Anti-thrombogenic coatings for devices in neurointerventional surgery: Case report and review of the literature.

BACKGROUND: Stent-assisted coiling and extra-saccular flow diversion require dual anti-platelet therapy due to the thrombogenic properties of the implants. While both methods are widely accepted, thromboembolic complications and the detrimental effects of dual anti-platelet therapy remain a concern. Anti-thrombogenic surface coatings aim to solve both of these issues. Current developments are discussed within the framework of an actual clinical case. CASE DESCRIPTION: A 33-year-old male patient lost consciousness while doing sport and was administered 500 mg acetylsalicylic acid on site. Computed tomography revealed a massive subarachnoid haemorrhage, and digital subtraction angiography showed an aneurysm of the right middle cerebral artery. Stent-assisted coiling using a neck bridging device with a hydrophilic coating (pCONUS_HPC) was considered as an appropriate approach. Another 500 mg acetylsalicylic acid IV was given. After the single anti-platelet therapy was seen to be effective, a pCONUS_HPC was implanted, and the aneurysm sac subsequently fully occluded using coils. No thrombus formation was encountered. During the following days, 2 × 500 mg acetylsalicylic acid IV daily were required to maintain single anti-platelet therapy, monitored by frequent response testing. Follow-up digital subtraction angiography after 13 days confirmed the occlusion of the aneurysm and the patency of the middle cerebral artery.
CONCLUSION: A variety of ways to reduce the thrombogenicity of neurovascular stents is discussed. Hydrophilic surface coatings are a valid concept to improve the haemocompatibility of neurovascular implants while avoiding the use of dual anti-platelet therapy. Phosphorylcholine and phenox hydrophilic polymer coating are currently the most promising candidates. This concept is supported by anecdotal experience. However, formalised registries and randomised trials are currently being established.

Introduction

Currently, coil occlusion (alone, stent-assisted, or using a compliant remodelling balloon), as well as extra- and intra-saccular flow diversion, are widely accepted methods for the endovascular treatment of intracranial aneurysms. Due to the thrombogenic surface of vascular implants, dual anti-platelet therapy (DAPT) has been considered mandatory since this treatment option was introduced.[1] Looking at large-scale meta-analyses, neither stent-assisted coiling[2] nor flow diversion[3] is associated with undue risks from thromboembolic complications. In daily practice, however, issues related to device thrombogenicity and DAPT (e.g. non-responder status, hyper-response and non-compliance) are frequent.[4] Implant thrombosis and haemorrhagic events remain a concern, especially in ruptured aneurysms.[5] The ability to implant stents and flow diverters (FD) in neurovascular arteries under single anti-platelet therapy (SAPT) or even without medication would be considered a major improvement. This so far unmet clinical need has prompted significant efforts from the medical device industry. This is a particularly complex problem for devices intended for the intracranial circulation, as the higher wall shear stress found here makes it an environment where platelets exposed to a foreign body may be more prone to aggregation.[6,7] Some of the currently available technology as well as some background information is summarised below. This article gives a review of the current knowledge of anti-thrombogenic surface coating of neurovascular implants. A case report illustrates the use of a pHPC surface-modified stent for assisted coiling in acute subarachnoid haemorrhage (SAH) aneurysm treatment under SAPT.

Case description

An otherwise healthy 33-year-old man lost consciousness during physical exercise and was administered 500 mg acetylsalicylic acid (ASA) and 5000 IU unfractionated heparin intravenously (IV) on site. Computed tomography revealed a SAH and ventricular haemorrhage. After an external ventricular drain had been inserted, digital subtraction angiography (DSA) showed an aneurysm on the right middle cerebral artery (MCA) with a 5 mm fundus and 4 mm neck diameter. His clinical condition was rated at Hunt and Hess IV, with a Fisher grade 3 haemorrhage. After interdisciplinary discussion, it was decided to treat this aneurysm by endovascular means. The poor clinical condition of the patient and the previous IV administration of ASA were considered arguments against microsurgical clipping of said aneurysm. The relation of the wide-necked ruptured aneurysm to the MCA bifurcation appeared well delineated on the 3D reconstruction of the rotational angiography (Figure 1(b)). Occlusion of the aneurysm sac without compromise of the inferior trunk of the MCA might have been possible with a WEB (MicroVention) or even with dual-catheter coil occlusion. The eventually possible 2D DSA in the working projection, however, did not unambiguously show the transition from the inferior trunk of the MCA to the aneurysm neck. We had to decide between a projection which showed the full depth of the aneurysm sac (without control of the bifurcation; Figure 1(c)), or a projection which visualised the MCA bifurcation (with foreshortening of the aneurysm sac; Figure 1(f)). The decision to use a pCONUS was made, with the expectation of predefining the level of final occlusion by the position of the implanted pCONUS and relying on the mechanical coil retention, preventing an inadvertent occlusion of the inferior M2 segment.

