Practical-Haemostasis.com



A Practical Guide to Haemostasis


Direct Oral AntiCoagulants [DOACs]

 

Introduction

The Direct Oral AntiCoagulants or DOACs [also known as Novel Oral AntiCoagulants] have a number of advantages over traditional Vitamin K antagonists such as Warfarin.  These include:
  - Rapid onset of action
  - Fixed dosing - in general
  - No effect from foodstuffs that contain Vitamin K
  - Limited drug interactions
  - Shorter time to recovery of normal haemostasis when discontinued compared to Warfarin.

The following tables summarise the DOACs and their effects on a number of tests used in the Haemostasis Lab.

 

Click HERE to see the tables and which may be easier to view...

















  Rivaroxaban Apixaban Edoxaban Betrixaban Dabigatran
Mode of action FXa inhibitor - both free and Prothrombinase-bound FXa FXa inhibitor - both free and Prothrombinase-bound FXa FXa inhibitor - both free and Prothrombinase-bound FXa FXa inhibitor - both free and Prothrombinase-bound FXa Direct IIa [Thrombin] inhibitor
Half-life 5-9hr
11-13hr - Age >80yr
8-15hr 10-14hr 19-27hr 12-17hr
Tmax 2.5-4hr 1-3hr 1-2hr 3-4hr 2hr
Binding to plasma proteins 95% 87% 80% 54% 35%
Elimination Renal 66% [36% unchanged]
Hepatic/Faecal 28%

Renal 27%
Hepatic 2-3%

[Faecal 46.7-56%]
Renal 35%
Hepatic/Faecal 46.7-56%
Renal 11%%
Hepatic/GI 82-89%
Renal 80%
Hepatic 20%

[Faecal 82-88%]
Metabolism Substrate for P Glycoprotein [P-gp] and therefore drugs that inhibit/induce P-gp can affect drug levels Substrate for P Glycoprotein [P-gp] and therefore drugs that inhibit/induce P-gp can affect drug levels Substrate for P Glycoprotein [P-gp] and therefore drugs that inhibit/induce P-gp can affect drug levels Substrate for P Glycoprotein [P-gp] and therefore drugs that inhibit/induce P-gp can affect drug levels Substrate for P Glycoprotein [P-gp] and therefore drugs that inhibit/induce P-gp can affect drug levels
Quantitative Assay Anti-FXa assay with Rivaroxaban calibrator Anti-FXa assay with Apixaban calibrator Anti-FXa assay with Edoxaban calibrator Anti-FXa assay with Betrixaban calibrator Dilute Thrombin Time [dTT] or Ecarin Clotting Time [ECT]
Reversal Agents Andexanet alfa - a modified recombinant Factor Xa molecule that is catalytically inactive but retrains structural similarity to endogenous Factor Xa and can, therefore, bind to FXa inhibitors.  it is used for the reversal of Apixaban and Rivaroxaban.  Idarucizumab - a humanized, monoclonal, antibody fragment that reverses the action of Dabigatran
Comments 1. Avoid in severe renal impairment [CrCl <15ml/min

2. Moderate liver impairment will increase drug levels. Avoid if ALT >2X upper limit of normal of Child Pugh Score B or C



2. Moderate liver impairment will increase drug levels. Can be used with caution in liver disease  - Child Pugh Score B or C

2. Avoid in severe renal impairment [CrCl <15ml/min
1. Adjust dose in moderate-severe renal impairment [CrCl 15-50ml/min].  Avoid if CrCl <15ml/min

2. Avoid in patients with significant hepatic impairment and associated coagulation and/ or clinically relevant bleeding. 
Use with caution in mild-moderate hepatic impairment
1. Batrixaban is largely excreted unchanged through biliary secretion.

2. Food (both high- and low-fat diets) reduces the mean bioavailability of Betrixaban by 50% to 60%.

1. Avoid in severe renal impairment [CrCl <30ml/min



The Effects of DOACs on Tests of Haemostasis

The DOACs can have a number of effects on both screening tests of Haemostasis and more specialised tests.  These are summarised below:

1. Screening Tests

Drug PT APTT Clauss Fibrinogen Thrombin Time Reptilase Time Comments
Rivaroxaban ↑↑

Not sensitive at low drug concentrations ie trough levels.

Results vary with reagents.

Mixing studies may demonstrate incomplete correction.



