physiological fluid such as, for example,
lymph, a~citic ~luid, etc., may be treated.
In FIGURE 1, blood is drawn from a patient
into line 10 and fed into a pump 12 from which it is
pumped into a line 14 and then into membrane filter 1.
In place of membrane filter 1, a centrifuge may be em-
ployed as the function at this point is to separate th~blood into a plasma solution stream (fed into line 18)
and a concentrated cellular element stream (which is fed
into line 19).
From the membrane filter 1, the plasma solution
is led down a line 18 to a cooling unit 20 where the
plasma solution is cooled to a temperature of between just
above the freezing point of the plasma solution and about
35 centigrade to cause the macromolecules to gel or
1 17~573
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precipitate. Next, the cooled plasma solution is led
down the line 22 to membrane filter 2, where the macro-
molecules are xetained (and the albumin and lowex molec-
ular weight components pass through).
From filter 2, the filtered plasma ~plasma)
minus larger molecular weight solute) is led through the
line 24 to the juncture 26, where the filtered plasma
stream and the concentrated cellular element stream are
joined or united ~to form a processed stream) and then
fed into line 28 and thence into the heater unit 30.
The heater unit 30 heats the processed stream to body
temperature. The heated processed stream is then fed
into the line 32 and returned to the patient in a con-
tinuous process.
In the FIGURE 2 modification, the cooling unit
20a i8 shown encasing the filter 2 (and a portion of the - '
incoming line 22) such filter 2 being enclosed in a layer
of,in~ulation 34. This structure assures proper (cooled)
temperature maintenance within filter 2 during the fil-
20 te~ing process~ -
It is to be understood that, if required, it
woul~ be in order to inject into line 22 (before cooling)
a complexing agent for effecting gelling or precipitation
or macromolecule formation. A complexing agent i~ an
agent which will allow single or multiple plasma factors
co form a complex of higher molecular weight. Such
agent could be a sorbing agent or ion exchange material
such as, for example, heparin which forms complexes with
cholesterol and lipid containing components.
~0 Thus, FIGURES 1 and 2 outline filtration for
the separation of plasma from whole blood. A cell centri-
fuge could also be used in place of membrane filter 1 for
the generation of the plasma flow stream. The plasma,
1 ~76573
which contains the factors of interest, is directed to
a membrane filter 2 designed to filter out the macro-
molecule(s) of interest, but pass those plasma ~olutes
of smaller size. The plasma is then reunited with the
blood flow (concentrated cellular element stream) from
filter 1 (or in the case of a centrifuge the blood flow
from the centrifuge) before being returned to the patient.
For filter 1, a membrane with a normal poro~ity
of 0.2-1 micron would be required to generate the plasma.
Past investigatiOnQ with membranes in the lower range
porosity have indicated ~hat sieving coef~icients of
certain plasma macromolecules in the normal and the diseas~
states are low (less than 0.8). In addition, operational
conditions of filter 1, including blood and plasma flow ,
and ~elocities and transmembra~e pressures may ~eriou~ly
affect the sieving pr0perties of the macromolecule~ o~
interest. The filtration of blood i~ filter 1 is cro~s
flow. Filter 2, which employs a mem~rane with a porosity
of nominally 0.01 to 0.2 microns, would be required to
remove macromolecules of 100,000 daltons molecular weight
or greater. For this porosity, essential substances as
albumin and l~wer molecular weight solutes will pass through
the membrane filter 2 and be returned to the patient. The
filtration of the plasma in this filter may be cross flow
or conventional (flow directly into filtration media~. In
cross flow, a recirculation circuit and an additional
pump are required. Ir this recirculation circuit a vari-
able resistor ~as a screw clamp) may be placed to regulate
the rate of filtration.
Serum glo~ulins that precipitate or gel on cool-
ing at low temperatures (nominally 35- 4C and generally
25-4C) and redissolve on warming may occur in a variety
of disorders such as myeloma, kala-azar, macroglobinemia,
- - u
~ 176573
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mali~nant lymphoma, collagen diseases as lupus, glomeru-
lonephritis, infectious mononucleosis, syphilis, cytome-
galovirus disease, rheumatoid arthritis, and other auto-
immune diseases. The globulins may represent homogeneous
proteins that have become physically altered (myeloma),
mixtures of immunoglobulins (as IgG and IgM~, or immune
complexes (such as antigen and antibody), possibly with
complement (as in systemic lupus erythematosus). The
term cryoglobulins refers to those abnormal globulin~.
