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Anticoagulants - Direct thrombin inhibitors and Factor Xa inhibitors: Nursing Pharmacology



desirudin (Iprivask), 
bivalirudin (Angiomax), 
argatroban (Acova), 
dabigatran (Pradaxa)
apixaban (Savaysa),
betrixaban (Bevyxxa),
edoxaban (Eliquis),
rivaroxaban (Xarelto),
fondaparinux (Arixtra)
Direct thrombin inhibitors
Factor Xa inhibitors
  • Reversibly bind to thrombin in the circulation and those already attached to a forming clot
  • Inhibit any further conversion of fibrinogen to fibrin
  • Without thrombin, factors V, VIII, IX, and XIII are also not activated, thus inhibiting clot formation
  • Reversibly bind to factor Xa and inhibit the coagulation cascade from progressing 
  • Inhibit thrombin activation by Xa and thus inhibit clot formation
  • Deep vein thrombosis, pulmonary embolism
  • Ischemic stroke, transient ischemic attack
  • Coronary artery disease
  • Cardiac valve replacement or coronary angioplasty
  • Coagulation disorders like antiphospholipid syndrome and DIC 
  • Dialysis 
  • Surgical procedures: cardiopulmonary bypass, ECMO, PCI
Bivalirudin, lepirudin, argatroban: IV
Dabigatran: PO
  • Undue bleeding (antidote: idarucizumab)
  • Nausea, dyspepsia, gastritis
  • Hypersensitivity reactions
  • Boxed warning: thrombosis and strokes if discontinued suddenly
  • Undue bleeding (antidote: andexanet alfa)
  • Boxed warning: thrombosis and strokes if discontinued suddenly
  • Active internal bleeding, recent trauma in the past three months, history of intracranial hemorrhage or ischemic stroke, gastrointestinal ulcers, coagulopathies or bleeding disorders
  • Surgery of the eye, brain, or spinal cord
  • Boxed warning: spinal anesthesia or spinal puncture
  • Pregnancy and breastfeeding 
  • Hepatic and renal disease
  • Alcohol use disorder

Drug interactions:
  • Antiplatelet medications like aspirin and clopidogrel 
  • Thrombolytic medications like alteplase reteplase, and tenecteplase
  • Factor Xa inhibitors: 
    • cimetidine, omeprazole, metronidazole, trimethoprim / sulfamethoxazole, and amiodarone (↑ effect)
    • griseofulvin, barbiturates, phenytoin, and carbamazepine (↓ effect)
Assessment and monitoring: apixaban
  • Vital signs
  • Laboratory results: renal and hepatic function, CBC, coagulation profile
  • Diagnostic test results: ECG

  • Side effects: excessive bleeding, clot formation
  • Therapeutic response: embolism prevention

Client education
  • Purpose of medication: helps to prevent clot formation, emboli
  • Take twice daily with or without food
    • Avoid grapefruit juice
  • Side effects: bleeding
    • Inform all healthcare providers of anticoagulant therapy
    • Bleeding precautions: brush gently with a soft toothbrush; shave with an electric razor; avoid scratching inside their nose or blowing their nose too hard; avoid walking barefoot, use caution with sharp objects; wear slip-resistant footwear, avoid falls and bumping into things, activities like contact sports that could result in injury
    • For bleeding
      • Apply firm pressure for at least five minutes
      • Contact healthcare provider if bleeding continues
    • Report signs of excessive bleeding
      • Blood in their urine or stool
      • Joint swelling
      • Unusual or excessive bruising; petechiae
      • Long or heavy menstrual flow
      • Spitting up blood
      • Sudden headache or abdominal pain
    • Avoid taking NSAIDs
  • Seek emergency medical treatment for clot formation
    • Weakness on one side of the body, trouble speaking, blurred vision, or sudden mental confusion
    • Wear a medical alert tag so first responders will know they are taking an anticoagulant

Anticoagulants are medications used to prevent the formation of thrombi, or blood clots, and they’re used to prevent or treat thromboembolic events, such as deep vein thrombosis, pulmonary embolism, ischemic stroke, transient ischemic attack, coronary artery disease or myocardial infarction.

They're also used in clients with coagulation disorders, including antiphospholipid syndrome and disseminated intravascular coagulation; as well as in clients who underwent coronary angioplasty or cardiac valve replacement; and during surgical procedures like cardiopulmonary bypass, percutaneous coronary intervention, extracorporeal membrane oxygenation, and in clients undergoing dialysis.