Figure 1.

Stent-assisted coil occlusion of a ruptured right middle cerebral artery (MCA) aneurysm under single anti-platelet therapy (SAPT) with acetylsalicylic acid (ASA) only. Non-contrast cranial computed tomography (CT) showing a massive subarachnoid haemorrhage (SAH) (a). Digital subtraction angiography (DSA) revealed a right MCA bifurcation aneurysm. Based on a 3D DSA (b), a working projection (c) was selected. Under SAPT with ASA given intravenously (IV) and using road map, a pCONUS1_HPC stent was deployed, with the distal end of the said stent at the neck level of the aneurysm (d). A 3D coil was inserted inside the aneurysm with coil retention by the pCONUS1_HPC (e). Another two coils allowed for sufficient occlusion of the aneurysm fundus. Coil loops projected on the MCA bifurcation are actually inside the aneurysm sac. The final DSA run one hour after deployment of the pCONUS1_HPC did not show any thrombus formation (f). DSA with diluted contrast 13 days later during endovascular vasospasm treatment confirmed the patency of the parent artery and the stent (g). Cranial CT four weeks after SAH and coil treatment did not show any ischaemic brain damage (h).

pCONUS_HPC has a CE mark, which allows the implantation under SAPT if justified by the clinical circumstances. Another 500 mg ASA IV was given. After Multiplate (Roche Diagnostics) and VerifyNow (Accriva) tests had confirmed efficient ASA-induced SAPT with no P2Y12 inhibition, a Prowler Select Plus micro-catheter (Codman Neurovascular) was inserted via an 8 F guide catheter into the aneurysm. A pCONUS1_HPC with a 4 mm shaft diameter, 20 mm shaft length and 5 mm distal petal diameter was implanted into the aneurysm sac, covering the entire aneurysm entrance. An Excelsior SL10 micro-catheter (Stryker) was used to obtain access to the aneurysm fundus. Through this catheter, sufficient coil occlusion of the aneurysm sac using three coils (Target XL 360 5/15, Helical nano3/8 and 3/6; Stryker) was achieved. No thrombus formation was encountered. During the following days, daily doses of 2× 500 mg ASA IV were required to maintain SAPT, monitored by response testing. Follow-up DSA after 13 days for vasospasm treatment confirmed the occlusion of the aneurysm fundus and the patency of the MCA (Figure 1). Follow-up computed tomography four weeks after the endovascular treatment did not show sequelae of cerebral ischemia. At the three-month follow-up, the clinical condition was mRS 1 (occasional headaches, impaired short-term memory). A DSA follow-up has been scheduled but has so far been refused by the patient. This case summary illustrates the use of a surface-modified stent for assisted coiling in acute SAH aneurysm treatment. The avoidance of DAPT was considered a significant benefit.

Discussion

The available anti-aggregants (e.g. ASA, clopidogrel, prasugrel and ticagrelor) are not approved for neurovascular procedures, and their use, although common practice, is off label. Cases of both non-response and hyper-response are encountered with all four drugs. ASA and clopidogrel are still the mainstays of DAPT. ASA has the advantage of a low rate of haemorrhagic complications. However, it is antagonised by ibuprofen and metamizole, and presence of a SAH, thrombocytosis, pregnancy or fever all require the daily dose to be increased from 100 to 500 mg, sometimes even to 1500 mg. Clopidogrel has a non-response rate of at least 30%, and it may take a whole day to work. Ticagrelor has a low rate of non-response and a rapid onset of two hours. The duration of action, however, is short, and skipping just one tablet may result in device thrombosis. Prasugrel has the fewest of such issues and has recently become quite popular for neurovascular indications.[8] The patent on prasugrel will expire in 2019, and the price is expected to change correspondingly. DAPT is known to increase the risk of haemorrhagic complications, including intracerebral haemorrhage from ventricular shunt procedures after SAH.[9] SAPT using either just ASA or prasugrel accompanied by response monitoring might be the future scenario once low-thrombogenic devices become available.