The molecular weight of cryoglobulins vary from 100,000
to 1,800,000 daltons molecular weight. By taking advan-
tage of the precipitation or gelling effect of cryoglobu-
lins their removal can be effected~ As the plasma i3
separated from blood it is cooled. While in some clinical
situations only a small temperature change ~xom phy~iologi-
cal temperature of 37C is needed to start gelling or
precipitation, in the clinical situation~ temperatures as
low as near freezing for extended times are necessary to
cause precipitation in collected serum.
Occasionally ~ryoglobulins will precipitate
out at room temperature, but as a rule, sera have to be
cool~d to 10C or lower, before precipitation occurs.
With the cryoglobulins cooled to a level to cause precipi-
tation or gelling the filtration of these substances from
the plasma is greatly facilitatedO ~he advantage of
~his scheme over the direct filtration scheme without
excessive cooling is that the membrane porosity or pore
size may be increased allowing for higher sieving of the
normal proteins in the plasma and therefore more efficient re-
turn to the patient. While cooling of the plasma wouldnormally take place in the circuit the temperature decrease
may not always be uniform or low enough therefore a heat
exchange system woule be most desirable to cool the plasma.
: ~76573
~ 16-
To avoid chills to the patient or precipitation or gel-
ling of the cryoglobulins i~ the blood circuit returning
to the patient, the blood should be rewarmed by heater 30
to physiological temperature on its return to the patient~
5 EXPERIME~rAL STUDIES
Ex~eriment #l
Asahi (Asahi Medical Co., Tokyo, Japan) S-type
filter containing cellulose acetate hollow fiber membranes
with a nominal pore size of 0.2 microns with 84% porosity
was evaluated for sieving properties of Clq binding L~mUne
complexes that are present in rheumatoid arthritis. Plas-
ma obtained by centrifugation from patient ~Lo who had
high values of Cl~ binding immune complexes was perfused
through the S-type filter. Sieving coefficients (concen-
tration of filtrate divided by the concentration in thefluid flow stream to the filter) for the Clq binding im-
mune complexes averaged 0.49 over a two-hour perfusion
period. This study demonstrated that, these complexe~
can be filtered from plasma but that i~s efficiency is
lo~, allowing only about 50~ of the complexes to be re-
moved. This would necessitate long~r treatment time.
Experiment #2
Due to the relatively low e~ficiency of the
Asahi*S-type filter various available membrane~ of nomi-
nal pore size of 0.2 to 0.1 micron were selected for~tudy. The membranes were Tuffryn ~T-100 (polysulfon~)
with pore size of 0.1 micron from Gelman Sciences ~Ann
Arbor~ Michigan), X~300 (acrylic copolymer)5~pproximate-
ly ~.02 micron pore size) from Amicon (Lexington, Massa-
chusetts), (VMWP-approximately 0.05 mi~ron pore size) MF
(mi~ed cellulose acetate and nitrate) from Millipore
Corp. (Bedford, Massachusetts).
Plasma from a patient suffering from rheumatoid
* trade mark
1 ~6573
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arthritis was procured by centrifugation. Such plasma
contained elevated levels of rheumatoid factox and Clq
binding immune complexes. The membranes were assembled
into small test cells gi~ing a total surface area of 56
S cm2. The plasma was recirculated through the test cells
at ambient temperature. For testing the XM-300 membrane
the plasma was filtered first through an Asahi ~ilter.
This filtration process reduces the concentration o~
macromolecules in the plasma. For one of the ~T-100
membrane, in addition to first filtering the plasma
through an Asahi filter, the plasma was used after decan-
tation following refrigeration. This procedure re~ult~
in the removal of a significant amount of cryoglobulins
from the plasma. For the other HT-100 membrane tested
and the MX 0.05 membrane tested the cryoprecipitate~
were resuspended in the plasma for the study. It is
noted that for all membranes, complete ~ieving ~no rejec-
tion) of small molecule weight solutes is achieved. Par-
ticularly noteworthy is the sieving of albumin. In the
initial stages of the filtration studies (less ~han 30
minutes) nearly complete rejection (low sieving coefficient)
was seen for the X~-300 membranes. There was about 2~
rejection of Cl~ binding immune complexes and 32~ re jec-
tion of rheumatoid factor for the HT-100 membrane at 10
minutes.
