Covid-19 associated coagulopathy- Recent updates and guidelines for thromboprophylaxis. It discusses different guidelines till date.

1. Dr Pritish Chandra Patra
Associate Professor
Department of Hematology
IMS and SUM Hospital
COVID-19 and Coagulopathy

2. Coronavirus (COVID-19)
Global status (at 9:00 am 12th Oct 2020)
https://www.google.com/covid19-map/

3. https://www.mygov.in/covid-19/?cbps=1&target=webview&type=campaign&nid=0
Coronavirus (COVID-19)
India status (at 10:00 am 12th Oct 2020)

4. COVID-19 Course of Disease

5. CAC-Plethora of data- what to follow?

6. Pathophysiology
COVID-19 and Thrombosis
Iba T, Levy JH, Levi M, Thachil J. Coagulopathy in COVID-19. J Thromb Haemost. 2020;00:1–7.
Sars-Cov-2

Uncontrolled activation
of lymphocytes, neutrophils
 cytokines and tissue factor expression

Endothelial injury+Hypercoagulability+Vascular stasis
(Virchow’s triad)

Activation of coagulation cascade
Microthrombi

7. Pathophysiology
COVID-19 and Thrombosis
Iba T, Levy JH, Levi M, Thachil J. Coagulopathy in COVID-19. J Thromb Haemost. 2020;00:1–7.

8. Covid-19 and hematologic abnormalities
• Most consistent abnormality
• Leukopenia, lymphopenia in ~30-50% of patients
• Mild thrombocytopenia
• Increased D-dimer levels
• PT- , aPTT- , TT- 
• Associated with risk of
• ICU admission
• Mechanical ventilation
• Mortality
• DIC- advanced stage, worse prognosis

9. D-Dimer and Mortality,
Fei Zhou et al, Wuhan
• 191 patients included in this study
• 137 discharged, 54 died in hospital.
• Increasing odds of in-hospital death
associated with
• Older age (odds ratio 1·10, 95% CI
1·03–1·17, per year increase;
p=0·0043),
• Higher Sequential Organ Failure
Assessment (SOFA) score (5·65, 2·61–
12·23; p<0·0001),
• d-dimer greater than 1 μg/mL (18·42,
2·64–128·55; p=0·0033) on admission.
Lancet 2020; 395: 1054–62
Duration of hospitalization (in days)

10. CAC Vs DIC

11. COVID-19 and Thrombosis
• Affects both large and small vessels
Bikdeli B et al, J Am Coll Cardiol 2020;75:2950–73

12. Rosovsky RP, Res Pract Thromb Haemost. 2020;10.1002/rth2.12414.
Incidence of Thrombosis in COVID

13. Incidence of Thrombosis in COVID
Rosovsky RP, Res Pract Thromb Haemost. 2020;10.1002/rth2.12414.

14. Incidence of Thrombosis in COVID

15. Incidence of Thrombosis in COVID

16. Incidence of Thrombosis in COVID
Occurrence of venous thrombo-embolism (VTE) is approximately in
20% of patients and with cumulative incidences up to 59% during
hospitalization
Al-Ani F, Thrombosis risk associated with COVID-19 infection. A scoping review. Thromb Res. 2020
Alhazzani et al, 2013
Placebo
LMWH/UFH
1434
1461
100%
100%
16.0% VTE
8.2% VTE
Historical comparator (Non-COVID, ICU)

17. Enoxaparin in
Thromboprophylaxis in Acute Medical illness
MEDENOX Trial
• Double-blind RCT
• N=1102 acutely ill hospitalized
patients (> 40 years)
• 40 mg enoxaparin vs 20 mg
enoxaparin vs placebo once
daily for 6 to 14 days.
• Primary outcome was
occurrence of VTE at 14 days
Enoxaparin 40 mg SC as prophylaxis safely reduces the risk of VTE
in patients with acute medical illnesses
Samama MM, N Engl J Med. 1999;341(11):793-800

18. Enoxaparin in
Thromboprophylaxis in Acute Medical illness
A consistent relative risk reduction across the group and predefined risk factors
in patients with acute medical illnesses
Samama MM, N Engl J Med. 1999;341(11):793-800

