DE3135814A1 - Method and apparatus for the selective extracorporeal precipitation of low density lipoproteins from whole serum or plasma - Google Patents

Abstract

A method for the selective extracorporeal precipitation of low density lipoproteins or beta -lipoproteins from whole serum or plasma is characterised in that heparin in a buffer is added to the whole serum or plasma, and the beta -lipoprotein-heparin complex which is formed is precipitated at the isoelectric point at a pH of 5.05 to 5.25 and then removed, or the precipitate or filtrate is analysed further for diagnostic purposes. An apparatus for the extracorporeal precipitation of blood constituents having a container to which blood or blood constituents from a patient are fed via a first pump, and having a filter which is downstream of the container and whose filter outlet is connected to a line leading back to the patient, is characterised in that the filter has a second outlet for the precipitate, which outlet is connected to a return line leading into the container, in that the container is connected via a second pump to the outlet of a first vessel containing a treating agent, and in that the filter outlet of the filter is connected to a third pump whose delivery essentially corresponds to the total of the deliveries of the first and of the second pump.

Description

Method and device for selective extracorporeal

Precipitation of low density lipoproteins from whole serum or plasma serum or plasma The advances in the field of analysis of the lipoprotein system in recent years have shown that the epidemiological data collected in older close correlations between plasma cholesterol levels and the risk of premature atherosclerosis, especially coronary sclerosis high cholesterol ß-lipoproteins are given. In human blood are found normally about 70 - 80% of the total cholesterol to the low density or ß-lipoproteins bound, the rest is distributed among other lipoprotein fractions (essentially VLDL, HDL and chylomicrons) (LDL = Low Density Lipoproteins; VLDL = Very Low Density Lipoproteins; HDL = high density lipoproteins). In disease processes that are associated with a disturbed lipid metabolism or increased plasma lipid concentrations and which lead to premature atherosclerosis, the percentage may change the LDL or B cholesterol (LDL = B lipoprotein) in the total cholesterol even more far raise. This means that there is usually hypercholesterolemia caused by hyper-ß-lipoproteinemia.

There has therefore been no lack of attempts in the past 1. to selectively measure the low density lipoproteins and 2. selectively measure those as selectively as possible to be eliminated from circulation.

Both the one and the other have been taken into account so far of the prior art has not been satisfactorily solved. The usual procedures To quantify low density lipoproteins rely on either the use of the Separation of the lipoprotein spectrum into density classes with the help of the ultracentrifuge -or on the separation of the lipoprotein spectrum in an electric field, a process that one looks at the so-called.

Makes use of lipoprotein electrophoresis. Furthermore on precipitation processes, based on the fact that apo-B-containing lipoproteins (VLDL and LDL) by polyanions and divalent cations of non-apo-B-containing lipoproteins by precipitation of the the former can be determined separately. It is the Apo-B protein the main protein content of the low density or ß-lipoproteins as also the VLDL resp.

pre-ß-lipoproteins and chylomicrons. The latter method (Precipitation techniques) was previously not suitable for separating VLDL from LDL. the the first two processes mentioned, ultracentrifugation Havel, R.J., Eder H.A. and Bragdon J.H .: The Distribution and Chemical Composition of Ultracentrifugally Separated Lipoproteins in Human Serum, J. Clin Invest. 34, 1345, 1955 and electrophoresis Wieland H. and Seidel D .: Advances in the analysis of the lipoprotein pattern, Inn.Med. 5, 290 - 300, 1978 ..

had when applying larger routine series the Disadvantage that they are either too expensive and time-consuming or cannot be automated was. In addition, a direct measurement of low density cholesterol was only available after Isolation of the fractions, usually using the ultracentrifuge, is possible. The mathematical determination of the low density cholesterol content via electrophoresis assumes certain premises of the protein lipid composition. Same goes for the processes that make use of precipitation techniques. The precipitation techniques the usual way have the additional disadvantage that they reduce the lipoprotein spectrum separate only into two main fractions (apo-B-containing and non-apo-B-containing), so no distinction or separation between VLDL and LDL is possible.

