Unusual Late Onset Recurrent Venous Thrombosis in Two Young Post Renal Transplant Recipients – Challenges in Diagnosis and Management with Review of Literature

Introduction

Recurrent venous thrombosis (VT) poses significant challenges in post-renal transplant recipients in the context of diagnosis, risk assessment, therapeutic choices, and strategies for preventing recurrence.^1,2 We report two such cases in young kidney transplant recipients (KTR), highlighting the complexity of diagnosis and management.

Case Reports

Case 1: A 33-year-old male KTR presented with sudden-onset dyspnea 7 years after renal transplant. He was anxious with tachypnea, tachycardia and hypoxia. Based on the confirmed diagnosis [Figure 1] of VT with pulmonary thromboembolism (PTE), thrombolytic therapy with bolus tenecteplase (40 mg) was given followed by heparin and later monitored oral anticoagulant acenocoumarol. Oral anticoagulation was discontinued after 1 year and he was kept on antiplatelet aspirin. Two years later, the patient had non-severe COVID pneumonia. A year later, he experienced a recurrence of sudden onset severe breathlessness. His repeat evaluation for dyspnea reconfirmed it as deep vein thrombosis (DVT) with PTE recurrence [Table 1]. The patient received similar therapy initially as his first PTE 5 years back (Tenecteplase 40 mg followed with heparin). He was continued on low-dose apixaban 2.5 mg twice daily (as he had epistaxis with initial 5 mg dose) with no recurrence till 1 year of follow-up.

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Figure 1:

(a) CT pulmonary angiogram – axial section at the level of pulmonary artery bifurcation reveals dilated pulmonary artery with large hypodense occlusive thrombus at right distal pulmonary artery and at the origin of left upper lobe artery. (b) Sagittal section reveals complete obstruction of left distal pulmonary artery with thrombus extending into lower lobar and segmental artery. (c) ECG – typical S1, Q3, T3 suggestive of PTE. CT = computerised tomography, ECG = electrocardiogram, S1 Q3 T3 = deep S wave in lead 1 Q wave in lead 3, inverted T in led 3, MPA = main pulmonary artery, RPA = right pulmonary artery, LPA = left pulmonary artery.

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Case 2: A 41-year-old male KTR presented with left lower limb pain and swelling during COVID lockdown 9 years post transplant. His vitals were normal. His evaluation confirmed proximal DVT with a high potential for embolism [Table 1]. He suffered with intense hemi cranial headache last year with vomiting due to cerebral venous thrombosis [Figure 2] and was treated elsewhere with heparin followed by warfarin, which he discontinued after 8 months during the COVID lockdown. He was treated for his new DVT with enoxaparin followed with apixaban 5 mg twice daily as antithrombotic. He is doing well on apixaban at 3 year follow up so far with no thrombotic episodes even during his COVID pneumonia that he suffered one year later.

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Figure 2:

(a) Non-contrast axial CT of brain reveals hyperdensity of left transverse sinus suspicious of thrombosis. (b) Phase-contrast 3D MRI coronal MIP shows absence of flow signal in left transverse sinus. Suggestive of thrombosis. CT - computer tomography, MRI- magnetic resonance imaging, MIP - maximum intensity projection.

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Discussion

Kidney transplant recipients are at an increased risk of venous thromboembolism (VTE). Timely diagnosis and adequate treatment with multidisciplinary support is essential. Estimates of thrombotic embolic (TE) risk have range between 0.6% and 25%. One of the detailed study conducted over 11 years observed a long-term risk of TE as 7.4%, a cumulative incidence at 5 years of 5.8% and an eightfold increased risk compared with the general population.²

The hypercoagulable state in KTRs is multifactorial; some of the risk factors are common with the general population while others are specifically related to transplant. Unique factors incriminated are post-transplant erythrocytosis, hyper homocysteinemia, chronic inflammation, proteinuria, GFR below 30 mL/mim, tacrolimus, sirolimus, hospitalization, low hemoglobin and lack of use of renin–angiotensin system inhibitors.² A recent Indian study indicates that VTE events are more common in KTRs with advanced renal impairment.³ Our patients developed thrombotic events in late transplant period with mild renal dysfunction and had no impact on survival nearly 5 years follow up post initial event though renal function did decline as part of chronic allograft non-immune injury to some extent.

Hemodynamic stability dictates the algorithm of evaluation like ECG, chest X-ray, D-dimer, NT pro-BNP, troponin T, echocardiography of heart, lower limb venous Doppler, computerized pulmonary angiogram (CTPA), and ventilation- perfusion scintigraphy (V/Q scan). Patients are categorized into low, intermediate (low intermediate or high intermediate) or high risk based on clinical, radiological and biomarkers. According to the recent guidelines, the use of thrombolytic therapy is for high risk only but can be considered in selected cases of intermediate-risk PE as was our first case.^4,5 Both low-dose thrombolysis and catheter-directed thrombolysis are effective with low bleeding risk in high-risk situations. Tenecteplase could be a good alternative to alteplase because of its easy availability and low cost. We employed in our case tenecteplase on both occasions with successful outcomes.

No overt detectable prethrombotic risk was noted in both the cases [Table 1]. KDIGO recommendation does not support routine screening of all transplant candidates for thrombophilia testing.⁶ Despite no consensus about the approach on risk assessment, treatment and follow up, we propose a clinical algorithm [Figure 3] that can be used in this situation based on KDIGO suggestion.

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Figure 3:

Proposed algorithm for VTE risk assessment and thromboprophylaxis in renal transplant. VTE: Venous thromboembolism, BMI: Body mass index, LMWH: Low molecular weight heparin, NOAC: novel oral anticoagulants, EPO: Erythropoietin, AF: atrial fibrillation, LV: left ventricle, PT: prothrombin time, aPTT: activated partial thromboplastin time, CTPA: CT pulmonary angiogram, NT pro BNP: nterminal pro brain natriuretic peptide.

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Six months of anticoagulant use in idiopathic or unprovoked first events, as recommended, may not be adequate in renal transplant, and the need for further treatment should be re-evaluated. Our patients had recurrence after stopping the prophylaxis in the follow up necessitating anticoagulation indefinitely.

The role of novel oral anticoagulants (NOACs) in renal transplant recipients, warrants careful attention, as recent studies have demonstrated its efficacy and safety in such transplant recipients with no drug interactions with calcineurin inhibitors.⁷

Conclusion

In the absence of identified thrombophilic risk factors, individualized algorithm use is needed for diagnosis and management of putative risk factors. It is of paramount importance to address the risk-benefit of appropriate thrombolytic therapy, choice of long-term oral anticoagulant and duration of prophylaxis based on clinical profile to ensure optimal outcome.