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Tonight's FLARE will discuss the relationship between coagulation and ARDS and apply this to a recently proposed intervention for patients with severe COVID-19.


This piece is courtesy of Dr. Rebecca Israel.
On March 20, 2020, Moore and colleagues proposed compassionate use of tissue-type plasminogen activator (tPA) as salvage therapy for COVID-19 associated severe ARDS (Moore et al., 2020). Here we will evaluate the scientific reasoning and evidence for this intervention.
The FLARE Four:
  1. Damage to the alveolar endothelium in ARDS activates the coagulation cascade, causing accumulation of platelet-fibrin thrombi in the alveolus. This can promote further lung injury.
  2. Case series of patients with severe COVID-19 have suggested that coagulation abnormalities in the serum are associated with ARDS and higher mortality.
  3. Anticoagulants and thrombolytics have been studied in both pre-clinical models and patients with ARDS, but studies have been plagued by heterogeneity in methods and study design.
  4. Though ARDS and COVID-19 are associated with hypercoagulability, the currently available evidence does not suggest that therapeutic anticoagulation or fibrinolytics will improve patient outcomes.
What is the relationship between hypercoagulability and acute respiratory distress syndrome (ARDS)?
ARDS is characterized by alveolar damage that triggers a robust proinflammatory and procoagulant response. Fibrin deposits within the alveoli and platelet-fibrin thrombi within the pulmonary microvasculature are characteristic pathologic features of ARDS (Tomashefski, 2000; Tomashefski et al., 1983). Intra-alveolar fibrin deposits are thought to compromise normal endothelial barrier function and lead to loss of surfactant, predisposing to alveolar collapse and impaired alveolar fluid clearance (Tomashefski, 2000). Thrombi within the pulmonary microcirculation are believed to increase the dead space fraction leading to right heart dysfunction (Tomashefski, 2000; Tomashefski et al., 1983). Changes in the hemostatic balance are also noted in the bronchoalveolar lung fluid (BALF) and serum of patients with ARDS. Multiple studies demonstrate decreased levels of anticoagulant proteins (protein C) and increased expression of procoagulant proteins (tissue factor) and anti-fibrinolytic factors (plasminogen activator inhibitor-1) in patient serum and BALF (Günther et al., 2000; Laterre et al., 2003; Ware et al., 2007). Altogether these findings suggest that a hypercoagulable environment favors formation of fibrin deposits in the airspaces and vasculature promoting lung injury in ARDS.
What do we know about the role of hypercoagulability in COVID-19 induced lung injury?
Although the evidence is limited, lung biopsies from two patients with early COVID-19 and an autopsy of a patient who died from COVID-19 associated respiratory failure suggest that pathologic findings are consistent with severe ARDS (Luo et al., 2020; Tian et al., 2020). The three patient tissue samples demonstrated fibrinous exudate within the alveoli and occlusion of small pulmonary vessels suggesting a hypercoagulable state similar to that described in ARDS from other causes.

Multiple large case series have also demonstrated a relationship between severe COVID-19 and coagulation abnormalities (Chen et al., 2020; Huang et al., 2020; Tang et al., 2020a, 2020b; Wu et al., 2020). In fact, two studies report an association between elevated d-dimer, prothrombin time, the development of ARDS and mortality from ARDS in patients with COVID-19 (Tang et al., 2020a; Wu et al., 2020). Tang et al. evaluated the impact of anticoagulation on 28-day mortality in a retrospective review of 449 hospitalized patients with severe COVID-19. Ninety-nine patients received ≥7 days of prophylactic anticoagulation with either unfractionated heparin (range 10000-15000 units/day) or low molecular weight heparin (range 40-60 mg/day). Mortality did not differ between heparin exposed and non-exposed patients at 28-days (30.3% vs 29.7%, p=0.910). However, in a prespecified subgroup analysis of patients with evidence of hypercoagulability, defined by a sepsis-induced coagulopathy (SIC) score ≥4, heparin use was associated with lower 28-day mortality (40.0% vs 64.2%, p=0.029). The authors did not report indications for anticoagulation (e.g. malignancy or symptoms) or control for the use of COVID-19 directed therapies like antivirals. Data on oxygenation and the need for mechanical ventilation were also not included. Although this study suggests that certain patients with COVID-19 may benefit from anticoagulation, further research is needed to systematically evaluate this association
Components of the Sepsis-Induced Coagulopathy Score.
Adapted from Iba et al. J Thromb Haemost, 2019 (Iba et al., 2020).
What do previous studies tell us about the efficacy of anticoagulants as a treatment for ARDS?
Why do Moore and colleagues suggest use of tissue-type plasminogen activator (tPA)?
Multiple studies have evaluated anticoagulants as pharmacotherapy for ARDS. A variety of coagulation inhibitors including heparin (Glas et al., 2016), antithrombin, tissue factor inhibitor, factor VIIa, activated protein C (Liu et al., 2008), and thrombomodulin have been tested in animal models and, in some cases, in humans (Glas et al., 2016; Liu et al., 2008). To date, no trials have reported significant clinical benefit in the treatment of humans with ARDS (Camprubí-Rimblas et al., 2018).
 