Therapeutic efforts to reduce the low density lipoproteins effectively so far have all been unsatisfactory.

A drug influence on the low density lipoprotein concentration is particularly extreme when it comes to the genetic forms of lipid metabolism disorders difficult and usually unsatisfactory. With those previously achieved with drugs The therapeutic success, -lowering the risk of atherosclerosis, cannot be proven with certainty. Surgical interventions that are essentially based on the creation of abnormal blood circulation conditions or the relocation of larger parts of the intestine, have indeed brought significant therapeutic successes however, because of the strong side effects to be expected, this is not generally acceptable be considered. Such drastic therapeutic manipulations have however shown that with a sufficient reduction in low density lipoproteins atherosclerotic Processes can not only be brought to a standstill, but already existing ones atherosclerotic vascular changes are capable of regressing.

Trying to "mechanically" remove low density lipoproteins from the blood eliminating, has so far essentially been done in zo i ways: By the treatment of the affected patient with a so-called plasmapheresis, a procedure, in which there is a complete exchange of all blood water. This Procedure has resulted in the low density lipoprotein content of the afflicted patient while lowering, but at the same time those lipoproteins that cause atherosclerosis counteract (high density lipoproteins) likewise eliminated from the blood, a total undesirable therapeutic effect. In addition, in the case of plasma exchange, all other plasma proteins, including coagulation factors, globulins and hormones, are also eliminated. Nonetheless, this procedure has been used so far and for certain Cases of hyper-ß-lipoproteinemia proved to be quite useful, albeit the Look for a selective elimination of the low density lipoproteins from the plasma is still a priority. A first attempt at the elimination of low density Lipoproteins from the blood were extracted with the help of specific antibodies that target coupled to a matrix. The antibodies were used for this purpose by immunization obtained from sheep or rabbits.

Although with such systems (habenicht, A. Inaugural dissertation, 1978, Heidelberg, Md. Faculty; Stoffel W. and Demant, Th. Selective Removal of Apolipoprotein Bcontaining Serum Lipoproteins frcm Blood Plasma, Proc.Nat.Acad.Sci. USA 78, 611-615, 1981 a drastic reduction in all apo-B-containing lipoproteins was achieved, this method has the disadvantage that during the therapeutic Application of the antibodies generated in an animal in small amounts, but not avoidable, get into the circulation of the treating patient. This must be on seen in the long run, trigger immunological problems in the person to be treated. This substantial objection to such a procedure is all the more weighty than that Treatment of lipid metabolism disorders must be a lifetime treatment they work effectively and sustainably. It is to be demanded that especially with the family Form the therapy must begin in adolescence in order to achieve the Process cl-.

early developing atherosclerotic vascular disease to stop or measurably slow down. Another disadvantage of using immobilized Antibody against Apo-B is that of the unspecific elimination of all apo-B-containing antibodies Lipoproteins. This method is therefore not suitable for use as low density lipoproteins selectively eliminate the only atherogenic lipoproteins. An essential one The disadvantage of the simultaneous removal of the VLDL is the stimulation it causes the synthesis of triglycerides and cholesterol in the liver.

A third method is to remove low density lipoproteins from the blood was based on the selective absorption of ß- and pre-ß-lipoproteins from whole blood to sulfated polysaccharides coupled to agarose beads, e.g. heparin or dextran sulfate according to US-PS 4,103,685.

A disadvantage that can be seen from the PS is its low capacity Procedure for the elimination of lipoproteins as well as the fact that not only low density lipoproteins, but also very low density lipoproteins can also be removed. Cholesterol reductions according to the method of US Pat. No. 4,103,685 are only for in vitro experiments described. The lowering of cholesterol appears as from the accompanying lowering Phospholipids and triglycerides emerge rather from a thinning of the blood of the patient than to have been caused by selective elimination.

