The potential of heparin-induced extracorporeal LDL/fibrinogen precipitation (H.E.L.P.)-apheresis for patients with severe acute or chronic COVID-19
- 1Lipidzentrum Nordrhein, Mülheim, Germany
- 2Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa
- 3Institut für infektiologische und mikrobiologische Beratung (Infactio®), Bedburg, Germany
- 4Institut tür Klinische Chemie und Laboratoriumsmedizin, Ludwig-Maximilians-Universität München, Munich, Germany
Patients with long COVID and acute COVID should benefit from treatment with H.E.L.P. apheresis, which is in clinical use for 37 years. COVID-19 can cause a severe acute multi-organ illness and, subsequently, in many patients the chronic illness long-COVID/PASC. The alveolar tissue and adjacent capillaries show inflammatory and procoagulatory activation with cell necrosis, thrombi, and massive fibrinoid deposits, namely, unsolvable microthrombi, which results in an obstructed gas exchange. Heparin-induced extracorporeal LDL/fibrinogen precipitation (H.E.L.P.) apheresis solves these problems by helping the entire macro- and microcirculation extracorporeally. It uses unfractionated heparin, which binds the spike protein and thereby should remove the virus (debris). It dissolves the forming microthrombi without bleeding risk. It removes large amounts of fibrinogen (coagulation protein), which immediately improves the oxygen supply in the capillaries. In addition, it removes the precursors of both the procoagulatory and the fibrinolytic cascade, thus de-escalating the entire hemostaseological system. It increases myocardial, cerebral, and pulmonary blood flow rates, and coronary flow reserve, facilitating oxygen exchange in the capillaries, without bleeding risks. Another factor in COVID is the “cytokine storm” harming microcirculation in the lungs and other organs. Intervention by H.E.L.P. apheresis could prevent uncontrollable coagulation and inflammatory activity by removing cytokines such as interleukin (IL)-6, IL-8, and TNF-α, and reduces C-reactive protein, and eliminating endo- and ecto-toxins, without touching protective IgM/IgG antibodies, leukocyte, or platelet function. The therapy can be used safely in combination with antiviral drugs, antibiotics, anticoagulants, or antihypertensive drugs. Long-term clinical experience with H.E.L.P. apheresis shows it cannot inflict harm upon patients with COVID-19.
In COVID-19 pandemic, the key question is: which therapeutic approach should be favored in order to save seriously sick patients? What kind of approach is suitable to prevent looming acute lung failure involving microthrombi and inflammation of the endothelium (1–5) as a result of an excessive immune response of the body when the host's first lines of defense have already failed? We know that SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane serine protease 2 (TMPRSS2) as gateways (6–8) to infect cells of the alveolar epithelium (1–4) and endothelial cells in the lungs, heart, kidneys, intestines, and liver (5). This is why patients with coronary artery disease (9–12), hypertension (3, 13), diabetes (3, 13), or obesity (3, 13) exhibit a higher mortality risk as their receptor density is up-regulated (14). Moreover, the binding of the SARS-CoV-2 spike protein inhibits and down-regulates ACE2 function which in turn promotes the inflammatory response (6–8). Diabetes for instance increases thrombogenicity and hyperactivates platelets, and so does hypertension by increasing shear stress in the vessels (15–17).
Histological studies confirmed the presence of the virus in both cell types: alveolar epithelium and endothelial cells (1–5). Alveolar tissue and adjacent capillaries reveal massive inflammatory and procoagulatory activation together with cell necrosis, thrombi, and massive fibrinoid deposits (1–5, 18, 19). It results in the clinical picture of an obstructed gas exchange. The enlargement of the diffusion barrier limits the benefits of artificial ventilation and extracorporeal membrane oxygenation (ECMO) (20–23). In addition, the latter promotes the formation of radicals as a side effect (20–23).
The application of H.E.L.P. apheresis could significantly contribute to the restoration of microcirculation in the lungs and other affected organs. The method, developed by Seidel and Wieland in 1984, primarily for patients with severe hyperlipidemia or familial homozygous hypercholesterolemia (24–30), has not only been proven beneficial as an ultima ratio treatment of arteriosclerosis and its atherothrombotic sequelae, it also has been successfully applied in coronary heart disease (24–27, 31–33) to prevent and treat graft vessel disease following heart transplantation (33–39), acute thrombotic graft occlusion following aortocoronary bypass surgery (40), preeclampsia (41, 42), strokes (43–46), unstable angina pectoris (47), and hyperlipoproteinemia (a) (32). It exhibits anti-inflammatory effects in chronic, and also acute inflammatory processes of the endothelium in the micro- and macrocirculation (26–36, 40, 48, 49) and has anticoagulant and anti-inflammatory properties (25, 50, 51).
