Method for treating pre-eclampsia with stationary phase heparin

Abstract

A method of treating or preventing eclampsia, pre-eclampsia, hypertensive disorder of pregnancy, or HELLP syndrome in a patient including contacting blood from the patient that contains circulatory soluble fms-like tyrosine-kinase-1 (sFLT-1) with an ex vivo filter, said filter having immobilizcd-hcparin or -heparin fragment, the immobil ized-heparin or -heparin fragment capable of binding the sFLT-1 under the contact conditions in the filter. Next, allowing sufficient time for the binding the sFLT-1 to yield depleted blood with less of the sFLT-1 and then returning the depleted blood to the patient to treat or prevent the eclampsia, pre-eclampsia, hypertensive disorder of pregnancy in the patient. Additionally, a system for performing the method of treating or preventing eclampsia, pre-eclampsia, hypertensive disorder of pregnancy, or HELLP syndrome in a patient.

Description

METHOD FOR TREATING PRE-ECLAMPSIA WITH STATIONARY PHASE HEPARINRELATED APPLICATIONS

[0001] This application claims priority benefit of U.S. Provisional Application Serial Number 63 / 648,908, filed May 17, 2024, the contents of which are hereby incorporated by reference.FIELD OF THE INVENTION

[0002] The present invention relates generally to a method for treating pre-eclampsia (PE), hypertensive disorders of pregnancy (HDP), and HELLP syndrome and in particular to a method using stationary phase-bound heparin to remove circulatory sFLT-1 as a treatment of these disorders.BACKGROUND OF THE INVENTION

[0003] Preeclampsia is one of the world's leading causes of maternal and fetal morbidity and mortality. Preeclampsia is a new onset hypertension and proteinuria or the new onset of hypertension plus significant end-organ dysfunction with or without proteinuria in a previously normotensive patient, typically after 20 weeks of gestation or postpartum. Eclampsia is tonic- clonic seizure in a preeclamptic patient without other neurologic causes. HELLP Syndrome is Hemolysis, Elevated Liver enzymes, and Low Platelets in preeclampsia patients. Pregnant women with pre-eclampsia have been found to have elevated plasma (serum) levels of soluble fms-like tyrosine-kinase- 1 (sFLT-1), which is a truncated form of the receptor for the placental growth factor (P1GF) and vascular endothelial growth factor (VEGF) (Zeisler et al., 2016). The full-length Fit- 1 has extracellular, intramembranous, and cytoplasmic domains and is the active form of the receptor anchored to the target cells. When activated by Pl GF and VEGF it stimulates theformation of new blood vessels (angiogenesis), vasodilatation, and maintenance of vascular health.However, in women with pre-eclampsia, a soluble form of the receptor (sFLT-1) circulates in the plasma and acts as a trap for P1GF and VEGF, limiting their availability to bind the full-length Flt- 1 needed for their physiological activity. In this fashion, sFlt-1 acts as an endogenous antagonist of P1GF and VEGF to prevent uncontrolled vascular growth and tumor formation. However, the placenta in patients with PE forms excessive sFlt-1, which leads to restriction in the growth of the placenta as inadequate vasculature is formed to support normal placental development resulting in fetal growth restriction (Levine et al., 2004). In addition, the sFlt-1 leakage into the maternal circulation leads to development of endothelial dysfunction, hypertension, proteinuria, and endorgan damage in the mother and can be life-threatening.

[0004] There are no definite treatments for PE except the delivery of the baby. The delivery of the fetus removes the placental source of sFlt-1 resulting in rapid fall in its serum concentration within 48 hours and the resolution of PE in most cases. However, the delivery of the baby is often difficult because the disease can present as early as gestational Week 20, and the baby is quite premature. The goal of all therapies in this syndrome is to prolong the pregnancy to allow fetal maturity while preserving maternal health. Recent efforts have explored the usage of apheresis with support-bound anti-sEng antibody and anti-sFlt-1 antibody on an ex-vivo column for removing circulator)' sEng and sFLT-1 as detailed in US20230056992A1. In addition, negatively charged Dextran Sulfate Columns have been used to lower the serum sFlt-I levels with a reduction in proteinuria and prolongation of the pregnancy in pilot studies (Thadhani et al., 2016). However, these approaches have met with limited success owing to the high cost and complexity of the reagents. More importantly, these interventions target only the maternal plasma volume of 1-3 L for sFlt-1 removal, whereas the volume of distribution of sFlt-1 is very large, and the plasma sFlt-1 constitutes only a tiny fraction of the total sFlt-1 , which is mostly located in the extravascular space and tissues.