19. Various LMWH trials
Thromboprophylaxis in Acute Medical illness
STUDY RRR NNT PROPHYLAXIS PATIENTS WITH VTE, %
MEDENOX1 63% 11
Placebo
Enoxaparin 4000IU
PREVENT2 45% 45
Placebo
Dalteparin 5000IU
ARTEMIS3 47% 20
Placebo
Fondaparinux
14,9’ (n=288)
5,5 (n=291)
5,0 (n=1,473)
2,8 (n=1,518)
10,5 (n=323)
5,6 (n=321)
‡
†

20. LMWH vs UFH trials
Thromboprophylaxis in Acute Medical illness
Kleber FX, et al. Am Heart J. 2003;145:614-21, Lechler E, et al. Haemostasis. 1996;26 Suppl 2:49-56.
Hillbom M, et al. Acta Neurol Scand. 2002;106:84-92. Sherman DG et al. Lancet 2007; 369(9570): 1347-55

22. Guideline recommendations

23. ACCP-CHEST Guidelines for Thromboprophylaxis
• In acutely ill hospitalized patients with COVID-19
• LMWH or fondaparinux over UFH
• LMWH, fondaparinux or UFH over DOAC
• In critically ill patients with COVID-19
• LMWH over UFH
• LMWH or UFH over fondaparinux or DOAC
Moores LK, Chest. 2020;S0012-3692(20)31625-1
Acutely ill
(general inpatient)
&
Critically ill (ICU)

24. ACCP-CHEST Guidelines for Thromboprophylaxis
• In critically ill or acutely ill hospitalized patients with COVID-19
• recommend against the use of antiplatelet agents for VTE prevention
• In patients with COVID-19
• recommend inpatient thromboprophylaxis only over inpatient plus extended
thromboprophylaxis after hospital discharge.
Moores LK, Chest. 2020;S0012-3692(20)31625-1

25. ACCP-CHEST Guidelines for Thromboprophylaxis
• In critically ill patients with COVID-19
• we suggest against the addition of mechanical prophylaxis to pharmacological
thromboprophylaxis
• In critically ill patients with COVID-19 with contraindication to
pharmacological thromboprophylaxis
• we suggest the use of mechanical thromboprophylaxis
Moores LK, Chest. 2020;S0012-3692(20)31625-1

26. ACCP-CHEST Guidelines for Thromboprophylaxis
• Diagnosis of VTE
• In critically ill COVID-19 patients
• we suggest against routine ultrasound screening for the detection of asymptomatic DVT
• For acutely ill hospitalized COVID-19 patients with proximal DVT or PE,
• we suggest initial parenteral anticoagulation with therapeutic weight adjusted LMWH or
IV UFH
In patients without any drug-to-drug interactions,
• initial oral anticoagulation with apixaban or rivaroxaban.
• Dabigatran and edoxaban can be used after initial parenteral anticoagulation.
• Vitamin K antagonist therapy can be used after overlap with initial parenteral
anticoagulation. Moores LK, Chest. 2020;S0012-3692(20)31625-1

27. ACCP-CHEST Guidelines for Thromboprophylaxis
• In critically ill COVID-19 patients with proximal DVT or PE
• we suggest parenteral over oral anticoagulant therapy
• In critically ill COVID-19 patients with proximal DVT or PE who are treated
with parenteral anticoagulation
• we suggest LMWH or fondaparinux over UFH
• For COVID 19 patients with proximal DVT or PE
• we recommend anticoagulation therapy for a minimum duration of 3 months
Moores LK, Chest. 2020;S0012-3692(20)31625-1

28. ACCP-CHEST Guidelines for Thromboprophylaxis
• Recurrent VTE despite anticoagulation with therapeutic weight adjusted
LMWH (and documented compliance)
• we suggest increasing the dose of LMWH by 25% to 30%
• Recurrent VTE despite anticoagulation with apixaban, dabigatran,
rivaroxaban or edoxaban (and documented compliance), or vitamin K
antagonist therapy (in the therapeutic range)
• we suggest switching to therapeutic weight-adjusted LMWH
Moores LK, Chest. 2020;S0012-3692(20)31625-1

29. Summary- ACCP Guideline and Expert Panel Report
• Anticoagulant prophylaxis with LMWH or UFH; no antiplatelets
• Standard dose anticoagulant prophylaxis
• Inpatient thromboprophylaxis only
• No routine screening for detection of asymptomatic VTE
• Don’t use systemic thrombolysis in most patients with COVID-19 and
acute objectively confirmed PE not associated with hypotension
• Systemic thrombolysis only if hypotension and no increased risk of
bleeding and patients with acute PE with cardiopulmonary
deterioration after initiation of anticoagulant therapy
Moores LK, Chest. 2020;S0012-3692(20)31625-1

