Hematological considerations in COVID-19

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