[0005] Still other approaches have used solid phase-bound heparin through LDL apheresis procedure. This again is inherently inefficient since it can only remove plasma sFlt-1, which is a mere fraction of the total sFlt-1. In addition, these interventions require apheresis, ex-vivo separation of blood and plasma, which increases the risk of complications, such as low blood pressure.

[0006] Thus, there exists a need for a safe and efficient way to remove the bulk of sFlt-1 from the entire volume of its distribution. This requires the circulation of the whole blood through a device to remove the intravascular sFlt-1 with high efficiency and creating a high tissue-to- intravascular concentration gradient, allowing rapid influx of tissue sFlt-1 into the intravascular space to effectively treat pre-eclampsia. The mobilization of the tissue sFlt-1 can be further augmented with the intravenous administration of unfractionated heparin either before or during therapy. Thus, there exists a need for a device having high loadings of stationary phase heparin for use therewith. In addition, a device to circulate the whole blood to this device safely, a blood tubing set to carry the blood to the device with stationary-phase heparin.SUMMARY OF THE INVENTION

[0007] The present invention provides a method of treating or preventing eclampsia, preeclampsia, HDP, or HELLP syndrome in a patient. The method includes contacting blood from the patient that contains circulatory soluble fms-like tyrosine-kinase-1 (sFLT-1) with an ex vivo filter, said filter having immobilized-heparin or -heparin fragment, the immobilized-heparin or - heparin fragment capable of binding the sFLT-1 under the contact conditions in the filter. Next,allowing sufficient time for the binding the sFLT-1 to yield depleted blood with less of the sFLT-1 and then returning the depleted blood to the patient to treat or prevent the eclampsia, preeclampsia, HDP, and HELLP syndrome in the patient. The present invention additionally provides a system for performing the method of treating or preventing eclampsia, pre-eclamp sia, HDP, or HELLP syndrome in a patient.BRIEF DESCRIPTION OF THE DRAWINGS

[0008] The present invention is further detailed with respect to the following figures that depict various aspects of the present invention.

[0009] FIG. 1 is a schematic of a system of blood flow that includes a heparin-coated hemofilter or hemoadsorber;

[0010] FIG. 2 is a schematic of a system of blood flow that includes a heparin-coated hemofilter or hemoadsorber in relation to a patient; and

[0011] FIG 3 is a graph showing an over 70% reduction in plasma (s)Flt-l level in a study of 33 patients with severe COVID-19, a 4-hour treatment with Seraph 100.DESCRIPTION OF THE INVENTION

[0012] The present invention has utility as a method for treating pre-eclampsia by directly removing sFLT-1 from the circulatory system of a patient with indirect removal from the tissues down the tissue-to-intravascular concentration, thus preventing the rise in blood pressure or lowering the elevated blood pressure and other life-threatening complications of pre-eclampsia. This allows the maintenance of pregnancy until the baby is mature. As a result, the likelihood of premature delivery is reduced. In some inventive embodiments, a hemofilter or hemoadsorbenthas higher loadings of support-bound heparin than those used to preclude the device clotting is also provided to more efficiently remove sFLT-1 from circulating patient blood.

[0013] The present invention will now be described with reference to the following embodiments. As is apparent by these descriptions, this invention can be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. For example, features illustrated with respect to one embodiment can be incorporated into other embodiments, and features illustrated with respect to a particular embodiment may be deleted from the embodiment. In addition, numerous variations and additions to the embodiments suggested herein will be apparent to those skilled in the ail in light of the instant disclosure, which do not depart from the instant invention. Hence, the following specification is intended to illustrate some particular embodiments of the invention, and not to exhaustively specify all permutations, combinations, and variations thereof.

[0014] It is to be understood that in instances where a range of values are provided that the range is intended to encompass not only the end point values of the range but also intermediate values of the range as explicitly being included within the range and varying by the last significant figure of the range. By way of example, a recited range of from 1 to 4 is intended to include 1-2, 1-3, 2-4, 3-4, and 1-4.

