Beyond lipids: Systemic effects of lipoprotein apheresis

Cardiovascular disease due to atherosclerosis remains a leading cause of mortality worldwide. Atherosclerosis is now recognized as a multifactorial and chronic inflammatory disease of the arterial wall, driven not only by elevated apolipoprotein B-containing lipoproteins (e.g., LDL) but also by inflammation, oxidative stress, and thrombosis.1, 2 Lipoprotein apheresis (LA) is a well-established therapy for patients with severe hyperlipidemia, such as familial hypercholesterolemia (FH) or refractory Lp(a) elevation, who do not reach lipid targets with maximal drug therapy. By physically removing LDL and other atherogenic particles from the circulation, LA markedly lowers LDL-C and Lp(a) levels (typically by 60%–80% acutely) and, through chronic weekly or biweekly treatments, can significantly reduce atherosclerotic event rates.3, 4 However, beyond cholesterol and Lp(a) reduction, LA exerts simultaneous effects on multiple atherogenic factors, offering a unique window into the interplay of lipids with inflammatory and hemostatic pathways.1, 5 Early observations that LA improved symptoms of ischemia and slowed atherosclerosis progression more than expected from LDL lowering alone spurred interest in these “pleiotropic” effects.5 During each apheresis session, blood passes through adsorption columns or filters that can remove or dilute various plasma components, many of which contribute to vascular risk. Consequently, LA has been shown to acutely reduce levels of inflammatory cytokines, adhesion molecules, fibrinogen, and other mediators.6 It also transiently improves endothelial function and microcirculatory perfusion, likely by reducing circulating inhibitors of nitric oxide (NO) and improving blood fluidity.7, 8 These effects, although often short-lived, may cumulatively benefit patients when LA is performed regularly. They also underscore the complex pathobiology of atherosclerosis, in which lowering lipids favorably impacts inflammation and thrombosis.2 In this review, we explore five major domains of LA's pleiotropic actions: anti-inflammatory effects, endothelial function, hemorheology, coagulation, and immune modulation. For each, we highlight mechanistic evidence and clinical data, and we discuss existing gaps in knowledge. Figure 1 provides an overview of these interrelated effects. We then consider the clinical implications of LA's pleiotropic benefits, particularly in the current era of potent lipid-lowering drugs. The advent of PCSK9 inhibitors and novel Lp(a)-lowering agents has raised questions about the ongoing role of LA. While these pharmacotherapies can achieve dramatic LDL-C and Lp(a) reductions, they may not replicate the broad spectrum of apheresis's effects on inflammation and hemostasis. Understanding LA's pleiotropic effects is thus important to appreciate its potential advantages in modern preventive cardiology (Table 1). One of the most prominent non-lipid effects of LDL LA is its acute anti-inflammatory action. Patients often exhibit a rapid decline in circulating inflammatory biomarkers immediately after apheresis. For example, in a study of FH patients, a single LA session reduced C-reactive protein (CRP) by approximately 52% (from 208 ± 89 to 99 ± 48 mg/dL) and decreased inflammatory HDL activity by 37%.12 Additional reviews and studies confirm that LA acutely lowers pro-inflammatory cytokines and adhesion molecules, further supporting its anti-inflammatory effects.12-14 Similarly, Kobayashi et al. reported that after 5 weeks of twice-weekly LA, serum CRP dropped from 9.1 to 5.6 mg/L (~39% reduction, p < 0.01).9 This anti-inflammatory effect extends beyond CRP: LA has been shown to reduce circulating cytokines and acute phase reactants. In one study, pentraxin-3. (PTX3), an inflammatory mediator, was acutely lowered by H.E.L.P. apheresis along with CRP.15 LA also decreases levels of soluble adhesion molecules and chemokines in some reports (e.g., intercellular adhesion molecule-1 and monocyte chemoattractant protein-1), although findings have been variable.9 Importantly, LA can diminish inflammation within the arterial wall. A landmark study by van Wijk et al. used fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging to assess arterial wall inflammation in FH patients before and after apheresis.2 FH patients showed higher arterial FDG uptake (target-to-background ratio, TBR) than controls at baseline, consistent with vascular inflammation. Remarkably, a single LA