Successful Thrombolytic Therapy for Mechanical Mitral Valve Thrombosis Using Bivalirudin-Based Thrombolytic Regimen

Abstract

Distinguishing the cause of a mechanical valve obstruction as a thrombus or a pannus can be difficult but is critical because pannus can be treated only with surgical valve replacement and thrombus can be treated with surgery or fibrinolytic therapy. This case report describes a patient with a mechanical valve thrombosis and reported allergy to porcine products who was treated by an unusual regimen: ultraslow-infusion, low-dose fibrinolytic therapy with administration of bivalirudin as a bridging anticoagulant.

Graphical Abstract

Valvular occlusion is a complication that can be seen in patients with mechanical heart valves. The causes of occlusion include pannus, thrombus, or both.¹ Differentiating between the 2 causes is critical when deciding on further management.² For pannus, the treatment option is surgical valve replacement, whereas for obstructing thrombosis of a left-sided valve, treatment can be with either surgery or thrombolytic therapy.^1,3 This case report exemplifies the challenge of diagnosing mechanical valve thrombosis along with successful treatment using an atypical thrombolytic regimen in a patient with reported allergy to porcine products.

Take-Home Messages

• •This case highlights the importance of multimodality imaging for determining the cause of mechanical valve obstruction (thrombus vs pannus).
• •Using bivalirudin as the bridging anticoagulant during thrombolytic therapy has not been studied before, but it potentially can be considered in patients with allergy to heparin products.

History of Presentation

A 43-year-old woman presented to the emergency department with a 2-week history of progressive dyspnea. The patient was afebrile, with a heart rate of 87 beats/min and a blood pressure (BP) of 97/70 mm Hg; oxygen saturation was 94% on room air. The results of physical examination included elevated jugular venous pulsation and muffled mechanical closure click.

Past Medical History

The patient’s medical history included rheumatic heart disease and mitral valve replacement with a 27-mm ATS bileaflet mechanical mitral valve (ATS Medical, Inc) 9 years prior to presentation. Her last echocardiogram from 6 years prior showed stable prosthetic valve with a mean gradient of 6 mm Hg at heart rate 62 beats/min, mechanical valve thrombosis (8 years prior; received tissue plasminogen activator [tPA]), and reported allergy (skin rash) to porcine-related products.

Differential Diagnosis

Prosthetic valve obstruction, acute nonvalvular heart failure exacerbation, pulmonary emboli.

Investigations

Laboratory studies showed hemoglobin of 10.4 g/dL (reference range 12.0-15.0 g/dL), brain natriuretic peptide of 241 pg/mL (reference <100 pg/mL), and INR subtherapeutic at 1.3 (last documented INR was 2.2 from 4 years prior). An electrocardiogram showed normal sinus rhythm with nonspecific ST-segment abnormalities. A chest x-ray showed diffuse mild interstitial prominence, and computed tomography scan of the chest with contrast material demonstrated bilateral moderate pleural effusions and enlarged pulmonary trunk. A transthoracic echocardiogram (TTE) showed a left ventricular ejection fraction of 50% with significant stenosis across the mechanical mitral valve with restricted leaflet motion. The mean pressure gradient across the mitral valve was 23 mm Hg at a heart rate of 79 beats/min (Figure 1). The patient was treated with intravenous (IV) diuresis. The cardiothoracic surgery team was consulted. Shortly after admission, her BP and urine output dropped, and she was transferred to the critical care unit. Later, her BP improved with discontinuance of her home BP medications. An urgent transesophageal echocardiogram (TEE) was obtained to better understand the cause of the valve dysfunction (thrombus vs pannus) and showed a bileaflet mechanical valve with an immobile anterior and restricted posterior discs, with a mean gradient of 22 mm Hg at a heart rate of 78 beats/min (Figures 2 and 3, Video 1). Further imaging with CT angiogram of the chest showed a possible thrombus that measured ≤1.0 cm in greatest dimension, attached to the mitral valve (Figure 4).