30. Extended (post-
discharge)
VTE prophylaxis
• Patients hospitalized for acute
medical illness are at increased risk
for VTE for up to 90 days after
discharge.
• A symptomatic VTE incidence
between 0-0.6% at 30-42 days post
discharge has been reported in
patients with COVID-19.
• What?
• LMWH or DOACs
• Risk- at the cost of increase in
bleeding events, including
major bleeding
• How long?
• Max up to 45 days
• In whom?- in those with elevated
risk of VTE
• reduced mobility
• active cancer
• elevated D-dimer > 2xULN

31. Critically Ill Patients
• The ASH guideline panel suggests using prophylactic-intensity over intermediate-
intensity or therapeutic-intensity anticoagulation in patients with COVID-19
related critical illness who do not have suspected or confirmed VTE (conditional
recommendation based on very low certainty in the evidence about effects).
Acutely Ill Patients
• The ASH guideline panel suggests using prophylactic-intensity over intermediate-
intensity or therapeutic-intensity anticoagulation in patients with COVID-19
related acute illness who do not have suspected or confirmed VTE (conditional
recommendation based on very low certainty in the evidence about effects).
Draft ASH Guidelines on Use of Anticoagulation
in Patients with COVID-19
https://www.hematology.org/education/clinicians/guidelines-and-quality-care/clinical-practice-guidelines/venous-
thromboembolism-guidelines/ash-guidelines-on-use-of-anticoagulation-in-patients-with-covid-19

32. Bikdeli B et al, J Am Coll Cardiol 2020;75:2950–73

33. For full guidance: https://www.mohfw.gov.in/pdf/ClinicalManagementProtocolforCOVID19.pdf

34. Various international guidances differ on
Dosage and Duration of Thromboprophylaxis
Rosovsky RP, Res Pract Thromb Haemost. 2020;10.1002/rth2.12414.

35. Various international guidances differ on
Dosage and Duration of Thromboprophylaxis
Rosovsky RP, Res Pract Thromb Haemost. 2020;10.1002/rth2.12414.

36. Various international guidances differ on
Dosage and Duration of Thromboprophylaxis
Rosovsky RP, Res Pract Thromb Haemost. 2020;10.1002/rth2.12414.

37. Various international guidances differ on
Dosage and Duration of Thromboprophylaxis
Rosovsky RP, Res Pract Thromb Haemost. 2020;10.1002/rth2.12414.

38. Various international guidances differ on
Dosage and Duration of Thromboprophylaxis

39. AKI and COVID-19
https://www.theisn.org/covid19/infographics#aki-1

40. Enoxaparin Dosing in
Renal impairment
• Enoxaparin is the most studied LMWH in patients with renal dysfunction
• Enoxaparin is approved for patients with renal dysfunction with adjusted dosing. (PI)
• Moderate and mild renal impairment: No dose adjustment is recommended.
• Severe renal impairment (crcl< 30 ml/min): Dose adjustment is required as below.
Standard Prophylactic Dosing Severe renal impairment
40 mg SC once daily 20 mg SC once daily
Standard Therapeutic Dosing Severe renal impairment
1 mg/kg SC twice daily 1 mg/kg SC twice daily
1.5 mg/kg SC once daily 1 mg/kg SC twice daily
Enoxaparin Prescribing Information, Hughes S et al. Clin Kidney J. 2014;7(5)442-449

41. Anticoagulant Drug-Drug Interactions
with drugs being tried in COVID-19
https://covid19-druginteractions.org/

42. Conclusion
COVID-19 and Thrombosis
• Hypercoagulability is a prominent feature of COVID-19 infection –
• especially in severely affected cases
• Microthrombi and macro thrombi (both small and large vessels)
• Many published guidelines, limited evidence base
• RCTs are in progress to determine optimal dose of anticoagulation for
prophylaxis
• Patients on anticoagulation at admission, switch to LMWH whilst unwell
• All hospitalized patients should receive thromboprophylaxis
• Documented VTE- continue anticoagulation for 3 months
• Extended prophylaxis- None Vs max upto 45 days

43. Thank You

44. Comparative analysis of academic society guidelines for COVID thrombosis
Aggarwal, M., Dass, J. & Mahapatra, M. Hemostatic Abnormalities in COVID-19: An Update. Indian J Hematol Blood

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