The procedure described in US Pat. No. 4,125,993, lipoproteins generally falling in their isoelectric point refers to the difference to the present inventive method to the use of sodium phosphotungstate. This polyanion is non-physiological and in contrast to the present one The method is therefore unsuitable to be used as a therapeutic principle. About that In addition, the use of phosphotungstate does not succeed in producing low density lipoproteins to selectively eliminate or determine, that is, the main objective of the present Invention is not achieved. That this does not succeed was stated in US Pat. No. 4,125 993, among other things, by recommending the low-density lipoproteins after a calculation formula (Friedewald formula) from the so-called HDL cholesterol with additional Into account to calculate the total cholesterol and the triglycerides. Essentially isoelectric point precipitation using phosphotungstic acid differs, as indicated in US Pat. No. 4,125,993, in its result not from the usual polyanion precipitation using divalent cations. A complete precipitation of VLDL and LDL in The aforementioned process is only achieved when using polymers such as polyvinylpyrolidone or polyethylene glycol precisely defined molecular weight of the precipitation solution can be added. That this cannot be achieved in an extracorporeal system is, is out of the question.

It should also be noted that US Pat. No. 4,125,993 is misleading the total of B-lipoproteins, pre-ß-lipoproteins and chylomicrons as low density lipoproteins. Since the stated aim of US Pat. No. 4,125,993 is To determine high density lipoproteins in the serum, emphasis must be placed on that the VLDL, chylomicrons and LDL can be eliminated through this precipitation process. A specific precipitation the real low density lipoproteins or β-lipoproteins were neither intended still achieved.

The object of the present invention is therefore to provide a method and to develop a device that will allow it to be selective and of high capacity low density lipoproteins or ß-lipoproteins from the blood, i.e. the whole serum or To remove constituents of the blood such as plasma and this principle for both therapeutic as well as diagnostic purposes.

The task is solved by providing one for it suitable method and apparatus.

specific The invention relates to a method for / extracorporeal Precipitation of low density lipoproteins or B-lipoproteins from whole serum or Plasma, which is characterized in that heparin is added to the whole serum or plasma is given in a buffer and the formed ß-lipoprotein-heparin complex im isoelectric point at a pH of 5.05 to 5.25 and then precipitated is separated.

The process is based on the absolutely specific precipitation of the ß-lipoproteins after crosslinking with heparin by precipitation in the isoelectric point of the complex at a pH of 5.05 to 5.25, especially at a pH of 5.13. Next to The specificity of this method is further characterized by the fact that it is the only one Substance used to precipitate low density lipoproteins, a Substance produced in the body (heparin) # is used. Precipitation in the isoelectric Point by lowering the pH using buffers can be done by appropriate filtration and pH adjustment after isoelectric point precipitation easily to physiological Conditions are corrected.

In particular, in the process according to the invention, the complex becomes off Heparin and B-lipoproteins precipitated at pH 5.13.

The heparin is dissolved in a buffer and mixed with the whole serum or Plasma mixed. The buffer is used to set and stabilize the specified pH values.

All buffer mixtures that are stable in the specified pH range secure, can in principle be used for the application of the method. As for therapeutic A phosphate buffer or a phosphate-citrate buffer has proven to be the most suitable buffer or a lactate buffer or an acetate buffer or mixtures thereof.

The ratio of buffer to serum or plasma or blood volume can be between 1: 5 to 5: 1. The most favorable concentration range has proven to be result in a ratio of about 1: 1 (these volume ratios apply to the elimination for therapeutic purposes). As the most favorable volume ratios for the selective Has elimination of low density lipoproteins from the blood for diagnostic purposes result in a ratio between 2 to 10: 1 buffer to serum.