Experiment #3
A 54-year old white female was selected with
extremely aggressive seropositive rheumatoid arthritis
who failed all accepted modes of therapy and in addition
failed cytotoxic drugs including Methotrexate and Cytoxan.
The only therapeutic modality to which she has transiently
responded has been plasmapheresis. The subject's blood
was treated by the method and apparatus of FIGURE 1, such
~ ~76~73
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treatment reducing her immune complex Clq Binding
( ~74 u/ml.) from 2256 units down to 688 units with a
resultant improvement in symptomatology.
Experiment #4
S Reerence is now made to FIGURES 3 and 4. In
this experiment, a patient's plasma was treated by the
method and apparatus of FIGURE 1. It will be noted in -
FIGURE 3 that the albumin loss was only about 20%, while
as shown in F~GURE 5, the cryo-protein reduction was
about 95%.
Both charts ~FIGURES 3 and-4) are from the same
single experiment, which was done under a cooled state.
Such experiment shows that the albumin substantially re-
mains in solution (which i~ hig~ly desirable) and the cryo-
protein (which represents the macromolecules) are almo~t
all removed from the plasma solution.
In the method and apparatus of FIGURE 1, treat-
ment time is normally about two to four hours, with roughly
1.7 to 3.0 liters of plasma being treated.
Controlled recirculation of the treated plasma
rrom line 24 over to line 18 could be effected if desired.
Thus, the invention provides a method of remov-
ing macromolecules from a plasma solutîon including pro-
viding a plasma solution containing macromolecules includ-
ing a minimum size thereof, cooling the plasma solution
to a temperature not lower than just above the fre~zing
point of the plasma solution, and filtering the plasma
solution with a membrane filter 2 having a porosity up
to said minimum size to remove macromolecules of predeter-
mined size from the plasma solution.
Also provided is a method of removing macro-
molecules from a physiological solution such as blood
including, securing a physiological solution from a
1 1~6573
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patient, separating the physiological solution stream
into a concen~rated cellular element stream and a plasma
stream containing macromolecules therein by either a mem-
brane filter or a centrifuge, filtering macromolecules
of predetermined size out of the plasma stream to fonm a
filtered plasma stream, combining the filtered plasma
stream and the cellular element stream to form a processed
stream, and returning the processed stream to the patient
in a continuous process. The step of heating the processed
stream to approximately body temperature before it is re-
turned to the patient may also be included.
In such method the membrane filter for re~oving
the macromolecules out of the separated stream has a por-
osity of nominally 0.01 to 0.2 microns to pass macro-
molecules of approximately ~0,000 molecular weight and be-
low and reject or collect macromolecules of approximately
100,000 molecular weight and over.
The invention also contemplates an apparatus ~or
removing macromolecules from a patient's physiological
solution including, plasma separation means 1 for divid-
ing a physiological solution such as blood containing
macromolecules into a concentrated cellular element stream
and a plasma stream, a cooler 20 in fluid flow communica-
tion with the plasma separation means 1 for receiving
the plasma stream therefrom and cooling such plasma
stream to cause the macromolecules therein to gel or pre-
cipitate, filter means 2 in fluid flow communication with
the cooling unit 20 for receiving the cooled plasma stream
therefrom and filtering such cooled plasma stream to re-
move macromolecules of a predetermined size therefrom,fluid flow communication means 26 for receiving the
filtered plasma macrosolute stream from the filter means
and for receiving the concentrated cellular element stream
~ ~76573
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and combining said two last-named streams to form a processed
stream for return to the patient in a continuous pxocess.
Further included is a pump 12 in fluid flow
communication with the plasma separation means 1 and with
the patient to pump the physiological solution from the
patient to the plasma separation means 1.
The cooling unit 20 cools the separated plasma
stream to a temperature of between just above the freez-
ing point of the separated plasma stream and approxLmately
35 centigrade, although it is to be understood that the
cooler 20 may be eliminated in certain instances.
Also, the heater unit 30 is preferred, but may
be eliminated if the temperature in the line 28 is near
body temperature.
The terms and expressions which have been em-
ployed are used as terms of description, and not of limi-
tation, and there is no intention, in the use of such
terms and expressions, of excluding any equivalent3 of
the features shown and described or portions thereof, but
it is recognized that various modifications are possi~le
within the scope of the invention claimed.
