key: cord-299024-jkqdzt87
authors: Mangner, Norman; Sveric, Krunoslav; Gerber, Johannes C.; Svitil, Jan; Linke, Axel; Jellinghaus, Stefanie
title: Paraneoplastic syndrome and SARS-CoV-2 – incremental effect of two thrombogenic conditions?
date: 2020-10-21
journal: CJC Open
DOI: 10.1016/j.cjco.2020.10.010
sha: 
doc_id: 299024
cord_uid: jkqdzt87

We present the case of a patient with a non-bacterial thrombotic aortic valve endocarditis experiencing severe thromboembolic complications and an acute right internal carotid artery occlusion in the context of a paraneoplastic syndrome and an asymptomatic SARS-CoV-2 infection, despite treatment with different and overlapping anticoagulant medication. Patients with increased thrombogenicity due to an underlying disease might be at increased risk for thrombotic events during a SARS-CoV-2 infection.

A 66-year old male patient was transferred from another hospital due to NSTEMI with mildly persisting chest pain for 5 hours.

Six weeks prior to this event, the patient had suffered from a Vena saphena magna thrombosis. Diagnostic testing in the referral hospital revealed a non-small cell lung cancer with histology suggestive of an adenocarcinoma on transbronchial biopsy. Due to lymphatic and contralateral lung metastases (cT4, cN3, cM1a), palliative chemotherapy was recommended but had not been instituted. The venous thrombosis was treated with rivaroxaban 20mg o.d., which had been taken continuously except for the day of transbronchial biopsy.

On presentation, the electrocardiogram was unremarkable and transthoracic echocardiography revealed moderate pericardial effusion, a normal left ventricular ejectionfraction without regional wall motion abnormalities, but thickened aortic valve cusps and moderate aortic regurgitation. Coronary angiography showed a 50% stenosis of the Ramus interventricularis anterior without hemodynamic impact as assessed by the resting full-cycle ratio (RFR=0.93) (Video 1). The RFR is a non-hyperemic index that scans diastole and systole for the largest drop in pressure over the entire cardiac cycle. A value ≤0.89 indicates a hemodynamically relevant stenosis.

To investigate for potential other reasons for the myocardial infarction, transesophageal echocardiography (TEE) was performed and showed oscillating masses on the native aortic valve up to 12x6 mm in size which involved all three cusps, predominately affecting the right coronary cusp ( Figure 1A , Video 2) . There was no patent foramen ovale, left atrial appendage thrombosis or large and mobile aortic atheroma. The patient was afebrile, inflammatory markers were not significantly increased (leucocytes 9. 

This case describes a patient with non-bacterial thrombotic aortic valve endocarditis that developed despite treatment with a factor-Xa-inhibitor and who subsequently suffered a myocardial infarction and two strokes within a short period of time in the context of a paraneoplastic syndrome and asymptomatic SARS-CoV-2 infection. We hypothesize that the myocardial infarction and the first stroke originated from thromboembolism, in particular due to the diffuse pattern of lesions detected by cerebral magnetic resonance tomography. The second stroke was caused by an acute right internal carotid artery occlusion, hypothetically triggered by spontaneous local thrombosis; however, embolism of a big thrombus cannot be excluded.

Paraneoplastic syndromes are often linked to increased thrombogenicity; however, non-bacterial thrombotic aortic valve endocarditis is rare even in the situation of cancer.

Adenocarcinoma seems to be associated with increased rates of this condition and the aortic valve is most often affected. 1 Current guidelines recommend anticoagulation with unfractioned or low molecular weight heparin or a vitamin k antagonist, although there is limited evidence to support this strategy. The use of factor-Xa-inhibitors or direct thrombin inhibitors have not been evaluated. 2 Some authors suggest not to use a vitamin k antagonist in patients with malignancy-associated NBTE, as recurrent thromboembolic events while on warfarin are common, although this was observed 30 years ago. 1 In our case, the patient developed the thrombosis under the treatment with a factor-Xa-inhibitor, therefore, we decided to use an overlapping anticoagulation with unfractionated heparin and a vitamin k antagonist.

J o u r n a l P r e -p r o o f SARS-CoV-2 infection is also associated with a high rate of thrombotic complications occurring even under prophylactic therapy. 3 Large vessel stroke including partial carotid artery occlusion has been described in younger patients suffering from Covid-19. 4 Others found a low risk of acute cerebrovascular events in patients hospitalized with COVID-19 with most patients presenting with classical vascular risk factors and traditional stroke mechanisms, although a substantial number of patients had new positive antiphospholipid antibodies. 5 Hypercoagulation during SARS-CoV-2 infection has been linked to cerebral embolism in several cases. 6;7 In our case, the patient was asymptomatic and, therefore, the duration of infection remains unknown. However, a second test performed 7 days after the positive one was already negative, thus suggesting that infection occurred earlier. Median duration of viral shedding was 20 days in survivors of Covid-19 according to a Chinese study. 8 Remarkably, native aortic valve thrombosis and its consequences occurred despite oral anticoagulation highlighting a possible incremental effect of two thrombogenic conditions. Both cancerassociated thrombosis and Covid-19 related thrombotic events share common features like coagulopathy and endothelial dysfunction secondary to systemic inflammation or potential local infection. The prothrombotic effect of SARS-CoV-2 coronavirus infection is thought to be mediated by binding to ACE2 receptors on the surface of endothelial cells, which leads to endothelial dysfunction und thrombosis. 8 As heart valves are lined with endothelial cells, SARS-CoV-2 infection might hypothetically induce dysfunction of the protecting valve surface. Anticoagulation in COVID-19 seems to be beneficial; however, the best strategy is still uncertain. 3 This case highlights the many-sided effects of paraneoplastic syndromes and SARS-CoV-2 infection in patients being already at increased risk for thrombotic complications due to underlying disease. The treatment of those patients includes several medical disciplines that

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