What Are Anticoagulants?
Anticoagulants are medications that are administered to prevent intravascular clot formation. They are used when there is an increased risk for thrombogenic disorders like ischemia, myocardial infarction, stroke, pulmonary embolism, and deep vein thrombosis. They prevent the clotting mechanism by interfering with the cascade pathways and inhibiting the formation of thrombin and other promoters of clotting. The anticoagulants that are most commonly used in clinical interventions include;
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Vitamin K antagonists - Phenprocoumon and Warfarin.
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Direct oral anticoagulants (DOACs) - Apixaban, Dabigatran, Edoxaban, and Rivaroxaban.
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Heparins (used only intravenously).
What Are the Side Effects of Anticoagulants?
Anticoagulants are life-saving medications that are used in emergency situations, but prolonged use or overdosage of anticoagulants can cause side effects and lead to adverse complications. Bleeding and delayed wound healing are the common side effects of anticoagulants. They are clinically seen as,
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Persistent bleeding from gums and nose.
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Delayed cessation of bleeding at any injury site.
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Delayed closure of wounds.
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Large bruises on the skin.
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Pink-colored urine due to bleeding in the urinary tract.
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Dark red or black colored stool (due to blood in stool).
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Blood during vomiting (bleeding in the gastrointestinal tract).
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Sudden headache and dizziness.
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Stroke (a rare complication).
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Heavy and profuse bleeding during minor trauma or surgery.
What Does Anticoagulant Reversal Mean?
Anticoagulant reversal refers to a critical medical intervention that neutralizes or antagonizes (reverses) the effect of anticoagulant therapy during emergency situations such as uncontrolled bleeding complications and overdosage of anticoagulants, or before surgical procedures. This is achieved by the usage of anticoagulant reversal agents. These medications, when administered timely and appropriately are like antidotes that reduce the incidence of life-threatening bleeding and thereby lower potential mortality.
Strategies for the use of anticoagulant reversal agents are gaining importance because reversal agents are not available for all the anticoagulants that are currently used. Each anticoagulant demands a specific reversal agent based on its mode of action. Also, the duration of the onset of action varies considerably in different reversal agents.
What Are the Commonly Used Anticoagulant Reversal Agents?
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Vitamin K - Inhibits warfarin interference in the clotting cascade and acts as a cofactor for the synthesis of clotting factors (II, VII, IX, X) in the liver thereby restoring clot formation. The recommended dosage is 1 to 10 mg intravenously (IV). The onset of action starts in one to two hours of IV administration and lasts up to 12 to 14 hours.
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Protamine Sulfate - It reacts with Heparin and neutralizes the anticoagulant effect. 12.5 to 50 mg is given intravenously and its action starts within five minutes. Its reversal effect lasts up to two hours.
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Prothrombin Complex Concentrate (25 to 50 Units/Kg IV) - It consists of vitamin K-dependent clotting factors II, VII, IX, X, and proteins C and S that promote clotting. It is the most potent reversal agent as the onset of action is within minutes of administration and has a variable half-life because of the combination of factors.
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Fresh Frozen Plasma (10 to 15 ml/kg) - It supplies all the essential plasma proteins and clotting factors necessary for the clotting mechanism. It has a rapid onset and is mostly used as a non-specific reversal agent for anticoagulants which do have specific antagonists.
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Idarucizumab (5 g IV) - It binds with Dabigatran and its metabolites to neutralize their effect. The onset of action is 10 to 30 minutes with an initial half-life of 47 minutes and a terminal half-life of 10 hours.
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Andexanet Alfa - It combines with and reverses the action of factor Xa inhibitors (Rivaroxaban, Apixaban). It is administered intravenously as a bolus dose of 400 to 800 mg and followed by 4 to 8 mg/min (milligram per minute) of IV infusions. The onset of action is within minutes of infusion and lasts till the duration of infusion.
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Aripazine - It reverses the anticlotting effect by noncovalently binding to low molecular weight heparin (LMWH), Fondaparinux, and factor Xa inhibitors. Dosage varies depending on the clinical complications of anticoagulants but the onset of action is within 10 minutes of IV infusions.
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Activated Charcoal - It adsorbs oral factor Xa inhibitors (Dabigatran, Apixaban, and Rivaroxaban) and inhibits absorption thereby neutralizing and preventing their toxicity. It is usually administered orally with a dosage of 50 to 100 g/dose. The onset of action is within 2 to 6 hours of ingestion.
When Is Anticoagulant Reversal Recommended?
The use of reversal agents is strictly regulated because inappropriate use or overdosage would increase the chance of thrombosis and embolism in high-risk patients. Under dosage would result in bleeding complications. Clinicians or healthcare providers must have a thorough knowledge of anticoagulation therapy, management, and reversal intervention. Minor bleeding symptoms or rare bleeding episodes need only symptomatic monitoring and evaluation and do not require the use of reversal agents. Anticoagulant reversal management is only recommended in the following situations,
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Excessive or recurrent bleeding incidents during minor trauma or injury.
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Prior to elective surgery (knee or hip replacement surgery) and dental extractions.
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Recurrent vomiting of blood.
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Delay in wound healing.
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An elevated international normalized ratio (INR) indicates reduced prothrombin levels and is suggestive of reversal therapy.
What Are the General Measures Taken for the Anticoagulation Reversal?
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Baseline Investigations and History - The type of prescribed anticoagulant, dosage, duration of medication, and history of last dosage and recent hemorrhagic incident. Evaluation of side effects must be essentially carried out. Anticoagulants must be stopped and interactions with other drugs have to be examined.
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Laboratory Screening - Blood screening tests including total blood count, bleeding time (BT), clotting time (CT), prothrombin time (PT), and activated partial thromboplastin time (aPTT) are mandatory. Liver function tests and renal function tests are done to assess the metabolism and elimination of drugs.
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Supportive Intervention - Bleeding in patients should be stopped immediately using appropriate resuscitation and supplemented with blood components.
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Administration of the First Line of Drugs - Tranexamic acid (1 g) is given every eight hours in case of bleeding following trauma or in case of urgent unplanned surgery. The use of synthetic clotting factors or vitamin K enhances the formation of blood clots faster.
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Local Intervention - Local measures include identification of the bleeding site and stopping of bleeding by pressure, endoscopy investigation, minor surgical procedure, or interventional radiology.
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Drug Elimination - The concentration of an anticoagulant drug in the blood needs to be assessed because it contributes to the severity of bleeding. Further, it helps to calculate the time required for its elimination as well as the appropriate reversal agent preferred.
Conclusion
Bleeding risks are concomitant with the use of anticoagulants. Also, it should not be stopped abruptly in patients with a high risk of thrombogenic effects. The use of reversal agents plays a beneficial role in neutralizing the excessive anticoagulant effect and controlling bleeding complications in patients under anticoagulation therapy. Therefore, reversal agents act as only palliative measures to control the side effects and do not hamper the long-term efficacy of anticoagulants.
