Therapeutic Plasma Exchange for Uncontrollable Bleeding After Platelet Inhibition with Ticagrelor: A Report of 2 Cases

Introduction

Platelet aggregation is one of the major drivers of coronary artery disease pathogenesis. Current guidelines recommend the initiation of dual antiplatelet therapy (DAPT) for patients with acute coronary syndrome to prevent future myocardial ischemic events and coronary artery stent thrombosis [1,2]. Antiplatelet agents have varying mechanisms of action, including thromboxane A2 inhibition, prevention of platelet activation, prevention of platelet aggregation, ADP (P2Y12) receptor antagonism, and inhibition of glycoprotein IIb/IIIa [3]. DAPT is typically initiated with a combination of aspirin and a P2Y12 inhibitor, such as clopidogrel, prasugrel, or ticagrelor.

Ticagrelor, a cyclopentyl-triazolopyrimidine, is an adenosine diphosphate analog and allosteric antagonist that inhibits platelet aggregation via reversible binding of the P2Y12 receptor [3–5]. Although ticagrelor is effective in preventing cardiovascular-related deaths, bleeding is a common adverse effect, and patients actively receiving ticagrelor therapy are at a high risk for bleeding if surgical intervention is needed [6]. Massive platelet transfusion can be used in emergency situations to alleviate bleeding risk, but this practice itself can pose significant risks [7]. Platelet transfusion is usually ineffective while ticagrelor is still circulating, as the drug inhibits the transfused donor platelets [7]. Preliminary studies have shown that intravenous monoclonal antibody bentracimab rapidly reverses the effects of ticagrelor in healthy adults, but clinical trials are still ongoing [7]. The Society of Thoracic Surgeons guideline recommends holding ticagrelor preoperatively for a minimum of 3 days, clopidogrel for 5 days, and prasugrel or 7 days to reduce bleeding in elective cardiac surgery patients [2,8]. There are unique challenges and clinical significance in managing ticagrelor-induced bleeding, especially in emergency open heart surgery in the absence of FDA-approved reversal agents and the potential risks associated with massive platelet transfusion.

Therapeutic plasma exchange (TPE) removes circulating pathological substances such as pathogenic antibodies, immune complexes, cryoglobulins, cytokines, and toxins; it is a standard therapy for select medical conditions [9]. The equivalent of 1 plasma volume exchange with TPE (~3 L) removes approximately 60% to 70% of all plasma solutes, including pathological substances, albumin, coagulation factors, and therapeutic medications [10,11]. Here, we present and discuss 2 cases in which TPE was safely performed as a salvage procedure for DAPT-induced coagulopathy and bleeding with successful post-procedure bleeding control.

Case Reports

CASE REPORT #1:

A 52-year-old man presented with ST-elevation myocardial infarction (STEMI), and emergency PCI was placed in the left anterior descending coronary artery. During PCI, he received a loading dose of ticagrelor (180 mg). He was started on DAPT with aspirin (81 mg/day) and ticagrelor (90 mg/twice daily) (Table 1). He was found to have a post-STEMI ventricular septal defect (VSD) and was placed on mechanical circulatory support via TandemHeart for cardiogenic shock. He was not a candidate for percutaneous VSD repair and underwent surgical VSD repair under cardiopulmonary bypass support. Following surgery, the VerifyNow P2Y12 result was 3 PRU (normal range 194–418 PRU), confirming a significant antiplatelet effect. The patient’s postoperative course was complicated by profuse bleeding from the chest wall despite extensive blood product and pro-coagulant support, including 15 doses of platelets, 7 units of FFP, 21 units of pRBCs, 6 doses of pooled cryoprecipitate, 1 mg of recombinant activated factor VII, 0.5 mcg/kg of desmopressin, and 10 g of aminocaproic acid. After multidisciplinary discussion, the persistent bleeding was thought to be due to ticagrelor-related thrombocytopathy as there was no identified anatomical source for the bleeding, no evidence of coagulopathy (INR at the time was 0.88, fibrinogen 438, PTT 40.7), and PRU laboratory data supported thrombocytopathy. TPE was initiated in the intensive care unit approximately 72 h after the last dose of ticagrelor. A single 1.0 plasma volume replacement TPE was performed with the use of an apheresis system (Optia Spectra Apheresis System, Terumo BCT, Lakewood, CO) on postoperative day (POD) 1 via the patient’s central venous catheter. The replacement fluid was 3.6 L of fresh frozen plasma supplemented with 4 g of calcium gluconate. Following TPE, there was a marked improvement in bleeding from the chest wall, and no further blood products were needed. Platelet function studies performed after the procedure showed increasing PRU values over the course of a few days, with a maximum value of 82 PRU 4 days after the procedure. Unfortunately, the patient’s condition became complicated by liver failure and multi-organ pneumonia, and care was withdrawn 1 month after TPE.