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0016] Unless indicated otherwise, explicitly or by context, the following terms are used herein as set forth below.

[0017] As used in the description of the invention and the appended claims, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0018] Also, as used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0019] According to certain inventive embodiments, a hemodialysis filter or similar hemofilter / hemo sorbent has surfaces that contact blood flowing therethrough that are coated with heparin, or a sFLT-1 binding fragment of heparin, given that all sFlt-1 variants have a heparin- binding domain and therefore bind heparin. As the heparin or fragment thereof is immobilized on the filter, sFLT-1 in blood that circulates through filter is removed from the patient blood. In some embodiments, the filter is operated by using the existing hemodialysis, apheresis, CRRT machine and tubing to remove sFLT-1. The usage of the aforementioned system means that a device already found in a hospital setting can now be used to otherwise treat pre-eclampsia. According to embodiments, this treatment uses a hemosorbent with bound heparin and does not require any other fluids except a couple of bags of normal saline to flush the filter for priming. This is done without any external infusion pumps. During actual therapy, no other fluids are used, as opposed to dialysis where a fluid is needed to remove toxins across the membrane, which adds complexity and all fluid reservoirs, etc. None of those are needed here. The machine simply pumps the blood with a pump through the filter using one of several existing dialysis devices. These devices have all the safety features for pressures, blood flow rate adjustments, etc. Advantageously, no specificdevice or fluid or alterations to the existing machines are needed. According to embodiments, only filtered blood is returned to the patient, not an additional substance like 02 in a typical ECMO filter. In addition, no fluid or electrolytes are removed from the patient like in hemodialysis or hemofiltration, thus reducing the risk of complications.

[0020] Typical operating parameters on an inventive filter to maintain membrane integrity and minimize the pressure resistance and shear stress on the blood, illustratively include a surface-to- volume ratio of blood in the range of 50 cm-1to 130 cm-1. The filter should exhibit a pressure of 1 mmHg to 20 mmHg, and a shear stress throughout the network that is below the blood coagulation threshold, that is between 0.4 and 12 pounds per square inch (psi). The filter core through which blood flows may be made of constructed from a variety of polymers that illustratively include silicone-based organic polymers which are inert and non-toxic, such as polydimethylsiloxane (PDMS), polycarbonates, polyethylene, and polyurethane. The filter core is readily formed by conventional such as soft lithography.

[0021] With reference to FIGS. 1 and 2, a system operative with the present method is shown generally at 10. The outlet 12 and inlet 14 are conveniently adapted for connection to patient’s vascular access, the access port carrying blood to the filter designated as “arterial”, the one carry blood back to the patient as “venous”, recognizing that both are using the same vascular’ venous access. A double-lumen catheter in a large central vein, such as internal jugular or the femoral vein (not shown) is readily used to engage the patient vasculature. The arrows in FIGS. 1 and 2 depict the direction of blood flow. The system 10 includes a filter 16 with a membrane coated or beads with immobilized heparin or fragment thereof 17 therein. In still other inventive embodiments, the filter 16 is SERAPH® 100 MICROBIND® (ExThera Medical) Affinity Blood Filter. The inlet 14 feeds fluid into the filter 16 via a bladder 18 that serves to stabilize flow dynamics via a peristalticpump 22. Tubing 24 provides fluid communication between the various components of the system 10. An intravenous pump and reservoir 26 provide additional blood compatible fluid, such as isotonic saline, to modulate volumes. A valve 28 also for control of fluid flow between the bladder 18, the intravenous pump and reservoir 26, and the filter 16. A second valve 30 controls flow from the filter 16 between the inlet 12 and the first valve 28.[00221 The ExThera Seraph 100 blood filter has beads coated with heparin and binds many ligands, including microorganisms. sFltl binds to the heparin, given its molecular structure containing a heparin -binding domain and confirmed in patients with the LDL-heparin pheresis.

[0023] Blood contacting surfaces of the system 10 may be coated with secondary anticoagulants besides the heparin, these secondary anti-coagulants illustratively include polyethylene oxide (PEO), mixed endothelial cells, silicone, and hydrophilic polymers, antithrombin, and an antithrombin-heparin (ATH) complex.

