Heparin

 Observational SARS CoV-2

 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).

• 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.

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

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.

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.

Ranucci et al - Prospective Observational Study aimed at characterizing the coagulation profile of Covid-19 patients

• 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

1. Wang et al - Denver
   • 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
2. Wu et al - China
   • 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
3. Moore et al - Denver
   • Commentary in Journal of Trauma and Acute Care Surgery discussing tPA in Covid-19

Mycroft-West: The 2019 coronavirus surface protein S1 receptor binding domain undergoes conformational change upon heparin binding

• 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

• 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

Bottom Line: Heparin should be preferred over LMWH given potential antiviral properties noted on in vitro experiments from SARS-CoV and SARS-CoV-2

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

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. 

• 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).

A webinar sponsored by the American College of Cardiology and the Chinese Cardiovascular Association recommended systemic anticoagulation therapy for patients with severe COVID-19

• In China it is common practice to anticoagulate all patients with elevated D-dimer with COVID-19

1. Gupta N, Zhao YY, Evans CE. The stimulation of thrombosis by hypoxia. Thromb Res. 2019;181:77-83.
2. 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.
3. 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.
4. 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.
5. 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.