During H.E.L.P. apheresis, blood cells are first separated from plasma in the extracorporeal circuit, then 400.000 units of unfractionated heparin are added to the plasma, and the pH is lowered to 5.12 using an acetate buffer. That is the isoelectric point for the optimal precipitation of the apolipoproteins from LDL cholesterol, lipoprotein (a) [Lp(a)], and VLDL, which are precipitated in the precipitation filter together with fibrinogen. The excess heparin is adsorbed, and bicarbonate dialysis balances the pH again. The blood cells of the patients are reinfused in parallel with a saline solution (24, 50). The duration of treatment-−2 h on average—can be shortened or extended to meet individual needs (50).
Rationale for H.E.L.P. apheresis
Patients with acute and long COVID-19 most probably will benefit from H.E.L.P. apheresis due to the following reasons:
1. It has no allocation problem and allows direct access to the entire macro- and micro-circulation owing to its extracorporeal access.
2. It uses 400.000 units of unfractionated heparin in the extracorporeal circuit, which was shown of being capable to bind SARS-CoV-2 spike protein (19, 52), and thereby could directly remove the virus and viral debris during viraemia.
3. The large quantity of unfractionated heparin allows the desolvation of forming microthrombi without a bleeding risk due to the heparin adsorber (50).
4. Heparin-induced extracorporeal LDL/fibrinogen precipitation (H.E.L.P.) apheresis removes about 50–70% of fibrinogen, the most important coagulation protein, within 2–3 h, that in turn immediately improves oxygen supply in the capillaries (50, 51).
5. In addition, it partially removes the precursors of both the procoagulatory and the fibrinolytic cascade by 35–50%, thus de-escalating the entire haemorheologic system (50). However, antithrombin III is only eliminated by 25% (50) ensuring minimized bleeding risk complications.
6. From the very beginning, H.E.L.P. apheresis is rheologically effective (30, 31, 33, 53): it increases myocardial (30, 53), cerebral (54), pulmonary blood flow rates, and coronary flow reserve (53). These effects facilitate oxygen exchange in the capillaries sustainably (51).
7. It removes cytokines such as interleukin (IL)-6, IL-8, and TNF-α, and reduces C-reactive protein (CRP) concentrations by more than 50% (41, 48, 49). The heparin adsorber completely eliminates endo- and ecto-toxins (48), so that the excessive inflammatory response, the so-called “cytokine storm”, can calm down (18, 19, 48, 49).
8. Heparin-induced extracorporeal LDL/fibrinogen precipitation (H.E.L.P.) apheresis has already been successfully applied for septic multi-organ failure in pilot studies by Bengsch et al. (48, 49). In modified form, it showed a successful outcome in the enterohaemorrhagic E.coli (EHEC) epidemic in patients suffering from the hemolytic-uraemic syndrome (HUS) (55).
9. Heparin-induced extracorporeal LDL/fibrinogen precipitation (H.E.L.P.) apheresis is an established, commercially available system (B. Braun AG, Melsungen, Germany) that has been in clinical use for 37 years. It is easy to handle and was shown to reduce complication rates in acute and chronic cardiac patients very effectively by 82–97% (27, 29, 30, 32, 34, 36). The long-term clinical experience with H.E.L.P. apheresis suggests, with a probability close to certainty, that it cannot inflict harm upon patients with COVID-19.
10. It does not remove protective IgM or IgG antibodies and does not affect leukocyte or platelet function. In the past, the therapy has been shown to be well-tolerated and safe during treatment with antiviral drugs, antibiotics, anticoagulants, or antihypertensive drugs.
