The target-specific direct oral anticoagulant (DOAC) medications include the direct thrombin inhibitor dabigatran, and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. They are gradually replacing the vitamin K antagonist warfarin (see), the former mainstay of oral anticoagulation for prevention and treatment of venous thrombus events and stroke risk reduction in atrial fibrillation. Compared to warfarin, these newer drugs inhibit a single target-specific step in coagulation rather than blocking multiple vitamin K-dependent blood factors.

1. Dabigatran is a competitive, direct inhibitor of both bound and free thrombin.
2. The factor Xa inhibitors rivaroxaban, apixaban, and edoxaban affect both free and bound factor Xa.
3. All of these agents also cause some small degree of indirect inhibition of platelet aggregation due to the decreased thrombin activity.
4. The resulting anticoagulation is both the intended benefit of these drugs and also the mechanism of toxicity in the event of adverse bleeding, ranging from minor to life-threatening hemorrhage.
5. Overdose during pregnancy. FDA pregnancy categories B (apixaban) and C (dabigatran, edoxaban, and rivaroxaban). A systematic review reported an increased incidence of miscarriages in pregnant patients taking therapeutic doses of these agents. The same study also demonstrated a 4% rate of fetal anomalies in patients taking rivaroxaban. There is insufficient information regarding overdose in pregnancy.
6. Pharmacokinetics.
   1. These agents have a more rapid onset of action and shorter half-lives than warfarin (see Table II-6).
   2. They also have the advantage of far fewer food-drug and drug-drug interactions compared to warfarin, although drug concentrations of all these drugs may be increased in the presence of p-glycoprotein (p-gp) inhibitors.
   3. Apixaban and rivaroxaban are highly protein bound, 87% and 92-95% respectively, whereas dabigatran protein binding is much less at 35%.
   4. Decline in renal function may lead to increased drug concentrations, especially with use of dabigatran.
   5. Dabigatran etexilate is a prodrug which is hydrolyzed to form its active moiety; its bioavailability is significantly increased (from 3-7% to 75%) when the pellets are ingested without the capsule shell.

1. Acute ingestion. Impaired coagulation can occur with any ingestion; however, this does not imply that bleeding will occur. Systemic absorption of rivaroxaban is thought to be self-limited with no further increase in plasma levels with oral doses above 50 mg. Apixaban has been shown to be well tolerated at doses up to 50 mg PO daily for 3-7 days without clinically significant events.
2. Chronic. The majority of reported clinically significant bleeding has occurred with chronic ingestion.

1. Bleeding has ranged from minor to life-threatening hemorrhage, including bleeding gums, ecchymoses, hematemesis, hemoptysis, hematochezia, melena, hematuria, menorrhagia, hematoma, or signs and symptoms of intracranial hemorrhage. Bleeding may be occult or may present with lightheadedness, fatigue, anemia, or hemodynamic instability if blood loss is severe or prolonged. Bleeding-associated fatalities have been reported.
2. Acute ingestion. There has been little symptomatic toxicity seen with intentional or accidental acute ingestions. In observational case series, low-dose single ingestions of dabigatran, apixaban, and rivaroxaban did not result in clinically significant bleeding. Acute self-harm ingestions in the absence of trauma have resulted in anticoagulation but rarely significant bleeding.
3. Chronic overmedication. The majority of adverse and significant bleeding events have been seen with chronic ingestions both with therapeutic use and unintentional overdoses.

Is based on history and evidence of excessive anticoagulation and/or bleeding.

1. Specific levels. Current laboratory diagnostic testing that reliably and accurately assesses the presence and degree of activity of these drugs is not available at most health centers.
   1. Specific drug levels are available from some commercial laboratories using liquid chromatography/mass spectrometry, but there is wide variability in results and therapeutic concentrations have not been established.
   2. Routine coagulation assays (PTT, PT) can be difficult to interpret and have limited use.
      1. A normal PTT likely excludes excess dabigatran concentrations.
      2. A prolonged PT indicates the presence of rivaroxaban and edoxaban but cannot differentiate between therapeutic or excess levels.
      3. Neither the PT nor PTT is useful in assessing whether apixaban is present in clinically important or excess quantities.
   3. The hemoclot assay, a diluted thrombin time assay, and the ecarin clotting assay provide the best correlation with plasma dabigatran concentrations but are not widely available.
   4. Anti-FXa activity calibrated to the specific FXa inhibitors is the best diagnostic test for the FXa inhibitors but is also not widely available.
2. Other useful laboratory studies include BUN, creatinine, CBC, blood type, and cross-match.

1. Emergency and supportive measures
   1. If significant bleeding occurs, attempt to identify the source of bleeding and provide local control or hemostasis if possible. Give intravenous volume replacement as needed and closely monitor hemodynamics. Obtain immediate neurosurgical consult if intracranial bleeding is suspected.
   2. For severe or life-threatening bleeding, use a specific reversal agent (see V.B., below). If specific reversal agents are unavailable, consider one of the prothrombin complex concentrates (PCCs) or activated PCC (APCC). For dabigatran, APCC is the preferred agent; for factor Xa inhibitors, a 4-factor PCC is preferred.
   3. Fresh-frozen plasma is likely of limited utility given volume constraints and the amount that would be required to overcome drug effect. However, it should be given if specific reversal agents and PCC are unavailable.
   4. Consider platelet transfusion for patients on concurrent antiplatelet agents.
   5. Desmopressin enhances hemostasis by increasing the release of von Willebrand factor and can be considered as an adjunct. The usual dose is 0.3 mcg/kg IV or subcutaneously, or 150-300 mcg intranasally.
   6. Tranexamic acid promotes clot stability by reducing fibrinolysis and can also be considered as an adjunct.
   7. Packed red blood cell transfusions should be administered as indicated for blood loss.
   8. Take care not to precipitate hemorrhage in severely anticoagulated patients. Proper fall precautions should be taken, and invasive procedures should be avoided if possible.
2. Specific drugs and antidotes.
   1. Idarucizumab, an antibody fragment, has been shown to rapidly decrease the plasma concentration of dabigatran, decrease ecarin clotting time and plasma-diluted thrombin time, and improve hemostasis.
   2. Andexanet alfa a recombinant derivative of factor Xa, acts as a decoy receptor for the reversal of anticoagulation by the factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban).
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Activated charcoal given 2 and 6 hours after single dose ingestion of apixaban reduced mean apixaban absorption by 50% and 27% in a healthy volunteer study.
4. Enhanced elimination.
   1. Hemodialysis (HD) can remove dabigatran, but the potential complications of placing an HD catheter (mainly bleeding) should be considered. HD has been shown to remove 62-68% of the dabigatran dose in patients with end-stage renal disease.
   2. The other newer anticoagulants are poor candidates for HD due to greater protein binding.