Having more than two year experiences, presently anticoagulant is an essential component of management of COVID 19 Its role is recommended in moderate to severe to critically ill patients with different opinion in the dosage Giving anticoagulants in asymptomatic or mild cases is still need to be validated though there are suggestions in favor. There is recommendation for post discharge patients who had clinically suspected/established thromboembolism events

1. Anticoagulants in COVID-19
Evidence Based Approach
Dr. Nayan Ray
MBBS
Mymensingh Medical College and Hospital

2. Introduction
• Having more than a year experiences, presently
anticoagulant is an essential component of management
of COVID 19
• Its role is recommended in moderate to severe to critically
ill patients with different opinion in the dosage
• Giving anticoagulants in asymptomatic or mild cases is still
need to be validated though there are suggestions in favor.
• There is recommendation for post discharge patients who
had clinically suspected/established thromboembolism
events

3. Intro….
• Both arterial and venous thromboembolism are prevalent in
COVID 19 patients
• Both macro and microvascular thrombosis are evident
• Overall incidence of VTE among inpatients with COVID-19 was
estimated at 17%
• Post mortem studies show the presence of thrombosis
• Thrombotic events occur in hospitalized patients - more in
ICU admitted than in ward patients (28% vs 7%)
JACC Vol 77, No 15, April 20,2021

4. • SARS-CoV-2 enters endothelial cells through ACE2 receptors and
may impair their intrinsic antithrombotic properties
• Endothelial activation takes place due to viremia, hypoxia and
inflammatory response and increased tissue factor
• There is activation of coagulation cascade and inhibition of
plasminogen activators
• Increased reactivity of platelets
• Excessive inflammatory response plays an important role in the
pathogenesis of thrombosis (thrombo-inflammation), including
pulmonary - and pulmonary intravascular coagulopathy
JACC Vol 77, No 15, April 20,2021
Intro….

5. Why Anticoagulants???
1. Therapeutic - signs of thromboembolism - DVT, PE
2. Primary prophylaxis - in anticipation of
thromboembolism
3. Ongoing anticoagulant - atrial fibrillation or patients
with mechanical valves
4. Secondary prophylaxis - post-discharge patients

6. Primary Prophylaxis
• Rationality of using anticoagulants
• Choice of anticoagulants
• Duration of anticoagulants
• Adverse effects

7. • Pathophysiology of the diseases process
• Epidemiological data
• Observational studies
• Autopsy studies
Primary Prophylaxis: Rationale

8. Clinical and Pathophysiological Staging in COVID
• Stage 1 Patients who are ambulant or admitted to hospital because of
other reasons
Symptoms
Mild, do not need respiratory support
Inflammatory reaction
Mild
Coagulation markers
D-dimer 2-3 times the ULN
Fibrinogen normal
Prothrombin time normal
Platelet count normal
Thrombotic events
Limited local pulmonary (inflammatory)
microthrombi
Lancet Hoematol | Published online April 27, 2021

9. Clinical and Pathophysiological Staging in COVID
• Stage 2 Patients who are admitted to hospital and need increased oxygen
supply
Symptoms
More severe, need respiratory support
Inflammatory reaction
Pronounced
Coagulation markers
D-dimer 3-6 times the UUN
Fibrinogen mildly increased
Prothrombin time mildly increased
Platelet count 100-500x109 platelets per L
Thrombotic events
Increased incidence of (inflammatory)
microthrombi and macrothrombi
Lancet Hoematol | Published online April 27, 2021

10. Symptoms
Critically ill patients who need organ support-eg, high flow
oxygen therapy or mechanical ventilatory support, or both
Inflammatory reaction
Cytokine storm
Coagulation markers
D-dimer more than 6 times the ULNFibrinogen markedly
increasedProthrombin time markedly increasedPlatelet
countless than 100 x 109 platelets per L
Thrombotic events
High incidence of microthrombi andmacrothrombi
Lancet Haematol Published online April 27, 2021
• Stage 3 Critically ill patients in need of organ support
Clinical and Pathophysiological Staging in COVID

11. • Post-discharge Patients who are discharged from hospital
Symptoms
Recovering. Functional limitations are often still
present 3 months after discharge
Inflammatory reaction
Restored
Coagulation markers
Restored
Thrombotic events
Unknown
Lancet Haematol / Published online April 27, 2021
Clinical and Pathophysiological Staging in COVID