CASE REPORT #2:

A 66-year-old man presented with unstable angina due to severe coronary artery disease and underwent attempted PCI complicated by left main coronary artery dissection. During PCI, he received loading doses of ticagrelor (180 mg) and eptifibatide (180 mcg/kg) (Table 1). Intravenous (i.v.) eptifibatide was discontinued after the PCI procedure. Surgical intervention was deemed necessary, and he underwent emergency 2-vessel coronary artery bypass graft surgery. Following surgery, the VerifyNow P2Y12 result was 2 PRU, confirming a significant antiplatelet effect. The postoperative course was complicated by profuse bleeding from the chest wall despite extensive blood product and pro-coagulant support, including 18 doses of platelets, 4 units of FFP, 4 units of pRBCs, 1000 units of prothrombin complex concentrate, 2 g of fibrinogen concentrate, 24 mcg of desmopressin, and 5 g of aminocaproic acid. After interdisciplinary discussions of the risks and benefits of different approaches, including recombinant activated factor VII and the theoretical benefit of TPE, the persistent bleeding was thought to be due to ticagrelor-related thrombocytopathy as there was no identified anatomical source for bleeding, no evidence of coagulopathy as the INR at the time was 1.3, and platelet reactivity unit (PRU) laboratory data supported thrombocytopathy. The decision was made to withhold recombinant factor VII and initiate TPE in the intensive care unit in the immediate postoperative period, approximately 24 h after administration of the only dose of ticagrelor. A single 1.0 plasma volume replacement TPE was performed with the use of an apheresis system (Optia Spectra Apheresis System, Terumo BCT, Lakewood, CO) on postoperative day (POD) 1 via the central venous catheter. Replacement fluid was 3 L of 5% albumin supplemented with 4 mEq potassium chloride and 3 g calcium gluconate. P2Y12 assay showed a pre-TPE value of 7 PRU. After TPE, the P2Y12 value increased to 98 PRU immediately after the procedure. A second TPE was considered on POD 1, but the bleeding was stabilizing, and the need for blood products was decreasing rapidly. No further blood products were required after POD 1. The P2Y value increased to 234 PRU on POD 2. The patient was discharged on POD 12 with a stable Hgb of 10.2 g/dL.

Discussion

We present 2 cases in which patients required emergency surgery before the recommended minimum wait time after discontinuation of ticagrelor therapy. Uncontrolled bleeding associated with a surgical procedure was refractory to conventional therapeutic approaches, including massive platelet transfusion and recombinant factor VII. However, bleeding was controlled, hemostasis was achieved, and platelet function was increased in both cases with the use of salvage TPE.

The clinical role of TPE is growing due to its versatile application and its ability to rapidly and effectively remove plasma and its protein components. In the blood, ticagrelor is highly protein-/albumin-bound (>99%), with a bioavailability of 36% [12,13]. TPE is typically recommended for removal of agents with a high plasma protein binding capacity and a low volume of distribution, ideally >80% and <0.2–0.3 L/kg of body weight, respectively [14,15]. While ticagrelor has a higher than ideal volume of distribution (88 L), the drug’s high percentage of plasma protein binding enables removal of the drug and its active metabolite from plasma via TPE, resulting in reduced intravascular drug concentration and improved platelet dysfunction. In addition, the partial removal of ticagrelor via TPE could be supplemented with perioperative platelet and FFP transfusions to prevent pathologic bleeding.

The use of TPE for the removal of drugs and other toxic agents is still not well understood and more research is needed to define the pharmacokinetics of drug removal and metabolism after TPE. Most reports describing the use of TPE for drug removal are case reports, and standardized studies are needed to better define this treatment modality in the setting of drug removal. In the 2 cases presented here, it is likely that the combination of drug removal and elimination of coagulopathic factors via TPE contributed to the correction of coagulopathic bleeding. It is difficult to determine the amount of ticagrelor removed from our 2 patients, as direct measurement of the drug was not performed. In future studies, it will be crucial to measure circulating ticagrelor concentrations before and after TPE to better understand the pharmacokinetics of this drug and help establish causality. Since PRU recovery may reflect the natural clearance of ticagrelor, future studies should measure ticagrelor levels in the plasma removed during TPE, as this is the most accurate way to determine the amount of drug removed.

Conclusions

TPE can effectively reduce ticagrelor levels and restore platelet function in emergencies.

TPE could be useful in 2 unique clinical setting: (1) emergency surgery <24 h after ticagrelor administration, and (2) life-threatening bleeding while on ticagrelor. In addition, ticagrelor removal by TPE could greatly decrease hospitalization time and costs, as this would eliminate the waiting period for the passive removal of ticagrelor. With these case reports, we hope to foster discussion for the use of TPE for removal of circulating ticagrelor and encourage further investigation into this novel treatment for refractory bleeding after ticagrelor therapy.