Now, anticoagulants work by interfering with the normal function of clotting factors involved in the coagulation cascade. One of the most important factors is factor X, which gets activated into Xa, and in turn activates factor II, also known as prothrombin, into factor IIa or thrombin. Thrombin further activates factors I, V, VIII, IX, and XIII. Factor I, also known as fibrinogen, is activated to form factor Ia, or fibrin, which binds to other fibrin proteins to form a crosslinked fibrin mesh.

Factor V gets activated and acts as a cofactor for factor X, while factor VIII acts as a cofactor for factor IX, and factor XIII helps fibrin form crosslinks. Ultimately, the fibrin mesh allows platelets to rapidly aggregate at the site of injury and form a platelet plug, which is a primary clot that can help stop the bleeding. So, based on the mechanism of action, some of the most important anticoagulants include direct thrombin inhibitors and factor Xa inhibitors.

Direct thrombin inhibitors include desirudin, bivalirudin, and argatroban, which are given intravenously; as well as dabigatran, which is given orally. Once administered, direct thrombin inhibitors act by reversibly binding to thrombin in the circulation and those already attached to a forming clot and inhibiting any further conversion of fibrinogen to fibrin. Without thrombin, factors V, VIII, IX, and XIII are also not activated, thus bringing the coagulation cascade to a halt. Direct thrombin inhibitors are especially useful in clients with adverse reactions to other anticoagulants like heparin.

Switching gears, direct factor Xa inhibitors include apixaban, betrixaban, edoxaban, and rivaroxaban, which are given orally; and fondaparinux, which is administered via subcutaneous injection. Once in the blood, direct factor Xa inhibitors reversibly bind to the activated factor Xa and inhibit the coagulation cascade from progressing. Overall, factor Xa inhibitors have a more significant anticoagulant effect than direct thrombin inhibitors, since factor Xa is higher up in the coagulation cascade.

Now, the main side effect of anticoagulants is undue bleeding, which can present as petechiae, ecchymosis, epistaxis, as well as bleeding gums, blood in stools, hematemesis, and uncontrollable internal bleeding from falls or even minor trauma.

Thankfully, there are antidotes that reverse the action of most anticoagulants if the bleeding gets severe. These include the antibody idarucizumab, which binds to and inactivates dabigatran; as well as andexanet alfa for apixaban and rivaroxaban. For anticoagulants that don't have a specific antidote, clients can be given prothrombin complex concentrate, which contains the clotting factors II, VII, IX, and X; fresh frozen plasma; or antifibrinolytic agents, such as tranexamic acid.

With respect to specific side effects, direct thrombin inhibitors can cause gastrointestinal side effects like nausea, dyspepsia, and gastritis, as well as hypersensitivity reactions, especially seen with desirudin and bivalirudin. Moreover, sudden discontinuation of direct thrombin inhibitors and factor Xa inhibitors leads to increased thrombosis and risk of strokes, and that’s a boxed warning!

Now, due to the risk of bleeding, all anticoagulant medications are contraindicated in clients with active internal bleeding, recent trauma in the past three months, as well as those with a history of intracranial hemorrhage or ischemic stroke, gastrointestinal ulcers and coagulopathies or bleeding disorders. In addition, anticoagulants should be used with caution in clients taking antiplatelet medications like aspirin and clopidogrel; or thrombolytic medications like alteplase, reteplase, and tenecteplase; which can increase the risk of bleeding.

Direct thrombin inhibitors and factor Xa inhibitors are also contraindicated for use in clients undergoing eye, brain or spinal cord surgery. In addition, these medications have a boxed warning against their use during or after spinal anesthesia or spinal puncture, as they can cause a spinal and epidural hematoma, which can lead to permanent paralysis. These medications should be used with caution in pregnancy and breastfeeding, as well as in clients with hepatic or renal disease, and alcohol use disorder.

Finally, factor Xa inhibitors are broken down in the liver by the enzyme CYP34A, so they should not be combined with medications that interact with it. On the one hand, any medications that inhibit this enzyme, such as cimetidine, omeprazole, metronidazole, trimethoprim/sulfamethoxazole, and amiodarone can cause the accumulation of factor Xa inhibitors in the body, increasing the risk of bleeding.