Confirming platelet function inhibition prior to stenting decreases the risk of stent thrombosis. There are a variety of methods available for platelet function testing (PFT), of which light transmission aggregometry, VerifyNow (Accriva), Multiplate (Roche Diagnostics) and the Platelet Function Analyzer (Siemens) are the most widely used devices. There are several potential mistakes which could occur in the testing process. However, even with accurate execution, these tests are unreliable to a certain degree, and there is significant inconsistency between the test results. The clinical value of PFT is the subject of a long-standing controversy.[10] Limiting or avoiding these tests would be another benefit of non- or low-thrombogenic implants.

Several tests and animal models have been deployed to determine the thrombogenicity of stents. The most straightforward way is to deploy stents in the arteries of pigs, rabbits or dogs and wait for thrombus formation.[11] In addition to angiography, optical coherence tomography (OCT) as a high-resolution intravascular imaging technology allows the identification of both thrombus formation and neointimal growth.[12] An ex vivo arteriovenous shunt (e.g. carotid artery to the jugular vein or femoral artery to femoral vein) allows a test tube loaded with stents to be inserted and thus exposed to circulating blood.[13,14] Together with ex vivo models, 111In radiolabelled platelets and 125I labelled fibrinogen can be used for quantitative measurement of the amount of local thrombus formation[13] and the contact activation system, which is relevant for thrombus formation induced by artificial surfaces, can be assessed by thrombin generation assays.[15] The Chandler loop and modifications thereof are an in vitro flow model. Stents are deployed in a plastic tubing system of a defined length and diameter. The tubes, either with stents or as empty controls, are filled with defined amounts of heparinised blood and rotated in a 37℃ water bath for two hours. The blood is then sampled and centrifuged and the platelet count, beta thromboglobulin (β-TG), thrombin–antithrombin III complex (TAT) and polymorphonuclear cells elastase are all measured. Increasing thrombogenicity correlates with decreasing platelet count and increasing values of the three other parameters.[16] Scanning electron microscopy (SEM) allows direct visualisation of the metallic surface and of adherent blood components.[16] Fluorescent monoclonal antibodies (e.g. CD41a for the glycoprotein IIb/IIIa receptor) can be used for quantitative analyses of platelet adhesion using flow cytometry or fluorescent microscopy.[17]

Thrombus formation on foreign body surfaces is a complex process. A brief overview is given in Figure 2. The first step in this cascade is the absorption of plasma proteins which activate the surrounding thrombocytes. Regardless of wetting and the biomaterial used, the initial adhesion of platelets appears to be mediated by GPIIb/IIIa binding to surface-adsorbed fibrinogen.[18] Thereafter, various activation cascades lead to a conformational change in the GPIIb/IIIa receptor, increasing the affinity of the receptor for van Willebrand factor (vWF) and fibrinogen. In detail, ADP binding to the P2Y12 receptor and thromboxane signalling leads to an increase in platelet activation. Now, the receptor binds even to soluble vWF and fibrinogen with high affinity, thus leading to the formation of a white thrombus in the vicinity of the implant. Impact on several levels of the cascade (Figure 2) will influence the thrombogenicity in either direction.

Figure 2.

Thrombus formation on foreign-body surfaces (upper row) and the effect of pHPC on the platelet activation cascade compared to ASA, clopidogrel and eptifibatide (lower row). pHPC interferes at the first step of the cascade with the adhesion of protein to the stent surface. The thrombogenicity of the coated implant is thereby reduced.

Surface passivation, electro-polishing and annealing (e.g. BlueXide and acandis) do not significantly reduce the thrombogenicity.[16,19] The published results for heparin coating are inconsistent. Tepe et al. found no benefit,[16] while several others describe a reduced surface thrombogenicity due to heparin coating,[17,20,21] or at least good clinical results.[22] Bivalirudin,[23] dopamine-immobilised heparin,[24] heparin-loaded graphene oxide on titanium surface[25] and combined chondroitin 6-sulfate and heparin[26] have been shown to achieve reduced platelet adhesion. Albumin may also be used as a surface coating with the aim of improving the haemocompatibility of stents,[21] and polyurethane coating does reduce the thrombogenicity of stents.[16]

The introduction of bare-metal stents (BMS) was a major advancement over balloon angioplasty in the management of coronary artery disease. However, the high rate of target lesion restenosis associated with the use of BMS has led to the development of drug-eluting stents (DES), which prevent the proliferation of the adjacent intimal cells. DES requires prolonged DAPT due to the increased risk of (very) late stent thrombosis.[27] While DES reduce the in-stent restenosis rate, they also increase the risk of thromboembolic complications. BMS therefore remains an option for patients who cannot complete the extended duration of DAPT because of non-compliance, the need for non-cardiac surgery or an increased risk for bleeding events.

