EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Key words : Bubble echocardiography, Renal transplant, Spontaneous venous thromboembolism

Introduction
Paradoxical embolism (PDE) occurs when a thrombus crosses an intracardiac defect into the systemic circulation.^1,2 Patient symptoms are based on the site of the resultant embolization, which may include the brain, heart, gastrointestinal tract, or extremities.^1,3

Patent foramen ovale (PFO) is associated with an increased risk of cryptogenic stroke.⁴ Valsalva maneuvers such as coughing, squatting, or defecating can transiently increase right atrial pressure and lead to a transient shunt reversal and the transfer of potential thrombi into the systemic circulation.1 The transient reversal of blood flow can also reverse the shunt of atrial septal defects (ASD) with an incidence of PDE in up to 14% of patients.⁵ On the other hand, ventricular septal defects and pulmonary arteriovenous malformations can result in left-to-right shunts under certain conditions that increase right atrial pressure, such as Eisenmenger syndrome, and can reverse the shunt, thereby allowing for PDE.6

Paradoxical embolisms should be suspected in all patients with an ischemic stroke without an identifiable cause. Up to 45% of ischemic strokes do not have identifiable causes, such as atrial fibrillation, and are referred to as cryptogenic strokes. Cerebrovascular incidents are the second most common cause of mortality worldwide and are the most frequent and relevant sequela of PDE.¹ A PFO may be found in up to 30% of the population, and studies have suggested that the annual risk of cryptogenic and recurrent strokes in patients with a PFO is 0.1% and 1%, respectively.^1,4

Deep venous thrombosis (DVT) is a risk factor for PDE. Studies have shown that cryptogenic stroke is 5 times more likely with pelvic vein thrombosis.^7,8 The pathophysiological mechanism of a PDE does vary. In the setting of a PFO, any permanent increase in right-sided cardiac pressures can increase the risk of a PDE.¹

Physicians should strongly suspect PDE in patients with an embolic event with a nonidentifiable source, such as atrial fibrillation, and when a concomitant intracardiac shunt or pulmonary arteriovenous malformation is known or suspected.¹ The treatment of PDE is based on medical (anticoagulation) and surgical approaches (close cardiac shunts percutaneously with minimal morbidity).^1,3,4

After renal transplant, venous thromboembolism (VTE) disease is not common but can be associated with frequent complications such as hemodynamic complications or infrequent complications such as PDE. Thrombi can pass into the systemic circulation through a pulmonary or intracardiac shunt. A PFO can act as a pathway for a thrombus from the peripheral veins, bypassing the lungs and entering the systemic circulation.⁹

Here, we present the case of a 35-year-old male kidney transplant recipient with a cerebral PDE associated with a spontaneous VTE.

Case Report
A 35-year-old male patient with chronic kidney disease stage 5 secondary to diabetic nephropathy had developed diabetic retinopathy. He had received repeated laser photocoagulation treatments and had been repeatedly admitted to the hospital for diabetic ketoacidosis. He started regular hemodialysis in September 2019, was known to have coronary heart disease, and underwent a living kidney transplant in Iraq in March 2021. His first graft biopsy showed calcineurin inhibitor toxicity, and he was converted from cyclosporine (Neoral)-based to tacrolimus-based maintenance immunosuppression, which resulted in stabilized graft function.

Near the end of June 2021, he was admitted with DVT of the right lower limb extended to right iliac veins associated with perigraft collection at the bifurcation of iliac vessels (Figure 1 and Figure 2). The following day, he experienced a pulmonary embolism (PE) evident by a ventilation-perfusion scan. His pelvi-abdominal contrast computed tomography (CT) scan showed an edematous graft with a small stone (3 × 4 mm) and a perigraft collection (65 × 45 × 35 mm) indenting the transplanted renal vein and right external iliac vein. Moreover, thyroid goiter with retrosternal extension and right middle lobe lung infarction were noted, in addition to moderate hepatosplenomegaly.

He was started on low-molecular-weight heparin (enoxaparin 80 mg twice daily) and warfarin, which was held before inferior vena cava (IVC) filter insertion. His thrombophilia screen was negative (protein C, protein S, activated partial thromboplastin test, anti-thrombin III, and lupus anticoagulant) repeatedly before and after the transplant.

Neck ultrasonography showed a right internal jugular vein thrombus with a small thyroid nodule. Eight days after admittance, an IVC filter was inserted in conjunction with the aspiration of the perigraft fluid collection, and the laboratory cultures did not grow any organism. Apixaban (5 mg orally, twice daily) was started 1 day later. The thyroid scan was normal, and the parathyroid scan showed a right lower adenoma. Several months later (February 2022), the IVC filter was retrieved, and apixaban was discontinued 1 year (June 2022) after his admittance.