12. Pathophysiology Supporting Anticoagulant
• In COVID 19, all the three components of Virchow's triad
come into play: endothelitis activation of coagulation
cascade as well as platelet activation-stasis (less
movement in general; prolonged bed confinement of ICU
patients).
• There are abundant ACE2 receptors on the vascular
endothelium, so the virus enters the endothelium
resulting in the endothelitis impairing intrinsic
antithrombotic properties.
• Hypoxemia takes part in the genesis of endothelial injury

13. Hypercoagulable State
• Inflammatory cytokines and endothelial activation results
in decreased anti-thrombin and plasminogen activators and
increased platelet activity.
• Increased level of plasminogen inhibitors, von Willabrand
factor, fibrinogen, factors V, VII, VIII and X-all lead to hyper-
coagulable state.
• COVID 19 is associated with excessive inflammatory
response in comparison with other viral/inflammatory
conditions resulting in more intense hyper-coagulable
state.
• Inflammation associated with SARS-CoV-2 infection leads
to a "COVID-19 related coagulopathy" resulting in
increased thrombosis
JACC Vol 76 No 16, October 2020; Vol 77, No 15 April 2021

14. Stasis
• Fatigue
• Hypoxemia
• Hospitalization
• Pneumonia
• Cardiac involvement - myocarditis, heart failure
• Connection with medical appliances
• ICU admitted
JACC Vol 76 No 16,October,2020; Vol 77, No 15 April 2021

16. Platelet and Endothelial Activation as
Potential Mechanisms Behind the Thrombotic
Complications of COVID-19 Patients
• JACC 2020;75(23):2950-73.June 16
• Several mechanisms can promote platelet activation in COVID-19:
• Endothelial dysfunction and lack of NO activity
• No direct effect of the virus
• Aspirin and P2Y12 inhibitors prevent platelet activation induced
by COVID-19 plasma.
• Severe COVID-19 patients may develop pulmonary
embolism/small local thrombi despite prophylactic and even
empiric treatment-dose anticoagulation suggesting that an other
antithrombotic therapy may be necessary for this therapeutic
goal

17. • In COVID-19 patients there is sustained platelet activation
with formation of PLA that may be involved in the
microthrombi found in autoptic specimens.
• COVID-19 plasma, added to the blood of healthy subjects,
induces platelet activation which is blunted by
pretreatment with tocilizumab.
• IL-6-mediated platelet activation that triggers the
hypercoagulable state in COVID-19, suggesting the
potential effectiveness of anti-IL 6 antibodies and
antiplatelet drugs
JACC Basic Trans Science 2021,6203-18
Platelet and Endothelial Activation as
Potential Mechanisms Behind the Thrombotic
Complications of COVID-19 Patients

18. • Quantitative analysis of 28,173 hospitalized patients of 66
studies
• VTE occurs in 22.7% of ICU and 7.9% of non-ICU
hospitalized patients.
• Thromboprophylaxis is a key element in the medical care
of patients with COVID-19, especially in those with severe
illness
• High incidence of VTE despite prophylactic or even
therapeutic anticoagulation.
• Ideal anticoagulation approach needs to be studied
further
• D-dimer guided anticoagulation
October, 2020, Vol 4, Issue 7

19. Observational Findings

20. Arterial Thromboembolism
• Patients with SARS-CoV-2 are at risk risk for acute arterial
thromboembolic complications (Journal Vascular Surgery.
Volume 73, Issue 2, February 2021, Pages 381-389.e1) In 40
diagnosed arterial thromboembolism, 37.5 % were COVID
positive.
• In another series of 20 patients with arterial
thromboembolic events have been reported in 209
admitted patients (9.6%) (International Journal of
Cardiology. Volume 323, 15 January 2021, Pages 281-284)