[0024] While FIGS. 1 and 2 only depict a single filter 16, it is appreciated that multiple such filters are readily deployed. The multiple filters being in either parallel or series, or a combination thereof. It is appreciated that multiple filters can vary in the density per unit area of sFLT-1 binding heparin and fragments thereof.

[0025] The target population for use of the present inventive method are pregnant patients diagnosed at or after week 20 of gestation with pre-eclampsia or hypertensive disorder of pregnancy with elevated serum sFlt-1 levels or sFIt-l / PIGF ratio. Target patients also include those who are at high risk of PE or hypertensive disorder of pregnancy with elevated sFlt-1 :P1GF ratio, that continue to increase during monitoring or those who develop clinical manifestations of PE, such as increased BP and / or proteinuria.

[0026] According to embodiments, the treatment involves circulating the whole blood through a hemoadsorbent, filter, or device with stationary -phase heparin to bind sFlt-1 to lower the sFlt-1 to P1GF ratio. The device does not remove P1GF and therefore does not result in any physiologically or clinically relevant lowering of the serum P1GF concentration. Given that the present invention cleans the whole blood, it is much more efficient than plasmapheresis-based removal. Circulating the blood through a device is more efficient, even if it removes only 50% of the toxin in a single pass (extraction ratio). At a blood flow rate of 300 ml / min, the clearance will be 300 x 0.50 = 150 mL / min. In 4 hours, we will circulate 72L of blood through the filter and clear 72 x 0.5 = 36L of body volume; this is 18 - 36 times higher than the pheresis-based removal. The CO VID study (discussed in Example 1) processed 100L of blood in 4 hours and delivered 50 - 60 L of clearance as opposed to 1-2 L of sFlt-1 clearance from any apheresis-based therapy

[0027] The overall objective of this therapy is to prolong the gestation to allow fetal maturation and avoid acute and chronic complications of fetal prematurity. Other goals include:• Normalization or near normalization of the serum sFlt-1 to P1GF ratio, ideally to less than 35.• Maintenance of the sFlt-1 to P1GF ratio as close to normal as possible with treatments with the device performed in a hospital, home, or an outpatient facility.• Normalization or near normalization of urinary protein excretion.• Normalization or near normalization of blood pressure. Prevention of end-organ damage, including damage to the liver, platelets, kidneys, vascular endothelium, and brain.

[0028] According to embodiments, therapy with the device is delivered using a double-lumen venous catheter at a blood flow rate of 200 - 400 ml / min for 2-4 hours. Depending on the serum sFlt-1 levels and response to its removal, more than one therapy session is performed onconsecutive days. According to embodiments, a bolus of intravenous heparin 5000 - 10000 units is optionally given at the beginning of a therapy session for anticoagulation and to “displace” the bound fraction of sFlt-1 for its immediate removal. Monitoring for fetal distress is performed during the therapy session. Any persistent fetal distress will result in the temporary cessation or discontinuation of therapy sessions.

[0029] According to embodiments, the system includes an access device, such as a catheter, needle, cannula, or the like, inserted into a blood vessel of the subject, for accessing the subject’s blood system; a conduit system, such as tubing, piping, or the like, which fluidly connects the access device to heparin bound to the Solid Support, thereby allowing the subject’s blood to flow to and contact the surface coated with heparin and a pump (e.g., a peristaltic pump) or the like, for moving blood from the subject through the access device and conduit system to device with stationary-phase heparin. According to embodiments, the system additionally includes a second conduit system, such as tubing, piping, hollow fibers, or the like, and a return device, such as a catheter, needle, cannula, or the like, where the return device is inserted into a blood vessel (e.g., a vein) of the subject, where the conduit system fluidly connects the blood in contact with the device surface that has stationary-phase heparin or heparin fragments , to the return device so as to allow for the return of the blood to the subject. Optionally, the second conduit system also comprises a pump (e.g., a peristaltic pump) or the like, for moving the blood from hemofilter or hemosorbent , through the conduit system to the return device. This pump or the like may be the same pump or the like that utilized in the first half of the system. Alternatively, the motive force for the second conduit system for conveying the blood or plasma to the Subject is a separate pump or the like, specific to the second conduit system. In certain embodiments, the first and / or second conduit system may also comprise one or more sensors for determining the pressure and / or theflow rate of the blood in the conduit system. The present invention also provides a device (hemofilter, hemosorbent) with a stationary phase heparin or heparin fragments bound to a solid support, where the device is suitable for use in treating or preventing a pregnancy-related hypertensive disorder.