This is the context in which Moore et al. propose the use of tPA for COVID-19 associated ARDS. A meta-analysis and systematic review of 22 preclinical studies evaluating the efficacy of plasminogen activators in animal models of acute lung injury suggests that treatment with tPA, urokinase, or streptokinase reduces 28-mortality (RR 0.21, 95% CI 0.08-0.52, P=0.0008), improves gas exchange (PaO2 improvement >15mmHg, 95% CI 8-23mmHg, P<0.0001), reduces pulmonary vascular leak (wet/dry ratio -1.8, 95% CI -2.4 to -1.3, P<0.0001), and suppresses histologic severity of lung injury without causing significant bleeding complications (Liu et al., 2018). Despite these promising findings, heterogeneity in study design, medication dosing, treatment duration, and route of administration (intravenous, intratracheal, intraperitoneal, nebulized) makes interpretation challenging. In a phase 1 trial, Hardaway et al. administered urokinase to 20 patients with severe ARDS. (Hardaway et al., 2001). Nineteen patients experienced an improvement in PaO2 within 24 hours of treatment (50.85±11.04 vs 229.65±141.12, p<0.0001). Although no significant coagulopathy or bleeding complications were reported, 14 patients died during the follow up period. The majority of the study population (n=11) were trauma patients including two diagnosed with fat embolism syndrome. These conditions are highly associated with disseminated intravascular coagulation (DIC) and may not be generalizable to patients with isolated respiratory failure. In fact, neither this study nor the animal models evaluated the impact of fibrinolytics on viral pneumonia
 
Despite this limited data, Moore et. al. nevertheless conclude that a trial of tPA (specific recommendations to follow) is reasonable during the current pandemic given that this therapy is widely available and that the risks of tPA are outweighed by “the certainty of death” among patients with COVID-19 and refractory ARDS. They recommend the use of tPA over urokinase and streptokinase given higher efficacy of clot lysis and comparable bleeding risk.
Are there specific recommendations for administration of tPA in COVID-19?
Moore et al. suggest that tPA be used as salvage therapy in COVID-19 patients with severe ARDS (P/F <50) and hypercarbia (pCO2 >60) despite low tidal volume ventilation and prone positioning who are not candidates for ECMO. They recommend using the same exclusion criteria currently applied to fibrinolytic therapy for patients with ischemic stroke and myocardial infarction. 
 
The exact dose, route of administration, and duration of treatment remains to be defined. In animal models, intratracheal and intravenous (IV) infusion were more effective than nebulized therapy. Intratracheal tPA has not been tested in humans. The authors recommend tPA infusion given presumed need for prolonged treatment, ease of use, and the large body of experience treating ischemic strokes and myocardial infarctions with IV tPA. They advise an initial bolus of 25mg over 2 hours followed by an infusion of 25mg over 22 hours with a dose not to exceed 0.9mg/kg. The authors suggest “responders” to tPA transition to therapeutic anticoagulation with a heparin drip but do not define criteria for treatment response.
Conclusions
While the current data suggest that ARDS and COVID-19 are associated with a hypercoagulable state, there is limited evidence that anticoagulation improves outcomes. Prophylactic anticoagulation is a mainstay of management for critically ill patients. This practice should be continued for patients COVID-19 as it reduces the risk of DVT and may have a secondary benefit for the lungs. Management of COVID-19 should focus on evidenced-based interventions and treatments with strong biologic plausibility. Speculative therapies such as tPA should be given only in the context of clinical trials. Furthermore use of tPA, even as salvage therapy, could lead to diminished supplies for patients with evidence-based indications for therapy including massive pulmonary embolism, myocardial infarction, and ischemic stroke.
FLARE is a collaborative effort within the Pulmonary and Critical Care Division and the Department of Medicine at Massachusetts General Hospital. Its mission is to appraise the rapidly evolving literature on SARS-CoV-2 with a focus on critical care issues.

