key: cord-254377-j8e8gb0l
authors: Ali, Sadaf; Pappachan, Joseph M.; Mathew, Smitha
title: Acute cor pulmonale from saddle pulmonary embolism in a patient with previous Covid-19 – should we prolong prophylactic anticoagulation?
date: 2020-06-13
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.06.039
sha: 
doc_id: 254377
cord_uid: j8e8gb0l

Abstract Severe corona virus disease 19 (Covid-19) is known to be associated with exaggerated risk of thromboembolism. However, the risk associated with mild and moderate illness from Covid-19 is unknown, and there is no current recommendation for prophylaxis against thromboembolism in patients after hospital treatment unless there are established thrombophilic risk factors. We report the case of a 52-year old woman, who presented with massive saddle pulmonary embolism after one week of initial hospital discharge, successfully thrombolysed that raises the question of consideration of extended prophylactic anticoagulation even in low risk Covid-19 cases.

The global pandemic from the corona virus disease 19 (Covid-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected >6.8 million people with a death toll >4,00,000 while writing this article, across the world affecting almost all countries. Although

Covid-19 has protean clinical manifestations involving almost every organ system in the human body, pneumonia, acute respiratory distress syndrome (ARDS), diarrhea, septic shock, acute kidney injury (AKI), disseminated intravascular coagulation (DIC) and rhabdomyolysis are the more commonly described clinical features. 1 Arterial and/ or venous thromboembolic events can also be important manifestations of severe cases with Covid-19, though the actuarial prevalence or the incidence of this complication is unknown, especially in those with mild disease. A recent autopsy series among 12 cases revealed that unsuspected venous thromboembolism was present in 7 (58%) patients, and pulmonary embolism (PE) was the direct cause of death in 4 (33.3%) patients. 2 Acute cor pulmonale and cardiac arrest have also been described in critically ill patients. 3 We report a case of acute massive PE successfully managed by thrombolysis in a patient who was discharged after one week of initial hospital treatment for Covid-19 pneumonia which raises serious concerns about the indication for extended prophylactic anticoagulation in such cases.

A 52-year-old woman presented with difficulty in breathing and productive cough for 2 weeks with previous history of well-controlled asthma and essential hypertension without any past or family history of thrombophilia. She had bi-basal lung crackles and an oxygen saturation of 93% while breathing 40% oxygen through venturi mask. Other initial investigations (and normal laboratory range) were as follows: white cell She was initially managed with intravenous hydration, oral doxycycline, oxygen, and prophylactic enoxaparin. Subsequently, she was weaned off oxygen and was discharged 4 days after initial admission.

One week later she presented again with a syncopal episode and severe breathlessness, chest tightness, tachycardia, hypoxia, and hypotension. Blood profile showed: serum troponin 205 ng/L (5-14), D-dimer 6.26 µg/ml (0-0.5), CRP 7 mg/L, and lymphocyte count 0.95 x 10 9 /L. Chest radiograph revealed improving bibasilar lung infiltrates in comparison to the radiograph 11 days ago. The electrocardiogram showed S1Q3T3 pattern suggestive of probable acute PE. An urgent computed tomographic pulmonary angiogram (CTPA) revealed bilateral extensive thromboembolism in the pulmonary arterial branches ( Figure 1A ) and a saddle PE in the main pulmonary artery bifurcation (Fig 1B) . There was right ventricular (RV) dilatation and deviation of the interventricular septum to the left ventricle suggesting RV strain pattern (Fig 2) . The lung windows of the CTPA showed resolving Covid-19 pneumonia ( Figure 3A & B) .

She was immediately thrombolysed with recombinant tissue plasminogen activator from the intensive treatment unit (ITU) with rapid improvement of hypoxia and hypotension. Within 16 hours of successful thrombolysis, she was able to maintain oxygen saturations of 98-100% on room air. After the initial management with therapeutic anticoagulation using subcutaneous Enoxaparin, she was discharged home on the fourth day of the second hospital admission on oral Rivaroxaban 15 mg twice daily for 21 days followed by a maintenance dose of 20 mg daily for 3 more months.

Based on the observations from multiple clinical studies, severe Covid-19 infection requiring ITU management is now established as a highly thrombophilic state with an estimated incidence of varying J o u r n a l P r e -p r o o f degrees of thromboembolic episodes ranging from 21-58%. 2-6 A significant chunk of these patients developed thromboembolic events even while on prophylactic anticoagulation therapy challenging our conventional concepts about anticoagulation protocols in the ITU management critically ill patients.

Emerging data and clinical experience suggest an increased prevalence of venous thromboembolic events (VTE) in COVID-19, especially in patients with severe disease requiring hospitalization, and even among those who are not critically ill.

The pathogenesis for COVID-19-associated hypercoagulability so far is explained by hypoxia and systemic inflammation secondary to COVID-19 that may lead to high levels of inflammatory cytokines and activation of the coagulation pathway. However, the exact mechanisms causing thromboembolic episodes remain elusive. Endothelial inflammation with very high levels of Von Willebrand Factor Antigen and Factor VIII, hypoxemia-induced vasoconstriction promoting vaso-occlusion, activation of hypoxia-inducible factors (HIFs) that results in induction or inhibition of many genes including tissue factor (TF) and plasminogenactivator inhibitor-1, elevated levels of lupus anticoagulant, direct activation coagulation cascades and endothelial injury by the virus were all proposed as putative mechanisms. 4 All hospitalised patients with Covid-19 infection should receive pharmacological thromboprophylaxis as per the standard international recommendations. 7 Some groups even recommend empirical therapeutic anticoagulation in severely ill Covid-19 cases treated in the ITU, based on past experience of very high risk of thromboembolism for these high risk patient groups. 7, 8 Fibrinolytic therapy or catheter-based intervention for the removal of thrombus is the treatment of choice for hemodynamically unstable patients with massive PE and acute cor pulmonale. Thrombolysis was found to reduce the odds of death (OR 0.57; 95% CI 0.37 to 0.87, P = 0.01) and recurrence of PE (OR 0.51; 95% CI 0.29 to 0.89, P = 0.02) although increased the risk of bleeding in patients with massive PE. 9 The risk of recurrence after an episode of unprovoked venous thromboembolism treated with anticoagulation for 3 months was found to be 10% within the first year, 16% at two years, 25% at five years, and 36% at 10 years. 10 The U.S. National Institute of Health (NIH) has recently updated the guidelines for antithrombotic therapy in patients with Covid-19 who are discharged from the hospital. 12 The guidelines state that routine postdischarge VTE prophylaxis is not recommended for patients with COVID-19. The benefits of post-discharge prophylaxis for certain high-risk patients without COVID-19 led to the Food and Drug Administration approval of two regimens currently: rivaroxaban 10 mg daily for 31 to 39 days, and betrixaban 160 mg on Day 1, followed by betrixaban 80 mg once daily for 35 to 42 days. 13, 14 Inclusion criteria for the RCTS that studied these regimens included: the modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE)-VTE score ≥4 or Modified IMPROVE-VTE score ≥2 and D-dimer level >2 times the upper limit of normal; 13 and age ≥75 years or age >60 years and D-dimer level >2 times the upper limit of normal or age 40 to 60 years, D-dimer level >2 times the upper limit of normal, and previous VTE event or cancer. 14 Post-discharge VTE prophylaxis should consider the individual patient's risk factors, including reduced mobility, bleeding risks, and feasibility before any treatment decision is made. 

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