key: cord-0855445-aj9q73f0
authors: Brosnahan, Shari B.; Bhatt, Alok; Berger, Jeffery S.; Yuriditsky, Eugene; Iturrate, Eduardo; Amoroso, Nancy E.
title: COVID-19 Pneumonia Hospitalizations Followed by Re-presentation for Presumed Thrombotic Event
date: 2020-06-23
journal: Chest
DOI: 10.1016/j.chest.2020.06.023
sha: 527df7b89b591bc0f30c7a6a054aabf163d1d6f4
doc_id: 855445
cord_uid: aj9q73f0

nan

Venous thromboembolism (VTE) is an important, dangerous, and sometimes fatal complication of coronavirus disease . 1, 2 Thrombosis, including ischemic heart disease and stroke, contributes to the overall disease burden in all non-COVID patient populations worldwide accounting for approximately 1 in 4 deaths. 3 Current guidelines recommend chemical prophylaxis in all COVID-19 patients admitted to the hospital, yet post-discharge recommendations are not addressed. 4 The benefit of extending VTE prophylaxis post discharge has been observed to be safe and effective in some high-risk populations. [5] [6] [7] [8] Simple laboratory makers, including D-dimer and C-reactive protein (CRP), can be especially important in choosing who may benefit from extended VTE prophylaxis. [9] [10] [11] [12] To date, there have been no randomized studies looking at extending VTE prophylaxis in the COVID-19 patient population.

This series describes clinical observations at a large academic hospital center (in New York City), related to increased rates of thrombotic events in patients re-presenting to healthcare within a short timeframe after an index COVID-19 admission. These patients re-presented with presumed thromboembolic complications, both arterial and venous. Most resulted in acute and rapid decline at re-presentation leading to death. These observations have raised our concern regarding a continued hypercoagulable state in COVID-19 patients despite clinical stability that exists post-hospitalization; patients with certain risk factors may benefit from extended VTE prophylaxis.

Re-presentation data exists currently under our institution quality improvement. We reviewed all confirmed COVID-19 patients who were discharged and then re-presented to any of our hospital or ED facilities located in the New York metropolitan area between the dates of March 3, 2020 and April 10, 2020. We reviewed the hospital records and filtered for patients that were presumed to have a deep venous thrombosis (DVT), pulmonary embolism (PE), limb ischemia due to arterial thrombosis, acute coronary syndromes due to coronary thrombosis (ST elevation myocardial infarction or STEMI), or acute stroke. However, given the under-diagnosis of these events, we also included rapidly evolving hemodynamic instability with elevated D-dimer at time of re-presentation.

We identified 9 patients who were discharged from an inpatient stay and returned with concern for a thrombotic event based on clinical review and laboratory findings. Thrombotic events accounted for the second most common reason for presentations following discharge during the monitored time. There were 1975 all-hospital discharges during the time. There were 68 adult medical re-presentations (number): pneumonia-bacterial or viral-(37), thrombotic events (8), cardiac, not myocardial infarctions (5) , syncope (4), acute respiratory distress syndrome (3), pancreatitis (1), failure to thrive (1), electrolytes (1), and renal failure (1). All patients were readmitted, except one case of a 68-year-old male who re-presented to the emergency department, was sent home, and died the same day. We included this patient, since there was no evidence of infection on evaluation in the emergency department, his hypoxia had improved, and his complaint on re-presentation was acute fatigue and near syncope.

Of the 9 patients, 3 were females and 6 were males. The median age of patients was 74 years old +/-6.4

years. On average patients were overweight, BMI 28.7 kg/m2 +/-6.3 kg/m2. Patients had varied past medical histories. The most common co-morbidities included (percentage): hyperlipidemia (55.6%), obesity (33.3%), hypertension (33.3%), diabetes (22.2%), chronic kidney disease (22.2%), and arrythmia (22.2%). Two people did not have any diagnosed co-morbidities. The average CRP prior to discharge was 111 +/-96 mg/L and the average D-dimer prior to discharge was 403 +/-253 ng/ml. Both markers significantly trended up between discharge and re-presentation. There was a high mortality rate as eight of the nine patients died during readmission or within 24 hours of presentation to the emergency department ( Table 1 ). All patients received chemical DVT prophylaxis during their initial hospitalization.