The heparin concentration is not a particularly critical point. Favorably However, one will fall back on heparin concentrations that are almost completely through the ß-lipoproteins are also precipitated out. For example, a given In the most favorable case, the amount of serum is approx. 10% by volume of a heparin buffer solution, which Contains 5,000 U / ml.

When combining e.g. a mixture of equal parts of the Whole serum or plasma with a phosphate-citrate buffer in which the heparin is dissolved is, at the pH value of about 5.13, the precipitation takes place immediately and complete and is specific.

That means that only the ß-lipoproteins or low density lipoproteins be precipitated. The precipitated B-lipoproteins can, for example, by a Membrane filter with a pore size of approx. 2 µm or by simple centrifugation in one Continuous flow method can be separated from the remaining serum.

The method according to the invention is suitable both for therapy as well as for diagnostic examinations.

In therapy, for example, from the blood that a patient has been removed, the plasma is separated and, according to the invention, with a solution of heparin can be mixed in a buffer. The ß-lipoproteins are thereby as a heparin-β-lipoprotein complex at a pH of 5.05 to 5.25, in particular of 5.13 precipitated. The remaining serum is removed by filtration from the precipitate separated and returned to the bloodstream.

In diagnostics, both the serum residue freed from B-lipoproteins, as well as the precipitated complex of ß-lipoproteins and heparin further investigations be subjected.

The specificity of the method according to the invention was both with quantitative immunological techniques and ultracentrifugation as well as quantitative Checked lipoprotein electrophoresis. The specific pH precipitation described here of low density lipoproteins leads to a complete precipitation of this B-lipoprotein class.

Only HDL and VLDL of lipoproteins are found in the remaining filtrate.

The specificity of the method according to the invention and the application Only physiological substances allow first of all an application on the extracorporeal Cycle of Patients with hyper- or dyslipoproteiemia secondly, allows the selective elimination of LDL from plasma in vitro a determination of this fraction either from the difference calculation to the total cholesterol and the remaining filtrate or by direct determination of cholesterol on the precipitate or by measuring the turbidity of the resulting precipitate. This direct determination of LDL or B cholesterol is new and has not yet been used in any competing process described. The same applies to the selective elimination from the whole plasma for therapeutic purposes.

The inventive method was used both with the preparative Ultracentrifuge and quantitative lipoprotein electrophoresis and has correlation coefficients of over 0.98 in a series with both methods from over 100 patient sera. The specificity of the method according to the invention is clearly superior to the ultracentrifuge. Compared to electrophoresis, this has methods according to the invention have the advantage of the possibility of a direct determination of cholesterol the ß-lipoproteins. The invention.

Method can be easily carried out both in a discrete machine and operate in a continuous flow machine as a mechanized method. The precision in the series as well as from day to day is below 2%.

The invention also relates to a device for extra-corporeal Precipitation of blood components, with a container, the blood or blood components such as plasrna of a patient are supplied via a first pump, and a the filter downstream of the container, its filtrate outlet with one to the patient returning line is connected.

The invention is based on the object of a device this Kind to design so that they can be used without complex flow rate regulation in the operating phase works continuously in order to burden the patient as little as possible and around to avoid complex and therefore failure-prone control systems.

To solve this problem, the invention provides that the Filter has a second outlet for the precipitate, which is connected to one in the container leading return line is connected that the container via a second pump connected to the outlet of a first vessel containing a treatment agent and that the filtrate outlet of the filter is connected to a third pump, whose delivery rate is essentially the sum of the funding rates of the first and corresponds to the second pump.

Here, the container forms together with the filter and the return line a closed circuit in which liquid circulates. Got into that circle external liquid over which into the container into it blood or The first pump conveying blood components and, via the second pump, the treatment agent, in the present case, heparin, pumps into the container. This closed cycle liquid is withdrawn at the filtrate outlet of the filter by the third pump. Because the delivery rate of the third pump is based on the sums of the delivery rates the first and second pumps are matched, the fluid balance becomes essentially maintained in the circuit, so that the liquid level in the container always remains approximately the same.