[0030] After an initial “induction” phase, the patient can be discharged home with a vascular catheter to return to a “facility” for continuation of 1-4 therapy sessions per week until the fetus is mature to be delivered safely or if there is a deterioration in the maternal or fetal health.

[0031] Clinical parameters, such as increased BP or proteinuria on a dipstick (done at home), will prompt a recheck of the serum sFlt-1 to P1GF ratio. An elevated ratio might be treated with an additional treatment session with the device or more frequent therapeutic sessions. Advantageously, risks associated with the inventive treatment for the target population are mitigated. For example, the risk of birth defects due to device-related chemicals is mitigated, given that the treatment is to be administered after 20 weeks of gestation. Fetal and maternal risks due to the removal of other factors are mitigated by the use of heparin and the fact that many crucial factors do not bind to heparin. Additionally, the risk of adverse maternal and fetal outcomes in preeclampsia is greater than the potential risk from the unintended removal of some factors, such as antithrombin III (ATIII). hi addition, the levels and activity of ATIII can be monitored and corrected if needed. Additional risks are mitigated by the fact that heparin is the safest and most often used anticoagulant during pregnancy.

[0032] Example 1

[0033] The circulating sFlt-1 levels in the blood are also elevated in severe sepsis and predict worse outcomes (Greco et al., 2018). In a study of 33 patients with severe sepsis due to COVID-19 infection, extracorporeal treatment using Seraph 100 Microbind Affinity Blood Filtercontaining beads coated with heparin resulted in over 70% reduction in the serum levels of (s)Flt- 1 (Rouse et al., 2024), as shown in the graph of FIG. 3. On average, the duration of treatment with Seraph 100 was 4-5 hours, during which approximately 100 liters of blood were filtered at normal pump speeds, typically 200 - 500 ml / minute. The extraction ratio for sFlt-1 during a single pass through the Seraph 100 hemofilter ranged from 50 - 58%. This roughly equates to a clearance value of around 40 - 60 L during a single treatment. This data confirms the concept of using a heparin-coated surface to effectively remove sFlt- 1 from whole blood without having to separate plasma from the whole blood by apheresis before its application to an ex vivo device. This makes the entire treatment much simpler and safer to implement with vastly better efficiency. Over 70% reduction in the circulating sFlt-1 is the most robust reduction ever reported using any other method of removal and is expected to be highly relevant clinically.

[0034] Notably, treatment of target patients with the inventive method results in about a 71% reduction in sFlt-1, particularly when using the Seraph 100 filter.

[0035] ReferencesGreco, M., Palumbo, C., Sicuro, F., & Lobreglio, G. (2018). Soluble Fms-Like Tyrosine Kinase-1 Is A Marker of Endothelial Dysfunction During Sepsis. Journal of Clinical Medicine Research, 10(9), 700-706. https: / / doi.org / 10.14740 / jocmr3505wLevine, R. J., Maynard, S. E., Qian, C., Lim, K.-H., England, L. J., Yu, K. F., Schisterman, E. F., Thadhani, R., Sachs, B. P., Epstein, F. H., Sibai, B. M., Sukhatme, V. P., & Karumanchi, S. A. (2004). Circulating angiogenic factors and the risk of preeclampsia. The New England Journal of Medicine, 350(7), 672-683. https: / / doi.org / 10.1056 / NEJMoa031884Rouse, M., Gann, E. R., Brandsma, J., Sugiharto, V. A., Robertson, H., Genzor, P., Chen, H.-W.,Simons, M. P., Schobel, S. A., Chenoweth, J. G., Jenkins, S. A., Clark, D. V., DellaVolpe, J., Chitty, S., Rivera, I. M., Lewis, M., Park, C., Parikh, A., Vir, P., ... Pratt, K. P. (2024). Seraph 100 Hemoperfusion for Management of Severe COVID-19: Assessment of Serum and Plasma Analytes Pre- and Post-Filtration. Blood Purification, 54(3), 200- 210. https: / / doi.org / 10.1159 / 000542995Thadhani, R., Hagmann, H., Schaarschmidt, W., Roth, B., Cingoez, T., Karumanchi, S. A., Wenger, J., Lucchesi, K. L, Tamez, H., Lindner, T., Fridman, A., Thome, U., Kribs, A., Danner, M., Hamacher, S., Mallmann, P., Stepan, H., & Benzing, T. (2016). Removal of Soluble Fms-Like Tyrosine Kinase- 1 by Dextran Sulfate Apheresis in Preeclampsia. Journal of the American Society of Nephrology: JASN, 27(3), 903-913. https: / / doi.org / 10.1681 / ASN.2015020157Zeisler, H., Llurba, E., Chantraine, F., Vatish, M., Staff, A. C., Sennstrbm, M., Olovsson, M., Brennecke, S. P., Stepan, H., Allegranza, D., Dilba, P., Schoedl, M., Hund, M., & Verlohren, S. (2016). Predictive Value of the sFIt-LPIGF Ratio in Women with Suspected Preeclampsia. The New England Journal of Medicine, 374(fi), 13-22. https: / / doi.org / 10.1056 / NEJMoal414838

