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Update 5/6/2020:
Update 5/6/2020:
Based on new evidence, clinical equipoise exists and it is reasonable to consider expanded systemic anticoagulation for patients with Covid-19.
Based on new evidence, clinical equipoise exists and it is reasonable to consider expanded systemic anticoagulation for patients with Covid-19.
Unfractionated Heparin may have antiviral properties based on in vitro studies discussed below
Patients with severe COVID-19 with an elevated D-dimer or SIC score ≥4 may benefit from systemic heparin
It is unclear at this time if systemic doses higher than standard prophylaxis should be used, although some are recommending it given the high rate of thrombosis with standard systemic prophylaxis (15,000 U/day) in the above studies
Encourage weight based or targeted VTE prophylaxis regimens as standard PPX doses may be inadequate to prevent VTE
Standard DVT PPx with 5000 SC Heparin results in a PTT of 38.6 +/- 15
Recommended Xa for DVT PPx range in general is 0.2 - 0.4 IU/mL
As patients with Covid-19 may be hypercoaguable higher doses of systemic PPX may be needed
Strongly recommend titration of systemic prophylaxis to achieve these targets in Covid-19 patients
Major peer reviewed studies
Major peer reviewed studies
- Tang N et al. (observational SARS-CoV-2 study)
449 patients classified as having severe COVID-19 were enrolled study to assess 28-day mortality between heparin users and nonusers
99 patients received heparin treatment for at least 7 days
94 received enoxaparin 40-60 mg/day
5 received UFH 10,000-15,000 units/day
No difference found in 28-day mortality between heparin users vs nonusers (30.3% vs 29.7%)
Heparin treatment was associated with lower mortality in patients with SIC score ≥ 4 (40% vs 64.2%) but not in those with SIC < 4
When D-dimer > 3 ug/mL (6x ULN), they found an approximate 20% reduction in mortality with heparin treatment (32.8% vs 52.4%)
SIC: The International Society of Thrombosis and Haemostasis (ISTH) has proposed a new category for identifying an earlier phase of sepsis-associated DIC called “sepsis-induced coagulopathy.” (2)
Bottom Line (Tang et al): Systemic Heparin for patients with Covid-19 and elevated D-Dimer (6x ULN) associated with 20% absolute reduction in mortality (32.8% vs 52.4%, p = 0.017).
Bottom Line (Tang et al): Systemic Heparin for patients with Covid-19 and elevated D-Dimer (6x ULN) associated with 20% absolute reduction in mortality (32.8% vs 52.4%, p = 0.017).
- Paranjpe et al identified that full dose anticoagulation was associated with improved survival (irregardless of D-dimer levels) on retrospective analysis for patients with Covid-19. Effect was most pronounced for ICU patients.
2. Helms et al (Multi-center Prospective SARS-CoV-2 Cohort Study) - Intensive Care Medicine
2. Helms et al (Multi-center Prospective SARS-CoV-2 Cohort Study) - Intensive Care Medicine
Propensity matched analysis of 77 Covid-19 ARDS patients with 145 non-Covid-19 ARDS patients
Covid-19 ARDS patients developed significantly more thrombotic complications (11.7% vs 2.1%, p < 0.008) despite routine VTE Prophlyaxis
Bottom Line (Helms et al): Covid-19 ARDS is likely more hypercoaguable than non-Covid-19 ARDS. Routine VTE prophlyaxis likely not adequate
Bottom Line (Helms et al): Covid-19 ARDS is likely more hypercoaguable than non-Covid-19 ARDS. Routine VTE prophlyaxis likely not adequate
3. Klok et al. Observational Study in Netherlands - Thrombosis Research
3. Klok et al. Observational Study in Netherlands - Thrombosis Research
184 patients Dutch Study
31% incidence of thrombotic complications in Covid-19 critically ill patients
All patients received standard thromboprophylaxis
- Authors suggest increasing prophylaxis towards high-prophylactic doses even in absence of randomized evidence
Bottom line (Klok et al): Covid-19 associated with abnormally high rate of venous and arterial thrombotic events
Bottom line (Klok et al): Covid-19 associated with abnormally high rate of venous and arterial thrombotic events
4. Panigada et al. Retrospective study - Journal of Thrombosis and Hemostasis
4. Panigada et al. Retrospective study - Journal of Thrombosis and Hemostasis
Published April 18, 2020
24 patient whole blood with 6 patients undergoing repeated measurements sent for thromboelastography (TEG)
TEG consistent with state of hypercoagulability
Decreased R and K times
Increased K angle and MA
Increased Fibrinogen and D-dimer
CRP increased
Factor 8 and vWF increased
Protein C increased
ATIII marginally decreased
Author Conclusions: Hemostasis derangements in Covid-19 historically described as DIC are not consistent with acute DIC but support hypercoagulability with a severe inflammatory state.