The first-generation DES have caused (very) late stent thrombosis related to an incomplete stent endothelialisation. This issue was addressed by Bito et al.[28] They analysed micro-patterning of a 2-methacryloyloxyethyl phosphorylcholine (PC) polymer surface by hydrogenated amorphous carbon thin films for endothelialisation and anti-thrombogenicity. They were able to show that the micro-patterned polymer substrates analysed effectively supported the human umbilical vein endothelial cell proliferation while suppressing the platelet adhesion. This platform may have the potential to be utilised as a base material for DES with cell controllability. DES coated with durable polymer might be less thrombogenic than their biodegradable counterparts.[14]

Bioabsorbable coronary stents are another device family. Polymeric-based bioresorbable stents show a high rate of implant thrombosis. Recently, Waksman et al. compared the thrombogenicity of metallic and polymeric bioabsorbable stents in a porcine arteriovenous shunt mode. They compared the acute thrombogenicity of the Magmaris sirolimus-eluting bioabsorbable magnesium scaffold and the Absorb bioresorbable vascular scaffold and stained CD61/CD42b-positive cells. The Magmaris (Biotronik SE & Co. KG, Berlin, Germany) sirolimus eluting bioabsorbable magnesium scaffold was significantly less thrombogenic than the Absorb (Abbott Vascular Inc, Santa Clara, USA) bioresorbable vascular scaffold.[29]

Another approach to accelerate endothelialisation and decrease thrombogenicity is the polyzene-F coating (CeloNova BioSciences). Polyzene-F is an ultra-pure, high molecular poly(bis(trifluorethoxy))phosphazen (PTFEP).[11,30,31] It has hydrophobic properties (water contact angle of approximately 112°) and can be applied on metal, ceramic and polymer surfaces. In a medical context, it has been used for contact lenses and as a coating for the coronary stents COBRA PzF und CATANIA (Celonova). Its mechanical properties are preserved in contact with blood for 24 months.[30] The anti-inflammatory and anti-coagulating effect of the polyzene-F coating is based on the fast adsorption of specific blood proteins. Human serum albumin (HSA) and immunoglobulin (HIgG) are preferred over fibronectin (HFn) and vWF.[11,30,31] The first step of thrombocyte adhesion on surfaces is the adsorption of human fibrinogen, HFn and vWF. A surface covered with fewer of these adherent proteins is less likely to trigger coagulation. The preferred adhesion of HSA and HIgG cause the surface to be anti-inflammatory. Furthermore, a significantly faster endothelial cell migration was observed on PTFEP compared to bare-metal surfaces, which indicates good biocompatibility and faster ingrowth of devices covered with PTFEP.[11,30,31] The anti-thrombogenicity and reduced restenosis rate of polyzene-F-coated stents has been examined in several in vivo studies (e.g. in mini-pigs and New Zealand white rabbits).[11,31] Kurz et al. found a favourable response of the vessel wall in a porcine model, without a clear advantage over bare stents in terms of thrombogenicity.[32] The COBRA/CATANIA coronary stent (coated with polyzene-F) has anti-thrombogenic properties, but only shortens the period during which DAPT is required.[33] This may reduce the overall risk of haemorrhagic complications for DAPT responders, but the thrombo-embolic safety margins for DAPT non-responders and for patients less suitable for DAPT due to haemorrhagic events is not improved in this scenario. Nevertheless, today polyzene-F is among the promising anti-thrombotic coatings for cardiac stents.

