Topline Presentation Points 

Inpatient anticoagulation management of patients with COVID-19

Up to 70% of hospitalized patients with COVID-19 have laboratory evidence of coagulopathy during hospital admission

  • Elevated D-dimer characterizes the coagulopathy
  • Elevated D-dimer correlates with need for critical care and death
    Guan et al. NEJM (2020); Huang et al. Travel Medicine and Infectious Disease (2020)

Thrombo-inflammation is a Key Pathophysiologic Mechanism of Severe COVID-19

  • COVID-19 appears to progress through various stages of thrombo-inflammation
  • Lower 28-day mortality among patients who received heparin thrombotic prophylaxis in Wuhan, China vs. those who did not, especially if they had a high D-dimer
    Tang et al. J Thromb Haemost (2020); Thachil et al. RPTH (2020)
The Value of Heparin Extends Beyond its Anticoagulant Effect
  • Numerous models show beneficial effect on endothelial function and capillary leak → improves acute lung injury
  • Heparin may bind directly to the SARS-CoV-2 spike protein interfering with viral attachment and entry;
  • Heparins have anti-inflammatory effects in acutely ill medical patients, including those with COVID-19;
    Tang et al. J Thromb Haemost (2020);
    Mu et al. Respir Res (2008);
    Li et al. Zhonghua (2019);
    Wang et al. Crit Care (2014);
    Liu et al. RPTH (2020);
    Helms et al . Intensive Care Med. (2020)
  • HEP-COVID and RAPID multiplatform Randomized Control Studies (mpRCT) of moderately ill patients, provide strong evidence for benefit of therapeutic heparin in moderately ill ward patients with COVID-19 irrespective of D-dimer levels, but not in severely ill ICU patients

However…

  • Dosing, Timing, and anticoagulant drug choice matter
    • No benefit when therapeutic vs. prophylactic anticoagulation provided to those with critical illness
      Goligher et al. NEJM (2021)
    • Lack of efficacy of intermediate dose LMWH compared with prophylactic dose LMWH in the critically ill
      Bikdeli et al. JAMA (2021)

 

What we know about VITT (Vaccine-induced Immune Thrombotic Thrombocytopenia)
What it is
  • Very rare, severe immunological reaction to adenoviral vector-based COVID-19 vaccines
  • Extreme activation of platelets and coagulation
  • High risk of death from venous or arterial thrombosis or secondary hemorrhage
    Greinacher Blood 2021;
    Makris, M Res Pract Thromb Haemost 2021;
    NICE rapid guideline July 2021 
Which vaccines

Non-replicant adenovirus vector-based vaccines:

  • ChAdOx1, AstraZeneca/COVISHIELD
  • Ad26COV2.S, Janssen, Johnson & Johnson
Incidence
  • varies according to region
    • AZ vaccine – 1/30,000 – 1/130,000 1st doses
    • J&J vaccine – 1/500,000 1st doses
VITT vs. Thrombosis with Thrombocytopenia Syndrome (TTS)
  • VITT
    • Very specific syndrome relating to vaccine associated anti-PF4 antibodies
  • TTS may occur with other disorders
    • HITT
    • ITP with thrombosis
    • Thrombotic microangiopathies: Cancer-associated DIC, Severe antiphospholipid antibody syndrome, TTP
Our Current Understanding: VITT Clinical Manifestations

Solely or in combination:

  • Cerebral venous sinus thrombosis (appears to be the most serious and life-threatening form of VITT)
  • Splanchnic vein thrombosis
  • VTE
  • Arterial thrombosis
  • May have multiple organ thrombosis
  • New symptoms in different organs or systems (must rule out additional thromboses)
    Makris, M Res Pract Thromb Haemost 2021;
    NICE rapid guideline July 2021
Timing of Symptoms
  • Symptoms develop 5 or more days after the vaccine
  • Symptoms typically do not occur beyond 30 days
  • Exceptions: isolated DVT or PE where disease may be subclinical
Screening Laboratory Tests
  • CBC: Platelet count
    • Repeated CBCs may be necessary
    • VITT is unlikely if the platelet count is persistently normal i.e. >150
  • D-dimer
    • D-dimer <4X ULN (i.e. >2000 or 2.0) -> VITT is unlikely
    • Repeated D-dimer monitoring may be necessary

Pavord NEJM 2021; Greinacher Blood 2021
Makris, M Res Pract Thromb Haemost 2021; NICE rapid guideline July 2021;
Ontario COVID Science Table Brief on VITT 2021

Advanced Confirmatory Laboratory Tests
  • Antibody Testing
  • Functional Assays
VITT Management

Considerations:

  • Deterioration can occur quickly
  • Treatment should not be delayed
  • Prompt consultation: hematology, neurology, cardiology etc.
  • Treatment in the inpatient setting with close monitoring
  • Prompt reporting to public health

Treatment:

  1. ANTICOAGULATION
  2. IMMUNE MODULATION

ASH Suggested Treatment:

  1. IVIG 1 g/kg daily x 2 days
  2. Non-heparin-based anticoagulation
  3. No consensus on steroids
  4. Avoid ASA – increases bleed risk
  5. Plasmapheresis not recommended unless continued thrombosis despite IVIG/anticoagulation
  6. Avoid platelet transfusions unless life threatening bleed or surgery
    ASH Apr2021

Additional Immune Modulation for Severe Cases:

  • Platelet count <30K and severe thrombosis
  • Small case series -> plasma exchange seems to improve outcomes
    Patriquin NEJM August 2021