Author Conclusions: Hemostasis derangements in Covid-19 historically described as DIC are not consistent with acute DIC but support hypercoagulability with a severe inflammatory state.
5. Ranucci et al - Prospective Observational Study aimed at characterizing the coagulation profile of Covid-19 patients - https://www.ncbi.nlm.nih.gov/research/coronavirus/publication/32302448
5. Ranucci et al - Prospective Observational Study aimed at characterizing the coagulation profile of Covid-19 patients - https://www.ncbi.nlm.nih.gov/research/coronavirus/publication/32302448
16 patients, 10 with multiple observations
At baseline patients showed pro-coagulant profile
Increased clot strength (CS 55 hPa median)
PLT contribution (43 hPA) and Fibrinogen contribution (12 hPA)
Elevated D-dimer
Hyperfibrinogenemia
Fibrinogen levels associated with Il6
Increasing thromboprophylaxis above standard associated with:
Significant time-related decrease in fibrinogen, D-Dimer, Clot Strength, and PLT and Fibrinogen contributions to clot strength (all P < 0.05)
Bottom Line: Patients with Covid-19 were observed to be hypercoaguable, extended thromboprophylaxis associated with significant improvements in hypercoaguable state
Bottom Line: Patients with Covid-19 were observed to be hypercoaguable, extended thromboprophylaxis associated with significant improvements in hypercoaguable state
6. Case Series evaluating tPA infusions / Plasminogen for patients with Covid-19
6. Case Series evaluating tPA infusions / Plasminogen for patients with Covid-19
Bottom Line: tPA infusions associated with 38-100% increase in P/F ratio for patients with severe Covid19 ARDS and P/F < 100
Limitations: Case Series, 3 patients
5 patients had pre - post CT scans, all 5 patients showed significant improvements in CT scans
8 patients had pre-post O2 saturations, 7/8 patients had increases in O2 within 1 hour of plasminogen
2 patients with lowest saturations improved from 79 -> 91 and 82 -> 91 within 1 hour of inhalation
Bottom Line: Inhaled Plasminogen associated with significant improvements in CT findings and improvement in O2 saturation within 1 hour
Limitations: Case Series, 13 patients
- Commentary in Journal of Trauma and Acute Care Surgery discussing tPA in Covid-19
7. Heparin (Unfractionated heparin, not LMWH) has potential anti-viral properties
7. Heparin (Unfractionated heparin, not LMWH) has potential anti-viral properties
- Mycroft-West: The 2019 coronavirus surface protein S1 receptor binding domain undergoes conformational change upon heparin binding - https://www.biorxiv.org/content/10.1101/2020.02.29.971093v1
Heparin binds to SARS-CoV-2 spike protein and results in structural change in S protein
Limitation: More studies are needed, but suggests antiviral activity for heparin in Sars-Cov-2
- Glycosaminoglycans induce conformational change in the SARS-CoV-2 Spike S1 Receptor Binding Domain
- Vicenzi et al: Coronaviridae and SARS-associated Coronavirus Strain HSR1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322807/pdf/03-0683.pdf
In Vitro - Heparin inhibited Vero cell infection by SARS-CoV by 50 %Bottom Line: Heparin should be preferred over LMWH given potential antiviral properties noted on in vitro experiments from SARS-CoV and SARS-CoV-2
- Inhibition of SARS Pseudovirus Cell Entry by Lactoferrin Binding to Heparan Sulfate Proteoglycans
In vitro heparin inhibited infection with SARS-CoV
Bottom Line: Heparin should be preferred over LMWH given potential antiviral properties noted on in vitro experiments from SARS-CoV and SARS-CoV-2
Bottom Line: Heparin should be preferred over LMWH given potential antiviral properties noted on in vitro experiments from SARS-CoV and SARS-CoV-2
8. Fox et al - Pulmonary and Cardiac Pathology in Covid-19: The First Autopsy Series from New Orleans
8. Fox et al - Pulmonary and Cardiac Pathology in Covid-19: The First Autopsy Series from New Orleans