[0036] Patent documents and publications mentioned in the specification are indicative of the levels of those skilled in the ait to which the invention pertains. These documents and publications are incorporated herein by reference to the same extent as if each individual document or publication was specifically and individually incorporated herein by reference.

[0037] While at least one exemplary embodiment has been presented in the foregoing description and attached appendix, it should be appreciated that a vast number of variations exist.It should also be appreciated that the exemplary embodiment or exemplary embodiments are onlyexamples, and are not intended to limit the scope, applicability, or configuration of the described embodiments in any way. Rather, the foregoing description and incorporated references will provide those skilled in the art with a convenient roadmap for implementing the exemplary embodiment or exemplary embodiments. It should be understood that various changes may be made in the function and arrangement of elements without departing from the scope as set forth in the appended claims and the legal equivalents thereof.

Claims

CLAIMS1. A method of treating or preventing eclampsia, pre-eclamp sia, hypertensive disorders of pregnancy, or HELLP syndrome in a patient comprising: contacting blood from the patient that contains circulatory soluble fms-like tyrosinekinase- 1 (sFLT- 1 ) with at least one ex vivo filter, the at least one filter having immobilized heparin or -heparin fragment, the immobilized heparin or -heparin fragment capable of binding the sFLT- 1 under the contact conditions in the at least one filter; allowing sufficient time for the binding the sFLT-1 to yield depleted blood with less of the sFLT-1; and returning the depleted blood to the patient to treat or prevent eclampsia, pre-eclampsia, and HDP in the patient.

2. The method of claim 1 wherein the at least one filter is a hemodialysis filter or hemosorbent filter.

3. The method of claim 1 wherein the at least one filter is a SERAPH® 100 MICROBIND® affinity blood filter.

4. The method of claim 1 wherein the patient has pre-eclampsia and the treatment prevents early delivery of a fetus from the patient.

5. The method of any one of claims 1 to 4 wherein the treatment reduced preterm delivery of a fetus.

6. The method of any one of claims 1 to 4 wherein the immobilized-heparin or -heparin fragment, the immobilized-heparin or -heparin fragment capable of binding the sFLT-1 is provided on surfaces of the at least one filter as a coating.

7. The method of claim 1 wherein the blood from the patient is circulated through the at least one filter by a hemodialysis machine, an apheresis machine, or a CRRT machine.

8. The method of claim 7 wherein the blood from the patient is circulated at a flow rate of 200 - 400 ml / min for 2-4 hours.

9. The method of claim 1 wherein the at least one filter includes a plurality of filters.

10. The method of claim 9 wherein the plurality of filters are arranged parallel or series, or a combination thereof.

11. The method of claim 1 further comprising first determining that the patient is pregnant and diagnosed with pre-eclampsia or hypertensive disorder of pregnancy with elevated serum sFlt-1 levels or sFIt-l / PIGF ratio.

12. The method of claim 11 wherein the patient is at least at week 20 of gestation.

13. The method of any one of claims 1 to 4 wherein said filter further comprises an additional anti-coagulant.

14. The method of any one of claims 1 to 4 wherein the method reduces the serum sFlt-1 in the blood from the patient by at least 50%.

15. A system for performing the method of any one of claims 1 to 4.

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