Anticoagulation in COVID – 19: An Update

Tiwari, Nishant R; Khatib, Khalid I; Dixit, Subhal B; Rathore, Prajay K; Melinkeri, Sameer; Ganapule, Abhijeet; Borawake, Kapil S; Mhatre, Ujwala

doi:10.2478/jccm-2020-0033

Figures & Tables

Summary of the interim guidelines published by some of the societies and forums_ (aPTT – Activated Partial Thromboplastin Time, DOAC – Direct Oral Anticoagulant, ESC – European Society of Cardiology, ISTH – International Society on Thrombosis and Haemostasis, LMWH – Low Molecular Weight Heparin, VTE – Venous Thromboembolism)

Society/Forum	Recommendations
European Society of Cardiology (ESC) [25]	1 – All admitted patients with COVID-19 related illnesses should get, at the least, prophylactic dose of enoxaparin (40mg daily). 2 - Depending on the clinical features, a patient at a high risk of thromboembolism should receive therapeutic dose anticoagulation. It can be in the form of a heparin drip (per parenteral protocol) or enoxaparin (1mg/kg twice a day) based on whether the patient is in the intensive care unit or not. 3 - Patients at low risk of thromboembolism are further classified based on the D-dimer levels. A) D-dimer <0.5 μg/mL = Prophylactic dose anticoagulation (Enoxaparin 40mg/day) B) D-dimer 0.5 to 3.0 μg/mL = Enoxaparin 40mg twice a day C) D-dimer >3.0 μg/mL = Enoxaparin 1mg/kg twice a day 4 - The patients at high risk of thromboembolism and having markedly elevated D-dimer (>3.0 μg/mL) should undergo a point-of-care ultrasound. Based on its results, a call should be on whether to continue therapeutic dose or switch to prophylactic dose anticoagulation.

International society of thrombosis and haemostasis (ISTH) on the management of coagulopathy [26]	1 - Patients having one/more of the following should be admitted to the hospital. A) Markedly raised D-dimer (>3-4 times of the normal) B) Prolonged prothrombin time C) Platelet count of <100 × 10⁹/L D) Fibrinogen concentration <2.0 g/L 2 - All admitted patients, in the absence of contraindications - should receive prophylactic dose anticoagulation (LMWH).

Scientific and standardization committee by ISTH - guidance on prevention and treatment of VTE [27]	1 - Universal routine thromboprophylaxis should be given in all admitted patients of COVID-19 related illnesses. (LMWH as preferred agent) 2 - Dose should be modified appropriately in patients with renal failure and obesity as required. 3 - Intermediate dose anticoagulation can be a reasonable option in patients admitted to ICU with COVID-19 related illnesses. 4 - Extended post-discharge thromboprophylaxis should be considered in patients that are a high risk of thromboembolism. The duration can be up to 30 days post-discharge.

Interim clinical guidance from the anticoagulation forum [28]	1 - All hospitalized patients, with COVID-19 related illnesses, should receive prophylactic anticoagulation. 2 - Escalated dose anticoagulation should be considered in critically ill (ICU) patients. 3 - To monitor the anticoagulant activity of heparin, an anti-factor-Xa assay should be used in place of aPTT as the baseline aPTT may be abnormal in some COVID-19 patients. 4 – Post-discharge VTE prophylaxis may be considered on a case-to-case basis in COVID -19 patients that have one/more of the following- A) Prolonged ICU stay B) Paralyzed for a long time C) Risk factor for VTE at the time of discharge (Decreased mobility, severe weakness) 5 – All pregnant patients of COVID-19 should receive prophylactic dose anticoagulation for the prevention of VTE. 6 – Patients on vitamin K antagonists (warfarin) should be transitioned to directly acting oral anticoagulants (DOACs), except for indications like mechanical heart valves, antiphospholipid antibody syndrome.

Summary of important studies looking at haematological parameters in COVID – 19 patients_ (aPTT - Activated Partial Thromboplastin time, FDP – Fibrin degradation products, PT – Prothrombin Time)

Authors	Sample Size (n)	Haematological Abnormalities (%)	Key Features
Chen et al. [29]	99	Elevated D-dimer - 36 (36%) Thrombocytopenia – 12 (12%) Prolonged aPTT – 6 (6%) Prolonged PT – 5 (5%)	The first study to report both the clinical and laboratory features of COVID-19 related illness.

Wang et al. [30]	138 (ICU – 36, Non-ICU – 102)	Prolonged PT – 80 (58%) Elevated D-dimer - (26% of the patients from ICU)	1 – The levels of D-dimer were significantly higher in ICU patients than non-ICU patients. (p<0.001) 2 – The levels of D-dimer were significantly higher in non-survivors than survivors. (p<0.05) 3 – D-dimer levels showed an increasing trend in patients who succumbed to the illness.

Zhou et al. [31]	191 (Survivors -137, Non-survivors – 54)	Elevated D-dimer Survivors – 67 (57%) Non-survivors – 50 (92%)	1 – A D-dimer level of >1.0 μg/mL at admission was associated with higher odds of mortality. OR=18.42 (p=0.0033) 2 – D-dimer levels were significantly higher in non-survivors than in survivors. (5.2 vs. 0.6, p<0.0001)

Huang et al. [32]	41 (ICU – 13, Non-ICU – 28)	-	1- Median D-dimer levels were significantly higher in ICU patients as compared to the non-ICU patients. (2.4 vs. 0.5, p=0.0042) 2 – Median prothrombin time was significantly higher in ICU patients as compared to the non-ICU patients. (12.2sec vs. 10.7sec, p=0.012)

Chen et al. [33]	21 (Severe cases – 11, Moderate cases – 10)	-	Compared to moderate cases, severe cases had significantly elevated levels of D-dimer. (2.6 vs. 0.3, p=0.029)

Guan et al. [9]	1099	Elevated D-dimer 260/560 (46.4%)	D-dimer levels were significantly elevated in a higher proportion of patients with severe illness than those with non-severe illness. (59.6 % vs. 43.2 %, p = 0.0021)

Han et al. [34]	94 patients 40 healthy controls	-	1- D-dimer levels were significantly higher in the patient group than the healthy control group. (10.36 vs. 0.26, p<0.001) 2 – FDP levels were significantly higher in patients than in controls. (33.83 vs. 1.55mg/L, p<0.001) 3- Higher D-dimer and FDP levels were found to be predictive of severe disease.

Li et al [35]	279 (Ordinary - 136 Improved - 23 Poor- 120)	-	The D-dimer levels on admission were significantly higher in the improved and poor group of patients than ordinary patients. (p<0.01)
			Ordinary – Mild disease, subsidedImproved – First deteriorated, then improved gradually with treatment Poor – Deteriorated or died

Tang et al. [12]	183 (Survivors – 162, Non-survivors – 21)	-	Abnormal coagulation tests (Elevated D-dimer, FDPs and decreased fibrinogen) were associated with a poorer prognosis, i.e. these parameters were significantly deranged in non-survivors than the survivors.

Anticoagulation in COVID – 19: An Update

Figures & Tables

Summary of important studies looking at haematological parameters in COVID – 19 patients_ (aPTT - Activated Partial Thromboplastin time, FDP – Fibrin degradation products, PT – Prothrombin Time)

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