Anticoagulant therapy in COVID COVID Management

1. ANTICOAGULANTS IN
COVID
DR A P NAVEEN KUMAR
DNB FICP
Chief Specialist
Visakha Steel General Hospital

3. PATHOPHYSIOLOGY
 COVID 19 causes -Severe acute respiratory syndrome
 COVID 19 patients frequently develop a pro-coagulative state
caused by
endothelial dysfunction
cytokine storm
complement cascade hyperactivation
 Diffuse microvascular thrombi in multiple organs, mostly in
pulmonary microvessels
 Thrombotic risk seems to be directly related to disease severity
and worsens patients’ prognosis

4.  It is a single strain RNA-virus that enters human
cells through the binding between the viral
structural spike (S) protein and the angiotensin-
converting enzyme 2 (ACE2) receptor
 ACE 2 is mainly expressed on the surface of
alveolar type II epithelial cells, cardiac myocytes
and vascular endothelial cells (EC)
 Viral entry is facilitated by a type 2
transmembrane serine protease, TMPRSS2, via
the S protein as well

7.  SARS-CoV-2 induced complement
hyperactivation, endothelial dysfunction and
cytokine storm have a pro-thrombotic effect
 COVID 19 patients develop a pro-coagulative state
directly related to disease severity
 In COVID 19 critical patients, thrombotic lesions
in pulmunary microvessels have a prevalence
twice higher than critical non-COVID 19 patients

8. MOLECULAR EVIDENCE OF HYPERCOAGULABLE STATE

9.  24 Female doctor
 Asymptomatic
 Tests done on 8th day
 P60 L 34
 LDH – 236 Ferritin – 326
 D Dimer – 0.614
 HRCT - Normal

10. MAJOR SOCIETAL RECOMMENDATIONS AND
GUIDELINES
 Centers for Disease Control and Prevention -(CDC)
 International Society for Thrombosis AND Haemostasis’s
interim guidance - (ISTH-IG)
 American Society of Hematology -(ASH )
 American College of Chest Physicians - (ACCP)
 Scientific and Standardization Committee of ISTH (SCC-
ISTH)
 American College of Cardiology - (ACC)

12. Thresholds for admission to the hospital
 D-dimer markedly raised three- to fourfold
 prothrombin time prolonged
 platelet count < 100 × 109
 fibrinogen < 2.0 g/L.

13. 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)

15. CHRONIC ANTICOAGULANT AND
ANTIPLATELET THERAPY
 Patients who are receiving anticoagulant or
antiplatelet therapies for underlying conditions
should continue these medications if they receive
a diagnosis of COVID-19
 For non-hospitalized patients with COVID-19,
anticoagulants and antiplatelet therapy should not
be initiated for prevention of venous
thromboembolism (VTE) or arterial thrombosis
unless there are other indications
(AIII)

16. SPECIFIC RECOMMENDATIONS FOR PREGNANT OR
LACTATING INDIVIDUALS WITH COVID-19
 If antithrombotic therapy is prescribed during pregnancy prior to a
diagnosis of COVID-19, this therapy should be continued (AIII)
 For pregnant patients hospitalized for severe COVID-19,
prophylactic dose anticoagulation is recommended if there are no
contraindications to its use (BIII)
 As for nonpregnant patients, VTE prophylaxis after hospital
discharge is not recommended for pregnant patients (AIII).
Decisions to continue VTE prophylaxis in the pregnant or
postpartum patient should be individualized, considering
concomitant VTE risk factors.

17. Management of anticoagulation therapy during labor and
delivery requires specialized care and planning and
should be managed similarly in pregnant patients with
COVID-19 as other conditions that require anticoagulation
in pregnancy (AIII)
• Unfractionated heparin, LMWH, and warfarin do not
accumulate in breast milk and do not induce an
anticoagulant effect in the newborn; therefore, they can be
used in breastfeeding women with or without COVID-19
who require VTE prophylaxis or treatment (AIII).
In contrast, direct-acting oral anticoagulants are not
routinely recommended due to lack of safety data

18.  There are no data on the use of scoring
systems to predict VTE risk in pregnant
individuals. Additionally, during pregnancy, the
D-dimer level may not be a reliable predictor of
VTE because there is a physiologic increase of
D-dimer levels throughout gestation

19.  72 old HTN T2DM COPD Old CVA
 Cough , BTLN with expectoration
 Hypoxia , hemodynamically stable
 HRCT – Mild involvement
 D Dimer - 0.324
 Started on Remdesivir ,steroids and
LMWH
 VTE Prophylaxis

21.  Patients with Covid-19 are clearly at risk for macrothrombosis, since
they exhibit all three components of Virchow’s triad (stasis of blood
flow, hypercoagulability, and endothelial injury)
 The hypothesis that there may be a unique pulmonary embolism
phenotype in patients with Covid-19 characterized by thrombi and not
emboli — that is, immunothrombosis
 In this context, increased doses of anticoagulants may be ineffective
 It may therefore follow that upstream therapies, such as antiviral and
immunomodulating agents, to reduce the development of
immunothrombosis will prove more efficacious than downstream
attempts to suppress the coagulation system.

22.  Critically ill patients have an increased risk -
VTE
 Poissy et al - 107 patients - ICU -PE - 20.6%
 In the reported PE cases there was a low
number of associated DVT suggesting that they
had pulmonary thrombosis rather than
pulmonary embolism from peripheral veins.