21. Anticoagulation. Bledding, Mortality
and Pathology in Hospitalized Patients
in Covid 19
• Retrospective analysis 4,389 patients including 72 autopsy
studies.
• Bleeding rates were low overall, but as expected, were
slightly higher in the therapeutic AC group (3%) compared
with the prophylactic (1.7%) and no AC groups (1.9%)
• Bleeding rates were higher in patients on LMWH versus
DOACs (2.6% vs 1.3%)
• Autopsy findings revealed high prevalence of
thromboembolism (42%) including those receiving AC. In
most cases there was no clinical suspicion of
thromboembolism. JACC Vol 76, No 16, October, 2020

22. Anticoagulation. Bledding, Mortality
and Pathology in Hospitalized Patients
in Covid 19

23. Therapeutic versus prophylactic
anticoagulation for severe COVID-19: A
randomized phase II clinical trial
(HESACOVID)
• Patients on mechanical ventilation – 10 received
therapeutic anticoagulation and 10 prophylactic
anticoagulation.
• Therapeutic enoxaparin improves gas exchange and
decreases the need for mechanical ventilation in severe
COVID-19.
Thrombosis Research , Volume 196, December 2020, Pages 359-366T

24. • Incidence of VTE ( met analysis of 66 studies) – 14.1%
• ICU patients – 45.6% ( 3 times higher than other viral
infection)
• Post-discharge within 90 days - 2.6%
• Pre-hospital ( mild cases) incidence is not recorded
• Increased prevalence of arterial thrombotic events such
as myocardial and cerebral infarction (up to 3%) in the
ICU setting
Lancet Haematol, April 27, 2021

25. MyoClinic Recommendation

26. • Fondaparinux - 2.5 mg sc once daily in patients with HIT
having acceptable renal function (Crcl 230 mL/min)
• 8.3% incidence of VTE for patients on hospital wards
• It is noteworthy that reports of excessive bleeding in
COVID-19– infected patients residing in the hospital have
not been published. Two groups with patients receiving
anticoagulants reported bleeding rates of 0% to 3%.
Myo Clinic Recommendation
Mayo Clin Proc. 2020 Nov; 95(11): 2467–2486

28. NIH Recommendations
• In non hospitalized patients with COVID-19, there are
currently no data to support the measurement of
coagulation markers (e.g., D-dimers, prothrombin time,
platelet count, fibrinogen) (AIII).
• For non hospitalized patients with COVID-19,
anticoagulants and antiplatelet therapy should not be
initiated for the prevention of venous thromboembolism
(VTE) or arterial thrombosis unless the patient has other
indications for the therapy or is participating in a clinical
trial (AIII).
• Patients who are receiving anticoagulant or antiplatelet
therapies for underlying conditions should continue these
medications if they receive a diagnosis of COVID-19 (AIII).
Alll: for Strong recommendation - expert opinion

29. • In hospitalized patients with COVID-19, hematologic and
coagulation parameters are commonly measured, although
there are currently insufficient data to recommend either for or
against using this data to guide management decisions.
• Hospitalized adults with COVID-19 should receive prophylactic
dose anticoagulation (AIII).
• Anticoagulant or antiplatelet therapy should not be used to
prevent arterial thrombosis outside of the usual standard of care
for patients without COVID-19 (AIII).
• For hospitalized COVID-19 patients who experience rapid
deterioration of pulmonary, cardiac, or neurological function, or
of sudden, localized loss of peripheral perfusion, the possibility
of thromboembolic disease should be evaluated (AIII).
NIH Recommendations

30. • Incident thromboembolic event or who are highly suspected to
have thromboembolic disease should be managed with
therapeutic doses of anticoagulant therapy (AIII).
• Extracorporeal membrane oxygenation or continuous renal
replacement therapy or who have thrombosis of catheters or
extracorporeal filters should be treated with antithrombotic
therapy as per the standard institutional protocols for those
without COVID-19 (AIII).
• DOAC is contraindicated in lactating mothers – UFH, LMWH and
warfarin not secreted in breast milk.
• Hospitalized patients with COVID-19 should not routinely be
discharged from the hospital while on VTE prophylaxis (AIII).
• Extended VTE prophylaxis after hospital discharge can be
considered for patients who are at low risk for bleeding and high
risk for VTE (BI). FDA approval of the use of Rivaroxaban 10 mg
daily for 31 to 39 days in these patients.
NIH Recommendations