Normal or slightly ↑

APTT is less sensitive than the PT

Mixing studies may demonstrate incomplete correction
No effect No effect No effect  
Apixaban ↑↑

Not sensitive at low drug concentrations ie trough levels

Mixing studies may demonstrate incomplete correction
Normal or
slightly ↑

Mixing studies may demonstrate incomplete correction
No effect No effect No effect  
Edoxaban ↑↑

Mixing studies may demonstrate incomplete correction


Mixing studies may demonstrate incomplete correction
No effect No effect No effect  
Betrixaban ↑↑

Mixing studies may demonstrate incomplete correction


Mixing studies may demonstrate incomplete correction
No effect No effect No effect  
Dabigatran

Mixing studies may demonstrate incomplete correction
↑↑

Mixing studies may demonstrate incomplete correction
May be falsely decreased ↑↑↑↑ No effect A normal Thrombin Time excludes significant Dabigatran levels.

The Dilute Thrombin Time [dTT] can be used to assay Dabigatran quantitatively.


2. Specialised Tests including Factor Assays and Inhibitor Assays

Drug ACT PT-based Factor Assays APTT-based Factor Assays Chromogenic FVIII Assay Inhibitor/Bethesda Assay Factor XIII Assays
Rivaroxaban Prolonged and concentration dependent

ACT is more sensitive to Dabigatran followed by Edoxaban, Rivaroxaban, Betrixaban and Apixaban.
May demonstrate a falsely low level May demonstrate a falsely low level May demonstrate a falsely low level May indicate the presence [incorrectly] of an inhibitor ↓↓

May give rise to falsely low levels using activity assays but no effect on immunological assays
 
Apixaban
ACT is more sensitive to Dabigatran followed by Edoxaban, Rivaroxaban, Betrixaban and Apixaban. 

Apixaban shows minimal effect on the ACT
May demonstrate a falsely low level May demonstrate a falsely low level May demonstrate a falsely low level May indicate the presence [incorrectly] of an inhibitor No effect
Edoxaban ACT is more sensitive to Dabigatran followed by Edoxaban, Rivaroxaban, Betrixaban and Apixaban. May demonstrate a falsely low level May demonstrate a falsely low level May demonstrate a falsely low level May indicate the presence [incorrectly] of an inhibitor No effect
Betrixaban ACT is more sensitive to Dabigatran followed by Edoxaban, Rivaroxaban, Betrixaban and Apixaban. May demonstrate a falsely low level May demonstrate a falsely low level May demonstrate a falsely low level May indicate the presence [incorrectly] of an inhibitor No effect
Dabigatran ACT is more sensitive to Dabigatran followed by Edoxaban, Rivaroxaban, Betrixaban and Apixaban. May demonstrate a falsely low level May demonstrate a falsely low level No effect May indicate the presence [incorrectly] of an inhibitor ↓↓

May give rise to falsely low levels using activity assays but no effect on immunological assays



3. Specialised Tests including Thrombophilia Testing

Drug Antithrombin Assays Protein C Assays Protein S Assays APTT-based APCr Assays
Ecarin Clotting Time
[ECT]
Comments
Rivaroxaban Xa Substrate: ↑
IIa Substrate: No effect
Chromogenic: Unaffected

Clot-based: Elevated levels
Chromogenic: ↑

Immunological: No effect
No effect Use of a Xa substrate in AT assays may generate false-normal results
Apixaban Xa Substrate: ↑
IIa Substrate: No effect
Chromogenic: Unaffected

Clot-based: Elevated levels
Chromogenic: ↑

Immunological: No effect
No effect Use of a Xa substrate in AT assays may generate false-normal results
Edoxaban Xa Substrate: ↑
IIa Substrate: No effect
Chromogenic: Unaffected

Clot-based: Elevated levels
Chromogenic: ↑

Immunological: No effect
No effect Use of a Xa substrate in AT assays may generate false-normal results
Betrixaban Xa Substrate: ↑
IIa Substrate: No effect
Chromogenic: Unaffected

Clot-based: Elevated levels
Chromogenic: ↑

Immunological: No effect
No effect Use of a Xa substrate in AT assays may generate false-normal results
Dabigatran Xa Substrate: No effect
IIa Substrate: ↑
Chromogenic: Unaffected

Clot-based: Elevated levels
Chromogenic: ↑↑

Immunological: No effect
↑↑ ↑↑

Can be used as a quantitative assay of Dabigatran
Use of a IIa substrate in AT assays may generate false-normal results



4. Specialised Tests

Drug D-dimer dRVVT
Rivaroxaban No effect ↑↑↑
Concentration-dependent effect noted
May lead to false positive LA detection
Apixaban No effect ↑↑
Concentration-dependent effect noted
May lead to false positive LA detection
Edoxaban No effect ↑↑
Concentration-dependent effect noted
May lead to false positive LA detection
Betrixaban No effect ↑↑
Concentration-dependent effect noted
May lead to false positive LA detection
Dabigatran No effect
Concentration-dependent effect noted
May lead to false positive LA detection