It is therefore not necessary to switch the first pump on and off frequently, so that blood can be drawn evenly from the patient. It must be taken into account that the three pumps mentioned are volumetric pumps whose Displacement is proportional to the drive speed. To prevent the too Pumping liquid is contaminated, it is expedient to use peristaltic pumps used.

The delivery rate of the first pump depends largely on its behavior of the patient's body determined, since it must be prevented from the patient too much or too fast blood is drawn. Hence the system is expedient created so that the delivery rate of the first pump can be changed without that the circulation system is unbalanced. This is more advantageous Further development of the invention provides that the delivery rate of the first pump changeable depending on the conditions of the patient's blood collection is and that the drives of the first, second and third Pump are coupled together in such a way that the ratio of the three delivery rates remains constant.

The advantage here is that the system with time-varying Flow rates can be operated without the fluid balance being lost goes. The pumps are either mechanically or electrically connected to one another via their drives coupled, the first pump takes the lead and the speeds of the automatically adjust the other two pumps accordingly.

Despite the mutual coordination of the delivery rates of the three pumps it can happen that if the device is used for a long time, the liquid level increases increasingly in the container. To set a limit for this increase, has the container has at least one level detector, which is at an upper level the first pump switches to a lower delivery rate or switches off.

On the other hand, in order to prevent the liquid level from dropping too much in To avoid the container, the third pump of the level detector is activated a lower pump output switched or switched off when a lower level is reached. These measures of limiting the level to the range between the lower and the upper value serve to keep the influence constantly adding up Incorrect deviations in the fluid equilibrium of the circulatory system.

Since the filter clogs up after a while, it is more advantageous Further development of the invention provides a rinsing phase. The device has a the flow resistance of the filter measuring device, which at an upper Flow resistance turns on the second pump, and from one a solvent containing second vessel promotes solvent into the container and a compound between the outlet and a drain. This is how the fluid cycle becomes interrupted or blocked behind the filter and both the container and The rinsing solution flows through the filter, which then flows together with the filter residue is fed to the drain.

The following is an embodiment of the device according to the invention for performing plasmapheresis with precipitation of the low-density lipoproteins explained in more detail with reference to the drawings.

The figures show: FIG. 1 a schematic representation of the system, wherein those lines through which there is a flow in the operating state, with a larger line thickness are drawn, and Figure 2 shows the system of Figure 1, with those Lines that flowed through when rinsing the filter, with thicker lines are drawn.

In the drawings, the patient-side is above the dashed line Blood collection and return system shown, which is known. via the patient connection 1 is the patient under constant monitoring by a pressure gauge 3 blood taken. This blood is fed to a plasma filter 6 via a pump 4 after 5 anticoagulant was added from a vessel. This flows from the filter 6 a certain amount of blood plasma reduced blood through an air trap 7 and a solenoid valve 9 to the return port 2 of the patient. The return pressure is measured by a pressure measuring device 8 monitors.

The branched off blood plasma leaves the filter 6 through its filtrate outlet 61. The filter 6 is, for example, a capillary filter that is removed from the blood is traversed, the finer blood components passing through the membrane walls escape laterally while the coarser blood components are passed on to the air trap 7 will.

The plasma filter 6 becomes a preselectable one by means of a pump 11 Amount of blood plasma withdrawn. In the case of the pump referred to here as the "first pump" 11 is, as is the case with the rest of the System used Pumps to use a peristaltic pump or

peristaltic pump that is self-priming and volumetric one the amount of plasma proportional to the drive speed. Between the plasma filter 6 and the first pump 11 is a blood leak detector 10 and a pressure measuring device 12. The outlet of the first pump 11 is connected to an inlet of a container 16.

Another inlet of the container 16 is to the outlet of a second Pump 13 connected, the inlet of which via a valve 14 with a vessel 15 which contains an acetate buffer solution with heparin, as well as via a further valve 30 with a vessel 29, which contains a rinsing solution, can be connected. The inlets are located at the upper end of the container 16. The container 16 is also provided with a level detector 17 equipped, which responds when a certain level is reached.