In patients who are suffering from severe COVID-19, the computed tomography (CT) scan of the lungs shows ground-glass-like interstitial thickening (5), (which presumably leads to acute respiratory distress syndrome (ARDS). As a result of an excessive immune response, it appears uncontrollable. The advanced disease stage develops after the initial antiviral defense lines of the innate immune system—such as protective effects of interferons and secretory IgA on alveolar epithelium—have failed to eliminate the virus. The presence of SARS-CoV-2 viraemia is the prerequisite for humoral antibody synthesis of IgM and IgG subtypes. They could lyse virus-infected cells in the presence of complement factors. As far as we know, the nature and extent of the cellular immune response to viral antigens are almost entirely dependent on T-lymphocytes (56). The cell-mediated antibody-dependent cytotoxicity is T-cell-dependent and, currently, is being the subject of intensive virological and cell biological research.
In principle, intervention in the inflammatory cascade takes place as early as possible before the onset of the “cytokine tsunami” in order to prevent uncontrollable coagulation and inflammatory activity (18, 19) harming microcirculation in the lungs and other organs. This may be the case in COVID, for example, as this cytokine storm likely results in the presence of microthrombi found in patients suffering from COVID-19 (57). These microthrombi have the ability to block microcapillaries and hence, inhibit oxygen exchange and supply at various organs, resulting in the various symptoms of long COVID such as muscle fatigue, breathlessness, sleep impairment, and anxiety or depression (58). The phenomenon of a “cytokine storm” was first described in 1973 in graft-vs.-host disease (GvHD) following organ transplantation, and later in ARDS, sepsis, Ebola, avian flu H5N1, smallpox, systemic inflammatory response syndrome (SIRS), and now in COVID-19 (59).
Cytokines are proteins that coordinate and modulate cellular immune responses: they guide and activate leukocytes–in particular, T-lymphocytes and monocytes–to the site of inflammation where cytokine secretion is regulated by positive feedback. During a “cytokine storm”, leukocytes are activated to such an extent that the immune response seems inexorable. High concentrations of IL-1ß, IL-6, and IL-8 are expressed (18, 19, 59–61). Furthermore, IL-1ß and IL-6, together with TNF-α —the latter being mainly expressed by macrophages-direct systemic inflammatory effects such as the increase in body temperature and blood flow, capillary permeability, and leakage. Due to the complexity of regulation and orchestral functions, IL-6 plays a key role in the transition of mechanisms of innate to acquired immunity (60, 62). The CRP triggers IL-6 (61) and IL-6 links procoagulatory activation, especially triggering fibrinogen production in the liver . Whenever the body's defense is not able to clear the virus from all sites, the inflammation may persist in macrophages, in vascular beds, or in the brain stem and chronify, as recently reviewed by Proal and VanElzakker (63) with the consequence of a wide range of long-lasting clinical symptoms and impaired host immunity. In recent years, Pretorius and Laubscher (64) proved the persistence of insoluble clots containing excess alpha2-Antiplasmin bound plasminogen fibrinogen and amyloid proteins, which results in hindered fibrinolysis in long COVID patients.
Discussion: Effects of HELP apheresis
The anti-inflammatory effects of H.E.L.P. apheresis had been intensively investigated by Bengsch et al. (35, 36) in the nineties. It has been applied by them in pilot studies to successfully treat sepsis and septic shock patients with multiple organ failures. In 2012, we were able to rescue a patient with EHEC-induced HUS from her comatose state within hours, and from kidney failure within 2 days (55).
In the case of COVID-19, H.E.L.P. apheresis could be of immediate benefit because this extracorporeal system can reduce the trigger and effector of the overwhelming immune response in a simultaneous manner. The SARS-CoV-2, circulating cytokines, CRP, on top fibrinogen are reduced drastically, the latter by 50% within 2 h. As a result, the rheology of the pulmonary microcirculation will immediately be relieved—without reduction of the erythrocyte concentration. Fibrinogen is the effector of plasmatic coagulation and decisive determinant in microcirculation, plasma viscosity, and erythrocyte aggregability (51). Owing to the use of unfractionated heparin, the antithrombotic effect is maximal.
Previous studies using positron emission tomography in heart transplant patients showed that the median coronary blood flow rate remains significantly increased by 17.5% for 24 h after a single 2-h apheresis procedure. It increases by 27% under simulated exposure to the administration of adenosine (33). In principle, the decreased fibrinogen concentration causes rheologically significant effects and facilitates oxygen exchange. Plasma viscosity is reduced by an average of 19%, and erythrocyte aggregability is significantly decreased by 60% (33). In addition, the vascular endothelial growth factor (VEGF) and nitric oxide (NO) release are favorably influenced (33). The improvements have also been demonstrated for cerebral blood flow in the cardiac patients, where they profit from a 63% increase in the CO2 reserve capacity (54).