session significantly reduced arterial TBR (from 2.05 to 1.91, p < 0.02), indicating an acute decrease in vessel wall inflammation.2 The authors concluded that apoB-containing lipoproteins causally drive arterial inflammation and that removing them via LA leads to a rapid anti-inflammatory effect in the vessel wall. This finding aligns with the broader concept that aggressive lipid lowering mitigates vascular inflammation, a key component of plaque instability. Mechanistically, several factors likely mediate LA's anti-inflammatory benefits. By clearing oxidized LDL and Lp(a) (which carry pro-inflammatory oxidized phospholipids), LA removes stimuli for monocyte and endothelial activation.8, 16 LA also transiently lowers fibrinogen, an acute phase reactant that can propagate inflammation. In addition, in vitro studies suggest that serum taken after LA is less activating to endothelial cells, possibly due to reduced cytokine content or other circulating immune mediators.1 Notably, LA has been shown to reduce circulating extracellular vesicles (EVs) derived from activated leukocytes and platelets, which are mediators of inflammation. In a 2024 study of patients with high Lp(a), a single LA session removed ~40% of circulating CD45+ leukocyte-derived microparticles and ~43% of platelet-derived microparticles (with levels returning to baseline by 7 days).3 These EVs carry inflammatory cargo; thus, their removal by LA may acutely temper inflammatory signaling. Despite these acute effects, it is important to recognize that inflammatory markers often rebound between LA sessions. CRP, for instance, may return to baseline within days as hepatic production continues.17 Chronic LA can still lead to a lower baseline level of inflammation over time (some studies note persistently lower pre-apheresis CRP after months of regular treatment18), but this is not universal. Moreover, certain immune parameters show no significant change with LA: for example, a 1990 study found no alteration in monocyte tissue factor expression or in plasminogen activator inhibitor-1 (PAI-1) levels after 5 months of biweekly LA.19 Thus, while LA clearly has anti-inflammatory effects, these appear to be driven largely by the acute removal of inflammatory stimuli and may be transient unless apheresis is frequent. Endothelial dysfunction is a hallmark of atherogenesis and is characterized by impaired endothelium-dependent vasodilation, largely due to reduced NO bioavailability. Elevated LDL and Lp(a) contribute to endothelial dysfunction by promoting oxidative stress and scavenging NO. LA has demonstrated the remarkable ability to rapidly improve endothelial function, even after a single treatment, by removing these offending lipoproteins. Classic studies in the 1990s provided the first proof-of-concept, showing that one LA session in hypercholesterolemic patients significantly augmented endothelium-dependent vasodilation in the forearm resistance arteries.8 In that study, forearm blood flow responses to acetylcholine (an endothelium-dependent vasodilator) improved post-apheresis, while responses to sodium nitroprusside were unchanged.8 The improvement in endothelial function correlated strongly with the reduction in oxidized LDL and was accompanied by a 40% increase in NO metabolites released during acetylcholine infusion.8 These findings indicate that LA acutely restores endothelial NO availability, likely by eliminating oxidized lipids that quench NO or cause endothelial NO synthase dysfunction. Similar effects have been observed in the coronary circulation. In one study,7 coronary endothelial function in FH patients was assessed via intracoronary acetylcholine infusion before and after apheresis. Prior to LA, acetylcholine caused the expected paradoxical constriction of epicardial coronaries and limited increase in coronary blood flow. Immediately after a single LA session (which lowered LDL by ~86%), the same acetylcholine doses led to significantly less epicardial constriction (diameter change improved from −20% to −3%, p < 0.01) and a greater increase in coronary blood flow (from +81% to +155%, p < 0.01).7 Endothelium-independent responses were unchanged. Thus, endothelial function in both macrovascular (epicardial) and microvascular domains was acutely normalized after LDL removal. Notably, these improvements occur within hours, highlighting that the functional component of endothelial dysfunction is rapidly reversible when circulating atherogenic factors are withdrawn. The mechanisms by which