Figure 1.

Transthoracic Echocardiogram: Before Treatment

Continuous-wave Doppler signal across the mitral valve inflow, which reveals significantly elevated gradients across the mechanical mitral valve (mean gradient 23 mm Hg at heart rate 79 beats/min).

Figure 2.

Transesophageal Echocardiogram 1

Mechanical mitral valve in the midesophageal 2-chamber view with an echo-density attached to the anterior leaflet suggestive of thrombus (red arrow).

Figure 3.

Transesophageal Echocardiogram 2

Continuous-wave Doppler signal across the mitral valve inflow, which reveals significantly elevated gradients across the mechanical mitral valve (mean gradient 22 mm Hg at heart rate 78 beats/min).

Figure 4.

Computed Tomography of Chest With Contrast Medium

Small thrombus attached to the mechanical mitral valve (arrow).

Management

After a discussion of treatment options with the patient, it was decided to proceed with medical therapy for obstructive mechanical mitral valve thrombosis, mainly driven by the patient’s preference. She had no contraindications for tPA. After laboratory coagulation study results confirmed an INR of <2.5 and activated partial thromboplastin time (aPTT) of <50 seconds, an IV alteplase slow-infusion protocol was initiated (25 mg alteplase over 6 hours). Given the patient’s reported history of allergy to pork products, bivalirudin was used as the bridging anticoagulant between tPA doses. The patient experienced severe intolerable headache and nausea 15 minutes into the tPA infusion. The tPA was discontinued, and urgent CT of the head showed no acute intracranial processes. The treatment was changed to a protocol of IV tPA ultraslow infusion (25 mg over 25 hours) because it was thought that her headache could have been an adverse effect from the tPA. The infusion was tolerated without any side effects. A bivalirudin drip 1.75 mg/kg/h was started after the tPA infusion was completed (no bolus was given). Anticoagulation between tPA doses was monitored with aPTT. Before next tPA dose was started, aPTT was confirmed to be <50 seconds and INR <2.5.

Outcome and Follow-Up

The patient received a total of 2 tPA infusions, with significant improvement in her symptoms. After the first tPA infusion, a follow-up echocardiogram revealed improvement of the mitral valve stenosis, with a mean gradient of 14 mm Hg at a heart rate of 70 beats/min and of 11 mm Hg at a heart rate of 71 beats/min after the second dose (Figure 5). Because of the patient’s personal and social circumstances she insisted on being discharged soon, so she again resumed warfarin, with bivalirudin bridge to obtain therapeutic INR. She was discharged with a plan for a close follow-up to reassess the prosthetic valve function for possible concomitant pannus formation.

Figure 5.

Transthoracic Echocardiogram: After Treatment

Continuous-wave Doppler signal across the mitral valve inflow, which shows elevated but significantly improved mean gradient across the mechanical mitral valve (mean gradient 11 mm Hg at heart rate 71 beats/min).

Discussion

Mechanical mitral valve obstruction is a challenging problem, with multiple complex diagnostic and management issues, not the least of which is the difficulty in differentiating pannus from thrombus. The recent acute change in our patient’s symptoms and the subtherapeutic INR were the clues in favor of a possible thrombus,⁴ although despite improvement of symptoms and mechanical valve gradients with thrombolytic therapy, the patient’s mitral valve gradient remained elevated at discharge. This can likely be attributed to the presence of a concomitant pannus. Pannus and thrombus have been documented to occur together in up to 45% of patients.^5,6

Patients with mechanical mitral valve thrombosis are usually sick and require early and quick assessment with TTE and TEE for evaluating the valve for possible obstruction. Additional imaging studies including cardiac CT can provide additional evidence and guide treatment. Initial evaluation of the cause of the obstruction in this case included a TTE. Although TTE provides limited evaluation of the valves because of attenuation and acoustic shadowing, it can still be helpful in differentiating between thrombus and pannus because thrombus typically causes restriction of leaflet motion along with a higher pressure gradient (19 ± 5 mm Hg), both of which were observed in this case.⁴ TEE is more helpful than TTE in determining whether a pannus or a thrombus is present by visualizing and measuring the size of the mass involved in the obstruction.^1,4