Another approach is bio-inspired engineering, where nature is reverse engineered to create biomaterials that are not recognised as foreign bodies by platelets. One example is PC, which is present in the cell membrane of red blood cells and has been known for many years to reduce the thrombogenicity of stents.[34] Medtronic has developed a 3 nm PC coating for the Pipeline embolisation device (PED) called Shield. This synthetic PC polymer is covalently bound to the surface. PC is naturally present on the surface of red blood cells. As PC resembles the polar head of the phospholipids of the outer side of the cell membrane, it has the ability to reduce protein adsorption and thrombin generation. Non-specific adhesion of proteins is known to be the beginning of blood coagulation which is thereby reduced.[15,35] This coating reduces the contact platelet activation of PED.[15] In an arteriovenous shunt model, Hagen et al. were able to show that Shield reduces platelet deposition on the FD without ASA, with ASA and under DAPT. The Shield-associated reduction of fibrin deposition, however, was not significant.[13] These results were essentially confirmed using a modified Chandler loop set-up, followed by SEM.[19] Matsuda et al. conducted a longitudinal study in pigs using OCT.[12] They did not address thrombogenicity, but rather found an earlier and eventually thicker neointima coverage associated with Shield. In a following study, the same group showed (again a porcine model and OCT imaging) a reduced thrombogenicity of PED Shield under SAPT.[36] Marosfoi et al. compared PED uncoated and PED Shield in rabbits with elastase-induced aneurysms, using DAPT or no medication, angioplasty and OCT. OCT was superior to DSA in the detection of micro-thrombi on the implant surface, and the authors confirmed the reduced thrombogenicity of PED Shield.[37] Despite the confirmed anti-thrombogenicity of PED Shield, the device labelling still stipulates DAPT should be performed. Although the Shield coating has an anti-thrombogenic effect in vitro and ex vivo, the patients in the first clinical in vivo studies were still supplied with DAPT according to the standard of care.[35,38] Initial clinical studies using DAPT found procedural early safety features of PED Shield similar to those known from the uncoated PED Flex.[35] Hanel et al. published the first clinical experience with PED Shield under ASA SAPT.[39] They treated an 8 mm dissecting V4 aneurysm after a SAH. After the implantation, the patient was maintained on 1×81 mg ASA per os daily. Due to an insufficient platelet inhibition, confirmed by VerifyNow, the PED Shield was found occluded 10 days after implantation. This event is explained by the low dose of ASA and does not allow any conclusion on the anti-thrombogenic efficacy of Shield. A patient of Orlov et al. had a reduced level of DAPT after the implantation of a PED Shield without thromboembolic complications.[40] Manning et al. reported on 14 patients with ruptured aneurysms treated during the acute post-SAH phase with PED Shield under ASA SAPT.[41] This is a retrospective series from three hospitals. Premedication with ASA was inconsistent in this group of patients, and response testing was not performed. Adjunctive coil occlusion was carried out in 12 patients. A periprocedural abciximab IV bolus and a post-procedural infusion of heparin were given to five patients. Complications included one stent thrombosis one day after implantation and two early rebleeding. This series is certainly an interesting first step towards the use of PED Shield under ASA SAPT in ruptured aneurysms. The use of GPIIb/IIIa antagonists, as well as post-procedural heparin infusion, appears problematic, and the authors identified heparin infusion as a reason for haemorrhagic complications.

A variety of hydrophilic coatings have been found to reduce surface thrombogenicity. Hydrolene (polyvinylpyrrolidone and polyacrylamide) reduces thrombus formation on micro-catheters.[42] pHPC (phenox) is a dedicated development of a biomimetic aiming to reduce the thrombogenicity of neurovascular stents and FDS.[43] It is a glycan-based hydrophilic multilayer polymer coating, approximately 10 nm thin, which can be applied to nitinol surfaces. It is supposed to simulate the biological properties of the glycocalyx, a coverage which can be found on the luminal surface of the endothelium. pHPC has no pharmaceutical effect, is biocompatible and does not interact with the physical properties of the metallic implant underneath.[44,45] pHPC makes the coated surface hydrophilic (Figure 3). When small droplets of water are applied to the surface of an uncoated specimen, these droplets maintain a spherical shape on the surface of the nickel-titanium (NiTi) plates, as well as on a braided FD stent (p64, phenox). Application of the same amount of water on a hydrophilic, pHPC-coated specimen now leads to a breakdown in the surface tension of the water droplet and dispersion of the water over the surface of both the NiTi plate and the FD. Changes in the hydrophilic properties, which indicate the successful coating of the samples, are used to monitor the coating efficiency.[43] The reduction of device thrombogenicity has been shown by in vitro tests using fluorescent-labelled monoclonal CD61 antibodies.[43] In this study, pHPC-coated and -uncoated small NiTi plates were incubated with heparinised human whole blood for 10 minutes in vitro. Adherent thrombocytes were visualised via a fluorescent CD61+ antibody using a fluorescence microscope. On the pHPC-coated small NiTi plates, very few CD61+ thrombocytes were detected. This effect was true for various blood donors. In order to show the coating’s ability to decrease platelet adhesion on more complex and more thrombogenic geometry, the coating was applied to a braided FD (p48, phenox). Platelet adhesion was compared to an uncoated p48. Both FDs were incubated in whole blood for 10 min under dynamic conditions on a platform shaker. Stents were analysed under a fluoroscopic microscope (Figure 4) and using SEM (Figure 5).