The outlet provided at the lower end of the container 16 is provided with a Another pump 18 connected to which a valve 31 is connected in parallel. The outlet the pump 18 is connected to the filter 21, the outlet of which via a valve 22 and a return line 221 is connected to a further inlet of the container 16 is. The pressures at the inlet and the outlet of the filter 21 are measured by pressure gauges 19 and 20 monitored. The filtrate outlet 211 of the filter 21 is via the third pump 23 and a valve 25 connected to the inlet of a dialylator 26 which, on the rinsing solution side a dialysis rinsing solution from a dialysis machine 27 flows through it. In to the The portion of acetate buffer and the remaining heparin are removed from the dialyzer 26 Container 15 eliminated, while the plasma via a pump 28 to the air catcher 7 and thus flows into the extracorporeal blood circuit.

The pump 28 runs at the same speed as the pump 11, so that the fluid balance of the patient to be treated is preserved. By the dialysis rinsing fluid from the dialysis machine 27 takes place in the filter 26 at the same time an increase in the pH value and the temperature of the refluxing plasma to the Body values. Instead of a dialysis machine, the Dialyzer 20 can be supplied with a liquid.

In the operating mode shown in FIG. 1, the Pump 11 pumped blood plasma into the container 16 while simultaneously using the pump 13 acetate buffer solution with heparin is supplied via the opened valve 14. In In this state, the third pump 23 is initially switched off. After reaching the The level detector 17 responds to the intended level in the container 16 and switches on the pump 23. The pump 23 now runs at a speed that corresponds to the sum of the speeds of the pumps 11 and 13. The third pump 23 thus promotes plasma from the filter 21, while the precipitate because of the selected Pore size in the filter 21 is retained. The other pump 18, which circulates the liquid maintains in the circuit, has a relatively large capacity, so that the precipitate containing the low density lipoproteins via the Return line 221 is flushed back into the container 16.

The plasma freed from the low-density lipoproteins is transferred via the third pump 23 and the opened valve 25 are supplied to the dialyzer 26.

Since the proportion of precipitate in the container 16 and in the filter 21 is constant increases, it is necessary to remove the precipitate from the container at certain intervals 16 and to remove the recirculation circuit, this is done in the in figure 2 operating mode of the device shown. First, the plasma inflow is over the first pump 11 and the inflow of acetate buffer with heparin via the second pump 13 stopped by shutting down these pumps. The pump 18 is also stopped and the bypass valve 31 is opened.

It may also be possible to let the pump 18 continue to run. In this case, the bypass valve 31 can be omitted. The third pump 23 sucks now through the filter 21 through plasma, which is from the low-density lipoproteins is freed and pumps this plasma through the dialysis machine 26 to the pump 28. If the container 16 has run empty, the pressure difference between the inlet increases and outlet of the filter 21. This increase in the pressure difference is applied to a differentiator 201, which is the difference between the signals from the pressure gauges 19 and 20, is detected. When the pressure difference has exceeded a certain threshold value, the Pump 13 on and valve 32 opens and valve 25 'closes. Also closes Valve 14 and valve 30 open. Now the vessel 29 becomes the container 16 Solvent supplied. The valve 22 is open and the recirculation pump 18 is running at. This is done in the lines and in the filter by recirculating the solvent 21 remaining precipitate dissolved. After reaching the working level in container 16 the third pump 23 starts up and conveys the solvent with the dissolved precipitate via the opened valve 32 into the container 33. When the precipitate is in sufficient Has solved dimensions, a lower pressure value is determined at the difference generator 201. The pump 13 is then switched off and the valve 30 is closed. Same Process can also be achieved in that the pressure gauge 24 has a relatively small Indicates negative pressure. The third pump 23 continues to run until the contents of the container 16 and the circuit is promoted in the drain 33. After that there is a new cycle started to precipitate the low-density lipoproteins.