Prior FLAREs can be found here, under "Fast Literature Updates".
Thank you for everything you are doing!
 - MGH FLARE
Interested in hearing more about a specific SARS-CoV-2 topic? Let us know via email. Interested in hearing more about a specific SARS-CoV-2 topic? Let us know via email.
References:
  • Moore HB, Barrett CD, Moore EE et al. Is There a Role for Tissue Plasminogen Activator (tPA) as a Novel Treatment for Refractory COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS)? Journal of Trauma and Acute Care Surgery, Published Ahead of Print. 
  • Tomashefski JF. Pulmonary Pathology of Acute Respiratory Distress Syndrome. Clin Chest Med. 2000;21:435-466.
  • Tomashefski JF. The Pulmonary Vascular Lesions of Adult Respiratory Distress Syndrome. Am J Pathol. 1983;112:112-126.
  • Ware LB, Matthay MA, Parsons PE, et al. Pathogenetic and Prognostic Significance of Altered Coagulation and Fibrinolysis in Acute Lung Injury/Acute Respiratory Distress Syndrome. Crit Care Med, 2007;35(8): 1821-1828.
  • Gunther A, Mosavi P, Heinemann S, et al. Alveolar Fibrin Formation Caused by Enhanced Procoagulant and Depressed Fibrinolytic Capacities in Severe Pneumonia-Comparison with the Acute Respiratory Distress Syndrome. Am J Resp Crit Care Med 2000; 161:454-462.
  • Laterre, PF, Wittebole, X, Dhainaut, JF. Anticoagulant Therapy in Acute Lung Injury. Crit Care Med, 2003;329-336.
  • Tian S, Hu W, Niu L, et al. Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients. J Thorac Onc. 2020.
  • Luo W, Yu J H, Guo J, et al. Clinical Pathology of Critical Patient with Novel Coronavirus Pneumonia (COVID-19). Preprints 2020.
  • Chen N, Zhou M, Dong X, et al. Epidemiological and Clinical Characteristics of 99 Cases of 2019 Novel Coronavirus Pneumonia in Wuhan, China: A Descriptive Study. Lancet. 2020; 395(10223):507-513.
  • Huang C, Wang Y, Li X, et al. Clinical Features of Patients Infected with 2019 Novel Coronavirus in Wuhan China. Lancet. 2020; 295(10223):497-506.
  • Tang N, Li D, Wang X, et al Coagulation Parameters are Associated with Poor Prognosis in Patients with Novel Coronavirus Pneumonia. J Thromb Haemost. 2020.
  • Wu C, Chen X, Cai Y, et al. Risk Factors Associated with Acute Respiratory Distress Syndrome and Death in Patients with Coronavirus Disease 2019 Pneumonia in China. JAMA. 2020.
  • Tang N, Bai H, Gong J, et al. Anticoagulation Treatment is Associated with Decreased Mortality in Severe Coronavirus Disease 2019 Patients with Coagulopathy. J Thromb Haemost. 2020.
  • Iba T, Levy JH, Warkentin TE, Thachil J, et al. Sepsis-Induced Coagulopathy and Disseminated Intravascular Coagulopathy.  J Thromb Haemost. 2019; 17(11):1989-1994.
  • Glas GH, Serpa NA, Horn J, et al. Nebulized Heparin for Patients Under Mechanical Ventilation: An Individual Patient Data Meta-Analysis. Ann Intensive Care.2016;6:33.
  • Lui KD, Levitt J, Zhuo H, et al. Randomized Clinical Trial of Activated Protein C Treatment of Acute Lung Injury. Am J Resp  Crit Care Med. 2008;178:618-623.
  • Camprubi-Rimblas M, Tantinya N, Bringue J, et al. Anticoagulation Therapy in Acute Respiratory Distress Syndrome. Ann Transl Med. 2018; 6(2):36.
  • Liu C, Ma Y, Su Z, et al. Meta-Analysis of Preclinical Studies of Fibrinolytic Therapy for Acute Lung Injury. Front Immunol. 2018; 9:1898.
  • Hardaway RM, Harke H,  Tyroch AH, et al. Treatment of Severe Acute Respiratory Distress Syndrome: A  Final Report  on a Phase I Study. Am Surg. 2001;67(4):377-82.






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