Heparin-induced extracorporeal LDL/fibrinogen precipitation (H.E.L.P.) apheresis reduces LDL cholesterol and Lp(a) concentrations with similar efficacy as fibrinogen (24, 25), thereby improving endothelial function (33, 53, 54). With regards to LDL reduction through apheresis, it remains unclear whether SARS-CoV-2 resembles delta coronavirus, which uses cholesterol as a vector due to its lipid envelope (65).
For practical reasons it is important to mention that H.E.L.P. apheresis is not restricted to a 2-h treatment time. The system can be recirculated for many hours—until the precipitate filter is saturated. The precipitate filter however can also be exchanged during the procedure, so the fibrinogen concentration theoretically could be reduced by up to 99.9999%. In-depth preliminary studies into the influence of H.E.L.P. apheresis on the kinetics of the procoagulation and fibrinolytic cascades have shown that the precursors of both cascades are also reduced by 35–50% within 2 h—with the exception of antithrombin III, which is reduced by 25% (50). Taking together, H.E.L.P. apheresis thus de-escalates the coagulation situation of both arms without any bleeding risk due to the complete adsorption of unfractionated heparin (50).
The heparin adsorber also has the ability to eliminate endo- and exo-toxins regardless of viral or bacterial origin (48, 49, 55). Recent data from Carlo Brogna indicate that the SARS-CoV-2 virus acts as a bacteriophage on the microbiome of the lungs and the guts of infected patients, thereby inducing the bacteria to produce neurotoxic “conotoxins”. These so-called conotoxins might also be eliminated by means of H.E.L.P. apheresis (64).
The use of H.E.L.P. apheresis should be considered for the treatment of patients with acute and long COVID in order to restore the vascular homeostasis, remove inflammatory and thrombogenic mediators, and to avoid unnecessary suffering. Our first experiences with patients with long COVID are promising and summarized in the corresponding article. Meanwhile, we could successfully treat hundreds of patients with long COVID with this method.
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
BJ created the working hypothesis and wrote the paper. HA helped in editing, proofreading, and discussing the theory. WK-M helped brainstorm, discuss the theory, and refine it. DS was the inventor of the HELP apheresis helped with the theoretical hypothesis and editing. All authors contributed to the article and approved the submitted version.
We thank Prof. Ashley Woodcock (Clinical Director for Respiratory Medicine at the University Hospital of South Manchester) and Dr. Asad Khan (Respiratory Medicine at the University Hospital of South Manchester) for their insightful scientific exchanges, proof reading, and encouragement that contributed immense value to this paper.
Conflict of interest
Authors BJ and DS filed a patent of the use of HELP Apheresis for long COVID to avoid misuse.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
2. Zhang H, Zhou P, Wei Y, Yue H, Wang Y, Hu M, et al. Histopathologic changes and SARS-CoV-2 immunostaining in the lung of a patient with COVID-19. Ann Intern Med. (2020) 172:629–632. doi: 10.7326/L20-0895
3. Epidemiologisches Bulletin 14/2020. Schwereeinschätzung von COVID-19 mit Vergleichsdaten zu Pneumonien aus dem Krankenhaussentinel für schwere akute Atemwegserkrankungen am RKI (ICOSARI) [Severity assessment of COVID-19 with comparative data on pneumonia from the hospital sentinel for severe acute respiratory diseases at the RKI (ICOSARI)]. (2020).