LA improves endothelial function are closely tied to reductions in oxidative and inflammatory stress. Oxidized LDL (oxLDL) is a potent cause of endothelial dysfunction: it reduces NO production and bioactivity by multiple routes (e.g., upregulating NADPH oxidase, increasing asymmetric dimethylarginine, and scavenging NO). LA drastically lowers oxLDL levels (Tamai et al. reported a ~73% drop in oxLDL concentration after one session8). The immediate improvement in acetylcholine-mediated dilation after LA was tightly correlated with the degree of oxLDL reduction,8 implicating oxLDL removal as a key factor. Additionally, LA may remove inflammatory mediators that impair endothelial function. For instance, tumor necrosis factor-α and interleukins can reduce endothelial NO synthase activity; by lowering these cytokines (as discussed earlier), LA creates a more favorable environment for NO production. Apheresis also eliminates blood components that increase endothelial adhesion and thrombosis, indirectly benefitting endothelial health. Clinical data further suggest that regular LA can help preserve or restore endothelial function in chronically affected patients. Some reports have documented improved brachial artery flow-mediated dilation (FMD) in patients on chronic LA therapy, although results vary depending on timing.20 In an interesting study on end-stage renal disease patients with peripheral arterial disease (PAD), serial LA over weeks improved endothelial-dependent vasoreactivity alongside reducing CRP, supporting a combined anti-inflammatory and endothelial benefit.9 However, if LA is stopped, endothelial function can deteriorate again, indicating the need for ongoing therapy to maintain the benefit. A unique aspect of LA is its impact on blood rheology—the flow properties of blood—which are crucial for microcirculatory perfusion. Hyperlipidemia is often associated with hemorheological disturbances such as increased plasma viscosity, elevated fibrinogen levels, and enhanced red blood cell (RBC) aggregation. By removing large lipoprotein particles and other macromolecules, LA acutely improves blood fluidity. Fadul et al. (1997) documented these changes in two homozygous FH patients: immediately after dextran-sulfate LDL apheresis, plasma viscosity fell by ~12% and whole blood viscosity by ~17%, accompanied by a 50% reduction in plasma fibrinogen concentration. Even just before the 12th weekly treatment, fibrinogen remained 22% lower than baseline and blood viscosity 11%–17% lower, indicating a sustained improvement relative to the pretreatment state.10 The viscosity reduction is partly due to the removal of fibrinogen, a major determinant of plasma viscosity and RBC aggregation. Certain LA methods (e.g., heparin-induced precipitation, or H.E.L.P.) are particularly effective at depleting fibrinogen (often by 40%–60% per session),15, 21 whereas others like dextran adsorption also incidentally remove some fibrinogen along with LDL.10 Improved rheology means that blood flows more easily through microvessels, potentially enhancing tissue perfusion. Patients on LA have reported relief of symptoms in microvascular angina and PAD that may relate to better capillary blood flow. In a study of dialysis patients with PAD, repeated LA led to clinical improvement in ischemic limb symptoms; investigators attributed this in part to reduced blood viscosity and improved red cell deformability, facilitating microcirculation.9 Indeed, LA has been shown to reduce RBC aggregation and increase RBC deformability transiently.22 By lowering fibrinogen, LA lessens the “bridging” between RBCs that causes aggregation. Additionally, hypercholesterolemic RBC membranes become cholesterol-enriched and rigid; over the long term, aggressive lipid lowering might normalize RBC membrane composition. Some immediate effect on RBC deformability post-LA has been noted, but it may be modest and method-dependent.22 Despite robust acute changes, the long-term hemorheologic impact of LA appears to plateau. In a trial of 23 patients on chronic weekly LA for ~7.6 years, single session apheresis significantly reduced plasma and whole blood viscosity each time, but the pre-apheresis viscosity measured just before treatment did not show sustained improvement over the years.22 In other words, hemorheologic parameters would return to baseline between sessions, indicating no cumulative enhancement in viscosity in the long run.22 This rebound makes sense: fibrinogen (with a half-life ~100 h) and other proteins