Successful Multi-vessel Percutaneous Coronary Intervention
with Bivalirudin In A Patient With Severe Hemophilia A:
A Case Rep

ABSTRACT: We describe a 64-year-old male with severe hemophilia A (factor VIII-dependent), acute myocardial infarction (MI) and congestive heart failure (CHF) who underwent successful multi-vessel percutaneous coronary intervention (PCI). The patient was administered factor VIII transfusion to maintain activity levels between 60–80%. Anticoagulation during the PCI procedure was maintained with the direct thrombin inhibitor, bivalirudin. There were no procedural complications and the patient was discharged home the following day. These results suggest that bivalirudin may be used effectively in patients at very high risk of bleeding with enhanced procedural safety. J INVAS CARDIOL 2004;16:330–332 Key words: percutaneous coronary intervention, hemophilia, bivalirudin, acute myocardial infarction This unique case report describes a patient with severe hemophilia type A who underwent successful and uncomplicated multivessel percutaneous coronary intervention (PCI) for acute myocardial infarction. Review of the medical literature revealed few reported cases of patients with hemophilia undergoing PCI. This is the first patient with severe hemophilia A reported to have undergone multi-vessel PCI for acute myocardial infarction using bivalirudin (Angiomax,® The Medicines Company, Parsippany, New Jersey) as the sole anticoagulant. Case Report. A 64-year-old white male with a medical history of severe hemophilia A (factor VIII-dependent) presented to an outside facility with acute non ST elevation myocardial infarction (MI) and congestive heart failure (CHF). Due to the hemophilia and high-risk nature of this case, the patient was transferred to our facility for further management. On admission to our facility, the EKG revealed ST depressions in leads V2–V6 and T wave inversions in leads 1 and aVL. An adenosine nuclear stress test revealed evidence of ischemia in the anterior, anteroapical and lateral distributions. After admission, the patient had recurrent chest pain compatible with unstable angina. The past medical history was positive for coronary artery disease, prior MI, hypercholesterolemia, hypertension and diabetes. The patient also had a large fluid collection (7 cm x 7 cm) in the right iliacus muscle, which was consistent with abscess formation and chronic osteomyelitis of the right hip. The patient had undergone recent surgery for the abscess and debridement of the hip joint and was on chronic antibiotic therapy. There was no history of smoking or alcohol use. The patient was initially administered diuretics and treated for congestive heart failure. After appropriate hematology consultation and prior to cardiac catheterization, the patient was administered 4,500 Units of factor VIII (FVIII) to maintain FVIII activity around 100%. Due to the presence of extensive scar tissue in the right groin, and a healing surgical incision and right iliacus abscess, a 6 French sheath was placed in the left femoral artery. The patient then underwent diagnostic cardiac catheterization and was found to have 80–90% stenosis of the proximal and mid segments of the LAD and an 80% lesion in the proximal circumflex coronary artery. The right coronary artery angiogram revealed only mild irregularities. A 2-D echocardiogram revealed an ejection fraction of 35–40% with anterior wall hypokinesis and mild mitral regurgitation. Because of the patient’s associated comorbidities, the patient was deemed too high risk for possible CABG by the cardiovascular surgeons and after discussion with the patient and family multivessel percutaneous coronary intervention was performed. For the percutaneous coronary intervention, the patient was anticoagulated with 11.3 cc bolus of bivalirudin (5 mg/mL) via peripheral IV followed by 1.78 cc bivalirudin (5 mg/mL) infusion. Coronary angioplasty of the LAD was performed using a Choice floppy guidewire, 014 x 300, (Scimed, Maple Grove, Minn.). The guidewire was advanced to the proximal section of the LAD and a Stormer 2.0 x 20 balloon (Medtronic, Santa Rosa, Calif.) inserted and advanced to the lesion site where it was successfully inflated at 10 atmospheres (atms). A Zeta Rx 2.75 x 28 mm stent (Guidant, Santa Clara, Calif.) was deployed at 12 atms for 40 seconds. The guidewire was removed from the LAD, then advanced to the proximal circumflex where a BX velocity Hep RX 3.0 x 13 mm stent (Cordis J& J) was successfully deployed at 12 atms. Angiography revealed no residual stenosis, with restoration of TIMI 3 flow distal to the treated vessels. The guidewire and catheter were removed and the sheath sutured in place. The sheaths were pulled 2 hrs later when the ACT was less than 150 and while the FVIII was still being transfused. There were no procedural complications and the patient was discharged home without complications the following day. Aspirin and clopidogrel were continued. Discussion. Hemophilia A is a sex-linked genetic bleeding disorder resulting in deficiency of plasma FVIII coagulant activity. Patients with severe hemophilia have Factor VIII levels of about 1% (1 UFVIII dL 1) of normal or less and tend to bleed frequently on minimal or unrecognized trauma, especially into joints or muscle or less frequently intracerebrally. The principles of modern hemophilia management, including safe and early treatment of bleeding and prophylactic use of FVIII concentrate in prevention of bleeding. Over the past decade, considerable experience has been collected illustrating that necessary major surgery may be performed quite safely in hemophiliac patients if hemostasis is assisted by recommended therapeutic products, with the aim of achieving a target concentration of 100% FVIII activity during the perioperative period.