Figure 3.

Changes in hydrophilicity due to pHPC surface modification. Uncoated nickel-titanium (NiTi) devices are hydrophobic and become hydrophilic when coated. This effect is shown quantitatively for NiTi plates using the Wilhelmy Plate method (graph) and qualitatively for the braided flow diverter stents. Water droplets on the uncoated specimens remain in a spherical shape, while the same amount of water on the hydrophilic-coated specimens leads to complete wetting of the sample (photographs).

Figure 4.

Representative fluorescence micrographs of uncoated and pHPC-coated p48 flow diverter (FD; phenox); overview (a and b) and detailed pictures (c and d). The specimens were incubated in whole blood for 10 minutes under dynamic conditions. Adherent platelets were stained with a CD61 antibody (yellow fluorescence). The uncoated (a and c) FD is completely covered with adherent platelets, whereas very few cells could be detected on the pHPC-coated specimen (b and d). pHPC coating inhibits adherence of platelets on the braided FD.

Figure 5.

SEM micrographs of uncoated (a and c) and pHPC-coated p48 FDs (b and d). The specimens were incubated in whole blood for 10 minutes under dynamic conditions. FDs and adherent cells were fixed and sputtered with gold.

The uncoated specimens showed extensive coverage of the wires with adherent CD61+ platelets (Figure 4(a)). The pHPC-coated FD exhibited a very low level of CD61 fluorescence (Figure 4(b)) with virtually no immunofluorescence visible in the low magnification. Nevertheless, at a higher magnification (Figure 4(d)), a few CD61+ platelets are visible.

In order to visualise the morphology of both the cells and the FD surface, SEM pictures of coated and uncoated p48 FDs were taken. Therefore, FD and adherent cells were fixed and sputtered with gold. The micrographs are shown in Figure 5. The uncoated FD shows a prominent layer of adherent cells (Figure 5(a) and (c)). Cells adhere on the stent surface and on each other, forming small agglomerates on and between the single wires of the stent. At a higher magnification, platelets on the uncoated FD form a dense layer of cells (Figure 5(c)). On the pHPC-coated p48, there are sparse cells adherent to the wires. Individual thrombocytes tended to adhere to the wire surface in the vicinity of defects (Figure 5(d)). Cell agglomerates were not detected on the pHPC-coated p48. While the adherent platelets on the uncoated surface are widely spread out, indicating a high activation state, platelets on the uncoated surface are sphere-shaped, indicating a low level of cell activation.

A significant decrease in the adhesion of CD61+ platelets on NiTi surfaces coated with pHPC compared to uncoated surfaces was seen. The coating can be successfully applied to the wires of FD, braided and laser cut stents made from NiTi. These in vitro results were the basis for the introduction of pHPC-coated FD and bifurcation stents. CE marking for these devices, awarded in Q4 2018, allows the implantation under SAPT if justified by clinical circumstances.[46]

A mitigated thrombogenicity of neurovascular stents and FD is expected to reduce the risk of thromboembolic events under DAPT and SAPT. This risk is higher in FD, since they come with more foreign-body surface than stents. Uncoated stents and FD implanted without DAPT will thrombose, sometimes within minutes. The anecdotal experience so far has shown that for unruptured aneurysms, pCONUS_HPC under ASA and p48_HPC under prasugrel (which has a much stronger inhibitory effect on platelets than ASA) can be implanted without thrombus formation. SAH triggers significant platelet activation. pCONUS_HPC under high-dose ASA (e.g. 500–1000 mg IV daily) still appears safe after SAH. p48_HPC under ASA only may thrombose after SAH, and ticagrelor or prasugrel should be considered instead.

Conclusion

Anti-thrombotic coating of neurovascular implants presents a major leap forward for the endovascular treatment of intracranial aneurysms. For the time being, phosphorylcholine and pHPC are the most promising concepts. SAPT with ASA is still required when using the technology currently available, and it is imperative to ensure the patient has responded adequately to the medication. The development of stents and FD with even better haemocompatibility, which can be used without any auxiliary medication, is the goal of future efforts.