During re-presentation, all patients who were admitted for more than 24 hours prior to death were given full dose anticoagulation-two died within 24 hours and had only received prophylactic dose heparin. There were no observed bleeding events, and no patients required transfusion.

The incidence of thrombosis in COVID-19 has so far been reported to be as high as 25-31%, with VTE making up the largest proportion. 2, 13 The precise mechanism of thrombosis remains unclear. Immune dysregulation and hyper-inflammatory states may lead to endothelial dysfunction and initiation of the thrombotic cascade. 2, 13, 14 Autopsy findings of SARS-CoV-2 patients have demonstrated circulating megakaryocytes, fibrin deposition, and microvascular injury in multiple organs supporting this theory. 15 While classic disseminated intravascular coagulation (DIC) has also been identified in certain COVID-19 patients, the incidence of this is seemingly rare. 1,16 Instead, COVID-19 patients more often develop a coagulopathy with elevations in D-Dimer, PT, and aPTT but high fibrinogen and lack of bleeding which is not typical for DIC. 16 Elevated D-dimer, prolonged prothrombin time (PT), and prolonged activated partial thromboplastin time (aPTT) have been identified as independent predictors of mortality in COVID-19. 14 This may represent either overt thrombosis or dysregulated systemic inflammation and requires further study.

Several different anticoagulants have been used as DVT prophylaxis both in hospital and post discharge. 6, 17, 18 Given the lack of knowledge surrounding thrombus formation, increase in platelet aggregation, increased megakaryocytes, and fibrin deposition, the class of drug for thromboprophylaxis and duration of treatment in COVID-19 remains unknown. The pathophysiologic findings to date can arguably be construed to support the use of anticoagulant, antiplatelet agents or possibly both. Current society recommendations support the consideration of extended prophylaxis in certain high-risk patients but lack the ability to further define the cohort. 19 Our method of data extraction lends to underreporting of post-hospitalization thrombosis. While we were able to capture all re-presentations within our own institution, we were not able to identify representations to other institutions, or death out of the hospital. Thus, we are not meaningfully able to comment on prevalence. Additionally, we do not know each individual's bleeding risk which would play a significant role in choosing to whether to extend DVT prophylaxis to the outpatient setting.

Despite these limitations, we identified 9 patients that were clinically stable when discharged from the hospital and likely went on to develop thrombotic complications. Our patients were all above 68 years of age, most had elevated D-dimer at discharge, and all had some immobility as they were confined to home post discharge given the current travel restrictions and quarantine instructions. Furthermore, no patient had both normal CRP and D-Dimer at time of discharge which is likely common in this patient population. Every patient with data showed both markers increased at time of re-presentation. All patients re-presented within 8 days of discharge, echoing prior studies that depict the highest risk for thrombosis post-hospitalization for a medical illness occurs within 9 days. 20 This shows that the postdischarge thrombosis risk in COVID-19 seems to behave similar to other medical admission thrombosis.

We believe this case series is a call for further studies regarding extended prophylaxis in this patient population. In line with previous trials of extended thromboprophylaxis in at risk medically ill patients, continued use of prophylactic anticoagulation or antiplatelet agents beyond the initial hospital stay may be required until complete recovery from the illness. 5, 6, 17, 18 Further research is necessary to identify which patients would benefit most, which medications should be employed and the duration of therapy.

Further studies are needed to assess the true incidence of post-discharge thrombotic events and to evaluate anticoagulation strategies in patients with COVID-19.

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SBB takes responsibility for the content of the manuscript, including the data and analysis. AB and EI contributed substantially to the study design, data analysis and interpretation, and the writing of the manuscript. NEA, EY, and JB contributed substantially to writing of the manuscript. JB conducts research with Astra Zeneca, Janssen, and Amgen. No other author has significant conflict of interest with the case series.