4. Bhatraju PK, Ghassemieh BJ, Nichols M, Kim R, Jerome KR, Nalla AK, et al. Covid-19 in critically ill patients in the seattle region—case series. NEJM. (2020) 382:2012–2022. doi: 10.1056/NEJMoa2004500
5. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endothelitis in COVID-19. Lancet. (2020) 395:1417–1418. doi: 10.1016/S0140-6736(20)30937-5
8. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. (2020) 181:271–80.e8. doi: 10.1016/j.cell.2020.02.052
10. Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol. (2019) 5:811–8. doi: 10.1001/jamacardio.2020.1017
11. Inciardi RM, Lupi L, Zaccone G, Italia L, Raffo M, Tomasoni D, et al. Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19). JAMA Cardiol. (2020) 5:819–24. doi: 10.1001/jamacardio.2020.1096
12. Yang C, Jin Z. An acute respiratory infection runs into the most common noncommunicable epidemic-COVID-19 and cardiovascular diseases. JAMA Cardiol. (2020) 5:743–4. doi: 10.1001/jamacardio.2020.0934
14. Caputo I, Caroccia B, Frasson I, Poggio E, Zamberlan S, Morpurgo M, et al. Angiotensin II promotes SARS-CoV-2 infection via upregulation of ACE2 in human bronchial cells. Int J Mol Sci. (2022) 23:5125. doi: 10.3390/ijms23095125
16. Morel O, Kessler L, Ohlmann P, Bareiss P. Diabetes and the platelet: toward new therapeutic paradigms for diabetic atherothrombosis. Atherosclerosis. (2010) 212:367–76. doi: 10.1016/j.atherosclerosis.2010.03.019
17. Chiva-Blanch G, Peña E, Cubedo J, García-Arguinzonis M, Pané A, Gil PA, et al. Molecular mapping of platelet hyperreactivity in diabetes: the stress proteins complex HSPA8/Hsp90/CSK2α and platelet aggregation in diabetic and normal platelets. Transl Res. (2021) 235:1–14. doi: 10.1016/j.trsl.2021.04.003
19. Mycroft-West C, Su D, Elli S, Guimond S, Miller G, Turnbull J, et al. The 2019 coronavirus (SARS-CoV-2) surface protein (Spike) S1 receptor binding domain undergoes conformational change upon heparin binding. BioRxiv. (2020). doi: 10.1101/2020.02.29.971093
20. Araos J, Alegría L, García P, Damiani F, Tapia P, Soto D, et al. Extracorporeal membrane oxygenation improves survival in a novel 24-hour pig model of severe acute respiratory distress syndrome. Am J Transl Res. (2016) 8:2826–37.
21. Neto AS, Schmidt M, Azevedo LCP, Bein T, Brochard L, Beutel G, et al. Associations between ventilator settings during extracorporeal membrane oxygenation for refractory hypoxemia and outcome in patients with acute respiratory distress syndrome: a pooled individual patient data analysis. Intensive Care Med. (2016) 42:1672–84. doi: 10.1007/s00134-016-4507-0
22. Helmerhorst HJ, Schultz MJ, van der Voort PH, de Jonge E, van Westerloo DJ. Bench-to-bedside review: the effects of hyperoxia during critical illness. Crit Care. (2015) 19:284. doi: 10.1186/s13054-015-0996-4
23. Helmerhorst HJ, Roos-Blom MJ, van Westerloo DJ, de Jonge E. Association between arterial hyperoxia and outcome in subsets of critical illness: a systematic review, meta-analysis, and meta-regression of cohort studies. Crit Care Med. (2015) 43:1508–19. doi: 10.1097/CCM.0000000000000998
24. Eisenhauer T, Armstrong VW, Wieland H, Fuchs C, Nebendahl K, Scheler F, et al. Selective continuous elimination of low density lipoproteins (LDL) by heparin precipitation: first clinical application. Trans Am Soc Artif Organs. (1986) 32:104–7.