The invention is further elucidated in the following exemplary embodiments.

1. Plasma is made with an equal amount of a citrate, or phosphate Acetate buffer (0.05 M ph 4.15) mixed.

After adding an amount of heparin (5000 U / ml), 1/10 of that used Plasma amount, a yellow-white precipitate is formed from the precipitated B-lipoproteins and mainly fibrinogen.

2. 100 μl of serum are mixed with 1 ml of a solution prepared as follows is composed: 0.0641 M Na citrate, pH 5.04 1% in Liqemin 25,000 (Roche). The mixture is in an Eppendorf centrifuge for 10 minutes centrifuged. The cholesterol content of the supernatant corresponds to the cholesterol content of VLDL and HDL.

The LDL have been precipitated and can be determined from the difference between full serum cholesterol and VLDL + Calculate HDL cholesterol.

Claims (12)

n p r ü c h e 1. Method for selective extracorporeal precipitation of low density lipoproteins or ß-lipoproteins from whole serum or plasma, thereby characterized in that heparin in a buffer is added to the whole serum or plasma and the formed B-lipoprotein-heparin complex in the isoelectric point at a pH of 5.05 to 5.25 precipitated and then separated or the Precipite or the filtrate is further analyzed for diagnostic purposes. 2. The method according to claim 1, characterized in that the precipitate of the ß-lipoprotein-heparin complex takes place at a pH of 5.13. 3. Process according to Claims 1 and 2, characterized in that as a buffer, phosphate buffer, citrate buffer, lactate buffer, acetate buffer or a mixture thereof be used. 4. The method according to claims 1-3, characterized in that the Ratio of buffer to serum or buffer to plasma or buffer to blood volume is between 1: 5 to 5: 1, in particular 1: 1. 5. The method according to claims 1-3, characterized in that the Volume ratio between buffer and serum for diagnostic purposes between 2 up to 10: 1. 6. The method according to claims 1-5, characterized in that the Heparin concentration corresponds to the concentration of B-lipoproteins. 7. The method according to claims 1-6, characterized in that according to separating the precipitated B-lipoprotein-heparin complex the remaining Serum or plasma becomes mixed with normal blood. 8. The method according to claims 1-6, characterized in that according to separating the precipitated B-lipoprotein-heparin complex the remaining Filtrate is further analyzed for diagnostic purposes or the precipitate or Parts of it can be quantified. g. device for extra-corporeal precipitation of blood components, with a container that holds the blood or blood components of a patient via a first Pump are supplied, and a filter connected downstream of the container, the filtrate outlet is connected to a line leading back to the patient, d u r c h g e k e n n -z e i n e t that the filter (21) has a second outlet for the precipitate which is connected to a return line (221) leading into the container (16) is that the container (16) via a second pump (13) with the outlet of a The first vessel (15) containing the treatment agent is connected, and that the filtrate outlet (211) of the filter (21) is connected to a third pump (23) whose delivery rate essentially the sum of the delivery rates of the first and second pumps is equivalent to. 10. Apparatus according to claim 9, characterized in that the delivery rate the first pump (11) depending on the conditions of the blood withdrawal on Patient is changeable and that the drives of the first pump (11), the second Pump (13) and the third pump (23) are coupled to one another in such a way that the The ratio of the three delivery capacities remains constant. 11. The device according to claim10, characterized in that the container (16) has at least one level detector (17), which at an upper level the first pump (11) switches to a lower delivery rate or switches off. 12. The device according to claim 11, characterized in that a the flow resistance of the filter (21) measuring device (19,20,201; 24) is provided which switches on the second pump (13) in the event of an upper flow resistance, and from a second vessel (29) containing a solvent, solvent in the container (16) and a connection between the outlet (211) of the filter (21) and the drain (33).