resynthesize and equilibrate, and any structural changes to blood elements require continuous therapy to maintain. An analogy can be drawn to a “reset” after each session: blood is temporarily closer to ideal rheologic state, then gradually drifts back until the next apheresis. Nonetheless, if LA is performed frequently enough (e.g., twice weekly), the overall time-weighted blood viscosity might remain lower than in the untreated state, potentially benefiting end organs that are sensitive to perfusion (e.g., the retina, myocardium). LA's influence on the coagulation and fibrinolytic systems is another critical pleiotropic effect with potential clinical significance. Patients with high LDL or Lp(a) often exhibit prothrombotic tendencies: elevated fibrinogen, enhanced platelet aggregation, impaired fibrinolysis, and increased levels of coagulation factors like factor VII and von Willebrand factor (vWF). By depleting some of these factors, LA can acutely tilt the hemostatic balance toward a less thrombotic state. One of the most consistent findings is the reduction in fibrinogen with each apheresis session. As noted earlier, certain LA modalities (e.g., H.E.L.P.) remove fibrinogen efficiently (on the order of 50% per session).23 Even dextran-sulfate LA, primarily targeting LDL, can halve fibrinogen acutely.10 Fibrinogen is not only a risk factor for atherosclerosis but also a key clotting substrate; lowering fibrinogen acutely can prolong clotting times and reduce plasma viscosity, thus conferring both antithrombotic and hemorheologic benefits. Additionally, LA lowers vWF levels significantly.11 conducted a randomized trial in patients with refractory angina and high Lp(a), weekly LA They found that LA reduced vWF by p and fibrinogen by (from to p < relative to These changes were accompanied by of time in a platelet function and a enhancement of time from to p < Notably, Lp(a) fell by during LA in that study, removing its influence this likely to the LA's effect on is indirectly by changes in platelet For instance, a of platelet and aggregation, was shown to decrease significantly after repeated LA In the Kobayashi PAD study, serum fell from to after LA < This that LA removes activated platelet-derived microparticles or that it creates less to platelet in to has been reported to decrease after LA, although studies in homozygous FH did not show a change in platelet aggregation with modest LDL the acute as as the removal of vWF (which to it is that LA a the fibrinolytic beyond lowering Lp(a), LA may reduce in some Early studies showed no change in or activity with LDL but more lipid-lowering might In the trial LA did not significantly change or levels indicating no rebound or coagulation The effect of LA appears to for fibrinogen, lower less platelet and improved of which would be expected to reduce thrombotic risk. Indeed, data from Lp(a) apheresis note a reduction in in patients regular LA, which may partly to these hemostatic improvements in to lipid It be noted that some coagulation factors (e.g., factor factor may also drop during apheresis, but these rebound components can be transiently lowered by this more to immune The clinical of these acute coagulation changes is still While it is to LA's demonstrated reduction in acute coronary and to its antithrombotic effects, is due to the of large Nonetheless, the reduction in major reported in one study of Lp(a) likely a of lipid-lowering and pleiotropic effects the blood less LA's with the immune are both removal of immune mediators and potential of immune Some of these effects with the anti-inflammatory but they beyond inflammation into like and cell LA is a that can and immune to some depending the For example, apheresis columns primarily in disease while LA columns are at they may still or a of in and after LA have been these proteins by the next transient be potentially reducing inflammation in but also One effect of LA is the of circulating A randomized clinical the study provides evidence that LDL apheresis the of circulating endothelial in In this patients with who lipid-lowering therapy, a of LDL apheresis, showed robust of in peripheral blood over to therapy Additionally, LA was reported to expression of certain in leukocytes and endothelial data are expression and post-LA has shown changes in to inflammation and cell A demonstrated that lowering atherogenic lipoproteins is associated with broad of pro-inflammatory in circulating and signaling. 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