Noted peripheral small vessel thrombi (see white arrows to right) in lung
Noted thrombotic microangiopathy restricted to the lungs
No patients were known at the time of death to have pulmonary thrombotic disease
- Of Note: Cardiac findings noted lack of myocarditis and autopsies concluded increased BNP due to acute RV dilitation
9. Deng et al Suspected myocardial injury in patients with COVID-19 - Int J Cardiology
9. Deng et al Suspected myocardial injury in patients with COVID-19 - Int J Cardiology
This study performed echocardiography on 112 patients with severe and non-severe Covid-19 and corroborate Fox et al.'s findings. Covid-19 patients with severe disease were more likely to have:
Segmental Wall Motion Abnormality (7.5% vs 0%, p = 0.06)
lower LVEF (58.5 vs 62, p < 0.01)
lower TAPSE (19.4 mm vs 20.8 mm), p < 0.01
TAPSE < 16 mm (6% vs 0%), p = 0.09
Pulmonary hypertension (20.9% vs 2.2%, p < 0.01)
PE (28.4% vs 6.7%, p < 0.01)
Of the 14 patients that died: 9 had TAPSE <= 18 mm
Bottom Line: More studies are needed to understand the myocardial injury observed in Covid-19; however, many sites are not doing autopsies. Only Oklahoma (n = 2) and New Orleans (n= 4) have published autopsy series in the U.S. Findings from these studies and this Deng et al's Echo series suggest pulmonary hypertension and right ventricular dysfunction as a potential contributor to the myocardial injury observed in Covid-19.
Bottom Line: More studies are needed to understand the myocardial injury observed in Covid-19; however, many sites are not doing autopsies. Only Oklahoma (n = 2) and New Orleans (n= 4) have published autopsy series in the U.S. Findings from these studies and this Deng et al's Echo series suggest pulmonary hypertension and right ventricular dysfunction as a potential contributor to the myocardial injury observed in Covid-19.
Precedent does exist for increased prophylactic anticoagulation for patients with severe viral pneumonias
Precedent does exist for increased prophylactic anticoagulation for patients with severe viral pneumonias
Patients with H1N1 ARDS were at significant risk for thrombosis despite prophylaxis due to exaggerated pro-inflammatory response, hypercoaguable state, and at risk for fatal thromboembolic events
In 2009, the CDC issued a statement warning physicians of H1N1 induced hypercoaguable state and many centers initiated routine systemic anticoagulation
In one series, 44% of patients with severe H1N1 ARDS developed thrombotic events. H1N1 was associated with a 17.9 increased odds of developing VTE (p = 0.004).
The use of systemic anticoagulation was associated with significantly reduced VTE events (OR 0.03, p = 0.001).
The use of systemic anticoagulation was associated with significantly reduced VTE events (OR 0.03, p = 0.001).
----- The Below References Expert Opinions -----
----- The Below References Expert Opinions -----
- In China it is common practice to anticoagulate all patients with elevated D-dimer with COVID-19
University of North Carolina Evidence-Based Anticoaguation in Covid-19 Website
University of North Carolina Evidence-Based Anticoaguation in Covid-19 Website
References:
References:
Gupta N, Zhao YY, Evans CE. The stimulation of thrombosis by hypoxia. Thromb Res. 2019;181:77-83.
Iba T, Levy JH, Warkentin TE, et al. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Thromb Haemost. 2019;17(11):1989-1994.
Tang N, Bai H, Chen X, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020. Doi: 10.111/jth.14814
Lin L, Lu L, Cao W, & Li T. Hypothesis for potential pathogenesis of SARS-CoV-2 infection–a review of immune changes in patients with viral pneumonia. Emerging Microbes & Infections. 2020;9(1):727-732, DOI: 10.1080/22221751.2020.1746199
Zhang Y, Cao W, Xiao M, et al. Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia. Zhonghua Xue Ye Xue Za Zhi. 2020;41(0):E006.
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