Two months later, he arrived at a trauma center in the postictal stage, as reported by his relative, and was hospitalized to investigate the cause of the seizures. His electrocardiogram results were unremarkable. The magnetic resonance imaging (MRI) of his brain (Figure 3) showed abnormal signal intensity in the corticosubcortical left posterior temporal-parietal-occipital region, which represented ischemia, and curvilinear areas of cortical T1 hyperintensity, which represented hemorrhage (Figure 3). Both magnetic resonance venography and magnetic resonance angiography revealed no vascular abnormalities. Fortunately, there were no residual motor or sensory defects. In mid-August 2022, he was readmitted with recurrent right lower limb DVT. The hemorrhagic transformation of the previous cerebral stroke and negative results of the follow-up CT brain scan for hemorrhage (Figure 5) raised the possible embolic nature of the cerebral stroke. Therapeutic enoxaparin was started after the exclusion of any active cerebral bleeding by CT brain scan. In an attempt to discover the source of emboli, carotid Doppler ultrasonography and pelvi-abdominal ultrasonography were performed and showed no abnormalities. However, bubble echocardiography (Figure 4) showed a small right-to-left ASD but without pulmonary hypertension. Thus, the source of the embolus was the right femoral DVT that paradoxically transferred to the cerebral circulation through the small ASD.

Thirty days after his readmission, the patient developed a third episode of DVT in the right popliteal and femoral veins, despite his full anticoagulation treatment with apixaban, possibly due to nonadherence to the regimen. An IVC filter was inserted, and he was anticoagulated with warfarin instead of apixaban (to check his adherence by testing the international normalized ratio [INR]). At the time of this report, he is doing well with accepted INR and has stable graft function. Transesophageal echocardiography was scheduled, to check for possible closure of the defect.

Discussion
Our patient fulfilled the 3 criteria for diagnosis of a PDE, which included recurrent DVT in the lower limb veins, the presence of ASD, and arterial embolism in the cerebral circulation. These criteria were mentioned previously by Windecker and colleagues, who emphasized that the following criteria must be present for a diagnosis of PDE: the presence of a VTE, an intracardiac shunt or a pulmonary fistula, and an arterial embolism.¹

Our patient had a DVT in his right lower limb complicated on one side with PE and on the other side with an ischemic stroke, which was due to a small PFO. A PDE often manifests as an ischemic stroke, and a PFO is often the cause.¹

Our patient’s treatment regimen addressed acute conditions such as PE and ischemic stroke, as well as the precipitating factors such as the closure of PFO.^10,11 We managed the initial episode of DVT associated with PE with anticoagulation therapy and a temporary IVC filter to avoid further emboli until the resolution of the perigraft collection. This is the established procedure, as reported by Powers and colleagues in a similar case report.¹¹

Later on, while our patient was on full anticoagulation, he developed an acute cerebral stroke, and MRI findings suggested embolic nature. The MRI brain scan showed abnormal signal intensity in the corticosubcortical left posterior temporal-parietal-occipital region, which represented ischemia, and curvilinear areas of cortical T1 hyperintensity, which represented hemorrhage. Both magnetic resonance venography and magnetic resonance angiography revealed no vascular abnormalities. The hemorrhagic transformation of the previous cerebral stroke and the negative results of the follow-up CT brain scan for hemorrhage raised the possible embolic nature of the cerebral stroke.

Therefore, we looked for the source of emboli by carotid Doppler ultrasonography (which produced results that were negative for any atheromatous plaques) and echocardiography, but there were no significant findings. Because of the suspicion of PFO, we performed bubble echocardiography, which showed a small right-to-left ASD (Figure 4) but without pulmonary hypertension.

Multiple randomized studies have demonstrated the superiority of percutaneous closure of PFO versus medical treatment for the prevention of recurrent stroke in high-risk patients with prior cryptogenic strokes.^1,12

Parikh and his colleagues¹³ also reported good long-term resolution when a PFO closure was added to long-term anticoagulation therapy for a patient with PDE, PE, a large PFO, and thrombophilia.

Percutaneous closure is justified in the case of recurrent cryptogenic stroke in patients younger than 55 years with evidence of VTE and should be considered in patients with first-time cryptogenic stroke, especially for patients with high-risk criteria. These criteria include the presence of an atrial septal aneurysm, septal hypermobility, large PFO, Eustachian valve, or Chiari network,¹ none of which were present in our patient. Therefore, we considered our patient to be a lower-risk phenotype. Moreover, his echocardiography results showed no evidence of pulmonary hypertension that might reverse the shunt. The explanation for the PDE could be due to repeated Valsalva maneuvers. Valsalva maneuvers such as coughing, squatting, or defecating can transiently increase right atrial pressure, which may lead to a transient shunt reversal and the transfer of potential thrombi into the systemic circulation.^1,14

We decided to assign our patient to a lifelong anticoagulation regimen with subsequent follow-up visits until the date of a complementary PFO closure. We favored long-term vitamin K antagonists versus direct oral anticoagulants (DOAC, which were initially used with a possible history of nonadherence) because of 2 issues: (1) proper monitoring of INR and (2) the lack of prospective studies that demonstrated the efficacy and safety of DOAC in patients who experienced PDE to the brain.¹⁰

The outcome for our patient was satisfactory, with stable normal graft function and acceptable anticoagulation monitoring.

Conclusions
This is the first successfully managed case of a kidney transplant recipient with recurrent idiopathic DVT, PE, and cerebral PDE. Bubble echocardiography was an excellent alternative to contrast angiography to avoid possible nephrotoxicity. Vitamin K antagonists are superior to DOAC, especially among noncompliant/nonadherent patients.

Volume: 22 Issue: 1 January 2024 - Supplement - 1

FULL TEXT