31. • In hospitalized, critically ill patients, LMWH or UFU is preferred
over oral anticoagulants due to shorter half-lives, can be
administered iv or sc, and have fewer drug-drug interactions
(AIII).
• Whenever anticoagulant or antiplatelet therapy is used, potential
drug-drug interactions with other concomitant drugs must be
considered (AIII).
• COVID-19 outpatients receiving warfarin may be candidates for
switching to DOAC therapy to avoid INR measurement.
NIH Recommendations

32. • In pregnancy, LMWH is recommended, rather than
unfractionated heparin, for the prevention and
treatment of VTE
• Warfarin to be avoided
• No safety data of DOACS
NIH Recommendations

33. Different Dosage of Anticoagulants

34. Antithrombotic in Outpatients

35. Anti Coagulants in Pre-hospital

36. Anticoagulants in Hospitalized Patients

37. Recommendation for ICU admitted

38. Covid 19 associated coagulopathy and
Anti thrombotic Agents – Lessons After 1 year
• High risk of bleeding despite high risk of thrombosis in
critically ill patients due to pronounced thrombocytopenia,
platelet dysfunction or coagulation factor deficiencies, or
both comparing to moderately ill patients.
• Overwhelming inflammatory reaction and accompanying
thrombotic complications in critically ill patients are too
pronounced to be restored; whereas in non-ICU patients,
therapeutic anticoagulation might still help to maintain an
adequate balance
• Routine dose thromboprophylaxis over intermediate dose
for all patients admitted to hospital (ICU and non-ICU
patients) is recommended.
Lancet Hematol, April, 27,2021

39. Antithrombotics in Post Discharge Patients

40. Recommendations of Bangladesh Guidelines

41. ACTIV Trials
ACTIV 1:
• Role of immune modulators in hospitalized adults with moderate to severe COVID-19
disease as add-on therapy to remdesivir and dexamethasone
ACTIV 2:
• Potential utility of monoclonal antibodies and other novel therapeutics in outpatients with
COVID-19
ACTIV 3:
• Similar questions of efficacy and risk in inpatients with COVID-19
ACTIV 4:
• COVID 19 antithrombotics
• 4a: Inpatient - prophylactic versus therapeutic dose heparin
• 46: Outpatient - Placebo vs Aspirin vs prophylactic apixaban vs therapeutic apixaban
• 4c: Convalescent - Placebo vs prophylactic apixaban

42. ATTACC, ACTIV-4a & REMAP-CAP
Multiplatform RCT
• Hospitalised non ICU patients: Therapeutic dose superior to
usual care venous thromboprophylaxis. Major bleeding rate <2%
• ICU admitted patients: Therapeutic heparin is inferior (harmful)
compared to thromboprophylaxis. Major bleeding rate 3.7%
Pre-publication Interim results. January 28,2021

43. • To evaluate the effects of intermediate-dose (1 mg/kg daily) vs standard- dose
prophylactic (40mg daily) enoxparin among patients with COVID-19 admitted to
the intensive care unit (ICU).
• 562 patients.
• Intermediate-dose prophylactic anticoagulation, compared with standard- dose
prophylactic anticoagulation, did not result in a significant difference in the
primary outcome of a composite venous or arterial thrombosis and 30 day
mortality.
JAMA, March 21,2021

44. Dose in Critically Ill patients
• In the INSPIRATION trial, there is no statistically significant
differences in the thrombotic events between intermediate
dose of LMWH (0.5 mg/kg twice daily or 1 mg/kg daily) vs
standard dose (40mg twice daily ) in critically ill patients with
COVID-19. Major bleeding occurred more in intermediate dose
(2.5% vs 1.4%).
• In a cohort of 2089 critically ill patients from 67 centres in USA
no benefit of therapeutic dose anticoagulation initiated within
2 days of ICU admission compared with standard-dose
thromboprophylaxis.
• Interim results of multiplatform randomized clinical trial, (a
collaboration between 3 trials - ATTACC, REMAP-CAP, and
ACTIV-4), not better with therapeutic with added bleeding risk.
Lancet Haematol, April 27, 2021