23.  Hyperinflammation mediated by IL-1,TNF-α and
IL-6 leads to an increase in
Fibrinogen
LDH
PAI-1
NLR
mainly due to T CD4+ lymphocytes reduction
 Reduction in
Antithrombin 111
Protein C
Tissue factor inhibition

24. THROMBOTIC MICRIO - ANGIOPATHY
 In severe COVID-19, the reported elevated levels
of LDH, d-dimer, and bilirubin, the mild
thrombocytopenia and anaemia, the diffuse
microvascular thrombi with renal and cardiac
injury make the complement cascade
hyperactivation a conceivable pathogenetic
mechanism.

25.  For hospitalized COVID-19 patients, the possibility of
thromboembolic disease should be evaluated in the
event of rapid deterioration of pulmonary, cardiac, or
neurological function, or of sudden, localized loss of
peripheral perfusion (AIII)
 Patients with COVID-19 who experience an incident
thromboembolic event or who are highly suspected
to have thromboembolic disease at a time when
imaging is not possible should be managed with
therapeutic doses of anticoagulant therapy as per
the standard of care for patients without COVID-19
(AIII)

26. Statins and ACE inhibitors (ACE-I) because of
their effect on reducing endothelial dysfunction,
might find a rationale in the management of
COVID-19 patients, as well as the reduction of
low density lipoprotein (which reduces eNOS
activity)

27.  55 year old HTN, T2DM
 Fever, cough and breathlessness – 5 days
 RAT was reactive – HRCT moderate severity
 Admitted – Hypoxic – Moderate severity
 Started on Remdesivir ,LMWH ,Steroids, Insulin
 Supportive treatment and oxygen inhalation
 Hypoxia corrected and improved clinically

28.  8th day - hemodynamically better- off oxygen
 Woke up- severe headache and blurring of vision
 BP 150/100m HR 76/mt
 Vision-PL and PR absent , Eye movements-N
 No other deficit except mild ataxia
 ECG , 2DEcho , Biochemistry - N
 MRI brain showed infarct in right thalamus, medial
temporal and left occipital region
 Anticoagulants increased to therapeutic range

29.  His vision improved gradually and PL and PR
was there at discharge a week later
 Ataxia improved and he was able to walk
 Discharged with tapering doses of steroids and
oral anticoagulant
 Developed AIDP after 15 days
 Recovered with supportive treatment

30. DATE TC DC ESR FBS CRP D
DIMER
18/8/20 10400 P 92 L 08 28 87 16.2 0.34
23/8/20 20800 P 76 L 18 86 196 94 0.58
29/9/20 8200 P 64 L 32 57 157 23.2 0.04

37. DURATION OF ANTI COAGULATION
 The ACF recommends at least a 3-month course of
anticoagulation for patients who are started on
anticoagulation for a presumed provoked thrombus
from the inflammatory state of CAC but did not have
imaging available for confirmation
 The ACF also recommends that standard
anticoagulation guidelines be used to determine length
of anticoagulation beyond the initial 3-month period
 Similarly, the ACCP and SCC-ISTH recommend a
minimum of 3 months of anticoagulation in those
patients with confirmed PE or proximal DVT.

38. THROMBO PROPHYLAXIS AT DISCHARGE
 FDA-approved post-discharge prophylactic
anticoagulation (PDPA) regimens (rivaroxaban and
betrixaban) may be considered in patients with high risk
for VTE and low risk for bleeding
 Duration of anticoagulation recommended by ACF is
based on the timing used in clinical trials which is 31–
39 days for rivaroxaban, 35–42 days for betrixaban, and
6–14 days for enoxaparin
 Extended prophylaxis with LMWH or DOACs for up to
45 days in patients at high risk for VTE (i.e., D-dimer > 2
times ULN, reduced mobility, active cancer) and low risk
of bleeding

39.  ASH mentions that aspirin can also be
considered based on studies for VTE
prophylaxis in low risk patients after orthopedic
surgery
 Aspirin is not mentioned in any of the other
guidelines and recommendations with the
exception of SCC-ISTH

40. CONSIDERATIONS FOR THROMBOLYTIC
TREATMENT
Indication
 ST elevation myocardial infarction
 Acute ischemic stroke
 Massive PE with hemodynamic instability
 In pregnant patients in particular, thrombolytic therapy
should only be used for acute PE with life-threatening
hemodynamic instability due to risk for maternal
hemorrhage

41.  ACCP suggests that in patients in whom
therapeutic anticoagulation fails and who
continue to have evidence of cardiopulmonary
compromise, thrombolytic therapy may be
beneficial
 Similarly, the ACC mentions that systemic
fibrinolysis is indicated in patients with
significant hemodynamically unstable high risk
PE and catheter-based therapies be reserved for
situations that are not amenable to systemic
fibrinolysis.

42. ONGOING TRIALS

43. MODERATE SEVERE

44. MILD TO MODERATE SEVERE
Inj ENOXAPARIN 40mg S/C 1-0-0
X 7 DAYS
(If d-dimer is more than
1000ng/ml
(Or)
X-ray/ct thorax showing
Ground glass opacities)
Inj ENOXAPARIN 1mg/kg body
wt s/c 1-0-1 X 7 days
Other options:
• Inj Fondaparinux 2.5mg OD SC
• Unfractioned Heparin 5000 Units BD SC
Contraindications:
ESRD, active bleeding, emergency surgery, platelets < 20,000/mm3, BP
>200/120 mmHg)

45. We recommend that providers manage
their patients in the framework of these
major societal guidelines, and where
discrepancies do exist, decisions be
made based on the practitioner’s
experience and their understanding of a
patient’s medical history, clinical course,
and perceived risk

46. THANK YOU