25. Seidel D, Armstrong VW, Schuff-Werner P, Eisenhauer T. Removal of low-density lipoproteins (LDL) and fibrinogen by precipitation with heparin at low pH: clinical application and experience. J Clin Apheresis. (1988) 4:78–81. doi: 10.1002/jca.2920040207
26. Seidel D, Armstrong VW, Schuff-Werner P. The HELP-LDL-Apheresis multicentre study, an angiographically assessed trial on the role of LDL-apheresis in the secondary prevention of coronary heart disease. I evaluation of safety and cholesterol-lowering effects during the first 12 months. Eur J Clin Inv. (1991) 21:375–83. doi: 10.1111/j.1365-2362.1991.tb01384.x
27. Schuff-Werner P, Gohlke H, Bartmann U, Baggio G, Corti MC, Dinsenbacher A, et al. The HELP-LDL-apheresis multicentre study, an angiographically assessed trial on the role of LDL-apheresis in the secondary prevention of coronary heart disease. II Final evaluation of the effect of regular treatment on LDL-cholesterol plasma concentrations and the Course of Coronary Heart Disease. Eur J Clin Invest. (1994) 24:724–32. doi: 10.1111/j.1365-2362.1994.tb01068.x
28. Thiery J, Walli AK, Janning G, Seidel D. Low-density lipoprotein plasmaphaeresis with and without lovastatin in the treatment of the homozygous form of familial hypercholesterolaemia. Eur J Pediatr. (1990) 149:716–21. doi: 10.1007/BF01959530
29. Jaeger BR, Tsobanelis T, Bengel F, Schwaiger M, Seidel D. Long-term prevention of premature coronary atherosclerosis in homozygous familial hypercholesterolemia. J Pediatrics. (2002) 141:125–8. 10.1067/mpd.2002.124384
30. Mellwig KP, Schmidt HK, Brettschneider-Meyer A, Meyer H, Jaeger BR, Walli AK, et al. Coronary heart disease in childhood in familial hypercholesteremia. Maximum therapy with LDL apheresis. Internist. (2003) 44:476–80. 10.1007/s00108-002-0832-1
32. Jaeger BR, Richter Y, Nagel D, Heigl F, Vogt A, Roeseler E, et al. Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein (a) levels and prevent major adverse coronary events. Nat Clin Pract Cardiovasc Med. (2009) 6:229–39. doi: 10.1038/ncpcardio1456
33. Jaeger BR, Bengel FM, Odaka K, Uberfuhr P, Labarrere CA, Bengsch S, et al. Changes in myocardial vasoreactivity after drastic reduction of plasma fibrinogen and cholesterol: a clinical study in long-term heart transplant survivors using positron emission tomography. J Heart Lung Transplant. (2005) 24:2022–30. doi: 10.1016/j.healun.2005.05.009
35. Jaeger BR, Meiser B, Nagel D, Uberfuhr P, Thiery J, Brandl U, et al. Aggressive lowering of fibrinogen and cholesterol in the prevention of graft vessel disease after heart transplantation. Circulation. (1997) 96: II 154–8.
36. Jaeger BR, Braun P, Nagel D, Park JW, Gysan DB, Oberhoffer M, et al. A combined treatment of statins and HELP apheresis for treatment of cardiac allograft vasculopathy. Atherosclerosis Suppl. (2002) 141:331–6.
37. Labarrere CA, Woods JR, Hardin JW, Campana GL, Ortiz MA, Jaeger BR, et al. Early Prediction of cardiac allograft vasculopathy and heart transplant failure. Am J Transplant. (2011) 11:528–35. doi: 10.1111/j.1600-6143.2010.03401.x
38. Labarrere CA, Woods JR, Hardin JW, Jaeger BR, Zembala M, Deng MC, et al. Early inflammatory markers are independent predictors of cardiac allograft vasculopathy in heart-transplant recipients. PLoS ONE. (2014) 9:e113260. doi: 10.1371/journal.pone.0113260
40. Oberhoffer M, Eifert S, Jaeger B, Blessing F, Beiras-Fernandez A, Seidel D, et al. Postoperative heparin-mediated extracorporeal low-density lipoprotein fibrinogen precipitation aphaeresis prevents early graft occlusion after coronary artery bypass grafting. Surg J. (2016) 2:e5–9. doi: 10.1055/s-0036-1584167
41. Wang Y, Walli AK, Schulze A, Blessing F, Fraunberger P, Thaler C, et al. Heparin-mediated extracorporeal low density lipoprotein precipitation as a possible therapeutic approach in preeclampsia. Transfus Apheres Sci. (2006) 35:103–10. doi: 10.1016/j.transci.2006.05.010
43. Walzl M, Lechner H, Walzl B, Schied G. Improved neurological recovery of cerebral infarctions after plasmapheretic reduction of lipids and fibrinogen. Stroke. (1993) 24:1447–51. doi: 10.1161/01.STR.24.10.1447
46. Jaeger BR, Kreuzer E, Knez A, Leber A, Uberfuhr P, Börner M, et al. Case reports on emergency treatment of cardiovascular syndromes through heparin-mediated low-density lipoprotein/fibrinogen precipitation: a new approach to augment cerebral and myocardial salvage. Therap Apheres. (2002) 6:394–98. doi: 10.1046/j.1526-0968.2002.00427.x
47. Khan TZ, Pottle A, Pennell DJ, Barbir MS. The impact of lipoprotein apheresis in patients with refractory angina and raised Lipoprotein(a): objectives and methods of a randomised controlled trial. Atheroscler Suppl. (2015) 18:103–8. doi: 10.1016/j.atherosclerosissup.2015.02.019
48. Bengsch S, Boos KS, Nagel D, Seidel D, Inthorn D. Extracorporeal plasma treatment for the removal of endotoxin in patients with sepsis: clinical results of a pilot study. Shock. (2005) 23:494–500.
