Perivascular Hyaluronidase With Alteplase as Treatment for Hyaluronic Acid Thrombosis

Abstract

Background Hyaluronic acid fillers are the second-most commonly performed nonsurgical procedure. Arterial thrombosis is their most devastating complication. Recent research shows that along hyaluronic acid thrombi, a platelet/fibrin thrombus forms in the site of injection. This is not addressed by current management protocols, which focus on perivascular hyaluronidase plus adjuvant strategies to increase blood flow. We experimented with an animal model utilizing both hyaluronidase and a thrombolytic agent for treatment of occlusion. Objectives The authors sought to evaluate the efficacy of a combined treatment of hyaluronidase with a thrombolytic agent applied perivascularly to an artery occluded with hyaluronic acid. Methods After direct intravascular injection into the femoral artery, rats were randomized to receive one of the following perivascular solutions: saline, hyaluronidase, alteplase, or hyaluronidase + alteplase. Reperfusion, distal bleeding, and microscopic findings were evaluated 4 hours after intervention. Results None of the subjects in the control group showed signs of reperfusion. In the hyaluronidase group, 60% reperfused, 10% completely, the rest only partially. In the alteplase group, 50% reperfused partially. In the hyaluronidase + alteplase group, 50% had partial and 50% complete prepermeabilization. Kruskal-Wallis test showed a P < 0.0001 favoring hyaluronidase + alteplase. Microscopic findings were compatible with bleeding rates. Conclusions Both hyaluronic acid and red thrombi play a role in the occluded vessel. Perivascular application of hyaluronidase with a thrombolytic agent seems to achieve greater reperfusion rates than either one alone. If proven safe in humans, this strategy could make treatment more effective while still being suitable for an outpatient setting.

Bridging a Century-Old Problem: The Pathophysiology and Molecular Mechanisms of HA Filler-Induced Vascular Occlusion (FIVO)—Implications for Therapeutic Interventions

“…This effect appears to be triggered by hemostasis and a direct HA–platelet interaction capable of initiating platelet aggregation [ 216 ]. Several studies in the murine epigastric and femoral artery models have confirmed this effect, in which the formation of an early platelet-rich “white thrombus” within the gel plug subsequently extends beyond the bolus to form a fibrin-rich “red thrombus” ( Figure 17 ) [ 160 , 175 ]. The immediacy of this thrombotic pathway suggests an inflammatory etiology initiated by the HA bolus rather than anoxic endothelial injury.…”

“…Once the dissemination of intraluminal filler is completed, the resulting distribution of gel fragments determines the extent of the occlusive injury. In several animal and human models of FIVO, this distribution typically consists of proximal intraluminal plugs with distally impacted filler microemboli (1–1000 μm), consistent with type III/IV vaso-dissemination ( Figure 13 ) [ 111 , 174 , 175 ].…”

“…Because type III/IV dissemination patterns have been most frequently implicated in human and animal instances of FIVO, both intravascular and extravascular delivery of hyaluronidase are likely to be of benefit. Multiple in vitro and in vivo animal studies involving the rat femoral artery and rabbit ear models have demonstrated that extravascular hyaluronidase is effective in penetrating through the arterial wall to induce the sufficient degradation of intravascular HA, averting necrosis [ 175 , 201 , 202 , 203 ]. Extravascular hyaluronidase was found to be most effective when given early (within 4 h), at high doses, and distributed over multiple treatment sessions [ 174 , 204 ].…”

“…Thrombolytic therapy, on the other hand, has recently been shown to improve outcomes in FIVO. Multiple studies in the rat epigastric and femoral vein HA-occlusion models have shown a significant flap survival benefit in animals treated with dual therapy—featuring thrombolytic agents (urokinase or alteplase) combined with hyaluronidase—compared with hyaluronidase monotherapy [ 160 , 175 , 216 ]. Furthermore, this benefit was present with both the subcutaneous and intravenous administration routes, which circumvented the arterial injury risk associated with intra-arterial interventions [ 225 ].…”

“… Histopathology of a hyaluronic acid (HA) filler-inoculated rat femoral artery demonstrating the thrombogenicity of HA gels. ( a , b ) Photomicrographs of hematoxylin and eosin (H&E) stained femoral artery sections at the site of arterial cannulation ( a ) and distally ( b ), showing the presence of intravascular thrombi associated with basophilic HA filler material, respectively; from Baley-Spindel et al [ 175 ], with permission. …”