Once the presence of a thrombus is suspected or confirmed, current guidelines of the American College of Cardiology (ACC) and the American Heart Association (AHA) indicate treatment options of thrombolytic therapy or emergent surgery.³ The HATTUSHA study compared mortality in patients who received thrombolysis (slow- and ultraslow-infusion protocols) with that in patients who underwent surgical replacement, in a total of 158 patients, and found that 3-month mortality was 2.4% and 18.7%, respectively; the thrombolysis success rate, which was determined by complete resolution of valve stenosis or partial resolution of stenosis with improvement in symptoms and reduction in thrombus size, remained high at 90.4%.⁷ A meta-analysis comparing the results of surgical intervention with the results of thrombolytic therapy found that surgery had a mortality of 18.1% compared with 6.6% in thrombolytic therapy. The causes of mortality in the thrombolytic group included embolic events, stroke, and bleeding events. The success rates were similar between the surgical and medical therapy groups, with rates of 81.9% and 80.7% respectively.⁵

Table 1 shows the different factors that support medical therapy versus surgery.^3,8 The factors in this case that supported surgical intervention included low surgical risk, recurrent valve thrombosis, and inability to initially rule out pannus.³ Although pannus had not been ruled out, the combination of the subtherapeutic INR and the echocardiogram and CT findings led the team in this case to suspect thrombus as the cause of the obstruction. From there, discussions between the multidisciplinary team and the patient led to the decision to attempt thrombolytic therapy first instead of operating.

Table 1.

Factors That Support Medical Therapy vs Surgery

Supports Medical Intervention	Supports Surgical Intervention
High surgical risk	Low surgical risk
First-time valve thrombosis	Recurrent valve thrombosis
Pannus absent	Uncertainty about pannus involvement
Shorter interval since valvular surgery	Longer interval since valvular surgery
Small clot (<0.8 cm2)	Large clot (>0.8 cm2)
Patient preference	Patient preference

With thrombolytic therapy, the ACC/AHA guidelines recommend slow-infusion low-dose therapy.³ In this protocol, patients receive a continuous IV infusion of 25 mg tPA over 6 hours, which can be repeated as needed ≤6 times while IV heparin is used between doses for bridging. Another studied protocol is the ultraslow-infusion, low-dose protocol whereby the patient receives 25 mg IV tPA infusion over 25 hours, which can be repeated ≤8 times with IV heparin administration between doses. The PROMETEE trial demonstrated that the ultraslow-infusion protocol was just as successful as the slow-infusion protocol and had the benefit of decreased risk of complications compared with the slow-infusion protocol (6.9% vs 10.5%).⁹ Initially, our patient was treated with the slow-infusion protocol. She could not tolerate it, and the treatment was successfully switched to the ultraslow infusion. The other unique aspect of our case was the use of bivalirudin instead of heparin in between tPA doses because of the patient’s reported allergy to porcine products. Although we had to change the tPA infusion rate and the bridging anticoagulant from the suggested first-line thrombolytic therapy, the treatment at least partially relieved the obstruction, with resolution of patient’s symptoms. Using bivalirudin for such indications can be challenging, given the absence of supportive evidence in guiding its use. To our knowledge, no other cases have been reported to use such an unusual thrombolytic regimen.

Conclusions

Treating patients with mechanical valve thrombosis medically can be challenging when the use of heparin-related products is not possible. Our case demonstrates that bivalirudin can be potentially used as an alternative to heparin in such cases, However, its use has its own limitations, and more studies are needed to address its safety and efficacy.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Appendix

Video 1

Transesophageal Echocardiogram

Mechanical mitral valve in the midesophageal 2-chamber view with immobile anterior leaflet caused by mechanical valve thrombosis.