45. Thromboprophylaxis
• Hospitalized non ICU patients may benefit from the
escalation of anticoagulant dose. escalated
thromboprophylaxis could be appropriate in moderately ill
hospitalized patients with COVID-19. Major bleeding <2%.
• Therapeutic anticoagulation decreased the need for organ
support from approximately 25% to 18% in patients with a
high D-dimer at baseline and from 19% to 13% in those with
a low D-dimer at baseline (Multiplatform RCTs).
• Effect of outpatient thromboprophylaxis for patients with
mild COVID-19 not requiring hospital admission is still
unknown.
• Utility of post discharge thromboprophylaxis is yet to be
decided.
Lancet Haematol, April 27, 2021

46. • Cases of immune thrombocytopenia and bleeding without thrombosis
that were induced or revealed after exposure to the messenger RNA
(mRNA)-based vaccines produced by Moderna (mRNA-1273) and Pfizer-
BioNTech (BNT162b2) and ChAdox1 nCOV-19 (AstraZeneca).
• High degree of suspicion when patients present with central nervous
system or abdominal symptoms after receiving any SARS-CoV-2 vaccine.
• High levels of d-dimers and low levels of fibrinogen were common and
suggest systemic activation of coagulation.
• The incidence of VITT, is perhaps 1 case per 100,000 exposures.
• IV immunoglobulins and high dose glucocorticoids along with LMWH/
Fondaparinux improve the condition.
• “The very low prevalence of this complication of vaccination, however
severe, relative to the benefits of preventing Covid-19 (a condition with 1
to 2% mortality and potential long-term sequelae) must be emphasized."
NEJM editorial, April 16, 2021

47. • Analysis of 28 patients (by the time > 82 million doses are
administered)
• All are tested positive for antibodies against PF4
• 9 had cerebral venous thrombosis,
• 3 had splanchnic-vein thrombosis,
• 3 had pulmonary embolism, and
• 4 had other thromboses; of these patients,
• 6 died.
• Five patients -DIC.
• Feature mimic HIT - VITT
• Treatment suggestions : Immunoglobulins + Non-heparin
anticoagulant
NEJM ,April 9, 2021

48. • 12 cases are reported
• The initial 12 US cases of cerebral venous sinus
thrombosis with thrombocytopenia 6-15 days after
vaccination.
• The condition mimics HIT
• Mortality 3
JAMA, 30 April, 2021

49. • Post COVID-19 thrombosis is mainly due to endothelial
dysfunction following overactive immune response leading
to prolonged vasculitis. Breach of endothelium causes
exposure of tissue factors and procoagulant cytokines
triggering tissue factor driven secondary hemostasis.
• Virus poses significant chronic immuno-thrombogenicity
which may cumulate eventually in a major thrombotic event
that occurs unexpectedly many weeks later in fit patients
with mild or asymptomatic COVID-19 infection.
Presentation:
1 Stroke
2. Myocardial infarction
3. Acute limb ischaemia
Semin Thromb Hemost, online 15.4.21

50. Issues Need to be Addressed
• Can we use DOAC in prehospital stage instead of LMWH
(ACTIV 4b trial is undergoing with apixaban; RIVACOD (
Bangladesh) – results pending )
• Whether we can use DOAC in moderate to severe cases
instead of LMWH?
• Role of Aspirin / P2Y12 inhibitors (ACTIV 4b, ACT- COVID
trial results are pending)
• Understanding thrombotic events in "Long COVID" patients

51. Take Home Message
• In COVID 19, thromboembolism is prevalent as evident
by clinical, biochemical, imaging and autopsy studies.
• Venous events are more common than arterial.
• There is interplay of virus entry into the endothelium
resulting in endothelitis, activation of coagulation
system, inhibition of plasminogen activators, increase in
platelet reactivity along with decreased mobility.
• Cytokines augments the process of thrombosis
• In mild form, there is no solid evidence of usefulness of
anticoagulants though there is weak suggestion.

52. • In moderate to severe form, thromboprophylaxis is
universally recommended. Recent evidence is in favour of
therapeutic anticoagulation.
• In ICU admitted cases, prophylactic dose is advocated.
• When DVT or PE is suspected/diagnosed – treatment is as
per protocol.
• Role of anti-platelets are logical but yet to be
substantiated
• Anti-IL6 is effective in "cytokine storm” in preventing
immunothrombosis
Take Home Message

53. Thank You