50. Jaeger BR, Goehring P, Schirmer J, Uhrig S, Lohse P, Kreuzer E, et al. Consistent lowering of clotting factors for the treatment of acute cardiovascular syndromes and hypercoagulability: a different pathophysiological approach. Therap Apheres. (2001) 5:252–9. doi: 10.1046/j.1526-0968.2001.00350.x
52. Paiardi G, Richter S, Oreste P, Urbinati C, Rusnati M, Wade RC. The binding of heparin to spike glycoprotein inhibits SARS-CoV-02 infection by three mechanisms. J Biol Chem. (2022) 298:101507. doi: 10.1016/j.jbc.2021.101507
53. Mellwig KP, Baller D, Gleichmann U, Moll D, Betker S, Weise R, et al. Improvement of coronary vasodilatation capacity through single LDL apheresis. Atherosclerosis. (1998) 139:173–8. doi: 10.1016/S0021-9150(98)00055-0
54. Pfefferkorn TK, Knüppel HP, Jaeger BR, Thiery J, Hamann GF. Increased cerebral CO2 reactivity after heparin-mediated extracorporeal LDL precipitation (HELP) in patients with coronary heart disease and hyperlipidemia. Stroke. (1999) 30:1802–6. doi: 10.1161/01.STR.30.9.1802
57. Grobbelaar LM, Venter C, Vlok M, Ngoepe M, Laubscher GJ, Lourens PJ, et al. SARS-CoV-2 spike protein S1 induces fibrin(ogen)resistent to fibrinolysis: implications for microclot formation in COVID-19. Biosci Rep. (2021) 41:BSR20210611. doi: 10.1042/BSR20210611
58. Pretorius E, Vlok M, Venter C, Bezuidenhout JA, Laubscher GJ, Steenkamp J, et al. Persistent clotting protein pathology in long COVID/post-acute sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin. Cardiovasc Diabetol. (2021) 20:172. doi: 10.1186/s12933-021-01359-7
60. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J. (2003) 374:1–20. doi: 10.1042/bj20030407
61. Jones SA, Novick D, Horiuchi S, Yamamoto N, Szalai AJ, Fuller GM. C-reactive protein: a physiological activator of interleukin-6 receptor shedding. J Exp Med. (1999) 189:599–604. doi: 10.1084/jem.189.3.599
62. Fiusa MML, Carvalho-Filho MA, Annichino-Bizzacchi JM, De Paula EV. Causes and consequences of coagulation activation in sepsis: an evolutionary medicine perspective. BMJ Med. (2015) 13:105. doi: 10.1186/s12916-015-0327-2
63. Proal AD, VanElzakker MB. Long COVID or post-acute sequelae of COVID-19 (PASC): an overview of biological factors that may contribute to persistent symptoms. Front Microbiol. (2021) 12:1494. doi: 10.3389/fmicb.2021.698169
64. Brogna C, Cristoni S, Petrillo M, Querci M, Piazza O, Van den Eede G. Toxin-like peptides in plasma, urine and faecal samples from COVID-19 patients. F1000Res. (2021) 10:550. doi: 10.12688/f1000research.54306.1
Keywords: H.E.L.P. apheresis, PASC, COVID-19, long COVID, SARS-CoV-2, heparin, fibrinogen, rheology
Citation: Jaeger BR, Arron HE, Kalka-Moll WM and Seidel D (2022) The potential of heparin-induced extracorporeal LDL/fibrinogen precipitation (H.E.L.P.)-apheresis for patients with severe acute or chronic COVID-19. Front. Cardiovasc. Med. 9:1007636. doi: 10.3389/fcvm.2022.1007636
Received: 30 July 2022; Accepted: 30 August 2022;
Published: 11 October 2022.
Edited by:Paresh Kulkarni, Banaras Hindu University, India
Reviewed by:Ilene Ruhoy, Cascadia Complex Health, United States
Copyright © 2022 Jaeger, Arron, Kalka-Moll and Seidel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Beate Roxane Jaeger, email@example.com