¹ Hemophilia has been reported to have a direct protective effect on the development of ischemic heart disease.² However, this was not the case with our patient who had a history of prior coronary artery disease and previous myocardial infarction. Whether FVIII transfusions are pro-atherogenic remains to be answered. There are however, case reports of patients having myocardial infarctions after receiving FVIII transfusions.^3,4,5 Our patient had received daily FVIII transfusions for severe hemophilia for at least the last 10 years. Hemophilia A, because it, increases a patient’s risk of hemorrhage, is particularly challenging to manage in the setting of PCI. In the classical coagulation cascade, FVIII is part of the intrinsic pathway and plays a role in the activation of factor IX and subsequent generation of factor X, which in turn converts prothrombin to thrombin. Thrombin is a potent procoagulant that accelerates the entire coagulation cascade and results in large amounts of fibrin formation. Factor VIII also binds to receptors on the platelet surface and allows for efficient propagation of the cascade to assure clot formation. To avoid excess hemorrhage during surgery in patients with hemophilia type A, administration of FVIII is necessary. Because some patients with hemophilia can develop antibodies and become resistant to FVIII transfusions, meticulous attention to FVIII levels prior to the procedure is essential. Since FVIII is an important component of clot formation and high FVIII activity has been identified as a risk factor for thrombosis, effective, reliable anticoagulation is also required during PCI. Heparin has a number of well-described limitations including: 1) an indirect mode of action (requires the cofactor, antithrombin, in order to inhibit thrombin),⁶ 2) an inability to effectively inhibit clot bound thrombin resulting in an active reservoir of thrombin capable of continued platelet activation and increased risk of ischemic events,⁶ 3) non-specific protein binding and neutralization by platelet factor 4 leading to interpatient variability, unpredictable anticoagulant response, and the need for close monitoring and dose adjustments,⁷ and 4) direct activation of platelets.⁸ These limitations have clinical consequences as illustrated in a post hoc analysis of 1006 patients stratified by thrombotic risk in the Bivalirudin Angioplasty Trial.^9,10 Patients were stratified into 4 categories; 1) no risk factors; 2) having had an infarct within 14 days; 3) unstable coming to the cath lab on heparin; or 4) unstable and post MI. For patients randomized to heparin, the risk of ischemic events (a composite of death, MI and revascularization) increased incrementally as the severity of the disease state worsened. Ischemic event rates doubled between patients with no risk factors versus those at the highest risk (unstable and post-MI) (7.0% vs. 14%). Major bleeding outcomes also increased incrementally from 8.3% in patients with no risk factors to 16.5% in patients who were unstable and post-MI. In contrast, among patients randomized to bivalirudin, ischemic (6.1% no risk; 5.8% high risk) and bleeding (3.6% no risk; 3.3% high risk) event rates remained consistent whether the patient had no risk factor or multiple risk factors. These data provide convincing evidence of heparin’s inability to effectively inhibit thrombin with increasing severity of thrombotic disease and thrombus burden. The direct thrombin inhibitor, bivalirudin was selected as the anticoagulant for this case. Bivalirudin has a rapid onset of action, a short 25-minute half-life and a predictable dose response that facilitated expeditious completion of the procedure and also allowed for early sheath removal while the FVIII transfusion continued. Bivalirudin inhibits both circulating and clot bound thrombin, unlike heparin.¹¹ Bivalirudin does not bind to non-specific proteins and is not neutralized by platelet factor 4.⁶ Consequently, dose response is more predictable than that seen with heparin. In clinical PCI trials, bivalirudin has been associated with consistent reductions in both ischemic and bleeding complications compared to heparin therapy.^{9, 12, 13} In the REPLACE-2 trial, bivalirudin with provisional GP IIb/IIIa inhibition (7.2%) demonstrated ischemic event rates equivalent to those observed with heparin plus glycoprotein IIb/IIIa inhibition in patients undergoing urgent or elective PCI. Importantly, bivalirudin was also associated with a significant reduction in bleeding events, transfusion requirements and thrombocytopenia.¹⁴Conclusion. In our case, the use of bivalirudin circumvented problems associated with unpredictable anticoagulation with heparin and the incremental bleeding risk due to the use of GP IIb/IIIa antagonists. The effects of inhibitors due to FVIII transfusions made the effect of FVIII transfusions short lived. Our experience suggests that bivalirudin can be used effectively in patients at extremely high risk of bleeding with high risk angiographic characteristics with enhanced procedural safety. The ability to treat a patient with hemophilia A undergoing PCI with an anticoagulant that reduces both ischemic and hemorrhagic risk provides an attractive alternative to current therapeutic options.